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Proceedings of the Annual Meeting June 1960.

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AMERICAN RHEUMATISM ASSOCIATION
10 Columbus Circle, New York 19, New York
President: EDWARD
F. HARTUNG,
M.D., 580 PARK AVENUE, NEW YORK 21, NEW YORK.
First Vice President and President Elect: JOSEPH L. HOLLANDER,
M . D . , 3400
SPRUCE STREET, PHILADELPHIA 4, PENNSYLVANIA.
Second Vice President: HANS
WAINE,M.D., 25 BENNET STREET, BOSTON 11, MASSACHUSETTS.
Secretary Treas2176r: FELIXE. DEMARTINI,
622 WEST 1 6 8 STREET,
~ ~
NEW YORK 32, NEW YORK
Executive Secretary: GERARDW. SPEYER,10 COLUMBUS CIRCLE, NEW YORK 1 9 ,
NEW YORK.
Proceedings of the Annual Meeting of the
American Rheumatism Association
June 9-11, 1960
Hollywood-By-The-Sea, Florida
Abstracts of Papers Preseiited and Read by Title
Eurron: W d h n S. Clark
PSOnIATIC AHTHHITIS:
A ROENTGENOLOGIC
STUDY
Rogelia Auila H . , David G. Pzigh and Charles €I. Slocuml?, Rochester, Minnesota
The arthritis that frequently accompanies
psoriasis resembles rheumatoid arthritis but
strong evidence is being compiled as the
result of clinical, laboratory and roentgcnologic observations which indicate. that
psoriatic arthritis is a separate entity. In
an endeavor to help clarify r?ie issue, the
roentgenograms of 155 patients having
psoriasis with arthritis wcre studied and
the changes seen were compared with
those that occurred in 100 patients who
had rheumatoid arthritis but who did not
have psoriasis. It was found that in niany
patients having psoriatic arthritis, changes
were evident that seldom or never Occurred
in rheumatoid arthritis.
Five roentgenologic signs of psoriatic
arthritis are offered as roentgenologic cri-
teria of psoriatic arthritis. These are as
follows: ( 1) arthritis resembling rheumatoid arthritis but involving entirely or predominantly the distal interphalangeal joints
of the hands and the interphalangeal joints
of the feet; ( 2 ) bony ankylosis of interphalangeal joints of the hands and feet;
( 3 ) destructive arthritis of the hands and
feet characterized by widened interphalangeal joint spaces with the ends of the adjacent bones sharply demarcated despite
the fact that the articular bony cortices
have been destroyed; (4) destruction of the
interphalangeal joint of the great toe with
bony proliferation a t the base of the distal
phalanx; and ( 5 ) resorption of the tufts
of the distal phalanges of the hands and
feet.
PATTERNS
OF SKINMOBILITY
CHANGEM SCLERODEI~MA*
Daniel hf. Bachnzun, Portland, Oregon
A new method of measuring skin mobility
in deroderma uot requiring s p e d tipparatus will be illustrated. This technique
'Read by title.
429
has proven useful in following the patterns
of change of skin mobility in nine patients
with generalized scleroderma for periods
up to two years.
During each measuring session, niaximum
AMERICAN RHETJhlATISM ASSOCIATION
skin mobility was determined a t each of
16 standard skin sites in each patient.
The skin mobilities of the individual skin
sites (component mobilities) were summed
to yield a total score of skin mobility for
each time of measurement. Component and
total skin mobility scores were plotted as
functions of time.
To assess the experimental error of the
technique, 10 sets of skin mobility measurements were performed serially by 4 observers upon 4 normal subjects for periods
up to 3 months. Standard deviations indicated excellent reproducibility of total skin
USE
O F THE
HYPOSPRAY
Jm I NJECTOH
mobility scores obtained by single observers
performing repeated measurements upon
the same subjects at different times.
Large serial changes in total skin mobility were quantitatively demonstrated in
some patients with scleroderma. In these
patients parallelism was noted in the direction of change of skin mobilities of nearly
all skin areas measured. Despite differing
degrees of sclerodermatous involvement at
individual skin sites, the skin in patients
with scleroderma appeared to react as a
unitarj organ to factors producing changes
in total skin mobility.
FOR
INTRA-ARTICULAR
IN JECTIONS"
John Raum and Morris Zif,Dallas, Texas
The validity of the hypospray technique
foc intra-articular injection has been previously demonstrated on the basis of controlled studies and recovery of injected
steroid and dye from the joint. In the past
six years, 504 injections have been given
to 156 patients. One hundred of these had
rheumatoid arthritis and the rest had other
arthritides or non-articular rheumatism. All
commonly injected joints but the hip have
been successfully injected by this method,
using hydrocortisone acetate, prednisolone
T.B.A. ( Meticortelone T.B.A.), and triamcinolone acetonide (Kenalog).
A total of 335 injections have been given
to 88 patients with rheumatoid arthritis in
whom adequate follow up is available. Major improvement was observed in 84 per
cent of 86 injections of the small joints
'Read by title.
of the hands and feet, 70 per cent of 158
injections of the knee, 49 per cent of 63
injections of the wrist, and 64 per cent
of 28 injections of ankles, shoulders, and
elbows. Duration of improvement in the
large joints usually ranged between 1 and
4 weeks. The small joints have tended to
show more prolonged improvement, in 13
instances from 3 to 11 months.
Momentary pain at the time of injection
is observed in some patients. Minor ecchymoses are often seen at the site of the injection and occasionally small hematomats.
but these have not led to complications. In
one case, trauma to a small cutaneous
nerve produced a small area of hypesthesia
on the dorsum of the hand.
Intra-articular injection by hypospray appears to offer the benefits of injection b,
needle with the additional advantage, of
ease and rapidity of injection.
:
GRADIENTTHERAPY"
LEG ULCERSIN RHEUMATOIDA R ~ ~ R I T I SPRESSURE
Joe Beninson and Dwight C . Ensign, Detroit, Michigan
Leg ulcers in patients with rheumatoid
arthritis have always presented a serious
therapeutic problem and have basically interfered with the management of the rheumatoid disease itself. Nine patients with
rheumatoid arthritis presenting such ulcers
have been treated with pressure gradient
therapy with excellent healing in a relatively short time.
Eight of the 9 patients were females. Age
"Read by title.
range was 54 to 68, average 59. Duration
of rheumatoid arthritis was from 6 years
to 23 years, averaging 12.5 years. Five of
the individuals were in Stage 111, and 4
were in Stage IV. Functional evaluation
showed 4 in Class 11, 4 in Class 111 and
1 in Class IV. Five of the 9 patients had
rheumatoid nodules; one had psoriasis; two
developed significantly positive LE teSt5.
The physiologic approach to the healing
of these ulcers and the maintenance of the
healed state has been detailed elsewhere.
431
AMERICAN RHEUMATISM ASSOCIATION
‘This method
ployed both
peutically by
over the past
of treatment has been emprophylactically and theraone of the authors (J. B.)
7 years in over 2000 patients
INTKADERMAL
with lymphedematous extremities and in
over 400 patients with leg ulcerations of
varying etiology.
SKIN TESTIN SYSTEILZIC
LUPUS
ERYTEIEMA.TOSUS
J. Claude Benn.ett and Howard L. Holley, Birmingham, Alabama
In the past three years, through the work
of Miesclier, Seligman, Holman, and their
colleagues, several factors which produce
serological reactions with various nuclear
components have been found in the serum
of patients with systemic lupus erythematosus. Reactions have been described with
DNA, nucleoprotein, and histone. This has
provoked much discussion as to whether
or not these factors represent autoaniibodies against nuclear material, and if so
what is their relation to the LE phenomenon. It was felt that another interesting
approach to this problem would be the
study of intradermal hypersensitivity by
the use of normal white blood cells as the
test substance. The latter were prepared
by the dextran separation method of Skoog
and Beck. Injections were made intradermally at concentrations of 5 to 10 x 10.7
cells per mm”. Two control injections, consisting of ( 1 ) saline and plasma suspen\ion of red blood cells and ( 2 ) dextran in
CORRELATION
saline, were also made on the test subjects.
The volume of solution injected in each case
was 0.1 ml. Positive reactions against WBC
have been obtained in 15 of a serieJ of
17 SLE patients. Rarely have reactants
among patients afflicted with rheumatoid arthritis and non-connective tissue
diseases been found. The reaction is maximal a t about 24 hours after injection and
consists grossly of 0.5-2 cm. of induration
and up to 4.5 cm. of erythema. The time
of reaction is somewhat short for the classical type of delayed hypersensitivity, and
the induration usually disappears by 72
hours. Biopsy of the reiction site reveals
an inflammatory response having histoIogica1
characteristics of both the Arthus and delayed-type hypersensitivity. Even though
this test may only demonstrate a non-specific reaction to tissue injury, it may serve
as a useful diagnostic procedure in the connective tissue group of diseases.
“TITRE”O F AGGLUTINATION AND THE ‘‘DEGREE”OF
AGGI.UTINATION
IN RHEUMATOID SERA”
O F THE
S i d n q Berkozoitz, Slavu Luce, Edoardo Guarigliu, Martin Lehmnn and
Otto Stelnbrocker, New York, N. Y.
Agglutination tests for the rheumatoid
factor in blood sera are usually reported
in the literature in terms of the “titre,” or
the greatest dilution showing agglutination.
The “degree” of agglutination, or the
strength of the agglutinating reaction as it
appears in the first tube, is rarely reported.
This is a study of the correlation of the
titre and the degree of agglutination in
829 Latex Fixation determinations using
the method of Singer and Plotz. The material consisted of 418 sera from patients
with rheumatoid arthritis, 289 sera from
patients with other musculo-skeletal disorders and 122 sera from patients without
‘Read by title,
musculo-skeletal disease.
1. Although a high degree of agglutination appeared in 62 per cent of sera from
patiznts with positive rheumatoid arthritis
and a high titre occurred in 70 per cent of
the same group, all but 2 of the 145 four
plus ( 4 f ) reactions occurred in patients
with rheumatoid arthritis. The exceptions
were found in sera from two patients with
typical juvenile rheumatoid arthritis.
2. Of the 411 sera from patients who did
not have rheumatoid arthritis, 26 had high
titres but only the sera from the two
patients with juvenile rheumatoid arthritis
had a high degree of agglutination.
3. Seven of 14 sera from patients with
Lupus Erythernatosus gave positive agglu-
432
AMERICAN RHEUMATISM ASSOCIATION
tination reactions with titres up to 2560.
All of these sera showed low degrees of
agglutination.
These findings suggest that the considera-
tion of the degree of agglutination in addition to the titre of agglutination in the interpretation of these tests may add to their
specificity and usefulness as diagnostic aids.
THEDEMONSTRATION
OF THREE
TYPESOF INHIBITORS
AND ONE TYPEOF STABILIZER
O F THE LATEXFIXATTON
TESTFOR RirEu,MaroiD ARTHHlI'IS*
Gerson C.Bernhard and David W. Talmge, Denver, Colorado
The demonstration of three distinct types
of inhibition and one type of stabilization
of the latex fixation system has been possible by varying the order of addition of
the inhibitor and the reagents in the standard test procedure. The Singer method
for latex agglutination with a positive
rheumatoid serum was performed in
cuvettes. Optical densities were measured
photometrically before incubation and subsequent to incubation and centrifiigation.
The per cent optical density (0.0.) remaining in the supernatants after centrifiigation was plotted against the dilutions of
rhcnmatoid serum. Standard curves without inhihitor were compared with those
oht'iined when conditions were altered by
addition of an inhibitor at varions steps
in the procedure.
Incubating bovine serum albumin (RSA)
or heat inactivated normal hnman senmi
( N H S ) with latex prior to coating the
latex with human gamma globulin ( H G G )
gave curves showing bath stabilization (in"Read by title.
creased per cent O.D. remaining in supernatants of controls) and inhibition (reduced agglutination by rheumatoid f x t o r ).
Neither BSA nor heated NHS produced
inhibition when added after latex was coated with HGG. However, fresh NHS produced inhibition when added at this stage.
Thz inhibition by fresh NHS wab greatest
when it was incubated with HGG coated
latex before the addition of rheumatoid
factor. Heating to 56 C a t this stage did
not destroy inhibition. However, fresh NHS
preincubated with rheumatoid factor and
then heated to 56 C before contact with
HGG coated latex was not inhibitory. Thercfore, the inhibitor in fresh NHS app-ars to
act on HGG coated latex. Aggregated HGG
and certain antigen-antibody precipitate\
arc known to remove rhenmatoid factor
from serum. Thus inhibitors can c w s e rcduced agglutination by reacting with: 1.
the uncoated latex; 2. the HGG coated
latex; 3. the rheumatoid factor. In addition
stabilizers can be distinguished from inhibitors by their effect on the latex siispension in the absence of rheumatoid factor.
OF POSTERIOR
SUHCAPSULAR
CATARACTS
IN PATIENTSWITH
THE OCCURRENCE
RHEUMATOID
ARTHRITIS TREATED W I l H CORTICOSTEROI1)S
Roger L. Block, Richard B . Oglesby, Ludu:ig von Sallmann and Joseph J . Bunim,
Bethesda, Maryland
Posterior subcapwlar cataracts (PSC )
are generally found to be associated with
exposme to toxic agents, intraocular disease, ionizing radiation and/or blunt
trauma. As a rule, these lenticular lesions
are differentiated from senile cataracts by
their location and appearance on slit lamp
examination. The development of PSC in
4 rheumatoid arthritis patients during administration of synthetic corticosteroids
( prednisone, prednisolone, dexamethasone )
-an observation which has not previoiisly
come to our attention-prompted
a siirvey
of oiir rheiimatoid arthritis patients nvail-
able for study between June 1959 and
January 1960. Patients were included only
when the A.K.4. criteria for definite or ~ 1 3 s sic rheumatoid arthritis were fulfilled and
when complete details of previous forms
of therapy were available.
A total of 66 patients were included in
this study and had careful ophthalmologic
evaluation. Seventeen of this group showed PSC. It was necessary to excliide 3 other
patients with PSC from the calcnlations
because of the presence of complicating
ocular disease which might have hwn relattd to 1'SC formation.
433
AMERICAN RHEUMATISM ASSOCIATION
The 63 patients included in the calculations were then classified according to
the maintenance dose of steroid received.
Four categories were formed: (1) No steroid therapy, ( 2 ) low dosage range (prednisone < 10 mg. or its equivalent), ( 3 )
mid-dosage range (prednisone 10-15 mg. or
its equivalent) and ( 4 ) high dosage range
(prednisone 16 mg. and over, or its equivalent), No PSC was observed in the 19
patients in group 1 or the 6 patients in
group 2. O n the other hand, 5 of the 22
patients ( 2 3 per cent) in the mid-dosage
range and 12 of the 16 (75 per cent) in
the high dosage range exhibited the PSC
lesions. The 3 other patients excluded from
the calculations were also in the mid and
high dosage range groups. The relationship between steroid dosage and the development of PSC was found to he highly
significant (.01 >P> 0.001).
Other factors in the experience and therapy of these patients, including radiation,
the administration of salicylate, heavy
metals, supplementary calcium, or antimalarials were found to have no significant
correlation with the occurrence of PSC.
SJ~GREN’S
SYNDROME:
OCCURRENCE
OF UNUSUAL
CLINICALFEATURES,
VASCULAR
LESIONS,
AND IMMUNOLOGICAL
REACTIONSIN THIRTY-ONE
CASES
Kurt J. Bloch, Martin J. Wohl, Notlacin J. Zuaijler, Richard B . Ogleshy,
Irwin 1. Ship and Joseph J. Bzrnim, Bethesda, Maryland
Clinical and laboratory studies have been
performed in 31 patients with Sjogren’s syndrome. Of these, 13 had classical or definite rheumatoid arthritis (group A ) , 3 had
possible rheumatoid arthritis ( group €3)
and 3 had scleroderma (group C ) . Thc remaining 12 patients had ocular and oral
manifestations of Sjiigren’s syndrome hut
did not have rheumatoid arthritis or other
recognized collagen disease ( group D ) .
Clinical and pathological evidence of
generalized disease occurred with unexpected frequency. Arteriiis was observed
in 4 of 12 patients in whom muscle biopsies were performed. Two of these patients
had rheumatoid arthritis, one being on
constant steroid therapy; the other two
patients (group D ) were not taking steroids. Peripheral neuropathy was present in
the latter two patients and was a severe
disabling complaint in one. Muscle weakness was the major complaint in three
patients; one of these had a plasma cell
myopathy. Focal, chronic myositis was present in the remaining 11 muscle biopsy
specimens.
Laboratory findings, previonsly reported
in part, included hypergammaglobulinemia
(61 per cent), eosinophilia (45 per cent),
and neutropenia ( 2 9 per cent), Positive
bentonite flocculation tests and sensitized
sheep cell agglutination tests were found
in 97 per cent and 90 per cent (respectively) of the entire group and in 92 per
cent and 75 per cent of patients in group
D. Antinuclear antibodies were present in
71 per cent of the whole series. Significant
titers were obtained in the thyroglobulin
coated, tanned red cell agglutination test
on sera from 6 patients. Three of these had
clinically abnormal thyroid glands and
biopsy disclosed Hashimito’s thyroiditis in
one. Sera from 9 of 12 patients in group
D, and several others, fixed complement in
the presence of suspensions of hnman salivary gland as well as other tissues.
Sjogren’s syndrome is accompanied by
vasculitis and other pathological changes
frequently present in connective tissue diseases, and also by unusual immunological
reactivity commonly associated with socalled “autoimmune” diseases.
VARIABLES
OF CONNECTIVE
TISSUEDEVELOPMENT
IN POLYVINYI.
SPONGES
Giles G. Bole, Soul Rosemon, William E . ill. Lands, and William D. Robinson,
Ann Arbor, Michigan
Connective tissnc formation in subcutaneously implanted polyvinyl sponges was
studied in 46 adult guinea pigs. Variables
were: ( a ) size, ( b ) location, ( c ) duration
of implant, and ( d ) sex of animal. After
removal and decapsulation sponges were
analyzed for ( a ) histological changes; ( b )
net dry weight; ( c ) chloroform-methanol
extractable lipids.
Complete penetration of the sponges with
434
AMERICAN RHEUMATISM ASSOCIATION
fibroareolar connective tissue varied from
3 to 6 weeks depending upon the sponge
dimensions. Neither fatty infiltration nor
degeneration was observed in serial implantations caudal to the interscapular fat pad
area. The smallest sponges (0.3 x 1.0 x
1.0 cm.), used for the remainder of this
work, contained maximum tissue in 10, to 14
days, with a 50 per cent decrement occurring by 6 weeks. Of five dorsal sites tested, the low dorsolumbar area gave the most
consistent values for net dry weight.
The lipid content of the tissues was unexpectedly high, varying from 20 per cent
at 7 days to 60 per cent of net dry weight
EFFECTSOF
ANTI-RHEUMATIC
at 42 days (low dorsolumbar area). Changes
with time in percentage lipid content presumably reflect alterations in other tissue
constituents, since the total extractable
lipid per sponge remained relatively constant from 3 to 42 days. The lipid content
of sponges from the interscapular area was
higher and inconsistent. Preliminary analysis of the lipid extracts indicate that a major fraction is phospholipid; cholesterol represents a minor component, and the fatty
ester content is quite high. The high lipid
content is not due to contamination by adipose tissue or capsule, and its function in
connective tissue remains to be determined.
