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Proceedings of the Annual Meeting of the American Rheumatism Association. June 1516 1967 New York N. Y. Abstracts of Papers Submitted

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AMERICAN RHEUMATISM ASSOCIATION
A Section of the Arthritis Foundation
1212 Avenue of the Americas, New York, N. Y. 10036
President: DONALD
F. HILL, M.D., 2430 EAST 6 T H STREET, TUCSON, ARIZONA 85719
First Vice President and President Elect: EVANCALKINS,M.D., 100 HIGH STREET, BUFFALO,
Second Vice President: LEONSOKOLOFF,
M.D., N.I.A.M.D., BLDG. 10, RM.
N. Y. 14203
3~114,BETHESDA, MARYLAND 20014 Secretary-Treasurer: CHARLES
M. PLOTZ,M.D., 125
EAST 73 STREET, NEW YORK, N. Y. 10021 0 Executive Secretary: MARGARET
M. WALSH,1212
AVENUE OF THE AMERICAS, NEW YO=,
N. Y. 10036.
Proceedings of the Annual Meeting of the
American Rheumatism Association
June 15-16, 1967
New York, N. Y.
Abstracts of Papers Submitted
EDITOR:
Stanley L. Wallace
SCINTILLATION SCANNING O F JOINTS WITH TECHNETIUhl-99-”1
Donato Ahrcon-Segovia, Miguel Trujeque, Enrique Tocar
and Marco Antonio Adame, Mexico City, Mexico
Isotopic scanning of joints within 3 hours of
intravenous administration of Technetium-99
(99MTc) shows higher uptake by joints affected by
inflammatory processes than by normal or degenerated joints. In some instances it has afforded
differentiation between periarticular and intraarticular inflammation and in others it has shown
a higher uptake in painful joints without clinically
detectable inflammation.
Advantages of 99MTc over other isotopes are its
short half-life, its pure gamma emission, its rapid
distribution, the lack of need of thyroid suppression, the absence of allergic reactions and the
minimal radiation exposure. Joint scans with this
isotope have nitid images that facilitate interpretation.
Scintillation counts over the knees done at 5
minute intervals after 99MTc injection in 2 patients
with unilateral knee involvement (1 gout, 1 rheumatoid arthritis) and in 2 normal volunteers
showed that, although all curves were similar,
reaching a plateau within 15 minutes and later
decreasing slowly, radioactivity counts were up to
55 per cent higher in affected knees.
Autoradiography in one and scintillation counts
in both synovial biopsies done within 30 minutes
of intravenous administration of 99MTc in 2 patients
with chronic synovitis showed no significant uptake by the synovial membrane. Synovial fluid
showed moderate radioactivity.
Increased uptake of 99MTc by joints affected by
inflammatory processes seems to be due to an increase in soft tissue volume and its blood supply,
and to joint effusion when present.
The clinical application of isotopic scanning of
joints with 9 9 M T c will be illustrated and discussed.
262
263
ABSTRACTS
RHEUMATOID FACTOR
I N ANKYLOSING
SPONDYLITIS
Clemente A. Amante and John J . Calabro, Jersey City, N. J.
Rheumatoid factor ( R F ) is rarely reported in
ankylosing spondylitis (AS). Yet, of 30 AS patients
carefully observed for almost 9 years, a positive
latex fixation (titer of 1:80 or greater) has been
noted in 9 patients at some time during the observation period.
The highest median titer was 1:1,280. The
range was 1:320 to 1:5,120. The mean duration
of titer was 27 months with a range of 10 to 44
months. Appearance of RF was transient; the incidence at any given point of time for the group
as a whole was not more than 10 per cent.
Of 9 seropositive patients, 2 have ulcerative
colitis, 2 regional enteritis, 8 active peripheral
joint involvement, and 2 vascular complications.
Two AS patients with ulcerative colitis and low
titers of RF initially developed high titers transiently with vascular complications. Vasculitis occurred in 1 patient and an infected ankle
AND
ulceration in the other.
Of 21 seronegative patients, 1 has ulcerative
colitis, 5 active peripheral joints and none with
vascular complications.
There was no difference between seropositive
and seronegative patients as to age of patients,
age of onset, modes of onset, duration of AS,
presence of aortic insufficiency or iritis, cerebrospinal fluid protein, X-ray changes or ARA functional class and anatomic stage.
