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Review of American and English literature for the years 1963 and 1964 Seventeenth Rheumatism Review.

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RHEUMATISM AND ARTHRITIS
Review of American and English Literature
for the years 1963 and 1964
(Seventeenth Rheumatism Review)
By CHARLES
L. CHRISTIAN,
M.D., N e w York, N . Y.
Chairman, Editorial Committee
VINCENTP. BUTLER, JR., M.D., N e w York, N . Y.
JOHNL. DECKER,M.D., Bethesda, M d .
DAVID
HAMERMAN,
M.D., N e w York, N . Y.
STEPHENM. KRANE,M.D., Boston, Mass.
WILLIAM
M. MIKKELSEN,
M.D., Ann Arbor, Mich.
CARLM. PEARSON,
M.D., Los Angeles, Calif.
HUGH
A. SMYTHE,M.D., Toronto, Canada
ANGELOTARANTA,
M.D., N e w York, N . Y.
THOMAS
B. TOMASI,
M.D., Buffalo, N . Y.
L. EMMERSON
WARD,M.D., Rochester, Minn.
HOWARD
J. WEINBERGER,
M.D., Beverly Hills, Calif
Pub1ished by
The Arthritis Foundation
1212 Avenue of the Americas
New York, N. Y. 10036
The last Review prepared by the Rheumatism Review Committee of the
American Rheumatism Association was the Sixteenth; it concerned the American
arid English literature cf 1961 and 1962 and was published in the Annals of
Internal Medicine, Supplement 6, Volume 61, November 1964.
The editorial comments in these Reviews express the opinion of the authors
and are not necessarily those of the Association.
Reprints of this Review (No. 17) can be obtained by sending $4.W to Miss
Margaret M. Walsh, Executive Secretary, American Rheumatism Association,
Section of The Arthritis Foundation, 1212 Avenue of the Americas, New York,
N. Y. 10036.
As a more permanent reference, this Review is also obtainable in hard cover
binding at $7.00 from the same address.
When ordering, please specify hard or soft couers.
Copyright @ 1966
Grune 8i Stratton, Inc.
381 Park Avenue South
New York, N. Y. 10016
Printed in the United States of America
RHEUMATISM AND ARTHRITIS
Contents
MANIYESTATIONS . . . . . . . . . . . . . . . . . 159
GOUTYARTHRITIS . . . . . . . . . 162
CHONDROCALCINOSIS . . . . . . . . . . . . . . . . 170
ALCAPTONURIAAND OCHRONOTIC
ARTHROPATHY
. . . . . . . . . . . . . . . . . . . 171
....................
171
OSTEOARTHRITIS
NONARTICULAR
RHEUMATISM . . . . . . . . 173
DISEASES
OF MUSCLE
. . . . . . . . . . . . . . . . 175
SYNOVIAL
TUMORS
AKD TUMOR-LIKE
CONDITIONS .....................
177
. . . . 17s
DISEASEOF BONEAND CARTILAGE
STRUCTURE
AND FUNCTION
OF JOINTS. . 181
THECONNECTIVE
TISSUES
. . . . . . . . . . . . 186
EXPERIMENTAL
MODELSOF ARTHRITIS,
ARTERITIS
AND SYSTEMIC
LUPUS
ERYTHEMATOSUS
AND
THEIR
NAT...
PSORIATIC ARTHRITIS
URALLY OCCURRING COUNTERPARTS I N
KETTER’S SYNDROME . . . . . . . . . . . .
ANIMALS. . . . . . . . . . . . . . . . . . . . . . . .
198
....................
204
MATORY INTESTINAL DISEASE
. . . . . . 152 INFLAMMATION
DRUGS-EFFECTSAND
sJOGREN’S SYPiDROME . . . . . . . . . . . . . . . 153 ANTI-RHEUMATIC
Tommy ........................
204
NEUROJROPHIC
ARTHRITIS. . . . . . . .
.......................
209
OTHERTYPES OF ARTHRITIS . . . . . . . . . . 157 REFERENCES
INDEX. . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
OTHERSYNDROMES
WITH RHEUMATIC
..............
1N’1 RODUCJ ION . . . . . . . . .
ARTHRITISASSOCIAT
k ECrIOLJS AGENTS
“ C ~ N E C T I V E TISSUE
DISEASES”. . . . . . 97
RHEUMATIC FEVER
( R A ) . . . . . . . . . . . . 99
RHEUMATOID
ARTHRITIS. . . . . . . . . . . . . 108
ANKYLOSING SPONDYLITIS . . . . . . . . . . . . 125
JUVENILE
RHEUMATOID
ARTHRITIS . . . . 130
SYS? EMIC LIJPUSERYTHEhfATOSUS (SLE) 131
POLYARTERIS
NODOSA
AND OTHERVASCULAR DISEASES
I’R E t.’AC 1%.
<;OUT APiD
Future reviews, which are projected as
biennial, will appear in Arthritis and Rheumatism. The editors of the Annals of Internal Medicine have expressed their intention
of publishing synopses of this and future
reviews.
The development of two other literature
review services-“The Index of Rheumatology” (1085)* and “Arthritis Abstracts”+
-has replaced the “Rheumatism Review”
as a bibliographic source. * Particularly, the
Preface
S
1935, sixteen issues of the Rheumatism Reviews have been published
periodically in the Annals of Internal Medicine under the auspices of the American
Rheumatism Association. This Seventeenth
i y s w contains an analysis of selected articles
from the English language literature dealing with the fundamental and clinical aspects of the connective tissue diseases for
the period 1963 and 1964.
Because of an ever-increasing diversity
and complexity of disciplines relevant to
the rheumatic diseases, serious consideration was given to the writing of two
separate reviews : one emphasizing clinical
aspects and another summarizing resexch
progress. The decision was made to adhere
t o the previous format of a single review.
INCE
“The Index of Rheumatology, American Rheumatism Association, 1212 Avenue of the Americas,
New York, N. Y. 10036. Domestic $6.00 per year,
foreign $7.00 per year.
+Arthritis and Rheumatic Diseases Abstracts,
National Institute of Arthritis and Metabolic Diseases, National Institutes of Health, Bethesda, Md.
20014.
93
94
“Index of Rheumatology” provides a more
current and comprehensive reference source
than previous Rheumatism Reviews. The
main concern of the Editors of the Rheumatism Review is the composition of a critical
and interpretive analysis of selected papers
from English language journals, which mark
progress in our understanding of the rheumatic diseases.
The Rheumatism Reviews thus provide
more current information than is generally
available but it cannot duplicate the detailed discussions that appear in Arthritis,
Hollander and collaborators, 7th Edition,
Lea and Febiger, in press. For a concise
background summary of the rheumatic diseases, the “Primer on the Rheumatic Diseases” is recommended ( 1006). (Reprints
of the Primer are available from the American Rheumatism Association, Inc., 1212
Avenue of the Americas, New York, N. Y.
10036, for One Dollar.)
RHEUMATISM AND ARTHRITIS
committee’s recommendation is strongly
urged. Ed.] A historical essay traced the
nomenclature of rheumatoid arthritis from
antiquity to the present time (953).
General Prevalence and Relative Incidence
of Rheumatic Diseases
Based on figures of the U. S. Public
Health Service, it is estimated that 12,000,000 persons in the civilian non-institutional
population of the United States suffer from
some type of rheumatism (529, 532). The
total would be greater if persons in institutions such as nursing homes, homes for
the aged, chronic disease hospitals, etc.,
were included. In a sample of 1,422 dockyard employees in Scotland, 37% experienced rheumatic complaints during a l-year
period (26). [In over half of these, a specific diagnostic label could not be applied.
Rheumatoid arthritis (R.A.), degenerative
joint disease and spinal disc disease were
observed in frequencies of 1.5%,6.7% and
10.2%,
respectively. Ed.] About one-fourth
Introduction
of the adult population (15 years of age
Definitions
and over) of a small island off the coast of
The terms “arthritis” and “rheumatism” Holland complained of rheumatism. Of the
are sometimes used synonymously. In a group with rheumatic symptoms, only about
stricter sense, arthritis describes inflamma- 6%had R.A., the majority having degenertory disease of articular structures, and ative joint disease and non-articular rheurheumatism, a more generic expression, in- matism (288). [Two to 3%of subjects in
cludes all pathology of the joints, tendons, seven northern European surveys had “defiligaments, muscle and supporting connec- nite R.A.” by A.R.A. Criteria (292). The
tive tissue. In a review of the rheumatic cnly comparable study in the United States
diseases, certain arbitrary limits are im- showed an incidence of 0.39% (842). Ed.]
posed, and, by custom, some subjects are The entire adult population of a New Zeaincluded which have somewhat tenuous but land Maori community was surveyed for
potentially important associations with the rheumatic disease and approximately half
general subject.
of them had rheumatic symptoms (1056).
A tentative nomenclature and classifica- [Again, specific diagnoses were possible in
tion of arthritis and rheumatism was form- a small minority of the group. The high inulated by a committee of the A.R.A. (923, cidence of hyperuricemia and of gout
924). [ A greater uniformity of terminology among the Maoris was confirmed. Ed.]
is needed. N o proposal will satisfy everyone
Social and Economic Importance
and the best of terminologies must be updated periodically, but acceptance of the
In the United States, it is estimated that
95
..\RTHRITIS AND KNOWN INFECTIOUS AGENTS
rheumatic disease accounts for the loss of
more than 115,000,000 work days annually,
resulting in $1.5 billion in lost wages annually (332). The estimated cost of medical
care for arthritis patients is $250,000,000.
U. S. Public Health Service surveys have
detailed the impact of rheumatic disease on
the health and economy of the nation
(529, 530, 531).
Arthritis and Metabolic Diseases, the Arthritis and Rheumatism Foundation and the
National Foundation ( 52).
The organization of rheumatic disease
services in the U. S. S. R. was described by
an American visitor (828).
Arthritis Associated With Known
Infectious Agents
GENERAL FEATURES
The Cnmpaign Against Rheumatism
The Eleventh International Congress on
Rheumatic Diseases, under the auspices of
La Ligue Internationale contre de Rheumatism was held in Buenos Aires in December
1965. The Congresses of European and PanAmerican Leagues continued to meet at
regular intervals and a new international
organization was founded-The Southeast
Asia-Pacific Area League Against Rheumatism.
Changes have occurred in the organization of the American Rheumatism Association and the voluntary effort directed
against rheumatic diseases. The Arthritis
and Rheumatism Foundation was reorganized in October 1964 as The Arthritis
Foundation, and the National Foundation
which had supported the study of rheumatic disease since 1959 announced its intention to concentrate its efforts in other areas.
In June 1965, the American Rheumatism
Association (A.R.A.) voted to amalgamate
with the Arthritis Foundation ( A.F. ), thereby becoming the A.R.A. Section of the A.F.
With this single agency under new leadership, there is expectation of a more effective
and concerted voluntary effort against rheumatism. [The need for a concentration of
effort was the subject of an A.R.A.Presidential Address in June 1963 (341). Ed.]
Annual expenditures (U. S. A.) for research in the rheumatic diseases were estimated at $10,400,000 for 1963-64. This is
understated as it includes only identifiable
amounts from the National Institute of
A retrospective study of septic arthritis in
children, age 13 years or less, included 35
cases in which the bacterial agent was
identified from joint fluid, 11 cases in which
other cultures were positive, and 6 cases
with “purulent joint fluid in which no culture was positive (143). In infants, staphylococcal and enteric organisms predominated and there was approximately equal
involvement of knee, hip, or shoulder
joints. In most of the older children the
knee was involved, usually with staphylococcus or streptococcus. Ncither synovial
fluid findings nor antibiotic therapy was
detailed. Only 6 cases required incision and
drainage. Osteomyelitis and dislocation of
the hip were described as the chief complications; the threat of the latter in infant
infection has been regarded by many as an
indication for prompt surgical intervention.
Staphylococcal and streptococcal septic
complications were serious and difficult to
diagnose in 5 elderly women with longstanding, advanced rheumatoid arthritis
(427). Three died. Four had septic arthritis
which included in all a sternoclavicular
joint; the fifth showed abscesses in large
muscles at postmortem. None had received
systemic adrenal corticosteroids nor local
steroids in any of the joints involved. Fever, chills, and leukocytosis were unreliable
diagnostic guides. In retrospect the 4 with
staphylococcic disease had had an antecedent, clinically apparent infection such as
furuncles. This fact plus subtle changes in
local symptoms and findings were the only
96
RHEUMATISM AND ARTHRITIS
first study the white blood cells would be
more numerous and the joint fluid sugars
loujer than in the second. The first illness
discussed is properly classified as gonococcal arthritis. Whether the second should be
called post-gonococcal arthritis or Reiter’s
syndrome is debatable. Ed.]
The relationship of the above “antibiotic
insensitive” arthritis to comparable syndromes associated with meningococcus
(990) and Salmonella typhimurium ( 1288)
is of great interest. Meningococcal arthritis
was carefully and beautifully described in
12 cases (990). The oligoarticular process
first began within 12 days of the onset of
meningococcal meningitis or acute septiARTHRITIS RELATED TO NEISSERIAN
cemia,
evolved in the face of adequate
INFECTION
antimicrobial
therapy, and cleared essentiTwo forms of arthritis related to gonally
without
residua
within 6 weeks. The
ococcal infection of the genito-urinary sysinitial
joint
fluids
were
characteristic of
tem appear to be partially distinguishable
septic
arthritis;
despite
prior
antibacterial
(393, 452). On the one hand, there was a
group of 92 patients, 77 of them women, therapy in all, meningococcus was rewho suffered an illness, frequently with covered from two fluids. Paradoxically, the
fever and chills, an early migratory phase, joint effusions, which are often painless but
and finally a “settling” in one or more joints accompanied by recrudescence of fever,
or areas such as the tendon sheaths of the may appear when the meningeal disease is
extensor surface of hand and wrist (452). under control and improving on antibacterIn 7 of 28 fluids cultured, the gonococcus ial therapy.
was recovered. In this group penicillin was
followed by marked subjective improve- OTHER ACUTE SEPTIC ARTHRITIDES
The fourth (927) and fifth (449) cases of
ment in 36 hours and “complete remission
Hemophilus
influenzae pyarthrosis in adults,
of symptoms”in an average of 6 days.
On the other hand, 16 episodes of arth- one with rheumatoid arthritis, were reritis associated with genital gonorrhea, a11 ported. In both instances the gram stain
in males, involved an average of 5 joints, of the synovial fluid sediment showed pleoevolved over 15 weeks despite antibiotic morphic organisms which were not recogtherapy, and was commonly accompanied nized until the cultures were reported. Five
by conjunctivitis (393). Only two synovial cases of pneumococcal pyarthrosis occurred
fluids were examined and no organisms in patients with chronic illness such as
were found. The extraurethral clinical man- rheumatoid arthritis, alcoholism, and diifestations of the illness were indistinguish- abetes (40).
able from those observed in 60 episodes
Enteric organism infection of joints apassociated with nongonococcal urethritis, peared among the terminal manifestations
[ I t is unfortunate that these t w o studies of 5 patients with leukemia or melanoma
do not provide more data on the synotiial (312). Cytotoxic drugs and adrenal cortifluids which tcould probably further dis- costeroids were thought to contribute to
tinguish the syndromes. Presumably in the pathogenesis. At autopsy, in one sterile
diagnostic keys. Management of septic
arthritis was discussed (231); grossly purulent joint fluid was considered by some to
be an indication for drainage but the general trend is toward earlier diagnosis and
proper antibiotic therapy. The majority favor immobilization of the joint in supporting splints with daily passive range of motion exercises as early as they can be tolerated. [There is no consensus regarding
the necessity of incision and drainage. The
wsults are usually good with surgical
druinagc plus antibiotics or antibiotics
aloric when the duration of the disease is
less than a week. Ed.]
97
CONNECTIVE TISSUE DISEASES
knee, cytomegalic inclusion bodies were
identified in synovial tissue for the first
time.
Acute hip disease in a boy was considered to be septic arthritis due to Salmonella
typhimtirium although the organism was
recovered from the feces only (1027). Enteric infection with the same organisms was
followed (average lag: 12 days) by a sterile
polyarthritis of migratory nature resembling acute rheumatic fever which persisted
for an average of 5 months. It cleared
without residua in all of the 12 cases
(1288). The 6 males and 6 females constituted 2.4% of all hospitalized patients with
Salmonella typhimurium infection; no pyarthrosis was seen in any. In one case,
conjunctivitis, iritis and renewed arthritis
appeared 6 months after the original arthritis.
CHRONIC INFECTIOUS ARTHRITIS
Four cases of arthritis associated with
congenital syphilis were described. In 1
case. labelled Clutton’s joint, synovial biopsy showed possible microgumma (39).
I n the other three, followed for longer periods, erosive bone changes were noted radiologically and the eponym “von Gies”
joint was applied to signify gummatous
disease of bone and synovium (467).
Tuberculous arthritis continued to produce diagnostically puzzling clinical pictures (595) but its management was easier
and more successful than in pre-antibiotic
days (1204, 1217). Arthrodesis, the usual
pre-antibiotic therapeutic approach, did
not improve results in sacroiliac disease
(1217) and was less frequently used than
debridement-synovectomy in knee infection
(1204).
SEPTIC SPONDYLITIS
The clinical pattern of hematogenous
pyogenic osteomyelitis of the spine was regarded as changing from a fulminating disease of youth to a slowly progressive disease of the elderly (994). Staphylococcus
aureus is the primary offending organism
and the 25%mortality noted was ascribed
to the decreased resistance of the elderly
patients. Antibiotics and immobilization
lead to ankylosis, a functionally good result; surgery is rarely needed. In Egypt 4
cases of spondylitis due to Brucella melitensis healed with astonishing bony overgrowth under treatment with tetracycline
and streptomycin (359).
Two extensive studies of the treatment oi
tuberculosis of the spine appeared (967,
1141). In England excellent results were
obtained with drugs, excision of disease tissue, and bone grafting for fusion; on the
average the patients were back at work 11
months postoperatively (1141). In Korea
drug treatment, radical surgical excision of
disease, and no attempt at immobilization
were found capable of returning 80% of
the patients to work (967).
EXPERIMENTAL STUDIES
In vitro cartilage destruction was gauged
by the degree of structural integrity and by
the amount of filtrable hydroxyproline appearing in the surrounding media. Neither
parameter showed cartilage destruction
upon incubation with staphylococcal pus
unless the cartilage had previously been
heated to the nonphysiologic level of 55” C
at which temperature thermal denaturation
of collagen takes place. Thus the exact
mechanism of in vivo collagen digestion,
shown to be necessary for the loss of cartilage structure, is unexplained (271 ) .
“Connective Tissue Diseases”
General Considerations
The terms “connective tissue disease”
and “collagen disease” were used interchangeably to describe that group of disorders characterized by multi-system clinical
manifestations together with diffuse vascular lesions, fibrinoid deposits, degenerative
connective tissue changes and frequently
98
associated with inflammatory cellular reactions (980, 1223, 1293); other terms such as
“collagenosis” (664) and mesenchymal discase (980, 1359) were less frequently used.
[“Connective tissue disease” is the term
most commonly w e d at present. Ed.] The
term “connective tissue disease” was generally considered to include rheumatoid arthritis, systemic lupus erythematosus (SLE ),
scleroderma, pcriarteritis nodosa, dermatomyositis and, in some instances, acute
rheumatic fever and thrombotic thrombocytopenic purpura (980, 1223, 1293); it was
recognized that the term as used did not
include congenital disorders of connective
tissue nor a large number of other disorders
in which the connective tissue involvement
was of a diff ercnt nature ( 1223). The clinical, pathological and immunological similarities among the various connective disorders were discussed (93, 664, 686, 980,
1149, 1223, 1293) and it was again noted
that individual patients may have combined features of two or more of these disorders (93, 664, 743, 1149). A family was
reported in which rheumatoid arthritis,
SIX, thymoma, rheumatic fever, regional
enteritis, thrombocytopenic purpura and
immunoglobulin deficiency were noted
( 1359) and the possible interrelationship
between these disorders was discussed
(980, 1359). Current concepts of the possible pathogenesis of the connective tissue
diseases were reviewed (1293).
Reviews of pulmonary (307), renal
(968), cutaneous (1352) and gastrointestinal (260, 313) involvement in the connective tissue diseases were published. Tyrosine metabolism was felt to be impaired in
connective tissue disease (921). A possible
relationship between neoplasia and connective tissue disease was discussed (194, 202,
290, 588, 673,727, 782, 850, 1107, 1237); in
addition to the well-recognized relationship
between dermatomyositis and carcinoma
(782, 850, 1107), the finding of L.E. cells
(588), clinical SLE (194), Sjogren’s syn-
RHEUMATISM AND ARTHRITIS
drome (1237) or dermatomyositis (290) in
association with lymphoma caused speculation that certain manifestations of the connective tissue disorders may result from an
accelerated rate of somatic mutation of
lymphoid cells, giving rise to clones capable of forming autoreactive antibodies
( 194). [See section on DERMATOMYOSITIS
regarding associations with neoplasia. Ed.]
Autoimmunity
Reviews (687), books (441, 976) and articles (173, 1201) dealt with autoimmunity
and its relationship to human disease.
There was speculation concerning mechanisms by which an individual’s tissue constituents may be rendered autoantigenic (152,
172, 178, 192, 255, 779, 930, 976, 1040,
1103, 1152, 1250, 1293, 1293, 1299). The
possible role of the thymus in autoimmune
phenomena (177, 457, 547, 580) and in
connective tissue disorders (14, 419, 456,
457, 508, 599, 673, 680, 707, 776, 777, 780,
980,1293) was considered.
The presence and possible significance of‘
autoreactive antibodies in the sera of patients with connective tissue disorders was
discussed (384, 398, 441, 537, 628, 678, 686,
687, 779, 840, 930, 949, 984, 1050, 1250,
1293). There was consideration of the possible pathogenetic role of autoreactive antibodies in the connective tissue disorders
(84, 95, 178, 232, 368, 779, 930, 1250, 1293,
1311), especially in SLE where autoreactive antibodies were found in the greatest
variety and highest incidence (398, 840,
1150, 1293). Further evidence was presented that antinuclear antibodies could
not enter intact cells (368, 1311) and it was
also shown that they had no effect on human amnion cells in tissue culture (1311).
There was no evidence for the pathogenicity of antinuclear antibodies in the healthy
relatives of SLE patients (571, 995), nor
was there evidence of disease in infants receiving antinuclear antibodies transpla-
99
RIIEUMATIC: FEVER
crntally from mothers with SLE (84) or in
(Jogs and guinea pig\ to which L.E. cell
tactor was passively administered (95).
hlost workers therefore felt that antibodies
to nuclear and cytoplasmic constituents
rarely entered normal cells in appreciable
amount and that no “auto-aggressive” effect
on normal tissue could be ascribed to these
antibodies (84, 779, 930, 1150, 1250, 1293,
1311). One report suggested possible in
vivo reaction of antinuclear factors with
the tissues of- rats injected with SLE serum
on the basis that weak antinuclear fluorescence disappeared within 24 hours while
human gamma globulin precipitin arcs persisted in recipient sera for 10 days (232).
[ Wucleoprotein-reactive gamma globulin
concentrations in SLE sera rarely exceed 80
pg. N / m l (1262, 1263); this c o u l d consfitute less than 6% of a normal gamma
globulin levels of 1.5 mgm Nlnzl. Until aprropriate quantitative kinetic data are obtnined, one cannot necessarily equate an
carly failure t o detect antinuclear antibody
toitill. a rapid disappearance rate. A rapid
disappearance ratc, if established, could be
related t o reaction with extracellular nuclear breakdown products rather than t o
entry into intact cells. Ed.] It was considered possible that antibodies to nuclear and
cytoplasmic constituents could combine
with antigens derived f r o n damaged cells
and that the resultant antigen-antibody
complexes could give rise to glomerular
and vascular lesions (81, 166, 176, 398, 456,
779, 956, 1239), decreased complement
levels (840, 1263) and cryoprecipitation
phenomena (227). It was also felt that antibodies to blood constituents might be
playing a role in hemolytic anemia, thrombocytopenia and, perhaps, leukopenia in
connective tissue disorders ( 1150); antibodies to clotting factors may also have
contributed to hemorrhagic phenomena in
some patients with lupus erythematosus
( 161, 585). No evidence was available to
detcwninc~whether or not autoreactive cel-
lular immune mechanisms were operative
in connective tissue disorders in addition to
the humoral autoantibodies (779). [Cellassociated immune phenomena appear to
play an important role in certain experimental autoimmune disorders (178, 1293).
Ed.]
Autologous rabbit connective tissue extracts produced antibody formation, delayed skin reactivity, and fixation of gamma
globulin to synovia and the interstitial
spaces of several organs in donor animals;
except for stunted growth no abnormalities
were noted (544).
The potential role of lysosomal enzymes
in the pathogenesis of connective tissue
disease and autoimmune phenomena was
discussed (1293,1320,1321).
In view of the appearance of certain
autoreactive antibodies following prolonged immunization of animals (223, 226,
1257) and certain infections in man (1250,
1299), the possibility of an infectious etiology for the connective tissue diseases was
considered anew (72, 577, 976, 1293). Certain mycoplasma caused chronic arthritides
in swine (1045) and mycoplasma were cultured from synovial fluid and tissues of patients suffering from connective tissue disorders (7 2 ). [See section o n REITER’SSYNDROME for discussion of mycoplasma and
joint disease. Ed.] One report described
lesions resembling those of connective disorders in rats infected with Candida albicans (792).
Rheumatic Fever
Epidemiology
RELATION TO STREPTOCOCCAL
INFECTIONS
A study of streptococcal infections and
rheumatic fever was carried out in the
whole population of a Dutch village. Peaks
of incidence were observed in November,
with secondary peaks in June. [This i s unlike the American experience of late winter
100
pcaks. Ed.] Kheumatic fever did not occur
among 65 patients with untreated streptococcal pharyngitis but 4 cases of rheumatic
fever occurred in patients who had not
consulted their doctor at the time of the
infection. In an extension of the study,
mentioned in the discussion, there were 70
more untreated infections, none of which
was followed by rheumatic fever, but there
were 3 more cases of rheumatic fever in the
rest of the population. [The attack rate in
p p t o m a t i c streptococcnl pharyngitis in civilian practice is lower
than 1%. The majority of rheumatic fever
nttacks occur in patients who are not sick
enough with theiy streptococcal infection to
see their doctor. (463, 1279) Ed.] Chil-
RHEUMATISM AND ARTIIRITlS
fever was put into prospective by pointing
out that the ratio of incidence of rheumatic
fever in siblings of patients to the incidence
in control groups is only 1.5, whereas the
same ratio is 5 in rheumatoid arthritis, 20 in
gout and 40 in ankylosing spondylitis
(654).
ETIOLOGY
No new information challenged the etiologic role of group A streptococci. The etiologic agent was studied in and by itself,
and in its relation to the host.
BIOLOGY OF GROUP A STREPTOCOCCI
The ability to produce erythrogenic toxin
was transferred from one group A strepdren with rheumatic fever did not have im- tococcal strain to another by means of inmunologic evidence of a greater number of fection with a temperate bacteriophage
previous streptococcal infections than suit- ( 1381). The cell wall location of M protein
was confirmed by direct observation of
able controls (794).
streptococci stained with fluorescein-laGENETIC PREDISPOSITION
beled anti-iM antibodies (494). M protein
Blood groups and secretor status were preparations were shown to contain several
5tudied in 600 patients with previous rheu- immunologically distinct type-specific commatics trver and in their non-rheumatic ponents (986, 1346). Streptolysin S wah
mates. Although non-secretors were more
found to be a complex of a hemolytic
frequent in rheumatics (30%)than in nonmoiety and of one of a number of carriers.
rheumatics (26%), the difference was which also act as inducers, and which inFlight and disappeared when sex was taken
clude ribonucleic acid, detergents and
into account. [However, the secretor gene
serum proteins. The hemolytic moiety can
i v known to be nutosomal and not sexbe transferred from one carrier to the other
linked: the difference between the sexes
wns probably accidental. Ed.] Contrary to
Glynn’s postulation, there were homozygous secretors among rheumatics (316).
Secretors were found among rheumatics
also by Glynn’s group, but with smaller
than expected frequency (627). In a preliminary report, it was noted that in a random sample of the total population of a
Dutch village the carriers of group A streptococci were more likely to be non-secretors than the non-carriers ( 1284).
In a comprehensive review of the epidemiology of rheumatic diseases, the possible genetic predisposition to rheumatic
(436,437).
EXPERIMENTAL STUDIES O F HOSTPARASITE RELATIONSHIP
Phagocytosis of encapsulated organisms
requires, in addition to anti-M antibody
and to complement, an accessory thermolabile factor, which has been called “coopsonin,” and is present in most, but not all
normal human sera (1211). The rate of hyaluronate production is related to virulence
(1342). In a particular host-parasite combination (BALB/sy mice and streptococcus
type 18) castration of the normally highly
susceptible male increased resistance
( 1343). A factor enhancing virulence of
streptococci was demonstrated in M-contaiiiing extracts (681 ). A hemagglutination
test may be inore sensitive than the classic
bactericidal test in detecting anti-M antih d i c s and rnay be specific if suitable absorptions arc carried out (1012). A4 protein
is digested by streptokinase-activated plasmiiiogcm as well as by human leukocyte
suspcmsioiis ( 633). An apparently primary
aIlti-h4 immune response was obtained in
10 of 16 patients injected with streptococcal cell walls emulsified in mineral oil
(1,‘360).Human cell lines were killed in tissue cultures by large inocula of group A, C
and G streptococci but not by their extracellular products (766).
Pafhology ccnd Clinical Pathological Studies
The origin of the Aschoff body continued
to he disputed. Preliminary observations
suggested that the Aschofl cells [also
called Anitschkozc cells. Ed.] differ substxntially in their ultrastructure from myoc*ardial fibers and are therefore unlikely to
tlrriie from them (704). With light micro+
cop! , ho\vever, transitional forms covering
the whole spectrum from normal myofibers
to Anitschkow cells have been observed in
tht heart of rats with foreign body reactions (841), [These observations which
confirm Anitschkow’s o w n investigations on
the origin of the cells he described indirccthj emphasize that Anitschkow or
Aschoff cells are not specific of rheumatic
fever. Ed.] Also with traditional techniques, the case for a myogenic origin of
the Aschoff body has been restated, with
the help of 125 new color photographs
(890). [ T h e Aschof body may well be the
most ouerrated lesion in human pathology.
I t is not regularly present in patients w h o
die of rheumatic carditis, ajid even when it
is present it can hardly explain the death.
Its most “characteristic” component, the
Asclzof cell, is probably identical t o the
Anitschkow cell, which is non-specific.
Ed.]
Laboratory Studies
ELECTROCARDIOGRAPHIC STUDIES
First degree A-V block was present in
2% of 50 healthy children, in 4% of 25
febrile children, and in 5% of 39 children
with glomerulonephritis. The incidence was
much higher in rheumatic polyarthritis
(33%of 46 patients) and rheumatic carditis (40%of 50 patients). In the latter two
categories many patients who did not have
a true block (i.e., a P-R interval longer
than the higher limit of normal) had nevertheless “longish P-R intervals, as evidenced by the ratio of their P-R interval
over the average P-R interval for their age
and heart rate. P-R interval, as in previous
studies, did not correlate with persistent
cardiac damage (852). [This study shows
that the P-R interval prolongation, though
not specific for rheumatic carditis or for
consequent permanent cardiac damage, is
niiich more frequent in rheumatic fever
than in other illnesses and rnay have therefore a diagnostic usefulness. Ed.]
ACUTE-PHASE REACTANTS :
C-REACTIVE PROTEIN
TWOnew methods for the purification of
C-reactive protein (CRP) were described
(569, 1364). Substances reactive with Cand Cx-polysaccharides, and therefore related to or identical with CRP, were found
in the albumin and gammaglobulin fractions of normal human sera, which were
non-reactive before fractionation ( 1292).
Cx-reactive protein ( CxRP) (the rabbit
analog of human CRP) was found localized in the ischemic area of the myocardium after experimental infarction (692).
[This observation supports the previously
proposed hypothesis that CxRP arises in
necrotic muscle. Ed.] The variability
among individual rabbits of the CxRP response to a constant simulus was empha-
102
si7ed. Of a large array of drugs only antiinflammatory steroids decreased the CxRP
re3ponse ( 1038). False-positive CxRP tests
were described in lipemic sera and the use
of Ouchterlony micro-plates with a referencc positive serum was advised to overcome this difficulty (335). The CRP test
was almost consistently positive in episodes
o f congestive failure associated with clinically active rheumatic fever; it was more
frequently negative in rheumatic patient?
with congestive failure not associated with
clinically active rheumatic fever, infection
or infarction (1190).
OTHER ACUTE-PHASE REACTANTS
The erythrocyte sedimentation rate
(ESK) was elevated in the majority of patients having episodes of congestive heart
tailure (CHI;) associated with clinical evidence of active rheumatic fever (1190).
[Although the ES R might theoretically
have been still higher in the absence of
C H F , these observations indicate that a
high E S R is not usually reduced to normal
htl C H F . Ed.]
The serum complement (C’) level was
determined serially in 40 patients with
acute rheumatic fever and was found elevatrd in slightly more than half (1116).
[Data on clinical manifestations which
could he related t o these changes were not
given. The hypothesis that changes in
serum C‘ levels were caused by penicillin
and were not influenced by salicylates does
not seem to be supported by the published
data. Ed.]
Alpha-2-globulins were almost regularly
increased in patients with acute rheumatic
fever (98% of patients, exclusive of
chorea). Gammaglobulins were less consistently elevated and albumin was often
decreased. The diagnostic value of these
findings was emphasized ( 109). [Only
mean values, not individual results, were
gitjen for the control groups of 8 patients
tcith systemic lupus erythematosus and 8
RHEUMATISM AND ARTHRITIS
patients with rheumatoid arthritis. The
mean alpha-&globulin value of the latter
toas higher than i n rheumatic fever. Ed.]
OTHER IMMUNOLO’GIC AND CHEMICAL
STUDIES
IgA’ immunoglobulin levels were increased in 74% of 31 patients with acute
rheumatic fever as opposed to 55% in
rheumatoid arthritis, 41% in acute glomerulonephritis and 21% in uncomplicated
streptococcal tonsillitis. [ T h e diagnosis of
streptococcal tonsillitis was corroborated
only by throat culture; they may therefore
represent viral tonsillitis i n streptococcal
carriers. Ed.] Forty-four per cent of 16
children with “inactive rheumatic fever”
had elevated IgA levels. [ T h e minimum
length of “inactivity” was 4 months but the
maximum and average periods were not
defined. Ed.] IgM globulins were increased in only 13%of the cases of acute
rheumatic fever. IgG globulins were also
elevated. In 70%of 27 patients studied the
elevations of each individual immunoglobulin fraction was independent from elevation of the others (582).
An abnormal product of tryptophan
metabolism, 5-methoxytryptamine, was
found in the urine of all of 48 rheumatic
subjects tested (active and inactive, with
and without heart disease) and in the urine
of only one out of 33 non-rheumatic subjects (491 ). [A cooperutive “blind” study
toas set up to test the validity of this claim,
but, unfortunately, it toas interrupted before completion and toas not reported.
Ed.] Another abnormal urinary metabolite, tentatively identified as 3-methoxy-4“A uniform nomenclature for the iinmunoglobulins has been proposed. IgG (or y G ) refers to the
main component of immunoglobulins previously
called varyingly 7s y globulin or y 2 globulin. IgA
(or y A ) refers to the component previously designated y,A or fi2A globulin and IgM (or y M ) is
the recommended abbreviation for the high molecular weight immunoglobulins (923). A fourth
class of immunoglobulin ( IgD) has been described
recently (1076).
103
RHEUMATIC FEVER
hydroxy-phenyllactic acid ( vanillactic acid)
was reported to be present in the urine of
active rheumatic fever patients (219). In a
later paper the same group confirmed the
identity of vanillactic acid and reported the
increased excretion of DOPA and of an indole compound, probably 3-methoxytryptophane, in rheumatic fever (220). In a
subsequent paper it was reported that erythrocytes from rheumatic fever patients
were not able to deaminate 5-methoxytryptamine while normal controls were (492).
[See .section on RHEUMATOID
ARTHRITISfor
further discussion of tryptophane metabolism in rheumatic disease. Ed.]
ELECTROENCEPHALOGRAPHIC (EEG)
STUDIES
Fifty-five per cent of 31 patients with
Sydenham’s chorea had abnormal EEGs
(611). Twenty-six per cent of 20 patients
with rheumatic fever, without chorea, had
abnormal EEGs (723). [One of these patients had hemiparesis and another had
conuulsions. I t is not clear whether this series way selected OT not. Ed.]
PATHOGENESIS
The hypothesis that a primary disturbance in lipid metabolism is an essential
factor in the pathogenesis of rheumatic
fever was restated (243). [ T h e lipid nature of the streptolysin S inhibitor of normal .serum is the one solid datum in favor
of this theory. Ed.] The biology of group
A streptococci was briefly reviewed and the
possibility that antibodies against the
group-specific carbohydrate of group A
streptococci cross-reacting with the Nacetyl-glucosamine of human connective
tissue was stated, discussed, and found in
need of additional evidence (824). The
possible significance for the pathogenesis of
rheumatic fever of the immunologic crossreaction between some group A streptococcal strains and human heart tissue was
briefly discussed (641) and extensively investigated. as detailed below.
AUTOANTIBODIES TO HEART
The presence of heart muscle antibodies
in rheumatic fever was confirmed in a
“blind study of sera from 624 subjects.
Among the patients with rheumatic fever,
heart antibodies were more frequent in patients with carditis (63.4%of 71) than in
those without (26%of 74). The pattern of
staining was subsarcolemmal-intermyofibrillar in all these patients but was diffuse
in 6 of 7 patients who developed antiheart
antibodies after a myocardial infarct. Heart
antibodies were found in 7.5% of 66 normal subjects, but were diffuse in 4.5%
(554). Sparse focal lesions not resembling
Aschoff bodies were obtained by prolonged
immunization of rabbits with heterologous
heart without Freunds adjuvants (642).
The serologic cross-reaction between human heart and group A streptococci was
studied further. Goat antisera to human or
rabbit heart precipitate with acid extracts
of some strains of group A streptococci
(644). A similar cross-reaction was also
shown in human sera by absorption of
streptococcal extract precipitating activity
with human heart. Such cross-reactive antibodies were present in 60% of 6 patients
with glomerulonephritis, 58% of 7 patients
with inactive rheumatic heart disease and
55% of 28 patients with rheumatic fever
(645). [ N o normal controls were included. Ed.] The three main types of immunoglobulin ( IgG, IgA, IgM globulins)
plus the beta l-C component of complement, were found in the extensive deposits
in the myocardium of 5 children who had
died of rheumatic carditis (643). [Normal
heart tissue was negative in these immunofluorescent tests, but other pertinent
controls were missing: heart tissue afected
by pathologic processes other than rheumatic carditis, and antisera t o serum proteins other than immunoglobulins. Ed.]
TOXIC EFFECT OF STREPTOCOCCAL
PRODUCTS
Streptolysins 0 and S disrupt isolatcd
103
RHEUMATISM AND ARTHRITIS
lysosomes in vitro (1323) and degranulate
intact polymorphonuclear leucocytes in the
process of killing them (563). Other hemolytic toxins from other microorganisms
were shown to disrupt lysosomes also
( 107). A chronic, relapsing nodular lesion
ot the connective tissue of rabbits previously described to follow injections of a C
polysaccharjde-peptide complex was shown
to 1)c independent of immunologic reactivity (1120). Some antiserotonin drugs afford
protection against the acute toxicity of
strt,ptolysin 0 (495).
Natural History
Among the various manifestations of
rheuinitic twer, chorea ha$ decreased
inuch more than the others. The incidence
ot carditi5 m d the mortality during the
acute attack may also have decreased (812,
816). I n a hosPit"l-as~ernb1ed population
rheumatic fever patients with arthralgia
had carditis more frequently and more
\e\ erely than patients with polyarthritiy
(364). [Patients with arthralgia may be
cdmitterl t o .some hospitals onlij if they also
haor carditis, while patients with polyarthriti.7 maiy he admitted regardless of their
cardiac status. Patients with polyarthritis
urv kept in bed by their pains, and bed rest
may ameliorate some manifestations of carditis. Ed.]
CONGESTIVE HEART FAILURE
Congestive failure in children with rheumatic heart disease was not always due to
rheumatic activity. The erythrocyte sedimentation rate was elevated in the majority
of patients having episodes of congestive
heart failure associated with clinical evidence of active rheumatic fever (1190)
which, in children, was manifested by right
inore than left heart failure and, with the
latter, more by svmptoms than by signs
(362).
CHOREA
Two cases of chorea associated with systemic lupus erythematosus were described.
Both had active lupus, one had a high A S 0
titer in addition ( 193).
RHEUMATIC FEVER RECURRENCES
These were found to follow only those
streptococcal infections which elicited an
antibody response, and the recurrence rate
per infection was found to increase gradually from 15% in 88 infections accompanied by a two-tube A S 0 rise to 70%in 10
infections accompanied by a 6+ tube rise
(1246). [Data on the persistence of streptococci in the throat were not given. These
observations were made on patients given
prophylaxis. Ed.] The recurrence rate per
infection was also found to increase from
10% in 189 patients with no pre-existing
rheumatic heart discase to 27% in 74 patients with heart disease but no or slight
cardiomegaly, to 43% in 21 patients with
marked cardiomegaly. The recurrence rate
showed a tendency to decrease with age
and with time elapsed since the last attack
(1245). [Whether the former or the latter
fuctor or 130th circ involved is not clear.
Ed.] Only half of the recurrences were
preceded by clinical pharyngitis ( 1246).
Twelve recurrences in 11 patients who had
had no carditis in the preceding attack
were characterized by carditis in 2 (17%)
(363). In a retrospective study recurrences
in 50 patients who had had no carditis with
their first attack were characterized by carditis in 13 (26%) and left permanent cardiac damage in 6 (12%) (693). [Four of
these 6 patients had chorea and not polyarthritis as manifestation of their initial attack. Since chorea has been shown t o have
a longer latent period than polyarthritis or
carditis, these 4 patients may have had
asymptomatic carditis months before their
chorea. By the time chorea brought them
to the hospital, the signs of heart involvement may have disappeared. Ed.]
UNUSUAL CLINICAL MANIFESTATIONS
Cutaneous papules were described in a
patient with arthralgia, erythema marginatum and elevated A S 0 titer (181).
105
REEUhIATIC FEVER
[Tlie evidence is not quite convincing that
this reprvsented a cutaneous variant of the
dwumatic subcutaneous nodules in a patient with rheumatic carditis. Ed.] Throm1x)ernbolic complications were described in
one case of rheumatic fever and one case of
rheumatic heart disease in a child (1218).
Two cases of isolated rheumatic-like subcwtaneous nodules were reported (21).
LONG-TERM SEQUELAE AND PROGNOSIS
Four hundred forty-one patients with
previous rheumatic fever were followed
over an 8 year period: 181 patients with no
{ignificant murmurs during their preceding
att‘ick remained frec of heart disease. Pure
mitral stenosis did not develop de now,
hiit appeared in 5 patients who previously
h w e d evidence ot mitral deformity.
Twelv(~patients died: 11 of them without
recurrences of rheumatic fever (364, 366).
[ A l l l)atients were on prophylaxis. In th.
pl.c-~,roi,hzilaxis era deaths due t o second or
third uttuckr. tcith carditis were common.
Ed.] Two rrports from India noted the
high incidence of severe mitral stenosis in
children and adolescents of that country
(217, 1078). Patients who develop rheumatic tever around puberty were found to
have ‘i higher incidence of psychiatric disorders than patients who deiTelop rheumattic fever at other ages or who develop other
diseases ( 1324).
In a clinico-pathological correlation
study, the most frequent cause of fever
among patients who died with rheumatic
heart disease was pulmonary infarction,
m d the next most frequent cause was
“rlieumatic activity” (338).
Diagnosis
Onc hundred children were referred to a
cardi,w cx~nsultationclinic because of a history of rheumatic fever or a diagnosis of
rhemiutic heart disease or both but in 35
(%%) thr diagnosis could not be confirmccl (123). Sixty-two per cent of 29 patients attending cardiac clinics with known
rheumatic heart disease were misdiagnosed
as “no heart disease” by qualified internists
or pediatricians doing a school health survey (897). Computer analysis of phonocardiograms resulted in a pilot multivariate
analysis program with a misclassification of
7% between mitral regurgitation and no
heart disease (1244). [This is hardly, as it
stands, a practical method of diagnosis, or
even of screening, but it takes the “mystiqtie” out of azcscultation, showing that
heart murmurs can he analyzed by a machine. In view of the high rate of error by
physicians, the “nutornaterl”‘ approach
shown feasible in this work may be worth
pursuing. Ed.]
Treatment
A retrospective survey indicated that
heart failure subsided more frequently and
death was less frequent in patients with
severe rheumatic carditis treated with steroids than in those treated with aspirin
(272). [Eliminating each possible bias at
a time-preuious
attacks, treatment with
penicillin, decreased severity in recent
years-the diference in favor of steroids
persisted, though smaller. I t is not quite
clear whether it would persist if all biases
were removed together. Ed.] Phenylbutazone was more effective than aspirin in
suppressing fever, tachycardia, joint pains
and ESR (1335). [ N o cardiac follow-up
zuas reported. Ed.] Heart failure occurring
in concomitance with clinical evidence of
active rheumatic fever often responded to
steroids; digitalis was not more toxic in “active” than in “inactive” patients (362).
[This study was done in a convalescent
home and most of the observed episodes of
failure occurred late in the attack. Ed.] A
case of aseptic bone necrosis occurred after
steroid therapy for rheumatic fever (1230).
Prevention
DIAGNOSIS AND TREATMENT OF
STREPTOCOCCAL INFECTIONS
(PRIMARY PREVENTION)
Although methods employing pourplates
106
may be more sensitive and thus result in
higher rates of streptococcal recovery than
the more commonly used surface streaking
technique, only 3.6% of 321 illnesses associated with negative surface cultures had a
rise in A S 0 titer. This indicates that very
few true infections are missed by the conventional method (860).
Eighty-eight per cent of 99 children with
tcbrile exudative pharyngitis had more
than 10 colonies of group A streptococci in
throat cultures as compared to 53%of 83
paticnts with moderate pharyngitis and to
12% of 65 patients with mild pharyngitis.
Because of the high frequency of streptococcal etiology, patients with febrile exudative phiryngitis may be treated even without waiting for the result of the throat culture, unless viral exudative febrile pharyngitis is present in the community (861).
Non-convalescent carriers of streptococcal
strains are not likely to develop streptococcal disease due to the strain they carry and
may even be protected from infections with
new strains (525). A review of previous
studies on the epidemiology of group A
streptococcal infections emphasized the importance of close contact rather than contaminated cnvironment in the transmis.;ion
of the infection ( 1018).
A high percentage of discrepancies (48%
in thi5 study, 12, 27, 49 and 63% in previous studies) between the fluorescent antibody technique and the conventional technique for serologic grouping of beta-hemolytic streptococci was noted. Most of the
discrepancies were due to the higher sensitivity of the fluorescent antibody technique,
and may be due to the enrichment inherent
in the growth in broth and subsequent examination of the sediment (48). Previous
incubation increased the yield of group A
streptococci both by immunofluorescence
and by conventional techniques (868). Immunofluorescent staining by direct smear of
thc throat swab (without prior culture)
w a s atternptcd with success. The im-
RHEUMATISM AND ARTHRITIS
munofluorescent technique used was indirect, which allowed dilution of the streptococcal antisera and therefore reduction of
undesirable cross-reactions without need
for absorption. When the number of organisms was moderate or small on a conventional plate, they were missed by this simplified fluorescent method in half the cases.
However, when the number of colonies on
a conventional plate was great, the immunofluorescent test was positive in 93%
of the cases (1021). [ I t thus appears that
immunofluorescent techniques may he both
more and less sensitive than conventional
techniques, according to the use of broth
cultures or of direct smears. Their greatest
asset is speed; but for screening they are
more tedious and time-consuming than inspection of plates. Ed.]
Mailing of dacron swabs to the laboratory was found to give very satisfactory results (710) and laymen were able to learn
to culture throats satisfactorily (811).
Erythromycin estolate, 1,000 mg daily, was
equally or more effective than oral penicillin, when both medications were administered for 10 days to patients with definite
streptococcal pharyngitis ( 859). Tetracyclines were less effective (162). An impending epidemic of streptococcal pharyngitis
among military personnel and their dependents was “diagnosed on the basis of rising
carrier rate, rising weekly rate of streptococcal pharyngitis, predominance of one
serologic type and abundant growth of
streptococci from throat cultures. Since it
appeared that the disease was transmitted
through the children in the families, and
treatment of symptomatic cases and of
their asymptomatic but bacteriologically
proved infected contacts was ineffective in
preventing the spread of the epidemic, prophylactic mass administration of 1,200,000
units of benzathine penicillin was instituted
in children and bachelor personnel. Although only 55% of the former and 81% of
the latter population were so treated, the
107
RHElJMATIC FEVER
epidemic was promptly and permanently
stopped (1110).