AGENTS ON CONNECTIVE TISSUEMETABOLISM
Alfred Juy BoZZef, Charlottesville, North Carolina
Metabolic effects of therapeutic agents
used in rheumatic diseases are under investigation in an attempt to elucidate
changes which occur during suppression of
inflammation. Thus far these studies have
primarily concerned the transamidase which
synthesizes glucosamine-6-phosphate from
fructose-6-phosphate and glutamine, in rat
liver and the connective tissue which forms
in polyvinyl sponges.
Gold chloride inhibited this transamidase;
the concentrations needed in connective tissue homogenates were in the range found
in serum of patients receiving gold therapeutically; higher concentrations were
needed in liver homogenates. Subcutaneous
administration of 10 pg. of gold sodium
thiomalate to rats resulted in a 70 per
cent decrease in activity of the transamidase in connective tissue homogenates, hut
no change in activity of the enzyme in
liver. Decrease in mucopolysaccharide content of the connective tissue which formed
in sponge implants also occurred after gold
administration.
Cortisol had no effect in vitro, but wbcutaneous administration caused diminished
activity of this transamidase and decreased
niucopolysaccharide content of sponge
granulomas.
Sodium salicylate also inhibited the activity of this transamidase in vitro, as did
phenylbutazone. Acetylsalicylic acid had
le\b inhibitory effect than sodium salicylate,
and p-hydroxybenzoate, which has no antiinflammatory effect, did not inhibit. These
results parallel those of Bostroni and Manson (1955) who found that salicylate inhibited the fixation of S35 by cartilage
slices, and Hershberger, Hansen and Raminey ( 1959), who found that phenylbutazone and cortisol inhibited S35 uptake by
cotton granulomas in rats.
These data point to the possibility that
anti-inflammatory agents produce an inhibition of glucosamine synthesis, and
thereby of mucopolysaccharide formation.
BASOPHU.LEUCOCYTES
IN RHEUMATOID
ARTHRITIS*
Abtlel-Wahed A. Boseila und Elgm C . Toonc, JT., Richmond, Virginia
Tissue mast cells are claimed to play a
role in the function of connective tissnes
in both health and disease. Basophil leucocytes (blood mast cells) bear functiond
similarities to tissue mast cells, although
morphogenetically independent, and are
--
*Read by title.
easily accessible in the peripheral circulation unlike the deeply seated tissue cells.
Using a simple chamber-counting method,
basophil counts were performed in 76 patients a11 fulfilling the A.R.A. critcria for
definite rheumatoid arthritis. The patients
were classified as to"stage, duration of the
disease, the presence or absence of nodules
435
AMERICAN RHEUMATISM ASSOCIATION
and reactivity to specific rheumatoid serology tests (Latex, SSC, and SHC).
The mean basophil count in 46 normal
persons was 39.8
20.1 (st.dev.) per
cu. mm. In 47 patients with stages 111 and
IV rheumatoid arthritis of over two years’
duration the mean count was 24.9 i: 8.8
per cu. mm., which is significantly lower
than the control county (P<O.OOl). In
the other patients with disease of less than
two years’ duration or of stage I and 11,
PATTERNS
OF
the mean basophil count was the same as,
or slightly higher than the mean control
value.
These changes encountered in the number of “circulating members of the mast
cell system” may reflect quantitative or
qualitative changes in mucopolysaccharide
production in rheumatoid subjects and
thus add some support to the suggested,
yet unclarified, role of the mast cells in
connective tissue pathophysiology.
LATEXAGGLUTINATION AND ITS INHIBITION
AND NORMALS
HYPERTENSIVES
IN
RHEC‘MAMIDS,
George W. Brooks and Sidney Cobb, Pittsburgh, Pa.
A sensitive latex system capable of detecting agglutinating substance in essentially all adults has been developed. Progressive twofold dilutions of serum in physiological saline are agitated with equal
amounts of an aqueous suspension of uncoated latex particles in depressions in plastic plates. The degree of agglutination at
each dilution is then read and recorded. Individual readings are averaged, forming
significant group patterns. It is emphasized
that while results have shown meaningful
relationships to the latex fixation test, this
is not a latex test. It has significance in
demonstrating group reactions and is considered an epidemiological rather than a
clinical tool. It is believed, however, that
this system can be modified for clinical
use. Differential heating of the serum reveals evidence of several agglutinating and
THEFEETAS
AN
AID IN
THE
inhibiting substances, which are differently
distributed in rheumatoids, hypertensives,
and normals.
The striking thing about the rheumatoids is that they have large amounts of a
heat stable (53 C. for 120 minutes) agglutinator which is found only in small
amounts in normals and hypertensives. This
is presumably what is usually referred to
as the rheumatoid factor. The most striking thing about the hypertensives is the
presence of a large amount of a heat labile
(53 C. for 15 minutes) inhibitor. However,
it is important to note that the agglutinator
in this group is also heat labile ( 5 3 C. for
120 minutes) like that found in normals.
Unlike the normals, one hypertensive in
five has a significant amount of the heat
stable “rheumatoid factor.”
DIFFERENTIAL
DIAGNOSIS
OF ARTHRITIS
John J . Cakbro, Jersey City, N. J.
Joints which are affected frequently by
arthritis are those of the feet and hands.
Though it is well established that the appearance of hands may aid the physician in
differentiating the type of arthritis present,
it is little recognized that changes seen in
the feet may also assist in one’s differential diagnosis. With this view in mind, and
in the hope that it may arouse interest in
an area often neglmted, the differential
features of arthritis ill the feet are outlined.
The features of rheumatoid feet include:
( 1 ) hallux valgus; (2) bilateral and symmetrical cock-up toes (hammer toes); ( 3 )
metatarsal head spread, prolapse and ten-
derness; (4)thickened and tender Achilles’
tendons; (5) associated corns, calluses and
bunions and ( 6 ) distinctive calcaneal and
metatarsal cystic lesions radiographically.
Feet changes in psoriatic arthropsthy
may be separated into two types. The classical type ( “psoriasis arthropathica” ) is
limited to characteristic nail changes, skin
lesions and terminal interphalangeal joint
involvement. Radiologically, resorption is
limited to the terminal phalanges. A second
type ( “rheumatoid-like” ) is associated with
the spectrum of features typical of rheumatoid arthritis, including metatarsal and calcaneal cystic leriorls on x-ray.
436
AMERICAN RHEUMATISM ASSOCIATION
Visible and radiographic tophi characterize chronic tophaceous gout. Hallux
rigidus should not be considered diagnostic since it occurs in less than 5 per cent
of gouty subjects and appears more frcquently with degenerative joint disease
and rheumatoid arthritis.
Though feet derangements of degenerative joint disease are not well defined clinically, the x-ray appearance of narrowing
CI1ROMOSOhIE NUMBERS IN
of joint space and sclerosis with osteophytic
spurs is distinctive.
Diabetes is by far the most common
cause of neuropathic joint disease occurring
in the feet. The progressively painless thickening and deformities of the feet are depicted radiographically by a unique attmuation of metatarsal shafts which taper
distally, metatarsal head absorption and
midtarsal proliferation.
CELLS CULTLIRE11 FROM HUMANSYNOVIAI. TISSUF:
C. William Cmtor, Ann Arbor, Michigan
Techniques for enumerating chromosomes in cultured cells provide an opportunity to “monitor” cells derived from
fresh tissue for evidence of aberration from
“normal.” Since chromosomal patterns may
he significant in tissue regeneration, snch
studies could provide information in the
“self perpetuating” chronic inflammatory
diseases. Our data is derived from seven
individuals, four with microscopically normal synovinm (two with SLE, two without rheumatic disease) and three with
rheumatoid arthritis possessing clinical m d
microscopic evidence of chronic synovitis.
In cells cultured from inclividnals with
normd synovium, deviation from the normal human diploid chromosome complement (2n = 46) occurred as early as the
second subculture. Aberrant forms in early
cnltnres were predominantly hypodiploid,
( 40-45 chroniosomes/cell), while Inter subcultures exhibited hypotetraploid and polypliiicl connts. In two persons where connts
were performed on early cellular derivatives, normal diploid cells accounted for
57 per cent and 58 per cent, respectively,
of the metaphase plates counted in the
second subculture. Cells from one of these
individual? still exhibited 62 per cent normal diploid counts at the third snhcnltiire
2nd in a third patient 59 per cent of the
cells examined at the 21st subcnlture had
thc normal diploid nnmber.
Early cultures from those with rheinnatoid arthritis revealed the normal diploid
number in 31 per cent, 28 per cent and
46 per cent of the cells examined from
these three donors. A wide range of hypodiploid, hypotetraploid and polyploid connts
were present.
Further study will be necessary to determine the reproducibility of these findings and their significance as a reflection
of a possible chromosomal defect in rheumdtoid synovium.
OF THE LATFX FIXATION
TE~T
TO TIIE
RELATIONSHIP
CLINICAL hfANIFEST4TTONS OF L E P R O ~ Y *
Edgar S. Cathcort, Rnlpla C. Willioms, Jr., Hilnry Ross und E z m Cnlkins.
Boston, Massachusetts
Numerous studies have emphasized that
the latex fixation test is positive in many
diseases other than rheumatoid arthritis.
Few reports have attempted to define posbible clinical implications of this reaction
in nonrheumatic diseases. In order to learn
more of the biological significance of this
reaction, 101 patients with leprosy in the
U.S.P.H.S. Hospital, Carville, were examined by ns with esprcial regard to inani-
*Rrad by title.
festations of leprosy and arthritis. X-rays
of hands and feet, and present and past
laboratory findings were reviewed and serologic studies carried out.
Twenty-four of these patients exhibited
positive latex fixation tests using inactivated serum. In an additional 20 patients tht,
test was positive nsing a englobulin fraction. Fiftcen patients had positive sheep
cell test\ on the serum. Independent clinical ctvalnation indicated that only 3 patients had probable rheumatoid arthritis.
437
AMERICAN RHEUMATISM ASSOCIATION
There were no differences in the clinical
manifestations, duration or course of leprosy between the groups with positive and
negative reactions. The incidence of amyloidosis was 30 per cent in the latex positive group and 20 per cent in the latex
negative group. There was also a higher
incidence of syphilis, diabetes and tubercdosis in the ’ positive group.
Prior absorption by lepromin or tuberSURGERY O F TIIE
culin removed the factor responsible for a
positive latex fixation test in all but 3 of
20 sera from leprosy patients used as controls. Serologic reactions with denatured
gamma globulin and antigen-antibody complexes, as well as ultracentrifuge studies,
indicate that agglutinating factors in leprosy and rheumatoid arthritis are similar if
not identical.
RHEUMATOID
HAND
Muck L. Clayton and Charley J. Smytla, Denver, Col.
Rheumatoid hand deformities are often
disabling and unsightly. The multiplicity of
deformities is due to tendon as well as joint
involvement. Evaluation of function and
exact diagnosis of the pathology is necessary before considering surgery.
This report concerns experiences with
over 30 cases in a imiversity clinic over a
C year period utilizing varied orthopedic
procedures.
In correction of iilnar drift failures occurred with simple repositioning of extensor tendons, or total excision of metacarpal
heads; improvement occurred with synovectomy, reposition of extensor tendons,
intrinsic releases, and a transplant to reinforce 1st Dorsal Interosseous. In more
severe deformities arthroplasty with partial
excision of metacarpal heads has been
added.
Repair of tendon ruptures over middle
finger joints have failed with free tendon
grafts. Arthrodesis seems preferable.
INTERPERSONAL
Thumb deformities were improved by
intrinsic releases, tendon transplants, arthrodescs, and excision of greater multangular.
Tenosynovectomy has been successful in
flexors and extensors; relief of median nerve
compression in th:: carpal tunnel has been
gratifying by release of the volar carpal
ligament.
Tendon transplants at the wrist havc
functioned after extensor tendon rnpture3.
Excision of distal nln? and radial head
have improved pronotion and supination.
Wrist arthrodesis has given long la\ting
improved function.
In most cases the patient, orthopedist
and internist have been pleased with resnlts
because all have realized that one is striving for a limited gain in function, and
that results in progressive rheumatoid disease cannot be compared with the results
in static conditions. Many patients deserve
evaluation for orthopedic reconstruction.
TRANSMISSION
OF RHETJMATOID
ARTHRITIS
Sidney cobl?, Pittsburgh, Pa.
It has long been known that rheumatoid
arthritis runs in families. It has usually been
assumed that this meant a genetic predisposition to the disease. The following evidence suggests that the clustering of this
disease in families is more likely person to
person transmission than genetic transmission. In a study of 322 employed men under
continuous observation for 28 months, 47
hnve been identified who have, at one time
or another, met the A. R. A. criteria for
probable or definite rheumatoid arthritis.
When coniparcd wit11 those free of rhnrma-
toid arthritis, these men report twice as
much arthritis in their parents, three times
as much in their siblings, and nearly four
times as much in their wives. Statistically,
this association in marital partners is highly
significant.
A simultaneous study of hypertension
and peptic ulcer showed these diseases to
be slightly associated in blood relatives,
but not in marital partners. This suggest7
that there is no pvticular tendency for a
man to pick a woman to be his wife beCRIIW $he has thr wme &\east, thnt he has,
438
AMERICAN RHEUMATISM ASSOCIATION
nor any particular tendency for him to report an excess of illness such as his own
in his wife.
This does not constitute proof that the
ON
THE
familial clustering of arthritis is not primarily genetic but it raises sufficient question so that future family studies should
include spouses.
FREQUENCY
Or’ INDIVIDUALS WHO SUFFER OCCASIONAL
O F RHEUMATOID
.4RTHRITIS
ATTACKS
Sidney Cobb, Pittsburgh, Pennsylvania and Thomas A. Liriroln, Oak Ridge, Tennessee
For twenty-eight months we have had
a group of employed men under continuous
observation for arthritis. They were screened
by a nurse monthly for the first 16 months
and every 3 months thereafter. Those on
whom there was any suspicion of joint
swelling were referred immediately for
examination by one of the plant physicians,
and later for review by the senior author.
On the basis of these examinations, the
men were classified with respect to rheumatoid arthritis according to the A. R. A.
criteris, 1058 revision.
At the first screening less than two per
cent of these men met the criteria for probable or definite rheumatoid arthritis. However, by the end of the study five per cent
hid inel the criteria for definite disease,
mct <in additional ten per cent had met
the ciiterid for probable disease. Thi,
high cumulated prevalence rate is not
due to an unusual age distribution, for the
average age of these men was 41. However, the rates do rise rapidly with age,
reaching 10 per cent definite plus 12 per
cent probable in those over 50.
The cases could be classified only rather
slowly; for example, after 18 months only
two thirds of those who were ultimately
to be classified as definite had met the
necessary criteria. It will be explained how
this slow rate of accumulation indicates
that most of the cases spend most of their
time in remission. Rheumatoid arthritis is,
therefore, seen as a disease that is common
and benign. There are large numbers of
people who are occasionally affected, only a
few of whom progress to continuously active disease that is crippling.
IN WHIPPIX’SDISEASE
CONNECTIVE
TISSUEFINESTRUCTURE
Alan S. Cohen and Kurt I . Isselba~lier,Boston, Maswchnsett;
Whipple’s disease, originally thought of
as an intestinal lipodystrophy, has been
demonstrated to be a systemic disorder with
niarked involvement of the connective tissue. Articular manifestations occur in the
majority of the patients and have led to
speculation on the relationship of this condition to other rheumatic diseases. The involved tissue contains macrophages staining intensely with the periodic acid-Schiff
(PAS) reagent. Since this stain has given
us only limited information about the abnormal cell, it was felt that definition of
its ultrastructure would help clarify the
nature of the lesion.
Fasting peroral jejunal biopsy was obtained. in a histologically confirmed case of
Whipple’s disease. Tissue was fixed within one minute in osmium tetroxide, dehy-
drated and embedded in methacrylate by
routine methods.
Electron micrographs showed two striking abnormalities: (1) large inclusion
bodies composed of filamentous membranes
and granules in the PAS positive macrophage; ( 2 ) dense ovoid bodies with distinct structure along the microvillous projections of the macrophages and within
the macrophages. It is pertinent that the
PAS positive material in the mucin cells
of the same sections had no recognizable
structure and had an amorphous appe-trance.
The morphologic relationship of these
membrane structures and dense bodies to
each other and to viral irlclusion bodies
will be reviewed.
439
AMERICAN RHEUMATISM ASSOCIATION
ANTINUCLEAR
ANTIBODIESIN EXPERIMENTAL
ANIMALS
Norman S. Cooper, Peter fifiescher and Baruj Benacerraf, New York, N. Y.
There is growing evidence that serum
from patients with systemic lupus erythematosus (S.L.E.) contains gamma globulin
which behaves like a series of antibodies
directed against various components of
nuclei, including nucleoprotein, DNA, and
histone. These findings have stimulated
attempts to induce the production of such
antibodies in experimental animals.
Rabbits and guinea pigs were injected
repeatedly with homogenates of Freund’s
adjuvant and ( a ) isolated whole nuclei
from several mamalian species, ( b ) nucleoprotein prepared from calf thymus, or ( c )
nucleoprotein
prepared from bacteria
( Brucella abortus). Upon serial bleeding,
the sera of several animals contained antibodies which reacted with mamalian and
bacterial nucleoprotein, purified calf thymus DNA, purified calf thymus histone,
and/or purified salmon sperm DNA. The
antigen-antibody reactions were demonstrable by complement fixation, by passive
cutaneous anaphylaxis and by immunofliiorescence, but not by a precipitin reABSORPTIONO F
BY
action. In most instances the antibodies
showed wide species cross-reactivity (e.g.
serum from an animal immunized with
bacterial nucleoprotein reacted not only
with the bacterial nucleoprotein but also
with calf thymus nucleoprotein, calf thymus DNA, calf thymus histone, and whole
guinea pig nuclei). In addition, it was
possible in some instances to “boost” the
antibody titer of guinea pigs, originally
immunized with heterologous whole nuclei,
by administering guinea pig (i.e. homologous) nuclei.
Morphologic studies were done in most
of the animals. Positive “LE” phenomena
were obtained with the blood of only a
single guinea pig, although equally high
titers of complement-fixing antibody against
various nuclear materials were present in
several other animals. Several animals
showed histologic changes in epicardium,
myocardium, and endocardium;
these
changes were similar to those found in
animals hyperimmunized with non-nuclear
antigens and in patients with S.L.E.
RHEUMATOID FACTOR
PREPARATIONS
ANTIGEN-ANTIBODY
COMPLEXES’
PURIFIED
Josue Corcos, New York, N. Y.
Selected rheumatoid sera, purified by
ultracentrifugation and by zone electrophoresis, were found to contain components having sedimentation constants of 7S,
19S, 22s and 27s. Such selected sera also
contained components sedimenting between 11s and 16s. The latter components
had been noted previously by Kunkel et al.
The interaction of the serum preparations
with various antigen-antibody complexes
was studied by serological techniques as well
as by analytical ultracentrifugation. It was
found that a complex of human serum albumin-rabbit anti-human serum albumin,
in quantities sufficient to abolish serological activity in the sensitized sheep cell
test but leaving latex fixation titers virtually unchanged, removed approximately
‘Read by title.
half of the 19s and 22s component. Complexes comprising human gamma globulinrabbit anti-human gamma globulin were
variably effective in the removal of serological activity. This variability was found
to be related to the amount of aggregated
gamma globulin present in the immune
complex. When gamma globulin was purified by removal of aggregates prior to formation of the immune complex, the antigenantibody complex behaved similarly to the
one containing human serum albumin.