Of 30 control patients with ulcerative colitis and
regional enteritis without AS, only 3 had RF.
These preliminary observations demonstrate that
rheumatoid factor may occur in the course of
ankylosing spondylitis. It is suggested that evolution of rheumatoid factor occurs among patients
with active peripheral joint involvement, vascular
complications and underlying gastrointestinal disorders.
INCORPORATION
OF P O 4
A COMPARISONOF THE SIMULTANEOUS
PRO-c14 INTO BONEMATRIXO F NORMAL AND DENERVATED
RAT LIMBS
Thomas G. Argyros and Marwell Schubert, New York, N.
The formation of the 2 major components of
bone matrix, collagen and chondroitin sulfate, was
studied quantitatively and simultaneously in rabbits and rats by injection of 9 5 0 , and proline-Cl4.
The animals were sacrificed 24 hours later; the
shafts of long bones were decalcified in a formalincitrate solution. The hydrolyzed samples of bone
matrix were analyzed chemically for hexosamine
and hydroxyproline, and by radiocounting techniques for S3504 and hydroxyproline-C14. The specific activity of hydroxyproline served as a
measure of collagen formation; 9 5 0 , CPM, of
chondroitin sulfate.
EVALUATION
OF
A
Y.
Synchronous formation of collagen and chondroitin sulfate was demonstrated in normal rabbit
and rat bone. Radioactive “hot and cold” areas in
bone were also demonstrated.
Unilateral osteoporosis was produced in the left
hind limb of rats by sectioning of the femoral,
sciatic and obturator nerves. Ten to 26 weeks after
denervation the rats were injected with labeled
sulfate and proline. There was an increased formation of labeled collagen and chondroitin sulfate
in the denervated limb as compared to the intact
right hind limb.
SEMI-QUANTITATNE
B E T A ~ J B E TCOMPLEMENT
A~~
ASSAY
Joseph P . Bailey,
The participation of complement in several disease states, and specifically in the glomerulonephritis of systemic lupus erythematosus, has led to
a search for complement assay lending itself to the
clinical laboratory. Betalc/Betala globulins are part
of the third component of complement, involved
after C‘l, C‘4 and C’2. There has been published
evidence that changes in concentration of these
globulins reflect change in total complement activity (Pediatrics 35:765, 1965). Micro-Ouchterlony plates were prepared and undiluted and
JT.,
Augusta, Ga.
serial two-fold dilutions of serum, ranging from
1:2 to 1:32, were placed in the 6 outer wells and
observed for precipitin lines against commercially
available
goat
anti-human
Beta l,/Beta l a
globulin in the center well. Normal sera consistently formed precipitin lines at dilutions of
1:32. Sera from patients with active systemic
lupus erythematosus with and without nephritis
consistently had titers of less than 1:32 (usually
1:8 or less) indicating decreased Betalc/Betala concentration. Corticosteriod therapy has resulted in
264
ABSTRACTS
return to normal titers in patients who improved
clinically. Variations in Betalc/Betal, levels have
been a useful guide to effectiveness of therapy.
Synovial fluids from rheumatoid arthritis patients
have consistently demonstrated decreased Beta,J
Betal, concentrations compared to levels in serum.
EFFECTOF AGINGON
We think this test provides a simple, easily
performed, semi-quantitative measurement of complement activity in serum and synovial fluid which,
because of the ease of determination, can greatly
increase the clinical usefulness of this test.
VISCOELASTIC
AND CHEMICAL
PROPERTIES
HUMANSYNO\’IAL FLUID
THE
OF
E . A. Balazs, P. 0. Seppala, D. A. Gibbs, I. F. Duff and E. W . Merrill,
Boston and Cambridge, Mass. and Ann Arbor, Mich.
Viscoelastic measurements and chemical determinations were carried out on synovial fluids
obtained from the knee joints of normal male
young and old donors and on fluids from osteoarthritic patients.
The concentration of hyaluronic acid and proteins, the total amount of hyaluronic acid per
joint, and its limiting viscosity number were essentially the same in fluids taken from young and
old normal donors. I n osteoarthritic fluids the
hyaluronic acid concentration and Limiting viscosity number were lower than in normal fluids,
while the total amount of hyaluronic acid and the
protein concentration were higher.