FAILURES O F PRIMARY PREVENTION
The limits of the preventibility of first
attacks of rheumatic fever have been explored in two studies. Of 110 patients admitted with rheumatic fever, 87% had a
history of antecedent infection, but in only
77% was the infection respiratory. Fifty-six
pvr cent were taken to a doctor, but throat
culture? were obtained in only 27%.Interestingly, throat cultures were positive for
beta-hemolytic streptococci in only 35% of
the 17 patients cultured. Finally, only 16%
of the whole group received antibiotic
treatment generally adequate to eradicate
the streptococcal infection (482). Another
retrospective survey pointed out that, although 80% of rheumatic fever patients
had a preceding illness, the latter occurred
10 to 35 days prior to the onset of rheumatic fever only in 56%of the cases, and only
these cases could be expected to be prevented by adequate treatment of the preceding infection (1100).
The kind of “eradicating” treatment preccribed for patients with streptococcal
pharyngitis should take into account the
frequency of failure to complete a 10-day
course of oral treatment. By viyiting the
homes of patients who had been given such
prescriptions, and counting the residual
pills or measuring the residual liquid, it
was found that 56% had stopped taking
penicillin by the third day, 71% by the
sixth and 82% by the ninth day (102).
[ Benzathine penicillin in a single injection,
600,000 to 1,200,000 units according to the
age, remains the most effective and practical trentment. Ed.]
The failure of standard treatment to
eradicate streptococci may be due to the
concomitant presence of penicillinase-producing staphylococci. Twelve cases of bacteriologic relapses of streptococcal pharyngitis were studied; all 12 had, in addition to
the streptococcus, a penicillinase-producing
staphylococcus. When tested in pure culture, the streptococci were sensitive to penicillin G, but in mixed culture with the
staphylococcus isolated from the same
throat culture they were resistant. Exacillin
was effective in eradicating both organisms
from the throat (1167).
CONTJNUOUS PROPHYLAXIS
(SECONDARY PREVENTION)
An extensive prophylactic trial compared
the effectiveness of benzathine penicillin,
1,200,000 units, by injection every 4 weeks,
oral buffered potassium penicillin G, 200,000 units in a single dose, 1/2 hour before
breakfast, and sulfadiazine, 1 gm per day
orally in a single dose. On admission the
patients were assigned to one of 8 groups
on the basis of the possible combination of
the following variables: presence or absence of RHD; age, 5 to 9 or 10 to 18; and
duration since end of the last rheumatic
attack, 3 to 14 months or more. Within
each group the patients were assigned by a
random process to one of the three prophylaxis regimens. Four hundred thirty-one
patients were admitted to the study and
were observed for a total of 1,681 patientyears. Only 10%of the patients had to be
dropped over the 5 years of the study because of lack of attendance.
Definite allergic reactions were remarkable for their absence, but 21 of 25 changes
in prophylactic regimens occurred from the
benzathine penicillin group because of
marked local inflammatory reaction ( 1365).
The administrative, financial, organization
and personal relation aspects of the study
were described in detail (428).
Injectable benzathine penicillin was the
most effective prophylactic agent resulting
in a rheumatic fever recurrence rate of 0.4
per 100 patient-years. Patients on sulfadiazine did better than those on oral penicillin (with recurrence rates of 2.8 and 5.5,
respectively) ( 1366). A subsequent study
108
has compared the effectiveness of a doublg
daily dose of penicillin, i.e., 200,000 units
taken 9; hour before breakfast and at bedtirnc. During the 322 patient-years of observation, there were 11 major post-streptococcal complications ( one glomeruloiic'phritis and 10 rheumatic fever attacks),
rvrnly distributed between the two groups,
giving an attack rate per hundred patientycws of 3 for penicillin and 3 for sulfadilie (365). The incidence of streptococcal
infections and rheumatic recurrences in
'idolescents and adults not on continuous
prophylaxis was studied in patients with
previous rheumatic fever or definite rheumatic heart disease or both. Twenty-two
streptococcal infections were observed per
IOO patien-year\, but only 5 per 100 113tiriit-ywi s wc'rc \ymptoinatic. Only the lattt,r were treated. The rheumatic fever recurrence rate in adolescents and adults was
1.3 and 0.7/ 100 patient-years, respectively,
but the incidence of streptococcal infection
was \imilar in both groups. [All these
rrrtes (ire loicer thun those obserzjed in
youngor age groups. Ed.] It thus appears
that the well-known decrease in the rheumatic fever recurrence rate per year is due
t o both a decre'ise in frequency of streptococcal infection and a decrease in the recurrence rate per infection. The latter decrease, on the basis of Iimited data, appears
not to be due to a decreased antibody response in the older patients (612).
Three types of oral penicillin preparation
were compared: buffered potassium penicilIin G, benzathine penicillin G, and
phenoxymethyl penicillin. Benzathine penicillin Cr was somewhat less effective than
the other two preparations. Rates of rheumatic recurrences and of streptococcal infections were lower than in other reported
studies and as low as those obtained with
injec>table benzathine penicillin ( 17).
1 This ILXS prohubli) t h e to the diferent uge
groups involved. The conclusion of thp
mcthor,c thnt ortll prophylaxis is us good as
RHEUMATISM AND ARTHRITIS
that obtainable with injections is not supported by controlled studies. Ed.]
A pioneer city health program for children with rheumatic fever was described
(167). The problems of prophylaxis of
rheumatic fever were discussed editorially
(361) and reviewed critically ( 1212).
FAILURES OF SECONDARY PREVENTION
Only 12.2% of 9,044 college students
with a history of rheumatic fever or with
rheumatic heart disease were found to have
remained on continuous prophylaxis, although 50.7% had been receiving prophylaxis at some earlier time. Of the patients
with definite rheumatic heart disease,
38.7%were still on prophylaxis at the time
the survey was made (793). Social factors
did not significantly influence the achievement of prophylaxis; illness in the family
and intra-family discord affected it tinfavorably (775).
A potential risk of pencilliii prophylaxis
is the development of subacute bacterial
endocarditis due to penicillin-resistant organisms. Penicillin resistant alpha streptococci were recovered from the throat or the
mouth in 81% of 21 penicillin-treated patients, but in none of the sulfadiazinetreated controls ( 897 ) . Penicillinase-producing staphylococci were harbored in the
throat of 56.5% of 92 patients on continuous penicillin prophylaxis, but in only
22.4% of 67 patients who were not receiving penicillin in any form. Relatives of patients on prophylaxis had an intermediate
incidence of penicillinase-producing staphylococci (838).
Rheumatoid Arthritis (RA)
Prevalence and Definitions
Problems arising in the estimation of the
prevalence of rheumatoid arthritis were
given special attention. Epidemiological
studies of RA in Britain were reviewed
(725). National statistics tierived from Hri-
RHEUMATOID ARTHRITIS
(R A )
tain and Europe provided data on mortality rate, hospitalization, frequency of medical visits, and time lost from work (1235).
Recorded mortality rates were low, and
even the discharge rates from hospitals
were surprisingly low; in England and
\,Vales rlicumatoid arthritis in males accounted for only 0.6% of hospitalizations,
m c 1 in women 1.2%. About 1%of the fem d e patients consulting family physicians
in Britain were recorded as having rheumatoid arthritis. In the 45 to 64 year old age
group, consultation for RA amounted to
2.3% of the total for females, and almost
1%for males. These data were considered
unsatisfactory. Diagnostic categories were
multiple and vaguely defined, so that patients with RA may have been listed under
“Klwumatoid Arthritis and Allied Condit ions,” “Arthritis and Spondylitis,” “Other
Forms of Arthritis,” “rheumatism unspecified,” or under their presenting complaint.
(:hanges such a s the recorded rise in mortality from RA since 1949 may have been
due to changing instructions or fashions,
rittlicr than to changes in the disease or its
treatment (306). Recorded morbidity in
this and other national surveys depends not
only on the prevalence of the disease, but
also on sociological factors.
The prevalence of RA in Haida Indians
was similar to that found in other racial
groups in northern temperate latitudes,
whereas the prevalence in a Puerto Rican
community was quite low (442, 835). The
prevalence of RA amongst the criminal
and the insane seemed low; only 30 patients with “definite” and “probable” RA
were found amongst 20,494 mental hospital
patients, and only 9 of 4,040 prisoners had
HA (1072). Seven surveys of the prevalence of RA in population samples from
northern Europe were compared, concentrating particularly on the age group 55 to
64 (2%). The prevalence of “definite” RA
varied in males from 0 to 3.4%, and in
females from 1.7 to 5.2%. The prevalence
109
of “definite” RA in Tecumseh, Michigan,
was comparable to the Iowest of these
figures (842). Even more striking variations
were seen in estimates of “probable” RA
These variations led to close examination 01
the use and usefulness of the A.K.A. criteria
for field surveys. Of the 11 criteria, only 8
are applicable to survey work, and these
were often modified to remove the time
factor (i.e., observe joint swelling at the
time of survey; no requirement of 6 weeks’
duration (35, 174, 842). Of these criteria, a
number were positive in a relatively high
proportion of the general population, and
many were subject to inter-observer variation. “Morning stiffness” was recorded in
about 65% of individuals in the EO to 69
age bracket in the Tecumseh study (842);
yet less than 2% of the females and 1% of
the males fulfilled the criteria for “definite”
RA. On a further study of 327 persons who
answered “yes” to the question about morning stiffness in a preliminary interview,
only 19% were recorded positive for this
criterion by the examining physician. Thus,
there could be a “tendency to use the criterion only for confirmation of a positive
clinical diagnosis” ( 5 ) .
Even with “objective” criteria such as
x-ray findings, there was a very high interobserver variation between clinicians with
long experience in diagnostic and survey
work (292, 442). Serological testing by
different methods or in different laboratories showed considerable disparities, and in
some populations a large proportion will
show rheumatoid factor-like reactivity, presumably due to parasitic or infectious disease (835, 1278). Additional criteria were
suggested. “Lateral pressure tenderness”
(positive when collateral pressure on metacarpo- and metatarso-phalangeal joints
gave more pain than dorsoventral pressure)
compared favorably with other criteria in
sensitivity and specificity in one study
(462). A scheme for the diagnosis of inactive rheumatoid arthritis was also pro-
110
RHEUMATISM AND ARTHRITIS
whose disease was of short duration irrespective of apparent severity at onset.
Prognosis was worse in those with disease
of prolonged duration, and those with high
titers of rheumatoid factor. It was noted
that activity of the disease tended to fluctuate within fairly narrow limits during the
follow-up period and only 14 patients remained inactive through the study. [ This
excellent series of reports presents its complicated findings with superb clarity and
imagination, and deserves detailed study.
Clinical and Pathological Studies
Ed.] (328). The rarity of prolonged remisSeveral well-conducted long-term studies sions was emphasized. Twenty-three of 250
have documented the possible courses that patients in a previous study had prolonged
RA may take. The patients in a report remissions, with an average duration of 22
from Scotland had been followed for at years. Most were in the group of patients
least 9 years. The number of patients in the that experienced acute onset of arthritis
study decrelsed from 307 to 200, because and who were hospitalized within one year
of the death of 75 patients and some losses of onset of symptoms. Most required only a
of follow-up. Mortality rates were more brief hospital stay (more than 4 weeks in
than 60% higher than in the general popu- only 3). However, the attacks preceding
lation. The increase was seen in all age the remission persisted from 7 months to 5
groups and no specific cause of death was years (median 13 months). None received
outstanding [in contrast to an earlier gold, and it seems unlikely that the favorstudy (1148) in which the mortality rate able course could be credited to therapy.
was higher than normal in younger pa- Although the patients (by definition) were
tients, atid deaths attributable t o infection free of objective evidence of active arthritis
were more frequent. These differences may during the periods of remission, the majorin part reflect the current use of antibiotics. ity reported symptoms from time to time,
Ed.]. Striking improvement usually oc- ininor elevations in ESR occurred, and
curred during the initial hospitalization, mild exacerbations interrupted the remisand slight further net improvement was sions a total of 31 times (1147). In another
observed in the succeeding two years. study from this center, 98 selected patients
Thereafter, there was a slight but progres- with RA were compared with a group of
sive decline in average functional capacity 27 patients with ankylosing spondylitis.
during each 2-year interval. Thus, only Age, sex, serology, and the presence of
35.4% were in functional Classes I and I1 nodules showed the usual contrasts. Iritis
on admission, 72.4% achieved these levels and hip joint involvement were much more
at 2 years, and 61.5% remained in these common in the spondylitic patients. The
classes after 10 years. In each 2-year pe- data “supported the conclusion that ankyriod, about 60% of the patients stayed in losing spondylitis and peripheral RA differ
the same functional class, and twice as sharply . . . . . and may be separate disease
many deteriorated as improved. Nearly a entities.” “If a patient has neither nodules
quarter of those in Class IV failed to sur- on the one hand, nor lumbodorsal spine
vive the %year intervals between each as- involvement on the other, our methods of
sessment. Prognosis was best in those classification as to the type of arthritis are
posed, the chief clinical criterion being the
presence of irreducible subluxations in the
metacarpo- and metatarsophalangeal joints.
The category of “possible” RA was
dropped and ankylosing spondylitis was
added to the list of exclusions (35). Preliminary screening of populations by means
of a questionnaire is a very attractive method for dealing with large populations efficiently, and further studies of the sensitivity of the method are in progress ( 5 , 835).
111
RIIEUMATOID ARTHRITIS ( R A )
inexact to some extent.” The occurrence of
nodules and positive serology was not related to the duration of the disease, but
correlated with a non-remitting course
(1138). In another study, patients fulfilling
A.K.A. criteria for definite and classical
HA were divided into two groups, 24 with
strongly positive latex fixation tests for
rheumatoid factor, and 23 with negative
tests. The seropositive group more commonly showed a positive family history and
involvement of metacarpal and lateral metatarsophalangeal joints (but no excess involvement of interphalangeal joints ). They
more commonly showed evidence of vasculitis and edema and had a lower serum
cholesterol. No differences in hip and
\boulder involvement were found, nor in
the. proportion developing joint instability
or lymphadenopathy. These authors felt
the evidence “insufficient to warrant categorizing seropositive and seronegative RA
as separate diseases” (241). In a study of
14 patients with chronic deforming RA
and positive L.E. cell tests, all were found
to have associated chronic infections, most
commonly secondarily infected necrobiotic
lcg ulcers (8 patients). In contrast to patients with SLE, rash, glomerulitis, and
histological hematoxylin bodies were not
found, and the antinuclear factors tended
to be macroglobulins ( 1341).
Five patients were described who presented with a newly recognized clinical
syndrome; that of acute synovial rupture in
patients with RA. By far the most common
site of rupture is the posterior aspect of the
knee joint, just lateral to the medial head of
hiceps. The clinical picture resembled
acute deep vein thrombosis, except for a
greater inflammatory reaction, usually a
negative Homan’s sign, and no palpable
evidence of venous thrombosis. In 3 patients, joint fluid was aspirated (with difficulty) from the calf, and in a fourth radioactive gold injected into the knee was
tracked down the calf. Experimental stud-
ies were designed to further explore this
phenomenon. The pressure required to
burst the knee capsule of cadavers ranged
from 74 to 690 mm Hg., and in live subjects whose knees had been distended with
plasma, a deep knee bend induced pressures of 1200 mm Hg. or more, with rupture in 2 instances. It was noted that the
condition occurred early in the course of
RA, (before substantial scarring of the
capsule occurred) (308). A second report
described acute pain and swelling in the
calf of patients with RA and popliteal
cysts; signs of phlebitis were absent. The
diagnosis of synovial rupture was considered among other possibilities (455).
[The acute inflammatory reaction masks the
underlying pathology; but this phenomenon should be watched for, and not dismissed as phlebitis. Ed.]
Arthritis of the crico-arytenoid joint was
reviewed in detail. Pathological studies
gave no support for the earlier suggestion
that the fixation of the cords may be due to
a neuropathy. In the acute stage, edema
may close the glottis and tracheotomy may
be required. When inflammation subsides,
resection of one cord may be necessary (79,
119, 120, 866, 867, 1178).
The vulnerability to infection of severely
ill rheumatoids was again emphasized. Five
rheumatoid patients were described who
developed septic arthritis. Four were in
Class IV, all had had previous sepsis in
other sites, and none had had systemic steroids, or steroids injected locally into the
joints which became infected. In 4, the infecting organism was a staphylococcus and
3 patients died. Infection usually was
found in multiple sites, but the sternoclavicular joints seemed especially vulnerable
(427).
VASCULITIS
Small-vessel arteritis has long been emphasized as an important and widespread
pathological feature of RA. Recently clini-
112
RHEUMATISM AND ARTHRITIS
patient with mutilating arthritis, which discharged fragments of bone and cartilage
ules. episcleritis, and pericarditis as mani- ( 1066).
festations of widespread vasculitis ( 124,
Edema in the lower limbs and occasion190, 191, 608, 688). The most common and ally hand and forearm may appear in rheutypical ksion was a tiny hemorrhagic in- inatoid patients for no apparent reason.
farct, usually seen about the nail fold or The protein content of such fluid from the
finger pulp. This sign was usually associ- feet was invariably low, and the occurrence
ated with active RA, the presence of rheu- was not related to the concentrations of
matoid nodules, high titers of rheumatoid serum proteins. It was suggested that this is
factor. nwropathy and visceral lesions, and a “venous edema,” but the exact origin was
with a high mortality (10 deaths in 34 pa- not defined (954,1233).
tients followed in a 6-year period (190).
An extensive study of the skin structure,
This severe course was not invariable, and and reactivity to various drugs and antisomc rctained excellent general health and gens did not disclose differences between
function. [These lesions are transient and rheumatoid patients and controls (182).
s!ymptomlcss, arid easily overlooked. They However, decreased axone reflex sweating
ure of sufficient diagnostic and prognostic on the volar aspect of the forearm, and ininiportnnce that they should be specifically creased sweating of the hands was noted in
srarched for and recorded. Ed.] A possible a series of 100 R.A. patients (631).
association of widespread arteritis with
steroid therapy has been noted by many THE RHEUMATOID NODULE
An electron microscopic study of the
authors (608, 688) but this complication
structure
of 7 rheumatoid nodules revealed
ma!; arisr in patients who have never redense
finely
filamentous granular aggrcwived stcroids. Brachial arteriography regates
in
the
palisaded
layer corresponding
vca1e.d rniiItipIe sites of narrowing and obto
the
distribution
to
fibrinoid. This mastruction of digital arteries in patients with
terial
failed
to
show
the
periodic banding
&deric-e of vasculitis with “compensatory”
of
fibrin
formed
i
n
vitro,
but closely redilatation of the distal capillary bed
1184 ). The occurrence of skin lesions was sembled in vivo deposits of fibrin (244).
apparently conditioned by trauma, and les- Two further patients were described who
sened with hospitalization. One patient developed nodules as the first evidence of
with a hemiplegia showed symmetrical an- rheumatoid disease (765).
giographic changes, but skin infarcts only NEUROMUSCULAR LESIONS
on the non-paralyzed side (190, 191). CalMany investigators continued to attempt
orimetric studies of the blood flow through to define specific nerve and muscle lesions
rheumatoid hands showed low resting lev- in rheumatoid patients. In recent electrofls, and a poor reactive hyperemic response myographic studies, no authors described
following temporary arterial obstruction, fibrillation in the muscles of rheumatoid
but a normal reflex response to warming of patients, and no specific myopathic patother parts (37).
terns were found. Reduction in amplitude
of potentials and in number of motor units
CI,’TRNEOUS MANIFESTATIONS
In addition to hemorrhagic infarcts, responding after voluntary contractions
other skin lesions described included a was common, but was explained as a nonniaculo-papular rash ( 190); necrotic leg ul- specific effect of atrophy. The mean potencers, (190, 1341); and gangrene of fingers tial duration was found to be decreased by
and toes (190). Fistulae developed in one steroid therapy, and was normal in 34 pac-ialis have viewed the presence of skin lesions, peripheral neuropathy, multiple nod-
tic.nt< \wth HA
not receiving steroids
( L376). HOM~WCT,
<I second study showed
nlmormally short mean potential dura t’ion
in 6 of i 0 RA patients studied (1068).
‘These investigators examined muscle biopsies taken adjacent to the area explored
hv the E.M.G. needle. Interstitial lymphoid
xcumulations were found in about onehalt ot each 5eries. [This finding mu!/ be a
locull!/ innocent manifestation of a general
I i p p h o i d hyperplasia. Thc term “nodular
r y o t i t i s ” niuy hc misleading. Ed.] In 9 of
50 biopsies, muscle fiber “change” was reported, and arteritis was found in 4 (1068).
The correlations among E.M.G., clinical,
nnd biopsy findings were not strong. Nerve
couduction velocities were reported in
rheumatoid patients with conflicting re4ults. One group found moderate to severe
impairment of conduction in velocities in
38 of 287 peripheral nerves studied (17%),
,ind in addition, evidence of further delay
iri t h r cbarpal tunnel in 22 of 113 median
nerLe.4 \va\ noted (566). IIowever, in another study, using similar techniques, conduction Lelocities were e.isentially normal;
I.?.. 3.5% of 143 deterinations wcre less
than t h r “limit ot normal,” compared with
25% expected. This author felt that RA
\+as “not a common cause of carpal tunnel
\yndrome” (873). [Neither author published the findings in controls or docurnented the e f c c t of therapy. Ed.] In both
studie\ there was a poor correlation between test results and clinical evidence.
[ T h e origin of the paraesthcsiae and rriuscle
atrophy of I heumatoid patients remains
unexplained. Ed.] Myelopathy in a patient
with RA was attributed to pachymeningitis (489). [ T h e most common basis for
cJ lesions in RA is atlantoaxial dislocation. Ed.]
CARDIOPULMONARY MANIFESTATIONS
Mild dilatation of the aortic root with
insufficiency of the aortic valve was reported in 5 patients with severe RA, and
the pathological and clinical features were
contrasted with those of spondylitic heart
disease. As in ankylosing spondylitis, the
major lesions were found in the aortic root
rather than in the valve leaflets, and an
exaggerated ringing second sound often accompanied the murmur. In contrast to
spondylitis, the insufficiency was usually
mild, The patients tended to be severely ill.
with clinical and pathological evidence of
widespread vasculitis, and rheumatoid
granulomata were described in the aortic
ring (1391). A retrospective review of 62
patients with RA autopsied since 1933 revealed a mild nonspecific endocarditis involving the roots of the aortic and mitral
valves in 4 patients. Only mild systolic
murmurs had been recognized during life.
Other patients showed pericarditis (18 patients), rheumatoid granulomata (2 patients ), interstitial lymphoid deposits in
myocardium ( 12 patients), and myocarditis
with necrosis (1patient) (731). The course
of 3 patients with RA who developed constrictive pericarditis was described. Pleural
effusions were present in 2, and in 2 constriction developed despite therapy with
steroids. The response to surgery was considered completely satisfactory. Specifically, rheumatoid features were lacking in
the pathological material ( 1268). Abnormal
electrocardiograms were found in 32% of
157 RA patients (45).
The pulmonary manifestations of RA
have been studied with increasing interest,
but many points remain unclear. Two separate patterns of pulmonary parenchymal
involvement are being reported; one of
diffuse interstitial fibrosis, the other of multiple nodules, some of which may cavitate.
The prevalence, interrelationships, and
pathogenesis of these lesions remain obscure. The chest roentgenographic findings
of 126 patients with high titers of rheumatoid factor were compared with those of
126 seronegative patients fulfilling A.R.A.
criteria for “definite” rheumatoid arthritis,
114
and with 94 seronegative non-rheumatoid
controls. Pleural thickening and parenchymal changes were found in 23%of the seropositive rheumatoids, and 7.9% of each of
the two control groups. The radiographic
findings, described as “striations,” “basal fibrosis,” or “reticular fibrous shadowing,”
were confined to the seropositive group
( 1159). A second study was less well controlled, but added information derived
from pulmonary function tests and lung biopsy. The radiological findings were similar
to the previous groups. Of 13 patients with
KA studied, 6 showed reduced oxygen saturation on exercise. Moderate reduction of
vital capacity was common but evidence of
obstruction was unusual and the maximum
breathing capacity was well preserved. The
diffusing capacity for carbon monoxide was
very low in the 3 patients tested. [This
reems to be the major functional defect.
Ed.] Three biopsies showed a non-specific
fibrosing pneumonitis. Therapy with steroids may have influenced the mild improvement in pulmonary functions recorded in one patient (912). Diffuse interstitial fibrosis was described in 2 additional
patients. In one of these, the pulmonary
vascular resistance was found to be normal
(1220). In a patient reported to have
“rheumatoid disease of the lung,” pulmonary hypertension was the outstanding
manifestation. This patient was a child,
with a negative latex fixation test and no
radiologically evident interstitial fibrosis
( 619). The prevalence, and indeed the existence, of an entity “rheumatoid pulmonary
fibrosis” remains in dispute. In one postmortem study, the clinical and pathological
findings in 37 patients with RA were compared with matched controls. Slight but
nonsignificant increases in pleural and parenchymal changes were found ( 1238). In a
second study, 77 patients with RA and
“idiopathic” pulmonary fibrosis were collected from a large but undefined and uncontrolled experience (157). The clinical
RHEUMATISM AND ARTHRITIS
course, radiological findings, and pathology
of diffuse interstitial pulmonary fibrosis
were beautifully described (142). An
attempt was made to exclude patients with
RA from this group of 45 patients, but at
least one subsequently developed RA
Clinical points of interest were the great
variability in the rate of progression, and
the frequency of rales, clubbing and cyanosis in the rapidly progressive or advanced
cases. Pulmonary function studies showed
restriction without obstruction so that alveolar ventilation was normal, but diffusion
was markedly impaired. The radiological
findings consisted of fine mottling, and later
tiny cystic translucencies in association
with the mottling, distributed in the outer
and basal portions of the lung. In late
phases, the translucencies largely replaced
the previously mottled areas giving the
“honeycomb appearance; and is reached
by a process of shrinkage rather than overinflation. The earliest pathological change
seemed to be edema, affecting both alveolar wall and alveolar space, with mild cellular accumulation and progressive fibrosis.
There was no evidence that steroid therapy
influenced prognosis in this series. [ T h e
&fuse fibrosis in rheumatoid subjects
seems clinically and pathologically identical t o the idiopathic form described i n this
report. Ed.] (756)
Patients with pulmonary nodules and
rheumatoid arthritis have usually had occupational exposure to dust, particularly silica or soft coal dusts. Three such patients
were reported as Caplan’s Syndrome. In
two of these some of the lesions developed
central cavitation. On biopsy, endarteritis
of the pulmonary vessels was prominent.
The nodules sometimes resembled silicotic
nodules, but often showed central necrosis
ringed with pallisaded fibroblasts and histiocytes as in a rheumatoid nodule (701,
1017). In one patient pulmonary asbestosis
was present in association with RA (871).
Fourteen patients have been previously de-
RHEUMATDID ARTHRITIS
115
( RA )
scrihed with similar nodular lesions, but
who have had no known dust exposure.
Two further patients were added to this
group. In both, the lesions had the structure of rheumatoid nodules, and in both
cavitation developed. There was little
background fibrosis, and in one it was determined that the tissues were free of silica
(323, 926). The pathogenesis of the progressive massive fibrosis in the lungs of coal
miners was carefully documented, but the
relevance to rheumatoid changes is not
clear (321,896).
T A PROIDITIS
The association of Hashimoto’s thyroiditis with rheumatoid arthritis has been discussed Tvith much interest. A series of 749
patients with thyroiditis was divided [ b y
criteria not specified. Ed.] into 506 with
IIashimoto’s thyroiditis, and 243 with acute
granulomatous thyroiditis. In the total
population there were 16 with definite
rheumatoid arthritis (2.1%), of whom 15
wercx found to be in the Hashimoto’s group.
Forty-two patients (5.6%) complained of
the widespread aching and tenderness of
the “fibrositis syndrome,” and 40 of these
were assigned to the Hashimoto’s group
(85). These observations were extended in
three subsequent papers (86, 87, 372). [In
compnrison, the incidence of RA and “fihrositis” in the acute thyroiditis group
.seems very loto. One wonders if these patients were studied as extensively, or, alternatively, if the thyroid diagnosis was made
by criteria influenced by co-existent disease. Ed.] Of 192 patients followed because of a chronic false-positive serological
test for syphilis, 3 developed Hashimoto’s
thyroiditis (1151). Three other patients
with this association were also reported. Of
these patients, 2 had Sjogren’s Syndrome
and other manifestations suggestive or diagnostic of systemic lupus erythematosus.
The possible significance of these findings
was discussed. [In a recent epidemiologi-
cal study of Hashimoto’s thyroiditis, there
were NO significant associations with RA,
SLE or other presumed “autoimmune” disorders (809). Ed.]
HEMATOLOGIC FEATURES
Five patients with Felty’s Syndrome
were reported, all of whom showed marked
improvement in hematological indices following splenectomy. In 4 of these patients,
radio-isotopic studies revealed marked
shortening of the red cell survival pre-operatively, the half-life being doubled postoperatively. Marked splenic sequestration
of red cells was indicated by the radiochromium studies. The authors noted that
in R.A. without splenomegaly shortening of
the red cell survival is not common (593).
[In pntients with RA, anemia and neutropenia, a rough guide t o the success of
splenectomy may be the size of the spleen.
Ed.] The spleen removed from one patient
weighed 2420 Gm, the largest ever reported in Felty’s Syndrome (810).
Earlier reports have suggested that the
erythrocytes of normal donors have a short
survival if transfused into patients with active RA, while their own have a normal
life span. Thirty patients with active RA
(without splenomegaly) were transfused
with labelled red cells from normal or
rheumatoid donors. The series included 3
scts of identical twins discordant for RA
In no instance was there shortening of
erythrocyte survival that could not be attributed to minor blood group abnormality
(862). The metabolism of iron was studied
in 36 mildly anemic rheumatoid subjects.
Two abnormalities were outstanding; a
diminished absorption of trace amounts of
iron, and a low plasma iron not accounted
for by low iron binding capacity. The turnover of plasma iron, however, was rapid, so
that the iron delivered to bone marrow appeared to be within the normal range
( 1047). Macrocytic anemia was described
in 35 of 2,544 patients with RA (1.38%)),
116
but only 15 of 5,515 controls (0.27%).Two
responded to prednisolone therapy, the remainder to €312. Eight of 20 tested showed
normal absorption of B12, leaving uncertainty about the mechanism of the anemia
(960).
RENAL STUDIES
Renal function was evaluated by means
of 24-hour endogenous creatinine clearances in 244 patients with RA, and in 247
control subjects. The values in female patients with RA were about 10% lower
than in the controls; and the values were
influenced by age and severity of disease.
The clearance values in male patients were
not different from controls (1188). No
effect of phenacetin, phenylbutazone or
other drug therapy on creatinine clearance
could be shown (18, 1187).
AMY LOIDOSIS
RHEUMATISM AND ARTHRITIS
ation with juvenile RA was the subject of
a clinicopathological conference (240). In a
large rheumatism center in England, 13 of
approximately 330 patients with juvenile
RA exhibited evidence of amyloidosis. A
case of amyloidosis secondary to multiple
myeloma presented with polyarthritis that
closely mimicked RA (444). Cases of amyloidosis in association with hypogammaglobulinemia ( 1247) and Whipple’s disease
(1095) were reported.
The pathological classification of amyloidosis into two types-perireticular and
pericollagen forms-was based on polarization microscopy (543).
The precise chemical composition of
amyloid deposits is not known but a constant feature of all clinical and experimental types of amyloid has been a fibrillar
pattern in electron microscopic studies
(248, 484, 1189). The amyloid fibrils were
resistant to digestion by hyaluronidase and
collagenase (248). Although some immunologic techniques suggest that gamma globulin may be a constituent of amyloid (883),
there was convincing evidence that the fibrillar component does not contain antigenic determinates of gamma globulin
(246, 964). In a recent study, antisera
against the amyloid fibrils reacted with an
alpha globulin present in normal as well as
pathological,sera, suggesting that a soluble
precursor of amyloid fibrils may be present
in serum (209). [Although the recognition
of the fibrillar component was of prime
importance in the characterization of amyloid, non-flbrillar components are undoubtedly present and may be of equal or
greater importance in the pathogenesis of
arnyloidosis.Ed.]
The reported incidence of amyloidosis
complicating rheumatoid arthritis varies
widely (3 to 60%) (38). This variation can,
in large part, be attributed to inconstant
pathological criteria and to case selection.
Rectal biopsy, a technique with approximately 75% accuracy for the diagnosis,
probably provides a more accurate estimate
of the incidence of amyloidosis in RA subjects. In a series of 115 patients with R.A.,
,5% of rectal biopsies showed amyloid
change (38). Amyloidosis was diagnosed in
17 of 24 patients (selected because of protinuria) on the basis of rectal and/or renal
biopsies (344). Of 9 patients having both
type5 of biopsies, there was agreement in 6,
1 was poqitive by rectal biopsy and negative by renal biopsy and 2 were doubtful as
a result of rectal biopsy but showed renal
amyloidosis. Aside from the association between amyloidosis and chronicity of RA, OTHER LABORATORY STUDIES
there is no very significant relationship to
Patients with amyloidosis frequently (5
clinical features. Three cases of ankylosing of 7 tested) showed bromsulphalein (BSP)
spondylitis complicated by amyloidosis retention ranging from 14 to 45% at 45
were reported (total of 6 cases in the Eng- minutes, in the absence of other evidence
lish literature (343). Amyloidosis in associ- of liver dysfunction (344). Using a 20 mg
RHFUMATOID ARTHRITIS (RA)
per kilo dose rather than the usual 5 mg
per kilo, impaired clearance of BSP was
found in 21 of 22 patients with RA; again
in the absence of other evidences of impaired liver function. This abnormality
seemed to correlate with disease activity
(204).
Serum viscosity was elevated in 32 of 37
patients with RA (1144) and serum sulfhydryl determinations gave low levels,
comparable to those seen in Waldenstrom’s macroglobulinemia (760). An increased turnover of gamma globulin was
observed in RA subjects (942). The serum
concentrations of five amino acids were estimated; glutamic acid levels were high;
arginine, glutamine, tyrosine and histidine
concentrations were low (906). Serum and
synovial complement levels were characteristically low in RA. This was in contrast to
acute inflammatory joint diseases, such as
gout arid Reitcr’s syndrome, in which the
complement levels correlated with the increased protein concentration in joint
fluids. This suggested that complement is
actively hound in RA and SLE (535,
536, 978). Lysosomal enzymes (acid phosphatase and cathepsins) were increased in
Concentration in rheumatoid synovial tissue
(767 ) . No significant differences in the urinary excretion of epinephrine and norepinephrine were found when rheumatoid patients were compared with controls (1181).
Rheumatoid Factor (RF) and Other
Serological Studies
Although a large number of publications
have appeared concerning the various
rheumatoid and anti-7-globulin factors,
their role in the pathogenesis of RA has
yet to be elucidated. Important developments have, however, occurred, particularly in relation to the antibody nature of
R F and the genetic control of y-globulin
synthesis. Many reviews pertaining to R F
have appeared (224, 349, 399, 414, 505,
685,834,845,1289,1357,1384).
117
Modifications of existing tests for Rl?
have included, among others (448, 856,
900, 1350), the use of 0.2 p diameter latex
particles ( 1171), formalinized sheep erythrocytes (847)) and immunofluorescent tests
using smears of sheep blood (613). Comparative studies of various serological
methods were reported (8, 113, 165, 675,
735, 900, 1351). Using the Waaler-Rose
test, an increase in positive reactions from
70% in serum to 83% in the euglobulin
fraction was found (133). Comparison ol
the titers in the latex and sensitized sheep
cell reactions obtained in 26 different laboratories showed remarkable variability
and argued for the establishment of an international standard (154). [ Through the
auspices of the American Rheumatism Association, samples of a lyophilized rheumutoid serum are available for standardization
of test systems. Requests are to be directed
t o the Ortho Research Foundation, Raritan,
N . J . , Ed.]
The RF was purified by elution from
specific precipitates ( 1168) and preparative
electrophoresis (665) followed in each case
by sephadex G200 chromatography. This
latter procedure has been of great assistance in preparing 19s macroglobulins free
of 7s material. In most cases, RF activity
has been found in preparations having
sedimentation coefficients in the 18-19s
range ( 1234). However, in some sera particularly those with intermediate (9-17s)
complexes, rheumatoid factor activity has
been found in lower molecular weight yglobulin fractions (218,224, 685). An anti-yglobulin factor with a sedimentation constant of 7 has been described in about 50%
of rheumatoid sera and 20% of normals
which reacts with the pepsin fragment and
not with the native y-globulin molecule
(946). The low molecular weight RFs so
far described are related antigenically to
IgG rather than to the IgM class of immunoglobulins. A serum factor reacting
with sensitized sheep cells but requiring
118
antiglobulin serum for its demonstration
was present in some sera having negative
Waaler-Rose tests ( 1232). However, the
molecular character of this presumed “incomplete rheumatoid factor” was not determined. [7S RFs immunologically related to I g M have not been described. In
view of the existence of low molecular
weight antinuclear factors related to ZgM,
this possibility seems worth investigating.
Ed.] In addition to anti-y-globulin factors,
rheumatoid sera often contain antinuclear
factors (ANF). These have been found in
all three (IgM, IgA and IgG) immunoglobulin classes (68). In one study (826),
the removal of RF with aggregated y-globulin and sensitized sheep cells also removed
ANF. Similar treatment of SLE sera did
not affect the ANF activity. It was suggested that the 7s ANF may be associated
with R F in a complex (22s) which is removed by the absorption procedures. [An
ulternative possibility is that rheumatoid
factors, via their afinity for any immune
complex, augment the antinuclear reaction
of small amounts of 7s A N F present in
rheumatoid sera. Ed.]
Considerable serological heterogeneity
has been noted in RFs. Three different reactivities of RF have been separated using
columns of conjugated y-globulin ( 1337).
One group reacted primarily with human yglobulin, a second with rabbit y-globulin
and a third showed reactivity with both
rabbit and human y-globulins. In the majority of rheumatoid sera, these three factors occurred together; however, in some
sera and particularly those from non-rheumatoid patients only the factor reacting
with human y-globulin appeared. In an occasional serum, a factor reacting only with
rabbit and not with human y-globulin was
found (7). Although the majority of RFs
reacted with the papain Fc-fragment or the
H chain of IgG (551, 1340), other factors
have been described which are reactive
with the L chains of y-globulins (1339,
RHEUMATISM AND ARTHRITIS
1340). Inhibition studies using purified
Bence-Jones proteins showed that heterogeneous sites were involved. Isolated RFs
were found to be of both type 1 and 2
although the percentage of type 1 (90%)
was significantly greater than in the normal
19s (70%).Cold agglutinins (also IgM immunoglobulins) were 100% type 1 (400).
[ Uniform terminology for immunoglobulins and their fragments have been proposed (925). Ed.]
Anti-antibody found in both human and
rabbit sera was separable from c:lassical
rheumatoid factor (28, 415, 846). It is a
19s anti-y-globulin, which, by definition, is
not inhibited by pooled native y-globulin.
Rabbit anti-antibody reacts with sites
present on the 5s pepsin F(ab‘)a fragment
whereas RFs react with the Fc-fragment. It
has been proposed that anti-antibody is
formed as a result of immunization with yglobulin altered by combination with antigen.
The genetically determined differences in
the human y-globulins and the antibodies
elicited by these determinants have continued to attract considerable attention.
Genetic factors appear to be controlled by
at least two non-linked loci (Gm and Inv)
(414, 505, 805). As a result of enzyme splitting and disulfide reduction experiments,
the Inv and Gm activities have been localized on different parts of the y-globulin
molecule indicating that different genes
regulate the synthesis of the different polypeptide chains of the y-globulin molecules.
It has been shown that multiple transfusions may elicit the production of anti-Gm
antibodies with specificity directed against
a Gm type absent from the patient’s serum
(20). The RFs and anti Gm factors are
clearly separable on a number of grounds
and may vary independently of each other
(606).
As a result of the serological and chemical studies and particularly the finding of
genetic specificity, there seems little ques-
K’JIEUMATOID ARTHRITIS ( R A )
tion that anti-7-globulin factors found in
rheumatoid sera are antibodies. A number
of experiments have provided clear evidence for isospecificity in addition to
auto-reactivity of the RF (505). It has been
suggested that the R F might be an autoantibody against the patient’s own y-globulin aggregated in an immune complex. It
was found (9) that RF reacts with specific
precipitates containing antibody of human
origin ( diphtheria toxoid-human antitoxin
precipitates). The distribution of P1labelled RF between precipitates and serum
suggests a stronger reactivity of RF with
the aggregates than with the native y-globulin (9). [Other evidence of the reactivity
of RF with native y-globulin derives from
studies of the 22s complexes in fresh whole
sera. Ed.] The demonstrations that antiGm antibodies may be present which react
with Gm groups other than those of the
patients, and that RFs may react with various animal y-globulins have raised questions regarding the validity of the auto-antibody concept. However, it has been
found that on denaturation, Gm(a-) yglobulin may acquire Gm( a+ ) reactivity
(505). Human specific precipitate with the
antibody from a Gm( a- ) person absorbed
anti-Gm( a ) activity from rheumatoid sera
although less efficiently than similar precipitates with the antibody from Gm( a + )
subjects (9).
The reactions of RF with animal y-globulins have been studied in detail (187, 988,
1256, 1259, 1289) and reactivity has been
tound with the sera of a variety of animals.
The results are most consistent with the hypothesis that the reactions with animal yglobulins represent cross reactions and that
the primary stimulus to R F production is
denatured autologous y-globulin ( 187,
1289). It has been clearly demonstrated
that slightly altered autologous y-globulin
can give rise to antibodies reactive primarily with the native y-globulin of
another species (1357). Prolonged immuni-
119
zation of rabbits with horse spleen ferritin
or with antibody-ferritin complexes gives
rise to anti-y-globulin factors corresponding
to human RFs (1338). Immunization of
rabbits with killed bacteria (E. coli and B .
subtilis) also produced RF-like substances
reactive with both homologous and heterologous y-globulins (223). [ I t seems that a
common factor in all these experiments is
denaturation of the y-globulin and exposure of the antigenic determinants. Perhaps
a buried determinant on a y-globulin molecule from one individual m a y closely resemEle a determinant present on the surface
of a y-globulin molecule derived from
another individual or even from a foreign
species. Ed.]
Cells containing and apparently forming
R F have been found in rheumatoid lymph
nodes and synovia using the fluorescent
technique (825, 834). Control studies made
on other forms of arthritis were negative.
Alcohol-fixed paraffin embedded tissues
were suitable for immunofluorescent demonstration of RF (57). Rheumatoid synovia
showed a striking deposition of IgG in the
early lesions, in contrast to the massive
deposition of both IgM and IgG in the
more longstanding rheumatoids with elevated rheumatoid factor titers. The question has been raised whether the deposition
of the IgG in the synovial membrane may
be a source of aggregated y-globulin, possibly antigen-antibody complexes, which in
turn initiates the formation of RF (834).
Small lymphocytes cultured from human
peripheral blood become transitional and
lymphoplasmacytoid cells. Such cells obtained from rheumatoid patients were
thought to produce RFs as evidenced by
reaction with fluorescent heat aggregated yglobulin (70).
The biological significance of the RF is
as yet unclear. Anti-y-globulins with some
HF properties have been found in the sera
of a variety of normal animals (1314,
1315). In a large study of normal humans,
120
RHEUMATISM AND ARTHRITIS
the latex slide test was positive in 4.1%,the tests, 7 developed rheumatoid disease. Five
sensitized human cell in 2.4%and the sen- of 57 seronegative controls manifested evihitized sheep cell in 0.18%of 5,461 individ- dence of rheumatoid disease after 5 years
LI&
(L306). The incidence of RP in- (58). [ I n view of the occurrence of RF in
C‘I ea5es considerably with age reaching
small amounts in normal serum and the in42%by the latex fixation test in individuals creased frequency of positive latex tests
over 65 years of age (540). [As more in- d t h the patient’s age, the question might
formation accrues, it is increasingly appar- be asked whether the RFs found in rheuent that the RF cannot be used as a “diag- matoid and other chronic disorders reprenostic” marker. The diagnosis of RA re- sent an increase in factors normally present
mains a clinical one. A procedure such as in amounts too small to measure. Such a
the latex fixation test (positive i n approxi- hypothesis would be consistent with the
mutely three-fourths of R A subjects and idea that RF is formed as a result of repositice in approximately 5% of controls) peated immunization with antigen-antiliar confirmatory ualue, but there are po- body complexes. Ed.]
tential hazards in the over-interpretation of
Plasmapheresis and penicillamine adminpositizie results. Ed.] A similar increase in istration decreased the titers of seropositive
the sensitized sheep cell test is not found. sera (607). The response to penicillamine
Sera from individuals with a negative latex was slow in onset and lasting in duration
test contain a factor which, when isolated, suggesting that it affected the level of RF
showed anti-y-globulin specificity. This was by interfering with its production or by
present in small amounts (.001-.005% of affecting the underlying disease. A favortotal serum proteins) in 39 out of 40 nor- able clinical change accompanied the demal sera (1384). Normal sera also contain a crease in RF titers. [Additional studies are
variety of inhibitors of the RF tests. Some needed. The cost of penicillamine therapy
are non-specific in that they inhibit the ag- is high. Ed.] Similarly, dexamethasone in
glutination test for trichinosis and phyto- large doses (6 to 8 mgm O.D.) and nitrohemagglutin agglutination of sheep cells as gen mustard cause a decline (approxiwell as the F-I1tanned cell test ( 130).
mately 10 days latent period) in RF titers
The level of a thermolabile F-I1 latex test (658). It has been suggested that, with
inhibitor was correlated with the clinical very high titers of rheumatoid factor,
findings in rheumatoid subjects. Constant changes in the serum viscosity of sufficient
unremitting disease was found most fre- magnitude may occur and lead to derangequently in patients with high titers of rheu- ment of blood flow in the small vessels
matoid factor and no thermolabile inhibi- (1142). Vascular effects of administered
tor. All rheumatoid patients (8 in a group R F and antigen-antibody complexes were
of 66) who underwent a definite remission also tested in the vessels of the rat mesenhad relatively low titers of RF and inhibi- tery (81). Following the intravenous injector was present although in varying tion of rheumatoid euglobulin thrombosis
amounts. No remissions appeared in the and hemorrhage occurred in the exposed
group of patients of high RF titers (1115). mesentery but these lesions were not obA series of 45 persons with positive sensi- served in the intact animal. Immunofluortized sheep cell tests and seronegative con- escent studies demonstrated localization of
trols matched for age and sex were re-ex- IgM globulin to the intima of mesenteric
amined after 5 years. Of 19 subjects who vessels. These changes did not occur folinitially had neither clinical nor radiologi- lowing the injection of a Waldenstrom’s
cal evidence of RA but had positive RF macroglobulin lacking RF properties. Solu-
RHEUMATOID ARTHRITIS ( R A )
ble antigen-antibody complexes also localized in the vessel wall, although no
pathological lesions developed.
The clinical significance of antinuclear
tactors in RA was studied (1309). Of 273
patients with definite RA, 19%had ANF
compared with 1%in normals. Although
the clinical course may vary independently
of the titer of antinuclear factors, those patients who had increased ANF had an increase in incidence of ocular lesions, nodules, vascular lesions, and Felty’s syndrome. [There are difficulties in the arbitrary sepurution of RA f r o m S.L.E. o n clinical arid pathological gmunds and the techiiiques for measurement of antinuclear factors vary enormously. T h u s the reported incidenee of antinuclear factors in RA subjects uaries widely. Ed.]
R F has been found in the serum of patients with a large variety of non-rheumatic
diseases (196). The latex fixation test was
positive transiently in about 40% of the
cases of viral hepatitis and was positive in
approximately 60% of the patients with
Laennec’s cirrhosis (47 ). [Approximately
half of the latex positive sera had titers of
1:80 or less. T h e significance of titers in this
range is less certain w h e n the latex fixation
test is the ONLY system studied. Ed.] Sera
of patients with liver disease showed essentially no reactivity with rabbit amboceptor
in the sensitized sheep cell test (141).
MISCELLANEOUS
R F was found to block the uptake of
complement by latex particles coated with
human y-globulin (539). The inhibition of
the mitochondria1 enzyme system (NADH
oxidase) by antibody and complement was
prevented by R F (282). The protective action of RF was related to its ability to
block the fixation by complement. The inhibition by complement of the agglutination of sensitized sheep erythrocytes by R F
was related to the fourth (C’4) component
(ill).
121
The effect of RF on survival of sensitized
cells in vivo was studied (639, 640). In contrast to the usual anti-globulins induced by
immunization, RF capable of agglutinating
Kh sensitized red blood cells in vitro did
not modify their destruction in viva. It was
suggested that native 7-globulins in plasma
competitively inhibits RF from reacting
with the antibody fixed on the blood cells.