Complexes, containing aggregated gamma
globulin, removed all serological activity
and caused the disappearance of 22s and
27s component, as well as most of the
19s component. All other components
seemed unaffected by this treatment.
The absorption studies confirm previous
observations of other investigators, namely
440
AMERICAN RHEUMATISM ASSOCXATION
that tlw 1SS coinponent is comprisetl of
one macroglobulin with serological specificity towards antigen-rabbit antibody
complexes and still another macroglobidin
devoid of such specificity. The studies c h i onstrate that the 2% component is siniilarly
coinprised of two serologically distinct n i x roglobulins. Macroglobulins, sedinicnting at
27s and possessing the serological characteristics of thc rheumatoid factors, were
also cncountercd.
PAPAINON CONNECTIVE
TISSUE“
Trrs ACTION01.‘
1’.
F. Crosti. C. L. Pironi m d H . R. Catchpole, Chicago, lllinois
Intravenous papain administration has
been shown to induce collapse of the ears
in rabbits, accompanied by histologic
chmges in cartilage generally, with appearance of chondroitin sulfate in the blood.
The objective of the present study has
heen to use this in vivo reaction to analyze
further the action of this enzyme on the
cartilage matrix of young rabbits. Blood
samples were withdrawn shortly before
arid at 9, 18 and 50 hours and 5, 10 and
17 days following the I.V. injection of
papain. Controls were injected with saline
or egg albumin solution and bled on :t
similar schedule. A i i d y ~ ewere
~
pcrforincd
for: total protein, protein-bound hcxosc
and hexosamine, seromucoid, sialic acid
and other serum components. Protein pat*Read hy titlc.
terns were analyzed by nicans of paper
and starch electrophoresis. Punch biopsicis
of ear cartilage were frozcn and dried for
histologic and histocheinical studies. Following enzyme injection there is a fall in
serum albumin by the 9th and 18th hour,
with gradual recovery by the 50th hour.
This fall coincides with maximal appearance of chondroitin sulfate in the blood.
All globulin fractions increase in absolutes
amounts. Protein-bound hexose and hexosainine increase, reaching maxima at 18
hours. Seromucoid is maximal a t 50 hours.
Sialic acid bound to protein is maximal at
5 days. These results may be interpretcd
as indicative of dissolution of cartilage with
liberation first of chondroitin sulfate froin
a chondrornucoid complex, and later of
other presiirnptive ground substance coinponents.
~ ~ Y I ’ E l I U l i I ( T M 1 AIN 17iI,IPINOS
John L. Decker, Jaincs J. Lane, Jr., und Williorn E . Rcynoltls, Seattle, Washington
Siricc gouty arthritis has been rcportcd
to he about 20 times more frequent in
Filipino inales as compared to a nonFilipino group of men, it was postulated
tliat it healthy Filipino population would
show serum uric acid (SUA) levels higher
than those in a comparable Caucasian
population.
Fasting early morning blood samples
were obtained from 113 Filipino workmen
between the ages of 40 and 60; the men
were employed in the Alaskan salmon
packing industry. Control samples were obtained in an exactly similar fashion from
88 Caucasian prison inmates between the
ages of 40 and 60. Data were obtained on
racial origins, drug ingestion and history
of joint pain. SUA was determined in triplicate with the Praetorius uricase method
and seruin creatinines were measured by
means of the alkaline picrate reaction.
The mean SUA in the Filipinos was 6.3
nip. per cent k S.D. 1.43 and in the Caucasians it was 5.0 ing. per cent rt S.D. 1.12.
The observed difference was thus 1.3 ing.
per cent and significant at less than the 0.1
per cent level. The mean serum creatinines
did not differ. The SUA was not correlated
with geographical origins within the Pliilippine Islands. The Filipinos who were using niedications or who had a history of
joint pains had a higher mean SUA than
those who did not; this was not true of the
Caucasians. Thc frequency distribution
curve of SUA in the Caucasians followed
a Gaussian pattern while that in the Filipinos was distinctly asyminetrical with a
greater proportion falling in the upper
ranges.
44 1
AMEKICAN KIIKU hlATISM ASSOCIATION
POLYMYOSI'IIS: A N EYI'ANI)ING CONCEPT*
Harry Decker, Suul Kay, Iiobert l r b y and E h i C. Toone, Richmontl, Viriginia
Nine cnrrcnt and ten retrospective cases
of polymyositis were studied at the Medical College of Virginia. Most had pathologic verification of their disease. There
were fifteen females and four males, with
no age or racial selectivity. Seven patients
had an acute multisystem onset; six had
only insidious muscle weakness; three had
established R.A.; three had probable S.L.E.
and one had episodic involvement limited
to skin and .iriuscle.
Seven currcnt cases had electroniyograpliic
abnorinalities which suggested polymyositis and assisted in the choice of suitable
biopsy sites. Sections of skin and muscle
from seventeen patients were reviewed and
additional tissues were obtained from five
necropsies. Characteristic histopathologic
reactions were noted. The SGOT was abnormal in four current cases (118-980).
Marked creatinuria was noted in each of
two patients studied.
The pattern of muscle weakness was
proximal in sixteen, generalized in two and
distal in one. Nine patients reported episodic muscle tenderness and three constant
shoulder or hip girdle pain. Episodic indurated distal muscles ( 8 ) , facial edema
( 4 ) , dependent edema ( 3 ) and heliotrope
discoloration ( 3 ) were noted.
Skin involvement was present in tcn patients. Synovitis was persistent with associated RA and episodic in five additional
patients. Dysphagia ( 6 ) , cardiac enlargement ( 4 ) and pulmonary disease ( 8 ) were
noted. Associated malignancy was present
in only one case.
Abnormal urine was common (14) but
renal failure was rare ( 2 ) . Anemia (lo),
leukocytosis (4),increased ESR ( 12), and
A X reversal ( 8 ) were inconstant findings.
L. E. cells were uniformly absent. Rheumatoid factor was present only with associated
H. A. The BSP was elcvatcd (S-30 per cent)
in fivc of six patients.
*Read by title
ROENTGENOLOGICAL
FEATURES O F
ANKYLOSINC
SPONDYLITIb
A N D RIIEUMATOII)
ARTHIIITIS"
A. N . Dilsen, C. B4cEwen, D . DiTotn, P. Cwmel uncl W. J. Gmsh, Ncw York, N. Y.
As part of a larger investigation of similarities and differences between rheumatoid
arthritis and ankylosing spondylitis, a roentgenological study has been made of the
spine, symphysis pubis, sacroiliac and maniibriosternal joints of 100 patients with each
of these diseases.
All patients with ankylosiiig spondylitis
had some roentgenological changes of the
spine. Sacroiliac joints were moderately to
severely involved in 100 per cent of the
patients with ankylosing spondylitis, but in
only 25 per cent of those with rheumatoid
arthritis. Changes in the latter group were
minimal or moderate, and none had complete sacroiliac fusion.
Changes in the symphysis pubis were
lound in 62 per cent of the spondylitic
group, compared with 17 per cent in the
patients with rheumatoid arthritis; and in
the case of spondylitics, 7 per cent had
complete fusion, whereas in the rheumatoid
group there was no obliteration of the joint
"Read by title.
space. The same was true for the manubriosternal joints.
A striking difference between the two
groups was in the incidence and degree of
paraspinal calcification. This was present
in 90 pcr cent of the spondylitic patients,
in most of whom it was severe or moderate.
In contrast, only 16 per cent of the rheumatoid patients showed this, and to only a
very minimal degree, and localized.
Another marked difference between the
two groups was in the various pelvic changes, including whiskering, osteitis, and soft
tissue calcification. These were present in
46 per cent of the spondylitic patients but
in only 3 per cent of those with rheumatoid
arthritis.
Bambooing and squaring were present in
72 per cent and 63 per cent respectively of
the spondylitic group, but in none of the
rheumatoid group. Apophyseal changes in
the cervical and lumbar spine were also
more frequent and more severe in the
spondylitic than in the rheumatoid group.
442
AMERICAN RHEUMATISM ASSOCIATION
AVASCULAR (ASEPTIC)BONENECROSIS
ASSOCIATED
WITH SYSTEMIC
L.UPUS
ERYTHEMATOSUS'
Edmund L. Duhois and Lewis Cozen> Beverly Hills, California
Eleven patients in a series of 400 cases
of systemic lupus erythematosus (S.L.E.)
developed avascular bone necrosis which
led to severe incapacitation in eight. There
was bilateral femoral head involvement in
eight and unilateral damage in one. Two
patients had bilateral knee changes. The
diagnosis of S.L.E. was proven in ten by
L.E. cells, while the remaining case had
rheumatoid arthritis with multiple system
involvement.
The average age of onset of these changes was 36 years with an average of 5.1
years after the onset of the underlying disease. There was no relationship between
corticosteroid therapy and the onset of
symptoms. Six patients subsequently received systemic steroids for the pain produced by the aseptic necrosis with symptomatic benefit in only two. Local hormonal
therapy was temporarily effective in one
out of three cases. Conservative treatment
with immobilization and salicylates was effective in four patients. The remaining
four cases were not benefited by any of
these forms of treatment. One case subsequently had a vitallium cup arthroplasty
with good results.
The clinical manifestation of this process
was persistent localization of pain to either
the hip or knee joint. Routine hip x-rays of
70 ambulatory cases of S.L.E. who had no
symptoms referable to that joint revealed
early changes in only one. Bone biopsy in
two cases revealed a rheumatic granuloma
in one with fibrinoid material on the villus
and bone necrosis with pannus formation in
the second.
The disease process when once started
was in\idioiisly progressive in all cases but
one, eventually in the majority leading to
severe destruction of the joint with loss of
mobility. Although therapy may yield
symptomatic relief there was no radiographic evidence of improvement.
'Read by title
THE~ORTICOSTEROID INDUCED
PEPTICULCER: A SERIAL ROENTGENO1,OGICAL
SURVEY
OF
PATIENTS RECEIVINGHIGII DOSAGES"
Edmund L . Dubois, James G. Bulgrin and George Jacobson, Beverly Hills, California
Ninety-four patients, most of whom had
systemic lupus erythematosus requiring
large doses of corticosteroids were given
serial upper gastrointestinal x-rays at intervals of three months. The incidence of peptic ulcer in 41 cases treated with salicylates
and n n t l i d a r i d s was iive per cent. Nineteen patients, or 20 per cent of the steroid
treated group, developed peptic ulcers,
In eighteen cases where definite ulcer
craters were found, 12 were gastric in location and six duodenal. The occurrence of
ulceration was directly proportional to the
dosage of corticosteroid employed. There
was no statistically significant difference in
incidence of ulceration between prednisone,
prednisolone, methylprednisolone, triamcinolone, or dewamethasone. Converting the
dosage of steroids utilized to prednisone
equivalents, the incidence ranges from the
'Read by title
occurrence of no peptic ulcers below 10 big.
per day, four to 23 per cent from 10 to 59
pg. per day, and 47 per cent when the
dosage was over 60 pg. per day for two
months or more. Prophylactic ulcer regimens
were not routinely emphasized, however,
four patients who developed ulcers had
been on such a program. One of them had
a deformed duodenal bulb and ulcer symptoms at the start of therapy and the other
three received the highest doses of the
steroid, namely 100 pg. per day of prednisone, 96 pg. per day of triamcinolone and
144 pg. per day of methylprednisolone.
Ulcer symptoms were present in 14 of
the 19 patients with lesions. Two others
were psychotic. Two additional patients had
their ulcer craters appear and fully heal
without symptoms, change in steroid therapy or ulcer regimen.
A total of 31 patients, of 94 given the
newer corticosteroids, had ulcer symptoms
443
.AMERICAN RHEUMATISM ASSOCIATION
and 14 of the symptomatic cases developed
proven peptic ulcers. Consequently, cornplaints of dyspepsia during steroid therapy
should be given serious consideration and
a full ulcer regimen begun. Prophylactic
IlYPERTROPHIC OSTEOARlHIiOPATHY
AND ITS
ulcer therapy should be used in all patients
with a history of this disease or those receiving over 10 pg. per day or more of
prednisone or its equivalent for periods of
several weeks or longer.
RELATIONSHIP
TO
INTRATHORACIC
DISEASE”
Arthur Evam, Charley J. Smyth and Oren B . Gum, Denver, Colorado
The relationship between intrathoracic
disease, clubbing, painful long bones, and
an associated arthropathy offers a challenging opportunity to study the pathogenesis of proliferative changes of connective tissues characteristic of many collagen
diseases.
Recent observations of a patient with
pleural inesothelioma showing cyanotic
clubbed fingers and toes, periosteal changes, acutely inflamed peripheral joints, periodic flushing, excessive salivation and gyneccmastia is presented. Eight months postoperatively, this patient continues asymptomatic after a dramatic response to resec*Read by title
tion of the mesothelioma.
Three main current theories of pathogenesis are reviewed and discussed. Evidence is presented for the first time that
mast cells are present in a mesothelioma.
The possible significance of these pleuripotential cells in relation to the ever present
finding in osteoarthropathy of increased
peripheral blood flow through A-V anastomoses is discussed. Evidence for the cholingeric control of these A-V shunts is reviewed. Further studies of the several mechanism controlling these A-V shunts and thus
the circulation in the extremities, may elucidate the fundamental defect in hypertrophic
osteoarthropathy.
INTERACTION
OF A POLYSACCHARIDE
wrm
FROM PATIENT’S
SERUM
AND
THE RHEZTMATOID
FACTOR
ERYTHROCYTES
Abraham E . Finkelstein, Greg09 y KwcJ.’~arid rhcotlore B. B ~ y l e s ,Boston, Massachusetts
Studies which were carried out to establish the effect of the infusion of the polysaccharide dextran ( clinical dextran commonly used as a plasma expander) in patients with rheumatoid arthritis produced
exacerbations of symptoms and signs in
those with marked disease activity.
‘The same polysaccharide in vitro interacts with sera from patients with rheumatoid arthritis giving a precipitate which contains all the rheumatoid factor activity from
the sera as evidenced by a positive Latex
Fixation Test and positive Sensitized Sheep
Cell Test of the precipitate; the supernatant
is negative. A method of precipitation and
isolation of the rheumatoid factor is described. This precipitation method can be
used instead of serum dialysis to concentrai e the rheumatoid factor. By this isolation method, the protein concentration of
the material which gives a positive Latex
Fixation Test at the highest dilution is
0.016 pg. protein/ml.
Using the polysaccharide in experimental
work with the patient’s red cells, it was
possible to detect the rheumatoid factor as
a coating of the erythrocytes. Packed red
cells (after removal of the buffy coat)
washed, and treated with dextran from 260
patients with connective tissue diseases
were tested, rheumatoid factor was found
to be present in 100 per cent with classical
R.A., in 96 per cent with definite R.A.,
in 88 per cent with probable R.A., in 64 per
cent with possible R.A. and 39 per cent
in other musculoskeletal disorders. Further,
a drop of blood from the above groups
of classical and definite R.A., incubated
at 37 C. with F I1 fraction shows a macroscopic agglutination of the patient’s own
red cells ( F I1 autohemagglutination phenomenon). This phenomenon is observed
in 100 per cent of the patients with R.A.
and 0 per cent in a control group of 56
healthy individuals.
444
AMERICAN RHEUMATISM ASSOCIATION
RHEUMATOID
( ANKYLOSING
) SPONI>YLITIS AYI) OSTEOCHONDRITIS
LUMBARVERTEBRA I N IIIENTICAL TWINS*
OF A
Donald T . Foxtcorthy, M a x M . Montgomery and Eean M . Barton, Hineb, Illinois
and Chicago, Illinoi\
A pair of 28 year old identical twin
males with classical symptoms and x-ray
evidence of ankylosing spondylitis were
treated at Hines, V. A. Hospital (1950-52).
In addition to conservative measures, each
twin was given two separate courses of
deep roentgen therapy with symptomatic
and objective improvement. In addition, a
defect of the fourth lumbar vertebra which
led to abnormal epiphyseal fusion was noted
in each man. Hereditary factors in ankylosing spondylitis have received considersRead by title.
THE EFFECTOF LE S E R U M
able attention in the literature. We are reporting the fourth set of monozygotic twin5
with this condition. The influence of heredity in spinal osteochondritis has received
scant attention; no instance in twins has
been previously reported.
Subsequent to therapy, each pati-nt r.!turned to active physical labor and hn.4
sired two normal children. There has been
no evidence of hematologic defect in the
fathers on periodic follow-up examinations.
Recent x-rays have not shown the expected
fusion of the sacro-iliac joints, and physical
disability in each patient is niininral.
UPON
L E U K O C Y h~I E
LTABOI15M
A. E . F r u e k n , A. J. Sbarru, W.A. Bnrdciwil and T . B. Bnylm, Boston, Massachualetts
We have studied the respiration of guinei
pig leukocytes, obtained from sterile peritoneal exudates, in the presence of human
sera. Normal serum produced a consistent
inhibition of oxygen uptake; eleven normal
controls averaged 40 per cent of the oxygen
consumption of cells incubated i n the absence of serum. Eighteen patients with
active LE showed complete absence of
this inhibitory effect (average 103 per
cent ) . Appearance of significant inhibition
could be demonstrated when the clinical
disease becaine asymptomatic ( 4 patients),
or was inactive ( 3 patients with a negative
LE preparation).
Patients with rheumatoid arthritis and ii
positive LE preparation ( l o ) , scleroderrna
( 51, ulcerative colitis without joint disease ( 2 ) , and rubella arthritis ( 3 ) showed
activity similar to that of LE serum. PRtients with rheumatoid arthritis ( l 6 ) , polyarteritis ( 6 ) , liver disease ( 7 ) , and other
joint diseases ( 9 ) showed significantly inore
inhibition. Thirty-four patients with nonrheumatic diseases showed respiratory inhibition not significantly different froin the
normal controls.
Investigation of some of the biochemical
aspects of this serum-leukocyte system revealed that: 1) Respiratory inhibition was
associated with inability of the cells to
exclndc eosin dye, a criterion wed to inclicatc nonviability. 2 ) The inhibitory cffects of normal and RA serinn were completely destroyed by prior heating to 56 C.
for 30 minutes. The addition of gninea pig
complement did not change these resiilts.
3 ) The specific respiratory effects of LE,
RA and normal serum were iodoacsetate
and fluoride insensitive but Antimycin and
cyanide sensitive, indicating cytochromdependence.
Limited observations with human lenkocytes revealed a similar difference between
the respiratory effects of LE and normal
serum.
BETWEEN RHEUMATOID FACTORS
AND
SPEcIFICITY OF TIIE REACTION
GAMM-4 GLOBULINFROM DIFFERENT INDIVIDUALS
H u g h H . Futlenbmg and Henry G. Kunkel, New York, N. Y.
When y-globulin froin single individuals
was fixed to red blood cells as anti-Rh
antibodies, a variety of agglutination patterns were observed with different rheuma-
tciid factors, with
on the individual
sera from different
high titers in the
the pattern depending
y-globulin. Twenty-fonr
patients which showed
latex fixation test were
445
AMERICAN RHEUMATISM ASSOCIATION
studied with cells coated with 20 different
Rh antibodies. An equivalent amount of
antibody, as measured by the indirect
Coombs test, was applied in each case.