Generally, fluids from normal young and old
persons exhibited comparable values for the shear
storage modulus G’ and the shear loss modulus
G” measured at low strain frequencies. The most
significant difference between these normal fluids
was in the G”/G ratio obtained at high strain
frequencies. This ratio was much smaller for fluids
from young donors compared to that from old
donors. Thus at high strain frequencies, the synovial fluid behaved like an elastic material in
young persons, while in old persons at the same
strain frequencies the synovial fluid showed a
much less elastic quality. This suggests that the
rheological quality of the hyaluronic acid in the
synovial fluid has changed with aging. This change
is not in the apparent molecular weight or in the
concentration of hyaluronic molecules, but is a
much more subtle physicochemical change, which
may relate to the interaction between the hyaluronic acid and the other molecules in the synovial
fluid.
The G‘ and G” values in the fluids from osteoarthritic patients were considerably lower than in
normal fluids. These low values were a consequence of the lower concentration of hyaluronic
acid and its lower limiting viscosity number.
LOCALIZATION
O F HYALURONATE-H3 SYNTHESIS IN SYNOVIAL CELLS
Peter Barland, Carol Smith and David Hameman, New York, N. Y.
Synovial membrane cells in tissue culture have
long been known to synthesize hyaluronate and
to secrete it into the medium. The intracellular
sites of hyaluronate synthesis and storage are unknown. We have studied this problem using high
resolution autoradiography of cell cultures derived
from normal and rheumatoid synovial cells. Glucosamine was found to be a specific precursor for
the hyaluronate these cells produce. Monolayers
of synovial cells were incubated in medium containing glucosamine-6-H3. The medium was dialyzed, and the remaining radioactivity was shown
to be in hyaluronate; over 80 per cent of the
counts were rendered dialyzable by testicular
hyaluronidase digestion. The hyaluronate-H3 was
isolated from the medium by zone electrophoresis.
Acid hydrolysis and paper chromatography showed
counts confined to glucosamine. Cell cultures incubated with glucosamine-6-H3 for varying times
were processed for electron microscopic autoradiography. By coating thin sections of the cells with
a photographic emulsion sensitive to the radioactive emission from tritium ( H 3 ) , it is possible to
visualize, as silver grains, the labeled material
within the cells. Grains were localized to the
vesicles of the Golgi apparatus, and to large clear
vacuoles occasionally merging with the cell membrane. Grains were not noted in the rough endoplasmic reticulum, the nucleus, mitochondria or
the prominent dense granules, residual bodies and
lipid vacuoles found in these cells. The presence
of the radioactivity in the hyaluronate in these
cells was established by successive extractions with
alcohol and acid. Paper chromatography of an
HC1 extract showed counts in glucosamine. These
studies show that the Golgi apparatus of these
synovial cells plays an important role in the cellular synthesis and secretion of hyaluronate.
265
ABSTRACTS
SEPTICARTHRITIS DUETO PASTEURELLA
MULTOCIDA
COMPLICATING
RHEUMATOID
ARTHRITIS
W . F. Barth, L. A. Healey and 1. L. Decker, Bethesda, Md. and Seattle, Wash.
Two patients with chronic active rheumatoid
arthritis on adrenocorticosteroid therapy developed
septic arthritis of the knee joint from which Pasteurella multocida was the sole organism recovered. In both cases the initial lesion was an
ulceration near the malleolus following a cat
scratch. Cellulitis subsequently developed involving the entire lower extremity with extension anteriorly to involve the knee joints in both cases. In
spite of in vitro sensitivity to the antibiotic prescribed, prolonged therapy was required before
complete resolution occurred.
P . multocida, while recognized as a cause of
human septic arthritis and osteomyelitis, has not
been reported in conjunction with rheumatoid arthritis. The organism is common in the oropharnyx
of healthy dogs and cats and was found in one of
the pets involved in these cases. Treatment of the
cat did not eliminate the organism. Infection in
man by this organism commonly follows dog or
cat bite or cat scratch and is probably more frequent than currently appreciated. In culture the
organism is readily confused with hemophilus,
neisseria, or proteus unless the source of the culture is specified. A short course of antibiotics often
eradicates the initial infection in normal individuals, but such treatment did not eliminate the
infection nor prevent joint involvement in our
cases.
Since the carrier rate in dogs and cats is high,
they should be regarded as a significant environmental hazard, particularly for the patient with
rheumatoid arthritis or other forms of chronic
synovitis.