It was found that 77% of patients with
myccardial infarctions had RF-like material
which could be eluted from red cells with
dextran. The possibility was suggested that
the coating protein which resembles K F
may have a detrimental influence on blood
flow during myocardial infarction (376).
There is, however, some question as to
whether the material eluted by dextran is
indeed RF. Similar material can be eluted
from the erythrocytes and platelets of normal humans, and from rabbit erythrocytes
(594).
R F has also been found in synovial fluid
(125, 1053). Usually the titer in the synovial fluid is slightly lower than that in the
serum. However, in an occasional case, the
joint fluid shows significant positivity while
the serum is negative.
Radiological Features of Rheumatoid Arthritis
The origin of juxta-articular erosions in
RA was studied in pathological specimens
by a variety of micro-radiographic and
pathological techniques. Evidence of communication with the joint space was rarely
found, and it was felt that current ideas of
the pathogenesis of these lesions (herniation of joint fluid or detritus through a defect in the subchondral plate) must be revised (1182). In another study, however,
the majority of juxta-articular cysts were
thought to communicate with joint spaces
(663).
In a well controlled retrospective study
of the radiological findings of the hip in
279 rheumatoid patients, abnormalities
were found in 29% of the RA patients, 4%
122
of controls. The most severe deformities
were produced by marked and widespread
erosions, by rapidly progressive collapse, or
by inward migration of the medial wall of
the acaetabulum ( protrusio acetabuli). The
changes were more common in older patients but ( surprisingly) did not correlate
with disease duration (439).
Rheumatoid involvement of the spine
has been well documented in several recent
papers. [Surely the term “rheumatoid
spondylitis” is confusing? The A.R.A. Nomenclature Committee recommends the
term “ankylosing spondylitis.” Ed.] A study
of the radiological findings in the neck recorded major lesions in 25 of 100 patients
and added a new sign, the “tipping atlas.”
Marked separation of the posterior arches
of C 1 and C 2 may be seen with or without subluxation in flexion films (126). Subluxations at several levels may occur, and
are usually best seen in lateral films taken
in flexion. The most common and serious of
these is atlantoaxial subluxation and 2 additional fatal cases were reported (804). Lateral radiographs of the lumbar spine of 50
subjects with RA were compared with controls; subluxation, disk narrowing without
osteophytosis, apophyseal erosions and
osteoporosis were more common in the
rheumatoid group ( 726). Sacroiliac
changes were studied in 278 females with
RA and compared with 147 controls.
“Changes” [not carefully described. Ed.]
were observed in 378 of the RA group,
16%of the control group. Four of the RA
patients showed bilateral sacro-iliac fusion
(1156).
Multiple fractures through osteoporotic
bone in a rheumatoid subject and erosion
of the ulna under a rheumatoid nodule
were described (682). Changes in the
sternoclavicular joint were observed with
laminography ( 347). A radiological differentiation between RA and S.L.E. on the
one hand, and scleroderma, dermatomyositis and polyarteritis was thought possible,
RHEUMATISM AND ARTHRITIS
chiefly because of the cartilage destruction
characteristic of the first two diseases
(1183). [This may be a general rule but
there are exceptions. Ed.]
Etiology and Pathogenesis of Rheumatoid
Arthritis
The hypotheses now being investigated
were reviewed (225, 655). Certain aspects
have received special attention, and in particular, the theories of autoimmunity were
discussed at length. (See section on CONNECTIVE TISSUEDISEASES
for discussion of
autoimmunity. ) The variety of antinuclear
antibodies seen in patients with chronic leg
ulcers suggested that chronic secondary infection was acting as a tissue-sensitizing
adjuvant (1341). The possibility that
mtigammaglobulin-gammaglobulin
complexes which are known to circulate in
some rheumatoid patients-could be responsible for serum-sickness-likelesions has
also been discussed (225). The existence in
rheumatoid sera of protein complexes in a
biologically active form has recently been
shown (142). Several authors pointed out
that the theory of specific infection and the
theory of autoimmunity are not necessarily
mutually exclusive, as many known infections are associated with the presence of
autoantibodies and pathologic findings
reminiscent of various hypersensitivity reactions (225,391).
Various studies of the reactivity of KA
patients to antigenic stimuli have given inconsistent results. RA patients of blood
group “ 0may have an isohemagglutinin
deficiency, but not those in group “A” and
“R” (1022). The antibody response to brucella antigens and diphtheria toxoid was
normal ( 1143, 1296) but following streptokinase-streptodornace injections, RA patients showed increased antibody response
but decreased cutaneous reactivity as compared with controls (583). Rheumatoid
sera decreased new tissue formation in carrageenin granuloma pouches (557), and
RHEUMATOID AHTHRJTIS ( R A )
likc other pathologic sera caused necrosis
ot p1inc.n pig skin (610).
The theory that infectious agents may relate to the pathogenesis of KA is still very
current. Recently, there has been a report
of the isolation of mycoplasma from the
joint fluid or tissues of patients with RA,
SLE and Keiter’s syndrome. (72). (See
section on KEITER’S SYNDROME
for discussion
of inycoplasma. )
Certain tryptophane metabolites have
been found in excess in the urine of patients with RA. This has led to two lines of
speculation: that tryptophane metabolism
is “shunted” along the kynurenine pathway
for reasons that are unknown or that a relative pyridoxine deficiency favored excretion
of primary derivatives by inhibiting further
breakdown. Kynurenine and hydroxykynurenine are derived directly from tryptophane, by reactions which are not dependent on pyridoxine. These two compounds are found to be increased in the
urine of rheumatoid patients, especially after tryptophane load (89, 389, 989). However, the increase is not specific for RA and
is seen in other collagen diseases (89), and
a wide variety of other diseases, such as
myocardial infarction, anemia, sarcoma,
pneumonia and various blood dyscrasias
(989). A rise in excretion of 3-hydroxyanthranilic acid ( 3 HAA) is also well documented (989, 1194). This: is derived from
hydroxykynurenine by a pyridoxine-dependent reaction and this finding could not be
ascribed simply to pyridoxine deficiency.
The excretion rate of pyridoxine in the
urine of rheumatoid patients was somewhat
low but no abnormal retention of an added
pyridoxine load was demonstrated (830). It
a.ould seem that there is chiefly an increased diversion of tryptophane into the
kynurenine pathway, perhaps through accelerated protein turnover. Hyperimmunization and salicylate failed to increase the
output of 3 HAA in rabbits (1195). [Per-
123
tabolites correlates with a high turnover of
fibrinogen, which is rich in tryptophane
and in excess is chiefly responsible for an
increused sedimentation rate. Recent unpublished observations have demonstrated
increased levels of tryptophane pyrrolase in
liver biopsies of RA subjects. Ed.] Param-
eters of adrenal function were found to
be normal in rheumatoid patients, or to
show minor changes common in other
chronic disease states (561).
Even the long-accepted belief in importance of genetic factors has been strongly
challenged. A study of Blackfeet Indians
showed no significant familial aggregation,
either for the presence of RA or RF. The
statistical treatment of this data was far
more rigorous than has been usual in such
studies. The adequacy of design of all previous genetic surveys was questioned on
the ground that families with multiple
cases have a multiplied chance of being
sampled ( 175). Further reports of remarkable pedigrees (464) and reviews of past
surveys (654) did not seem to answer these
criticisms.
The many psychological studies which
have attempted to define a “rheumatoid
personality” were critically reviewed, with
particular emphasis on the diametrically
opposed conclusions regarding the passive
or aggressive way in which rheumatoid patients handled anger, rage, or physical activity. It was felt that previous studies were
poo;ly controlled, and the methods of observation, too, subject to observer bias.
Certain consistent findings were explicable
on the basis of the presence of a painful,
chronic, crippling disease (869, 870). The
use of the otherwise excellent Minnesota
Multiphasic Personality Inventory in assessing rheumatoid patients was found to be
compromised by the inclusion of such questions as “I wake up fresh and rested most
mornings.” A negative response elevates
the scores on the hypochondriasis, depresImps the high excretion of tryptophane me- sion, and hysteria scales (899).
124
RHEUMATISM AND ARTI-IRITIS
Finally, a carefully designed study
showed that rheumatoid patients ate a diet
similar to that of control groups (333).
[Thus, in summary, the etiology of rheumatoid arthritis remains unknown. Ed.]
Treatment
GENERAL
The treatment program for rheumatoid
patients was reviewed (283, 345, 864, 1101,
1303) arid past therapeutic trials, con[rolled or otherwise, were discussed in critical detail (1370). New studies of two
classic remedies, rest and salicylates, were
especially welcome. Of great interest was
the Edinburgh controlled trial of the antiinflammatory effect of total immobilization.
Thirty-four patients with RA were confined
lo bed, with all four limbs immobilized by
plaster splints for 4 weeks, without physiotherapy. Thirty-four control patients were
given rest and splints, but allowed toilet
privileges and gently exercised twice daily.
Both groups received calcium aspirin, 60 to
80 grains daily. The immobilized group
had lost range in their knees and elbows
when the splints were first removed, but
regained this within 2 weeks. All measures
of function and disease activity favored the
rest group, although few of these differences reached significant levels. In particular, those with most active arthritis, as indicated by a sedimentation rate greater than
60, seemed to benefit. In 9 of 11 such patients treated with total rest, the sedimentation rate fell below 60, but only 4 of 11
controIs exhibited comparable change.
Complications included episodes of phlebitis, bronchitis, pneumonia and cardiac
failure occurring during or shortly after the
rest period (959). [ T h e incidence of complications precludes general use of this
therapy, but the rapid control of pain and
local inflammation may justify its use in
special circumstances. One might hesitate
to use similar measures in treating Still's
Disease or spondylitis. Ed.] The benefits
to be derived from hospitalization at critical phases of illness were stressed and the
lack of available beds deplored (864).
[Relatively brief hospitalization t.o solve
problems early in the disease is so much
more eflective than attempts at late salvage
that the continuing shortage of special
treatment beds presents a msjor challenge.
Ed.] The usefulness of a sanatorium-type
regimen, with average hospital stay of over
8 months, was reported. Seventy-four of
200 patients achieved major benefit ( 1382).
Steroid toxicity contributed significantly to
the number of patients making unsatisfactory progress. [Difficulties arise in this
kind of program. After such a prolonged
stay, patients are extremely reluctant t o return for a second sentence. Furthermore,
medical complications are recognized and
treated with difficulty in a sanatorium .setting. Ed.]
SALICY LATES
An international sympcsiuni discussed in
detail the pharmacology and toxicity of salicylates (1093). The value and even necessity of blood levels in controlling salicylate
dosage was emphasized (30, 1303). Tinnitus may be an unreliable guide to toxicity.
In children, serum levels of 30 to 35 mgm
per 100 ml may be safely attained, in adult
20 to 25 mgm per 100 ml. [Some patients,
particularly elderly ladies with hearing loss,
tolerate less than this. Ed.] The anti-inflammatory properties of salicylates were
demonstrated in a controlled trial in rheumatoid patients (402). The possible mechanisms of this anti-inflammatory action,
with particular reference to the kinin system, was explored extensively (1093). Patients rarely tolerated anti-inflammatory
doses of plain aspirin for prolonged periods, and enteric-coated preparations were
preferred for clinical use. It was emphasized that measurable levels of salicylate do
not appear for 8 hours after ingestion of
enteric-coated tablets (30). [Thus, pa-
125
HHEUM A I V I D ARTHRITIS ( R A )
ticnts should not use such tablets for quick
rdicf, hut f o r smooth continuous effect.
Ed.] Adequate absorption of A.S.A. in
suppository form occurred, at the cost of
slight but variable local initiation (342).
The synovial and plasma concentrations of
free salicylate were similar (1065). (See
section on ANTI-RHEUMATIC
DRUGS
for discussion of salicylate therapy and toxicity. )
Histological study of synovial tissue obtained by biopsy before and after oral and
intra-articular phenylbutazone showed no
consistent change despite clinical benefit
(420). A serotonin antagonist, cyproheptadine, had no apparent anti-rheumatic effect
in patients with RA (855).
that toxicity was additive (1157). (See section on ANTI-RHEUMATIC
DRUGS
for discussion of anti-malarial toxicity. )
GOLND COMPOUND’S
A warmly personal account of the history
of gold therapy was given by Forestier,
whose studies in 1929 stimulated the worldwide use of this treatment (396). Combined therapy with gold and chloroquine
was evaluated (1157, 1158). (See section
on ANTI-RHEUMATIC
DRUGS
for further discussion of gold therapy. )
ADRENOCORTICOSTEROID THERAPY
The course of 50 patients begun on longterm adrenocorticosteroid therapy between
ANTI-MALAKIALS
1950 and 1952 was described. In 25, treatA carefully designed, carefully controlled ment was stopped because of an unsatisfac\ t i d y of the ef€ect of hydroxy-chloroquine tory response or death; there were 9
on the course of RA, based on 121 patients deaths, the majority of which were probin multiple centers followed for 6 months, ably attributable to therapy. Only 16 reshowed 29% greater rate of improvement mained on therapy at the time of the rein the treated groups. Side effects were fre- port, most of whom showed side effects,
quent in the treated group, but notably but who continued treatment because of
common also in the group receiving place- improved ability to work (11 patients) or
1)os (783).
greater sense of well-being (916). Systemic
Tm70 controlled studies of the antirheu- steroid therapy by spaced intramuscular inmatic effects of amopyroquin (Propoquin) jections was further explored, using 100
achieved maximum return of information mgm doses of various preparations of tritor minimum numbers of patients studied. amcinalone, and 6-methyl prednisolone,
Using a cross-over technique, with 5 and hydrocortisone acetate in 500 mgm
months treatment and 5 months control, doses. The proportion and duration of satsignificant benefit from therapy was dem- isfactory responses was low with hydrocoronstrated in a series consisting of only 15 tisone, but the other preparations each
patients. The most sensitive indices were gave improvement in about 75% of pagrip strength, sedimentation rate, and tients, lasting about 18 days. Peptic compli1,ansbury’s Indices (71) . Amopyroquin was cations were said to be less, although 11 of
compared with chloroquine in a second 86 patients described gastrointestinal comstudy involving 25 patients, and appeared plaints; barium meals were not routine, and
to have equal effect,with low toxicity, each there was no control group (1389). [In
drug being given in a dose of 250 mgm per most of these reports, salicylates were used
day (706). A retrospective comparison was minimally, for analgesic effect only, and no
made of 248 patients treated with both attempt seems to have been made to rechloroquine and gold and 240 treated with duce steroid requirement by use of antichloroquine alone, and showed that com- infEammatory doses of salicylates. Ed.]
hitied therapy gave no further benefit, but
The use of a single evening dose of 5
126
mgm prednisolonc was found to be much
superior to a morning dose in a well designed, double blind trial, and the incidvnce of side effects on “rebound” exacerlicitions following withdrawal very low
(287). A double blind trial failed to confirm earlier reports of a “steroid sparing
c&ct” of nialamide, a mono-amine oxidase
inhibitor (1373). There continues to be
general satisfaction with the efficiency and
relative safety of intra-articular steroids
( 1123). A double blind trial showed reduction in edema in rheumatoid hands treated
with fluocinoline under an occlusive dressing (19).
OTHER MEASURES
Penicillamine was administered to a patient with RA complicated by arteritis, with
interesting and unexpected results. The
drug is a sulf~ydrylamino acid, and in
[>ityosplits the disulfide bonds of rheumatoid factor. Systemic administration of the
drug produced no apparent dissociation
und no early fall in RF titer. After prolonged administration of penicillamine, a
fall in the R F titers occurred and persisted
despite interruptions in therapy. Clinical
improvement was associated in time with
the fall in RF (608).
Treatment with alpha methyl dopa (Aldomet), designed to deplete tissue catecholamine and 5-hydroxy-tryptamine levels
had no beneficial effect on RA (630). Improvement in HA during therapy with sodium EDTA and with pantothenic acid
was claimed, but poorly documented (74,
153). The administration of Triparanal decreased serum cholesterol levels, reduced
the urinary excretion of 17-keto steroids,
did not change 17-hydroxy corticoids, but
was associated with increased symptoms in
6 of 8 patients (629). In a blind, cross-over
trial, a new analgesic and antipyretic compound, 4-isobutylphenyl acetic acid ( Ibufenac) was as effective as aspirin, but associated with far fewer gastric symptoms
(212). [There haoe been recent reports of
RHEUMATISM AND ARTHRITIS
elevated serum transaminases in 20 to 30%
of patients treated with this drug, and at
least 5 cases of jaundice. (518) Ed.] (For
discussion of Indomethacin, see section on
ANTI-RHEUMATIC
DRUGS.
)
The intra-articular administration of radioactive gold or osmic acid for the treatment of synovitis or recurrent effusions was
described. Radio-active gold emits gamma
and beta rays; the latter are absorbed within 1 mm and are responsible for most of
the tissue effect. Early responses were disappointing but following 30 therapeutic injections a result classed as “good at one
year was seen in 16 patients. In 10 of 14
patients with bilateral knee effusions, the
treated knee was dry after one year. The
tissue dose was estimated at 480 to 1000 r
(32). A second group claimed success in 22
of 25 joints; 5 to 10 mc were injected to
yield an estimated dose of 5000 r. There
was little immediate effect but a marked
increase in effusion after 1 week, and recovery after a few weeks (787). Osmic acid
was injected intra-articularly with similar
effects. (101, 597). The drug was combined
with an anesthetic and hydrocortisone to
reduce early discomfort. [Studies of the
systemic toxicity of these procedures have
been disturbingly incomplete. Ed.]
PHYSICAL MEDICINE
The value of physical measures in the
treatment of RA still seems controversial.
The general objectives and methods of a
special unit directed by a rather unique
physiatrist were well described (511), but
the disenchantment with routine measures
was also colorfully stated (806). [Physical
measures must be prescribed as specifically
and evaluated as carefully as other treatments. Close working contact between
physician and therapist is essential, and
routine therapy in remote large depnrtments is often unsatisfactory. Ed.]
SURGERY I N RHEUMATOID ARTHRITIS
The necessary background information
needed to guide the decisions concerning
RHEUMATOID ARTHRITIS ( R A )
surgery in patients with RA is not available. There is almost no knowledge of the
factors affecting the probability of development of local disabilities, and poor documentation of the results of surgery. Satisfactory criteria for the assessment of physical arid psychological variables are only beginning to be developed. The pathogenesis
of important deformities is still debated,
the importance to function of various structural changes are incompletely assessed
arid the recommendations of leading practitioners are in conflict (6, 256, 326, 385,
796, 797, 1176, 1290). A noteworthy effort
to explore these problems was the A.R.A.
conference held to establish “Criteria for
mid Evaluation of, Orthopedic Measures in
the Management of Deformities in Rheumatoid Arthritis” (256). The discussions reviewed the areas of difficulty with frankness, and perhaps defined areas most suitable for future constructive work. Another
careful discussion of presently available
techniques of general assessment was published by Lansbury, long a pioneer in this
field (705).
HAND:A detailed format for the assessment of the function of the rheumatoid
hand was published and made widely
available (386). [The scheme is excellent
h i t time consuming. I t is concerned u i t h
range, strength and function, and does not
attempt to measure disease activity or to
record the progress of destructive change.
Ed.] One of the most important basic contributions was a study of the forces operative at the metacarpophalangeal joints. The
most powerful deforming forces were exerted by the flexor tendons. A tip pinch of
3 pounds was calculated to produce 9
pounds of force in the direction of volar
subluxation, and up to 2 inch-pounds of
ulnar-deviating torque in the index finger.
The rheumatoid process weakens opposing
structures, allowing these forces to create
deformity. In the fifth finger, the abductor
digiti quinti was the most powerful deforming force. These hypotheses are con-
127
vincingly argued, and important corollaries
were indicated. During Hexion exercises,
patients should keep their MCP joints extended, and the old exercise of squeezing a
ball should be condemned. Current surgical approaches that ignore the flexor tendons can be expected to show disappointing results ( 1176). [ Older theories, invoking spasm and contracture of the intrinsic
muscles in rheumatoid hands, have long
warranted attack, as these muscles are
charactcristically weak, under-active and
taut only in extreme positions. Ed.]
A new operation for the correction of the
extension contracture of proximal interphalangeal joints (swan neck deformity)
consisted simply of mobilization of the lateral bands of the extensor tendons. It was
shown that the adhesion of these bands to
the extensor aspect of the capsule was the
chief force restraining Hexion (898).
Follow-up data were given on the fate of
Flatt prostheses after several years of use.
The author emphasized that these prostheses will not stand heavy forces, and thus
are more appropriate to severely deformed
rheumatoid hands. Indications for their use
have been expanded to include the MCP
joint of the thumb (385). The more usual
operative procedures available are discussed in several reviews (6, 346, 796, 799,
1290). [ N o data were given in support of
their recommendations. Good results were
illustrated; unsatisfactory results not described. Ed.]
WRIST:Follow-up investigation of patients with surgical arthrodesis at the wrist
was reported. Of 9 joints fused in rheumatoid patients, 8 were stable. Grip strengths
were always weaker on the operated side.
In the complete series of 43 arthrodeses, 13
were not fully consolidated; success was
better when bone grafting was combined
with cartilage excision or wedge osteotomy
(1206). Similar results were reported in a
smaller series (274). The diagnosis of median nerve compression at the wrist was
rcviewed, with emphasis on the reproduc-
128
tion of symptoms by tapping the median
iiervc at the wrist (Tinel’s sign) or by extreme flexion of the wrist. Conservative
measures had been found ineffective and
surgical decompression was recommended
(801).
KNEE: The results of synovectomy were
rlescribcd in two recent series. After an
avcrage follow-up of 4 years, only 11 of 26
vnovectornized knees were free of pain
jvith 90” of movement and no flexion deformity (10). In a second series, 12 of 42
patients improved from “limited or worse
to “adequate” or better (872). [These results, and in particular the frequent loss of
lunge of movement, hardly support the
plea for “early synovectomy.” A well controlled prospective study is needed. Ed.]
The history of efforts to reconstruct knee
joints was reviewed, and experience with a
new hinged prosthesis was described.
Wound infection was a common complication, and good results were obtained in
only 2 of 8 attempts by the author and 6 in
11 attempts by others (1377).
OTHERJOINTS: Experience with the Austiii-Moore prosthesis for arthroplasty of the
hip joint was reported, after a follow-up
averaging 5.8 years. Generally good results
were obtained in 42 patients with recent or
old femoral neck fractures, but 3 of 5 with
RA had unsatisfactory results. The authors
believed that the mold arthroplasty was
preferable for rheumatoid patients (69).
The indication for other orthopedic procediires performed on the lower extremitics were reviewed in detail (238). In particular, the surgery of the rheumatoid forefoot was described (798, 800). It was
stated that good results were obtained in
90% of 150 operations on the forefoot surveyed by the Committee on Arthritis of the
American Academy of Orthopedic Surgeons (237). The problems arising in the
course of anesthesia of rheumatoid patients
were reviewed (329).
RHEUMATISM AND ARTHRITIS
Ankylosing Spondylitis
A general description of the illness (913)
again emphasized the good prognosis in
terms of employment; 44 of 60 cases followed for an average of 24 years were fully
employed. Ankylosing spondylitis was
found to produce thoracic pain in a large
proportion of patients and in the great
majority of these the pain was localized to
two “islands,” one near the dorsal spine and
the other at the corresponding segmental
level on the anterior chest wall (453). A
report describing 3 cases with onset between 10 and 15 years of age made the
appropriate point that the possibility of juvenile onset is not sufficiently well recognized (605). The chief problem lies in the
roentgenographic recognition of the disease
in the immature sacro-iliac joint and lumbar spine. Periarticular sclerosis is the
“most useful early sign” but is admittedly
non-specific.
Declining enthusiasm for x-ray therapy
(913, 1312) is based on the statistical evidence that it is associated in subsequent
years with a higher incidence of leukemia.
The findings led to a search for chromosomal changes in irradiated spondylitics;
none were found (910). There was some
disagreement on the role of adrenal corticosteroid therapy (913); some have found
them ineffective in pain control and especially threatening in accelerating osteoporosis. Various forms of back and neck bracing
were advised by some and avoided by others. Phenylbutazone was regarded as a
mainstay of medicinal therapy and early
evidence found indomethacin useful. In the
advanced cripple, wedge osteotomy is
sometimes advised but the resulting extension of long-flexed anterior soft tissue elements (including aorta and vena cava) can
be catastrophic. This stretching of the anterior elements can be avoided if, in addition to the removal of the posterior neural
129
ANKYLOSING SPONDYLITIS
lmny elements, a triangular piece of the
vertebral body is removed (1128).
RELATION TO OTHER CONDITIONS
The recognized relationship of ankylosing spondylitis to prostatitis and chronic
ulcerative colitis provoked further studies.
A series of 74 females selected for chronic
salpingo-oophoritis ( averaging 18 years in
duration) were carefully examined for ankvlosing spondylitis and rheumatoid arthritis (624); 3 cases of each disease were
found. The RA frequency corresponded to
that in the general population but there is
no cornparable population data on females
with ankylosing spondylitis; certainly it
would be below the 4% detected in the
prewnce of pelvic inflammatory disease.
Using survey techniques which certainly
missed some cases of bowel disease, ulcerative colitis was found in 16 and regional
ileitis in 4 of 870 patients with ankylosing
spondylitis (817). It was particularly notable that x-ray control studies of a sub-series
of 67 consecutive spondylitic patients without gastrointestinal symptoms revealed 2
patients with small-bowel disease. The conwise study, examining patients with ulcerative colitis or regional ileitis for ankylosing
spondylitis disclosed 4 with spinal disease
among 170 with bowel disease. The occurrcnce of both types of disease within families was also cited (817). The pathogenetic
relationships are entirely unexplained as is
well illustrated by 2 patients reported
( 120.5); in one, regional ileitis antedated
the spondylitis by 10 years, and in the
other the spondylitis had been present for 5
years before regional ileitis developed.
The familial clustering of ankylosing
spondylitis appears to be greater than for
:my other inflammatory disease of connectivc tissue. Accordingly various genetic relationships (567, 1253) were of interest.
The haptoglobin phenotypes differed little,
if at all, from control and RA groups (245).
COMPLICATIONS O F ANKYLOSING
SPONDYLITIS
The spinal disease itself was reported to
be complicated by traumatic rupture of the
anterior spinal ligament (353) and by traumatic prolapse of a lumbar intervertebral
disc with nerve root compression (1198).
The latter finding, unequivocally demonstrated and relieved by surgery, means that
sciatica appearing in ankylosing spondylitis
should not automatically be ascribed to thc
inflammatory disease itself.
An analysis of 25 cases at postmortem
and 1,000 consecutive clinical cases confirmed that, in ankylosing spondylitis, a
non-specific tissue reaction involving the
aorta and aortic valve can result in aortic
insufficiency (280). The point was also
made that a mild form of aortic insufficiency is seen in peripheral rheumatoid
arthritis (1391). Four cases of complete
heart block in ankylosing spondylitis, apparently without aortic insufficiency, were
reported (623). In 3, improvement was
achieved with artificial pacemaker implantation. With the note that, in 2 of the 3, the
spondylitis was recognized only in postoperative follow-up, the possibility that
conduction defects are more likely in mild
or atypical spondylitis was raised. In patients with complete heart block of obscure
origin, the proportion with ankylosing
spondylitis is unknown.
Careful pulmonary function studies using
a variety of techniques were performed on
a total of 54 patients with ankylosing spondylitis at three different centers (516, 849,
1139). All the studies agreed that the lungs
per se were normal. The decrease in total
compliance noted was ascribed to decreased thoracic compliance. Vital capacity
was diminished due to reduced inspiratory
capacity. In a large proportion of the patients, the functional residual capacity was
increased above normal largely because of
the increased residual volumes found.
130
These changes were interpreted as due to
thc tendency for the chest to become fixed
in a position of partial inspiration. Tight
corseting of normal volunteers reproduced
all of the findings except for reducing the
functional residual capacity by reducing
the expiratory reserve volume. The corseting was, perforce, in an expiratory phase
thu5 tending to confirm the suggestion that
incrcxsed functional residual capacity in
thc diseased state was due to inspiratory
position fixation (516). Withal, clinical pulmonary disease and symptomatic functional deficiency were most uncommon.
Three cases of ankylosing spondylitis
complicated by amyloidosis were reported;
2 renal and 2 rectal biopsies were positive
(343). Systemic features of spondylitis such
as weight loss were prominent, the erythrocyte sedimentation rates were rapid, and
peripheral joints were invdved in all 3.
RHEUMATISM AND ARTHRITIS
was found to be positive in 87% (1261).
The latter finding has not been confirmed;
the procedure is not widely used. The 40%
positive reactors in the sensitized sheep cell
test represents a substantially higher proportion than has been noted elsewhere
(751 ). Antinuclear factors were demonstrated by fluorescent methods (31) and by
an anti-human gamma globulin consumption technique (410) in 13% and 45% of
rheumatoid children, respectively, but the
LE. cell preparations were almost invariably negative. Starch-gel electrophoresis
showed haptoglobin group 1-1 in 42% of
90 cases with juvenile RA, a significantly
elevated proportion (586).
SPECIAL FORMS
Several reports described illnesses in
children which may or may not be special
forms of juvenile RA. An analysis of 21
cases of RA with onset between age 15 and
25
revealed good functional capacity in
Juvenile Rheumatoid Arthritis
spite of advanced antomical changes and
Several extensive descriptions of the dis- despite prolonged duration of disease avercwe based upon 316 (31), 50 (1261) and aging 27 years; the same “rheumatoid
31 (721) cases of the illness were pub- arthritis of adolescence” was proposed for
lished. Fever, lymphadenopathy, hepato- the group (618). “Pauciarticular arthritis”
splenomegaly, and rash were seen much (475) is common in early phases of juvenile
more frequently than in the adult disease, disease; a series of 78 patients who had
were considered systemic manifestations, involvement of no more than five joints,
but were not regarded as resulting from a usually large ones, and few or no systemic
distinct form of RA. Cervical spine in- manifestations was reported. With adevolvement was noted by all but involve- quate local joint care, the prognosis waq
mrnt of the sacro-iliac joints in 24% (31) excellent in 54 patients followed for an
was not otherwise mentioned. Knee and average of 4 years.
ankle joints were involved early. The proxiTwo non-rheumatoid illnesses of children
mal interphalangeal, wrist, and elbow joints were described under the names transitory
were involved in more than half of the sub- synovitis of the hip and spondylarthritis.
jects. Spindling of the former joints in a Transitory synovitis of the hip in children,
child was regarded as pathognomonic. Sub- commonly aged 4 to 8 years, is charactercutaneous nodules were present in about ized by sudden, often nocturnal, onset of
10%.
pain (851). Motion is limited, x-rays show
The sensitized sheep cell test was posi- soft tissue swelling, no systemic or labtive, at least in low dilution, in 40% (31, oratory manifestations are prominent, and
1261), the latex test was positive in 13% recovery within a few weeks is the rule. At
(721, 1261 ) but the inhibition technique follow-up averaging 6 years, only 8 of 81
131
SYSTEMIC LUPUS ERYTHEMATOSUS
children showed minor abnormalities
which may have been related. This syndrome, usually treated on an outpatient
basis, is of unknown etiology. [ I t can raise
difficult (and crucial) problems in diferential diagnosis. Ed.] Spondylarthritis develops gradually in infants and young childrcm and often presents as low back, hip or
abdominal pain. The chief physical finding
is paravertebral muscle spasm. Biopsies
suggest purulent disease of either disc or
vertebral body and x-ray changes, although
delayed, are consistent. In some instances,
crganisms, such as Staphylococcus aureus,
are recovered from the disease area but
most cases heal without residua whether or
not antibiotics are used (857).
THERAPY
A thorough discussion of the therapeutic
attack on juvenile RA emphasized important and practical aspects of the home
treatment program describing appropriate
exercises in detail ( 163). Salicylate, soluble
gold salt, and adrenocortical hormone therapy werc discussed. Intermittent steroid
therapy was successful in a small, uncontrolled study and the plan seemed to limit
side effects (379). [Some of the reviewers
have not been so fortunate. Ed.]
PROGNOSIS
Two divergent sets of figures appeared.
In a New York City hospital only 10%of
50 children were in Functional Class I11 or
IF7 after a period of between 1 and 13 years
(1261). In B Copenhagen hospital, 22% of
75 consecutive juvenile rheumatoid arthritic patients were in these poorer functional
classes after an average of 10.6 years; another 7% were dead (751). The difference
is probably due to the nature of the cases
seen, a factor emphasized elsewhere to explain the excellent results (98% in best
classes) in patients admitted to hospital
during the first year of disease as contrasted to those admitted later (61% in
best classes) (31).
SPECIAL FEATURES
In a series of 101 arthritic children, micrognathia was present in 19, x-ray evidence of temporomandibular joint disease
in 17, but the two conditions occurred together in only 4 (1092). It was concluded
that temporomandibular joint disease was
not the major cause of micrognathia. On
the other hand, detailed analysis of jaw
and dental growth in 19 patients ascribed
the condition to insufficient condylar
growth, assumed to be due to temporomandibular arthritis (51) . Radiological
studies of unilateral arthritis of the knee in
children between 1 and 5 years of age revealed significant overgrowth of the involved femoral epiphysis and patella and
lengthening of the involved leg developing
within 4 to 6 months of the onset of local
infiammation ( 158). [This overgrowth
phenomenon is often followed by premature epiphyseal closure and cessation of
growth. Ed.]
Ocular disease (320), secondary amyloidosis (240), and pericarditis (749) in juvenile RA were discussed. Ophthalmic
difficulties, occuring in 5 to lo%, can impair vision and require prompt steroid
therapy. Amyloidosis, detected clinically in
about 4% of a large series, is often fatal;
there is no adequate treatment. Pericarditis, diagnosed clinically in 7% of a large
series, is usually benign and without residuum; no treatment is usually required.
Systemic Lupus Erythematosus
(SLE)
Clinical Features
The natural history of SLE with particular reference to duration of the disease
process was the subject of several reports
(297, 318, 657, 1002, 1055); in one of these
the clinical manifestations of SLE in a
group of 520 patients were analyzed statistically (318). Two reviews of childhood
SLE appeared (604, 981).
132
CARDIOVASCULAR
Pericarditis, with or without effusion,
was observed clinically at some time in the
course of 30% of 520 patients with SLE
(318); one case of cardiac tamponade was
reported (1111).Pericarditis was also frequently observed on postmortem examination (297,542,981).
Myocarditis, of varying degrees, was
noted pathologically in a large number of
SLE patients on whom autopsies were
done; Libman-Sacks endocarditis likewise
was demonstrated pathologically in about
half of the autopsy specimens studied (297,
542, 981). In many patients with SLE,
however, the myocarditis and endocarditis
caused little or no clinical symptomatology;
in the aforementioned series of 520 cases a
clinical diagnosis of myocarditis was made
in only 8%and the authors were unwilling
to make a diagnosis of Libman-Sacks endocarditis on clinical grounds alone (318). In
this and other series (542) there were significant incidences of cardiomegaly, EKG abnormalities and cardiac murmurs. [Since
anemia, feuer, hypertension, azotemia and
coexistent heart disease may also contribute
to these non-specific cardiac abnormalities,
it is often &@cult t o be certain that myocarditis and/or endocarditis present histologically is clinically significant; it is
probably fair to say that they are symptomatic in less than 10%of all patients with
S L E (318,542). Ed.]
AIthough the characteristic vascular
changes of SLE are most often encountered in the small vessels, isolated reports of
involvement of medium-sized and large arteries have appeared (956, 981, 1317). One
patient was reported in whom erythromelalgia ( erythermalgia) antedated the onset
of other symptoms of SLE by four months
and was felt to be an unusual manifestation
of lupus vasculitis (13).
RHEUMATISM AND ABTHRITIS
Pleurisy, often with effusion, was a common finding (318, 1300). Pulmonary infiltrates were usually ascribed to secondary infection and a diagnosis of lupus pneumonitis, due to vasculitis, rarely could be made
(318). Pulmonary dysfunction was frequently encountered in SLE patients, even
in the absence of x-ray abnormalities (590,
912). An impaired diffusing capacity of the
lung attributed to increased membrane resistance was an early and characteristic
finding (590) and was associated with a
restrictive pattern of respiration, alveolar
hypoventilation and mild arterial oxygen
desaturation in many patients; dyspnea, OCcasionally occurring even at rest, was a
definite clinical symptom in some patients
(590,912).
GASTROINTESTINAL
Dysphagia, associated with esophageal
aperistalsis and dilatation, similar to that
seen in scleroderma, was observed in some
patients with SLE (318, 1203); this impairment of esophageal function was often
correlated with Raynauds phenomenon
(1203). The nonspecific upper gastrointestinal symptoms of anorexia, nausea and
vomiting were again noted to be extremely
common during exacerbations of SLE
(318). A less common symptom was abdominal pain (318), related to mesenteric
vasculitis (690) or peritoneal serositis
(297). “Nonspecific” ulcerative or granulomatous colitis appeared in some patients
with SLE (419, 690). The surgical aspects
of the gastrointestinal complications of
SLE were discussed (260).
HEPATIC
Clinical evidence of hepatic dysfunction
was rarely encountered in SLE (981) and
jaundice, when present, was most often
ascribed to a hemolytic process (318).
Despite the paucity of evidence for
hepatic involvement in classical SLE, many
PULMONARY
The intrathoracic radiologic changes in authors continued to describe as “lupoid”
78 SLE patients were reviewed (1300). a form of chronic hepatitis characterized by
133
SYSTEMIC LUPUS ERYTHEMATOSUS
plasma cell infiltrates, hypergammaglobulinemia, positive L.E. cell tests and positive
tests for antinuclear factors and other autoreactive antibodies (778, 781, 935, 1029,
1153). [This interesting disorder bears no
apparent clinical or histopathological relationship to SLE: hence, despite the serological similarities, many clinicians feel that
the use of the adjective “lupoid is misleading in referring to this form of chronic hepatitis. Some authors have referred to it as
“plasma cell hepatitis” (949, 981). Ed.]
Corticosteroids remained the therapy of
choice in this disorder (778, 1029); however, 6-mercaptopurine and azothioprine
were used on an experimental basis in some
patients with initially encouraging results
(778,781,949).
mother had SLE (603). In one group of 4
patients with discoid lupus, erythema multiforme-like lesions were described in association with a characteristic immunological pattern in the serum, consisting of
“speckled antinuclear fluorescence, precipitating antibody to saline extract of human tissues, and rheumatoid factor (1077).
Twenty-two discoid LE patients gave negative reactions to intradermal injection of
autogenous leukocytes (433).
Another patient was reported with spontaneous, painful, tender ecchymoses of the
extremities without clinical features of SLE
but in whom the skin lesions could be reproduced, clinically and histologically, by
the intradermal injection of DNA (755).
RENAL
JOINTS
Of 520 SLE patients, approximately 90%
had arthritis or arthralgias (318). The radiologic findings in the joints in SLE and
other connective tissue disorders were discussed (1183).
NEUROLOGICAL
Psychoses and convulsions, presumably
on the basis of cerebral vasculitis, were
frequent manifestations of SLE (318, 417).
Other neurological manifestations included
cerebrovascular accidents ( 1166), Sydenham’s chorea (193) and peripheral neuritis
(318,424).
SKIN
The cutaneous manifestations of SLE in
520 patients were reviewed (1273). In this
and other reports (318, 981, 982, 1352), the
wide diversity of skin lesions occurring in
SLE was emphasized.
The relationship of chronic discoid lupus
erythematosus to SLE remained unclear
(93, 331, 433, 1073, 1149). In one series of
65 patients with discoid lupus, 12 had developed widespread lesions at the time of
the study (1073). A case of discoid lupus
was reported in a newborn infant whose
Observations were reported on the incidence (318, 604, 968, 981, 1074), histopathology (968, 981, 996, 1063, 1074,
1349), natural history (996, 1083, 1074,
1349) and response to corticosteroid therapy (996, 1063, 1074) of the renal lesions in
several large groups of patients with SLE.
About half of the adults with SLE had
clinical evidence of renal involvement ( 318,
1074) while incidences as high as 70%
(604) and 80% (981) were noted in children with SLE. It was suggested on the
basis of two clinical studies (996, 1074)
that, if renal involvement were not present
when SLE was first diagnosed, it rarely appeared later during the course of the disease. [This suggestion was in conflict with
earlier, less extensizje studies and requires
further evaluation. Ed.]
Mild focal glomerulitis, usually accompanied by mild proteinuria without
hematuria or other clinical manifestations
of renal involvement, was a common finding (996, 1074). One report suggested that
such mild focal glomerulitis rarely progressed to the more active forms of glomerulitis and glomerulonephritis, and, in
fact, occasionally regressed (996). Other
134
RHEUMATISM AND ARTHRITIS
workers, however, felt that such inactive received the high doses of prednisone recrenal lesions merely reflected inactivity of ommended by the other authors (996). It
the generalized systemic disease process was concluded that “in the majority of patients with renal disease in SLE the glo(1074).
Active lupus glomerulitis, a more severe merular lesion was a focal one, subsiding
proliferative and membranous process, was when adrenal corticosteroids were given in
frequently associated with hematuria and doses sufficient to suppress activity in other
heavy proteinuria; the nephrotic syndrome systems” and that “in a minority of patients
was observed in many cases (996, 1074). In the glomerular lesions were severe and
one study, the presence of active glomeru- diguse, and the renal disease usually prolar damage correlated closely with activity gressed to fatal renal insufficiency” ( 1074).
of SLE in other systems (1074). One group The authors suggested that this latter proof workers emphasized the frequency with cess may reflect simply a severe form of
which tubular and interstitial involvement lupus glomerulitis that is more difficult or
was associated with active glomerulitis and impossible to control with steroids, or, alreferred to the process as “active lupus ternatively, that severe diffuse glomerular
glomerulonephritis.” They felt that most involvement may represent a process differpatients with “active lupus glomeruloneph- ing in some fundamental way from focal
ritis,” either untreated or treated with small glomerulitis and less susceptible to the acdoses of corticosteroids, died in renal fail- tion of steroids.
ure. They reported, however, that the clini[A cooperative study is n o c being carcal and histological progression of this le- ried out in several institutions in which
sion was slowed or halted in many in- paired patients with “active lupus glostances by prolonged (6 months or longer) merulitis” receive either high doses of predtreatment with high doses (40 to 60 mgm nisone for 6 months or doses of prednisone
daily) of prednisone, irrespective of clinical sufficient to suppress disease activity ckinisymptoms, followed by a gradual reduction cally; serial clinical and histological evaluato lower (15 to 20 mgm daily) maintenance tions are being made. Until sufficient clinilevels if histologic evidence of activity was cal material has been accumulated for stathen minimal or absent; clinical improve- tistical evaluation, it would seem reasonment was not noted, however, if the renal able to follow the approach recommended
lesion had progressed sufficiently to pro- by either group of authors (996, 1074).
duce nitrogen retention prior to the institu- One approach is to use high doses of,predtion of high-dosage steroid therapy (996). nisone in patients with severe, difluse gloIn contrast, other workers described pa- merular lesions and to use doses sufficient
tients with active “lupus glomerulonephri- to suppress generalized disease activity in
tis” characterized by severe, but focal, patients with focal glomerular lesions.
glomerular involvement together with con- There is a very high incidence of severe
spicuous interstitial inflammation and tubu- steroid-induced complications in patients
lar atrophy in whom remission of “lupus receicing long-term high-dosage steroid
glomerulonephritis” was induced and then therapy and it would seem prudent to
sustained by doses of 5 to 15 mgm/day of avoid its use in the less setiere forms of
prednisone ( 1074). These workers observed “lupus glornerulonephritis” unless its efremission in only one of 7 patients with ficacy can be more convincingly estabdiffuse and severe glomerular lesions, char- 1ished:in controlled studies. Ed.]
acterized by proliferative and membranous
Another histologic pattern, “diffuse memchanges which tended to involve the entire branous glomerulonephritis,” was described
glomerulus; some of these patients (1074) in 7 SLE patients. Diffuse thickening of the
SYSTEMIC LUPCS E:HYTIIEMATOSCS
g l o m t d a r membrane was noted without
associated hypercellularity, necrosis, wire
loops or othcr indications of activity. There
was striking uniformity of the basement
membrane changes (in contrast with the
great variations in severity and distribution
notcxd in SLE glomerulitis and active g10merulonephritis). Abnormalities of the tubular and interstitial tissues werc the only
other lesions found in patients with membranous lupus glomcrulonephritis. All 7 patients with this lesion were living an average of 44 months after initial study and
nonc had a serum urea N of greater than
20 mgm% Onc patient developed the
ncphrotic syndrome, but protcinuria in the
othcrs was not heavy, uwally Icss than 1
gram per 24 hours. Five patients had follow-up renal biopsies; no significant change
occurred and no patient developed histologic evidence of active lupus glomcrulonephritis (996). Similar abnormalities were
describcd in renal biopsies in other reports
(1074, 1349), including one from a patient
with the, nephrotic syndrome ( 1074).
The nephrotic syndrome was observed in
about 15 to 20% of SI,E patients (318,
1074) and was almost invariably associated
with activo lupus glomcriiloncphritis ( 996,
1074); some patients had rapidly progressivv rcnal failure but others entered sustained pcriods of remission after steroid
therapy (1074). Among 18 patients with
SLE and the nephrotic syndrome, 5 had
normal serum cholesterol values and a review of 15 rcportcd normocholesterolemic,
iwphrotic S I X patients suggcsted that normal cholesterol values occurred mainly in
azotcmic patients with a poor prognosis;
thc adjective “normocholesterolcmic” was
preferred to “pseudonephrotic” in describing this form of the nephrotic syndrome
( 114~5). [Neither term seems worth arguing about. Ed.]
THYM[7S AND MYASTHENIA GRAVIS
A considerable amount of evidence has
accumulated which suggests that the thy-
135
mus has an important role in the development of immunological reactivity (457).
Hence, there has been interest in thymic
changes in SI,E, a disorder characterized
by abnormal immunological reactivity.
Large thymic shadows were noted on
pneumomediastinography in some SLE patients (508). The thymuses from many patients with SLE werc examined and found
to have abnormal epithelial hyperplasia
and other features believed to be secondary
to the epithelial change (599, 776, 780);
these changes were not considered specific
for SI,E (599). Several instances of SLE or
the L.E. cell phenomenon occurring in association with thymoma were reported
(570, 680, 707, 1359). Additional cases of
myasthenia gravis and SLE occurring in
the same patient were reported (14, 419,
786, 985); in some instances the clinical
manifestations of SLE antedated the onset
of myasthenic symptoms (786) while in 3
other cases, SLE (together with cirrhosis
and ulcerative colitis in 2 instances) appeared after thymectomy for myasthenia
(14, 419). IIowever, the significance, if
any, of the association of these thymic abnormalities with SLE remains to be established (599).
PREGNANCY
The incidence of abortions and stillbirths
appeared to be higher in 43 women after
the onset of SLE than it had been prior to
the appearance of this disease. There was
no evidence that pregnancy mitigated the
course of SLE and, in many instances,
either onset or exacerbation of SLE occurred, especially during the third trimester
or early postpartum period (888).
OTHER FEATURES
Of 520 SLE patients, 84%had fever and
59%had lymphadenopathy at some time in
the course of their disease (318). Aseptic
necrosis of bone, usually involving the hip
was again reported (318, 1084); this complication was observed in 27 of 520 patients
and was considered an effect of the under-
136
lying disease, perhaps aggravated by corticosteroid therapy (318). Keratoconjunctivitis sicca (Sjogren’s syndrome) was observed in a small hut significant number of
SLE patients (93, 318). Also reported were
instances of the association of SLE with
lymphoma ( 194), thrombotic thrombocytopenic purpura (743), sickle cell anemia
( 1347), myxedema (672), bronchiectasis
(235), and band-shaped keratitis with iridocyclitis (500j .
In most large series, 80 to 90% of SLE
patients were female (318, 657, 1055). In
contrast with earlier suggestions that SLE
was rare in Negroes, several studies suggested that the incidence may actually be
higher in Negroes than in white individual?
(318,1154,1155).
Renal insufficiency was listed as the most
common cause of death in SLE in several
reports (318, 349, 981, 1002), but other
authors emphasized the frequency with
which infections, including pneumonia,
septicemia and tuberculosis, were the cause
of death (297, 1055, 1063, 1074). [Infectious processes present a dificult problem
in detection and treatment in steroidtreated SLE patients i n w h o m both the underlying disease and the iatrogenic hypercidrend state are believed to contribute t o
the increased susceptibility t o infection
(318, 1055). Ed.] Fulminating lupus activity, particulary in the form of central
nervous system vasculitis (297, 318) or
carditis was felt by some authors (297,
1055, 1074) to be a more common cause of
death than lupus nephritis.
There was general agreement that the
diagnosis was being made with greater frequency than in previous decades. There
was some speculation that the incidence of
the disease might be increasing, but one
epidemiological study suggested thit, during the 1956-1959 period in one locale, the
incidence of newly recognized cases had
leveled off (1154).
RHEUMATISM AND ARTHRITIS
Pathology
The pathologic features of SLE in 43
adults (297) dying of this disease were reviewed and correlated with the clinical
findings.