The results obtained indicated a marked
specificity of individual rheumatoid factors
for certain 7-globulins and served to distinguish a wide assortment of rheumatoid
factors. The following is one example: Cells
coated with anti-%( a ) reacted strongly
with rheumatoid serum (1) but not at all
with rheumatoid serum ( 2 ) , while cells
coated with R h ( b ) reacted strongly with
rheumatoid serum ( 2 ) and not with ( 1 ) .
Both ( a ) and ( b ) reacted with serum ( 3 ) .
A few of these patterns correlated with the
known genetically-determined Gm systems.
One anti-Rh antibody reacted with all
24 of the sera containing rheumatoid factors. Six of the latter sera were from a
variety of disorders of a non-rheumatoid
nature such as sarcoid. These could be distinguished from the rheumatoid group by
their very restricted pattern of reactivity.
Rh antibodies were also obtained in two
patients with rheumatoid factors, and the
prrtients’ own antibody studied with his
rheumatoid factor. These results will be
discussed. Further evidence for the antibody nature of the rheumatoid factors was
obtained.
HISTOLOGIC
STUDIES OF SYNOVIAL
TISSUEBEFOREAND AFTERTHERAPY
WITH
PHENYLBUTAZONE
ADMINISTERED
ORALLYAND INTRA-ARTICULARLY“
George Ganter, John J . Btidd, Raymond G . Slavin and Jack Zmkner, St. Louis, Missouri
The present study was designed to determine alterations in the histologic pattern
of synovial tissue after administration of
p henylbutazone. The latter was administered
either intra-articularly into a knee joint
in a single dose of 600 mg., or orally, 600
mg. daily until the biopsy was performed.
Biopsies were obtained as controls and 4
to 10 days after the start of therapy.
A total of 41 biopsies were obtained in
17 patients with either rheumatoid arthritis or osteoarthritis. Synovial tissues were
examined utilizing the following histologic
stains: H & E, Goniori’s trichrome, toluidine
blue, periodic-acid Schiff, Alcian blue,
elastic tissue and methenamine silver. Sec*Read by title.
CLINICAL
AND
tions were studied without knowledge of
the clinical diagnosis, the route of administration of the medication, or the nature
of the biopsy, i.e., whether it was a control or post medication specimen. Comparisons were made with reference to fibrin and fibrinopurulent material, appearance
and thickness of synovial lining cells, edema,
stromal hyalinization, inflammatory cell
types and their distribution, vascular alterations and other changes which might be
delineated with the special stains.
Despite clinical relief of symptoms in
most of the patients at the time of rebiopsy,
no constant histologic alteration was demonstrated. This was true for both methods
of administration of phenylbutazone for
both rheumatoid arthritis and osteoarthritis.
LABORATORY STUDIES OF RELATIVESOF PATIENTS
SYSTEMIC LUPUS ERYTHEMATOSUS*
WITH
0. Garcia-Morteo, Edward C . Franklin, C Z ~ T T&lclhen
~W
and Rlartin il’unner,
New York, N. Y.
Forty-six close relatives of 20 patients
with systemic lupus erythematosus were
examined. Three had clinical rheumatoid
arthritis and one had lupus erythematosus.
This patient was the only one with a positive L.E. preparation.
Sixteen relatives (35 per cent), 14 of
whom were asymptomatic, had positive
*Read by title.
sheep cell inhibition tests; five of these also
had positive sheep cell agglutination or latex
fixation reactions. In two fanlilies two and
three relatives had positive tests.
Five relatives (11 per cent), including
two in the same family, had biologic false
positive tests for syphilis. Three of these
also had positive rheumatoid factor tests.
Marked hypergammaglobulinemia was
present in eight (17 per cent). This was
446
AMERICAN RHEUMATISM ASSOCIATION
associated with clinical and laboratory evidence of rheumatoid arthritis in three, and
lupus in one. Slight elevations of gamma
globnlin were present in six additional relatives (13 per cent).
Positive fluorescent ‘ antibody reactions
were obtained in 6 relatives ( 13 per cent);
3 of these had also positive rheumatoid
factor tests and another had a positive L.E.
preparation.
Three families (15 per cent) had clinical and laboratory abnormalities; 12 families (60 per cent) had laboratory abnormalities only, and 5 families ( 2 5 per cent)
showed no abnormalities.
Forty-six control subjects matched for
age and sex have been examined. None
showed clinical evidence of a collagen disease. Four ( 9 per cent) had positive
sheep cell inhibition tests; one of these
also had a positive sheep cell agglutination
test. Marked hypergammaglobulinemia was
present in one control ( 2 per cent) and
slight elevations of gamma globnlin were
present in an additional 8 controls (17 per
cent). None had biological false positive
tests for syphilis. The fluorescent antibody
reaction was performed on sera of 40 of
the 46 controls, with negative results in all
cases.
The high incidence of rheumatoid factor in sera of relatives of patients with
lupus erythematosus is similar to that demonstrated before in relatives of patient5
with rheumatoid arthritis, and suggests that
resemblances in the clinical and laboratory
manifestations of these diseases are accompanied by similarities in certain genetic
factors.
HEREDITARY
FACTORS
IN RHEUMATOIDARTHRI
rxs
Arnold Goldenberg, Jacyzies A4. Singrrr cmd CliarleJ AI. Plotz, New I’ork, N. I’.
A family study was carried out in order
( 1) t o detect rheumatoid factor or related
macroglobulins in kindred of rheumatoid
persons by 5 serologic tests and ( 2 ) to
determine the valiie of these tests in hereditary studies. The study groups consiated
of 106 relatives of 27 rheumatoids and
106 controls.
Forty per cent of relatives and 14 per
cent of controls were positive by at least
one of the 5 procedures. Twenty-nine per
cent of the relatives and 7.5 per cent of
controls gave a positive Euglobulin Inhibition Test. The Sensitized Sheep Cell Test
yielded positive results among 14 per cent
oi relatives and 4.7 per cent of controls.
The figures were slightly lower with the
Euglobulin Sheep Cell Test. Less than 5
per cent of both groups were positive by
the F11 Latex Fixation and Sensitized
Human D Erythrocyte Tests.
There was an equal distribution of positive results according to age group and
relationship to the index rheumatoid case.
Female kindred had a positive test by at
least one method nearly twice as often a s
males.
The results indicate that kindred of rheamatoids have positive tests for rheumatoid
factor or related niacroglobulins 3 to 4 times
more often than controls. The Sensitized
Sheep Cell, Euglobulin Sheep Cell and
Eilglobiilin Inhibitjon Tcsts arc. uscf‘ul procedures in genetic. studies for rheumitoid
arthritis.
The significance of the results will be
discussed.
SPONTANEOUS
ATLANTO-AXIALSUBLUXATIONIN RHEUMATOID
ARTHRITISAND ANKYLOSINGSPONDYLITIS’
Donald C. Graham, Toronto, Canada
This easily overlooked, potentially dangerous complication, more common than
generally appreciated, was observed in
twelve adults with rheumatoid arthritis and
three with ankylosing spondylitis. All had
‘Read by title.
severe, long standing, “classical” disease.
Presenting features in the majority were
cervico-occipital pain and/or progressive
cervical deformity in the form of either
anteflexion of the head or a complex torticollis. Subluxation was reiEaIed by flexionoxtension x-rays of some withont significant
A MERKAN RHEUMATISM ASSOCIATION
cervical complaints. Manifestations of cord
compression were relatively minor despitz
inarked displacement in some cases.
Subluxations were of 2 major types: ( 1 )
symmetrical forward displacement of both
inferior facets of the atlas over the respective superior facets of the axis, and ( 2 )
wsymetric or unilateral forward subluxation
confined to one atlanto-axial joint or more
pronounced on one side than the other.
Commonly noted in the latter group were
lateral displacement of the atlas over the
axis and widening or opening out of the
utlanto-axial joint opposite to the side of
major forward displacement. Compression
collapse of one or both lateral masses of
the atlas, or of the axis was observed in
several with rheuniatoid arthritis.
Autopsy of one rheumatoid patient who
died of unrelated causes, revealed erosion
of articular cartilage and subchondral bone
in the atlanto-axial and atlanto-occipital
joints and articulations of the odontoid, compression collapse of the lateral masses of
the atlas, and protrusion of the odontoid
through the foramen magnnni. The transverye ligament of the atlas showed no evidence of degeneration or disruption of its
fibers or weakening of its bony attachments.
The spinal cord and medulla were intact
in the gross and microscopically.
Recognition and prompt treatment are
important. Reduction by gradual traction
with skull tongs followed by atlanto-axial
fusion is recommended for patients with
marked subluxation, persistent disabling
pain or deformity, or significant nerological
manifestations. For those with minor displacement, mild symptoms and no neurological changes, traction, cervical collars,
protection from even minor trauma and repeated observation to detect any increase in
subluxation or cord involvement are indicated.
IN SERUMAND SYNOVIAL
FLIJID*
LATEXAGCLUTINATION
Edoardo Gunriglia. Sidney Berkowitz and Otto Steinbrocker, New York, N. Y.
Synovial fluid and blood specimens were
obtained at the same time from each of
39 patients with clinically detectable effusion due to Rheumatoid Arthritis. Latex
agglutination was then performed in serum
and synovial fluid.
The purpose of this paper was to establish the relationship or difference of the
rheumatoid factor concentration between
the two media. The results were:
48 per cent had equal titers; one tube
dilution difference was not considered
because of possible technical error.
35 per cent had a synovial fluid titer at
least of two tubes’ dilution higher
than the serum,
17 per cent had a synovial fluid titer at
least of two tubes’ dilution lower than
the serum.
I’recipitin reactions of a few samples
were in exact agreement with the Latex
titer in each medium.
Of particular interest was the fact that
a11 6 patients of the probable and possible
rheumatoid arthritis groups (revised A.R.A.
criteria) had positive synovial fluids while
the sera were negative. This finding is
worthy of further investigation for its
diagnostic value.
Thirteen other patients wit!; various rheumatic diseases were also included, as were
two synovial fluids obtained from leg amputation.
Of these 15 samples the sera were all
negative, while the synovial fluids were
also negative, with the exception of 2,
one with what appeared to be a traumatic
effusion, and the other with a lymphosarcoma (biopsy diagnosis) of the tibia with
secondary invasion of the knee joint where
the fluid was obtained.
“Read by title.
EFFECT OF INTRA-ARTICULAR
SEROTONIN
AND OTHERAMINESON
CONNECTIVE TISSUEPROLIFERATION OF RABBITJOINTS*
0. R. Gum, C. J. Smyth, P . K . Hamilton, Jr. and C. Moens, Denver, Colorado
The clinical picture of the carcinoid synclrome includes fibroblastic proliferation of
-
*Read by title,
the subendocardium and valves of the right
side of the heart, pelvic inflammatory
masses, and occasionally arthritic and sclerodermatous changes. Serotonin, or a degrada-
AMERICAN RHEUMATISM ASSOCIATION
tion product, has been implicated as responsible for these changes. Dermal fibrosis
in rats has been produced by the long-term
injection of serotonin subcutaneously.
To test the influence of serotonin upon
connective tissue, daily intraarticnlar injections of this amine were carried out
using one knee joint of the rabbit. As a
control, the opposite knee of the same
animal received normal saline. After 30
days hyperplasia of the synovial epithelial
cell layer was noted on the serotonin-treated
side but these changes were minimal.
In an attempt to accentuate the influence
of serotonin on the proliferation of connective tissue, iproniazid ( Marsilid), an
inhibitor of the enzyme monoamine oxidase catalyzing the breakdown of serotonin,
was studied in a similar manner. Within
three days progressive enlargement of the
joints was noted, and marked proliferation
of the synovial membrane and joint capsule was observed after 10 daily injection\
ranging from 10 to 75 mg.
Similar changes were produced by isoniazid and beta-phenylisopropyl hydrazine
(Catron). Two other amines, histamine
and hydralazine, produced no significant
proliferative changes. Injection of l-methylmethergine-tartrate ( UML 491 ), a serotonin antagonist, likewise produced no
changes.
Additional studies are needed to determine whether these marked proliferative
changes are due to a direct action of these
compounds in stimulating fibrous proliferttion or are a reflection of their effects on
serotonin metabolism.
INTRAMOLECULAR
DISTRIBCTION
OF URIC A c I D - N ~AFTFX
~
GLYCINE-N~~
ADMINISTRATIONTO GVUTYAND NON-GOUTY
SUBJECTS
A. B. Gutman, T . F. Yii, L. Sharnaj and M . Adler, New York, N. Y.
Previous studies demonstrated that when
gouty subjects who regularly excrete excessive urinary urate ( “over-excretors” ) are
given glycine-NlG, 100 mg./Kg., the peak
atom per cent excess uric acid-Nl5 is 2-3
times that of normal subjects given glycine-Nl“, whereas the uric acid-Nl5 abundance of gouty “normal excretors’’ is indistinguishable from the normal. In the
present study, these observations were extended to determine the distribution of
uric acid-Nls in positions N-7 and N( l + 3 + 9 ) of degraded uric acid samples,
procured from 3 gouty “overexcretors,” 2
gouty “normal excretors” and 3 normal
subjects. In the normals, the NlS abundance
in positions N-( 1+3+9) was 25-30 per
cent of the total uric acid-Nlb on day 1,
increasing to 40-50 per cent by the end of
the first week. In both “over-excretor” and
“normal excretor” gouty subjects, the frac-
tion N15-( 1+3+9),ltotal N15 was consistently higher, 30-50 per cent, on day 1,
and remained at about 50 per cent.
The data indicate that in gouty “overexcretors’’ there is (I) an abnormally high
peak uric acid-Nla, due to excessive N1;
incorporation both a t N-7 and at N-( 1 +
3 + 9 ) ; ( 2 ) an initial abnormally high N15(1+3+9)/total Nla ratio. In gouty “normal excretors” the latter abnormality appzars
to be present without appreciable increase
in atom per cent excess uric acid-Nls. It
is inferred from these data that the metabolic pathways responsible for transfer of
nitrogen from glycine to glutamine and/or
aspartic acid, and thence to uric acid positions 3 + 9 and/or 1, are involved in thz
disturbed uric acid biosynthesis of both
“over-excretor” and “normal excretor” gouty
subjects.
STAINING
FOR DPNH - DIAPHORASE
ACTIVITYTO STUDY
LININGC n ~ OF
s SYNOVIAL
MEMBRANE*
David Hamerman and Mallcry Stephens, New York, N. Y.
We have continued our studies of the
lining cells of synovial membrane with
the tetrazolium technique for localizing
“Read by title.
oxidative enzymes (Arth & Rhcum 2:
553, 1959). Synovial membrane was obtained from essentially normal knee joints
( 5 cases) and from knees involved by
osteoarthritis ( 3 cqses) qr active rheuma-
449
AMERICAK RHEUMATISM ASSOCIATION
toid arthritis ( 3 cases), and fixed i n cold
formol-calcium. Frozen sections (10 p ) of
synovial membrane were cut and incubated
in a buffer containing DPNH and terazoliinn
salt (Nitro-BT). Oxidation of DPNH by
diaphorase and transport of
DPNH
electrons to tetrazolium was indicated by
precipitation of dark blue deposits of rednced tetrazolium ( formazan ) within the
cells. These formazan deposits made it
possible to visualize the multiple fine
branches of the processes of the lining cells
as they extended to the free joint space.
Synovial membrane from some normal and
all the oateoarthritic joints showed apparent clear aress formed by the intertwining
of these branches. These areas contained
-
material that stained metachromatically
with toluidine blue in both frozen and
paraffin embedded tissue. In the latter, the
inetachromnsia disappeared following treatment with streptococcal hyaluronidase, and
would thus appear to be due to hyaluronate
( Arth.& Rheum. 2:546, 1959). Synovial
membrane was obtained from 3 patients
with active synovitis due to rheumstoid
arthritis of 1 week, 6 years and 12 years
duration. With the tetrazolium technique,
the lining cells stained much more intensely
than the many inflammatory round cells in
the synovial membrane. The processes of
the lining cells were markedly thickened
and frequently appeared to be elongated.
n B E U M A T K SYMPTOhlS ASSOCIATEDWITH CARCINOMA OF THE PROST.4TE IN ELBEKL
Y hfALES*
John W. Harrison and Aitlaur L. Scherbel, Cleveland, Ohio
One of the cryptic symptoms of malignant disease may be the development of
rheumatic pain in a site remote from the
primary neoplasm and independent of
metastatic lesions. Typical and atypical
forms of rheumatoid arthritis and dermatomyositis beginning suddenly after the
age of 60 years may be found to be associated with a malignant process somewhere
in the body.
Approximately 90 per cent of patients with
classical rheumatoid arthritis develop the
disease before the sixth decade. Recent
reviews concerning the age of onset of
dermatomyositis point to the fact that mslignancies are frequently encountered in
those deveIoping the disease in the fifth
and sixth decades while there is little if
any association when the disease develops
a t a younger age.
An association between carcinoma of the
proytate and a rheumatic disease in seven
rnale patients is reported and attention is
drawn to the fact that estrogen therapy
in these coexisting conditions may result in
control of both the carcinoma and the
rheumatic symptoms.
Six patients who sought medical treatment for “rheumatoid arthritis” which began after the age of 60 years were found
to have carcinoma of the prostate. One
patient who developed the classical clinical
and pathological features of derinatomyositis was also found to have carcinoma of
the prostate. Case histories in these patients
emphasize the disabling symptoms which
led them to seek medical aid.
All patients received only estrogen therapy. Five patients responded with complete disappearance of their rheumatic
symptoms; two patients responded initially
but were unable to continue therapy.
The importance of searching for a malignancy in patients in whom rheumatic
symptoms develop after 60 years of age
is stressed. The disappearance of rheumatic
symptoms in these patients with estrogen
therapy adequate enough to control the
carcinoma suggests that the malignancy
may activate and perpetuate a connective
tissue disease in some unexplained manner.
‘Read by title.
A STUDY OF
CRYOCLOBULINS I N PATIENTS WITH
CONDITIONS
FOR
THEIR
SYSTEMIC
LUPUS
ERYTHFMATOSUS
FORMATION
Wendell B . Hatfield und Charles L. Christian, New York, N. Y.
Spontaneous precipitates from the refrigerated serum of some patients with systemic
lupus erythamatosus have bees studied.
They have had the properties of true cryoglobulins, forming at 0-4 C. in 12-72 hours
and redissolving completely, or nearly com-
450
AMERICAN RHEUMATISM ASSO( XATION
pletely, on rewarming to 37 C. Sedimentation studies of the redissolved precipitates
demonstrated a major component which was
not separable from added 7 s gamma globulin. There is some evidence that Complement, specifically (3‘1, may be involved in
the formation of these precipitates:
( 1 ) If the serum is heated to 56 C. for
30 minutes prior to refrigeration, little
or no precipitate is formed.
( 2 ) The property of cryoprecipitation
can be restored to the heated serum by:
a. addition of whole normal serum.
b. addition of euglobulin, prepared
from normal serum by dialysis
c. addition of “purified” C‘1 from
euglobulin precipitate
d. addition of normal serum treated
with Zymosan and/or NH, (deficient in C’3 and/or C’4)
e. addition of an 11s component of
normal serum, prepared essential-
ly by the method of Muller-Eberhard and Kunkel. This material
may represent altered C’1 or n
“new” component of complement.
( 3 ) The property of cryoprecipitqtion
was not restored to a significant degree by:
a. addition of whole, normal serum,
heated to 56 C. for 30 min.
b. supernatant of dialyzed, normal
serum
c. normal serum absorbed by antigen-antibody precipitate
d. normal serum absorbed by aggregated gamma globulin (partial effect)
It is suggested that the cryoprecipitatr
thus described may represent thr rraztion
of C‘1 with an antigen-antibody co,npIeu
present in the sernm of these patients wit!)
111pus.
THE RELIEF O F INTRACTABLE ARTIIRITIC PAIN BY EXTENDED SYMPATHETIC
DENERVATION:AN APPRAISALAFTER FIVE YEARS*
Robert A. Herfort, White Plains, New York
The principal source of disability presented by most patients with chronic arthritis is pain originating in the weight bearing joints. Over the course of the past five
years, the author has employed a technique
of so-called extended sympathetic denervation in 64 patients with advanced painfnl
rheumatoid arthritis and osteoarthritis of
the hips and/or knee joints. The surgery
consists of a retroperitoneal resection of
the lumbar sympathetic trunks from the
superior margin of the common iliac vessels to the second lumbar vertebra encompassing accessory ganglia on the raini communicantes and also decussating fibers in
the retro-aortic prevertebral plexus. The
procedure is, at present, carried out bilat-
erally at one sitting. This surgery in middle
aged and elderly arthritic invalids hxs had
no mortality. In the immediate postoperative period, the patients exhibit, consistently, relief of arthritic pain with concomitant
improvement in joint mobility and general
functional capacity. The patients have been
followed by periods up to five years aftcr
surgery; the relief of pain and improved
range of motion have been maintained.
There have been no undesirable effects noted after extended sympathetic denervation.
Neuropathic disorganization of the affected
joints has not occurred.
It is suggested that the principal afferent
pain pathways froiii the articular surfaces
of the hip, knee and ankle joints traversg
the lumbar sympathetic trunks and plexuses.
“Read by title.
HEACTION O F
RIIEUMATOIDLEUCOCYTES
WITH FLUORESCENT AGGREGATED
GAMMA
GLOUULIN
Evelyn Hew and Mowis Ziff, Dallas, Texas
In it study of the binding of rhenmatoid
factor to cellular elements in human and
animal tissues, it was observed that washed
‘lencocytes and platelets of rheumatoid
arthritis patients with high titers of rheuma-
toid factor were agglutinated by aggregated
human gamma globulin ( Cohn Fraction I1 ) .
Leucocytes and platelets from non-rheumatoid individuals were rendered agglutinable by incubation with rheumatoid serum.
451
AMERICAN RHEUMATISM ASSOCIATlON
These observations suggested that the cells
were coated with rheumatoid factor.
In order to further establish this fact,
leucocytes were separated by a phytohemagglutin sedimentation method and
stained with fluorescein isothiocyanate labeled heated F 11. The presence or absence of fluorescent staining of the leucocytes was observed grossly under a long
wave ultraviolet lamp. Microscopically,
staining of the individual cell? was noted.
Fluorescence occurred with 56 of 60 adults
and 11 of 16 juveniles with rheumatoid
arthritis. The reaction, which could be
blocked by prior treatment with unlabeled
F 11, was observed even when the titer
of rheumatoid factor in the serum wris
low or negative. Sera from 5 of the 11
positively reacting juvenile preparations
LONGTERM(TENY E A R ) STUDY
OF
gave negative serological tests. Among 64
non-rheumatoid preparations, there were
3 positive tests from patients with erythema
nodosum, lues, and ankylosing spondylitis.
The first two patients also gave positive
latex fixation tests.
In addition to providing the basis fot
a sensitive test for the rhenmatoid factor
the phenomenon described indicates that
these proteins avidly adhere to leucocytes
and platelets. Animal experiments have
demonstrated the binding of these factors
to vessel walls. The suggestion is made
that a reaction between circulating F 11
and rheumatoid factor bound to blood element\ and vessel walls may play a role in
the pathogenesis of vascular lesions, at
least in patients with markedly elevated
titers.
RHEUMATOID
ARTHRITIS TREATMENT
BY STEROIDS*
Thomas G. Kantor, Westport, Connecticut
Fifty-six rheumatoids have been placed
on long term steroid therapy at this clinic
since 1950, the criterion for selection being
severity of disease and lack of control by
other agents. None was started after 1954.
Five were later rediagnosed as non-rheumatoids; six were followed less than six
months and were dropped. Nine have been
lost to follow-up. The remaining 36 are
25 females and 11 males who have been
treated an average of 51 months (range
5-120) and followed an average of 82
months (range 12-120). Overall treatment
result is not impressive. More striking is
the incidence of major complications which
are defined as major G.I. lesions, sustained
hypertension, fracture, mental disorders,
reduced resistance to infection, sustained
glycosuria and death. Twenty-nine or 80
per cent had one or more of these despite
careful follow and adherance to the lowest
possible maintenance dose of steroid. There
were 11 deaths or 31 per cent from a variety
of causes; eight of them women. There were
9 proven ulcers and .5 more instances where
there is strong presumption of ulcer for a
total of 14 or 39 per cent. Five (14 per
cent ) had sustained hypertension and seven
(19 per cent) had fractures. There was one
adrenal deficient baby born to a treated
mother. Cortisone, hydrocortisone and prednisone were the steroids used for msiritenance.
These data contrast strongly with a series
collected from these same patients six y x r s
ago in which long-term steroid therapy
was considered favorably.
*Read by title.
TO RHEUMATOIDARTHRITIS*
RUBELLAARTHRITIS: PossimE RELATIONSHIP
Thomas G. Kantor, Westport, Connecticut
Twelve women, who were diagnosed as
having rubella during local epidemics, were
found to have moderately severe rubella
arthritis. One of these has been followed
for four years, two for three years, five
for two years and four for one year follow*Read by title.
ing their illnpsses. All were tested by the
Ziff modification of the sheep cell agglutination test and 10 by the capillary latex test.
All capillary latex and euglobulin agglutination tests were negative during the diselw
process and have remained so since. One
euglobulin inhibition test was positive and
has remained so in a patient whose nnthher
452
AMERICAN RHEUMATISM ASSOCIATION
has severe rheumatoid arthritis. Two patients (not the positive reactor) have continued to have athralgia in one or niore
of the originally affected joints for one and
three years respectively.
The clinical characteristics of the disease
are that of a small or inedimn joint, syinmetrical arthritis occurring an average of
4.3 days after onset of the disease and
o m day after onset of the rash. The arthritis
lasts an average of seven days, the longest in this series being 20 days. Westergren sedimentation rates as high as 31)
nini./hr. were obtained. The remainder of
the hemogram was unrevealing.
\Vith the development in recent yeiirs of
niethocls for the quantitative separation of
the different inucopolysaccliarides ( MPS ) ,
it has become possible to determine the
content of these substances in different tissues by actual isolation, rather than by inference from various analytical procedures
meastiring components of the polysaccharides, such as uronic acid, hexosamine, sulfate, etc. As a baseline for the stndy of
diseases of connective tissue, two studies
have to date been done measuring the
“normal” change with age of the several
htPS - namely, on rib cartilage in this
laboratory, and on nucleus pnlposns by
Ihvidson. The present work is concerned
with the aortic wall. Hnman aortas obtained at autopsy were segregated into
seven age groups, the average of each grorip
ranging from 21 to 72 years of ape. With
advancing age, there was also a graclnul
incresse in the degree of atherosclerosis.
The hlPS were isolated and found t o Iic
four in number - hyaluronate, chondroitin
sulfate C, chonclroitin snlfate B and hep:tritan. The total amount of XfPS/clry weight
of aorta was about I per cent, and no
variation with age could be detrcted in
this small series - nor was there any
variation in total hexosamine done on a
large number of individual aortas. The relative amounts of each MPS, however, tlicl
not remain constant, there being a fall with
age in the concentration of hyaluronate
and chondroitin sulfate A with a concomitant rise in the amounts of chondroitin
sulfate R and heparitin.
Since platelets from patients with rhenmatoid and non-rheumatoid inflammation
showed. mild impaimient of ability to absorb serotonin in vitro, other evidences of
impaired activity of thrombocytes were
sought. The redox systeni of Martin and
Chauduri was adapted to the study of
thrombocytes. The method required intact
platelets, all activity disappearing with rupture of the wall. Redox activity was studied
under varied conditions and on addition of
serotonin to the various systems tested.
In the presence of added plasma, redox
activity of platelets was enhanced by the
addition of serotonin and markedly so by
the fnriher addition of cyanide. The eflc:.t
was rediiced by adding reserpine in rclitively large amounts to the system. Phosphate buffcr as used by Weissb:irh et at.
could not be substituted for plasma. The
enhanceinent of redox activity increaseil
with dilution of added plasma to a inaximum beyond which no further enhancement
occurred. The effect of added dilute plisma
was not significantly altered by prior dialysis of the plasma against balanced buffer
salts or by extraction of the plasma with
butanol. Englobulin obtained by isoelectric
precipitation could not be substituted for
dilute plasma, and Cohn fractions 11 and 17
to only a small extent. The factors affecting
redox activity of platelets on addition of
_s_c--i__
_.&%
-. . ,-
“Read by title,
-
453
AMERICAN RHEUMATISM ASSOCIATION
serotonin were then related experimentally
to uptake of serotonin by platelets. Rheuinatoid patients are being investigated for
possible differences in these factors.
Basic redox activity of thronibocytes in
saline and cyanide was slightly decreased
( p < 0.05) in rheumatoid patients compared to normals. The difference was abolished by addition of glucose to the system.
THE ROLE OF MICROCIRCULAT
ORY DYSFUNCTION
IN FIRRINOID
NECROSIS:A CORRELATIVE
STUDYOF VASCULAR
AND CONNECTIVE
TISSUE
CHANGES
IN EXPERIMENTAL
COLI)INJURYAND RHETJMATOIO
I>ISE.M~
J. Peter K d k a , Boston, hlass.
Fibrinoid necrosis of blood vessels and
connective tissue characterizes several etiologically unrelated human and euperiniental lesions including those of systemic r1i-mniatic diseases and cold injury. Since thew
conditions may be preceded by vasospastic
disorders and the anatomic features of e x l y
lesions suggest a primary circulatory defezt,
we investigated the possibility that local
vascular dysfunction is the common denominator in their pathogenesis. As an experimental model for this study we selected
the focal lesions which develop in the ears
of mice kept individually caged at 3 C .
This mode of injury is readily controlled.
Moreover, the mouse ear is ideal for correlating the functional and anatomic vascular changes both temporally and spatially
with the development of extravascular tissue
damage. The following sequence of microcirculatory changes was shown to precede the onset of the cold-induced fibrinoid
necrosis: 1. vasospastic ischemia of the
terminal vascular bed; 2. relaxation of
veins and venules with persistence of segmental arteriolar constriction; 3. focal
JOINT
“leakage” of plasma and extravasation of
erythrocytes from dilated venules; 4. venular and capillary stasis and obstriiction
by compacted erythrocytes; 5. arteriolsrvenous shunting with bypassing of capillary
and venular plexi. The development of stasis
appeared to depend on both restriction of
capillary inflow by arteriolar spasm and pooling of blood in dilated, “poorly drained”
venules. Venular leakage favored irreversible
obstruction by compacting of erythrocytes.
Where venular stasis remained segmental, it
resulted in mild inflammation and lytic necrosis of occluded vessels followed by connective tissue proliferation. Focal fibrinoid
necrosis developed, first in those venules in
which blood flow persisted despite confluent stasis of surrounding vessels. Ultimately the arterioles and connective tissue
also became involved.
The few lesions of rheumatoid arthritis
examined at early stages in the development of fibrinoid necrosis showed histologic
changes compatible with a similar mechanism of tissue injury.
INVOLVEMENT
IN SAHC:OILXXIS
Keith A . Mnnley and Lawrence E. Slaulmm, Baltimore, h1nryl:md
There has been increasing awareness of
rheumatic manifestations in sarcoidosis, accentuated by a recent report (Sokoloff and
Bunim) of sarcoid lesions in synovial tissue obtained by needle biopsy. In previously reported series containing significant
numbers of cases, joint involvement is mentioned either not at all, or incidentally. The
study to be presented is an analysis of 90
cases of biopsy-confirmed sarcoidosis, in
whom careful inquiry and physical examination for articular abnormalities were performed by the authors.
The mean period of observation was 6
years. Joint involvement was a significant
feature in 23 per cent of cases. In the majority there was swelling (and in some
cases other inflammatory signs) in addition to pain. Characteristically the arthritis
occurred at the onset of the disease and
was often the presenting feature. It affected. primarily large joints: knees, ankles,
elbows and wrists in that order, and in
this respect resembled rheumatic fever, although it was symmetrical in most instances. There were no residual deformities.
454
AMERICAN RHEUh'lATlShI ASSO~XATION
Only one-fifth had coincident erythem3
nodosum, and in these the articular dise ise
did not differ from the remainder.
In 4 of the 7 cases with radiological bony
lesions, phalangeal deformity was obvious
on examination. In the other 3 a single
small lesion was seen on x-ray, and the
diagnosis was apparent on other grounds.
Thr: latex fixation was positive in 6 per
cent, none of whom had joint involvement.
The highest titre observed, 327,680 units,
was found in a man with no symptoms, no
hepatic involvement and a serum globulin
concentration of 1.8 g. per 100 ml. Positive
latex fixation tests may he no more common
in sarcoidosis than in the general nonrheumatoid population.
CERVICAL VERTEBHAL EROSIONSAND SUBLUXATIONS IN
RHEUMATOII) ARTHRITIS AND ANKYLOSING
SPONDYLITIS
William Martel and Jesse W.Page, Ann Arbor, Michigan
It is well recognized that the cervical
spine may be affected in ankylosing spondylitis and juvenile rheumatoid arthritis,
but insufficient attention has been given to
this region in rheiimatoid arthritis. The
periodontoid region is of particular significance in these diseases because it contains
synovirrl cavities and important ligaments
closely arranged around the odontoid
process.
Radiographs of the cervical spine in
flexion and extension, and laminagrams,
were obtained in selected patients with
rheumatoid arthritis or ankylosing spondylitis. Cervical subhixations, especially of the
atlanto-axial joints, were frequently present.
Vertebral erosions, particularly of the odontoid process, were common, and in ankylosing spondylitis the odontoid was sometimes eroded and sclerotic niimicing the
bony lesions that are known to occur in
IDENTIFICATION OF IJRATE
the vertebral bodies and pzlvis in this
disease. A vertical displacement of the
cervical spine with respect to the skull
was often present and was, at times, associated with invagination of the foram-n
magnum ( basilar invagination).
Histologic evidence of rheumatoid arthritis of the atlanto-odontoid joints is presented. It is questioned whether pro1ongc.d
steroid therapy predisposes to rupture of
cervical ligaments invoIved by rheumatoid
disease. Neurologic complications were
usually absent in these patients but consideration should be given to whether
neurologic manifestations are being overlooked in some cases. The spondylitis that
occurs in typical rheumatoid arthritis is of
interest for it differs both clinically and
radiologically from classic ankylosing spondylitis.
CRYSTALSIN
GOUTY
SYNOVIAL
FI,Ull>
Doniel J . McCorty and Joseph L. Hollander, Philadelphia, Pa.
Urate crystals have been observed occasionally in aspirated synovial fluid from
gouty joints in the past. The frequency and
ease with which we were able to demonstrate such crystals microscopically, stimulated a full scale study of the synovial
fluid obtained from all patients in our
clinic with proved or suspected gout. To
date we have been able to identify by
ordinary light microscopy the rod-like,
mate crystals in the fluid from 23 of 32
patients. All 7 who had tophaceous gout
showed abundant urate crystals. Of the 22
with non-tophaceous gout, 16 showed typical crystals in the fluid. In 4 of the 9 patients who showed no crystals, the diag-
nosis of gotit still has not been established
by the usual criteria. In 4 patients, identification of these crystals w a s the first lahoratory evidence of gout, corroborated by
subsequent findings of hyperuricemi:i, and
in one case, typical siibchondral changes
by x-ray.
To differentiate the urate crystals from
the cartilage fibrils found in osteoarthritic
fluid, and from other particulate matter,
two methods have been employed in addition to their mopliologic appearance. hficroscopic examination with polarized light
has shown the urate crystals to be negatively birefringent with extinction approximately on the long axis of the crystal,
455
AMERICAN RHEUMATISM ASSOCIATION
Digestion by incubation with nricase has
consistently destroyed such crystals.
Comparison of the results obtained by
polarized light microscopy with those obtained by ordinary light revealed that the
pzrcentage of positive identification fell
from 83 to 61 per cent when ordinary light
was used.
Two specimens contained numerous crystals by ordinary light which were not birefringent by polarized light and which were
not digested by uricase. One of these specimens was from the knee of a patient with
classical acute gouty arthritis and the other
was from a case of atypical osteoarthritis
of the knees and shoulders. This finding
raises the possibility of an hitherto unrecognized metabolic abnormality which can
mimic the syndrome of gout.
Our experience indicates that these rapid
simple tests are helpful in establishing the
diagnosis of gout.
OF CARTILAGE M4THIX IN
THE REMOVAL
VIVO BY PAPAIN. FACTORS IN SERUM
INFLUENCING
THE EFFECTS
OF PAPAINON CARTILAGE
T . F. McElZigott, J. L . Potter, G. Weissmunn and R. T . RlcCluskey, New York, N. Y.
In young rabbits, marked depletion of
the basophilic and metachromatic material
occurs in the matrix of cartilage thronghout the animal following an intravenous
hjection of papain protease, provided that
the enzyme is injected in the oxidized,
inactive form. Reduced, active p:ipain has
no such effect in rabbits. This difference
iin the in vivo effects of the two forms of
the enzyme is attributable to an interaction with serum, which impairs the entry
of reduced papain into isolated cartilage in
vitro. In the same circumstance, oxidized
papain enters cartilage in amounts snfficient to produce depletion following reactivation in the tissue.
Electrophoretic studies with iodine labeled pap-tin have shown that amounts up to
50 fiGm./ml. of either form of the enzyme
are bound by alpha globulin, in both rabbit and human serum. At higher concentrations, the excess of the oxidized enzyme
retains free mobility on starch block electrophoresis, while a similar excess of the reduced enzyme is partly linked with albumin. These findings have been confirmed
by immuno-electrophoretic studies with
unlabeled papain.
THE PATTERN
OF
It 112s been found that normal rabbit
serum will diminish by 30 per cent the
availability of papain to precipitate with
specific antibody. Moreover, alpha-globulin
inhibits the in vitro proteolytic activity of
papain by as much as 60 per cent. Since
partial inhibition occurs also with albumin
and gamma-globulin, this effect of the
alpha-globulin fraction need not be regarded as evidence that it contains a specific inhibitor. Such alterations in the antigenic and enzymatic properties of papain
could result from binding by alpha-globulin
or other serum proteins.
The foregoing supports the view that in
vivo depletion of cartilage matrix following the injection of oxidized papain is produced by a small percentage of the enzyme which exceeds the binding capacity
of alpha-globulin. Being inactive, this portion does not immediately link with other
protein in the circulation, but instead diffuses into cartilage.
It is possible that the binding of papain
by alpha-globulin may exemplify a mechanism which can prevent damage to the
tissues by potentially harmful agents which
have entered the circulation.