The histopathologic changes in biopsy
and autopsy material from several groups
of SLE patients with renal involvement
were reported (996, 1063, 1074, 1349);
some of the observed abnormalities are discussed in the above section on renal involvement in an attempt to correlate them
with the associated clinical manifestations.
In addition to previously described abnormalities, two reports called attention to the
presence, in some specimens, of “fibrinoid”
deposits in the peritubular capillaries (166,
477).
Distortions in the pattern of palmar
capillaries, visualized by staining for alkaline phosphatase activity, were demonstrated (689).
Gamma globulin and components of
complement were demonstrated in the
basal membrane of skin (180, 259, 632)
and in the glomeruli (956) of patients with
SLE, using immunofluorescent techniques.
The fixation of guinea pig complement was
demonstrated in the glomeruli of 7 patients
with renal lesions of SLE ( 176).
Laboratory
Antibodies to various nuclear constituents in SLE sera were studied extensively. The L.E. cell phenomenon was
still considered to represent the most suitable diagnostic antinuclear reaction (840).
The presence of the L.E. cell phenomenon,
in up to 75% of all SLE patients (318),
could be correlated reasonably well with
the level of nucleoprotein-reactive gamma
globulin (1262). Positive L.E. cell tests reverted to negative in two SLE patients receiving h e p a r i n for unrelated thromboembolic complications (522j; the L.E.
SYSTEMIC LUPUS ERYTHEMATOSUS
cell phenomenon was not affected by laboratory temperature changes from 4” to
37” C (94). Another method for performing the L.E. cell test was described (501).
The significance of extracellular hematoxylin bodies in L.E. cell tests was discussed;
in one study they were considered suggestive of the presence of SLE or a related
disorder (43) while other authors considered them a rather non-specific abnormality (1202), L.E. cells were encountered in
patients with rheumatoid arthritis (93,
1224, 1341), Sjogren’s syndrome (840),
discoid lupus (1149), chronic (778, 781,
1029, 1153) and acute (445) hepatitis, and
lymphoma (588). [The incidence of positive L.E. cell tests in these disorders is low
if a relatively insensitive method is used.
The need for a sensitive method employing
glass beads to traumatize nuclei would
seem to have diminished with the advent
of the more sensitive immuno9uorescent
tests. The use of a relatively insensitive
L.E. cell method increases the specificity of
the method considerably. Ed.]
A number of immunofluorescent methods
were used for the detection of antinuclear
antibodies, also referred to as antinuclear
factors or ANF, in the sera of patients with
SLE (200, 201, 1150, 1231, 1291) and other
diseases (83, 356, 559, 570, 691, 1309,
1341). ‘The effects of difference in antigen
substrate, potency and specificity of antiserum and other factors on the variations in
results obtained in different laboratories
were discussed (411, 559, 571); repeated
freezing and thawing of normal serum was
shown to increase the incidence of positive
results (699). ANF could be detected in
almost all SLE sera, using the immunofluorescent technique ( 1150, 1224). Instances in which a positive L.E. cell test
was associated with a negative ANF test
were unusual (68); in two such instances,
nuclear reactivity could be demonstrated
only after mechanical trauma to leukocyte
137
nuclei (68, 1231). ANF could be demonstrated by the immunofluorescent method
in the sera of some patients with RA (68,
356, 1224, 1309, 1341), Sjogren’s syndrome
(840, 1224), scleroderma (570, 1224),
myasthenia gravis ( 1224), thymoma (570,
680), tuberculosis (559), and various other
disorders, ANF was present in three immunoglobulin classes, IgG, IgA and IgM in
both SLE and RA sera, but elevated levels
of IgG ANF were more characteristic of
SLE than of rheumatoid sera (68).
Characteristic patterns of nuclear fluorescence were found to be associated with
specific antinuclear antibodies. “Diffuse” or
“homogeneous” nuclear staining was associated with antibodies to the DNA-nucleoprotein complex (411, 698). [This is
the staining pattern most commonly encountered in SLE sera; it is, however, also
encountered in RA, Sjogren’s syndrome,
other connective tissue diseases and hypergammaglobulinemic disorders associated
with antibody to nucleoprotein. Ed.] The
“shaggy” or “peripheral” staining pattern
was associated with antibodies to DNA itself (200, 201, 411) and has to date only
been reported in SLE sera. “Speckled nuclear staining had previously been shown
to be due to antibodies to soluble antigens
present in a “phosphate extract” of the nucleus (1291). The speckled staining pattern
was not ordinarily observed in SLE unless
prior absorption with nucleoprotein had
been carried out (1291); the speckled pattern alone thus was usually associated with
disorders other than SLE such as Sjogren’s
syndrome and other connective tissue disorders (698, 1150, 1291). A pattern of “nucleolar” fluorescence was recognized, particularly in scleroderma sera (1150), but was
not completely characterized (411).
Antibodies to specific nuclear constituents were studied, using a variety of immunochemical techniques (200, 201, 250,
944, 1009, 1209, 1210, 1224, 1239, 1262.
138
1263). Elevated levels of nucleoprotein-reactive gamma globulin were encountered
in all sera tested and in the sera of some
patients with KA, scleroderma, dermatomyositis, liver disease and glomerulonephritis; with few exceptions, higher levels were
characteristically found in SLE sera
( 1262). [ T h e eleoations in disorders other
than S L E are presumably responsible for
thP “diffuse” antinuclear fluorescence and
positioe L.E. cell tcsts sometimes encountered in the seru of patients with these diseuses. Ed.] Two-thirds of the SLE sera in
another study flocculated bentonite particles coated with thermally denatured DNA
while 29%reacted in lower titer with bentonite particles coated with native DNA
(1224); the preferential reactivity of more
DNA-reactive SLE sera with thermally denatured DNA correlated well with prior
observations using a quantitative complement fixation technique (1131). Using this
latter technique, the reactivity of one unusual SLE serum with denatured DNA was
shown to be due largely to antibodies with
purine specificity (1209) and it is shown
that chloroquine, by virtue of its binding to
DNA, was capable of inhibiting the reaction of DNA with the anti-DNA antibodies
of SLE sera (1210). DNA-reactive antibodies in SI,E sera were also studied by
means of an immunofluorescent spot test
(200, 201) and it was stated that a striking
correlation had been observed between the
presence of anti-DNA and the acute phase
of SLE (200). More recently, a patient was
reported in whom the disappearance of anti-DNA antibodies was followed by the appearance in the serum of free DNA; sera
from 7 SLE patient.; were found to contain
DNA at some time, particularly during febrile periods, and it was suggested that circulating DNA-antibody complexes might
be giving rise to renal damage in this disorder (1239). Positive delayed skin reactions to intracutaneous DNA were described in a group of patients whose sera
also reacted with DNA (944).
RHEUMATISM AND ARTHRITIS
Antibodies reacting with cytoplasmic
constituents were recognized in the sera of
patients with SLE (840, 1225); some of
these antibodies in SLE sera appeared to
have specificity for ribosomal RNA (1225).
Other immunological abnormalities were
detected in SLE sera. Serum complement
levels were frequently depressed, particularly during phases of disease activity associated with renal involvement (840,
1263): the 11s component of complement
was shown to participate in the cryoprecipitation observed in some SLE sera (227).
The circulating gamma globulin anticoagulant frequently encountered in SLE was
variously reported to behave as an inhibitor
of prothrombin (585) and as an inhibitor
to the formation of “prothrombinase,” the
enzyme which converts prothrombin to
thrombin (161). Thrombosis, as well as
hemorrhage, was reported in patients with
circulating anticoagulants ( 149). Positive
tests for rheumatoid factor (68, 318), and
antibodies giving rise to biologic false positive serological tests for syphilis (384, 678,
1156,1386) were again described.
Therapy
Salicylates and antimalarial drugs, either
alone or in combination (317, 813), were
sufficient to suppress only mild disease activity; synthetic corticosteroids remained
the most effective means of suppressing
SLE. The minimum dosage of corticosteroid sufficient to suppress disease activity
was used in most instances, supplemented
in some patients by salicylates and/or antimalarials (317), although some patients
with active lupus glomerulonephritis received high doses of prednisone for long
periods (996), as discussed in the Renal
section above. The toxicity of corticosteroid
therapy in SLE was well recognized (317,
981); instances were reported in SLE patients of subcapsular cataracts with glaucoma (568) and of spontaneous rupture of
tendons, perhaps already weakened by
disease (1276).
SYSTEMIC LUPUS ERYTHEMATOSUS
In two studies, 55% and 71%, respectively, of patients were alive 4 years after
the diagnosis of SLE was made (657,
1055); these figures were in contrast with a
4-year survivorship of less than 20%in the
1932-19413 period (1055). Survival of 10
years or longer was not uncommon (318,
657). These figures reflected, in part, improved and earlier recognition, particularly
of milder cases; nevertheless most workers
felt that the advent of corticosteroid and
antibiotic therapy had made a significant
contribution to the improved prognosis in
this disorder (317,318,1002).
The use of nitrogen mustard (656), 6tnercaptopurine ( 983), and 6-thioguanine
(295) in SLE was reported; isolated instances of the use of heparin (522) and of
thymectomy (777) were reported. [ T h e
authors were all favorably impressed but
insufficient clinical data were reported. I t
toas particularly difficult t o draw any conclusions about a beneficial effect in the single thymectomized patient, hut caution
inust b p exexised in this area in view of
the report*s of 3 patients in whom SLE first
appuared after thymectomy for myasthenia
gravis (14, 419). Ed.] (See section on AntiRheuinatic Drugs for discussion of antimetabolite therapy.)
Experimental Models
In all mice of the NZB/BL strain, hemolytic anemia of the “autoimmune” type appeared in association with positive Coombs
tests; renal lesions resembling those of human lupus nephritis were seen and a small
proportion of animals had positive L.E. cell
tests. The syndrome was diminished in severity by early splenectomy and by the administration of ACTH (546). Similar andings have been described in high incidence
in the NZB strain and other hybrid strains
derived therefrom (579, 580, 581, 759) and
thymic lesions were described in many of
these mice (177). In a hybrid strain derived by crossing the NZB/BL and NZW
strains, all animals developed positive L.E.
138
cell tests and died within 8 to 10 months of
renal failure with renal lesions resembling
those seen in human SLE. Fibrinoid necrosis and thickening of the basement membrane together with wire loops and occasional hematoxylin bodies were described
(545) and gamma globulin was demonstrated in the glomerular lesions (1);some
animals had fibrinoid necrotic lesions in the
walls of medium and small vessels in the
kidney and other organs (545). Thymectomy did not prevent the development of
lesions in these animals (547). The spontaneous appearance of antinuclear antibodies in other strains of mice was reported
(412, 928); antinuclear antibodies were
also described in the lymph and serum of
skin-homografted dogs (380). A spontaneously occurring disease, characterized by
autoimmune hemoIytic anemia, thrombocytopenic purpura, nephritis, positive L.E.
cell tests and other serological abnormalities was described in 7 dogs and was referred to as canine SLE (748). (See section
on Experimental Models for further discussion of disorders in mice and dogs.)
DNA-reactive antibodies were experimentally induced. Purines (186, 188), pyrimidines (1130, 1240), nucleosides and nucleotides (350, 993) were coupled as haptens to protein or polypeptide carriers; rabbits immunized with the hapten-protein
conjugates formed hapten-specific antibodies which reacted with DNA. Similar
antibodies were elicited by the injection of
DNA complexed with methylated bovine
serum albumin (992). DNA-reactive antibodies appeared in the sera of some rabbits
hyperimmunized for prolonged periods
with killed bacteria (226, 1257). In every
instance reported, experimentally induced
anti-DNA antibodies, like most encountered in SLE sera, reacted better with thermally denatured than with native DNA
(91). [Some animals have been examined
pathologically, but no lesions have been
consistently observed other than those attributable t o prolonged immunizutimz.
140
RHEUMATISM AND ARTHRITIS
Ed.] DNA-reactive antibodies, both in
SLE sera (150) and experimentally induced (186, 1062, 1169), were capable of
interfering with certain biological properties of DNA.
Etiology and Pathogenesis
The etiology of SLE remained unknown.
An infectious etiology, e.g., viral or mycoplasma1 (72, 976, 1250), was considered
possible but required further study with
new isolation techniques. (See section on
Heiter’s syndrome for discussion of mycoplasma.) The possible role of autoimmune
mechanisms in the etiology and pathogenesis of SLE and other connective tissue disorders has been discussed. (See section on
CONNECTIVE
TISSUE
DISEASES.
)
The role of genetic factors in the etiology
of SLE was discussed (456, 577, 955). Two
additional pairs of identical twins, both of
whom had SLE, were reported (132, 621)
and the occasional familial incidence of
SLE was again noted (219, 318). The occurrence of other connective tissue diseases
(1274, 1359) and unusual cutaneous disorders (1274) in families of SLE patients
was again reported. Antinuclear antibodies
were detected in a small, but apparently
significant, number of sera from relatives of
SLE patients (571, 995); other serological
abnormalities in relatives were also reported (574). Similar findings were reported in the family of a discoid lupus patient (96). The high incidence of connective tissue disease and immunological abnormalities, including antinuclear antibodies and tissue-reactive antibodies in relatives of hypogammaglobulinemic patients
was noted (577, 686, 980, 1359). [ I t
should be noted that some family studies of
rheumatoid arthritis revealed a high incidence of familial connective tissue disease
and serological abnormalities. However,
carefully conducted family and genetic
studies in American Indian populations
failed t o reveal any evidence of familial aggregation of RA or RF (175, 931); the fallacies inherent i n studies of familial incidence of disease by studying the genetic
backgrounds of affected individuals were
pointed out (931) and should lead t o caution in interpreting the significance of familial clusters of SLE or associated serological
abnormalities. Ed.]
DRUG-INDUCED SLE
Clinical manifestations suggestive of
SLE again appeared after administration of
hydralazine (294), antituberculous drugs
( 1385), procainamide (493), trimethadione
(574, 604, 981, 1149) and dilantin (574,
604, 1345), the latter a drug known to
cause serum sickness (160) and lymphomalike lymphoid hyperplasia (191). Withdrawal of the presumed offending agent
was sometimes followed by clinical remission (604, 981, 1149, 1385) but this did not
always occur (604, 1149). Drug-induced
SLE appeared in one patient in whose
family multiple immunological aberrations
were detected (574). Some patients may
have had previously unrecognized or latent
SLE (573, 1149), but the complete remission of clinical and laboratory abnormalities in many patients suggested that this
may not always be the case. [One would
hope that (1) in instances where drugs induce SLE de novo in a normal or “lupus”
diathesis (573, 574) the disease is reversible, and (2) that the irreversible cases represent instances wherein S L E was already
present and merely accentuated by drugs.
Prospective evaluation of large groups of
patients receiving implicated drugs would
be desirable. Ed.] A mechanism of cell destruction in individuals sensitized to foreign
drugs was described 2nd its implications in
autoimmune phenomena were discussed
(1152). The hyperreactivity of SLE patients to certain antigenic challenges was
commented upon (1386).
POLYARTERITIS NODOSA AND OTHER VASCULAR SYNDROMES
Polyarteritis Nodosa and Other
Vascular Syndromes
Polyarteritis Nodosa
141
the aorta, especially in the branches of the
superior mesenteric artery, developed in 8
of 33 patients who underwent surgical repair of the coarctation ( 1267). Overstretching of the media of the vessel wall by unaccustomedly high systolic and pulse pressure was suggested as a possible cause of
this arteritis. Treatment with antihypertensive medication, especially reserpine, was
advised for those patients in whom the
brachial blood pressure did not decrease
after operation.
Polyarteritis nodosa was reported to have
occurred after prolonged treatment of hypertension with guanethidine in 3 patients
(302). These patients were considered not
to have had hypertension related initially
to polyarteritis because of the long duration of hypertension prior to development
of manifestations of polyarteritis. The development of polyarteritis was attributed to
the administration of dexamethasone in a
patient with multiple myeloma (1172).
Biopsy of skin (1353), of the peroneus
brevis muscle and musculocutaneous nerve
with nutrient artery or of the first interdigital nerve of the foot with its nutrient artery
and the extensor digiti brevis muscle (127,
762), was recommended for tissue diagnosis.
Treatment of necrotizing arteritis often
was found unsatisfactory; steroids seemed
to provide the most help (76, 302, 879,
1287). One patient who had allergic vasculitis of the skin seemed to respond well to
hyposensitization against bacterial vaccines, inhalants, and insect bites (677).
The group of diseases characterized by
necrotizing arteritis and once known generally as polyarteritis nodosa lately has
been subdivided, on the basis of histopathologic and clinical differences, into major
subgroups: so-called classic polyarteritis
nodosa, allergic angiitis, angiitis granulomatosis, rheumatic arteritis, and temporal
arteritis (15, 229, 309, 879, 947, 1086).
[These diuisions merge subtly, one into another, so that clear-cut distinctions are not
always possible; but continued efforts to
separate them seem worthwhile. Ed.] In
certain instances the major features of the
necrotidng arteritis seemed largely confined to the skin, yet most also exhibit
widespread systemic involvement (381,
1353). Various complications of necrotizing
arteritis were reported: massive retroperitoneal and perirenal hemorrhage arising
from rupture of an aneurysm of an intrarenal artery (41S), perforation of the bowel
( 261,375,1061 ), exophthalmos ( 1286), and
mononeuritis multiplex (127, 762). The
possibility of diagnosis of polyarteritis on
the basis of the pattern of simultaneous
progression and regression of infiltrates: in
serial roentgenograms of the thorax was
suggested (1099). A relationship between
polyarteritis and thrombotic thrombocytopenic purpura was suggested on the basis
of their concurrence in one patient (97),
and between streptococcal infection and
polyarteritis in 3 patients in whom polyarteritis developed during the course of ap- TAKAYASU’S ARTERITIS
parent acute poststreptococcal glomeruIn addition to the more obvious circulalonephritis (394).
tory manifestations secondary to stenosis,
The clinical characteristics of polyarteri- and occasionally dilatations, of the aorta
tis nodosa occurring in infants were de- and its major branches in Takayasu’s arteritis, systemic manifestations similar to those
tailed ( 1046).
A necrotiring arteritis and arteriolitis in in many “collagen diseases” were reported,
vessels distal to the site of coarctation of especially at onset: fatigue, fever, sweat-
142
ing, cough, hemoptysis, pericarditis, polyarthralgias, leg ulcerations, intestinal hemorrhage, anemia, and increased erythrocyte
sedimentation rate, plasma globulins, and
fibrinogen (564, 1034, 1114, 1216, 1277).
Study at autopsy of 21 instances of Takayam’s arteritis indicated that the essential
pathologic change was mesarteritis of the
aorta and its branches, with granulomatous
or diffuse inflammation of the media and
adventitia (901). Although the aortic arch
and its branches have been the principal
sites of involvement, other segments of the
aorta and its branches and also the pulmonary arterial trunk may be involved
(901, 1114, 1216, 1277). Involvement of renal arteries has led to hypertension (273).
Cardiac involvement was thought to be
secondary to hypertension, aortic or coronary disease and possibly the result of an
inflammatory process in the heart (1114).
The association of the aortic arch syndrome
and a rheumatoid-like arthritis was noted
in the case of a young Negress (358).
A somewhst different type of nonsyphilitic panaortitis was described in 11 patients
who did not exhibit narrowing of the ostia
of arteries branching from the aorta; because 3 of these had rheumatic heart disease, 2 had rheumatoid spondylitis with
peripheral joint involvement, and one had
scleroderma, a possible relationship between the aortitis and the “rheumatic diseases” was suggested (538,1071).
Arterial surgery was recommended for
selected patients (273, 564, 1034, 1277),
and in the early phase of the disease, steroid and anticoagulant therapy.
GIANT CELL ARTERITIS
In a series of 10 patients who had a clinical syndrome compatible with the diagnosis of polymyalgia rheumatica (see Diseases of Muscle) and who did not have
palpably thickened or tender temporal arteries or headaches, biopsy of temporal arteritis in 9 patients revealed giant cell arte-
RHEUMATISM AND ARTHRITIS
ritis in 7. A good response resulted from
treatment with steroids. One of these 10
patients also had the aortic arch syndrome,
suspected in this instance to be secondary
to giant cell arteritis (16). [ N o one seems
t o have confirmed this observation, i.e.,
that a high incidence of giant cell arteritis
is associated with the syndrome of polymyalgia rheumatica. Ed.] One patient
with giant cell arteritis exhibited, on cerebral angiography, scattered focal areas of
stenosis and ectasias in branches of the anterior and middle cerebral arteries, which
at postmortem seemed to be involved by
the granulomatous process (562). Attention
was called to the occurrence of necrotic
areas on tongue and scalp in giant cell arteritis; these areas were considered to follow ecchymoses resulting from hemorrhage
through areas of arteritis rather than from
arterial occlusion (666). Giant cell arteritis
led to painful thrombosis of the radial, ulnar, or median artery in 3 patients (169).
Giant cell arteritis occurring in children
differed from that in adults, clinically and
histologically. In 2 children, involvement of
aorta and large systemic arteries led to
multiple aneurysms ( 1301).
Wegener’s Granulomatosis
Additional cases of Wegener’s granulomatosis were reported (90, 105, 351, 382,
401, 407, 506, 772, 827, 1252), including
cases with cranial arteritis, some of which
had rather unusual features (401), aneurysm of the left vertebral artery (401),
thin-walled pulmonary cavities (401, 772),
myocarditis (827), involvement of prostate
and pancreatic duct (407), Mikulicz syndrome (105), orbital granuloma (505), and
survival for the unusually long time of 4%
years (351). Synovial biopsy revealed acute
synovitis and fibrinoid necrotic regions surrounded by palisading fibroblasts in one instance, and non-specific chronic inflammation in another (105). The cause remained
unknown: a basic pathologic lesion was
SCLERODERMA
143
Although Goodpasture’s syndrome USually has proved fatal within months, 1 unusual case involving 2 spontaneous remissions for 7 and 4 years was recorded. During the first attack no clinical evidence of
nephritis was noted; in the second attack
nephritis occurred transiently, then reappeared in the third attack (1105).
No satisfactory treatment for Goodpasture’s syndrome was reported. General supportive measures were used; steroids did
Goodpasture’s Syndrome
not seem helpful (98, 1003, 1105). The use
The combination of pulmonary alveolar of other immunosuppressive agents was
hemorrhage and glomerulonephritis, com- suggested, The cause of Goodpasture’s synmonly known as Goodpasture’s syndrome, drome is not known, but hypersensitivity
produces a rather distinctive clinical entity and autoimmune mechanisms have been
characterized by hemoptysis, renal failure, suggested (291, 933, 1105). Caution was
anemia, and, roentgenologically, a floccu- suggested in the use of bronchography in
lent pulmonary infiltrate extending out these patients owing to possible hypersensifrom the hilar regions toward the bases. tivity reactions to iodized oil (1109).
This syndrome was considered by some to
Scleroderma (Progressive Systemic
he related closely to polyarteritis nodosa
Sclerosis)
and to idiopathic pulmonary hemosiderosis
(291, 933). Others preferred to exclude ETIOLOGY AND PATHOGENESIS
The cause of scleroderma remains unfrom Goodpasture’s syndrome those cases
in which diffuse arteritis occurred. Possible known. The occurrence of hyperglobulinedistinguishing features between Goodpas- mia, abnormal serologic reactions, and
ture’s syndrome and idiopathic pulmonary serum gamma globulins possessing properhemosiderosis were noted: patients with ties of antinuclear antibody indicated the
idiopathic pulmonary hemosiderosis had existence of an “unusual state of the imtheir disease at a younger age, survived mune system,” but the exact role of imlonger after onset of disease, were equally munologic reactions in scleroderma redivided as to sexes (in contrast to prepon- mained to be determined (1051). The frederant involvement of males in Goodpas- quent association of aperistalsis of the
ture’s syndrome), and relatively rarely had esophagus and Raynauds phenomenon in
renal involvement ( focal glomerulonephri- scleroderma suggested an underlying detis) which when it did occur generally did fect in the autonomic nervous or vasomotor
not lead to renal failure; certain changes in system (1203). The lack of demonstrable
the alveolar capillary basement membrane abnormalities of collagen in esophageal
were reported to be found in patients with muscular layers or submucosa of scleroGoodpasture’s syndrome but not in those dermatous patients exhibiting atrophy of
with idiopathic pulmonary hemosiderosis. esophageal muscles seemed to exclude di[Whether these three diseases are sep- rect pressure from sclerotic, proliferating
arate entities or part of the spectrum of a collagen as the cause of the esophageal
single disease remains t o be determined. I n muscle atrophy (1264). It was postulated
the meanwhile, attempts t o separate them that the main abnormality in scleroderma is
seem justified. Ed.]
in the ground substance ( 159,387).
suggested to be subendothelial deposition
of an unidentified material in capillaries,
arterioles, venules, and smaller arteries, to
which the associated angiitis might be secondary (351). Pathologic criteria for diagnosis of Wegener’s granulomatosis continued to be necrotizing granulomatous lesions in upper and lower respiratory tract,
focal necrotizing vasculitis of arteries and
veins, and glomerulitis.
144
CLINICAL FEATURES
The features of scleroderma in 66 patients were detailed. Eighty-nine per cent
of the patients were women. The most frequent initial manifestations were: Raynaud's phenomenon in 53%,skin lesions in
18%, and arthralgia or arthritis in 15%.
Twenty-four of 46 tested had abnormal
electrocardiographic findings: low-voltage
QKS complexes, arrhythmias and signs of
left ventricular hypertrophy, coronary artery disease, and pericarditis. Uremia occurred in 9, congestive heart failure in 7,
anemia in 28, and false-positive serologic
tests for syphilis in 3. Pleural and pericardial eftusions were not uncommon ( 1 0 4 ) .
That idiopathic retroperitoneal fibrosis
might be related to scleroderma was suggested by the presence, in a patient with
the former condition, of Raynauds phenomenon, pulmonary fibrosis, keloid formation in scars, antinuclear factors in serum,
globulin abnormalities, a n d basophilia
(1010). The importance of differentiating
wleredema from scleroderma was emphasized again (472, 1049). Pregnancy did not
affect the course of scleroderma in many
patients although some became worse, others temporarily better; scleroderma did not
aftect the pregnancy in most instances although some complications were reported
in a few (289, 485, 615, 1192). Individual
patieiits manifesting features of scleroderma, RA and SLE were described. (904,
1051,1203).
GASTROINTESTINAL.
In a series of 47 sclerodermatous patients, 74%had symptoms referable to the esophagus (761), and esophageal as well as other symptoms referable
to the gastrointestinal tract were common
in another large series (1041). One patient
presenting with vomiting and abdominal
distention had scleroderma of the gastrointestinal tract, kidneys, and myocardium
without dermal involvement (313). Esophageal motility studies, revealing aperistalsis
in 21 of 25 sclerodermatous patients, were
RHEUMATISM AND ARTHRITIS
the most sensitive clinical indicator of
esophageal involvement; roentgenologic
studies were somewhat less sensitive, and
symptomatology the least sensitive of the
three (1203, 1264). A high degree of association was noted between aperistalsis of
the esophagus and Raynaud's phenomenon
in scleroderma, and between aperistalsis
and telangiectasia (1203). Of 727 patients
with scleroderma, 8 had evidence of serious
hepatic disease but the relation, if any, to
scleroderma was uncertain (73). The
abrupt onset of dysphagia in a patient with
longstanding scleroderma heralded an epidermoid carcinoma in the distal part of the
esophagus (815).
CARDIOPULMONARY.
The earliest and most
consistent abnormal pulmonary finding in
scleroderma was decreased diffusing capacity (208, 592, 1039, 1091, 1348). Restrictive defects were less common. Results of
pulmonary function studies did not correlate well with roentgenologic appearance
of the lungs (208, 1039). Pulmonary hypertension was common in scleroderma, independent of alterations in pulmonary function. Impaired cardiac function usually was
attributable to right ventricular insufficiency secondary to pulmonary hypertension or left ventricular insufficiency secondary to systemic hypertension resulting
from renal involvement (1091). A patient
who had had scleroderma for 3 years demonstrated aortitis, aortic valvulitis, and perforation of an aortic valve leaflet (1071).
Bronchiolar carcinoma with scleroderma
was noted in 9 patients (865). [Since
bronchiolar carcinoma seemingly can arise
in regions of chronic fibrosis, since carcinoma developed in all 9 patients after
many years of scleroderma, and since no
other carcinomas seem t o occur with unusual frequency in scleroderma, the bronchiolar carcinomas may have been secondary t o the scleroderma Tather than the
cause of scleroderma. Ed.]
ROENTGENOLOGIC
FEATURES.
Roentgeno-
SCLERODERM A
145
logic features of scleroderma generally inhibition of monoamine oxidase ( 168).
(803) and in the gastrointestinal tract par- Chemical analysis of dermis in scleroderma
ticularly (313) were reviewed. Fourteen of revealed a normal concentration of water
32 patients with scleroderma had abnormal- and hydroxyproline, suggestive of no inities of the roentgenologic pattern of the crease in collagen; roentgenographic difsmall intestine, and 10 of 19 had multiple fraction patterns and amino acid analysis
square-shaped, wide-necked diverticula of of collagen fibers disclosed no abnormalithe colon (541). Angiographic studies re- ties, although bound hexose was increased
vealed, in scleroderma, a general tapering (387).
off arid disappearance of the main vessels
supplying the fingers, without compensatory PATHOLOGY
The general pathology of scleroderma
collateral circulation, hypervascular regions,
or venous abnormalities such as are seen in was reviewed ( 1051). Palmar capillaries,
KA ( 1184). Roentgenologic manifestations visualized by staining for alkaline phosof sternoclavicular arthritis in scleroderma phatase, revealed in scleroderma great reresembled those of RA; involvement of pe- duction in the number of and some irreguripheral joints also resulted in rheumatoid- larity of capillaries, but no “double looplike changes, although destruction tended ing” of dilatation as seen in lupus erythemto be less in scleroderma. The sacro-iliac atosus (689). Study of the esophagus in
joints were fused in one patient with scler- 10 sclerodermatous patients revealed atrooderma (347). Roentgenograms of the phy of smooth muscle in 7, esophagitis in 5,
hands in 46 sclerodermatous patients re- internal proliferation of small arterioles in 5
vealed destructive lesions of terminal pha- but no abnormalities of collagen in sublanges in 29, soft-tissue calcification in 15, mucosa or in the stroma of muscular layers
osteoporosis in 14, and destructive articular or of the striated muscles (1264). In the
lesions in 9 ( 1041).
small intestine, focal atrophy of smooth
LABORATORY
FINDINGS.
In 32 patients with muscle replaced by fibrous tissue and ocscleroderma, antinuclear antibodies were casional infiltration of the muscular layer
found in 25 and precipitating autoanti- by lymphocytes and monocytes were
liodies to saline extracts of human tissues in found; the colonic diverticula showed al6; antinucleolar antibodies were said to be most complete replacement of smooth musmore common in scleroderma than in other cle by dense connective tissue, and nearby
connective tissue diseases (83). Electro- arterioles exhibited medial hypertrophy
phoretic studies of serum proteins in 7 (541).
sclerodermatous patients showed increased
Proliferative intimal changes were found
content of sevcral fractions; during remis- commonly in small and medium-sized syssions of the disease these abnormalities re- temic arteries (1041) and in muscular arturned toward normal (388). Urinary ex- teries and small precapillary vessels in the
cretion of 5-hydroxy-indoleacetic acid was pulmonary circulation (895). Electron minormal in scleroderma, indicating that sero- croscopy revealed thickening of the basetonin was not a direct factor in pathogen- ment membrane of small pulmonary aresis (1271). Kynurenine was not found in teries and veins and of alveoli in sclerothe hair of normal or sclerodermatous sub- derma (1348). Study of the fine structure
jects, despite the increase of kynurenine in of dermal collagen fibrils in scleroderma rethc urine ia scleroderma (744). Studies of vealed in some areas an increase in thin
urinary catecholamines and their metab- fibrils, possibly a sign of increased fibrilolites in scleroderma indicated possible loneogenesis ( 159).
146
THERAPY
matomyositis was primarily a vasculitis.
This was quite different from the adult
forms of myositis in which vasculitis was
mild or relatively insignificant. From a
study of biopsies and 7 autopsy cases, it
appeared that the cwliest changes consisted of pc.rivascular accumulations of inflammatory cells, followed in rapid succession by arteritis and phlebitis. Later intimal
tissiw syndromes usually r ~ s p o n dto udren- hyperplasia of both arteries and veins was
ocorticul steroid therapy-not
so with seen along with the formation of fibrin
sclerociwmn. Ed.]
thrombi in somc vessels. Such thrombi
w ( w found in all stages of organization
Polymyositis and Dermatomyositis
and recanalization. A number of the chilThe cause of this syndrome of proximal dren developed acute episodes of abdomimuscular weakness is not known. The most nal pain, a feature which was unknown in
helpful diagnostic tests included an evalua- adults. Thromt:osis of mcsentcric vessds
tion of sevcwl serum enzymes, which com- was common and apparently was the cause
monly w ( w clcvatcd in the active stages of of death in some of these cases. Since simithis discase, abnormal &ctromyography
lar vascular pathologic alterations occurred
arid abriormal muscle biopsy (555). It ap- in muselc, it was felt that the primary lepeared quite likely that polymyositis was sion within muscle, accounting for most of
riot a single disease, but rather a series of thc muscular weakness, was vascular inclisordcrs that had as a common dcnomina- sufliciency and multiple areas of infarction
tor wc&ncss of muscle and inflammatory Icading directly to ischemic compromise of
infiltrates in the striated muscle. When a muscle tissue or to neurogenic weakness
typical skin rash was fomid, thc condition secondary to thrombosis of nutrient artr:rim
could then bt. diagnosed as dcrmatomyosi- supplying motor nerws. It should be noted
tis. Ilowever, only about 40% of c a s r ~ that visctml malignancy of any type is a
couid b c , givrw this diagnosis. Scveral gen- very icncoinnzon occurrence in the childwal rclvir.ws of scries of cases appeared hood form of dermatomyositis, in contrast
(75, 221, 974),and each stressed the uni- to its presence in about 15%of adult paformity of muscle wcaknrw including ticnts.
dyspliagia. loss of strength of the proximal
In on(’ report (700) a possiblc familial
musculature and the frcqucnt association occurrcmx of dermatomyositis was sugwith fcatures of certain othcr conncctivc gested since 2 femalrx who were first
tissue diseases, especially progrwsivc sys- cousins, were affected. The entire family
and RA. [Our urhitr6rrj was surveyed for the possibility of clinical
tiefinitions of syndromes make no sense or laboratory cvidcncr: suggcstivc of a consometimes. Ed.] An extensive article de- nective tissue disease. Borderline or defiscribed 40 cascs of dermatomyositis in nitely elevated serum gamma globulins
childhood (257). This was thc largest series were found in onc propositis and 6 relathat has so far bren reported in children. tives. Two relatives were found to have a
The most irnprcssive feature of this series weakly reactive latex slide test for the
was the description of thc pathology in rheumatoid factor and a positive antinuchildren. It was shown that the predomi- clear test was noted in one relativc.. [One
nant pathological lesion in childhood der- of the reoietcecs has c o d i c t e d a lab-
Treatment of scleroderina continued to
be w r y unsatisfactory in the view of
most obscwers; improvement that follows
tlic use of potassium para-amino-benzoate
(465) and relaxin ( 104) was mentioned.
Rcthanechol chloride was noted to improve
esophageal transport in some sclerodcrmatous patients (761). [The otlzer connective
147
I’SORlAlT(: ARTHRITIS
oratory and clinical survey of relatives of
20 patients with polymyositis or dermatomyositis and has not found a statistically
significant incidence of serological or other
abnormalities in relatives. Ed.] Circulating
antibodies were searched for in polymyositis and in other diseases in which muscle
wasting occurred (203) and were found
with almost equal frequency in several of
thc conditions and in controls. Antibodies
tested for were antimyosin, antinucle~rand
iinmunoconglutinin. [This single negative
w p r t does not, of course, rule out an immune reaction as a significant feature of
polymyositis, but it indicates the complexity of the search for the possible antigenic
stimuli. Ed.]
The coexistence of polyomyositis with
pulmonary disease has been infrequently
reported in the past. During the past year
three reports, describing 6 cases of the
combination of polymyositis with pulmonary disease, were published (319, 553,
948). [Again there are problems of definition. Some of the patients appeared to have
systemic sclerosis. Ed.] In another, probably fortuitous occurrence, polymyositis
was described in conjunction with aplastic
anemia (528). In the discussion following
this report, it was pointed out that perhaps
one of the drugs which the patient had ingested (perhaps Probenecid) may have
been responsible for the aplastic anemia, or
that the coexistence of an occult neoplasm
(which was not demonstrated even at autopsy) could possibly have been respon{ible for the two coexistent diseases.
The existence of malignancy in conjunction with polymyositis and dermatomyositis
continued to be stressed-approximately
20% (75, 969, 974) of adult cases of polyrnyositis harbor coexistent malignancy of
somc type, generally a carcinoma. (See section 011 ‘Connective Tissue Diseases.”) An
additional case was reported with acute
monocytic leukemia (352) and one in conjunction with ovarian carcinoma and Ha-
shimoto’s disease (214). Remarkably, 3
cases of polymyositis in conjunction with a
thymoma were also described (673, 1087).
Speculations were made in one of these reports (673) about the existence of thymoma, polymyositis, and myasthenia gravis, and one wonders whether these myopathic conditions might be different expressions of autoimmune disease.
In one report (969) polymyositis was
classified into six distinctive types according to whether there was a presence or allsence of skin rash, associated malignancy,
or other disease.
The most satisfactory therapy available
for polymyositis and dermatomyositis was
corticosteroids, especially Prednisone (886,
969). Apparently the earlier the disease
was diagnosed and treatment started, the
more likely was a beneficial result to be
achieved (969). The majority of patients
with typical polymyositis and dermatomyositis responded to steroid therapy although continuous maintenance treatment
was needed. [Some of the reviewers are
not this optimistic. An appreciable number
of patients experience insignificant gains on
steroid therapy. Ed.] On the other hand,
those patients with associated malignancy
responded very poorly to corticosteroids
and many died of their muscle weakness
rather than directly from the effects of the
tumor. If the tumor could be discovered
and resected completely, a “cure” was possible but, unfortunately, this has been a
rare event.
Psoriatic Arthritis
IS THIS A SEPARATE ENTITY?
Although it was held that there are no
universal clinical or radiological criteria by
which psoriatic arthritis can be differentiated from RA, certain clinical and serological features tended to differentiate the two
( 5 5 ) . There was general agreement that
the triad of inflammatory arthritis involving
148
RHEUMATISM AND ARTHRITIS
dermic psoriasis in association with arthritis
was noted to be 13%as contrastcd with
1%
in psoriasis cases alone.
The severity of the arthritis varied directly with the severity of the cutaneous
involvement in a group of patients with
“arthritis mutilans.” However, there was no
correlation with the extent and distribution
of nail involvement ( 5 5 ) . The mode of onset and number of joints initially involved
was not found to be materially different
from rheumatoid arthritis. Significant
morning stiffness occurred in 55% and
acroparesthesias in 38% of patients. Terminal interphalangeal joint involvement occurred exclusively in only 4 to 11%and in
association with other joint involvement in
about 30%of patients in 2 series (55, 709).
Pain and limited motion of the cervical
spine occurred in 16 of 53 patients and was
associated with radiological evidence of sacro-iliitis in 11 ( 5 5 ) .
Radiological findings in 169 patients with
CLINICAL FEATURES
seronegative psoriatic arthritis were comThe ratio of women to men in a group of pared with 149 seropositive rheumatoid
53 patients with psoriasis and arthritis was subjects. There was not much difference in
found to be 5.5 to 1, contrasted with 3 to 2 the incidence of osteoporosis or osteoarthrofor psoriasis subjects without arthritis. Ele- sis. Erosions were approximately equal in
ven had “arthritis mutilans” (severe osteo- the two groups although distal joint erolytic disease) in which no sex difference sions occurred in 43.7% of patients with
was noted ( 5 5 ) . In another group of 94 psoriatic arthritis and 12.8%of rheumatoid
patients with psoriatic arthritis, the sex ra- subjects and exclusive terminal interphatio was approximately one (709). Psoriasis langeal joint involvement occurred in 10%
preceded the onset of arthritis by 2 to 4 of psoriatic arthritis patients versus 0.8%
years in 64% of 53 patients and simultane- for RA subjects. Sacro-iliac involvement
ous onset of skin and joint manifestations was seen in 3.6%of psoriatics versus 12.9%
occurred in approximately 25% of cases for rheumatoid patients (709). In another
( 5 5 ) .Arthritis preceded skin manifestations series erosive sacro-iliitis occurred in about
in one series by 6 to 25 years in 13%( 5 5 ) 30% of 53 patients with psoriatic arthritis
and in 23% of patients in another series ( 5 5 ) . A specific cervical lesion was de(709). It was suggested that seronegative scribed in a radiographic study of the spine
RA (especially in patients with family his- in 52 psoriatic patients, 18 with psoriatic
tory of psoriasis) may later prove to be arthritis and 34 without arthritis. Findings
psoriatic arthritis (55, 708). The extent of were compared with a control group withcutaneous involvement varied from trivial out joint or skin involvement matched for
to generalized exfoliative psoriasis. How- age and sex. Apophyseal sclerosis was
ever. the incidence of generalized erythro- found in 35% of the psoriatic subjects and
the terminal interphalangeal joints (often
with adjacent nail involvement), psoriasis
and a seronegative test for the R F formed
a distinctive though relatively uncommon
syndrome which clearly was different from
RA. The arthritis in other psoriatic patients
which more closely resembles rheumatoid
disease (often without terminal interphaInngeal joint involvement) has been separated from RA rather arbitrarily on the
basis of negative tests for RF. [Both forms
of seronegative arthritis are referred t o as
“psoriatic”in this section, although there is
much disagreement on this point. Ed.] Patients with polyarthritis, psoriasis, and RF
have been considered by most authors to
have RA and psoriasis occurring independently (55, 122, 708, 709) [although the
incidence of these t w o diseases in the same
patient appears to he greater than would
he anticipated on the basis of chance alone.
Ed.].
149
PSORIATIC ARTHRITIS
15% of controls, apophyseal joint narrowing usually involving more than one level
in 46% of psoriatics and 27% controls and
anterior ligamentous calcification in 19%
versus 6% of controls. The incidence of
these alterations surprisingly was found not
to be statistically different in psoriatic patients with or without arthritis. The findings were similar to those seen in ankylosirig spondylitis although none had clinical
evidence of lower spine involvement. Xrays of sacro-iliac joints in a separate group
of 50 patients with psoriasis alone were entirely normal (636).
FAMILY STUDIEiS
Forty per cent of 60 patients with psoriatic arthritis had close relatives with psoriasis, 13 had 2 or more affected relatives, 4
had 3 or more and 2 had 4 or more. Ten
patients had a psoriatic parent and in 2,
both parents had psoriasis. Ten per cent of
I85 siblings of the 60 propositi had psoriasis. Of 11 propositi with psoriatic parents,
24.6%of their siblings had psoriasis-a frequency four times that found in siblings
without psoriatic parents. The familial incidence of psoriasis in patients with arthritis corresponded to that described in families of patients with uncomplicated psoriasis ( 5 5 ) . Of 16 patients with polyarthritis,
a11 of whom had one or more close relatives
with psoriasis, 15 had consistently negative
Waaler-Rose tests, and 3 had psoriasis. One
of the patients had erosive arthritis predominantly involving the terminal interphalangeal joints, the absence of psoriasis
and a negative Waaler-Rose test, possibly
representing psoriatic arthritis without skin
involvement (56). [A likely possibility
since arthritis may precede psoriasis in approximately 10 to 25% of patients with
psoriatic arthritis. Ed.]
A possible link between psoriasis and
keratosis hlennorrhagica of Reiter’s syndrome was suggested. Of 12 patients with
psoriatic arthritis, one had coincident psori-
asis and Reiter’s syndrome. The remaining
11 manifested both types of skin lesions in
a temporal relationship which seemed more
than chance. The striking similarity clinically and histopathologically in psoriasis
and keratosis blennorrhagica was re-emphasized (1372). Episcleritis and conjunctivitis were noted in 14 of 53 patients (55).
Sacro-iliac and spinal changes “indistinguishable” f r o m ankylosing spondylitis
were observed in a patient with psoriasis
and aortic insufficiency (1391).
LABORATORY FINDINGS
Serum protein determinations in 50 patients showed hyperglobulinemia in 56%.
Abnormalities in serum electrophoretic patterns were characterized chiefly by elevation of alpha-2 and gamma globulin levels
in 44% in 23 patients. Hyperuricemia was
noted in 20%of 45 patients (55).
Incidence of positive Waaler-Rose and
latex tests was determined in 3 groups of
patients: Group A, 104 cases of psoriatic
arthritis, Group B, 140 cases of RA without
psoriasis and Group C, 80 cases of uncomplicated psoriasis. The results were as follows: in Group A, Waaler-Rose 12.2 and
latex 16.8%,Group B, 69.3 and 85.7% and
Group C, no positive test with either test.
[For reasons unknown, patients with uncomplicated psoriasis in some studies have
not shown the usual 5% ‘‘false positive” latex test seen in the general population.
Ed.] No patient with psoriatic arthritis involving exclusively the terminal interphalangeal joints had a positive test and only 1
of 22 patients with terminal interphalangeal joint plus other joint involvement
had a positive Waaler-Rose test. Seven of
22 patients with psoriasis and arthritis excluding the terminal interphalangeal joints
had positive Waaler-Rose tests (708). Of
60 patients with psoriasis and polyarthritis,
7 had positive tests and were considered to
have both diseases for this reason ( 5 5 ) .
[This is an arbitrary distinction with limita-
150
tions considering the clinical and radiographic similarities of psoriatic arthritis and
RA and the vagaries of serological testing.
Ed.] Several seropositive rheumatoid arthritis patients with subcutaneous nodules
subsequently developed psoriasis. No
change in the titer for the RF or in the
appearance of the nodules was noted (55,
709).
Anti-staphylococcal alpha toxin ( ASTA)
and antistreptolysin ( ASL-0) antibodies
were determined in 100 patients each with
psoriatic arthritis and uncomplicated psori,isis. Elevated ASTA was found in 24% of
psoriatic arthritis and in 11%of uncomplicated psoriasis patients. The percentages
for ASL-0 were 19 and 24, respectively.
Stnphijlococcus aweus was cultured from
the ukne in 7%of the patients with psoriatic arthritis, suggesting to the authors that
occult staphylococcal pyelonephritis might
be of significance (893). [ T h e relevance
of these observations to psoriasis seems remote. Further investigations of possible
rend disease in these patients were not reported. Ed.]
RHEUMATISM AND ARTHRITIS
tients responded to re-treatment after relapse. Employment of this form of treatment was not recommended in patients
with mild disease because of the serious
risks of hematopoietic and hepatic toxicity
(122). Two reports dealt with the use of
the folic acid antagonists, aminopterin and
methotrexate, in the treatment of uncomplicated severe psoriasis. Although favorable results were observed in two-thirds to
four-fifths of patients, serious side effects
occurred ( 1026, 1090). [Dermatologists
seem to have more enthusiasm for the use
of folic acid antagonists than rheumatologists. Ed.]
Reiter’s Syndrome
CLINICAL FEATURES AND COURSE
Reiter’s syndrome continues to be recognized as a clinical triad of arthritis, urethritis and conjunctivitis occurring almost
exclusively in males usually in the 20 to 40
year age group (863, 1000, 1369). The literature of Reiter’s disease in childhood was
reviewed together with a case report of the
illness in a 10 year old child. Iritis and kerTREATMENT
atitis occurred more frequently in children
The possibility of precipitating acute ex- and were more severe than in adults. Diarfoliative psoriasis with administration of rhea was a prominent feature of Reiter’s
anti-malarial drugs was mentioned (55, disease in children (881). Rare instances of
122). [The frequency of this response of the syndrome were reported in women
psoriatic subjects to anti-malarial therapy is (267, 1000, 1369). Some authors accepted
probably not great but the risk of exfoli- the diagnosis of Reiter’s syndrome in the
ative dermatitis, albeit small, outweighs the presence of nonspecific urethritis and arthriequivocal benefit of treatment. Ed.] Re- tis without eye manifestations especially
sults of treatment with corticosteroids were if typical mucocutaneous lesions were prenot considered encouraging in view of the sent (1000, 1369). The importance of the
tendency for relapse after discontinuation mucocutaneous involvement as a manifesand the relatively large dosage required to tation of Reiter’s syndrome was re-emphacontrol skin and joint manifestations (122). sized (863, 1369, 1372). Concomitant gonIn a double blind study, improvement in orrheal infection was noted in 20 of 82 pahoth skin and joint manifestations was tients (1000) and in 23 of 51 patients
noted after aminopterin treatment (1 to 3 (1399). [ N o instances of Reiter’s synmgm per kilogram body weight, admin- drome were reported in which gonococci
istered at lO-day intervals) : Remission last- were recovered from the synovial fluid,
ing 1 to 3 months was observed and pa- however. Ed.] Gross hematuria was noted
151
REITER’S SYNDHOME
as the presenting manifestation of Reiter’s
syndrome in a woman (267 ) .