ANITBODY RESPONSEI N RHEUMATIC
DISEASE
L. E . Meiselus, S. L. Lee, S. Richman and S. B. Zingale, Brooklyn, N. Y.
Patients with rheumatoid arthritis ( RA ),
rheumatic fever ( R F ) , systemic lupus erythematosus (SLE) and acute glomerulonephritis ( GN) have been studied immunologically. Patients with diverse diseases unrelated to the above group acted as controls. Circulating antibodies to Brucella vac-
cine given intramuscularly were measured
at 1, 2 and 3 week intervals. Delayed hypersensitivity was measured by the reaction
to the Frei test. Iso-hemagglutinins, electrophoretic patterns, anti-streptolysin titers,
anti-nuclear antibody titers using a fluorescent technique, and latex particle fixd-
456
AMERICAN RHEUMATISM ASSOCIATION
tion ( L P F ) were also measured. Almost
all patients with RF, RA, SLE and GN had
significantly increased titera of circulating
antibodies when compared with control
patients. The study patients reached their
peak level of circulating antibody between
7 and 14 days after challenge. Although
two of the patients with SLE had measurable antibodies to Brucella before vaccination, this group did not show as high a rise
of circulating antibody as did the other
studied patients. Serum protein fractions
and iso-hemagglutinins did not show any
significant alteration following the challenge.
ASL titers in the patients with GN and
R F were similarly unaffected. However, in
several patients the LPF showed a concomitant rise in titer with the rise in Brucella
titer. The addition of mercaptoethanol to
the serum removed both the rheumatoid
factor and almost all of the Brucella antibodies, suggesting that both activities consisted largely of 19s gamma globulin.
In no instances did challenge came any
recrudescence of symptoms. All patients
had negative Frei tests.
Family studies of these patients are now
in progress to determine whether this response is of an acquired or an inherited
nature.
OF PGRIARTERITIS
YODOS
A: A REVIEWOF 56 CASES*
HISTOPATHOLOGIC
CLASSIFICATION
Roland W. Moskowitz, Arcliir. H . Baggemtoss cinrl Charles H . Slocumb, Rochester, Minnesota
Fifty-six cases of necrotizing systemic arteritis were studied histologically. They
were classified in three group.;. Croup 1
included 34 case : of necrotizing arteritis
without associated pulmonary arteritis, necrotizing alveolitis, or numerous extravascular lesions; group 2 included 16 cases
of pulmonary arteritis and either necrotizing alveolitis or niimerous extravascular
lesions or both; group 3 included six cases
of so-called secondary periarteritis nodosa.
The numerous extravascular lesions in
group 2 were similar to lesions associated
with allergic disease processes, and contrasted greatly with the infrequency of extravascular lesions in group 1. Clinically,
group 1 had a significantly higher frequency
of hypertension and uremia than the other
groups, while group 2 had a higher frequency of prior respiratory illness or allergic drug reaction as well as nasal granulomas, sinusitis, middle-ear infection, eosinophilia, and splenic vasculitis.
"Read by title.
SCME PSYCHOSOCIAL
In group 2, lesions were classified as
hypersensitivity angiitis and included Wegener's granulomatosis and allergic granulomatous angiitis as well as lesions similar
to those described as allergic angiitis in the
literstare. Group 1 was felt to represent
idiopathic periarteritis nodosa. Hypertension was considered as a probable contributing factor in the development of idiopathic
pcriarteritis nodosa while prior respiratory
illness or chug allergies were considered
etiologic factors in hypersensitivity angiitis. The abnormal auto-immune reaction
of both groups niay be similar; however,
the sensitizing agent t o which the pntient
responds abnormally appears to be different
in selected cases.
Secondary periarteritis nodosa was considered to be a separate entity. The healing cffect of steroids on periarteritis was
confirmed in a study of 10 cases. I t is felt
that adrenal steroids act in a precipitating
manner rather than as a specific cause of
diffuse angiitis in patients with rheumatoid
arthritis and systemic lupus erythematosus.
FACTORS
It. PATIhNTS
WITH
RHEUMATOII,
ARTHRITIS+'
Alfred D. Mueller, Aaron M . Lefkouits, John E. Bryant and &lax L. I\larshall,
Memphis, Tennessee
The effects of various psychological, socia1 and economic factors were investigated
in a group of male patients with rheumatoid
arthritis by means of the Cornell Index, a
"Read by title.
personal data and life events questionnaire,
selected TAT cards, and a trait-type questionnaire about the male figure drawn by
the patient. For control, a group of similar
hospital patients with diseases other than
rheumatoid arthritis were used.
457
AMERICAN RHEUM.kTISM ASS0C:IATION
The results of the Cornell Index indicate that patients with rheumatoid arthriti:;
show a significantly greater incidence of
psychophysiologic reactions; namely, psychosomatic symptoms, hypochondrixk and
asthenia, and a trend toward greater neuroc.irculatory symptoms and startle reaction.
The results obtained by means of the
pxsonal data and life events questionnaire
indicates that rheumatoid arthritics suppress and/or repress their feelings toward
changing jobs and that they are unwilling
to express their feelings toward changing
itheir residences; they do. not differ significantly, however, from controls in showing
‘concern for and in their tendency to complain about family difkulties, finances, personal routines, and global affairs.
These findings are interpreted as indicating that patients who have rheumatoid
arthritis are either unwilling or unable to
express openly feelings of dissatisfaction
against many stressful aspects of their environment and that they are unable to admit to themselves and to others their negative feelings toward their lot in life.
The results from the questionnaire about
THE I’A
rJIOGENES1S OF
the traits, attitudes, and characteristics of
the male figure drawn by the subject indicate that arthritic men generally ascribe
the same traits to their figures as do the
controls. They differ from the controls,
however, in that a significantly greater proportion of their group regards the figure
as being unsure of himself and getting along
easier with men than women.
Results of the Thematic Apperception
Test show no significant differences between
the two groups for themes involving physical and non-physical aggression, as well
as thcmies of emotions1 tension and stress.
There is a trend, however, for the arthritics to give more themes involving sorrow, remorse, and repentance than do the
controls, suggesting a tendency for the
arthritics to direct feelings inwardly and/or
suppress overt aggression.
While the two groups do not differ
significantly in the types of TAT outcomes,
or how things will turn out, there is a trend
for the arthritics to express outcomes that
are either neutral, unpleasant, unsatisfactory, or tension producing.
OCHRONOTIC ARTHROPATHY
William O’Brien, Willicirr1 Banfidd uiad Leon S o k o l o f f , Bethesda, Maryland
Although the biochemical defect in alcaptonuria has been well delineated, the
pathologic consequences of this defect are
little understood. Anatomic material from
the knees in three verified cases of ochronosis has provided the basis for a systematic
approach to genesis of the degenerative
articular changes that constitute the principal deleterious result of the enzyme defect. In the articular cartilage, pigmentation was confined to the radial zones, while
the tangential (surface) portion was spared.
The findings suggest that specific local binding sites for homogentisic acid (HGA) in
the matrix of the cartilage are required for
thi: arthropsthy to dcvelop. The formation
of “joint bodies” represented a secondary,
polypoid osteochondromatous reaction to
displaced cartilage detritus. The pigment
was not electronopaque but abnormalities
of collagen fibrils were present. Cartilage
became pigmented in vitro upon incubation
with HGA, but this wa5 a nonspecific
phenomenon.
EFFECTOF ADRENOCORTICAL
HORMONES
OX CUTANEOUS
BLOODVESSELS
OF RI-IEUMATOII)
PATIENTS
Joachihim L. Opitz, Grace M . Roth, E,dward L. Buldes nnd Charles I I . Slocumh,
Rochester, Minnesota
The cutaneous blood vessels of the extensor surface of the forearm were studied
in ( 1) ten healthy subjects, aged 30 to 88
years, who were used as controls, ( 2 ) five
patients with acute bronchial asthma who
never had received steroid therapy, ( 3 )
five patients with definite rheumatoid arthritis who had never received steroid therapy, ( 4 ) five patients with definite bronchial asthma during long-term ( a t least 3
months ) therapy with cortisone-like compounds and ( 5 ) 15 patients with definite
AMERICAN RHEUMATISM ASSOCIATlON
rheumatoid arthritis during long-term ( at
least 3 months) therapy with cortisone-like
compounds. The daily amount of cortisonelike compounds administered ranged in
equivalents of prednisone from 4.5 to 20
mg. for the rheumatoid patients, and from
10 to 24 mg. for the asthmatic patients.
The skin was observed directly with a
capillary microscope yielding magnifications
from rj to 10 times, while the patient was
under strict resting and fasting conditions
a t a room temperature of 25 C., and with
the foreann at heart level. Photomicrographs of the same area were made at
regular intervals before, during and after
periods of controlled venous occlusicn. The
visible blood vessels were counted on thc
photomicrographs under thre-fold inagnification along three straight lines, each
representing 3 mm. of skin of thr: individual
patient.
Abnormalities of blood vessels that were
consistently present in rheumatoid patients
during steroid therapy but absent or min-
imal in all other groups studied were as
follows: 1. segmental aneurysmal dilatations of subpapillary blood vessels (1Fj of 1Fi
patients), 2. diapedesis of red blood cells
from dilated vascular segments (five of
15 patients), and 3. (with venous occlnsion) a decrease in the number of visible
blood vessels associated with an abnormal
increase in the engorgement of the preexisting dilated vascular segments.
These abnormalities are seldom seen
with hypercortisonism from usual doses of
steroids or with rheumatoid arthritis; they
are not a part of initial therapy with cortisone and they occur predominantly in
rheumatoid patients who have chronic hypercortisonism. The occurrences of these
visible vascular reactions appear to be associated with the mesenchymal reaction
of chronic hypercortisonisni in rhenmatoid
patients. Since capillaries also are affected.
it is apparent that the basement membranes
or the endothelium or both are affected.
FLUORESCENT
ANTIGLOBULIN STUDIES
OF
ERYTIIEMATO5US
A SERUE~I
REACTANT
’ro DNA
( S L E ) A V D OTHER I h S E A S E S *
IN
SYSTEMIC
LUPUS
Carl M . Pearson cind Bruce Gillikind, Los Angles, California and Chicago, Illinois
Previous studies have shown that many
persons with SLE possess a serum factor
which will react with desoxyribonucleic
acid (DNA) in a complement fixation or
precipitin test. In addition, an interaction
has been observed between nucleoprotein
or tissne nuclei and lupus globulin when
fluorescent antihuman globulin was usecl
as an indicator. DNA has not previously
been used in the simple fluorescent test
because of its poor adherence to the slide.
This difficulty has been overcome by the
nse of glass slides which were precoated
with formalinized gelatin. DNA, without
detectable protein, from human spleen or
calf thymus cells was dried on slides and
used as the substrate for the antiglobulin
method.
In this study, sera from 30 persons with
SLE and positive LE cell tests gave a
__-
positive DNA fluorescence reaction. Four
others with weakly positive LE cells did
not contain DNA reactants while six with
repeatedly negative LE cells but with
biopsy (renal or skin) and clinical evidence
of SLE gave a positive DNA test. All of
45 cases of rhenmatoid arthritis gave a
negative test as did sera from 20 other
persons with connective tissue diseases and
40 with miscellaneous disorders. All 6 sera
from Felty’s syndrome, 4 of which had
typical LE cells, were negative for DNA
reactants.
Of particular interest were 6 sera with
negative LE cell reactions and positive
DNA fluorescence. Two of these patients
had thrombocytopenic purpura, one had
polyarteritis and three others had a bizarre
clinical course which was characterized by
an episodic dermatitis and biopsy evidence
of vasculitis.
*Read by title.
ACID
HYALUHONJC
AND
ThSUE PEHMEAHII.I.rY
W a r d P i g m n , S . Rizui and Howard L. Holley, Birmingham, Alabama
Considerable evidence exists that tissue
permeability is enhanced in diseases such as
rheumatoid arthritis. “Complexes” between
hyaluronic acid and serum proteins have
been demonstrated earlier by Ogston and
in the present work. This “complex” forma-
tion seems to prevent protein niigration
through hyaluronic acid as it occnrs in the
intracellnlar ground substance. Since hyaluronic acid can be depolymerized by substances such as natural thiols, ascorbic acid,
ferrous and cnprous ions in the presence of
oxygen and water, probably by a free radical
iiiechanism, the “complexing” ability can
be altered. This reaction, called the OR11
reaction, may thus control the permeability
of the ground substance and itself be mediated by the state of oxidation of the cells.
Synovial fluids contain a non-dialyrahle
factor causing the degradation of h yaluronic
acid under acid conditions, such as exist
during iiiucin clot formation. The nature of
this factor has not been established. Probably, it is a protein.
Substances have been found which inhibit the ORD reaction. These include
sodium diethyldithiocarbamate, thiourea
and penicillamine. Their possible stndy as
therapeutic agents for control of tissue
permeability is suggested.
WlTJX PROTEIN IN SYNOVIAL YLUII>*
Wurd Figtnun, S. Hizri unsl Edgcii. Crumling, Birmingham, Alabama
Evidence will be presented that hyaluronic acid forms “complexes” with the proteins of synovial fluid, whose physical form,
stability and composition vary markedly
with pH, salt concentration and probably
the molecular size of the hyaluronic acid.
The nature of these “complexes” has been
stndied by chemical, electrophoretic and
iiltracentrifugal analyses of human and
bovine synovial fluids and of synthetic mixtures. Studies were made over n range of
p H of 1 to 9.
At low ionic strengths, mucin clots or
precipitates form between pH 2 and 5.
.411 of the hyalnronic acid is found in the
precipitates formed between pH 2.5 and
5, but the protein content decreases with
decrease of pH.
As shown by electrophoretic studies in
the p H range 7.3 to 8.6, highly polymerized
hyaluronic acid affects the mobility of seruin
and synovial fluid proteins. At p H 8.6 in
veronal buffer, the component previously
described a s the Pi component may he
formed by binding with serum albumin.
At pH 7.2 to 7.4 in phosphate buffers, a
distinct Pi component may be formed if
degradation of the hyaluronic acid is avoided. Often, its presence may be shown by
an asymmetry in the advancing side of the
albumin peak. Presinnahly these complexes
are related to thosc shown earlier by Ogston
and Curtain.
*Rrad by title.
THE EAHLY
CHAKAC T E R l b T I C b O F R H E r i i A r o l I)
SPONDYLITIS
Howurd F . Polley a i d S. Matthew Bevge, Rmhesttr, Minnesota
A stndy was undertaken to determine
whether rheuinatoid spondylitis could be
reliably recognized clinically in advance
of the development of roentgenographic
evidence of typical changes in the sacroiliac joints, Eighty-four patients seen in
rheumatologic consultation from 1944
through 1958 were included initially, and
the subsequent course of 54 was determined
by re-examination or follow-up inquiry. A
definite diagnosis of rheumatoid spondylitis
was established in 16 (30 per cent) of the
54 patients. Fourteen of the 16 were males;
the average age at the onset of symptoms
generally recognized as characteristic of
rhenmatoid spondylitis was 21.6 years.
The duration of symptoms prior to a
definite diagnosis of rheumatoid spondyliti,
ranged from less than 1 year to 19 years;
but 11 of the 16 patients (69 per cent)
had received the definite diagnosis in less
than 10 years after the onset of symptoms
attributed to the disease. No pertinent or
distinguishing differentiating features were
recognized in the clinical or usual laboratory findings that would help separate patients with definite rheumatoid spondylitis
from those who did not receive this diagnosis.
Patients and physicians apparently are
still dependent on development of typical
roentgenographic evidence of destructive
arthritis in the sacro-iliac or apophyseal
joints of the spinal column for a definite
diagnosis of rheuinatoid spondylitis. However, some patients have symptoms of this
disease for many years before such changes
can be recognized roentgenologically. The
absence of roentgenographic changes does
not warrant excluding the possibility of
THEFAMILIAL OC CUHXFNC E
rheumatoid spondylitis in patients whosc
clinical features suggest the possihility of
this disease.
OF SYS?.EMI(
LUIU ERYIHFMATOSLl\a
Robert M . Rene and Carl M . Pearson, Lo\ Angeles, California
Familial systemic lupus erythematosus
as confirmed by the presence of the LE
cell factor and clinical features, is reputedly uncommon as evidenced by the fact
that in the 12 years since the disaxery
of the LE cell test only 6 reports on this
subject have appeared in the literature.
Additional reports on 3 families are strongly suggestive of this association. These are
based on clinical description and the presence of a positive LE cell test in one meniber of each of the families described.
We have had an opportunity to study
members of 3 families in which there has
been definite or highly suggestive evidence
for SLE. The most thoroughly investigated
family has 3 members with SLE in 2, generations. They consist of the mother, age
38, who has a long history of renal disease
-
-~
with recurrent “nephritis” during each of
2 pregnancies, the daughter, age 19, who
has arthralgias, sunlight sensitivity and a
butterfly eruption, and the son, age 16,
who has had two episodes of fever, arthralgias and facial rash. All 3 memhers of
this family have had repeatedly positive
LE cell tests and have a serum factor which
reacts against purified desoxyribonucleic
acid when tested by the fluorescent doublelayered technic. We have been able to
study only one member of the other 2.
faniilies but the evidence for SLE in the
sibling, in each case, is fairly well documented. A fourth family has one sibling
with SLE and one with rheumatoid arthritis. The serologic differences in this family will be described and the general problem of familial and congenital SLE will
he discussed.
“Read by titIe.
THEANEMIAOF RHEUMATOIDARTHRITIS*
Frunk E . Roberts, Albert B . Hagedorn, Charles A. Owen, Jr. tind Chtrrles H . Slocumh
Rochester, Minnesota
Production and destruction of red cells,
as measured by radioiron and radiochroniium in 33 patients with active rheumatoid
arthritis were studied. In 12 patients, evaluations of ferrokinetics, erythrocyte survival times and gastrointestinal bleeding
were done with the use of radioiron and
radiochromium simultaneously in each patient. The plasma volumes and whole blood
volumes were elevated. The plasma iron
clearance rate was increased; the serum iron
and plasma iron pool were decreased; liowever, the daily plasma iron turnover rate was
normal. Incorporation of intravenously administered radioiron into circulatory erythrocytes was normal both in rate and amount.
The apparent half-survival time of autotransfused radiochromium-labeled erythrocytes
“Read by title.
was within the normal range. There was
evidence of gastrointestinal bleeding in only
one patient.
In a group of 21 patients, serum iron and
the total iron-binding capacity of the serinn
were decreased.
The gastrointestinal absorption of orally
administered radioiron and its subsequent
utilization were determined in another
group of 12 patients. The absorption of
orally administered radioiron was less than
in a group of control subjects. In addition, incorporation of orally administered
radioiron into circulatory erythrocytes was
less than normal.
The study demonstrated that intravenously administered radioiron is utilized normally in patients with active rheumatoid
arthritis. In contrast, it would appear that
orally administered radioiron is not com-
461
AMERICAN RHEUMATISM ASSOCIA‘IIOK
pletely available to the bone marrow for
hemoglobin synthesis. Possibly then, is
selective trapping by the reticnloendothelial
5ysteni of iron absorbed from thr gartrointe~tinaltract.
A GALLERYOF GOUT”
Geruld P. Rodnun, Pittsburgh, Pa.
Gout occupies a prominent place in the
history of medical art, and continues to
hold a fascination for the graphic humorist
of the present day. Woodcuts of the gout
are found in some of the earliest illnstrated
printed books; the occurrence of the disease
in caricature dates to the origin of this
fi:)rni in the Renaissance. All in all, the
patient with gout appears in hundreds of
woodcuts, line-engravings, and color prints.
It is clear that the special popularity of
gout stems from the centuries-long-held bzlief that over-indnlgence in food and drink,
and luxurious living in general were among
the most important causes of the disease.
This concept is epitomized in more recent
times in the cynical definition of gout as
“a physician’s name for the rheumatism
‘Read by title.
of a rich patient.” (Bierce) The gouty
foot was thus used as a convenient symbol
to mark the subjects of social and personal
political satire.
The greatest number of gouty prints derive from the brushes of British caricaturists of the late eighteenth and early nineteenth centuries, a period during which
gout was “the favorite disease” of the English, affecting many controversial public
figures. The disease has maintained a vigorous existence in English and continental
hnnior and is found in this country in a
number of contemporary comic strips. This
paper is concerned with a presentation of
gouty prints and caricatures drawn from
the sixteenth century to current times in
relation to an historical review of concepts
concerning the origin and management of
the disease.
THE RENALLESIONIN I~SSEMJNAX
m LUPUSERYTHEMATOSUS”
Nnoiui
F. Rothfieltl, Robert T . McCluskq c i n d Duoid S. Baldzciia, New York, N. Y.
The renal lesion in disseminated lupus
crytheinatosus has assumed increased importance as control of other inanifestation:
of the disease has become possible with
steroid therapy, In the present study, clinical observations have been made in 65
patients; in 27 of these pathologic material
for correlation has been obtained by percutaneous renal biopsy or postmortem examination.
Patients were divided clinically its follows: no renal disease (absence of urinary abnormalities), mild renal disease (proteinuria andlor hematuria), severe renal
disease (functional impairment).
Fifteen patients had no clinical renal discase. Tissue was obtained from 7 and
showed unequivocal glomerular changes
(basement membrane thickening and hypercellularity ) in one.
Thirty-four patients had mild renal disease. Tissue was obtained from 9 and
showed glomerular changes consisting of
‘Read by title.
basement membrane thickening, hypercellularity and nentrophil infiltration.
Severe renal disease was present in 16
patients. Tissue was obtained in 11 and
showed the aforementioned glonierular
changes with additional findings of epithelial crescents, hyalinization, necrosis and
“wire loops.” The nephrotic syndrome was
commonly observed in those patients with
rapidly progressive renal disease and severe
gloinerular damage. However, in some instances, it was associated with a ineinbranous lesion and slowly progressive functional impairment.
Glomerular necrosis and neutrophil infiltration correlated well with clinically active lnpus, even when clinical evidence of
renal involvement was minimal. The presence or severity of glomerular changes or
functional impairment did not depend on
the number of acute lupus episodes, snggesting that control of lupus activity by
steroids may have little influence on the
evolution of the renal lesion.
462
AMERI(:AN HHEIJMATIShl ASSOCXATION
THEPRINCrPLEh
AND PRACTICE OF
SPLINTING
IN
IWF
TREATMF"
Ob
~HFWMATOIIA
) RTHRITI~~
Jerome Rotstein and R. 1. C;. Sinclaii, New York, N. Y. ,ind Edinhiirgh, Scotland
Until the present time no method for the
cure of rheumatoid disease has be:m founcl.
Medical therapy is used to suppress symptoms; in the amelioration of these symptoms, undesirable side effects may he produced.
A much neglected form of treatment of
the arthritic side of the disease is the
splinting of the affected joints. This therapy
is the only one known which may have
one, or all, of the desirable effects of the
prevention, the amelioration and the correction of crippling deformities, without
any unwanted side effects. Through the
*Read by title.
limitation of movement, the protectioii
against weight bearing, the correction of
early deformity, the proper mobilization
of joints and the assistance of defective
muscles, the preservation of joint function
to as large a degree as possible may be
maintained.
Splints can he made from a variety of
materials which are easy to handle, inexpensive and durable. The principles of
splinting, a denionstration of the production of splints in treating commonly met
clinical conditions and a discussion of
what can be expected from the rational
nstr of splinting will be presented in this
paper.
THERMOLABILE
INHIRITOR, 'rITER OF RHEUhdArOII) E'AC IVH,
DISEASEACTIVITY IN RHEUMATOID
ARTHRITIS
AM)
Adalbert F . Schuhart, E c n n Cmlkins trrul Alan S. Cohen, Baltimore, Maryland
Previous reports from this laboratory
have demonstrated a thermolabile inhibitor
in the serum of many patients with rheninatoid arthritis and (based on a retrospective study) have suggested that the
presence of the rheumatoid factor in high
titer may have adverse prognostic implications. Therefore, 66 patients with definite
rheumatoid arthritis were independently
studied clinically and serologically at 2 to
4 month intervals for more than 2 years.
Clinical evaluations were perfomied according to predetermined protocols. The serological data expressed in titers of the F-11
L.P. test and of thermolabile inhibition
were correlated with the clinical conrse of
the disease.
Constant activity of the disease was
found in 9 (60 per cent) out of a group
of 15 patients with consistent F-11 L.Y.
titers of 1:5120 m d higher without thernmolabile inhibition. Remissions were not observed in this group.
A varying course of the disease was
experienced by 38 (80 per cent) of 48
patients who had varying F-11 L.P. titers
ranging between 1:160 and 1:5120 with
varying thermolabile inhibition. Temporary
remissions were observed in 6 ( 1 2 per cent)
of these patients.
Two patients with persistent negative
F-11 L.P. tests exhibited minimal disease
activity throughout.
Thus variable activity of the disease was
inore commonly associated with varying
titers and varying thermolabile inhibition in
the F-11 L.P. test.
CASE REGISTRY FOR b U M . 4 T I C FEVEX< 1 N I)ADE
Morton
INVESTI(:AYION*
N . Schwartzman and Milton S. S a s h o , Miami, Florida
An intensive case register for rheumatic
fever was maintained over a three year
period (September 1, 1955-October 1,
1958) in Dade County, Florida. Special
forms were used to collect all data related
"Read by title.
COUNTY: THREEYEAR
to rheumatic fever subjects. These forins
contained questions concerning past and
present illness, sex, race, age, etc., syniptoms and signs, treatment, subsequent attacks, progress of the patient and other
information relative to rheumatic fever.
The purpose of the report is twofold:
463
AMERICAN RHEUMATISM ASSOCIATION
first to record all known active and suspected
active rheumatic fever episodes in Miami,
Florida, so that more accurate data on the
frequency of this disease in a tropical climate might be available for comparisons
with other geographic areas; and second,
to evaluate the method of reporting to
determine its accuracy, and to bring forth
problems that are encountered in thr: use
of case registry.
Eighty-three episodes of acute rheumatic
fever were reported in Dade County; 53
were diagnosed a s definitely active. This
finding indicated that there is a low rheumatic fever attack rate (less than 5 per
cent of the expected rate), and recurrence
rate in this southern geographic area.
The peak incidence for first attacks occurred in a higher age group than reported
in other studies. Negroes had a higher attack
r.ite for rheumntic fever than whites (Negro
males had four times the attack rate of
whitc males, and Negro females twice the
attack rate of white females). Negroes
also had higher AS0 titers and more preceding infections (both p hemolytic streptococcal and other infections). Sex distribution correlated with other studies.
Factors such as climate, location, other
environmental factors, socio-economic conditions, genetic predisposition, habitat of
the streptococci, and geographic effects
upon these bacteria and upon host resistance
were mentioned as possible influences to
explain the lowered incidence of rheumatic
fever in this southern city, and also to
cxplain why the Negro race had n higher
attack rate for rheumatic fever than the
whites.
THE PATHOLOGY
OF THE COLLAPSING FEhlORAL HEADANI)
DETERIOHATION
O F THE HIP JOINT
Golden Selin, Allentown, Pennsylvania
The collapse and ultimate destruction of
the aseptically necrotic femoral head is dependent on the size and location of the involved area of infarction, the degree of
revascularization and repair, and the duration of weight bearing. The etiology is
usually of minor importance.
The end stage of collapse in aseptic necrosis is grossly and histologically identical
to end stage collapse of the femoral head in
rheumatoid and osteoarthritis.
The deterioration of the hip joint in
aseptic necrosis, unlike that associated
with degenerative and inflammatory arth-
ritis is secondary to the destruction of the
femoral head.
The presentation will be illustrated by
Kodachrome transparencies ( 2 x 2 ) of gross
specimens, microscopic sections, specimen
x-rays and clinical x-rays.
The specimen material will be correlated
with the case histories to reproduce a step
by step progression of the collapse and
destruction of the femoral head and the
ultimate destruction of the hip joint in
rhcumatoid arthritis, osteoarthritis, and all
f m n s of aseptic necrosis.
PATHOGENESIS
OF ADJUVANTINDUCEDARTHRITISIN
THE
RAT
John T. Sharp, Byron 11. Waksmn, Carl M. Pearson and Sarabelle Madof,
Boston, Massachusetts
Several observations have suggested that
immunological factors are important in the
pathogenesis of the arthritis which follows
the injection of mycobacterial adjuvant in
the rat. However, in one set of experiments,
p1t:iiropneumonialike organisms ( PPLO )
were isolated from the lungs and injection
sites of a small proportion of affected animals (Pearson). Since PPLO may cause
arthritis in rats further bacteriological
stiidies were conducted in a separate lab-
oratory. Cultures from joint capsule and
synovial fluid of uninvolved and severely
affected joints and from inoculation sites
in 42 diseased rats were negative for PPLO.
Bacteria were isolated infrequently. Fourteen blood cultures taken during the acute
phase or just before onset of disease were
negative. Attempts to transfer disease to
eighteen recipient rats with periarticular
tissue and blood from severely affected
animals were unsuccessful. In contrast to
464
AMERICAN RHEUMATISM ASSOCIATION
these negative findings, the following positive evidence for an immunological pathogenesis of the disease was obtained: the
occurrence of a regular latent period of
10-16 days between the injection of adjnvant and onset of disease, a shortened
latent period following the reinoculation
of adjuvant, and a flareup following the
injection of tuberculin in convalescent ani-
THE NATUREOF
mals. Disease could not be produced in
the immature rat, in the adult rat recently
treated with 6OOr whole body irradiation,
or in the adult rat treated with tubercle
bacilli at birth. It is concliided that the
disease is probably a disseminated hypersensitive reaction of the delayed type to a
tubercle bacillus antigen and not infectious
in origin.
DRUG-INDUCED SYSTEMIC
LUPUS ERYTHEMATOSUS
Lawrence E . Shulman and A. McGehee Hnrcey, Baltimore, Maryland
Many drugs have been associated with
the onset or, more commonly, an exacerbation of systemic lupus erythematosus
(SLE). Perhaps, most notable of these
are the reactions described in 1954 by
several investigators in patients given hydralazine for hypertension. These reactions
occurred after several months of treatment
;it high (loses, mostly after the blood pressure had fallen to normal; and resembled
initially early rheumatoid arthritis, antl
siibsequently, if the drug was continued,
systemic lupus erythematosus withont or
with L.E. cells (less than one per cent
of the treated population). It was assnmed
that hydralazine had induced reversible
lnpus in patients in whom there was no
prior evidence of connective tissue disease.
No reports of follow-up observations are
available.
Of 105 hydralazine-treated hypertensive
patients studied at the Johns Hopkins Hos-
pital, two developed a lupus-like syndrome
with L.E. cells. In both, the illness subsided in 2-3 months after discontinuing
hydralazine. Follow-up observations, over
4% and 5 % years respectively, revealed:
( 1 ) no rernrrence of disease in spite of
subsequent lowering of the blood pressurr
by other means; ( 2 ) persistence of ;ihnormal L.E. cell preparations for 4 years
in one, and elevated seruni globulins and
sedimentation rates in both. In both, fortuitous measurements of seruim globulins
jiist before the hydralazine was started revealed them to he elevated; and one h d
had previous episodes of arthritis antl
pleurisy. It is suggested that in both patients
there may have been some underlying
mechanism, either genetic or acquired, that
influenced their response to hydralazine.
Two similar cases of presumed trimethadione-induced SLE will be described and
the implications discussed.
A CONTROLLEI) STUDY OF STREPTOCOCC.4L PI-IARYNGITIS IN CHILI)REN:
RELATEDTO THE ATTACK RATE O F RHEUMATIC
FEVEH
FACTORS
A h C . Siegel, Gene €1. Stollerman and Eloise E. Johnson, Chicago, Illinois
The attack rate of rheumatic fever in
the general pediatric population following
sporadic streptococcal pharyngitis is unknown. A controlled study was undertaken
to define the relative risk of giving or
withholding antibiotics in the management
of nasopharyngitis to a pediatric clinic group
in Chicago. Previous observations indicated
R low incidence of rheumatic fever in this
group.
Children with pharyngitis and a positive
throat culture for beta hemolytic streptococci were divided, by a random method
of selection, into either a benzathine penicdlin treatment gronp or a symptomatically
treated control group. Twenty-one hundred
and fifty children with nasopharyngitis were
examined, of whom 1013 (47 per cent)
harbored beta hemolytic streptococci. Eight
hundred and eighty-eight patients (41 per
cent) harbored Group A strains. The 1013
patients with positive cultures were equally
divided into the treated and control groups.
Among 512 patients in the control group,
there were 2 cases of rheumatic fever (0.37
per cent) and 1 case of acute nephritis
(0.19 per cent). No similar complications
occurred in the penicillin treated group.
In view of the low rheumatic fever attack rate in the control group, the clinical,
465
AMERICAN RHEUMATISM ASSOCIATION
bacteriological and immunoligical features
of the streptococcal disease encountered
were compared to previous epidemic control groups in a military population (Warren A.F.B., Wyoming) in whom previoiisly
published reports indicated a rhenmatic
fever attack rate of 2.8 per cent. This analysis indicated that the streptococcal disease
was considerably milder in the children’s
group.
Only 73 of 512 control patients in the
THEGM
SYSTEM TN
SERA
FROM
children’s group were comparable by clinical, bacteriological and immunological
criteria t o the infections of the military
group. The attack rate of rheumatic fever
in this group of 73 children was 2.7 per
cent.
The results indicate that the risk of
developing rheumatic fever following sporadic nasopharyngitis in a given pediatric
population is conditioned by the virulence
of the streptococcal disease encountered.
PATIENTS
THEIRRELATIVES
4ND
WITH
RHEUMATOID
ARTHRITIS,
NORMALS‘
Jacques M . Singer, Arnold GnldeitheTg and Charles M . P l ~ t - ,New York, N. 1’.
In 1956, Grubb and Laurel1 in Sweden
developed a method which permitted the
grouping of human sera by an agglntination-inhibition system using a rheumatoid
serum, the test serum and human erythrocytes coated with incomplete Rh antibody.
They found that 60 per cent of normal
sera inhibited the agglutinating activity
of the rheumatoid serum. The inhibitory
substance for this system was located in
the gamma globulin fraction and appeared
to be genetically determined. Hence, the
term Gm ( a plus) was adopted for the
phenotype of inhibitory sera and Gm. ( a
minus) for the non-inhibitory ones.
During the course of a hereditary study
for rheumatoid arthritis, the Gm. serum
groups were determined on 350 sera from
normal and rheumatoid persons as well as
their relatives. The findings were also com-
pared with the results of tests for rheumatoid factor.
Among normal New York City residents,
63 per cent of whites, 87 per cent of Puerto
Ricans and 95 per cent of Negroes were
Cm. ( a plus). The occurrence of Gm.
serum groups in rheumatoid subjects was
similar to that for normals. Among relatives
(if the white rheumatoid subjects, a Gm.
( a plus) type was detected in only 43
per cent of sera. Furthermore, the distribution of Gm groups among white offspring
from matings involving a rheumatoid parent
was distinctly different from that for normal
families.
The Gm phenotype showed no correlation with sex and ABO or Rh blood group
systems, nor did they affect serologic tests
for rheumatoid factor such as the Sensitized
Human D Erythrocyte and Euglobulin Inhibition Tests.
*Read by title
EXPERIMENTAL
OBESITYAND OSTEOARTHRITIS
Leon Sokolof, Olaf Mickel.son, Emunusl Silverstchi, George E . Jay, Jr. and
Richard S. Yamatnoto, Bethesda, Maryland
Four groups of experiments were carried
out in rats and mice to elucidate the relationship between obesity and osteoarthritis.
Obesity was produced in rats and in three
strains of inbred mice by several dietary
means. The obese animals were from 39
to 76 per cent heavier than those on a
stock diet. One diet, containing 60 per cent
vegetable fat, increased the amount of degenerative joint disease in the rats and
two strains of mice t o some degree, but
no increase occurred as a result of a 37.4
per cent fat content in the diet or from
obesity produced by Ingle’s diet which has
a relatively low fat content. To determine
whether the susceptibility of an arthritisprone strain (STR/lN) was related to its
spontaneous obesity, attempts were .made to
1 ) prevent obesity by restriction of caloric
intake and 2) to dissociate obesity and
osteoarthritis by hybridization with an
arthritis-resistant strain. Dietary restriction
466
AMERICAN RHEUMATISM ASSOCIATION
in the STR/lN mice failed to decrease the
osteoarthritis in them. The hybrid (A/LN X
STR/lN) F, mice were obese hut resistant
to articiilar degeneration. The observations
provide no support for the view that excessive weight-bearing has a causal relation
to degenerative articular changes, at Imst
in experimental animals.
THE CLINICALSIGNIFICANCE
OF EXTRACELLULAR
MATERIAI,( ECM )
IN L.E. CELL PREPARATION’
M a y Betty Stevens and Lawrence E . Shulman, Baltiinorc, Maryland
Homogenous,
extracellular
material
( E C M ) represents a stage in L.E. cell
formation. The clinical significance of ECM,
which may occur in the absence of typical
L.E. cells, has not been investigated. The
initial report of a study to establish its
significance, if any, is presented.
The Special Hematology Laboratory of
the Johns Hopkins Hospital performed one
or more L.E. cell preparations (ZinkhamConlry method) on 3660 patients during
the interval January 1955 to December
1958. 169 patients had ahnormal preparations for the first time, the initial abnonnality being ECM (without L.E. cells) in
121 and typical L.E. cells in 48. Patients
with abnormal L.E. cell preparations prior
to Janmry 1955 were not included. Random
sampling of the remaining patients with
entirely negative preparations constituted
‘Read by title
Selected clinical data and the postmortem
findings on the kidney of 200 cases of
gout will be discussed. Many of the cases
were followed prior to death. The ohservations on the remainder were obtained
from the clinical records, and the postmortem protocols from a number of general
hospitals throughout the country.
The cases were divided into four clinical
types. ( 1) The clinical diagnosis was mild
gout in 54; ( 2 ) it was moderate gouty
arthritis in 83; ( 3 ) the diagnosis was severe
gouty arthritis in 35; ( 4 ) the disease was
a control group of 123 cases.
Clinical Analysis: A comprehensive chronologic medical abstract was prepared on
each of the 292 patients with purposeful
omission of lupus and rheumatoid factor
data and pathologic information. Each summary was coded and specific patient identity withheld. With defined clinical criteria,
diagnoses were tabulated for each case
at the date of (1) initial L.E. cell preparations and ( 2 ) last observation.
Slide Anulysis: All slides on patients witli
abnormal hnffy preparations and a single
slide on each control pitient were coded
and reread by one of us. Qiialitative gradation of ECAI and L.E. cell positivity w i t s
tabulated on ,592 slides.