A retrospective comparative study of
gonococcal arthritis and Reiter’s syndrome
was presented (1369). The development of
postgonococcal rheumatoid arthritis was
considered rare in this series (1 of 152 patients). Features of Keiter’s syndrome
which were not characteristic of gonococcal
arthritis were the predominance of nail involvement, polyarticular involvement at the
onset, less pyrexia, infrequent upper joint
involvement and commonly heel and lumbar spine involvement and the symmetrical
nature of the peripheral arthritis. Migratory
arthritis, tenosynovitis, monoarticular arthritis and infrequent recurrences were more
commonly associated with gonococcal arthritis. Mucocutaneous involvement manifested by keratosis blennorrhagica and circiriate balanitis were found only in patients
with Reiter’s syndrome. Ocular complications occurred in 22 of 51 Reiter’s subjects
as compared with 5 of 101 patients with
definite or probable gonococcal arthritis
(1369).
Radiological bone alterations were noted
in 15%of patients at the time of their first
examination and first attack (1000) and
were present more frequently after repeated recurrences. Sacro-iliac alterations
were present in 10 of 81 cases (1000) and
in 31%of patients in another series (1369).
Attention was directed to the unusual type
of “calcific bridging” of the lumbar spine
seen radiographically in Keiter’s syndrome.
Unlike the ordinary osteophyte, this
“bridge” arose from the lateral surface of
tlie vertebral body some distance away
from the end plate. It was not part of the
annulus of the intervertebral disc (863).
The similarity between the cutaneous involvement in Reiter’s syndrome and that
seen in psoriatic arthritis was demonstrated
110th clinically and histologically ( 1372).
Lcsions of keratosis blennorrhagica and
manifestations of psoriasis elsewhere on the
body were noted to develop in a temporal
relationship that suggested more than
chance occurrence. In this series of patients, mucous membrane involvement was
not mentioned but there was a high incidence of ocular manifestions and sacroiliac joint involvement ( 1372). The occurrence of the mucocutaneous lesions in Reiter’s syndrome ( keratosis blennorrhagica)
occurring 8 years after onset of classical RA
along with other manifestations of Reiter’s
syndrome was considered evidence that
Reiter’s syndrome is not a variant of RA
(1134). [One of the reviewers has seen
patients with classical Reiter’s syndrome
with cutaneous involvement u h o recovered
completely except for the persistence of
chronic skin involvement that was indistinguishable from psoriasis. Other patients
had typical rheumatoid spondylitis and
later deueloped a superimposed acute attack of Reiter‘s syndrome. A third group of
patients had typical Reiter’s syndrome with
cutaneous involvenient unrl developed
chronic articular involvement that ioas indistinguishable clinicallty aizcl by synodal
biopsy from RA. A si finificant percentage
of Reiter’s patients will develop chronic
spondylitis resembling rheumatoid spondylitis. The relationships between psoriatic
arthritis, R A with psoriasis, and Reiter’s
syndrome require further definition. Ed.]
The occurrence of aortic insufficiency in
patients with Reiter’s syndrome has recently been re-emphasized (1054, 1372,
1391). Two fatalities in Reiter’s syndrome
were due to heart disease (1054, 1372). A
third fatality was due to necrosis of the
gastric mucosa and massive gastric hemorrhage (298).
ETIOLOGY AND PATHOGENESIS
A venereal origin for Reiter‘s syndrome
was suggested by the frequent concomitant
occurrence of gonorrheal urethritis ( 1000,
1369). Although an infectious origin has
been suggested, no definite etiological
152
agent has been identified. Virus culture
studies in non-gonococcal urethritis (45 paticnts ) failed to locate cytopathic changes
in cc~ll lines and egg cultures were uniformly negative (876). Of 203 men with
urethritis, 117 had uncomplicated gonorrhea and 22 had gonorrhea additionally
aysociated with Mycoplasma (PPLO). An
additional 64 men had non-gonococcal urethritis, 33 of whom had the T-strain Mycoplasma. In 30 of these 33 men, this organism was the only Mycoplasma recovered in culture. The incidence of joint involvement was only 0.5%in the total of 203
men in the study and no articular involvement was noted in the group of patients with the T-strain associated non-gonoccal urethritis ( 1146). Extensive microbiological studies in Reiter’s disease including
the search for viruses and Mycoplasma in
body fluids and synovial tissues yielded essentially negative results. In this study Mycoplasma, however, were cultured from
synovial tissues in one patient with Reiter’s
syndrome and intracellular granules resembling large bodies were seen in the
synovial tissues of a second patient but the
cultures were negative in this instance.
Complement fixation tests for Mycoplasma
were negative in 9 patients with Reiter’s
disease including the 2 in whom synovial
tissue was thought to have shown Mycoplasma (234).
There has been renewed interest in the
possibility that Mycoplasma may be associated with articular disease. Variouy species of Mycoplasma cause arthritis in several animal species and they are intimately
associated with non-gonococcal urethritis
(1137). Isolation and characterization of
Mycoplasma (PPLO) from patients with
RA, SLE and Reiter’s syndrome were recently reported ( 7 2 ) . Tissue culture methods were employed utilizing specimens
from synovial fluid, bone marrow, kidney
or blood. In 14 of 17 patients, positive cultures were obtained ( 3 of whom had Reit-
RHEUMATISM AND ARTIIRITIS
er’s syndrome). Only minor antigenic
differences among the strains were demonstrated except for one strain which appeared culturally and antigenically distinct.
Growth inhibition against several recognized human Mycoplasmae was demonstrated. [ Confirmation of these findings
has not yet been reported. There is a distinct possibility that the isolated organisms
were contaminants but it has stimulated
renewed interest in the possible relationship between Mycoplasmnl infection and
joint disease. Ed.] Circulating antibodies
were demonstrated in Reiter’s syndrome
and ankylosing spondylitis against an antigen prepared from healthy human prostate
gland. Significantly different results were
obtained with antigens from human liver
and kidney tissues. RA sera tended not to
react with any of the three antigens (476).
PATHOLOGY
Clinico-pathologic study of a fatal case
of Reiter’s syndrome showed cytotoxic degenerative changes in many organ systems.
There was severe degeneration of the
spleen, liver, muscle and lymph nodes together with inflammatory changes in the
synovial membrane and cutaneous lesions
consistent with Reiter’s syndrome. It was
postulated that pleomorphic gram-positive
micro-organisms in the gastric mucosa seen
at postmortem on histological examination
were Mycoplasmae ( 298). [Cultures of the
gastric mucosa were not obtained. I t seems
unlikely that the organisms were Mycoplasma inasmuch as these are grnm-negative, sub-microscopic organisms usually
recognizable only by colony morphology.
Ed.]
Arthritis Associated With Inflammatory
Intestinal Disease
WHIPPLE’S DISEASE
Arthropathy was described in 64 of 95
cases with typical histological changes of
Whipple’s disease (85 males and 10 fe-
SJ&:REN’S
153
SYNDROME
males) (659). The arthritis usually con- sixth patient. Three of the 6 patients had
qisted of an acute, intermittent and often associated peripheral arthritis. Radiological
migratory polyarthritis which was followed evidence of sacro-iliitis was present in a toby varying periods of complete remission. tal of 18 of the 91 patients; however, 2 of
Residual articular changes were only rarely these had psoriasis and 1 had had Reiter’s
vncountered.
syndrome. In only 2 of the patients did
LABORATORY
EXAMINATION.
Serum pro- symptoms of ankylosing spondylitis anteteins in SS patients showed no abnormalities date those of the bowel disorder. (See secSPONDYLITIS.
) There
in 22; 8 had increased globulins in the gam- tion on ANKYLOSING
inti range and 25 patients shcwzd a low alwas no relationship between the activity of
himin. None of the patients with low al- the bowel manifestations and joint sympbumin showed an elevated serum globulin. toms. The arthritis tended to be self-limitPeroral jejunal biopsy showed typical find- ing and did not lead to clinical deformities.
ings of Whipple’s disease. Rectal biopsy as The peripheral polyarthritis preceded the
well a s examination of peripheral and re- bowel symptoms in only one patient ( 3 3 ) .
gional mesenteric lymph nodes showed Two additional instances of ankylosing
pclriodic acid-Schiff positive staining gran- spondylitis associated with regional enteritis
ii1t.s characteristic of Whipple’s disease.
were described. Maintenance steroid therSynovial fluid analysis in one patient apy in the form of methyl-prednisolone
showed large vacuolated macrophages. The acetate provided relief of the arthritis
total white cell count was 6,000 per cm (1205).
with a differential count showing polys
30%. lymphs 17%, macrophages 48%, syn- ULCERATIVE COLITIS
[There has been no new data of signiovial cells 4% and plasma cells 1%.The
mucin test was within normal limits. Cul- ficance. The rheumatic manifestations of
ture was negative. Synovial biopsy showed ulcerative colitis parallel, in general, those
mild hyperplasia, some increase in vas- of Regional Enteritis. Ed.]
cularity in subendothelial tissues and peri- MISCELLANEOUS
v‘iscular cuffing with lymphocytes (210).
Malabsorption syndrome with peroral jeTREATMENT.
Improvement on corticosterjunal biopsies consistent with non-tropical
oids previously reported was confirmed and
sprue were described in 2 patients with
significant improvement resulted from treat“collagen disease.” One of the patients had
ment with tetracyclines given over profindings consistent with polymyositis
longed periods (210, 659).
( 1258).
REGIONAL ENTERITIS
Thirty-three of 91 patients with regional
ciiteritis had symptoms related to the joints
at some time. The polyarthritis tended to
he mild and migratory resolving without
residua but frequently recurring, Occasionally it was severe enough to warrant steroid
therapy. In 2 patients the arthritis was associated with erythema nodosum. Ankylosing spondylitis was diagnosed clinically
and confirmed radiologically in 5 of the 91
pitients and was thought to be present in a
S jogren’s Syndrome
CLINICAL FEATURES AND COURSE
The vast majority of patients with keratoconjunctivitis sicca had neither signs nor
symptoms of salivary gland involvement,
rheumatoid arthritis or other connective tissue diseases. Since eye involvement is an
unusual initial manifestation of Sjogren’s
syndrome, it was re-emphasized that keratoconjunctivitis sicca per se should not be
considered the hallmark of Sjogren’s syn-
154
tlrome. On the basis of findings in 52 p a tients, criteria were proposed for the diagnosis of Sjogren’s syndrome. Major criteria
included objective evidence of RA, keratoconjunctivitis sicca and salivary gland involvement. Minor criteria were history of
joint involvement compatible with RA, history of salivary gland swelling, history of
symptoms of keratoconjunctivitis sicca in
the absence of objective evidence of xerostomia. Definite Sjogren’s syndrome required three major criteria, probable Sjiigren’s syndrome required two major criteria and possible Sjogren’s syndrome required one major plus one or more minor
criteria (1285). In a series of 62 Sjogren’s
c:ases, 5 clinical sub-groups were recognized. Group A included those with definite or classical RA (30 patients), group B
patients with probable rheumatoid arthritis
(2 patients), group C cases with scleroderma (3 patients), group D cases associated with polymyositis (4 patients), and
group E cases of keratoconjunctivitis sicca
and xerostomia not associated with RA or
any other connective tissue or muscle disease (23 patients) (170). Patients in this
latter category showed a higher concentration of serum gamma globulin and a
greater frequency of diverse circulating antibodies to tissue and subcellular components (111,129, 170,265).
Female preponderance was consistently
observed. Fifty-four of 57 (129), 49 of 52
(1285), and 27 of 30 patients (265) were
females. A majority in one series experienced the onset of disease before the agk
of 30 (1285). Arthritis or arthralgia was the
most common initial manifestation (54%);
parotid swelling in 20% and keratoconjunctivitis in 10% were the presenting
symptoms (1285). Sicca components were
noted on the average 8 years later in patients whose disease began with joint involvement ( 129). Forty-seven of 52 patients (90%)related a history of arthritis or
arthralgia compatible with RA but only 29
RHEUMATISM AND ARTHRITIS
of the 52 had objective evidence of RA
(1285). None of 19 patients with Sjogren’s
syndrome in one study had arthritis (111).
[ T h e findings in this group of patients resembled those i n group E referred t o
above, emphasizing the importance of
categorizing patients into clinical subgroups. Ed.]
In a series of 280 unselected patients
with RA, keratoconjunctivitis sicca was
found in 58.4% and xerostomia in 14%.
Characteristic x-ray changes in the esophagus consisting of circular folds, web-like
structures and oropharyngeal membranes
in the upper part of the esophagus were
found in 26.6%of the patients. In 105 additional patients diagnosed as RA (roughly
one-third in each of stages 2, 3 and 4), it
was shown that the incidence of keratoconjunctivitis sicca, xerostomia and typical
x-ray changes in the esophagus increased in
accordance with the more advanced stages
of the disease (736). Three of four signs of
Sjogren’s syndrome were found in 12 out
of 90 rheumatoid patients in this study.
The sicca components were demonstrated
by objective examination and did not include symptomatic evidence for these components. [ I t was suggested from this
study that Sjogren’s manifestations i n RA
are far more common than has been recognized. Ed.]
Clinical findings in RA alone and in patients with Sjogren’s syndrome were compared (1285). The age at onset and the
incidence of anemia, eosinophilia, thyroid
enlargement, and subcutaneous nodules
were similar in the two groups. The striking differences were in the increased incidence of Raynaud’s phenomena, splenomegaly and leukopenia in Sjogren’s syndrome. [Though not specifically stated, it
would seem that these diferences occurred
primarily in the group of Sjogren’s patients
without RA, emphasizing again the value
of separating Sjogren’s patients into clinical sub-groups, particularly into those with
sJOGREN’S
155
SYNDROME
and without RA. Ed.] The clinical and
laboratory features in 4 patients with Sj6gren’s syndrome associated with a malignant lymphoma and one patient with
“atypical lymphoid infiltrates” suggesting
Wddenstrom’s disease were described.
Pour of these patients exhibited splenomegaly, vasculitis and non-thrombocytopenic purpura. Two of the patients had low
levels of total globulin in association with
~~ascuXitis.
All had leukopenia. One of the
patients showed a progressive decrease in
gamma globulin from elevated to markedly
low levels during the year preceding the
diagnosis of reticulum cell sarcoma. The
KF and anti-tissue antibodies ultimately
disappeared in this patient (1237). Two of
62 patients with Sjogren’s syndrome developed an illness suggestive of pancreatitis. Secretin tests performed on 11 other
patients with Sjogren’s without clinical
evidence of pancreatic disease showed diminished volume of pancreatic secretion in
3 and a borderline secretion in one after
secretin injection (369).
In addition to the commonly recognized
signs and symptoms in Sjogren’s syndrome,
lower respiratory signs characterized by
pleural thickening or small effusions and
mottled pulmonary parenchymal infiltrates
near the lung bases were noted (129).
Chest roentgenograms showed inflammatory lesions at the bases or in the mid-zone
in 4 of 30 patients (265). A diastolic murmur at the base was present in 3 of 52
patients. KA was present in 2 of these and
possibly sclcroderma in the third ( 1285).
Kccurrent, non-thrombocytopenic purpura
with and without hyperglobulinemia was
observed ( 129).
Vasculitis, at times histologically resembling polyarteritis nodosa, was observed
in skin and muscle biopsies in patients
without associated hypergammaglobulinemia. Thrombocytopenic purpura occurred
in one patient ( 1285). Splenomegaly was
noted in 13 of 62 cases, 6 of whom had
associated RA. The remainder were in the
group without associated connective tissue
disease ( 129).
Associated connective tissue diseases in
addition to those already mentioned included scleroderma in 3 of 50 patients and
SLE in 2 of 50 (1285). Raynauds phenomena were observed in approximately
20% of patients and appeared to be more
common in the group without RA or other
connective tissue diseases ( 129, 265, 1285).
A clinical diagnosis of Hashimoto’s thyroiditis was considered in 2 of 10 patients
(1285). Thyroid enlargment was noted in 6
of 60 (129) and 6 of 30 patients (265)
without clinical evidence of thyroid disease.
PATHOLOGICAL FEATURES
Pathological criteria for the diagnosis of
Sjogren’s syndrome (based on salivary
gland biopsies of unequivocal cases) were
expanded to permit diagnosis even in the
absence of epimyoepithelial transformation
of intralobular ducts. Other changes consisted of extensive lymphocytic and lymphoid tissue infiltration simulating neoplasm on one hand and, on the other extreme, massive replacement of atrophic
parenchyma by adipose tissue with little or
no lymphoid infiltration. Vasculitis was observed in skin and muscle biopsies from 7
patients, 3 of whom had arteritis histologically resembling polyarteritis nodosa without clinical evidence of that disease (129,
170). Similarities in certain pathological
features in the parotid and thyroid glands
were noted (170). Lesions resembling
Waldenstrom’s macroglobulinemia in 1 patient and reticulum cell sarcoma in 3 patients were observed. The histological
changes of malignancy were present in
lymph nodes and organs exclusive of the
salivary and lacrimal glands. The lymphomas developed predominately in the
group of patients who had Sjogren’s syndrome without RA, or other connective tissue disease (1237).
156
RHEUMATISM AND ARTHRITIS
LABORATORY FEATURES
ETIOLOGY AND PATHOGENESIS
Anemia in 25 to 40% of patients, persistent leukopenia in 14 to 30%, and eosinophilia approaching 20% were observed
( 129, 265. 1285). Hyperglobulinemia with
hypergammaglobulinemia occurred in u p
to 40% of patients. Hypergammaglobulinemia was approximately twice as common
in patients with the sicca complex alone
(129). Serological tests for the RF were
positive in all but one of 62 patients (129).
Antinuclear factors were detected by the
indirect immunofluorescent technique in 31
of 44 sera examined. L.E. cells were demonstrated in approximately 10%of patients
in one series and in only 2 of 50 patients in
another (129, 1285). All patients with salivary gland enlargement or a history of such
had precipitating antibodies against salivary gland components and complement
fixing antibodies to salivary gland in high
titer were observed in 4 of 7 patients examined (265). A “specific antibody” against
the epithelium of salivary ducts was demonstrated in sera from patients with Sjogren’s syndrome. In addition to nuclear
fluorescence, there was cytoplasmic fluorescence in 11 of 19 Sjogren’s sera demonstrated by the immuno-fluorescent technique with tissues from the parotid, submaxillary and sublingual glands. Similar
cytoplasmic fluorescence was seen with
sera from 4 of 16 SLE patients. Sera showing positive nuclear fluorescence in salivary
tissue also showed nuclear fluorescence on
sections of thyroid tissue, but cytoplasmic
fluorescence was never found in thyroid tissue utilizing Sjogren’s sera (111). Thyroid
antibodies were demonstrated in 30% of
patients (129). The tanned red-cell test for
thyroglobulin antibodies was positive in 16
and negative in 14 patients. Precipitating
antibodies to thyroglobulin were found by
the agar gel method in 10 patients. Antibodies reactive with thyroid antigens were
studied with complement fixation techniques (265).
A possible genetic basis for Sjogren’s
syndrome was suggested by family studies.
The prevalence of RA, positive Schirmer
tear tests, abnormal circulating antibodies
to thyroglobulin and elevated levels of
gamma globulin were significantly greater
in first degree relatives of patients than in
control relatives. The frequency of these
findings in relatives other than parents,
siblings, or children was consistently intermediate between that of first degree relatives and controls (129). Family histories
of 30 Sjogren’s patients suggested an increased incidence of RA in relatives (265).
The occurrence of antibodies to multiple
tissue components, the pre5ence of RFs in
almost all cases of Sjogren’s syndrome, the
frequent occurrence of lymphocyte and
plasma cell proliferation, hypergammaglobulinemia and possibly a familial predetermination all suggest that an abnormal
immunological response may underlie the
pathogenesis of Sjiigren’s syndrome. Interestingly, the alterations in gamma globulin
and the diverse wrological abnormalities
were most prevalent in the group of Sjogren’s patients without RA or other connective tissue diseases. [This paradox raises
questions concerning the pathogenic significance of so-called auto-antibodies in the
production of R A and other syndromes.
(See section on CONNECTIVE
TISSUE
DISEASES
-GENERAL CONSIDERATIONS.
) Ed.]
TRESATMENT
The administration of corticosteroids resulted in improvement in the associated RA
and other connective tissue diseases but
had no definite therapeutic benefit on the
keratoconjunctivitis sicca or the xerostomia
(265). Subjective benefit was attributed to
hydroxychloroquine therapy ( 533j. Objective phenomena, however, tended not to
vary, except for the sedimentation rate
which returned to normal after 6 months in
7 of 9 patients.
157
OTHEK TYPES OF AHTHHITIS
Neurotrophic Arthritis
Two relatively large series of neurotrophic arthropathy were reported. In
on(. series of 45 cases, 40 had diabetes, 3
hvphilis, 1 traumatic neuritis and 1 alcoholic neuritis (233). In the second series of 52
cases, 37 had tabes dorsalis, 10 syringoinyelia, 4 diabetes mellitus and 1 an injury
to the. sciatic nerve (1213). In a case of
Charcot’5 arthropathy due to neurosyphilis
thrrc wa5 severe polyarticular involvement
including not only the commonly involved
\wightbearing joints but also arthropathic
changes of the elbows, wrists and hands
which had rarely been described previously
( 88 ). Secondary staphylococcal arthritis
complicated otherwise typical Charcot
joints in 4 patients (1213). A neuropathic
degenerative arthritis of the knee joint developed in a patient with congenital inwnsitivity to pain (2).
Emphasis was directed to the occurrence
ot perforating ulcers of the feet in patients
11 ith neurotrophic arthropathy. Although
the appearance ot the ulcers suggested an
inflamniator!, infcctious origin, roentgenogram\ ot the feet demonstrated absorption
of bony, a pencilling of the metatarsal
shaft, fracture of metatarsal heads, destructiori and obliteration of joints, disarticulatioii of phalanges and/or periosteal thickening remote from the ulcer site. At times xray changes were not evident until 6
months after cartilage was first rejected via
skin ulcers (233). Varying degrees of sensory impairment were noted in patients
with neuroarthropathy especially in those
due to diabetes (1048). Mild neurological
deficits were sometimes associated with
severe neurotrophic changes.
The pathogenesis of Charcot joints was
studied ( 1213). Although the mechanical
theory of causation could explain most of
the observed phenomma, it was suggested
that there was involvement of some vasomotor mechanism. It was not certain
whether the postulated vasomotor disturbance was nervous in origin or whether
blood supply was compromised by local
pressure. An active phase of the disease
was described in which the onset was acute
and the joint rapidly destroyed. Radiologically the bone developed a sclerotic and
chalky appearance with cyst formation. At
a later stage when the disease was stable,
the joint became hypertrophic, the bone
pattern reformed and the sclerotic appearance was lost. The nature of the inflammatory episodes occurring in the
course of Charcot arthritis was not identified. Biopsy examination of synovial
membranes from a patient with polyarthritis due to neurotrophic arthropathy showed
no proliferation of the lining layer of
synovial cells and only a few scattered cells
characteristic of inflammation in the subsynovial layers. There was very little evidence of an inflammatory reaction of the
synovial membrane. Perivascular focal cell
infiltration was noted in some of the synovial villi.
TREATMENT
Excision of the bony structures underlying ulcerations of the foot was recommended in patients with neurotrophic
arthropathy and ulceration (233). Successful arthrodesis of a Charcot knee was
accomplished in a patient with congenital
insensitivity to pain (88). Relief of weightbearing with casts for the foot and braces
for the knees was also recommended (233).
Other Types of Arthritis
ARTHRITIS IN HEMOCHROMATOSIS
It was suggested that some patients with
hemochromatosis have a specific arthritis,
and 2 illustrative cases were presented
(1118). The arthritis had persisted for
years in both patients; in one patient pain
and stiffness without obvious synovial
swelling had been prominent, whereas, in
the other, fusiform swelling of the proximal
158
interphalangeal joints was noted. Roentgenologic changes, most marked at the interphalangeal joints of fingers included
generalized osteoporosis with and without
periarticular accentuation and irregular articular surfaces, subchondral cystlike regions, periarticular bony proliferation, and
irregular narrowing of joint spaces. The
arthritis seemed to have involved, at least
symptomatically, most of the peripheral
joints at some time in one or the other of
the 2 patients. Synovial tissue from the
knee of each patient showed hemosiderin
in the synovial lining cells, with little or
none in the deeper synovial tissue and
without synovial proliferation or inflammation, but similar findings occurred in synovial tissue from hernochromatotic patients
without arthritis.
RUBELLA ARTHRITIS
Synovial fluid from the knees of 5 patients with acute polyarthritis associated
with rubella revealed: lower concentration
of protein (1.9 to 3.4%)than that found in
rheumatoid arthritis, a predominance of
mononuclear cells with almost complete
absence of polymorphonuclear cells, and
high viscosity. In these patients the arthritis
developed a few days after the rash ( 3
cases), before the rash ( 1 case), or concomitant with the rash ( 1 case); sedimentation rates were normal or relatively low,
and results of flocculation tests for rheumatoid factor were negative. Small joints
were more commonly involved (215). Both
arthritis and erythema exudative multiforme developed in another patient after
rubella (413).
EPIDEMIC POLYARTHRITIS
Results of serologic tests indicated that
epidemics of polyarthritis with rash occurring in several Australian communities in
1961 and 1962 probably were related to infection with group A arthropod-borne
viruses; strain T48 may have been closely
RHEUMATISM AND ARTHRITIS
related, if not identical, to the causative
agent (310). In an Indian family of British
Columbia with a predisposition to rheumatic disease, 4 members experienced a severe but self-limited polyarthritis and 4
other siblings noted severe temporary arthralgias after a flu-like illness that seemingly did not lead to rheumatism in other
families in the community ( 1005).
ACROMEGALIC ARTHROPATHY
Pain and swelling of joints, for years misinterpreted as rhsumatoid arthritis, dominated the symptomatology in a patient
with acromegaly. After the removal of an
eosinophilic adenoma of the pituitary, the
swelling and much of the articular pain
disappeared from peripheral joints, but the
hip, the site of marked degenerative and
hypertrophic changes, continued to interfere significantly with walking. Overgrowth
of cartilage susceptible to degenerative
changes was suggested to be the main factor in production of the arthropathy (454).
PIGMENTED VILLONODULAR SYNOVITIS
Case reports described radiological features of pigmented villonodular synovitis
(740,1028).
In a patient with pigmented villonodular
synovitis of the knee, contrast arthrography
demonstrated a markedly enlarged, distorted suprapatellar bursa with numerous
recesses and filling defects. An arteriogram
revealed hypervascularity with no vessel
displacement, slight arteriovenous shunt,
vessels of varying caliber, and diffuse contrast “stain,” a pattern which easily could
be confused with arteriographic findings in
malignant tumors ( 1028). Pigmented villonodular synovitis and tenosynovitis involved the peroneal tendons and synovial
membrane of the ankle in 1 patient, the
peroneal tendons in a second, and the
flexor tendon and synovial membrme of the
distal interphalangeal joint of the index finger in a third, Possible differentiation of
pigmented villonodular tenosynovitis from
OTHER SYNDROMES WITH RHEUMATIC MANIFESTATIONS
the common giant cell tumor of tendon
sheaths on the basis of gross appearance
and anatomic location was suggested
( 853). The roentgenographic appearance in
pigmented villonodular synovitis included
lohiilated soft tissue densities which resembled those seen in synovioma and chonclrosarcoma. Villonodular synovitis sometimes caused cystlike radiolucencies in
bone, but in most patients the bones and
joints appeared normal and no calcification
of synovial tissues was evident on roentgenograms (722).
HEMARTHROSIS
Aspiration of joint fluid in 15 patients
who had simple contusion of the elbow revealed hemarthrosis in 14, but such aspiration was recommended only for those with
severe pain and marked limitation of motion (421).
Other Syndromes With Rheumatic
Manifestations
Sarcoidosis
Twelve patients (all Negroes) were observed in an arthritis clinic during an 18month period (114). Ten presented with
objective evidence of arthritis in 2 or more
joints and the remaining 2 gave a history of
polyarthralgia at the onset of symptoms. A
review of the literature confirmed that arthritis is a common and early manifestation
of sarcoidosis. In 95 cases reviewed, 3 general types of arthritis were seen: (1) migratory polyarthritis with erythema nodosum,
fever and hilar adenopathy, (2) single or
recurrent bouts of polyarticular or monoarticular arthritis with or without a migratory component, ( 3 ) persistent polyarticuJar or monoarticular arthritis. The first type
was associated with a good prognosis and
complete remission was the rule. Eventual
deformity of the joints was not uncommon
in the latter two types. [In patients with
prythpma nodosum, it is often dificult to
know if pain in joints such as knees, ankles
159
and feet results from arthritis or from the
soft tissue inflammation that characterizes
the erythema. Ed.] Arthritis in patients
with cutaneous sarcoidosis or radiographically demonstrable pulmonary parenchymal sarcoid tended to be more chronically disabling than in those without these
associated lesions. There was no correlation
between joint disease and the clinical evidence for sarcoid involvement of other systems. Only rarely was the chest x-ray normal in patients with sarcoid arthritis (637).
Carpal tunnel syndrome was noted in 2 patients with sarcoidosis. One had coexistent
psoriasis and the other had mild diabetes
mellitus ( 1135).
Of 12 patients with sarcoidosis and arthritis, 5 had skin lesions compatible with
sarcoidosis, 1 had subcutaneous nodules of
the Dariar-Roussy type, 3 had widespread
ichthyosis and 2 had erythema nodosum. In
this series, 8 patients had generalized
adenopathy peripherally and hilar adenopathy was noted in 9. Radiological skeletal survey showed no abnormalities apart
from narrowing and sclerosis of the radial
articular surfaces of the wrists in 1 patient
(114). In 95 cases of sarcoidosis with
arthritis reviewed from the literature, skeletal x-ray changes were observed in as many
as one-third of patients but a 15 to 20%
incidence was considered more representative. Bone and joint alterations were demonstrated more commonly in patients with
persistent joint symptoms than in those
with recurrent polyarthritis. Chest x-rays
were abnormal in 70 of 79 patients reported in the literature. Deforming arthritis
was found in 45% of patients with parenchymal lesions in contrast to 17%of those
with hilar adenopathy alone (637). [A
good TeaSon for making a chest x-ray part
of the diagnostic work-up of any patient
with arthritis. Ed.]
PATHOLOGY
Open synovial membrane biopsies were
obtained from 6 patients (114). In the
160
chronically involved joint, biopsy revealed
only a non-specific chronic synovitis with
no evidence of granulomatous formation.
I n contrast, the S more acute cases demonstrated marked synovitis with hyperplasia and some hypertrophy of the lining
cells, but no villus formation. Subsynovial,
noncaseating, discrete granulomata were
seen. One patient with severe acute arthritis originally considered to be infectious arthritis of 5 weeks’ duration had the most
marked granulomatous involvement of the
4ynovium. The synovial lining cells had
completely disappeared and multiple granulomata covered by a few strands of fibrin
tormed the joint surface. Necrotizing arteritis W‘IS dernonstr,ited in a biopsy of purp l i 5 h , non-tender nodular lesions on thc
lower legs of one patient (638).
LA BOKATORY INVESTIGATIONS
Positive latex fixation tests were noted in
association with hypergammaglobulinemia
(114). There were no new reports of hypcruricernia in association with sarcoidosis
and arthritis.
TREATMENT
Three additional patients with sarcoidosis and arthritis were treated with colchicine (638). Full therapeutic doses of
colchicine administered to 2 of the patients
with acute sarcoidosis arthritis resulted in
prompt amelioration of fever and joint
pains. In one patient, skin lesions appeared
to regress. The third patient had had
chronic arthritis for 4 years’ duration in addition to vasculitis demonstrated by biopsy
of the skin. Clinical evidence of vasculitis
which developed in this patient together
with joint pains apparently responded to
maintenance colchicine therapy. Upon sub4titution ot a placebo for the colchicine,
there was recurrence of joint pains within 1
week which again were relieved by the reinstitution of colchicine after 10 days. None
of the 3 patients had hyperuricemia.
RHEUMATISM AND ARTHRITIS
Behcet’s Syndrome
CLINICAL FEATURES AND COURSE
A broader clinical spectrum of the
“mucocutaneous ocular syndrome” (originally characterized by recurrent oral and
genital ulceration and relapsing iritis ) has
evolved, resulting in earlier and more frequent recognition of Behcet’s multiple
symptom complex. Reports of sporadic
cases appeared from widely separated geographical areas of the world (215, 747, 875,
1081, 1113, 1222). Eighty-five cases were
observed in Japan (945) and 28 cases in
Lebanon (789). The disease was more
common in males and the onset occurred
most frequently in the 20 to 30 year age
group, although rarely it occurred in children and the aged. Two brothers were ohserved with the disease (789).
The disease tended to be chronic and
progressive with exacerbations and remissions (789, 945). The onset was associated
with fever and generalized weakness, at
times; following repeated episodes of
pharyngitis. Six months to 5 years (range
of 1 month to 15 years) usually elapsed
before the appearance of all the mucocutaneous-ocular symptoms. Arthritis or
arthralgia preceded, coincided with or followed the triad (1215). Aphthous ulcerations of the oral mucosa usually preceded
genital ulcerations and eye involvement.
The latter included iritis (often with hypopyon), choroiditis, chorioretinitis, and
retinal and macular hemorrhages. Erythema nodosum was observed in up to onethird of the cases (789, 945, 1215). Other
cutaneous manifestations included various
forms of pyoderma.
Articular involvement was observed in 54
of 85 cases (945). Arthralgia and more often arthritis, frequently with effusion, involved the knees, ankles, elbows and wrists.
The smaller joints were affected less often.
Koentgenographic alterations were rarely
seen. The articular involvement tended to
161
OTHER SYNIIHOMES WITH RHEUMATIC MANIFESTATIONS
be episodic, at times migratory but was
chronic in some patients ( 1215).
Thrornbophlebitis was considered an essential feature of the disease (789). Central
nervous system involvement was a late and
iiifrequent manifestation of the illness and
w;is usually fatal (1081, 1113, 1222). Multiple cranial nc‘rve palsies, seizures, organic
mental syndromes, extrapyramidal signs
m d manifestations of meningo-encephalitis
wew encountered. Involvement of the
peripheral nervous system was not describc‘d. Carditis (747) and gastrointestinal
symptoms (diarrhea, abdominal pain, abdominal distention and tenderness associated with roentgenographic abnormalities of the small 1)owel) (945) were observed.
I’ATWOI,OGY
Postmortem examination of the central
iiervous system revealed low grade diffuse
ineningo-encephalitis with severe destructive focal lesions. The appearance was
thought to be consistent with a viral etiology (1081). Biopsies of aphthous oral and
5crotal ulcers showed polymorphonuclear
cell infiltration at the base of ulcers and a
lymphocytic reaction in deeper layers.
Viere was perivascular infiltration with
lymphocytes and plasma cells and endothelial proliferation in some instances.
The pathological changes observed in 5
enucleated eyes showed essentially a perivascular infiltration with lymphocytes and
plasma cells and foci of polymorphonuclear
cells, monocytes and macrophages. All of
the eye structures were involved but the
lesions were most marked in the uveal tract
(789). Panvasculitis and endothelial proliferation obliterating lumina together with
vascular thrombi were noted in scrotal,
nxillary and buccal ulcer biopsies (875).
ETIOLOGY
A n autvirrrriiurir etiology was suggested
because of hypergammaglobulinemia ob-
served in 77%of cases and the demonstration of autoantibodies against oral mucous
membrane utilizing a tanned-cell hemagglutination test in 43%of 40 cases (945). A
possible virus etiology of Behcet’s disease
was reported from Egypt (875). Scrapings
from scrotal and oral ulcers showed epithelial intranuclear inclusion bodies and a
virus was isolated from the blood and from
scrapings of the scrotal and buccal ulcers as
well as from hypopyon fluid after inoculation of specimens on chorio-allantoic membranes. Virus neutralization tests were confirmatory. Antigen prepared from infected
chorio-allantoic membrane was used in a
complement fixation test on 4 sera from patients with Behcet’s disease. Positive titers
up to 1:32 were reported. [Although viral
isolations have been reported sporadically,
this is apparently the first observation of
inclusion bodies. This report should stimulate further virologic studies. Ed.]
Results of corticosteroid treatment have
been equivocal considering the tendency
for spontaneous exacerbations and remissions. A favorable neurological course was
reported in a severely ill patient with neurological manifestations treated with high
steroid dosage (1113).
Schonlein-Henoch Syndrome
A group of 131 children admitted during
an 8-year period from 1955 to 1962 with
this syndrome was studied (121). The incidence was strikingly increased over that
noted previously from this childrens’ hospital in England. The duration of illness
varied from 6 to 16 weeks. Two of the patients died, l from renal and cerebral complications and the other from pulmonary
infarction and peritonitis. In addition to
joint pains (especially of large joints), abdominal pain, vomiting, malaise and
anorexia were noted. Rash developed 2 or 3
days after the foregoing symptoms. The
larger joints were primarily involved.
162
RHEUMATISM AND ARIHRITIS
Headache was noted in 43% of the patients. Renal involvement occurred in
nearly half of the patients within the first
month of the illness. In some it was associated with hypertension and was manifested by albuminuria and cylinduria.
Cerebral complications resulting from arteriolitis of the cerebral vessels was noted
in one patient (121).
Treatment with corticosteroids in 14 patients was considered ineffective. Empirically, prevention of streptococcal infection
was undertaken with the use of penicillin
and less commonly broad Fpectrum antihiotics. The prognosis is usually good.
Kashin Beck Disease
This disease is a chronic, disabling, degenerative generalized osteoarthrosis involving symmetrical peripheral joints and
spine usually unassociated with systemic or
visceral manifestations. It occurred principally in childhood and resulted in severe
growth disturbances. It has been observed
endemically in eastern Siberia, northern
China and northern Korea and was believed to be due to ingestion of a cereal
grain infected with the fungus, Fusaria
sporotrichiella. Soviet authors distinguished
three degrees of the disease related to the
age of onset and severity of joint involvement. In its most severe stage there was
involvement of all of the articulations with
limitation of movement, articular pain and
rnuscle atrophy. There was also marked reduction in height and shortening of the
fingers and extremities.
Thc author quoted animal experiments in
which a comparable disease was produced
in puppies by the feeding of grain contaminated with the suspected fungus
(905).
[ T h e recognition of a type of genwalized osteoarthrosis due to environmental factors and unrelated to genetic factors or inborn errors in metabolism is o f
considcvahle importance. W e will probably
hear more about mycotoxic syndromes.
Ed.]
Gout and Gouty Arthritis
Prevalence and Geographic Distribution
The average prevalence of gout in a
number of European and North American
populations was less than 0.3% (654). Two
reports indicated that, contrary to traditional teaching, gout was not a rare disease
in Brazil (140, 242). Of more than 43,000
rheumatic patients reported from various
Brazilian cities, 2.43% had gout. In Vancouver, British Columbia, there appeared
to be a greater than expected prevalence of
gout in Chinese males (392).
Unusual Clinical Manifestations
A case report described a 33 year old
truck driver, with two previous episodes of
podagra, who presented with persistent
dull aching pain in both hips unresponsive
to colchicine administration ( 1356). Open
biopsy was performed with demonstration
of urate deposits in the synovial tissue. A
36-year old woman with tophaceous gout
was reported to have developed a saltwasting renal disease with azotemia during
her tenth pregnancy (80). The occurrence
of recurrent acute pericarditis in 2 patients
with definite, and one with suspected, gout
suggested that pericarditis might be of
gouty origin (966). The unusual case of a
54-year old gouty male with chronic
hoarseness was reported (938). At autopsy
a large tophus was imbedded between the
true and false vocal cords.
Renal Involvement Associated with
Hyperuricemia and Gout
A review was presented of the relationships between gout and kidney disease
(1305). A male infant (age 7 weeks) developed renal failure and was found to be
markedly hyperuricemic (1064). The renal
manifestations responded well to hydration
GOUT A h D <:OtJTY ARTHRITIS
163
and alkalinization of the urine. A subse- SECONDARY GOUT
Of 101 patients with polycythemia Vera,
quent metabolic study was performed in
14
( 9 males and 5 females) presented cliniwhich the patient was found to incorporate
cal
evidence of gout (299). Only one of
increased amounts of N1>-glycineinto urinary uric acid. Evidence of gout was pres- these subjects had a positive family history
ent in the maternal and paternal families. of gout. The case of a 13-year old Negro
[A very iriteresting case. The evidence boy with acute lymphatic leukemia and asclearly favors a primary overproduction of sociated hyperuricemia, acute gout and reuric acid with secondary renal involvement. nal failure was reported (1327). The demonstration of an elevated serum uric acid
Ed.]
level
in the father raised some doubt as to
The uric acid nephropathy associated
whether
the patient’s gout was truly seconwith acute hyperuricemia was investigated
in 26 patients with leukemia (1035). The dary.
Five of 6 patients with severe renal
condition was rapidly reversible with
vigorous hydration and urinary alkaliniza- failure maintained by periodic hemodialtion with acetazolamide (Diamox) and yses were observed to experience acute atsodium bicarbonate. It was emphasized tacks of arthritis or peri-arthritis (195). Althat the renal deposits in leukemic cases though urate crystals were not demonconsist of uric acid, generally in amorphous strated, it was considered that the clinical
form (1129). Thus, it WAS considered prop- evidence favored a gouty basis for these
er to use the term uric acid nephropathy attacks. Four patients developed, in addito distinguish the condition from the urate tion, x-ray evidence of soft tissue calcificanephropathy (crystalline deposits of uric tion attributed to renal phosphate retention. Examination of material from one
acid salts) associated with primary gout.
Several studies concerned the renal subcutaneous nodular lesion revealed no
ef€ects of induced hyperuricemia in ex- urate crystals and suggested that hyperimental animals. The intravenous ad- droxyapatite was the major component.
ministration of uric acid to dogs and rats [These patients might have had chonwas shown to produce blockage of the dis- drocalcinosis (pseudogout) or something
tal convoluted and collecting tubules with related t o it. Ed.] Study of a group of
dilatation of the more proximal tubules patients with chronic renal disease revealed
(325). When lithium urate was infused into that gout occurred in about half of those
dogs, renal urate concentrations increased considered to have lead nephropathy but
from cortex to medulla to papilla (348). was infrequent in those with renal disease
With large urate infusions the papillary tis- of other etiologies (339).
sue concentration was equal to or exceeded ETIOLOGY AND PATHOGENESIS
that in the urine. In spite of the high tissue
HEREDITARY
STUDIES.Collected data from
concentrations achieved, microscopic ex- several European and North American
amination failed to reveal any visible urate studies indicated a prevalence of gout
deposits. The renal accumulation of urate among relatives of gouty probands of apdid not correlate well with urinary urate proximately 5%, as compared to less than
concentration or with total urinary urate 0.3% for control populations (654). The
excretion but was roughly proportional to genetic implications of distribtion curves of
plasma levels. Diuresis induced by water serum uric acid concentration in several
loading or mannitol administration ap- population samples were reviewed, and the
peared to prevent urate accumulation in potential importance of environmental as
medullary tissue.
well as genetic factors stressed.
164
iin 18 year follow-up study of 19 families
of propositi with gout revealed an increased prevalence of hyperuricemia and
gout among the relatives of gouty subjects
( 1016). IIyperuricemia appeared to become manifest in males after adolescence
and in females after the menopause. In
both sexes hyperuricemia, once manifest,
appeared to persist and to subject the individual to an increased risk of developing
clinical gout.
PATHOGENESIS
OF HYPERURICEhlIA. A comprehensive and authoritative review of uric
acid metabolism and of the multiple pathways by which hyperuricemia might be
produced was presented (1129).
OVERPRODUCTION.
In a study of incorporation of glycine-Nlj into urinary uric acid, it
was found that subjects with primary gout
incorporated a disproportionately large
amount of isotope into the N-9 and N-3
positions, both of which are derived from
the amide nitrogen of glutamine, and excreted a lesser amount of ammonium-N15
in the urine (488). These findings implied a
defect in the urinary production of ammonia from glutamine, possibly a deficiency of glutaminase. Such a defect, it was
hypothesized, might enhance the first irreversible and apparently rate-determining
reaction in de nouo purine biosynthesis, the
enzymatic reaction of glutamine with 5phosphoribosyl-1-pyrophosphateto form 5phosphoribosyl-l-amine. It would also
further predispose to uric acid stone formation by producing a more acid urine. [ A
recent report (997) of glutaminase activity
in homogenates of renal biopsies showed
no decrease i n 4 gouty as compared t o 6
nongout!~subjects. Ammonia excretion following a measured load of ammonium
chloride was within normal limits i n the
gouty subjects, one of whom was a marked
hyperexcretor. Ed.]
DECREASED
RENAL EXCRETION. Renal
handling of uric acid was compared in
gouty and nongouty subjects under three
RHEUMATISM AND ARTHRITIS
sets of circumstances: first, hyperuricemic
gouty subjects versus nongouty controls
made hyperuricemic by administration of
urate precursors for periods of 3 to 42 days;
second, renal urate excretion in gouty and
nongouty subjects in response to a rise in
plasmic urate concentration produced by 3
days of oral urate precursor loading; and,
third, similar to the second, except that the
nongouty subjects were hyperuricemic as
the result of prolonged ribonucleic acid ingestion before they were given the additional 3-day load (929). In each situation
most gouty subjects demonstrated impaired
renal urate clearance and excretion as
compared to the controls. A different interpretation was placed on the results of
these and other studies of renal uric acid
excretion in gouty and nongouty subjects in
an editorial review (487). It was suggested
that the relatively low clearance of uric
acid in normal man and other species lacking uricase protects the kidney from the
threat of excessive urinary uric acid excretion. The generally lower urate clearances
observed in hyperuricemic subjects were
viewed, by this interpretation, not as abnormal glomerular or tubular retention but
rather as a normal renal response to endogenous hyperuricemia.
The Dalmatian coach hound appeared to
have a generalized defect in a specific uric
acid transport system (524). [ T h e extension of such studies t o normal and gouty
human subjects might be profitable. Ed.]
The occurrence of increased blood lactate levels, hyperuricemia and clinical gout
in 2 of 3 siblings with glycogen storage disease of the glucose-6-phosphatase deficiency type was reported (575). In such
cases the lacticacidemia was responsible for
the diminished renal excretion of uric acid
and resultant hyperuricemia.
PATIIOGENESIS
OF ACUTE ATTACKSAND
CHRONIC
MANIFESTATIONS.
Urate salts were
directly implicated in the pathogenesis of
acute attacks and tophaceous deposits
165
GOUT A S D GOUTY ARTHRITIS
(1129). The hypothesis that the acute attack represented an inflammatory response
to the local precipitaion in joint tissues of
monosodium urate crystals was reviewed.
Synovial fluid lcukocytes, as a consequence
of increased phagocytic and metabolic activity. were considered to produce increased amounts of lactic acid, thus lowering pH and tending to maintain the cycle
of urate crystallization and inflammatory
response. The pH of canine joint fluid decreased by about 0.5 units within 6 hours
after injection of urate crystals (821). The
successful production by Freudweiler in
1899 of inflammatory lesions in man and
experimental animals by the injection of
crystalline sodium urate was recalled
(821), and a translation of this investigator’s classic but long-ignored account of his
studies on the nature of gouty tophi was
presented (164).
The injection of microcrystalline adrenocorticosteroid esters into normal human
and canine joints induced a sterile inflammatory process which was occasionally
painful in the humans but generally asymptoniatic in the dogs (823). Th‘is was regarded as the basis for the occasional “postinjection flare” following therapeutic intraarticular injection of these compounds,
which was considered an iatrogenic example of “crystal-induced synovitis.”
The formation under certain in vitro conditions of highly supersaturated solutions of
uric acid in plasma and protein-free solutions was described (1129). Tophaceous
gout was rarely encountered until serum
urate levels rose to values consistently
higher than 8 mgm per 100 ml. It was suggested that local decrease in pH and temperature might be factors favoring urate
deposition in characteristic sites. In an in
vitro experiment, it was found that the
solubility of sodium urate in solutions of
rhondroitin-4-sulfate decreased as the concentration of the latter substance was
raised (719). X-ray diffraction studies con-
firmed previous reports that the urate deposits in gouty tophi were monosodium
urate monohydrate, while a urinary stone
from a gouty patient was composed primarily of uric acid (587).
LABORATORY DATA
URIC ACID DETERMINATIONS.