After completion of clinical ;ind slide
analyses, data was decoded and analyzed
with pathologic information added for final
evwliiation. The clinical-laboratory correlations will he presented.
associated with a blood disease in 28. The
ages ranged from 13 to 87 years. A number
of patients in the first category had experienced only one typical attack of gouty
arthritis. The majority of the deaths were
not related to the basic clinical disease.
The kidneys were normal histologically in
only three cases. The evidence pathologically for pyelonephritis appeared to he as
prevalent as the vascular changes. In a
number of cases, the pathological findings
in the kidney were inconsistent with the
clinical severity of the articular disorder.
“CHRONIC”RHEUMATICFEVER
Angelo Taranta, Mario Spagnuolo and Alvan R. Feinstein, New York, N. Y.
Although “chronic” or “smoldering” rheiimatic fever is often mentioned, little factual
information is available about it. The present stiidy deals with some clinical and
laboratory observations on patients with
unusually prolonged attacks of rheumatic
fever ( R F ) .
The mean dnration of RF in a previoiisly
AMEIlICAN RHEUMATISM ASSOCIATION
467
samp!ed population was 109k57 days. A
rheumatic attack was classified as “chronic”
when the continued presence of clinical or
laboratory manifestations of RF extended
over 223 days ( M + 2 0 ) . Seventy such attacks occurred among 1169 consecutive
RF admissions. In 30, not further considered here, the course was benign and
the only abnormalities were persistent elevations of the erythrocite sedimentation
rate in 16 and chorea in 14, the latter often
occurring after long “silent” periods. In
the other 40, 35 had or developed severe
heart disease, and the “chronic” clinical
abnormalities usually involved the heart,
with or without congestive failure. Retrospective titration of antibodies in 29 patients
showed previously unrecognized intercurrent streptoccal infections in 2. The “chron-
ic” attacks: (1) had an incidence of 1, 6,
17, 22 and 50 per cent respectively in
patients with 0, 1, 2, 3 and 4 previous R F
attacks, ( 2 ) were more frequent with increasing severity of previous heart disease,
( 3 ) often had clinical relapses unrelated
to preceding suppressive therapy and posttherapeutic rebounds which generally occurred later than those of unselected R F
patients and ( 4 ) had a 4 year mortality
rate of 27 per cent.
This survey indicates that “chronic” RF
is an uncommon and often fatal syndrome,
whose incidence increases with previous
R F attacks and severe heart disease, whose
course frequently fluctuates independently
of treatment and whose occurrence may
occasionally be precipitated by nnrecognized streptococcal infections.
Previously we reported a test in which
sera of acutely, severely ill systemic lupus
erythematosus pstients gave a precipitate
on the addition of para-toluene sulfonic
ncid and that the positivity of the test
paralleled the intensity of this disease. This
study (see table) of 50 systemic lupus
erythemstosns psiients, 18 untreated, severely and acutely ill, 32 mild or in remission,
plus the examination of over 4000 sera
from over 2400 patients, revealed that all
sera from acute, severely ill, untreated
systemic lupus erythematosus patients were
positive, 67 per cent were 3 to 4 plus.
Those in remission or mild cases were negative or weakly positive. Other collagen
diseases, rheumatic fever and gout were
negative. One to 2 per cent of positives
appeared in osteoarthritis and non-rheumatic diseases. Precipitates were found in
4 per cent adult, I 0 per cent spondylitic
and 42 per cent juvenile rheumatoid arthritis sera. Positive results appeared in hepatic
disorders and proteinemia.
ciirrence in systemic lupus erythematosus) .
In 20 per cent it is present either withont
hypergammaglobulinemia or in essentially
normal electrophoretic patterns. This has
been demonstrated by several investigators.
Sylvester et al. tested eluted paper electrophoretic strips of 6 per cent of 3650 nonsystemic lupus erythematosus strongly positive sera and found false-positives in beta
fractions. Lee, Abrahamsen et al., Myhre
and Geyer found no correlation between
the strength of the reaction and the amount
of gammaglobulin. However, Hoffman, Bottiger, Ekelund and others noted correlation
of the positive reaction and gammaglobulin
by paper electrophoresis or in some studies
the addition of gammaglobulin to sera. The
latter method is unreliable since most
separated globulins are partially denatured
and do not represent a “native” globulin.
Also excessive amounts cannot be dissolved
by para-toluene sulfonic acid. The results
of these investigations suggest that the
precipitable protein is not normally found
except when produced by systemic lupus
erythematosus and certain other diseases.
Its presence is dependent on disease activity
and availability to the blood and because
of its ubiquitous nature may be found in
any of the globulin fractions.
Our first reports as well as this study
indicate that positive tests would be obtained only in severely ill, untreated sys-
Rciation of test to hypcr,globulinemia:
Our studies indicate that the precipitable
protein is a macroglobulin and may be
found in any fraction of the globulin
moiety. In 80 per cent it appears with
hypergammaglohnlinemia ( a frequent oc___--__“Read hy title
468
AMERICAN RHEUMATISM ASSOCIATION
matoid arthritis sera may show weak titers
but serial testing reveal them to be transient. Juvenile rheumatoid arthritis freqnently shows positive tests. In routine
tesiing of. rheumatic &isensis, one to two
plus tests are not diagnostic and yet they
are very significant in known or suspected
systemic lupus erytheinatosus patients.
Plasma and other than chemically pure
reagents give unreliable results. False-positives may occur in a few hepatic disorders
and some dysproteinemias. Most of these
can be ruled out by other means.
In summary, the para-toluene test serves
as a prognostic aid in estimating the disease
activity in systemic lupus erythematosus.
It is valuable in differentiation of other
collagenous, rheumatoid and non-rheumatic
diseases from systemic lupus erythrmntosus.
The test relies on a precipitahle protein
which is a macroglobulin most probably
prodiiced by the disease. While this is not
a perfect screening test, nevertheless, hrcause of its simplicity and availability it is
a useful routine clinical test when properly
executed and interpreted.
teniic lupus erythematosus patients aqd as
the disease regressed or went into remission, they would be negative or at the
most one plus. This has been amply confirmed. Testing of all systemic lupus erythematosiis cases regardless of disease activity h x been reported from 30 per cent
to 80 per cent positive. For this reason it
is not a good screening test although its
specificity is as great as other tests for
systemic lupus erythematosus or the flocculation tests for rheumatoid arthritis.
Diagnostically this test is most valuable
in severely ill, untreited systemic lupus
erythematosus patients. It is of prognostic
value in following the course of the disease.
Response to therapy or remission induced
by any means will show a fall in positivity.
This parallel has been noted by others.
Fixed positivity indicates an iinfavorable
prognosis. As noted in this study, 11 patients
who died exhibited this fixation. Serial testing of those with mild disease or in remission is indicated since positivity or an
increasing positivity may indicate an inipending crisis or exacerbation. Adult rhen-
Table showing the disease, the total niunber of patients, the results of the lest and t?ie
Tests-4,300; Individiials--2,415ils--2,41S
percentage of negative and positive tests.
-
% of Total
Test Results
Disease
(: 1,wpiis En~?hernatohtcs( 2 1
Acutely, severelv ill, unti,eated ( 3 )
Not Acut,e or in Remission
Total
O:Iwr Collagen Piwanea ( 4 )
Polgarteritis ( 5
Scleroderma
Derniatomyositis
Uixcoid L u p u s
Rl&eumatie Disoases
Adult Rheumatoid Arthritis
(acute-7 and chronic-195)
Juvenile Rheumatoid Arthritis
Rheumatoid Spondylitis
Total Rheumatoid
Degenerative Joint Disease
(Osteoarthritis)
Metabolic Joint Disease (Gout)
Rheumatic Fever
Misoellaneoun (Non-RlteumaLic) ( 6 )
N o A p p a r e n t Ih’seaae
Total
Patients
Neg.
1
0
22
‘22
1
10
2
4
3
Neg.
101’2
3 or4
0‘$,
:33./,
67%,
SVatcnL
18
k2
50
11
6
2
6
1
2
0
10
7U%,
3ogo
44q
32%,
3
6
3
3
100%
4
100~0
12
x
4
202
193
4
14
10
226
X
108
13
26
1,678
290
100%
67%
5
3
9
210
4
10;
13
26
1
1.669
288
9
2
8
3
1
4
6
5
395;
56%
4%
Enyo
21yc
00%
92%
6%,
99%
100%
100%
98%
99%
2454,
21yo
lo70
2%>
1%
1%
1%
1%
( 1 ) The greatest positivity obtained in each patient was recorded only once although on aerial iestina
it waa less positive or became negative.
( 2 ) All proven cases by adequate number of T , - E raell. a t some time 0 1 hy autopsy or biopsy.
( 3 ) Eleven died-six autopsied.
( 4 ) All pioven cases by biopsy or autopsy.
( 5 ) Two died-bth autopsied.
( 6 ) 1.375 patients’ sera weir t a t e d at Veteran% Admiliivtratioli Hospital, Tucson, A 1 izoiia. under
direction of DI.. J . Plummrr. Chief of Medicine
469
AMERICAN RHEUMATISM ASSOCIATION
SEROLOGICAL
TESTSIN
JUVENILE
RHEUMATOIII
ARTHRITIS
*
Peter W. Vnnace, Philadelphia, Pa.
This is a preliminary report of the results of the latex slide, standard latex fixation (SLF), ammonium sulfate-standard
latex fixation ( AS-SLF) and bentonite
flocculation ( B F ) tests performed on the
sera of 40 children with proven juvenile
rheumatoid arthritis studied for 1-3 years.
The sera from 37 children with rheumatic
fever and associated connective tissue
diseases and 30 normal children were similarly studied. An average of three sera
from each child with juvenile rheumatoid
arthritis was tested with this battery of
tests during the period of study. The
eriglobulin sensitized sheep cell ( E u g SSC),
euglobulin sensitized sheep cell inhibition
and euglobulin latex tests were carried out
on selected serum samples from children
in each group. Clinical, laboratory, and, in
certain cases, synovial membrane histological
evaluation of disease activity was tabulated.
Two children with nodnles, one child with
ii fatal diffuse vasculitis and one child
with ulcerative colitis associated with arthritis were included in this study.
The percentages of positive results on
163 serum samples from 40 cases of juvenile rheumatoid arthritis are as follows:
slide latex - 22 per cent, SLF - 38 per
cent, AS-SLF - 46 per cent, BF - 27
per cent, Eug SSC - 20 per cent and
Eug SLF - 42 per cent. The euglobulin
sensitized sheep cell inhibition test in our
hands has been disappointing. As yet a
significant number of sera has not been
tested utilizing the latex inhibition procedure. Sera from children with other connective tissue diseases were positive in
approximately 20 per cent and in normal
children in less than 5 per cent of cases
studied. In the rheumatoid group, the
highest incidence of positive tests was
noted in sera from children 10-16 years
of age with multiple joint involvement bnt
without associated visceral manifestations.
In contrast, sera from children with typical
Still’s disease with marked visceral involvement were only rarely positive regardless
of age. There was little correlation of a
positive test or titer with the degree of
disease activity or, in the few cases studied,
with the presence or absence of nodnles
or vasculitis.
‘Rrad by title
THIMETIIYLCOLCNICINIC
ACID IN
THE
TREATMENT
OF
ACUTE Gem*
StanZeTy L. Wallace, Brooklyn, N. Y.
Thirty-four patients with acute gout
were treated with trimethylcolchicinic acid
(TMCA). Doses ranged from 5 to 16
milligrams; the entire dose was taken at
once in all but two patients.
Twenty-six patients responded classically,
four responded partially but incompletely,
and four did not respond a t all. Inadequacy of response was related generally
either to prolonged duration of attack prior
to therapy or to colchicine unresponsive-
ness. Seven of the “failures” were promptly
treated with colchicine; only in three did
the attack of gout then snbside.
Two patients had minimal diarrhea after
TMCA. No other toxicity was found. Seven
additional patients were given small daily
doses of TMCA prophylactically for periods
of one to three months. No attacks of gout
occurred during these brief periods, hut
more important, no cumulative blood, bone
marrow, skin, gastrointestinal or other
toxicity was seen in this group.
“Read by title
THERADIOLOGICAL
AND CUTANEOUS
MANIFESTATIONS
OF R E I T F ~ S
SYNDROME”
Robert F . Willkens and John L. Decker, Seattle, Washington
Eleven cases of Reiter’s triad have been
observed during the past two years. Five
“Read by title
of these cases have shown either keratodermia blenorrhagica ( 3 individuals), oral
mucns membrane lesions ( 2 individuals ) ,
or nail bed lesions ( 2 individuals). Six in-
470
AMERICAN RHEUMATISM ASSOCIATION
dividiials have had recurrent episodes of
the disease; five of these have developed
permanent joint changes demonstrable by
x-ray.
The most common radiological manifestations were plantar calcaneal spurs associated with a fluffy appearing periostitis,
posterior calcaneal erosive and proliferative
changes of the achilles tendon insertion, cir-
THEPATTERN
AND
cumscribed triangular patches of increased
bone density of the ileum adjacent to the
inferior portion of the sacroiliac joints,
and e r o h n s of the sacroiliac joints.
These patients are presented to emphasize and illustrate the diagnostic significance
of the cutaneous lesion and the permanent
joint changes which may develop.
RATE OF RESPONSEOF PATIENTS WITH
TREATED
WITH CHLOROQUINE*
RHEUMATOID ARTHRITIS
J. Paul Young, Asheville. North Carolina
Detailed study of the patterns of response obtained with chloroquine treatment
shows several important differences from
the type of response obtained with other
methods of treatment. Serial determinations
of the latex titre were made in 14 patients
during 6 to 18 months of therapy with
chloroquine and salicylates. There was a
iiiedian decre.ise of three tube dilutions
tluriiig treatment. Agglutination became
completely absent after treatment in three
patients and fell below the diagnostic titre
in two more. Comparison with serial deterininations of titre in a series of patients
treated by various other methods, (Jacohson et al.: Am.J.Med. 20:490, 1956) showed
i i highly significant difference ( P < 0.01 ).
The electrophoretic patterns of the serum
proteins in six patients with classical rheumatoid arthritis showed consistent improvement during chloroquine treatment. Before
treatment the average A/G ration was 0.67,
(range 0.51 to 0.99). After 6 months treat-
ment the A.'G ration improved to an average of 1.46 (range 1.20 to 1.89). The
first improvement was an increase in serum
albumin and subsequently a decrease in the
globulin fractions.
A series of 119 patients with definitv
rheumatoid arthritis has been treated with
chloroquine for 6 to 48 months. They were
divided into groups according to the stage
and tluration of disease. The length of
treatment required to obtain a Grade I
or I1 response in SO per cent of the patients
in Stage I was 2% months, in stage I1
4% months, while the stage I11 plus IV
group required 18 months. Patients with
longer durations of disease required longer
periods of treatment to obtain a good response. Some patients required as mnch a s
30 months of treatment to obtain a good
response and continued to improve after
48 months of treatment. These factors
should be considered in deciding how long
an antimalarial drug should be continued
before concluding that it is ineffectual.
"Read by title
TOXICITY
O F SOLUBLE ANTIGEN-ANTIBODY
COMPLEXES
ROLE I N EXPERIMENTaL IIYPERSENSITIVITY DISEASE
STUDIES ON THE PRIMARY
THEIR
AND
Solomon J. Znk, Minneapolis, Minnesota
Previous reports have suggested that
soluble antigen-antibody complexes are
capable of producing the following effects:
( 1 ) production of anaphylactic death in
the guinea pig and in the white mouse,
( 2 ) stimulation of guinea pig smooth
muscle, ( 3 ) production of a glomerulonephritis in the white mouse, and ( 4 ) the
induction of primary capillary toxicity in
guinea pig skin. These experimental findings provide presumptive support for the
widely held hypotheses relating the genesis
of serum sickness lesions to soluble antigenantibody complexes formed in vivo.
The frequent occurrence of rheumatoid
arthritis and presumptively related so-called
collagen diseases in patients with agammaglobulinemia led to a series of experiments
designed to test an hypothesis which relates
the genesis of hypersensitivity lesions to
the irritant effects of otherwise innocuous
antigen. Careful examination of the afore-
471
AMERIOAN RHEUMATISM ASSO(XATI0N
mentioned studies revealed in all instancea
that the soluble antigen-antibody complexes
utilized, merely consisted of a macromolecule whose components were heterologous
with respect to the test animal employed.
An attempt was therefore made to confirm
and to extend these studies by employing
homologoussoluble antigen-antibody coniplexes with respect to the experimental
animal in question. The results obtained
suggest that soluble antigen-antibody complexes, employing BSA-rabbit anti-BSA
were, in fact, capable of producing an
immediate death in the white mouse. When
the sterility of the reagents was ensured,
and pyrogen free diluents employed, however, neither BSA-rabbit anti-BSA nor
BSA-mouse anti-BSA soluble complexes
ARTICULARMANIFESTATIONS
were capable of producing‘ the lesions of
glomerulonephritis or arteritis in the white
mouse.
The passive cutaneous anaphylaxis method
described by Ovary was extended and
found to apply to the guinea pig using
homologous antibody. In confirmation OP
Ishizaka and Campbell’s detailed studies,
it was found that soluble complexes consisting of BSA-rabbit gamma, anti-BSA
globulin were capable of altering capillary
permeability in guinea pig skin; however,
no toxicity conld be demonstrated for the
complexes consisting of BSA-guinea pig
anti-BSA when tested in the guinea pig.
The significance of these findings is dibcussed.
IN PRIMARY HYPERPAHATAYHOIUISM
Nuthan J. Zwifler, Willium E. Heefe uncl Roger L. Black,
Bethesda, Maryland and Washington, D. C .
It is well known that extensive osseous
involvement in hyperparathyroidism can
produce severe bone pain which may be
confused with arthritis. Many authors,
however, have denied the presence of actual
joint involvement during the course of this
disease. It is the purpose of this paper to
describe the articular manifestations present
in three patients with functioning, demonstrable parathyroid adenoma.
All of the patients were female. All had
symptoms referable to the joints for at
least one year prior t o the establishment
of the diagnosis of hyperparathyroidism.
Two had been receiving anti-rheumatic
agents at the time the diagnosis was made.
One of them had been followed for one
year in a medical outpatient clinic with
the diagnosis of “early rheumatoid arthritis.” Objective evidence of joint disease
with swelling and effusion was uoted in
two, and the third patient reported having
had tender, swollen joints on several occasions. Each had laboratory and radiographic
evidences of bone disease. Serologic reactions for the rheumatoid facter were negitive in all three. Two patients showed nn
uiiusual fomi of articular carti!age and synavial calcification, most marked in the
knees, but present in niultiple joints, large
and small. The third patient showed erosions involving several of the small joints
of the hands. One patient died and the
available pathologic material demonstrating the synovial calcification noted on x-rays
will be discussed.
Case histories and representative radiograms will be presented, and the generill
question of articular calcifications will be
discussed.
A.R. A. N E W S
SZVENTH INTERIM SESSION:
DALLAS, DEC. 9-10, 1960
To accommodate more papers on the
program, the traditional one-day interim
session has been extended to a Ilh-day session in Dallas, Texas, December 9-10,
1960. Room reservation forms for the Sheraton-Dallas Hotel, site of the meeting, will
be mailed to all members of the American
Rheumatism Association during October.
Single rooms range from $8.50 - m . 5 0 ;
doubles from $15.00-$21.00.
The Dallas meeting will be held in con-
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