An automated modification of the carbonate colorimetric method for measurement of uric acid
was described (268). Reproducibility appeared good, and there was little interference from added salicylate, ascorbic acid or
glucose. In a study comparing results obtained in measurements of uric acid content
of three standard sera in 36 centers in Great
Britain, it was concluded that the colorimetric autoanalyzer technique was the “method
of choice” for routine examination of large
numbers of samples (189). The uricase
spectrophotometric method was recommended for investigational or special projects. The importance of maintaining rigid
quality control was emphasized and it was
suggested that each laboratory establish its
own normal ranges for men and for preand postmenopausal women. An evaluation
of the normal range of urate levels, based
on colorimetric measurements in 100 male
and 100 female subjects without evidence
of renal disease or a family history of gout,
suggested that 7.0 mgm per 100 ml and 5.7
mgm per 100 ml were satisfactory upper
limits of normal (340). The importance of
understanding the statistical basis for establishment of the “normal” range, and the
wisdom of obtaining several determinations
in evaluating a patient for hyperuricemia,
were stressed (1316). Measurement of
plasma uric acid levels in a small group of
French schoolboys age 6 to 17 showed an
increase which correlated better with body
weight and urinary creatinine than with
age or height and was therefore thought to
be related to muscular development and
male hormone production (552).
Several reports were concerned with uric
166
acid levels in individuals of varying racial
or ethnic backgrounds. In British Columbia
the mean serum uric acid level of Chinese
males (5.44 mgm per 100 ml) was significantly higher than the mean for Caucasian (4.55) or Haida Indian (4.41) males
(392). In a comparative study of serum
uric acid levels in Arab villagers, Bedouin
natives and 3 Israeli population groups, it
was concluded that the observed differences were probably related to nutritional,
and perhaps other environmental factors
(315).
Evidence was presented of a relationship
between social class and uric acid levels
(326). Executives were found to have a
mean level of 5.73 mgm per 100 ml as
compared to 4.77 mgm per 100 ml for a
group of craftsmen. Examination of serum
uric acid levels of high school students revealed some relationship with intelligence
and participation in extracurricular activities, but not with the social class of the
family.
Study of 5 obese female subjects during
a total fast of 3 to 10 days revealed a mean
maximal rise of plasma uric acid concentration to 13.7 mgm per 100 ml (891). Glomerular filtration rates decreased so that
there was no increase in urinary urate excretion. In these subjects hyperuricemia
appeared prior to qualitative detection of
ketonemia or kentonuria. [ I t was subsequently demonstrated that infusion of kstone bodies interfered m5th the r e n d excretion of uric acid and it was postulated
that “starvation ketosis” mediated the hyperuricemia or starvation (732, 1126).
Ed.] The association of hyperuricemia and
hyperparathyroidism was reported in 11
patients, 5 of whom also had clinical gout
( 1125). Decreased glomerular function was
thought to be only a contributory factor,
the postulated primary mechanism being a
renal tubular lesion secondary to calcium
deposition. Kadiologic evidence of nephrocalcinosis was prcsent in 6 patients.
RHEUMATISM AND ARTHRITIS
[Thus there is ezjidence linking hyperparath!jroidism t o hyperuricemia and gout as
a e l l as t o chondrocalcinosis (pseudogout).
Precise identification of crystals in such
cases is essential. Ed.] It was found that of
105 hypertensive patients subjected to
adrenalectomy and sympathectomy, 11 developed clinical gout and 67% of 56 who
were tested were hyperuricemic ( 602). Hyperuricemia appeared to be on the basis of
decreased renal excretion and was thought
not to be related to adrenal insufficiency or
thiazide therapy. A small group of 16 male
and 9 female mongoloids, age 2 to 12, were
found to have significantly higher serum
uric acid levels than a comparable group of
no-mongoloid mentally retarded children
(837).
A case report described a patient who
developed, after 4 years of chlorothiazide
therapy, hyperuricemia and clinical gout
followed shortly by hyperglycemia and
coma (1121). The effect of chlorothiazide
on renal excretion of uric acid in the
chicken was studied (205). Active tubular
secretion of chlorothiazide occurred, and
was inhibited by the concurrent administration of uric acid, suggesting that both
substances competed for the same transport system. It was demonstrated in man
that oral administration of 40 grains of
acetylsalicylic acid daily produced a mean
fall in serum uric acid level of 1.1 mgm per
100 ml, whereas 20 grains daily effected a
mean rise of 1.4 mgm per 100 ml (1004).
Pyrazinamide-induced hyperuricemia was
shown to he inhibited by the daily administration of 2.4 gm acetylsalicylic acid
(984).
Gouty subjects were found to have
greater uric acid clearance and excretion
values when symptomatic than when
asymptomatic (50). This WAS attributed in
part to increased production of uric acid
associated with leukocytosis and in part to
uricosuria induced by increased secretion
of adrenal steroids.
GOIT
A N D c;oui-Y
ARTHRITIS
167
SYNOVIALFLUIDFINDINGS.
Enumeration findings might be of significance in view of
of the total leukocyte count and percentage the apparent frequent association of gout
of polymorphonuclear cells served to dif- and vascular disease.
ferentiate gouty effusions from those of
DIAGNOSIS
traumatic origin and those associated with
The cardinal features for the diagnosis of
pyogenic infection (1180). Of much greater
acute
gout were the characteristic clinical
significance was the demonstration of urate
course, hyperuricemia, and a typical
crystals, often within leukocytes, in acute
response to colchicine or phenylbutazone
gouty effusions (819, 1390). Such crystals
were seen in 141 of 150 fluids from 109 (1180). [A response t o colchicine is of
more value. Phenylbutaxone has a broader
gouty patients, but in none of 792 fluids
anti-rheumatic efect. Ed.] A family history
from 591 patients with nongouty arthritis,
of gout, demonstration of hyperuricemia in
even though ,S7 of them were hyperuricea near relative, or association with recmic (821).
ognized precipitating factors were other
SERUMTRIGLYCERIDE
AND CHOLESTEROL
helpful features. The demonstration of
LEVELS.Serum triglyceride levels were
intra- or extra-leukocytic urate crystals in
found to be significantly elevated in 34
synovial fluid was regarded as pathoggout patients as compared with 28 control
nomonic (818, 1390).
subjects (367). No significant differences in
serum cholesterol or lipoprotein profile TREATMENT
An intriguing illustrated historical acwere noted, and there appeared to be no
correlation between uric acid and cho- count of early measures employed in the
lesterol levels in either group. The possi- treatment of gout was presented ( 1052).
ACUTEGOUTY
ARTHRITIS.
Prompt adminisbility of linkage of the genetic factors concerned with uric acid and triglyceride me- tration of colchicine to the point of relief of
tabolirm was suggested. A study of 50 pa- pain, onset of gastrointestinal side-effects,
tients with normal lipid values, 100 with or to a total dose of 6 mgm in one day was
hypercholesterolemia (of whom half also advised (936, 1023). The case report of a
had hypertriglyceridemia), and 25 with young male who developed vascular purgout also suggested a close correlation of pura following colchicine therapy of an
serum uric acid with levels of triglycerides, acute olecranon bursitis was presented
but not cholesterol (103). A study of (1170). Phenylbutazone, 600 to 800 mgm
fluctuations in serum uric acid and cho- on the first day, followed by 300 to 400
lesterol levels in a small group of 14 pa- mgm daily for two additional days (936),
tients with cardiovascular disease examined or 400 to 600 mgm daily for 4 to 6 days
weekly for 6 to 10 weeks was reported (1023), was regarded as equally effective.
( 1112). An apparent correlation was found ACTH and corticosteroids were seldom inbetween the direction and magnitude of dicated. Griseofulvin, although effective,
change of the two substanceq. Evidence possessed no advantage and was not recwas presented that sulfinpyrazone therapy ommended (936).
It was suggested that colchicine interexerted a cholesterol-lowering as well as a
rupts the cycle of urate crystallization by
uricosuric effect ( 695).
A decrease in platelet survival and in- inhibiting phagocytosis and the resultant
crease in platelet turnover were described increased local production of lactic acid
in male gouty patients (894). In vitro stud- (1129).
INTERCRITICAL
PERIOD.Therapy during
ies turther suggested an increased thromhoplastic activity. It was thought that these the intercritical period was related to the
168
frequency and severity of acute attacks, and
to the extent of tophaceous deposits
(1023). Colchicine (0.6 to 1.2 mgm daily)
was described as a useful and safe agent
for prolonged prophylactic use. Uricosuric
drugs were employed to prevent acute attacks, reduce the serum uric acid level to
normal, and prevent or ameliorate the
complications of the disease.
CHRONIC
TOPHACEOUS
GOUT.A valuable
historical account of the evolution of present day uricosuric drugs appeared (486).
It was emphasized that use of these agents
should be “in judicious balance with other
modalities of prevention and treatment”
and should not lead to overliberalization of
the diet. [Some of the reviewers favored a
simplified regimen in which dietary restrictions are minimized. Avoiding foods with
high purine content makes sense but a patient on uricosuric therapy has little to gain
by restriction of protein. Ed.] Indications
for uricosuric therapy were stated to be
frequent acute attacks with persistent hyperuricemia of 8 mgm per 100 ml or
higher, progressive chronic gouty arthritis,
and demonstrable tophaceous deposits
(936). The opinion was expressed that too
much emphasis was sometimes placed on
uricosuric drugs for prevention of acute attacks and not enoilgh on colchicine or combined therapy (486). [Editors agree.]
The uricosuric effect of dicumerol was
confirmed (222). Little enthusiasm was expressed for the use of large doses of salicylates to achieve uricosuria (936, 1023).
Probenecid and sulfinpyrazone were generally recommended, several authors regarding the latter drug as preferable (694,
1023). [There would seem t o be relatively
little busis for preference of one agent over
the other. Both are efective uricosuric
agents with gratifying small risk of serious
toxicity. Ed.] A pharmacologic study indicated that probenecid was rapidly and
almost completely absorbed from the gastrointestinal tract and had a half-life rang-
RHEUMATISM AKD ARTHRITIS
ing from 4 to 17 hours (285). Less than 5%
of the unchanged drug was excreted in the
urine in 24 hours, indicating the probable
formation of unknown metabolites.
Results of uricosuric therapy for periods
of one year or longer in 114 cases of tophaceous gout were reviewed (486). Initially,
39% had advanced, extensive deposits,
33% moderately advanced, and 28% only
one or two visible tophi. After therapy, 73%
had minimal or no apparent tophi. [This
enviable result may be related in part to
more stringent dietary restrictions of purine
and, in many cases, protein foods. Ed.]
Symptoms of chronic gouty arthritis in
these patients were slowly relieved or improved in almost all instances. The chief
causes of failure were inability to achieve a
uricosuric effect despite adequate dosage in
subjects with renal failure; insufficient drug
dosage because of carelessness, drug intolerance or precipitation of urate calculi;
immoderation in diet; and inaccessibility of
some deposits, presumably because of poor
vascularization.
Administration of sulfinpyrazone in doses
ranging from 50 to 800 mgm daily to 229
patients with primary gout was reported to
have lowered serum uric acid levels to 6
mgm per 100 ml or less in 85% of males
and 96% of females (694). Tophi decreased significantly in size in 27 of 39 patients. Mild side-effects, chiefly gastrointestinal, occurred in 13.9% but required
discontinuance of therapy in only 2.6%.
Eight patients (3.5%) experienced acute
exacerbations of gout in the early weeks of
treatment. No instances of rash or hematologic complications were recorded. These
investigators, in a separate communication
(695), presented evidence of a cholesterollowering effect of sulfinpyrazone in a random sample from this group of gouty patients. This was regarded as of possible
benefit because of the relationship of gout
to atherosclerotic disease. It was demonstrated that in man, but not the dog, there
GOUT AND GOUTY ARTHRITIS
was suppression of the uricosuric effect of
sulfinpyraLone by salicylate and vice versa.
(1379). The two drugs were found to compete for binding sites on plasma proteins as
well as for renal tubular transport. Probenecid and, to a lesser extent, sulfinpyrazone
were shown to inhibit tubular secretion of
phenolsulfonphthalein, an effect to be considered when evaluating renal function of
patients on these agents (911).
HEMODIALYSIS.
Multiple hemodialyses
were employed in the treatment of a gouty
subject whose renal impairment rendered
him unresponsive to uricosuric therapy
(324). It was possible by this means to reduce the miscible pool to about half of its
pretreatment value; some of the smaller,
superficial tophi disappeared and acute attacks were decreased in frequency during a
follow-up period of 6 months.
DRUGS
INTERFERING
WITH URICACIDFORMATION. A brief review of therapeutic
agents interfering with the formation of uric
acid appeared (293). Azmerine (O-diazoacetyl-I-serine) and DON ( 6-diazo-5-0x0-Inorleucine), which interfere with the utilization of glutamine, the nitrogen donor in
the transformation of formyl-glycinamide
ribotide into glycinamidine ribotide, were
described as too toxic for clinical use. Orotic acid, thought to act by interference with
utilization of phosphoribosyl-pyrophosphate, was found to decrease serum uric
acid levels significantly without increasing
urinary excretion and with a concomitant
decrease in urinary uric acid in some cases.
Most recently, 4-hydroxypyrazolo (3 4-d),
pyrimidine has been demonstrated to inhibit the action of xanthine oxidase resulting
in decreases in serum and urinary uric acid
values. The latter drug, the generic name
of which is allopurinol, was first employed
in the treatment of leukemic disease because of its ability to suppress the oxidation
of 6-mercaptopurine to 6-thiouric acid
( 1088). The compound ( a potent inhibitor
of xanthinc oxidase) was capable of pro-
169
ducing marked reductions in serum and
urinary uric acid levels. The relatively
small increase in urinary excretion of the
oxypurines, xanthine and hypoxanthine, in
comparison to the larger decrease in urinary uric acid excretion suggested a suppression of de novo purine biosynthesis or
re-utilization of xanthine and hypoxanthine. This disproportion was also noted by
other investigators (496, 1380). [However, a more recent report described relatively little change in total purine excretion
with allopurinol administration (676).
Ed.] No untoward effects were described
relative to the rise in serum and urinary
oxypurine levels. Maintenance doses
ranged from 200 to 600 mgm daily (496,
1380). In one study, serum uric acid values
were reduced to less than 7.0 mgm per 100
ml in 70% of subjects given 300 mgm of
allopurinol daily and in “most” of those
given 400 to 600 mgm daily, urinary uric
acid values were reduced by about one-half
(1380). Some patients were observed long
enough to establish that tophaceous deposits could be arrested or reversed, a process that in some instances was facilitated
by the concomitant use of uricosuric drugs
(1380). The drug was effective even in patients whose renal damage rendered the
uricosuric drugs ineffective (496, 1380).
In general, the drug was well tolerated,
although an apparent ability to precipitate
acute gouty attacks was noted (496, 1380).
[A curious complication (precipitation of
acute gout) also observed with uricosuric
therapy. N o one seems t o know why it
happens. Ed.] Other side effects included
skin rash (496) and diarrhea (1380). The
report of a patient with xanthinuria and
hemochromatosis associated with a marked
decrease in xanthine oxidase activity in
liver tissue was presented (49). [This report raises the possibility of the interference with iron metabolism during
chronic allopurinol administration. There
are also reports, not yet i n print, of several
170
RHEUMATISM AND ARTHRITIS
instances of hepatic toxicity associated with
allopuririol therapy. Further experience will
be necessary t o assess the risks of longterm
therapy with this agent. A recent editorial
summarizes the current status of allopurinol (1375). Ed.]
Several reports were concerned with the
effects of “hepatocatalase,” an enzyme prepared from ox liver (61, 62). Administration of this preparation was reported to
lower serum urate and cholesterol levels
and to decrease urinary uric acid excretion.
Cholndrocalcinosis
The recently described syndrome of
chondrocalcinosis ( “pseudogcut” ) continued to be the subject of much interest.
The disorder occurred in both sexes, being
somewhat more frequent in males in one
series (822) and in females in another
( 1387). Rheumatic symptoms appeared in
middle or late life, the mean age at onset
being 53 years in one group of 27 cases
(822).
The most dramatic clinical manifestation
wa.; an acute, recurrent arthritis having
many of the characteristics of classic gout.
The large joints, especially the knees, were
involved, while the smaller joints were
spared. The degree of discomfort varied
from mild aching to excruciating pain.
Symptoms usually reached maximal intensity in 12 to 36 hours and persisted for
12 hours to 4 weeks (mean 8.6 days).
Acute attacks were sometimes associated
with systemic symptoms, including mild
fever, anorexia and weight loss (822, 1387).
Chronic joint symptoms indistinguishable
from those of osteoarthritis were present in
a majority of patients, and in some represented the only clinical manifestation. In
some instances characteristic radiologic
changes were present in the absence of any
history of rheumatic symptoms.
Diabetes mellitus, hypertension, atherosclerosis and arcus senilis occurred com-
monly in association with “pseudogout,”
but the significance of the associations was
unknown (822).
ETIOLOGY AND PATHOGENESIS
The occurrence of 21 cases among the
members of 5 families was regarded as evidence for the hereditary nature of the diseasz (1280). Pedigree analysis did not permit identification of the mode of transmission. Several subsequent reports described
2 or more cases within single families (822,
880).
Although the etiology was not known
(822), it was considered that the precipitation of crystals in cartilage might be the
result of a metabolic disturbance, possibly
an enzyme deficiency, rather than purely
local factors (820). The earlier report by
other investigators of production of calcium
pyrophosphate crystals by the hydrolytic
degradation of calcium polyphosphate gel
was quoted (820, 822), with the suggestion
that this mechanism might be involved
qiiice cartilage contains both calcium and
polyphosphates.
The presence of crystals was demonstrated in the synovial fluid, often within
leukocytes, in almost all acute attacks.
These crystals were identified as calcium
pyrophosphate dihydrate by infrared spectrophotometry, x-ray fluorescence and
emission spectroscopy (822). Crystals were
present in both monoclinic (needle) and
triclinic ( parallel-piped) forms, the latter
being predominant. They differed from
urate crystals in being weakly positively
birefringent under polarized light and in
resisting digestion by uricase. Crystals from
chronically involved joints were generally
extraleukocytic. Crystals teased from human postmortem fibrocartilaginous structures were identified as either calcium
pyrophosphate dihydrate or calcium orthophosphate dihydrate (820). Injection of
suspended microcrystals into joints of normal humans and dogs produced an acute
171
OSTEOAKrIIRlTIS
irihnmatory rclaction with phagocytosis of
crystals,
1,ABOIZATOIIY DATA AN11 DIAGNOSIS
Mild lcukocytosis and elevation of the
erythrocyte sedimentation rate and alpha-2
globulin fraction were sometimes observed
during the acute attack. Serum uric acid,
calcium, phosphorus and alkaline phosphatasc levcls were charactc.ristieally normal. In onc paticnt metabolic balance and
radioactivc calcium kinetic studies failed to
demonstrate any gross defect in calcium or
phosphorus metabolism (880). A “low excretion of androgen hormones” was reported in a 35 year old malc patient (843).
Hadiologic examination played an important rolc in diagnosis (609). Calcification was ryccially frcyuent in fibrocartilagenoils striictitrrs, including the,
mcnisci of thc knee, the articular disc of
thc distal radio-ulnar joint, the annnlus
fibrosus of thc intorvertebral discs arid the
syinphvsis pubis (819). Such deposits w ( w
usually synimctrical, whereas calcification
in articular cartilagc was often asyminctrical appcaring as a fine radio-opaque
line in thc superficial layers of the cartilage
(819). It was suggested that the following
roentgcnograms could be employed in
scrwning patic,nts for pseudogout: an anteroposterior vicw of cach knec,, an anteroposterior view of the pelvis and a posteroantc3rior view of both wrists ( 8 9 2 ) .
Diagnostic criteria and categories for the
syndromc were described (819). A definite
diagnosis rcquircd the demonstration in
synovial fluid or biopsy material of crystals
having the cliaractcristic x-ray dilfraction
pattern of calcium pyrophosphate. A probable diagnosis was based on the presence
of intra- or extra-leukocytic non-urate crystals in synovial fluid, or the characteristic
radiologic appcarancc of calcified cartilage.
A possiblc diagnosis should be suspected in
cases of acutc synovitis, or of chronic synovitis with acute cxacerbations, of the large
joints, especially the knees, in the face of
normal serum uric acid levels. The importance of ruling out hyperparathyroidism
in patients with cartilaginous calcification,
and ochronosis in patients with calcification
of the annulus fibrosus, was stressed (609).
TREATMENT
The acute attack of “psmdogout” was
stated to respond well to phenylbutazonc
or oxyphenbutaxonc in doses of 400 to 800
mgm daily (819). Some paticnts appeared
to be benefitted by colchicine therapy
(880), but others developed acute attacks
while taking colehicine to toxicity (819).
Thorough aspiration of the affected joint,
followed by injection of corticosteroids,
was reported to be successful (819). It was
recommended that the chronic symptoms
be treated with the same conservative moasurcs employed for osteoarthritis ( 819). No
measures were available to remove the crystalline deposits from the cartilage (819).
Alcaptonuria and Ochronotic
Arthropathy
A thorough review of the clinical, biochemical and pathologic aspects of the disease apparcd, based on analysis of 604
cascs in the world litcrature (932). A case
report emphasixod the fact that backache
and sciatica are frequent initial or early
manifestations of the disorder (374).
Osteoart hritis
GENEKAI,
Clinical aspects of osteoarthritis were rcviewed (115, 275, 523, 724, 1032, 1075).
Costovertebral joints commonly revealed
degcncmtive changes, especially at the
first, elevcnth, and twelfth vertebrae where
there are full facets; in the vertebrae with
hemifacets there was an increasing incidcnce of such change from the second to
about the seventh vertebra, followed by a
decreasing incidence through the tenth ver-
172
tebra. Upper hemifacets showed more
degeneration than did lower ones. These
changes, which increased with age of patient, were suggested to be the cause of
some instances of back pain, and intraarticular injections of steroids gave relief
RHEUMATISM AND ARTHRITIS
Koentgenogram of the cervical spinal
column in symptomatic and asymptomatic
patients with degenerative changes of cervical intervertebral d i s k s showed the
changes to increase with age of patient in
both groups and to be most marked at the
level of C5-6 and Cfi-7 spaces; although the
roentgenographic evidence did not provide
a good measure for estimating severity of
symptom? in individual cases, in the symptomatic group there was a greater incidence of degenerative changes at the
above mentioned levels (408, 409). Variations iii mobility of healthy cervical spinal
columns were attributed to differences in
extensihility of the controlling ligaments.
Disk degeneration was associated with progressive restriction of motion at the affected leF-el (60).
Patients with osteoarthritis (and those
with rhcumatoid arthritis ) were reported to
have less base excess in their diet than did
a group composed mainly of patients with
neurologic disease; their daily intake of vitamins and minerals also was below recommended amounts (333). [Of doubtful
significance. Ed.]
cartilage of the anterior surface of the
femur leads to degeneration of that cartilage. Preservation of the patella with capping of its articular surface by means of a
Vitallium mold was recommended in cases
of degenerative disease of the patellar cartilage requiring surgery (300). The intraarticular injection of radioactive gold was
reported to be effective in reducing synovial effusion and articular pain in 9 of 11
patients who had osteoarthritis of the knee
resistant to “orthodox” forms of treatment
(787). [Same study included patients with
RA. See elsewhere. Ed.] Triamcinolone
acetonide was effective when used intraarticularly for osteoarthritis (1123). [But
apparently no more so than steroids previously used. Ed.] Short-wave diathermy
was preferred to intra-articular injection of
steroids by one author (1371). [A moot
point which generally must be settled on
the basis of the circumstances of each case.
Ed.] Indomethacin, employed in a doubleblind study in doses of 75 to 100 mgmlday,
was found to give “significant” relief (less
pain, better abduction) in patients suffering from osteoarthritis of the hips, with
minimal adverse egects (1307). [This
drug currently is under intensive study in
many centers; its ultimate place in treatment of rheumatic diseases remains to be
determined. Initial reports are encouraging,
but much more experience is necessary in
order to assess its relative value. Ed.]
TREATMENT
HEREDITY
Considerable interest was expressed in
the value of osteotomy for treatment of
osteoarthritis of the hip (131, 370, 371,
679) and of the knee (1313). Various
standard measures of general treatment for
osteoarthritis were reviewed (131, 523,
1032, 1075). The importance of the patella
in proper function of the knee joint was
emphasized, and evidence was presented to
suggest that any operative procedure which
brings soft tissue in contact with articular
An extensive study of genetic factors in
generalized osteoarthrosis led to the conclusion that more than one common inherited factor may give rise to this condition; severe forms seemed more closely related to the occurrence of Heberden’s
nodes, whereas less severe forms were related to inflammatory, preponderantly
seronegative polyarthritis (653). A study of
800 patients with osteoarthritis of the
spinal column revealed a family history of
(902).
173
h ONARTlCULAR RHEUMATISM
“rheumatism” [type unspecified. Ed.] in
33.5%; women seemed more susceptible
than men to hereditary influences, and
transmission of the tendency seemed to occur more from father to son and from
mother to daughter than to members of the
opposite sex (903).
PATHOLOGY
Detailed microscopic study of the lumbar synovial (apophyseal ) joints revealed
some degenerative joint disease in 90% of
spinal columns in persons more than 45
years of age. The relation to aging and the
histologic pattern of osteoarthritis in those
joints was like that previously described for
osteoarthritis in other joints. The earliest
changes were detected in articular cartilage; latcr changes occurred in subchondral bone and joint capsule-a mixture
of degeneration and restoration but without pannus formation. Most marked
changes were found at L4-5 space, next
most at the lumbosacral space. No differentiation in the degenerative changes could
be made on the basis of sex (745). Study of
the cervical spinal columns of 41 cadavers
revealed small disk protrusions at 12 inters p e 1 - ‘ The
~
associated reactive osteophytosis was larger than the displaced cartilage.
The protrusions were posterior rather than
lateral. Roentgenographic changes at
Luschke’s processes and narrowing of the
intervertebral foramina were found to be
related to disk degeneration, but the
changes in the facet joints were not (408).
BIOCHEMlCAL STUDIES
Osteoarthritic cartilage contained decwa.;ed concentration of chondroitin sulfate and qualitative changes in the proteinpolysaccharide complex; the concentration
of collagen was unchanged (139). A prot ein-polysaccharide complex containing a
1:l ratio of chondroitin sulfate-C and keratosulfate was found in both the nucleus
pulposus and annulus fibrosus of human intervertebral disks. The limiting viscosity
number of this complex decreased gradually with age of normal subjects, and was
markedly lower in the complex obtained
from herniated disks. An insoluble complex
having considerable chondroitin sulfate-B
was found in normal disks of aged patients
and in all herniated disks (773). But in
another study, in which 60 specimens of
human cartilage were analyzed for collagen, mucopolysaccharide, sulfur, nonprotein nitrogen, and noncollagenous protein, there was no significant difference between these substances in normal cartilage
and in cartilage surrounding lesions of osteoarthritis. Until they reached the age of
40 years, patients showed a steady increase
in the collagen content of both types of
cartilage; the content decreased after that
age (25).
TEMPOROMANDIBULAR JOINT
A study of 40 patients who had symptoms referable to the temporomandibular
joints revealed normal joint surfaces by
routine roentgenograms but abnormal motions of those joints when visualized by
cineradiography. The abnormality was ascribed to “painful contractive muscle
spasm,” and it was “successfully” treated by
reassurance and exercises for muscles of
mastication ( 1310).
Nonarticular Rheumatism
Carpal Tunnel Syndrome
Causes, diagnosis, and treatment (mainly
surgical) of the carpal tunnel syndrome
were reviewed (774). The frequent occurrence of median nerve compression at the
wrist in rheumatoid arthritis was emphasized; surgical decompression of the nerve
often was necessary (801). A detailed
study of the anatomic relations of the
median nerve within the carpal tunnel was
reported (1042). The carpal tunnel syndrome was noted to result from acute
thrombosis of a persistent median artery
174
RHEUMATISM AND ARTHRITIS
(169, 179) and from rubella tenosynovitis
at the wrist (215).
WeherChristian Disease
In one patient with presumed WeberChristian disease, a nodular lipogranulomatous infiltrating lcsion was found involving
practically all the fat in the body except
subcutaneous fat (42). Oxyphenbutazone
was reported to have provided effective
suppression of the manifestations of WeberChristian disease in one patient (99).
ture of hydrocortisone, hyaluronidase, and
procaine into the calcareous deposit was
recommended treatment lor some patients
with calcific deposits at the shoulder
(1011). [In many instances calcific tendinitis may be asymptomatic and require
no treatment or may be managed by conservative measures such as physical therapy, simple analgesics, rest, and time. Ed.]
DeQuervain’s Disease
The feature of DeQuervain’s disease,
stenosing tenovaginitis at the radial styloid
Shoulder-Hand Syndrome
process, was reviewed, and 12 cases were
presented.
Surgical decompression was the
In 73 patients with shoulder-hand syndrome, the occurrence in 40%of associated most effective therapy. The tendon sheaths
cardiovascular disease, especially recent were found to be markedly thickened; the
myocardial infarction (18 patients, 25%), tendons appeared normal ( 1378). [This
was emphasized. The incidences of left- condition, frequently overlooked, is a relsided, right-sided, and bilateral involve- atively common cause of pain at the wrist.
ment were equal. Early treatment with Ed.]
physical therapy was recommended; other
Bursitis and Tendinitis
adjunctive therapy including stellate block,
Principles and details of the conservative
steroidal therapy, manipulation of the
management of bursitis and tendinitis were
shoulder under anesthesia, and roentgen
outlined; various combinations of rest,
therapy were mentioned (327, 1058).
splinting, heat, and other measures of physical therapy, analgesics, phenylbutazone,
Tietze’s Disease
and local injections of hydrocortisone were
The features of Tietze’s disease (painful recommended (764). The possible role of
swelling of one or more costal cartilages, psychologic factors in patients with painful
especially the second costal cartilage) were shoulders (764) and with other musreviewed (171). In this disease, histologic culoskeletal aches (934, 957) was conexamination of the cartilage reveals normal sidered. Manifestations and treatment of
cells.
lateral epicondylitis (tennis elbow) and
frozen shoulder were discussed (327).
Calcinosis
The natural history of calcified deposits
Tissue from patients who had calcinosis, in the rotator cuff of the shoulder involves
with and without dermatomyositis, were six stages: the silent phase; the mechanical
studied by means of histochemical, histo- phase in which the deposit painfully
enzymatic, and analytic chemical methods. impinges against the coraco-acromial ligThe protein of the calcinotic matrix con- ament in abduction through 70 to 120”;
tained a high hydroxyproline content and subbursal rupture of calcific deposit out of
hence was suspected to be collagen, al- the tendon under the floor of the bursa;
though it was unaffected by collagenase intrabursal rupture, the most severely painand did not contain fibers identifiable by ful phase; adhesive periarthritis with an
light microscopy (757). Injection of a mix- adhesive bursitis and single or multiple
calcific deposits in the rotator cufF; and the
intraosseous loculation in which the deposit
extends into cavities in the adjacent greater
trochanter and often produces a constant
boring pain (877). Operative treatment
was advised only for the large deposits in
the mechanical or acute phases or in cases
of chronically stiff and painful shoulder resistant to other treatment (831,878).
“Beat knee,” defined as a subcutaneous
cellulitis or acute bursitis at or about the
knee, was found in 233 of 579 coal miners.
Three types of lesions were noted: infections ( folliculitis, cellulitis, or septic bursitis) in 28 patients; acute simple bursitis
(mainly prepatellar, sometimes infrapatellar) in 109; chronic simple bursitis in 96.
The primary etiologic factor was trauma
secondary to kneeling; the immediate cause
of acute simple bursitis seemed to be rupture of a blood vessel in the wall of the
bursa, for which aspiration was recommended. Padding of the knee at work or
abstinence from prolonged kneeling was
helpful in treatment; occasionally, excision
of the chronically involved bursa was required ( 1140).
pers have appeared on such conditions as
specific infectious myositis, sircoid myopathy or steroid myopathy. (See previous
Rheumatism Reviews. )
PQLYMYALGIA RHEUMATICA
This condition was not well known until
recent years. A series of articles have described its various features (53, 213, 460,
739, 941, 1133). Myalgia was the most
prominent clinical feature. Pain, aching,
and stiffness, sometimes to a very distressing degree, appeared chiefly in previously
healthy individuals beyond the sixth
decade. It was located predominantly in
the neck, shoulder-girdle, perispinal musculature and less commonly in the low
back and the pelvic girdle. Peripheral rheumatic signs and symptoms were infrequent
but did occur in severe or acute cases.
Headache was a common feature-located
in the occipital and upper cervical areas in
the majority of cases but on occasion OCcurring elsewhere.
There was no evidence of objective joint
involvement and no joint effusions were
described, except for brief mention of transient swelling of joints in an occasional
Myositis
case. Clinical features in the early phase
(See sections of POLYMYOSITIS
and DIS- included slight fever, sweating, fatigue and
EASES OF MUSCLE
).
malaise, anorexia, weight loss and occasional diarrhea. These occurred espeFibrositis
cially in those patients who had a more
[Nothing new can be said about this acute onset.
syndrome. “Fihositis” is more concept than
An elevation of the sedimentation rate
diseuse. The sume clinical picture is called was always observed. Mild hypochromic
“psychogenic rheumatism” by some. For a anemia was sometimes present and certain
succinct summary of the problem, see “The acute phase reactant tests were positive in
Primer on Rheumatic Disease” (1006) or many cases. Hence, the alpha globulin and
Hollander’s Textbook ( 4 4 ) . Ed.]
sometimes beta globulin were increased in
amount and hyperfibrinogenemia occurred
Disease of Muscle
in many cases (53, 1133). Other serological
PQLYMYQSITIS AND DERMATOMYOSITIS tests, including those for the rheumatoid
(See sections elsewhere.)
factor, L.E. cells, antistreptolysin and Wassermann
reactions were invariably negaOTHER FORMS OF INFLAMMATORY
MYOPATHY
tive.
During the past 2 years, no significant paAlthough this condition has been
176
RHEUMATISM AND ARTHRITIS
brought to the attention of the medical steroid therapy in such elderly patients but
profession recently (941), a similar dis- apparently they responded to relatively
order has been described under various list- small doses ( 5 to 10 mgm of prednisone
ings since Bruce in 1888 used the term daily).
“senile rheumatic gout.” Other labels have
S T I F F - M A N SYNDROME
included: peri-extra articular rheumatism,
The Stiff-Man Syndrome was first demyalgic syndrome with systemic reaction,
scribed from the Mayo Clinic in 1956
pseudo-polyarthritislique, and anarthritic
(940). It is a musculoskeletal syndrome
rheumatoid disease (53). Much debate has
characterized primarily by tautness of the
centered around whether this condition is
trunk muscles, especially the extensors of
related to giant cell arteritis. (See section
the back and the abdominal wall muson Polyarteritis ) . Certain workers (941 )
culature. Occasionally it affects the exfound that random temporal biopsy
tremities. Because of muscular rigidity, the
showed a significant incidence of giant cell
patients tend to move en bloc. The neuroarteritis and that some of these patients delogical examination reveals only the musveloped ophthalmic arteritis. In one series
cular tenseness. Electromyography shows
(965), 7 of 15 biopsies showed evidence of
constant activity of the motor potentials in
arteritis and several of the patients in that
the affected muscles but no evidence of
series developed bilateral amaurosis, 2 of
fasciculation or fibrillation. Muscle biopsies
whom became permanently blind. In the
of affected muscles in 13 patients (940)
experience of a majority of the other auwere normal.
thors, however, temporal artery biopsy has
Initially, many clinical observers classinot been rewarding. In one series of 7 cases
fied this condition as a hysterical disorder.
(460) in which synovial biopsies were
However, with additional reports and folmade, synovium was described as benign
low-ups, sufficient evidence has accumuwithout arteritis.
lated to signify that the stiff-man syndrome
One of the most heartening of the feais unquestionably an organic illness. It retures of polymyalgia rheumatica was its
sembles chronic tetanus and it has been
prognosis. Despite the fact that during the
postulated that the pathogenetic mechacute stages it may be symptomatically seanism is a block at the synaptic junction of
vere, its course was usually benign and selfa specific interneuron between a fairly well
limited. In one series the average duration
defined inhibitory pathway and the motor
of symptoms was 18 months, and in anneuron in the spinal cord.
other (460) in which 50 patients were folBased upon this hypothesis, a therapeulowed for a period which ranged up to 16
tic trial was made with the compound didyears the mean overall duration of sympzepan (Valium) with an initial satisfactory
toms was 7.1 years although many had
result in 2 or 3 patients so treated (940,
much shorter courses.
1133).
During the acute phase, therapy for
symptomatic relief of symptoms was quite MYOSITIS OSSIFICANS
successful. The majority of the patients
Metastatic calcification may occur in a
could be managed with a program of sa- variety of diseases of man, among which
licylates or phenylbutazone. In a few pa- may be listed hyperparathyroidism, hytients with very persistent symptoms, cor- poparathyroidism, hypervitaminosis D, calticosteroid therapy appeared to be indi- cinosis universalis, myositis ossificans traucated and successful. It was pointed out matica and myositis ossificans progressiva.
(53) that one should be cautious in using In the first three diseases, calcium occurs as
177
SY NOVIAI, TUMORS AND TUMOR-LIKE CONDITIONS
scattered amorphous deposits, whereas in
the latter two categories there is formation
of true bone (with marrow) in unusual locations. A thorough review has been presented (770). [ N o doubt the most comprehensive and critical review that has
uppeared within the past 25 years. Ed.]
The review encompassed a complete compilation of 260 cases which had been reported during the past 200 or more years,
and 6 new cases were added.
Myositis ossificans progressiva is a generalized, presumably systemic, disorder. It
is usually manifested congenitally or early
in life and a diagnostic feature of the progressive disease is the presence of
associated congenital anomalies of the
digits, usually expressed as microdactylia or
adactylia of the thumbs and of the great
tom The age of onset was usually within
the first few years of life and the initial
manifestation of a lesion was characteristically an area of heat and edema, frequently associated with extreme pain, in
some part of the body musculature or associated tendons. After several days, the
edema, heat and pain subsided leaving a
residual area of doughy firmness which
gradually ossified over the course of a few
weeks, resulting eventually in the formation of bone in the position originally occupied by tendon and muscle. The most
frequent sites of involvement were the
paravertebral and cervical musculature, followed by the muscles of the shoulder girdle
and proximal musculature of the arms; the
pclvic girdle muscles were next most frequently involved, and then those of the
jaws and of the head. Death usually occurred as a result of respiratory embarrassment secondary to involvement of
the muscles of the thorax, or of inanition
due to involvement of the masseter or
temporalis muscles.
There was occasionally a family history
of digital anomalies, which implied a
hereditary etiology and there was at least
one report of concordance in monozygotic
twins. The histopathology of the initial
events were hemorrhage and intense fibroplasia. These were followed by progressive
deposition of collagen in which were eventually deposited masses of bone.
The pathogensis is unknown although it
has been postulated that an abnormal collagen is deposited which has a greater than
normal potential for ossification. Another
possibility is that in normal individuals
there exists a circulating inhibitor for calcium and phosphate crystallization and
that this hypothetical inhibitor is absent or
deficient in myositis ossificans.
Extensive metabolic studies were carried
out in one case (770) and in 2 other cases
therapy was attempted with such substances as hydrocortisone, triiodothyronine,
propylthiouracil or disodium ethylenediaminetetraacetate (EDTA). None of these
substances had any significant effect upon
the relentlessly progressive course cf this
disease. Studies of calcium kinetics using
radioactive calcium demonstrated the anticipated increase in pool size and gave an
indication of increased rates of bone deposition and absorption in this disease.
Synovial Tumors and Tumor-Like
Conditions
SYNOVIAL SARCOMA (SYNOVIOMA)
The clinical features of 25 patients with
synovial sarcoma were presented (41). The
lower extremity was the site of tumor in
72%of the cases. Over 60%of the patients
were under 40 years of age. From a review
of the literature and a presentation of 12
cases, it was concluded that the course of
synovial sarcoma was too capricious and
unpredictable to allow accurate evaluation
of therapy (106). This author recommended local excision followed by irradiation of the area and regional lymph
nodes, rather than amputation. A case
report concerned a 7-year “cure” of a pa-
178
RHEUMATISM A S D ARTHRITIS
genetic pattern was that of a sex-linked autosonial dominant with low pcnctrance for
females. The authors suggested that an underlying genetic defect may 1)c responsible
for clubbing, even in thr: acquired form.
Other reviews doscribing the clinical picture have also appeard (438, 702). The
association of bronchogrnic carcinoma and
pulmonary hypertrophic ostcoarthropathy
was the subject of another case report
( 104). The rare occurrcmx’ of hypertrophic
osteoarthropathy with centrally located
metastatic tumors was commented upon,
and found to be associated with primaries
SYNOVIAL CHONDROMATOSIS A N D
in
the nasopharynx in 3 instances (950). A
CMONDHOSARCOMA
case
of so-called pachydermoperiostosis
Synovial chondromatosis of the knee was
the clinical diagnosis of 3 cases that sub- with acanthosis nigricans was reclassified
scywntly were labcled chondrosarcoma on on the basis of autopsy findings as seconthc. basis of histopathologic changes. Am- dary hypertrophic osteoarthropathy (795).
putations were performed on 2 patients An interesting case report appeared of a
that w r ( ~“lost to follow-up.” [In a pre- patient with patent ductus arteriosus and
cious stiicly (88Y), 23 of 32 patients with reversed shunt who had hypertrophic ostesynoviol chondroniutosis had histological outhropathy occurring solcly in the legs
( 1336). Two patients with typical clinical
foci tliut suggested chondrosarcomu. The
and
radiographic findings with hypertrophic
c.linicul coiisse toas benign in all. There is
osteoarthropathy and cystic fibrosis were
110 dotilit thut true synocial chondrosarcoma exists hut the disease is vesy rare and described as well as 3 others with the
tlicre uppcuss t o he risk of erroneous his- radiographic findings alone (483). These
tological diagnosis, and over-aggressive patients all had severe pulmonary manifestations of cystic fibrosis.
t/leXL]l!J.Ed.]
The etiology of hypwtrophic ostcoI’IGMMEISTED VILLONODU1,AR SYNOVITIS arthropathy is still not clear. Proponents of
(see s(’ctioi1 on O‘IIIER TYPESOF ARrH- its ncurogenic origin presented further obnrns ) .
servations on humans and dogs in support
of their hypothesis (576). Studies of digital
Disease of Bone and Cartilage
blood flow in patients with clubbed fingers
due to cyanotic congenital heart disease as
HYPERTROPHIC I’IJLMONARY
compared
to normals and patients with
OSTEOAltTHIlOPATIEY A N D
CLC‘RHIIYG OF FISGERS
other forms of clubbing revealed small
The problem of clubbing (or acropathy ) differences which are difficult to interpret
was reviewed with emphasis on hereditary (36). Samples of systemic arterial plasma
c1rrbl)ing (378). It was pointed out that hy- from some patients with digital clubbing
pc,rtrophic osteoarthropathy with painful contained reduced ferritin which was not
and still‘ joints and radiological evidence of found in arterial plasma of patients withsubperiostcal ~ i e wbone formation is not out clulhing (497). It was suggested that
scen in thc hcrcditary as opposed to the reduced ferritin is normally inactivated by
acquircd form. It was proposed that the passage through the lungs and that in cases
tient with sttmoclavicnlar joint synovioma
trcated by excision and x-ray (802). In a
rcvicw by a large surgical service, “radical
surgical extirpation” (usually including amputation) was recommended (41). The 5y c w “cure” rate was 29%. [ I n a recent
.rtiidy (1014), it teas concluded that the miurn1 clrrrutioii of the diseuse is highly curialde untl that tcide local excision followed
h j irsudiu f ion tcus the treatment of choice.
F o r tuntoss of die distal parts of extremities, heloic-knee 0 s helow-elbow amputations tccre reconimended. Ed.]
179
DISEASE OF BONE AND CARTILAGE
with clubbing such a mechanism is ineffective. Others have found aspects of this hypothesis attractive but have commented
that “a great many obstacles to its acceptance remain, including a general disillusionment with Shorr’s concept of ferritin
as a ‘veno depressor material’.” ( 3 7 8 ) .
Whatever the cause of the increased vascularity in the digital vessels, evidence obtained by postmortem injection of pulmonary and digital vessels suggested that the
peripheral vascular changes identified in
the fingers may be a part of a more wide4pread change affecting many tismes
( 1275)
RELAPSING POLYCHONDRITIS
Relapsing polychondritis has been the
subject of several reports (451, 614, 649,
1294). Although, until this time fewer than
20 cases had been reported in the English
language literature, the series from the
Mayo Clinic included 14 cases, 4 of which
had been seen by the authors during a 1year period (649). The clinical features in
these patients involve inflammation of cartilagenous structures particularly chondritis
of the ear and nose. Other cartilagenous
structures have also been involved including those of joints, larynx, trachea, epiglottis, costocartilages, thyroid cartilages and
bronchi and eye. Fever and malaise are
frequent. A relapsing course is common
with episodes lasting from a few days to
several months. Relapsing polychondritis
has been described in association with
definite RA and 1 case “displayed good
clinical evidence of lupus erythematosus.”
The disease varies from one with a benign
course to a fulminating disorder, in which
death results from involvement of the
tracheobronchial tree. Abnormal laboratory
findings include elevated ESR, anemia,
eosinophilia and leukocytosis in some patients. Occasional cases have had biological
f d h positive tests for syphilis and others
positive tests for rheumatoid factor. Two
necropsied patients were studied in detail
(1294). The lesions of the cartilage consisted of diffuse destruction, collapse, focal
calcification, dystrophic bone formation,
plasma cell infiltration and partial replacement with fibrous tissue. Histochemically there was evidence of decrease in the
amount of acid mucopolysaccharide. The
lesions were similar to those produced experimentally by the intravenous injection
of papain to rabbits. In this regard, it is of
interest that patients with active polychondritis excreted increased amounts of
acid mucopolysaccharide in the urine
which reverted to normal levels during periods of remission (649).
The Problem of Osteoporosis
Osteoporosis has been the subject of several reviews (78, 301, 512, 769). The clinical and radiological picture was considered only briefly whereas most of the
emphasis was placed on theories of pathogenesis. Most authors considered osteoporosis as a metabolic disorder characterized by a decrease in bone mass, with the
remaining bone normal in mineral content
and structure. By this definition osteoporosis is a response of the skeletal system
to many stimuli and thus may be seen in
many disorders where the etiology of the
loss of bone may be clearly ascribed to the
primary pathology. No such etiology is obvious, such as hyperadrenocorticism, scurvy
or immobilization to account for the majority of patients with what is called osteoporosis. There are data which indicate that
by the usual clinical and radiological criteria, idiopathic, postmenopausal and/ or
senile osteoporosis does not represent one
disease, but a heterogeneous group of disorders with certain superficial characteristics in common (301). However, whatever
the etiology, estimates of the incidence of
osteoporosis in the population over the age
of 50 have been as high as 10% (769). In
consideration of the pathogenesis of the
disorder in the patient with postmeno-
180
pausal or senile osteoporosis, most of the
reviewers tended to discount earlier hypotheses that the primary defect is a failure
of matrix formation secondary to estrogen
deficiency, since kinetic studies with radiocalcium or stable strontium concluded that
rates of bone formation were normal or increased (512, 769). One report called attention to the association of osteoporosis
with fractures and anicteric cirrhosis of the
liver in alcoholics ( 1226). Quantitative
evaluation of microradiograms of bone biopsies in 2 of these subjects suggested both
decrease in the rate of bone formation and
increase in the rate of bone resorption. In
another study, the rates of bone formation
were estimated by different techniques
(
data, urinary hydroxyproline excretion and serum alkaline phosphatase levCIS). Within the small group of postmenopausal and idiopathic osteoporotic patients
studied, normal, high and low values were
found for the accretion rates (674).
In general, the view was favored that
osteoporosis resulted from a relative nutritional imbalance of calcium, leading to increased hone resorption. Some osteoporotic
patients were found to have consumed
diets too low in calcium relative to losses
(769). It was possible to place these patients in positive calcium balance by increasing calcium intake. In other patients
indistinguishable clinically, this was not
possible. However, in the latter group with
doses of vitamin D of 5,000 to 10,000 units
daily positive calcium balance was
achieved. Similarly a 23-year old woman
with typical clinical and radiological osteoporosis, without widened osteoid seams on
hone biopsy, and with normal rate of bone
accretion (strontium*") was studied (887).
This patient was in negative calcium bal;mce on high as well as low calcium intake,
h t had normal urinary calcium excretion
arid no evidenc-e tor intestinal malabsorptioii. Positive calcium balance was achieved
with large oral doses of vitamin D. It was
RHEUMATISM AND ARTHRITIS
concluded that this patient had selective
malabsorption for calcium. [The data for
fecal calcium in this study show tremendous uariation, and therefore the author's conclusions may he questioned. Ed.]
Three female patients (ages 63, 67, and 77)
with osteoporosis underwent balance studies for extended periods while on low and
high calcium intakes (1193). The addition
of calcium gluconate tablets to the low calcium diet improved the calcium balance
but not to the extent observed in young
persons or in elderly subjects without osteoporosis. The suggestion was therefore
made that patients with osteoporosis have a
decreased ability to absorb calcium from
the intestine. The significance of small
changes in metabolic balance studies, as
usually performed, has been questioned.
The marking of the stools with chromium
sesquioxide to permit eytimation of recovery of fecal collections was evaluated.
When such studies were performed in osteoporotic subjects, it was impossible to obtain prolonged large positive calcium balances on either high calcium intake, anabolic hormones or scdium fluoride ( 1057).
Calcium infusion studies have revealed
that low retention of calcium was observed
only in the minority of patients with osteoporosis of various etiologies, including none
of the more frequent forms of osteoporosis,
i.e., the postmenopausal and Cushing's
types (490). In the latter two conditions,
retention of infused calcium was normal or
greater than normal. The authors suggested
that this indicated an admixture of osteoporosis and osteomalacia, a possibility also
supported by their observations of frequent
elevation of serum alkaline phosphatase,
findings also supported by others (526,
525). Although similar results with calcium
infusion tests were obtained by other workers in patients with Cushing's syndrome,
patients with postmenopausal osteoporosis
were unable to retain calcium by the techniques used (301). [Such discrepuncies in
SrHUC:’l’UHEAND FUNCTION
181
OF JOINTS
results are not yet understood. Diferences
in technique of calcium infusion do exist.
Ed.] Studies in rats on the complex interrelationship between adrenocorticosteroids
arid parathyroid activity and speculations
concerning a role in osteoporosis were reported ( 1208). Cortisol suppressed the
serum calcium concentration in parathyroidectomized rats and increased the requirement for parathyroid extract to maintain the serum calcium. The whole idea
that mineralization is normal in “osteoporosis” has been questioned (1368) by the
findings of low ash weight/dry weight ratios in biopsies of the femoral cortex from
patients with fractured hips. No correlation
was found between mineral content and
radiological assessment. [The confusion that
tlicsr) conflicting stzitlies generate will hopefully he resolved when complete data inclu&~g biopsies will be presented for each
siihject investigated. Quantitative assessment of biopsy material by microrndiography or by special staining techniques
(12998) will he helpful. Ed.]
The choice of therapy in osteoporosis of
whatever etiology was closely related to the
authors’ ideas concerning pathogenesis.
The use of calcium supplements to induce
calcium retention and bring the patient
into positive balance was advocated by
several (78, 512, 768, 769). Under circumstances in which a positive balance did not
result, supplements of vitamin D were also
suggested (769, 887). A role was still seen
for the use of sex hormones (78, 301, 914)
even though it was emphasized that no
convincing reversal of bone disease had
been seen with any form of therapy. Anabolic steroids with various modifications of
chemical structure to reduce undesirable
side effects, such as masculinization, were
rvaluated. Among these, ethylestrenol was
touiid to be effective iii stimulating appetite and weight gain in institutionalized
children (199). Other studies reported the
rffectiveriess ot ethylestrenol in preventing
negative nitrogen balance in patients receiving dexamethasone ( 1083). Similar anticatabolic effects of nandrolone decanoite
were described in 2 patients (646). [The
data in the last two studies are not very
convincing. Ethylestrenol, said t o be safe as
well us eflective, produced increases in
hromsulfalein retention and serum transaminase levels in a significant number Of
children tested (199). Ed.] The hypothesis
that physical activity stimulates osteoblastic
activity and is beneficial to the immobilized
patient received some support from studies
using radiocalcium in 3 subjects ( 1015).
[ Dificulties in the inteypretatiolz of the re-
ported isotopic data detract from the conclusions of this study. Ed.] The effects of
sodium fluoride have been evaluated in patients with osteoporosis and Paget’s disease
of bone (1031). In 3 of 4 subjects who
were in negative balance during control
periods, the calcium balance became positive during treatment with sodium fluoride.
Urinary calcium tended to fall as did fecal
calcium in some patients. Three patients
experienced aching pain in knees and
ankles upon weight bearing during the period of fluoride therapy. No other serious
toxicity was noted. [The place for fluoride
therapy in osteoporosis is still to be established. Although osteosclerosis may result
from long-term fluoride ingestion, whether
or not this change is beneficial to the patient is not certain. The changes observed
in the balance studies reported are suggestive, although not impressiue. The proper
time to produce increased density of the
osteoporotic skeleton with fluoride therapy
might be of considerable importance. Ed.]
Structure and Function of Joints
ANATOMY AND MECHANICS
A brief review of normal joints appeared
(423) and shoulder joint development was
studied by light microscopy (22, 422) and
electron microscopy (249). The formation
182
of the joint cavity illustrated the close
embryological, anatomical and biochemical
interrelationship of the chondrogenic zones
of articular hyaline cartilage and the cellular and vascular parts of the synovial membrane (25). The intra-articular temperature
of the normal knee was found to be about
35" C, which was slightly higher than previously reported values of 31 to 33", and
temperature rose with inflammation (155).
Manometric measurements of intra-articular pressure in joints containing effusions
showed that each joint assumed a characteristic position which was associated
with minimum pressure. It was concluded
that a patient with a swollen joint puts his
joint in a position that results in minimum
pressure, and presumably minimum discomfort (355). Flexion contractures of
knees with chronic effusions were attributed to the assumption of a position
which reduced tension on joint components
(360). However, one of the diagrams in
this paper seemed to show a rise in intraarticular pressure with extreme flexion,
which was in accord with the findings of
Caughey and Bywaters (211 ). Functional
movement of the knee joint was analyzed,
particularly the rotary movement of the
femur on the tibia during the last part of
full extension (703). Variation in the mobility of normal unfixed specimens of human cervical spines was attributed to
differences in extensibility of the ligamenta
flava. Disk degeneration was associated
with progressive restriction of movement at
the affected level (60). In a study of the
transmission of forces from the hand to the
humerus, it was found that 57% of the
force crossed the radiocapitular joint, and
43% the ulnar-trochlear joint. The interosseus membrane did not play a major
role in transmission of forces (499).
HISTOLOGY OF T H E SYNOVIAL
MEMBRANE
A new synovial biopsy needle of smaller
diameter than the well-known Polley-Bickel
RHEUMATISM AND ARTHRITIS
needle was described (955). Lining cells in
the guinea pig synovial membrane revealed
a complex fine structure adapted for both
phagocytic and secretory activities ( 1374).
Ferritin injected into a rabbit knee joint
was rapidly phagocytized by synovial lining cells of the vacuolar type, and only to a
very slight extent by the less common cell
type containing much endoplasmic reticulum. Within 18 hours after injection many
lining cells showed evidence of cytoplasmic
degeneration, and such cells were OCcasionally shed into the joint cavity. There
was a mild polymorphonuclear leucocytic
infiltration, and macrophages engulfing cellular debris were also observed (59). Vascular patterns in the capsule of the synovial
membrane showed long arteriolar-capillary
loops, with many arterio-venular shunts
(752, 753). Hyaline sclerosis was observed
in capillaries and venules in the synovial
membrane from essentially normal joints.
There was no lipid in the hyaline material,
and no correlation with vascular degeneration elsewhere. It was suggested that the
findings were not related to aging, but
were a response to local circulatory
changes associated with joint movement
(336). Capillaries in the fibrous capsule of
rat synovial membrane were of the continuous kind. The capillaries in the fat pads
were different; these capillaries, situated
just below the synovial surface, were strikingly polarized toward the surface. The
wall of the capillaries was extremely attenuated, and contained numerous fenestrae closed by a diaphragm (1229). Fragments of explanted human synovial membrane cultivated in vitro showed branching
projections, which developed into anastomosing vascular networks (54). The vascular bed in the rheumatoid synovial membrane or capsule was sometimes normal,
and if altered, showed dilated irregular
venules, which could slow blood flow
(156). Synovial membrane obtained from
rheumatoid knees by a pleural biopsy nee-
183
STRUCTVRE AND FUNCTION O F JOINTS
dle showed typical histologic findings. In
six instances of biopsy within 3 months of
the onset, changes were “strikingly confined
to the synovial cell layer and immediate
subsynovial zone,” and polymorphonuclear
leucocytes were often present. In osteoarthritis, changes ranged from normal to
those approaching RA; the best distinguishing feature was the paucity of cellular infiltrate (1332). Needle biopsy of the synovial membrane was used to determine the
anti-inflammatory activity of a number of
drugs, and very little change in the histologic picture was found, although local
clinical improvement was noted (420).
(:hloroquine, phenylbutazone, salicylates
and aurothiomalate all decreased the permcability of the synovial membrane in rabbits, as measured by the rate of absorption
of phenolsulfonphthalein from the talocrural joint (1136). [In this well-conducted study, saline was used as a control.
The author points out that all drugs tested,
including chlorpromazine, decreased the
permeability of the synovial membrane. I t
is thus dificult to distinguish between the
potential anti-rheumatic activity and the
nonspecific, general effects of the drugs.
Ed.] Fragments of rheumatoid synovial
iriembraiie grown in tissue culture showed
the same morphology and types of cells as
non-rheumatoid membranes ( 1197). Compared to normal, rheumatoid synovial
membrane showed a marked increase in
activities of lysoyomal enzymes, such as
acid pliosphatase and cathepsin (767). Another enzyme, /?-N-acetylglucosaminadase,
was markedly elevated in most rheumatoid
synovial membranes studied (548). [This
is a lysosomal enzyme. Ed.] Both by light
and electron microscopy, a marked increase
in lysosomes, as indicated by acid phosphatase activity, was found in the lining
cells of the rheumatoid synovial membrane
( 65). It is becoming increasingly likely that
lysosomal enzymes in synovial fluid and
synovial membrane play a role in cartilage
erosion (66) and joint inflammation (572).
Biochemical and pathological events in
joint diseases have been reviewed (270,
503).
SYNOVIAL FLUID
VISCOSITY. The viscous or rheological
properties ( 1329, 1330) [excellent reviews. Ed.] of synovial fluid appear particularly suited for lubrication in the joint.
In normal joints, proper lubrication may
depend on the integrity of the macromolecules which account for the non-Newtonian
properties ( i.e., decreasing viscosity with
increasing shear rates) and elasticity of
synovial fluid, and on the smooth-surfaced,
elastic articular cartilage (305). Compared
to normal, rheumatoid synovial fluids appeared to show loss of non-Newtonian
properties (128). [While this loss has often been attributed to “depolymerization”
of hyaluronate, there may be other explanations. The hyaluronate concentrations of
normal or traumatic fluids, and rheumatoid
fluids were said t o be similar; actual determinations (1196) always show much
lower values in rheumatoid fluids. At the
very low concentrations present i n most
rheumatoid fluids, hyaluronate molecules
are less entangled, and this could account
for reduced or absent non-Newtonian viscosity. Ed.] When viscosity measurements
of synovial fluid were extrapolated to zero
concentration of hyaluronate, figures for
“intrinsic viscosity” showed low values in
osteoarthritic and rheumatoid fluids compared to normal; values for fluids from patients with systemic lupus were normal
(1196). [This last finding might be related
to the low cell count and, therefore, presumably low levels of hydrolytic enzymes
in these fluids. However, osteoarthritic
fluids also have low cell counts and low
levels of hydrolytic enzymes, and yet these
fluids show lozu viscosity, which is somewhat surprising and puzzling. Ed.]
PROTEINS.
Studies of certain glycolytic en-
1 R4
/ymes (such <is lactic dehydrogenase and
:~ldolase) and a few oxidative enzymes
(such a s malic and isocitric dehydrogenMY ) showed increased levels in rheumatoid and pyogenic synovial fluids compared
to fluids from knees with degenerative
changes. Highest levels occurred in those
pathological fluids with the highest leukocvtc count (247, 1325). Acid phosphatase
levels were clevated in many rheumatoid
\yno\ial fluids, while alkaline phosphatase
Lvere normal (733). [These authors
vtcitetl that acid phosphatase was present
primarily in lymphocytes, not granulocytes,
and suggested that the high acid phosphatase levels i n synovial effusions arose
from cells in the synovial membranc. This
could certainly be so, but cytoplasmic
granules of granulocytes contain large
umounts of acid phosphatase (253). Ed.]
Paper electrophoresis of the proteins of
\ynovial fluids in a variety of diseases
\ h o ~ two
~ d patterns: ( 1) in osteoarthritis,
trarim,i, gout, wrcoid, etc., the protein pattern i n \vnovial fluid mimicked that of
\eriim, ( 2 ) in RA. ankylosing spondylitis
aiid Ikiter'\ \yndrome. y globulin in synovial fluid was often higher than in serum.
Thl\ w'i\ correlated with plasma cell infiltration i n tl-iesc-1 synovial membranes
1333). There is increasing evidence that
proteins of high molecular weight, or those
with highly asymmetric shape, may be excluded from synovial fluid in the normal
joint. Thus, IgM-macroglobulin, p-l-lipoprotein, fibrinogen, and a-2 macroglobulin
were either absent or markedly reduced in
uormal synovial fluid?, but were present in
pathological effusions (1119). The total lipoprotein in normal synovial fluid was 40%
of that in serum; only a minute amount of
low density lipoprotein was present, while
the high density ones were increased. In
active HA, total lipoprotein in synovial
fluids was higher than in normal fluids, although still lower than in serum (1173).
The presence of hyaluronate in the normal
RHEUMATISM AND ARTHRITIS
synovial membrane or synovial fluid may
explain the reduction or the absence of
large proteins from the synovial fluid
( 1117). Hyaluronate's enormous molecular
volume can exclude large proteins from its
domain (429). In an experiment designed
to test this, synovial fluid was ultrafiltered,
and to the gel retained on the filter, normal
serum was added. The pattern of serum
proteins emerging from the gel was very
similar to that in normal synovial fluid
(907).
The important observation (978) that
levels of complement in rheumatoid synovial fluids were only slightly higher than
normal, while in effusions from other
causes of synovitis, complement levels were
much increased has been confirmed and extended. The lowest levels of complement
occurred in fluids from patients with classical RA and subcutaneous nodules, but
there was no relation between complement
activity and latex titer of the synovial fluid
(535). In juvenile HA decreased synovial
fluid complement was found mainly in
those patients with elevated titers of H):
(536). [ The working htpthesi.s of all
these corkers is that presumed antigenantibody reactions in the synovial membrane may bind complement. Ed.]
HYALUHONATE.
Cetylpyridinium chjoride
was used to isolate hyaluronate from bovine synovial fluid. Very little degradation
of the hyaluronate occurred, and after
treatment with Fuller's earth, the hyaluronate contained less than 2%protein (814).
The electrostatic interaction of native hyaluronate and albumin was observed during moving boundary electrophoresis by
the appearance of a peak, termed Pi, intermediate between the two (466). Hyaluronate from rheumatoid synovial fluids
was digested with bee venom hyaluronidase. The oligosaccharides, recovered in
88%yield, contained glucosamine and glucuronic acid, as in normal hyaluronate
(64). Hyaluronate isolated from rheuma-
185
S’1 KLTC‘’1UllE ,4hD FUNCTION OF JOINTS
toid arid other pathological synovial fluids
appeared to contain more protein (about
108) compared to nomal (about 2%).At
131 i 3.5, the so-called pathological hyaluronatc.-protein ( HP) showed unusual physical propcrties, such as electrophoretic immobilimtion and gel formation, neither of
uhich was shown by normal HP (502).
The higher protein content and unusual
propc~ties of pathological HP were attributed in large part to the binding of a
single serum protein, an a-globulin, which
\\.a\ drtected by immunological studies
( 1097). [This a-globulin was recently
idcntified as an inter-alpha trypsin inhibitor
(1098). Ed.]
~IISCELLANEOUS.
While vitamin C depo1ymerir;ed hyaluronate in uitro, no reduction in the viscosity of rheumatoid synovial
fluid occurred when vitamin C was added
or injected into the knee joint. Serum proteins, particularly the a-2 globulin fractions,
inhibited the action of vitamin C on hyAiironatcl in the whole synovial fluid ( 4 ) .
1 1 1 -3 ot 3 patients with SLE, and 7 ot 15
with “c-lassiral”RA. mononuclear cells isolated from svriovial fluids induced a “cytotoxic. change” on human embryo skin fibroblasts in tissue culture (537). [ 7t is stirprising that (-ellsfrom fluids obtained from
pntients with “definite” R A had no such
~ f f e c t . Ed. J Cholesterol crystals were
identified in the synovial fluid of 2 patients
with RA, and biopsy of the synovial membrane showed cholesterol crystals in clefts
on the surface and multinucleated giant
cells ( 1388). The free (or diffusible) salicylate concentration was the same in rheumatoid synovial fluid and plasma, but protein-bound levels were consistently lower in
the synovial fluid, possibly due to lower albumin concentration in the joint fluid
( 1085’). A brief description appeared on
the routine examination of normal and
pathological synovial fluids (560).
Examination of synovial fluid from caiiine joints was useful in excluding septic
arthritis (1102). A beneficial effect of 6 amethylprednisolone on non-septic joint
effusions in horses and cattle was observed
( 1283).
ARTICULAR CARTILAGE
The “health“ of rabbit articular cartilage
cells was studied by autoradiography following exposure of cartilage to H3-cytidine
or €I3-glycine to reveal RNA or protein
synthesis. If rabbits were first killed and
cartilage then obtained, or if cartilage was
exposed to cyanide or iodoacetate, a
marked decline in the number of cells engaged in synthesis was observed (791). Incorporation of H”-thymidine demonstrated
mitotic division and proliferation of cartilage cells in growing rabbits (790). In
growing mice, cartilage cells studied by
electron microscopy showed increasing
complexity of cytoplasmic organelles. At
the height of deiTelopment glycogen appeared in the cells, and with aging, hydration and swelling of the cytoplasm occurred (1163). Cartilage cells in mice injected with somatotropin were unusually
large and contained increased amounts of
glycogen ( 1162). Articular cartilage
showed remodelling in several ways in response to stresses, even after body growth
had stopped (858). Slices of articular cartilage immersed in solution containing monovalent cation showed essentially perfect
elastic recovery from deformation (337).
Trivalent cations caused shrinkage, increased deformability and decreased recovery. These changes could be due to the
highly charged cations reducing the molecular volume of the proteinpolysaccharides
of cartilage (1185). After the first decade
little change occurred in the mucopolysaccharide content of aging cartilage (25,
844). [ T h e most marked decrease in cartilage polysaccharides occurs in the first
decade: chondroitin sulfate decreases
sharply and keratin sulfate increases
slightly. Rosenberg and Schubert, personal
186
communication. Ed.] Electron microscopy
of the articular cartilage of old rabbits
showed a surface less smooth than in young
animals and a cell-free region beneath the
surface that was considerably deeper. Loss
of definition of nuclear and cell membranes, disintegration of cytomembranes,
and other degenerative changes in chondrocytes of the middle and deep zones suggested cell death in situ, rather than shedding of surface cells due to wear and tear.
Increasing coarseness of the fibers of the
matrix was also observed (67). Aging of
cartilage was associated with decreased
penetration of protsrgol, a silver proteinate, into the matrix (1207). It appeared
that if limbs of rabbits were fixed, surfaces
of opposing articular cartilages remained
normal or even hypertrophied during continuous compression, provided fixation was
not so rigid as to prevent all motion (263,
498). Compared to the contralateral control
joint, enhanced uptake of radioactive sulfate occurred in articular cartilage in a joint
subjected to various surgical procedures
not directly involving the articular surface
(832).
RHEUMATISM AND ARTHRITIS
strated (1199). Although modifications in
collagen and elastin structure have been
produced in experimental diseases, distinctive qualitative abnormalities of these components in human disease have not yet
been conclusively demonstrated. A review
of the pertinent literature through 1962
covering certain aspects of the morphology
and metabolism of connective tissue cnmponents has appeared (46).
COLLAGEN
COLLAGEN
SYNTHESIS.
Studies have been
performed on the metabolism of citratesoluble and “mature” (insoluble) collagen
in the skin and bone of rats of varying
ages, utilizing measurements of specific activity of the appropriate fractions versus
time following injection of g l y ~ i n e - 2 - C ~ ~
(1177). The time for the specific activity of
glycine from citrate-soluble collagen to decrease to that of glycine in the insoluble
collagen increased with increasing age. The
“turnover” of collagen from the femora was
faster than that from skin. The administration of cortisone produced significant
changes in specific activity only in weanling and young adult rats. In another study,
The Connective Tissues
proline-C14, excreted as hydroxyproline
GENERAL
( Hypro)-C14 in the urine, was compared
The structure, properties, synthesis and with that in soluble (0.9%NaC1) collagen
degradation of the various components of and insoluble collagen of skin and carcass
connective tissues have been the subjects of ( 1008). The specific activity of the urinary
numerous reports. Considerable informa- hypro-C14, 15 hours after injection, was
tion is now available on collagen structure, comparable to that of the soluble collagen
biosynthesis and degradation. Knowledge whereas that of the insoluble fraction
about another connective tissue protein, was low. By 4 weeks, the specific activity of
elastin, has been advanced with the dis- the soluble collagen had fallen below that
covery of two new amino acids, desmosine of the urinary hypro whereas the insoluble
and isodesmosine, which presumably ac- fraction had levels of specific activity comcount for the unusual crosslinkkg prop- parable to that of the urinary hypro. The
erties of elastin (961, 962). It has been results suggested that endogenous hyproshown that the pathway of biosynthesis of peptides excreted in the urine were derived
desmosine and isodesmosine is from lysine from the degradation of both soluble and
(818). Alterations in the content of lysine insoluble collagen.
in the elastin of the aorta in experimental
Several systems have been devised for
copper deficiency has also been demon- the study of collagen synthesis in &To to
THE CONNECTIVE TISSUES
evaluate effects of various hormones and
drugs. Collagen synthesis in rat uterine
slices, measured by incorporation of lysineC14 into hydroxylysine-C14, was greatest
at the height of follicular hormonal activity
( 634). Inhibition of proline-H3 incorporation by rat femoral bone chips and
mouse embryonic radii was observed in the
presence of salicylates (258). [The concentrations of salicylates used in these studies were high and the significance may
therefore be questioned. Ed.] Collagen
was produced by mammalian fibroblasts in
tissue culture after the period of rapid
growth was completed (469). Clones of fibroblasts have also been shown to synthesize both hyaluronate and collagen,
thereby establishing that both synthetic
functions are carried out by the same cell
(470). Similarly, chondrocytes freshly liberated from chick embryonic vertebral cartilage with trypsin were able to synthesize
both chondroitin sulfate ( Sa5 sulfate incorporation) and collagen (1007). However, when such cells were grown on fibrin
clots for several generations, they lost both
the capacity to incorporate sulfate and synthesize hypro. Human fibroblast strains
produced more collagen in culture when
ascorbic acid was added to the medium
(468). The ability of such cells to produce
collagen persisted for several months after
removal from the donor (206). Hydrocortisone suppressed collagen formation in such
cultures. Although cortisone and dexamethasone injected directly into cotton
gauze-induced granulomas in rats reduced
the wet and dry weights and total hypro
content, the latter remained a constant
fraction of the dry weight (922). In growing rats, corticoid treatment decreased the
turnover rate of all fractions (NaClsoluble, citrate soluble and insoluble) and
decreased the amount of collagen extracted
from skin by neutral salt (919). In chick
embryos, cortisone decreased the content
ot free hypro per unit of dry tissue, but
187
when cortisone was given as a single injection, a marked increase later occurred in
the content of free hypro (668). Histological and electron microscopical observations on the effects of prednisone, phenylbutazone and sodium salicylate on induced
granulation tissue have also been reported
(620). In guinea pig wounds, the concentration of collagen in the total granulation
tissue was found not to increase linearly, as
previously reported, in the central core but
leveled off with time. It was suggested that
collagen is concentrated in the core of the
granulation and resorbed in the peripheral
region ( 147).
In keeping with current concepts of the
mechanism of protein synthesis, it has been
found that the rate of ribonucleic acid
(RNA) synthesis paralleled the rate of
cellular synthesis of collagen in implanted
polyvinyl sponge granulomata (77). It has
been shown that the assembly of polypeptide chains during protein synthesis occurs
on clusters of ribosomes called polyribosomes or polysomes. In one collagensynthesizing system (polyvinyl sponge
granulomata), polyribosomes containing
labeled protein sedimented rapidly, possibly representing particles heavier than
450s (788). Further studies in chick embryos suggested that similar large ribosomal aggregates were involved in collagen
synthesis (683). It was postulated that
these particles would contain a minimum
of 100 ribosomes. Since a messenger strand
capable of accommodating 30 ribosomes
could code for a single polypeptide chain
of approximately 110,000 molecular weight,
the large polyribosomes observed would
represent “triple polysomes” capable of
coding for the entire tropocollagen molecule (approximately 300,000 molecular
weight ) .
Although it is not certain exactly at what
point in collagen synthesis proline is hydroxylated to hydroxyproline, it is clear
that free hydroxyproline is not incor-
188
porated into the polypeptide chain. It has
been shown, however, that the hydroxyl
group of the hydroxyproline in collagen is
derived from atmospheric oxygen, similar
to othrr biological hydroxylation reactions.
These observations were extended in chick
embryos using atmospheric oxygen labeled
with O'# (416). The results of analyses of
0lx abundance revealed greater enrichment of the neutral salt a5 compared to the
insoluble fraction. The results are in accord
with those obtained with labeled amino
acids which suggested that the neutral saltsoluble collagen is the precursor of insoluble collagen.
COLLAGEN
STRUCTURE.It is now generally
agreed that the collagen molecule consists
of three polypeptide chains, each having a
left-handed, three-fold screw axis and
wound about each other in a right-handed
coil arrangement (510). The structure of
collagen has been interpreted in relation to
the model ot poly-L-proline I1 which exists
in solution in a left-handed helical configuration stabilized by restrictions to rotation of the pyrrolidine rings (proline and
hydroxyproline) about the peptide backbone. Recent studies confirmed earlier reports that the total pyrrolidine contents of
various collagens correlate with thclir respective shrinkage (T,) and denaturation (Tn) temperatures (622). These results were obtained by comparing the
properties of two neutral soluble invertebrate collagens from earthworm and ascaris
cuticles which have markedly different total amino acid and hydroxyproline contents. The T, of ascaris collagen with high
total pyrrolidine residues but low hydroxyproline was much higher than that of
earthworm cuticle with high hydroxyproline content and low total pyrrolidine.
Important new information about collagen structure was obtained when it was
possible to separate and characterize the
component chains of collagen after denaturation to gelatin. It is now thought that
RHEUMATISM AKD ARTHRITIS
the collagen monomer contains three
chains, two of which (a1 chains) are apparently identical while one ( a 2chain) is
different in amino acid composition. Recent
work also suggests that in some species the
three chains may be distinct, thus another
designation, a3 (987). Apparently covalent
crosslinks form between the chains to produce p-components ( p12is the dimer of a,
and a2;Pl1 is the dimer of al and a l ) . A
new P-component has been identified as
p 2 2 which has an amino acid composition
identical with a2 and therefore would represent an intermolecular crosslink ( 144).
The various collagen components of skin
from a newborn infant were analyzed and
characterized (145). The neutral salt extract contained approximately 70% a
chains whereas the acetic acid extracts contained approximately % p components. A
fraction containing an even larger percentage of p chains as well as the & chains
described above was obtained by further
extracting the skin in 5 M guanidine. The
molecular weight of the a chain was 103,000 and that of the /3 chain 170,000. These
values were in substantial agreement with
those found for the chains from rat skin
(746). Further evidence has been obtained
which supports the hypothesis that the a
subunits are synthesized first and represent
the precursors of the p chains, by measuring the rate of incorporation of glycine-C14
into the various fractions (808).
Careful determinations by a variety of
techniques have provided further data on
the molecular weight and dimensions of
the tropocollagen molecule from calf skin
(1030). The molecular weight was calculated to be at most 310,000 and the length
2800A. Reconstituted calf skin eucollagen
(obtained by solubilizing with cold alkali)
had structural characteristics by electron
microscopy similar to those of tropocollagen (556). The nature of the intra- as
well as the intermolecular crosslinks which
is unknown at present is the subject of a
’TIIE CONNECTIVE TISSUES
recent review (507). It has been proposed
that the interchain crosslinks occurring naturally are external to the body of the macromolecule and probably involvc peptides
(1080). Whatever the site and character of
thew bonds thr denatured collagen (gelatin) can be riiiatured with a rate of recovery 30-fold greater for the crosslinked
vcrsus the non-crosslinked components
(313).
The factors involved in the denaturation
of collagen have been studied by several
groups. The thermal denaturation temperature (T,,) was 10” higher for newly
reconstituted fibrils compared to neutral
solutions (478). It was suggetsed that the
increased concentration of collagen within
the fibrils increased the stability of the individual molecules, the absence of firm intc,rmolecular bonds in these fibrils ruling
out crosslinking as an explanation for this
phenomenon. “Aging” the newly reconstituted fibrils at 37‘ up to 1 year raised the
shrinkage temperature and increased resistance to dissolution at high temperature.
In oico, the thermal shrinkage temperature
J s o increased with increasing age (230). It
11 as also shown that variations in shrinkage
temperature were greater in the same fiber
than they were in the samr part? of differcnt fiben. The thermal shrinkage temperature ot a variety of collagenous tissues
w a s 60 to 61°, typical of mammalian collagen (1036), despite the large variation in
the tissues tested in the content of lipid and
muc.opolysaccharide. The presence or absenrc of the tendon membrane did influence the swelling and thermal stability
(697 ) . Others have implicated non-collagenous, protein components of tendons in
stabilizing the native fibers (958). Studies
of mechanical factors such as cyclic extensions on the properties of tendon have suggested that a more oriented structure results when the fibers are repeatedly
stretched (1037). Small changes in shrinkage temperature and changes in contrac-
189
tion-relaxation curves were found in tail
tendons from rats treated in vivo with several anti-rheumatic drugs ( 1265). The
shrinkage temperature of human tendon
collagen has been estimated after immersion in a variety of biological amines (558).
[The concentrations of these substances
toere enormous and the results therefore of
questionable significance. Ed.]
COLLAGEN DEGRADATION
AND REMODELLIXG. The process of metamorphosis in amphibia has been studied in detail with emphasis on connective tissue components
(479). The rate of collagen synthesis (proline-H“ incorporation) was the same in the
resorbing tailfin as in the back skin. The
transformation of newly synthesized molecules (salt extractable) into the insoluble
collagen fraction occurred at an extremely
rapid rate. In the resorbing tail fin the specific activity of the insoluble fraction rose
rapidly despite a diminishing total amount
of insoluble collagen. Using collagen gels at
neutral pH, which were not digested with
trypsin, tail fin, back skin, gill and gut tissue showed lysis of the gels. By using
larger amounts of tissue in this culture system, it was possible to purify a soluble enzyme which appeared to cut across the rodshaped collagen molecule producing a few
long fragments without disrupting the helical conformation of the polypeptide chains.
Thus, this collagenase was distinctly different from the enzyme obtained from cultures of Clostridiuni histolyticwn which extensively breaks the molecule into small,
mostly dialyzable fragments. Using a similar system collagenolytic activity war also
found in cultures of human and rat endometrium and in metaphyseal bone from parathyroid treated rats.. Others have described collagenolytic activity that differs
from that just described (450). Isotonic saline extracts have been obtained from normal and necrotic rat skin which were capable of releasing peptide-bound hydroxyproline from insoluble collagen only after
190
RHEUMATISM AND ARTHRITIS
prior limited activation with trypsin. More disease, it is difficult to evaluate the relative
prolonged treatment with trypsin destroyed contribution of the two processes to the urall activity. The enzyme had its maximal inary hypro, although the urinary excretion
activity at pH 5.5, but no activity at neutral appeared to reflect bone collagen turnover
pH. It was not inhibited by soybean tryp- (322). From studies in rats it was essin inhibitor, produced no proteolysis with timated that relatively large changes in the
denatured hemoglobin as substrate; rate of collagen degradation would be refurthermore it was not inhibited by EDTA quired to produce significant changes in
(0.01 hl ) which would inhibit the bacterial the amount of hypro excreted in the urine
collagenases. [ T h e importance of each of (1008). The peptide fractions containing
these distinct enzymes remains t o be estab- hydroxyproline were characterized and one
lished. The tadpole-type of enzyme, active was identified which contained glycineat neutral pH, has been purified and the proline-hypro, a tripeptide sequence known
reaction products characterized. I t prom- to occur in the collagen molecule (833).
iscs to provide new insight into collagen The importance of age-matching controls
structure. The enzyme active at acid p H in the evaluation of hypro excretion in dishas still t o be purified in order t o establish ease was emphasized (616). High levels
its specificity. Ed.] In a study of resorption were found in normals, aged 13 to 15, in
of uterine collagen, incubations of uterine some subjects as high as 698 mgm per 24
homogenates were carried out at 37” and hours, compared to normal adults, aged 33
pH 3.5 for 16 hours, resulting in release of to 49, where excretions of 13 to 29 mgm
soluble hydroxyproline (874). High con- per 24 hours were found. The effects of
centrations of heparin inhibited the “prote- hyperthyroidism in increasing and hypoase activity.” [ T h e probability that incu- thyroidism in decreasing hypro excretion
bation at this p H and temperature gelatin- were particularly noted (669, 670, 671). Paized tlxe collagen was not adequately con- tients with chronic acidosis due to renal
trolled. The observed inhibition by heparin disease and emphysema had low levels of
in high concentrations is in striking contrast h y p o excretion (377).
to the stimulation of bone resorption of
The presence of hypro in plasma in a
mouse calvaria in the presence of heparin nondialyzable form, precipitable with the
and parathyroid extract in small doses usual protein precipitants was reported
(447). Ed.]
(650). Gel filtration and enzymatic digesURINARYEXCRETION
OF HYDROXYPROLINE.
tion indicated that the hypro was contained
Of all animal tissues only collagen contri- in a large molecule resistant to hydrolysis
butes significantly to urinary hydroxyproline by chymotrypsin and Pronase, characterispeptides. The conclusion was reached that tics consistent with those of collagen (738).
the level of excretion of urinary hydroxy- [ T h e significance of this interesting hyproproline (hypro) reflects the metabolism of protein in plasma, the levels of which are
collagen. Processes such as growth which elevated in a variety of diseases, is yet to
accelerate collagen formation with concom- be established. Ed.]
itant increases in the extractable fractions
The urinary excretion of a dipeptide
are associated with moderate increases in (glycyl-proline) has been found in 3 pahypropeptide excretion (1174). In condi- tients with different forms of active rickets
tions in which both synthesis and break- ( 1127). Glycyl-proline excretion paralleled
down actively occur, such as hyperpara- that of hypro-peptides, suggesting that
thyroidism, hyperthyroidism and Paget’s bone collagen was its likely source.
THE CONNECTIVE TISSUES
MUCOBOLYS ACCHARIDES A N D
MUCOPOLY SACCHARIDE-PROTEIN
COMPLEXES
The term mucopolysaccharide refers to
the general class of high molecular weight
polysaccharides found in connective tissues.
h4ucopolysaccharide-protein complexes refers to the binding of these polysaccharides
to proteins, in some instances by covalent
linkages. The structure and pathways of biosynthesis of these substances have been
reviewed (311). Hyaluronic acid is a pl-3,
pl-4 high molecular weight polymer of Nacetyl glucosamine and glucuronic acid.
The chemical synthesis of the heptacetylmethyl ester of 2-amino-2 deoxy-3-0(p-Dghicopyranosyl-uronic acid ) -D-glucose, the
repeating unit of hyaluronic acid, has
been described (390). Chondroitin sulfate
A is a pl-3, pl-4 polymer of D-glucuronic
acid and N-acetyl galactosamine with one
mole of ester sulfate. In chondroitin sulfate
C the disaccharide repeating unit is the
same as in A except that the sulfate is at
position C-6 instead of C-4. Chondroitin
sulfate B contains iduronic acid instead of
glucuronic acid. Keratosulfate is composed
of alternating units of N-acetylglucosamine
and the neutral sugar, galactose. Heparin is
also a polymer of glucosamine and glucuronic acid in a-glycosidic links but the
amino group is N-sulfated in addition to
the ester sulfate. Iduronic acid is present in
heparin in addition to the glucuronic acid.
Although in mammalian species these sulfated polysaccharides (with the exception
of heparin) have one mole of sulfate per
disaccharide unit, the chondroitin sulfate C
and keratosulfate of skin and cartilage of
sharks are uniquely oversulfated (1132).
Biosynthesis of all mucopolysaccharides
probably involve uridine nucleotide sugar
intermediates. Incorporation of label from
UDP glucuronic acid and UDP-N-acetylglucosamine into hyaluronic acid has been
demonstrated in the presence of particulate
191
enzyme systems (23, 311). Similarly, incorporation of label from the sugar moiety of
UDP glucuronic acid and UDP-N-acetyl
glucosamine into nonsulfated polysaccharide has been observed with microsomal
preparations from the heparin synthesizing
mouse mastcell tumors (1164). Using
labeled UDP glucuronic acid and UDP-Nacetyl galactosamine, incorporation has
been shown into a nonsulfated “chondroitin” using microsomal preparations
from embryonic chick cartilage (1165).
The mechanism of sulfation and exactly
when in the course of synthesis sulfation
occurs is still under investigation (311).
The relationship of protein synthesis to
polysaccharide synthesis also requires clarification.
Several in vitro systems have been examined, in which polysaccharide synthesis
is occurring. Clones of fibroblasts in culture
have been shown to synthesize both hyaluronate and collagen, demonstrating that
both synthetic functions are ascribable to
one cell (470). Fragments of beef embryonic epiphyseal cartilage when grown in
tissue culture produced chondroitin sulfate
A and C (481). Epiphyseal cartilage from
chick embryos was treated with trypsin to
remove the extracellular matrix and the
chondrocytes isolated by centrifugation
and washing. Such cells readily incorporated radioactive sulfate into both intracellular and extracellular chondroitin
sulfate (1255). At early time periods of incubation most of the incorporated radiosulfate was present intracellularly and, after disruption of the cells and differential
centrifugation, was found in the fraction
that sedimented at 10,000 to 20,000 x g. At
later times (1hour) the extracellular polysaccharide was labeled. The intracellular
and extracellular polysaccharides consisted
of a mixture of chondroitin sulfate A and
C. The ability of such isolated chondrocytes to incorporate radiosulfate as well
I92
as incorporate labeled proline into labeled
hydroxyproline was also shown by others
( 1007). However, such cells when incubated in culture over several generations
were unable to perform these synthetic
fuiictions.
Studies of the turnover of the polysaccharides in rats in oivo revealed that the
chondroitin sulfate of ribs was metabolized
at a much faster rate than that from the
epiphyseal plate ( 151). The chondroitin
sulfate extractable only with alkali was distinguishable from that extractable with water by its lower rate of metabolism and
lower content of chondroitin sulfate C. The
chondroitin sulfate B and hyaluronic acid
of rabbit skin were found to exist in more
than one physical state and testosterone
produced marked increase in the hyaluronic acid content (278). In the rabbit
nucleus pulposus, the ratio of keratosulfate
to chondroitin sulfate C was found to increase uniformly as a function of the age of
the animals. Several hormones, notably
growth hormone, estrogens and androgens,
were able to alter the composition of the
mature tissues towards that represented by
a younger age (277). The keratosulfate of
the mature animal appeared to be inert following synthesis and had a half-life probably in excess of 120 days. In human intervertebral discs, although the “limiting viscosity number” of the purified protein polysaccharide-complex fell with increasing
age, the ratio of chondroitin sulfate C and
keratosulfate remained 1:1 regardless of
age (773). In rib cartilage, injected labeled
glucose appeared in the galactosamine
moiety of the light protein-polysaccharide
fraction first, and then rapidly disappeared
accompanied by appearance of the isotope
in the insoluble residue (279). Appearance
of the label in the chondroitin sulfate,
which accounted for 80%of the total polysaccharide, preceded appearance in the
keratosulfate fraction.
Attention has also been focused on the
HIXEUMATISM AND ARTHRITIS
possible mechanisms of removal of polysaccharide from cartilage ( 137). In addition to proteolytic enzymes which can
cause release of polysaccharide from cartilage and alter the physical properties of
the protein-polysaccharide complex, enzymes which degrade the polysaccharide
itself have been partially characterized. It
has now been shown that, following proteolytic digestion of chondroitin sulfate preparations, the content of all of the amino
acids present decreased except that of serine ( 2 4 ) . The results of alkali treatment,
with accompanying chemical change in the
serine residue suggested that the hydroxyl
of serine was involved in the linkage of the
polysaccharide to protein. In another report, the chondromucoprotein from bovine
nasal septa was subjected to degradation
with testicular hyaluronidase and a variety
of proteolytic enzymes (474). Following
hyaluronidase treatment and exhaustive
proteolysis, glycopeptides were obtained
which were non-reducing, and contained
serine as the only amino acid. In addition
to uronic acid and galactosamine, galactose
and xylose were identified. It was suggested that the chondroitin sulfate chains
are joined to galactose by a glucuronidic
linkage and that the bond to protein is a
glycosidic one between galactose or xylose
and the hydroxyl group of serine (474).
Enzymes capable of depolymerizing hyaluronic acid, chondroitin sulfate and protein-chondroitin sulfate have been demonstrated in rat and guinea pig lung, liver and
kidney, rat spleen and in several human
tissues and fluids including kidney, urine,
plasma, synavial tissue and synovial fluid
(138). The enzymatic activity had a pH
optimum in the acid range and properties
similar to those of testicular hyaluronidase.
The changes observed in cartilage in osteoarthritis, decrease in the chondroitin sulfate and relative increase in the protein of
the protein-polysaccharide complex, suggested that a hyaluronidase-like enzyme is
responsible (139). In contrast to this hyaluronidase, enzymatic activity has been
described in extracts of human articular
cartilage which r d u c e the viscosity of
chondromucoprotein ( 373). Although the
reaction products were not thoroughly
characterized, it was suggested that the
protein portion of the protein-polysaccharidr was degraded at or near the chondroitin sulfate-protein bond.
The localization and identification of
rnucopolysaccharides in tissues has to a
great extent been possible through the use
ol histochemical trchniques. The rationale
of such techniques has been reviewed
( 1236). The developmellt ot methods for
the 5pecific determination of microgram
cjuantities of polysaccharides, on the basis
of tractional elution of cetyl pyridinium
complexes will undoubtedly supplement
the information obtained with histochemical methods alone (34).
Although the intravenous injection of papain into young rabbits: produce.; marked
softening of the ear cartilage, such gross as
well as microscopic changes are not produced in similarly treated mature rabbits
(471). However, chemical analysis of th?
cartilage in mature male animals did reveal
'in increase in extractable chondromucoprotein tollowing papain injection, which occurred at a later time after injection than in
the younger animals. These findings were
interpreted as a decreased permeability of
the cartilage matrix with aging. Effects similar to those of papain were observed in
animals made acutely toxic with large
doses of vitamin A, interpreted as due to a
liberation of proteolytic enzymes induced
by the vitamin (1251). The alterations
were largely prevented by the simultaneous
administration of cortisone. The hypothesis
was offered that the protective effect of the
adreriocorticosteroids: was due to an increased stability of lysosomes. The results
ot chemical analysis suggested that the initial primary effects of hypervitaminosis A
were a marked loss of hyaluronic acid and
chondroitin sulfate from the saline-soluble
components of the connective tissue (228).
The effects of the adrenocorticosteroids
on polysaccharide metabolism were studied
in other systems. Injections of methylprednisolone to rabbits resulted in an increase
in the polysaccharide-uronic acid of the vitreous humor and an increase in the polysaccharide-glucosamine in the costal cartilage compared to controls (635). It was
felt that this steroid hormone caused an
overall inhibition of degradation of these
polysaccharides. In contrast, in adrenalectomized rats, untreated or treated with cortisol, the steroid treatment resulted in
greater decreases in the content of acid
mucopolysaccharides of c o t t o n ball-induced granulomata (750). In human fibroblasts cultured in vitro, the intrinsic viscosity of the hyaluronic acid elaborated
into the culture medium was reduced during rapid cell growth and in the presence
of hydrocortisone (207). Histochemical
staining with toluidine blue and periodic
acid-Schiff reagents showed alterations in
the trabecular bone of cortisone-treated
rats suggesting abnormalities in the acid
mucopolysaccharides which were not
further characterized ( 108).
The effects of hormones other than
adrenal corticosteroids on polysaccharide
metabolism in several tissues have been investigated ( 277, 278, 279). In hypophysectomized rats, growth hormone pre-treatment increased sulfate uptake by various
cartilage fragments in vitro (1094). Testosterone irregularly produced increased uptake by nasal, xjphoid, and articular cartilage but an additive effect was seen in the
presence of growth hormone (1094). Stimulation of sulfate uptake by costal cartilage from hypophysectomized rats was
observed following treatment with testosterone, norethandrolone and methandrostenolone, which supported other evidence
that sulfation is closely linked to protein
194
synthesis. Estrogen treatment of male rats
decreased the hexosamine content of skin
as compared to controls (696). It was suggested that estrogen inhibited the synthesis
of chondroitin sulfate B of the skin. In contrast, in rabbits, estrogens increased both
chondroitin sulfate B and hyaluronic acid
content (278). The most striking hormonal
effect observed by the latter investigators
was the marked increase in hyaluronic acid
content of skin resulting from testosterone
administration. Evidence has been presented, supporting previous findings, of decreased synthesis of acid mucopolysaccharides in the skin of diabetic animals ( 1108).
Other factors influencing mucopolysaccharide metabolism have also been examined. The analysis of the components of
tendons from control and immobilized
knee joints of dogs showed decrease in
the total acid mucopolysaccharide of the
experimental limbs, 4 to 12 weeks after immobilization ( 12).
A series of papers has appeared on studies on the interaction between polysaccsharides and other macromolecules. The
decreaye in the diffusion behavior and the
sedimentation rate in the ultracentrifuge of
several proteins and other macromolecules
in the presence of hyaluronic acid was interpreted as the result of a molecular-sieving effect of the polysaccharide (714, 716).
The osmotic pressure of solutions of hyaluronic acid and serum albumin was
found to be greater than the sum of the
osmotic pressures of solutions containing
hyaluronic acid and albumin separately at
the same concentrations. The results were
consistent with the hypothesis that albumin
was “excluded from the part of the solution occupied by the hyaluronic acid (715).
Similar conclusions were reached using
dextran instead of hyaluronic acid (712,
713, 717). The behavior of crosslinked hyaluronate gels was also investigated (718,
720).
The properties of antibodies to a protein-
RHEUMATISM AND ARTHRITIS
polysaccharide preparation from bovine
nasal cartilage were described (303, 304).
Two types of antibodies were found, one of
which was directed against the proteinpolysaccharide and was species specific.
The other was directed against the carbohydrate moiety, chondroitin sulfate A, and
was not species specific.
HERITABLE DISORDERS OF
CONNECTIVE TISSUE
HURLER’SSYNDROME. Several patients
with Hurler’s syndrome were studied including those with the classical autosomal
recessive form, those with the sex-linked
recessive form and others with atypical disease (1249). The subjects with the classical
disease may show dwarfism, skeletal deformities, restriction of joint motion, deafness, hepatosplenomegaly and mental retardation. The sex-linked cases are usually
less severely affected, show no corneal
clouding and in general live longer. In this
report, quantitative and qualitative determinations of urinary acid mucopolysaccharicle
excretions were performed. The patients
with the autosomal recessive form excreted
approximately 80%chondroitin sulfate B and
about 20% heparitin sulfate. A large proportion of the chondroitin sulfate B was
precipitable as the calcium salt with 10%
alcohol in contrast to the chondroitin sulfate B of other origin. The patients with
the sex-linked form of Hurler’s syndrome
excreted about 55% chnndroitin sulfate B
and about 45% heparitin sulfate. In 2 patients with an “atypical adult form” both
chondroitin sulfate B and heparitin sulfate
were excreted in excess 1ut none of the
former material was precipitable as the calcium salt with 10%alcohol. Patients with
another atypical form excreted only heparitin sulfate in excess. It had previously been
shown by these same investigators, confirming the work of others, that the mucopolysaccharide of normal urine consists of
about 80%chondroitin sulfate A (754). Although the remainder consists of chon-
THE CONNECTIVE TISSUES
chitin sulfate B and heparitin sulfate, the
absolute amounts excreted by normals are
than those excreted by patients with
Hurler’s syndrome. The peripheral blood
lymphocytes of patients with Hurler’s syndrome contain inclusions demonstrable
with May-Grunwald-Giemsa stain (854,
885). The correlation was excellent between the presence of these lymphocytic
inclusions and the excretion of abnormal
amounts of mucopolysaccharides in the
urine. In another patient with Hurler’s syndrome, using electrophoretic techniques,
only chondroitin sulfate B was identified as
the abnormal urinary acid mucopolysaccharide (236). Postmortem examinations
with special histochemical examination
were performed on 2 patients with Hurler’s
syndrome (1361). The tissues had been
fixed in dioxane and after paraffin embedding were treated with cetyltrimethylammonium bromide to precipitate the very
water-soluble polysaccharides prior to contact with aqueous solutions. The patient
who had been mentally retarded had accumulations of both acid mucopolysaccharide and an abnormal glycolipid both in
the central nervous system and viscera,
whereas in the patient with normal intelligence only the acid mucopolysaccharide
accumulation was seen. It was suggested
that the fibrocyte w7as the most likely site of
the polysaccharide synthesis. The diagnostic use of the rectal biopsy with special staining procedure was suggested. One
patient with Hurler‘s syndrome demonstrated clinical and roentgenological improvement while on prolonged adrenocorticosteroid therapy over a 30-month period
until the time of cardiac failure and death
at the age of 38 months. The excretion of
urinary acid inucopolysaccharides was reduced during the period of therapy (1362).
Repeated clinical observations on 21 patients with Hurler’s syndrome revealed a
high frequency of heart disease usually detrctecl early in life and of a progressive
nature ( 100). Diffuse or localized endocardial thickening, histologically identical with
the lesions of endocardia1 fibroelastosis was
observed in addition to myocardial hypertrophy. So-called “gargoyle” cells were also
seen.
MORQUIO’SDISEASE.
The results of the
necropsy in an ll-year old boy with clinical
and radiological features of Morquio’s disease in addition to patent ductus arteriosus
were described (1105). The pathological
findings were limited to cartilage and consisted of abnormal accumulations of mucopolysaccharides in foam cells and the cartilagenous matrix. No visceral lesions were
found. The Morquio-Ullrich syndrome was
characterized by the roentgenological and
external appearance of Morquio’s disease
plus other abnormalities such as corneal
opacities, leukocytic granulations and hepatosplenomegaly (443). Three patients were
described who excreted increased amounts
of polysaccharides in the urine of which
the largest fraction was keratosulfate.
Chondroitin sulfate B and heparin monosulfate were absent (443). In a patient
with Morquio-Ullrich syndrome studied by
a different group, no keratosulfate was
found in the urine, but increased amounts
of chondroitin sulfate B and an “altered
hyaluronic acid” were identified by electrophoretic behavior and infra-red analysis of
fractions obtained by ethanol precipitation
(236). [ W h a t is called Morquio’s syndrome may well be a mixture of entities
similar t o the Hurler’s syndrome (1249).
The problem may be resolved w h e n the
same analytical techniques are applied by
diferent investigators. Ed.] One intriguing
case report describes an 11-year old girl
whose father had the Morquio-Brailsford
type of osteochondrodystrophy and the
mother osteogenesis imperfecta. The child
showed features of both disorders ( 1020).
MARFANSYNDROME.
Tissues from 6 autopsied cases of the Marfan syndrome were
examined by special histochemical tech-
196
nique\ to determine if any clues might be
derived as to the fundamental nature of the
di.;ease (136). It was concluded that the
basics lesion i\ an overaccumulation of
chondroitin siilfate followed by disruption
of elastic fibers. Electronmicroscopy of collagen fibril.; revealed no significant changes
in the major banding periodicity. [This
criterion in itself is inadequate to rule out
changes in the molecular structure of collagen. Ed.] The urinary excretion of hydroxvproline was studied in 17 patients
with hkrfan’s syndrome compared with
age-matched controls (616). High levels in
normals at the time of puberty were often
seen. However, pre-adolescent and adult
patients with Marfan’s syndrome consistently excreted greater amounts of hydroxyproline than controls. For the 13- to 18year old group the variation was too great
;o show definite differences. [ T h e meaning o f the elevated hydroxyproline excretion in some, but not all patients with Marfan’s syndrome is still obscure. Ed.]
Thc cardiac complications of the Marfan
syndrome were subjects for several reports.
The lesions noted included disswting aneurysms of the aorta and sinuses of Valsalva ( 1363), coarctation of the aorta (334,
527 ), rupture of the pulmonary artery
( 527), ruptured abdominal aneurysm
(601), complete heart block (82) and myocardial infarction and unusual myocardial
degeneration (1104).
The skeletal manifestations of the Marfan syndrome were reviewed, where it was
emphasized that the diagnosis should be
made only when abnormalities are found in
at least 2 of the 4 areas of involvement
(cardiovascular system, eye, skeletal system
and f-nmilv history). Arachnodactyly alone
is not an adequate criterion for diagnosis
( 1344). Further observations were reported
on a large Canadian family in which 42
members have had manifestations of the
Marfan syndrome ( 148). Arachnodactyly
HHEUhIATISM AND ARTHRITIS
and other skeletal abnorm.tlities were observed in a male descendant of Abraham
Lincoln. It was suggested that the President’s morphological characteristics were
manifestations ot the Martan syndrome
(1122).
Chromosomal analyses were made on 8
patients with the Marfan syndrome and 4
unaflected relatives ( 504). Heterozygosity
in the size of the satellite was seen in 5 of
the Marfan cases. However, none of the
satellites was more prominent than those of
either the unaffected relatives studied or
other individuals without stigmata of the
Marfan syndrome, indicating a lack of correlation between enlarged satellites and the
Marfan syndrome. In another report no
chromosomal abnormalities were found in
either of 2 sisters with the Marfan syndrome, although their brother similarly
affected had the rare XYY pattern (598).
Review of the literature did not reveal any
specific clinical picture characteristic of the
XYY chromosomal pattern. [ T h e clinical
similarities between Marfan’s syndrome
and homocystinuria, or inborn error of metabolism, have been emphasized (197) and
the enzymatic defect in the latter has been
defined (884). Eetopia lentis and abnormalities of the skeletal and mscular systems with affected relatives have prompted
the reporting of several patients as examples of Marfan’s syndrome who have
turned out t o have homocystinuria. The
cyanide-nitroprusside test, although not
specific for homocystine, is a useful screening procedure which can be follotoed by
the diagnostic identification of homocystine
in the urine. Ed.]
PSEUDOXANTHOMA
ELASTICUM.
An extensive review of pseudoxanthoma elasticum
has appeared (459). The typical skin lesions, angioid streaking, chorioretinal
changes and the gastrointestinal lesions
were described in detail. It was emphasized
that asymptomatic occlusion of the ulnar
and radial arteries secondary to medial proliferation is a frcyiient vascular change in
thi5 disorder. hluco5nl lesions with a gross
appearanc'c similar to those in the skin.
mouth ;tiit1 rectum arc also seen in the stomach. On the hasis of histological observations alone. it was postdated that the prirnary lesion in pseudoxanthoma elasticum is
cdciuor deposition in elastic fibers.
EHLEHS-DANLOS
SYNDROME.
Skin biopsies
from patients with Ehlers-Danlos syndrome
reek ealcd decrease in collagen and increase
in elastic fibers, both of which were qualitatively indistinguishable from controls, by
histochemicd arid electron microscopical
appearance (1318). On the basis of these
observations it was concluded that the disorder was principally one of the collagen
fibers. [More data are needed t o establish
this. Ed.] In other reports the clinical features were reviewed and unusual manifestations considered such a s multiple intrac*ranialaneurysms ( 1O82), sinus of Valsalva
arieurysm and aortic insufficiency ( 1269)
m d 5pontaneous rupture of large arteries
srich as the popliteal and subclavian (829).
One patient presented with manifestations
ot dermal fragility and multiple ecchymoses (446).
OSTEOGENESIS I~UPERFELTA.
The roentgenological features of osteogenesis impertecta in the adult were presented (741). The
occurrence of multiple fractures in long
hones with nearly normal appearing O S S ~ O U S
structure, platybasia and unusually large
paranasal and mastoid sinuses were considered characteristic. It was felt that the
gloomy prognosis usually extended in cases
of osteogenesis imperfecta did not adequately describe the natural evolution of
the disease. In contrast was a necropsy report of a case of osteogenesis imperfecta
congenita in which abnormal PAS staining
was observed in the skin, cornea and sclerae in addition to abnormal skeletal findings (589). Nephrocalcinosis was an addi-
tional feature noted. A lesion resembling
human osteogenesis imperfecta which had
previously hecn described in dogs and cats
was reported as occurring in lambs (578).
EXPERIMENTAL LATHYRISM
The experimental disease, osteolathyrism,
can be produced in a variety of animals by
the administration of extracts of the sweet
pea, Lathyrus odoratus, or by several simple chemical compounds such as p-amino
propionitrile (1243). The disease is characterized by a variety of connective tissue
deformities such as kyphoscoliosis, exostoses, hernias, and dissecting aortic aneurysms, loss of tensile strength and
marked increases in the extractability of
collagen (1355). Disturbances in endochondral ossification may be seen (1282).
Kadioisotope incorporation studies of normal and lathyritic chick embryo hone collagen did not demonstrate any interference
by lathyrism with collagen synthesis or
fibril formation ( 1241). The results of these
experiments suggested that a portion of the
extractable collagen represents newly synthesized protein as well as protein derived
from old insoluble fibrils. While the molecular dimensions, conformation and fibrilforming ability of lathyritic collagen did not
seem to be grossly altered there is evidence
for a failure of intramolecular crosslisking
characteristic of the maturation process.
Failure of the maturation process of collagen has been shown in several systems in
vitro. The addition of aminoacetonitrile
to cultures of mouse calvaria resulted in
increased extractability of the collagen
( 807). In the presence of p r ~ l i n e - C ~ ~ ,
the specific activity of the hydroxyproline in the salt extracts was the same in the
treated and control samples whereas the
specific activity of the insoluble collagen
was depressed by the aminoacetonitrile.
Similar findings were reported in a system
containing costal cartilage segments from
198
rapidly growing rats, in the presence and
absence of p-aminopropionitrile (977). The
defect in intramolecular crosslinking was
further shown in experiments involving incorporation of g 1 y ~ i n e - Cinto
~ ~ collagen of
normal and lathyritic rats (808). In the
lathyritic animals, the proportion of pchains (dimers) was decreased compared
to the normals. The labeled glycine in the
normals and lathyritics appeared earliest in
the a chains (monomers) and later in Pll
and /I1.. Labeling of the p chains was
markedly reduced in the lathyritic animals.
Differences in “chemical contraction and
relaxation” of collagen fibers from rats with
lathyrism versus normal are consistent with
defects in intramolecular crosslinking
( 1266). Salt extractable collagen was purified from rapidly growing normal and lathvritic guinea pigs ( 480). No differences
in the two preparations were found in
terms of total amino acid composition, carbohydrate content, denaturation temperature in both dissolved and reconstituted
state, optical rotatory dispersion at 304 to
589 mp, intrinsic viscosity and flow-birefringence measurements. However, a distinct difference was seen in the dissolution
of the thermally reconstituted fibrils. The
normal fibrils, after several days at 37”
tended to remain as precipitated fibrils
when cooled whereas the lathyritic fibrils
promptly redissolved. It was suggested that
the lathyritic collagen as well as the normal
is in the fibrillar form in connective tissues
but that there is an increased fraction in
lathyrism which may be dissolved in cold
neutral or acid buffers. Abnormalities in
the reconstitution properties of collagen
from lathyritic rats have been described by
others (918). The concept that a portion of
the extractable lathyritic collagen is recently synthesized and is in fibrillar aggregates in uivo is supported by an autoradiographic study of normal and lathyritic
embryonic chick bones (1242). Newly synthesized bone collagen, primarily in the
RHEUMATISM AND ARTHRITIS
periosteum, was organized as radioactive
spicules. Saline extraction of the lathyritic
bone removed the radioactive spicules, although they eventually became non-extractable. That collagen formation is not
inhibited by lathyritic agents was supported by studies using the rabbit ear
chamber (239). Growth of repair tissue
and the morphology of the collagen fibrils
were indistinguishable in the lathyritic versus the control animals.
Alterations in collagen are not the oidy
abnormality in experimental lathyrism. In
the presence of p-aminopropionitrile, cultured fibromatosis gingivae cells showed an
increase in the ratio of protein-bound hexose to protein tyrosine (185). Alterations in
staining properties of the ground substancc
were observed in the bony matrix of lathyritic rats ( 1282). Cultured fibroblasts
showed increase incorporation of radiosulfate in the presence of di-p-aminoproprionitrile, early in the life cycle of the culture
(116). Some of the material into which sulfate was iiicorporated had properties similar to chondroitin sulfate. However, in
mice, feeding of /3-aminopropionitrile resulted in decreased and delayed radiosulfate uptake into cartilage cells and matrix
(11). In the turkey, increasing levels of Pamino propionitrile in the diet decreased
the levels of free proline and alanine in the
plasma and increased those of valine, isoleucine and leucine (1302). Decrease in the
amino acid pool of lathyritic chick embryos
has also been observed (625).
Experimental Models of Arthritis,
Arteritis and Systemic Lupus
Erythematosus, and Their Naturally
Occurring Counterparts in Animals
An increasing variety of experimental
and naturally occurring models of arthritis
and/or vasculitis have been described. It
should be noted that none of the models SO
far described is identical with any human
EXPERIMENTAL MODELS
articular or connective tissue disease. HOWever, a few of them are sufficiently similar
to human syndromes (considering the species differences involved) to stimulate continuing interest in their study and their
possible relevance to human disease.
ADJUVANT ARTHRITIS
Adjuvant arthritis is a disorder resembling in some respects KA and Reiter’s syndrome. It can be induced in standard laboratory rats by the injection of either complete Freund’s adjuvant or some product of
mycobacteria (whole mycobacteria or components such as the wax D fraction). Polyarthritis and certain visceral lesions appenred approximately 12 to 15 days following a single injection of adjuvant, and the
arthritis frequently persisted or sometimes
waxed and waned over a period of several
weeks or months. Two general reviews
were published on the topic (970, 973). Inhibition of arthritis was observed when the
injection of complete adjuvant was preceded by the injection of various bacterial
lipopolysaccharides in incomplete adjuvant.
hIoreover, when certain potent protein antigens such as ovalbumin were administered in adjuvant prior to inoculation of
complete adjuvant, arthritis did not develop
but the animals became intensely sensitized
to the protein antigens. This appeared to
be an example of antigenic competition, although other explanations were possible. A
detailed gross and histologic study of the
pathologic details of the joint and other
connective tissue lesions appeared from
three laboratories (183, 617, 972), and
these studies revealed that the disease consisted of an acute arthritis and tenosynovitis which later passed through more
chronic stages including invasion by fibrous
pannus and ankylosis. A spondylitis occurred in the more caudal spine in some
animals. A study of the earliest histological
lesions in the joints and periarticular tissues
in this diseaw revealed that lesion forma-
199
tion was initiated by perivascular accumulations of mononuclear cells resembling
medium lymphocytes ( 183, 184). Several
hours or days later there was an increase in
number and size of the individual lesions
and a progressive increase in the number of
cells of monocytic or histiocytic type. Foci
of necrosis, polymorphonuclear leukocyte
infiltration, proliferation of fibroblasts, synoviocytes and osteoblasts occurred somewhat later.
The suggestion of infection, which constantly plagued workers on this mode during the early stages of its investigation,
seemed finally to have been ruled out, not
only by the fact that cultures for bacteria
and mycoplasma were almost constantly
negative in affected animals but also that it
was possible to induce adjuvant arthritis
quite readily in germ-free rats (971). Even
these results did not completely rule out
the possibility that a widespread dormant
virus was activated by adjuvant injection,
but this seemed most unlikely since such an
organism would have had to be uniformly
distributed throughout rats of many strains
in many parts of the world in order to account for the rather regular 80 to 90%incidence of this disease following a single
injection of adjuvant. [ N o other animal
species was known to develop adjuvant arthritis although a wide variety of laboratory species such as mice, guinea pigs,
rabbits, gerbils, kangaroo rats and squirrels
have been investigated. Ed.]
On the other hand, evidence seemed
strongly to suggest that the lesions of adjuvant arthritis appeared secondary to an
hypersensitivity type of reaction (970).
Foremost among the additional evidence
was the observation, from two separate
laboratories (975, 1304) that adjuvant arthritis was transferable with the use of living lymphoid or spleen cells from sensitized
donors to normal recipients of the same inbred str.iin. The transferred disease had the
same pathologic characteristics of the ori-
200
RHEUMATISM Ah’D ARTHRITIS
ginal disease except for a lesser severity. HOMOLO,GOUS DISEASE
This model was produced in the rat by
The transferred disease also appeared
much earlier than did the original disease, injecting large numbers of viable lymphoid
the latent period averaging about 4 to 5 cells which were collected from several
days rather than the standard 11 to 15 days members of an inbred strain of rats and
for primarily inoculated animals. When given to a single animal of another strain,
appropriate controls were used, utilizing that had been previously rendered tolerant
killed sensitized cells or living cells from by neonatal exposure to the lymphoid cells
the control rats sensitized with mineral oil of the donor. Animals injected with these
alone, arthritis was not transferred. The immunologically competent cells then contime for harvesting cells from sensitized tained more viable foreign types of lymphdonors for successful passive transfer was oid cells than they did cells of their own
restricted to the period 6 to 11 days after genotype. A disease was produced in these
adjuvant inoculation. Passive transfer was rats in an incidence approaching 100%.
not accomplished with thymocytes.
Such animals showed the well-known charOther studies wcrc directed at the distri- acteristics of homologous disease, including
h t i o n of adjuvant following injection into pancytopenia, wasting, and a high mortality rate (1200, 1201), and a number of
a singly site (909). It was shown that,
when colored adjuvant was used, and the other lesions, including ( a ) a chronic derinjectioii site was a foot pad or the tail, matitis which was said to have had some
colored adjuvant was found in at least one similar pathological characteristics to the
lymph node in all rats which developed skin lesions of lupus erythematosus as well
arthritis. A follow-up experiment (908) dis- as scleroderma [One must be extremely
closed that if all of the draining lymph careful not tct correlate too closeltj the
nodes were removed within 5 days of in- overall histologic picture in one organ bejecting adjuvant into the foot pad then cause it is well knotvn that tissues such as
arthritis did not develop. If, however, the skin have a limited way in which theti can
nodes were not removed until the 7th day, react pathologically t i a wide oariety of
arthritis did develop in a proportion of stimuli. Ed.], ( b ) a polyarthritis which
these animals. Such experiments served to was transient and migratory and occurred
emphasize the importance of the lymphatic in about one-half of the animals, and ( c ) a
system in the pathogenesis of adjuvant low grade chronic cardiac valvulitis in a
arthritis.
few animals. An interesting feature noted
Several additional studies emphasized in conjunction with the dermatologic lethat serum protein changes occurred in rats sions was the rejection of autografts and
which were injected with adjuvant arthritis acceptance of homografts derived from the
(397, 763). The changes were principally a inbred strain that had previously contrilowering of the serum albumin and eleva- buted large numbers of lymphoid cells.
tion of the alpha-2 and beta globulins
which occurred 3 or 4 days after adjuvant AUTOIMMUNITY IN NZB/BL MICE
injection when local inflammation deThis disease was discovered and first reveloped at the injection site. These altera- ported in 1959 (117). The authors noted
tions then returned to normal but reap- that by 5 months of age more than 95% of
peared again when the acute arthritis de- mice of the NZB/RL strain developed a
veloped. They seemed to be acute phase disease characterized by Coombs-positive
responses to tissue inflammation and injury hemolytic anemia. Studies of the natural
rather than being specific for the induced history of this disease (545, 546, 579) demdisease.
onstrated that over 5056 of these animals
201
EXPERIMENTAL MODELS
developed, latc in the course of the disease,
;L severe membranous glomerulonephritis.
The similarity of the renal lesions to SLE in
man was striking although the mice developed more severe lesions than those seen
in the human disease. Over 95% of the
mice 8 months of age or older showed proliferation of lymphoid tissue in abnormal
locations with abundant plasma cells.
About one-half of males also showed thymic germinal centers when they were bevond 240 days of age while females revealed this feature by the 175th day. Later
the germinal centers lost their activity and
11etramr a mass of small and medium
Ivmphocytes, most of the plasma cells having disappeared by this time. However,
I I ~ W germinal ceiiters continued to arise.
Mast cells were conspicuous in the cortex.
Tlie microscopic
and
ultrastructural
changes of the thymus gland were descrilwd (177). Approximately 4% of the
affected mice showed a positive serum LE
factor. and all of them had a positive
(bombs test. Antibody was eluted from the
red blood cc~lls and found to be a 7s
gamma globulin which reacted only with
red cells of the mouse. The arteritis and
renal lesions resembled lesions of serum
sick~iesshut the suggestion that deposition
of antigen-antibody complexes mediated
the lesions of NZB/BL mice was not supported by direct evidence. It was also
noted (928) that 40% of NZB mice developed antinuclear factor ( ANF). F1 generation animals of a cross between NZB x
C3H strains showed a varied incidence of
ANF which was dependent on sex (greater
in females). A number of hybrid groups
were established by mating NZB mice to
other inbred strains, and in all of these evidence of an autoimmune disease developed
in the F1 and F2 generations. This indicatrd inheritance of the tendency through
a dominant gene. It was also reported that
neonatal thymectomy accelerated the disease:. hforeover, it was noted that when
NZH/RI, mice were crossed with NZC/BI,
mice virtually all F1 hybrids developed the
autoimmune disease ( 118). This was
further strong evidence of inheritance by a
dominant autosomal gene, rather than
vertical transmission of a virus which
would preferentially affect offspring derived from the NZB female crossing with
the NZC male. The genetic predisposition
underscored the importance of heredity in
this group of disorders in the mouse.
ALEUTIAN DISEASE O F MILK
It is now known that all mink can contact this disease although there appears to
be a greater hereditary predisposition in
the Aleutian Blue Mink (au gene type)
(728). This disease is a chronic progressive
infectious process, characterized by ( 1) hypergammaglobulinemia, ( 2 ) glomerulonephritis, ( 3 ) marked plasmacytosis of the
spleen, liver, kidneys, lymph nodes and
bone marrow, and commonly also (4) a
significant arteritis, accompanied by fibrinoid changes in the connective tissues. For
years the disease was thought to be contagious, in 1982 its transmission by cell-free
filtrates was described. More recently, it
was shown that the filterable agent, causative of this disease, could be transferred
through 12 serid mink passages and that
the agent was present in whole blood,
serum, bone marrow, spleen, feces, urine
and saliva (198). The agent was infective
orally or as an aerosolized spleen suspension. These studies, and others, left little
doubt that this interesting disease, with all
its histopathological ramifications, was infectious and probably of viral origin (461).
Histopathological studies of hepatic and
renal lesions and the arteritis have been
reported (729). The increased gamma
golbulin was primarily 7 s globulin and did
not differ in physicochemical properties
from the 7s gamma globulin of normal
mink sera (660).
A number of theories concerning the unusual host-parasite mechanism that must
operate in this disease have been advanced
202
(730). These theories dealt with the possibility that virus in tissue cells, or more
likely in reticuloendothelial cells or plasma
cells, may redirect the production of protein through altering cellular RNA. Side
effects of this deviation may be seen as the
histopathological features of the disease.
The precise relationship between a marked
hypergammaglobulinemia and the tissue
lesions was not fully clarified. A direct relationship between the severity of the hypergammaglobulinemia and the severity of the
tissue lesions was reported (1001). What
seemed originally to be a most promising
hypothesis, namely that antigen-antibody
complexes were rapidly formed and deposited in tissues, and therefore caused tissue damage, has not been borne out by
further study, since: ( a ) there appeared to
be a marked excess of antigen in the blood
stream if the viral agent was the antigen,
and ( b ) attempts to localize antigen-antibody complex in damaged tissues have so
far failed. Other aspects of this disease
have been reported (432, 648, 661, 1089).
One interesting, although as yet highly
speculative supposition, is that Aleutian
disease may be contracted by man. A recent case report concerned a mink farmer
u7ho died of a chronic granulomatous discase that resembled, in some respects,
Aleutian mink disease (216).
RHEUMATISM AND ARTHRITIS
there was fibrinoid degeneration of some of
the small blood vessels in the renal glomeruli and what appeared to be “wire
loop” formation.
All of the animals which were studied
exhibited a Coombs-positive hemolytic
anemia. Of 13 dogs that were tested for the
presence of L.E. cells, 9 were positive. It
was interesting that the Coombs reaction
became negative when a remission was induced in the disease with corticosteroid
therapy (748). Canine SLE differed from
the human disease in its lack of elevated
gamma globulins but in many other respects it showed striking similarities. Antinuclear antibody was found in the serum of
an apparently healthy female offspring of
one of the cases. Several breeds of dogs
were involved. Four of the 7 which were
intensively studied were females.
INFECTIOUS ARTHRITIS
Various types of infectious arthritides
have been found to occur naturally in several animals, especially in swine, and miny
of these have been cxperimentally reproduced in the laboratory. The most common
cause of arthritis in swine is the organism
Erysipelothrix insidiosa (formerly Ery.
rhusiopathiae). The disease was primarily a
spontaneous polyarthritis which followed a
progressive but irregular course and produced severe distortion with particular affiCANINE SYSTEMIC LUPUS
ERYTHEMATOSUS
nity for the small distal joints. PathologiA disease in dogs which resembled hu- cally the lesions resembled rheumatoid
man SLE has been recently reported (748). arthritis [with some reservations. Ed.].
The authors reported 19 instances of na- Rheumatoid nodules, of the type seen in
t urally occurring illness characterized by RA in man, were not described but an ochemolytic anemia, thrombocytopenia and casional animal showed a very low sensinephritis. Seven of these animals were the tized sheep cell agglutination titer. [ T h e
subjects of the main report. The animals latter probably reflects persistence of bacdemonstrated a dry scaly eruption of the terial antigens rather than the arthritis per
face. Hepatic necrosis and myocardial in- se. Ed.] It was interesting that organisms
farcts due to thrombosis of small muscular could not be recovered from chronically inarteries were found. There was, in addi- volved joints-thus
a hypersensitivity
tion, segmental arteritis and fibrinoid de- phenomenon was postulated. It was shown
generation of blood vessels. In the kidneys (405, 406) that when swine were prc-
203
EXPERIMENTAL MODELS
viously sensitized by sterile supernatant of
cultures which had been destroyed by ultrasonic treatment, these animals developed synovial lesions which were rather
mild and unconvincing as an experimental
model. In support of the hypersensitivity
theory, it was also observed (403, 404)
that, when animals had been previously
sensitized with sterile non-viable Ery. insirliopu antigen and then inoculated with
liable organisms, a severe and rapidly developing arthritis occurred. The serum electrophoretic changes in protein patterns in
swine with this arthritis were primarily
conyistent with those which occurred in
acute and subacute inflammatory states
(951,952).
Another type of swine arthritis, produced
by a mycoplasma organism, Mycoplasma
hyorhinis, was similar in many respects to
that of erysipelothrix arthritis. Intraperitoneally inoculated pigs developed polyarthritis 5 to 12 days later and the disease
continued for many weeks thereafter
( 1045). Pathologically there was subacute
and chronic synovial membrane inflammatory reaction, hyperemia and adjacent bone
and cartilage destruction. Organisms could
be cultured from nearly all joints, even in
the very late stages of the disease.
Another sporadic naturally occurring inflammatory disorder consisted of a polyarthritis which developed in sheep during
certain seasons of the year and was caused
by an organism of the psittacosis-lymphogranuloma group ( 1214). An infectious
synovitis was also commonly associated
with Mycoplasma (662, 943) and with an
L-phase bacterial form in poultry ( 1044).
A chronic joint disease was produced in
rabbits and guinea pigs 3 to 6 months following the p a r e n t e d injection of viable
atypical Mycobacteria (684, 836, 1334).
The pathology of this disease was primarily
that of a chronic inflammatory reaction
with caseous necrosis at the site of the tendinous and articular lesion\, in conjunction
with multiplication of acid-fast bacilli. The
predilection for the joints and other tissues
was an interesting facet of this induced disease.
DEGENERATIVE JOINT DISEASE
The osteoarthritis previously induced in
certain strains of laboratory mice has been
studied in more detail (1160). It was
found that in female mice of particular
strains the administration of testosterone
significantly increased the incidence of
osteoarthritis if the female had been previously ovariectomized ( 1160). A high incidence of osteoarthritis in at least one
strain was explained by a genetically determined characteristic dyschondrogenesis
which caused an increase in growth and
vulnerability of the cartilage of the epiphysis of the tibia and femur (1161). This lesion was intensified by mechanical trauma
in poorly formed and poorly fitting joints.
Spontaneous osteoarthritis which is common in many animals had not previously
been reported in birds. Careful review of
this subject (1186) dispelled this fallacy
since significant primary osteoarthritis was
found in one or more joints in 15 of 48
captive birds.
OTHER MODELS
An experimentally induced arthritis was
observed following the intra-articular injection of the enzyme papain (892). This proteolytic enzyme has a profound effect upon
cartilage, disrupting the mucopolysaccharide complex. In rabbits it was noted
that during a 6-day period severe degeneration of the articular cartilage occurred
in the joint which was injected, with
loosening of the cartilage, especially in the
weightbearing area. This was followed by
thinning and fibrillation of the remaining
surface. Ultimately the changes in the articular cartilage and surrounding bone were
similar to those noted in clinical forms of
degenerative arthritis.
SO4
RHEUMATISM AND ARTHRITIS
An experimental vasculitis was induced
in rats (1328) immunized with an extract
of isologous arterial tissue, incorporated
into Freund's complete adjuvant. Gamma
glol)ulin was observed by the immunofluorescent technique in the walls of involvcd vessels.
Inflammation
The relevance of the study of inflammation to the rheumatic diseases is unquestioned. The complexity and diversity of the
topic. prcdudeq any consideration in depth.
[ A n excrdlent and comprehensive volume
hus. becii published in which all known
aspects of tlic inflamrnutory process are reuieuetf (1392). Ed.] The chemistry of inflarnmatioii ( changes in coll~~gen,
mucoplysaccharides and mucoproteins) has
\wen reviewed (334). A study of inflammation induced by a variety of injuries documented the adhesion of leukocytes to injured endothelium and subsequent migration of leukocytes through gaps that developed between endothelial cells (882).
TI-ic. r d y phases of injury and inflammation in response to many stimuli may be
mediated by common events, i.e., liberation
of histamine or serotonin (112, 1281). During the past few years, increasing attention
has been devoted to the inflammatory potential of released lysosomal hydrolytic enzymes (651, 1320, 1322, 1323). A variety of
stimuli (ultraviolet light, vitamin A excess,
exposure to streptococcal streptolysins and
thermal injury) are capable of releasing
degradative enzymes from lysosomes of
leukocytes and other phagocytic cells.
The inflammatory effects of a pyrogenic
steroid ( ll-ketopregnanolone) were studied in man. Local sites of injection were
biopsied and revealed massive leukocyte infiltrates, panniculitis, myositis and angiitis
(440). [As with other types of inflamma-
tion. the humoral andl or cellular events
that mediate this response to pyrogenic
.strroids is not knoujn. Ed.]
Anti-Rheumatic DrugsEffects and Toxicity
All antirheumatic drugs have the potential for serious toxicity. Gastrointestinal irritation with or without peptic ulceration is a
significant consequence of therapy with salicylates, adrenocortical steroids, phenylbutazone and its analogues, antimalarials,
and indomethacin. Idiosyncratic and allergic reactions can, to varying degrees, complicate the us3 of any therapeutic agent.
Cytopenic responses (i.e., agranulocytosis,
thrombocytopenia, or aplastic anemia) are
rare but have been attributed to the administration of gold compounds, phenylbutazone, aspirin and antimslarials (917). The
list of anti-rheumatic agents capable of inducing hemolysis in patients with glucose-6phosphate dehydrogenasr deficiency continues to increase and includes, to date, aspirin, antipyrine, phenacetin, phenylbutazone and probenecid. Hemolytic reactions
to such drugs are not invariable in enzyme
deficient subjects. The presence of deficiency is not an absolute contraindication
to administration of the drugs, but awareness of the problem is important. [For review of the suhiunct, .see ( 6 2 ) . Ed.]
The Problem of Analgesics and Nephritis
During the past decade, there has been
an expanding literature suggesting that the
chronic ingestion of large amounts of common analgesic drugs may produce renal
disease. Recent reviews of the subject have
been published (435, 1079, 1383). Although phenacetin has been incriminated
in most reports, with rare exceptions the
analgesics ingested have been mixtures of
drugs-varyingly salicylate, caffeine, antipyrine, aminopyrine and codeine. Phenacetin is the most common denominator in
these compounds, but the possible role of
the other ingredients cannot be dismissed
(435). There is no evidence that salicylates
alone cause renal damage. It is interesting,
ANI‘I-HHEUMATIC DRUGS-EFFECTS
AND TOXICITY
however, that an increase in urine cell
count (presumably from tubular epithelium) follows salicylate, but not phenacvtin, administration ( 1124). Chronic interstitial nephritis is invariably reported in
“analgesic nephropathy.” Papillary necrosis
and bacteriological evidence of infection
are common (395, 513, 1067). Aiitemortem
diagnosis of renal papillary necrosis could
be made radiographically (513). Kegres\ion of the process has been described following discoiitinuation of analgesics and
c.ontrol of infection with antibiotics.
Most experimental efforts to demonstrate
iiephrotoxicity of phenacetin, alone or in
compounds, have failed (330). Eats fed
phenacetiii or varying combinations of aspirin, pheriacetiri and caffeine for periods
up to 16 months developed tubular, interstitial and papillary lesions ( 3 ) . [Similar
changes of mild degree icere observed in
“control” animuls. Of possible significance
I C U S the ohscrzjation that the most severe
papillary lesions occurred in rats receiving
d l three of the aholje drugs. Ed.]
Although analgrxsics appear to render
rats more wsceptible to pyelonephritis induced by intravenous injection of E . coli,
ascending infection (bladder instillation of
E . coli) was not favored by drugs (284).
Renal concentrating capacity was reduced
in rats receiving phenacetin or N-acetyl-parninophenol (main metabolite of phenacd i n ) (29).
The pathogenesis of analgesic nephropathy is not known. Possible mechanisms
include drug-induced hemolysis or methemoglobinemia, lowered resistance to infection, and direct cytotoxic effects of phenacetin, its metabolites or trace contaminants.
[Of these, decreased resistance to infection has the best experimental supportstudies of liematogenous pjelonephritis.
Ed.]
S ALICY LATES
The analgesic property of salicylates is
iindoihted. Anti-inflammatory effects are
205
unequivocal in laboratory models (434)
and in certain clinical states such as acute
rheumatic fever. The question whether or
not salicylates are anti-inflammatory in subjects with KA has been answered in the
affirmative (402,785).
Although several biochemical effects of
salicylates are known, there is no knowledge of the specific events that mediate
their pharmacologic action. The uncoupling
of oxidative phosphorylation by salicylate
has been further studied (357, 1331). Several effects of salicylates on amino acid metabolism have been reported. Salicylates
caused decreased incorporation of glutamate (CI4) and proline (C14) into rat cartilage and an increase in liver concentration
of glutamate and alanine (92, 591). Salicylate intoxication in rats produced a
prompt increase in glutamic acid excretion
(100 times control levels) and, within 24
hours, a generalized amino-aciduria ( 110).
Salicylate effects on vascular and permeability phenomena, which may mediate inflammation, have been studied. Sodium salicylate in high doses inhibited testicular
hyaluronidase (1069) and aspirin (3.6 Gm
daily) inhibited the vasomotor effects of
epinephrine and norepinephrine in man
(1221). There was no measurable inhibition of pancreatic, salivary or serum kallikreins by sodium salicylate (534). The
competition between salicylate and thyroxine for thyroxine-binding prealbumin of
serum was confirmed ( 1358).
TOXICITY.
The value of alkaline diuresis
(intravenous administration of glucose, sodium chloride and sodium bicarbonate) in
the treatment of acute salicylate poisoning
was emphasized (269). Pulmonary edema,
attributed to salicylate intoxication was the
subject of a case report (473). [“Pulmonary edema” was diagnosed radiographically-rales were not heard. Most reports
of this complication have been in patients
with intrinsic heart disease where the role
of salicylates can be questioned. Ed.] The
206
RHEUMATISM AND ARTHRITIS
influence of salicylate on hemostasis was unresponsiveness to stress in steroid-treated
studied in RA and control subjects. After 2 subjects. The practice of periodic adminisweeks of treatment (3.0 Gm daily) signifi- tration of corticotropin ( ACTH ) to steroidcant prolongation of bleeding times and treated patients was reviewed and condecreases in platelet-stickiness were ob- demned (1043). Patients on long-term corserved (426). The potential for salicylate- ticotropin therapy did not have normal reinduced hypoprothrombinemia and bleed- sponses to mepyrapone ( 1024). [ Although
ing was re-emphasized (998). The anti- a few studies in the past have suggested
genicity of salicylate-protein conjugates in that the adrenal response to stress may be
rabbits was demonstrated and a hemag- normal after long-term corticotropin therglutination test devised for the detection of apy, current evidence argues against it.
antibodies in patients allergic to salicylate Ed.] In rats, estradial therapy, concomitant to cortisone treatment minimized ad( 1319).
Additional clinical and experimental renal unresponsiveness to stress (667).
studies of salicylate-induced gastritis and [Interesting. The clinical relevance is not
gastric ulcers have been reported (27, 383, known. Ed.] The pituitary-adrenal respon596, 737, 771, 1070, 1275). In an experi- siveness of patients on varying steroid
mental study in rats, the ulcerogenic poten- regimens was reviewed (276). Patients taktials of salicylates and adrenocortical ster- ing only 5.0 mgm of prednisolone in a sinoids appeared to be synergistic (425). In gle daily dose in excess of 100 weeks had
approximately 70% of normal individuals, normal responses to mepyrapone (286). Inthe ingestion of salicylate caused blood loss termittent, every other day, administration
of 2 to 6 ml per day, and in a small propor- of steroids was recommended in an effort
tion the loss was much greater (1367). to minimize side effects and adrenal unreThere was no correlation between occult sponsiveness (521). [There is good evibleeding and dyspeptic intolerance. Bleed- dence that these goals were, at least in
ing was reduced by simultaneous adminis- part, achieved; but only 3 of the 58 patients
tration of a great excess of antacid, or by had RA. In the experience of some of the
the use of enteric coating. The gastroscopic reviewers, patients with active RA or SLE
observations of erosions surrounding parti- will not tolerate this regimen, i.e., they excles of ingested salicylate were repeated, acerbate on the day steroid is withheld.
with better controls (991). The reports that Ed.]
bleeding may follow intravenous adminisExperimental studies of steroid-induced
tration of salicylate were criticized and dis- gastric ulcers were described (626, 915).
missed, but not repeated (1367). The The problem of posterior capsular cataracts
mechanism of the irritant action was hotly complicating chronic steroid therapy has
debated.
been reviewed (262, 264, 600, 734, 1227).
[Since most previous cases were rheumaADRENOCORTICAL STEROIDS
toid arthritis subjects, there has been a
No other class of drugs approaches the question whether the underlying disease or
anti-inHammatory potency of the adreno- the therapy was to blame. The association
cortical steroids. Of the several forms avail- now with a variety of diseases incriminates
able, i.e., prednisone, dexamethasone, tri- steroid therapy. Ed.]
amcinalone, etc., none is clearly “better” or
Aseptic necrosis of the femoral head
less toxic than the rest (135).
complicating steroid therapy has been reRecent comments and observations have viewed (134, 963). Three pediatric cases of
bctn directed at the problem of adrenal pseudotumor cerebri were attributed to
ANTI-RHEUMATIC DRUGS--EFFECTS
AND TOXICITY
201
reversible (266, 549, 550, 1248). The incidence of this complication is in question. In
one study (222 RA subjects receiving antimalarials
for 2 or more years and 98 control
in rabbits that received cortisone or triHA subjects), there was no significant assoamcinolone.
ciation between retinopathy and antimalarANTIMALARIALS
ial treatment (1248). In a review, it was
Hecent therapeutic trials ( A.R.A. Co- estimated that no more than 1 out of 1,000
operative Clinics ) have confirmed the anti- to 2,000 patients on long-term chloroquin
inflammatory effect of hydroxychloroquin therapy will develop retinal damage
in rheumatoid arthritis sLibjects (783). (1297). In another report, 18%of 45 pa[Fine statistical control and analysis were tients receiving chloroquin for 6 months or
required t o detect slight, but significant, more had retinopathy (550). Techniques
differences between placebo and drug for early diagnosis of chloroquin retinopagroups. Ed.] Antimalarials continue to be thy have been described (549, 939). [ T h e
the drugs of choice in management of dis- safest course t o follow (for those who think
coid lupus erythematosus but there is not antimalarial therapy has value) is t o secure
iinanirnity regarding their usefulness in the an ophthalmologic examination before
treatment of SLE. The dermatological indi- therapy and then re-examine the patient
cations for antimalarial therapy have been every f e w months during treatment. Unoutlined and toxicity, in general, reviewed doubtedly, some of the cases of “chloroquin
(1025). The mode of action of antimalar- retinopathy” would not be so labelled if a
ials is not known. Chloroquin did not inter- pre-treatment examination had been perfere with cutaneous anaphylaxis, delayed formed. Ed.] Pigmentary changes which
hypersensitivity, contact dermatitis, or the have been attributed to antimalarial therinflammatory stimulus of intracutaneous apy include loss of hair pigment and hyadministration of silica (999). Chloroquin perpigmentation ( 1272). [ I t is interesting
was capable of preventing ultraviolet dena- that the retinal accumulation of chloroquin
turation of serum proteins and modifying i n animals correlates with the degree of
heat denaturation of serum albumin (430, pigmentation. Ed.]
Cases of peripheral neuropathy and neu937). The effect of heat denaturation was
attributed to the blocking of the sulfhydryl romyopathy attributed to chloroquin were
disulfide interchange reaction. [ Chloro- reported (758, 1326). Two cases of toxic
p i n has a high affinity for cell nuclei and psychosis were described in patients receivfor purified preparations of deoxyribonu- ing small amounts of chloroquin (1013).
[ T h r e are clinical impressions that anticleic acid (251).Ed.]
TOXICITY.Several reports have empha- malarials may exacerbate psoriasis. Alsized ocular complications of antimalarial though this reaction is not invariable, psoritherapy. Corneal deposits of drug have asis should probably be considered a relubeen encountered frequently (30 to 86%) tive contraindication to antimalarial therin patients on long-term therapy with vari- apy. Ed.]
ous antimalarial agents (550, 647, 1099).
The corneal changes are not serious and GOLD COMPOUNDS
appear to be reversible if therapy is disconOne issue of the Archives of Inter-Amertinued.
ican Rheumatology contained several reRetinopathy. as a complication of anti- ports on gold therapy (A.I.R. 6: 1963). Tho
malaria1 therapy, is serious and is often not experience of the Empire Ilheumatisni
steroid therapy (252). Experimental studies
of “steroid myopathy” were described
( 1175). Severe muscle necrosis developed
'08
(:ouncil's trial of gold therapy for RA was
sumrnari/;ed (514). Although this trial
cicmonstrated improvement after a course
of sodium aurothiomalate (50 mgm weekly
tor 20 to 26 weeks), further therapeutic
trials \I ere recommended (784). [ A n
rl.K.A. L'ooperatice Clinic trial is in pro. Ed.] The chemistry of gold compounds was reviewed (920) and experiences with gold therapy presented (254,
1019, 1179). The disposition of large
:~rnoniitsof gold in articular and periarticular structures of mice was studied by
autoradiography after neutron activation
(1260). One to 2 months after administration. gold was localized at the surface of
the synovium in the periosteum, reticulocndothelial cells of marrow, osteogenic
c ~ l l sand secondary centers of ossification.
The valuc of penicillamine in treatment of
gold toxicity was demonstrated in clinical
m d experimental studies (281, 354).
<;old thiomalate was shown to alter denaturation of wrum albumin, probably by
hlocking thc sulfhydryl disulfide interchangr. reaction (431 \.
RHEUMATISM AND ARTHRITIS
of phenylbutazone therapy is appropriute.
Ed.]
INDOMETHACIN
Indomethacin
( 1-p chlorobenzoyl-5
methoxy-2-mcthylindole-3-acetic acid), a
new compound with antipyretic, analgesic
and anti-inflammatory properties was
marketed in the United States in mid-1965.
In certain laboratory models of inflammation, it was more effective than phenylbutazone and hydrocortisone ( 1354). Its
pharmacologic effects are independent of
adrenal function. In clinical studies, 50
mgm of the drug were equivalant to 600
mgm of aspirin in analgesic potency
( 1228). Clinical trials of indomethacin in
rheumatic disease subjects have been reported (515, 517, 839, 979, 1308). There is
general agreement that patients with acute
gout and ankylosing spondylitis respond
favorably to indomethacin therapy. Several
workers have reported favorable effects in
patients with degenerative joint disease, especially degenerative disease of the hip.
Clinical impressions suggest it may be of
some benefit to patients with HA but its
P M ENY LBUTAZONE
eflects in such patients are often equivocal.
Oxyphenbutazone inhibited the increase [ A double-blind, statistically controlled
in Yeromucoid levels which follow the in- study has been completed (A.R.A. Coduction of sterile peritonitis in rats (63). operative Clinics) but not reported. Ed.]
Phenylbutazone and its derivatives in- In man, the drug exists in blood only in the
hibited the uptake of sulfur ( S R 5 )by car- unconjugated form but appears in the urine
tilage and the stomach of rats (298). The exclusively as the glucuronide-the conjusvnthcsis of sulfated polysaccharides in rat gation presumably occurring in the kidney
cartilage was diminished by phenylbuta- (509).
TOXICITY.To date there has been no un/one and other anti-inflammatory drugs
( 146). Acute reversible renal failure (pro- equivocal evidence of hematopoietic, hepatteinuria and azotemia without oliguria) ic or renal toxicity. At dose levels of 300
was attributed to phenylbutaTone therapy mgm/day, side effects (varyingly head( 1033). The possibility that acute leukemia ache, nausea, epigastric pain, diarrhea and
may br a rare complication of phenylbuta- mild mental disturbances) are frequent
m n e therapy w a s suggested (519, 520). (approximately 30 to 50% of patients).
[ 18 C U I J C Sare reported in the literature. The Some authors have reported better tolerrelutionship to the drug is not certain but ance by initiating therapy at 50 to 100
the warning that the risk of developing leu- mgml day levels and gradually increasing
kcrnia might be greater as a consequence the dose to 200 to 300 mgmlday. [Al-
HE,FFRk
\(
209
ES
though phc.n!ylhutazone is an efcctivz
cigeni for the management of ankylosing
.cpndyliti.s .sornr physicians p r e f w indom&acin M a n y patients (qwrience mayor
improccmmt on (lows in the range of 100
t o I S O mgrnIda!l. I t is interesting that tzoo
tlrz~g., U P dissimilnr chemically as indomcthacin und phenylbutazone have similar
therrrpeictic c#ects, i.e., useful in gout and
yiondylitis. Ed.] Skin rashes have been reported infrequently. Occult gastrointestinal
bleeding was cstiinated with the radioactive chromate technique. There was less occult blood loss in patients receiving indomethacin (200 to 300 mgm/day) than in
patients taking salicylates [dose not stated
Ed.]. Although frank gastrointestinal
hemorrhage has been attributed to indomethacin, most reports concern patients recrGving other drugs (salicylates andlor
adrenocortical steroids) either concurrently or ju\t prior to indomethacin ther-
qy.
OTHER AGENTS
AN‘IIMETABOLITE DRUGS.In recent years,
driig\ which were developed for cancer
cbhemotlicrapy ( 6-mercaptopurine, 6 thioguanine and alkylating agents, etc. ) have
been administered to patients with connective tissue diseases. [The rationale, which
n q be fallacious, is that a disease such us
STJE will he modified via suppression of the
immune response. Ed.] 6-Mercaptopurine
(2.5 mgm/Kg) treatment of 6 patients with
neoplastic disease suppressed the immune
rc\ponse to a primary antigenic stimulus
and prevented induction of delayed hypersensithity (742). Two of 4 patients with
S I X treated with 6-thioguanine experienced symptomatic improvement (458).
The clinical effects were transient and significant bone marrow depression occurred.
In another study, 5 patients with SLE, 2
patients with systemic sclerosis and one
each with dermatomyositis and “necrotixing angiitis” were treated for varying periods with 6-thioguanine (295).In the majority of patients, the results were equivocal
and the remissions t ncountered were
temporary. [One patient with SLE ex-
perienced a prompt and dramatic remission
hut died of a gastroiritestirml liemorrhage.
There are indications, f r o m such studies,
that antimetabolite therapy m u / suppress
the activity of diseases siich us SLE. However, the risks are grent und the agents
auailable are too toxic for mqintenance therupy of those pntients that improve. Direct
evidence that remissions are mediated viu
suppression of the immune response is lacking. The drugs have unti-inflammatory
effects also. Ed.]
DIMETHYLSULFOXIDE
( DMSO ) . Reports
from one center have ascribed therapeutic
benefit to DMSO for a variety of musculuskeletal syndromes (1059, 1060). This interesting compound has had several industrial applications but its potential as a
pharmacolcgic agent or as a vehicle for
various drugs needs confirmation. [ Severul
clinical trials are in
perience of many
that the widespread
was not warranted.
progress. The early exinvestigators suggests
publicity gizjen DMSO
Ed.]
IBUFENAC (4-ISOBUTYLPHENYL-ACETIC
ACID).
Ihufenac-treatment of RA was evaluated
with a double-blind crossover (1254) and
found to be superior to calcium aspirin.
Gastrointestinal blood loss (radiochromate
technique) was less than with aspirin
(1270). [In the former study, however, 14
of 36 patients developed luboratory evidence of hepatic dysfunction and 2 of the.se
became jaundiced. Ed.]
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