PLACEBO
RESPONSIVENESS-INFLUENCE
OF PREVIOUS
THERAPY
Robert C . Buttemnun and William R. Lower, Berkeley, Calif.
It has been demonstrated (J. New Drugs
6: 137, 1966) that analgesia attained for musculoskeletal disorders persists for days or weeks after
cessation of drug trial. A further review of 173
patients who received placebo therapy for 230
trials indicates that responsiveness is dependent upon effectiveness of previous therapy, diagnosis, sex and race. Placebo, as an initial trial
(71 patients), was effective for satisfactory analgesia, regardless of musculoskeletal condition, in
28.1 per cent. If placebo therapy followed an
ineffective drug trial (45 patients) analgesia was
obtained in 17.7 per cent. Following an effective
drug trial, placebo therapy was still responsive
at one week (103 patients) for 66.0 per cent,
2 weeks (107 patients) for 52.3 per cent, and 3
weeks (111 patients) for 43.2 per cent. In most
categories osteoarthritic patients were more responsive to placebo therapy. Rheumatoid patients
noted a poor response to placeboes, for an initial
trial (15.9 per cent), and after an ineffective
trial (0.0 per cent), but continued to respond to
a placebo following an effective drug trial (54.5
per cent) for the first wek, and with more rapid
loss of effectiveness, 36.3 per cent by the second
week and 26.1 per cent for the third week. Negro
patients were more responsive to placebo therapy
following an effective drug trial than Caucasian
patients. Since the interaction of drug trials is
highly significant ( p <0.001), classical crossover
evaluation of analgesic and antirheumatic agents
requires modification.
ANTIGEN
HYPOREACTIVITY TO AN EXOGENOUS
IN SYSTEMIC
LUPUSERYTHEMATOSUS
( SLE )
John Buum, Dallas, Tex.
Systemic lupus erythematosus (SLE) is often
considered a disease of immunological hyperreactivity. A number of studies in which patients
with SLE have been immunized appear to support this concept.
The responsiveness of patients with SLE to an
exogenous antigen has been studied by immunization with a dose (0.1 ml.) of brucella antigen
(2,OOOX 10 6 killed bacteria per ml. ) sufficient
to produce a measurable response in all of 18 normal female subjects (av. age 19). Twenty-three
female patients with SLE (av. age 34) were similarly immunized. At immunization, the average
dose of prednisone was 10 mg. (range 0-25 mg.);
7 received no steroid. Agglutination titers were
measured at 1, 4 and 12 weeks. All sera showing
activity were subjected to sucrose gradient ultra.
centrifugation to determine the distribution of
IgG and IgM antibody activity.
The geometric mean titers at 1, 4, and 12 weeks
in the normals were 285, 233, and 179 respectively, while in SLE they were 34, 45, and 47.
266
ABSTRACXS
IgC and IgM antibody activity showed parallel
reductions in the SLE group.
These results indicate that patients with SLE
were hyporeactive to stimulation with an exogenous bacterial antigen when compared to normal controls. Since the amount of prednisone
administered was not in the immunosuppressive
range, and there was no difference in antibody
response between patients on or off prednisone at
the time of immunization, it may be assumed
that this agent did not play a role in the diminished response.
The observed hyporeactivity to an exogenous
bacterial antigen in SLE may be in accord with
the apparent decreased resistance to infection
commonly observed in patients with SLE.
CORRELATION
BETWEENTHE RHEUMATOID
BIOLOGICALLY
ACTIVEFACTOR
( RBAF )
AND CLINICAL
FEATURES
OF RHEUMATOID
ARTHRITIS(RA)
D . A. Bell, D. A. Gordon, R. Baumal and I . Broder, Toronto, Canada
We previously described a factor (RBAF)
found in RA serum and synovial fluid, which had
the properties of a soluble antigen-antibody complex (Arthritis Rheum. 8:433,1965). This factor
was not found in healthy persons or in forms of
arthritis other than RA. I t sedimented with the
serum macroglobulins but was specifically precipitated by anti-human IgG. The RBAF showed
the capacity to stimulate histamine release and
was assayed on the basis of this property.
We have been conducting a prospective study
to determine whether the RBAF occurs systematically or at random in persons with RA. The
present report describes the data obtained at the
time of the initial examinations in this study. The
mean duration of disease was equal in persons
who were RBAF-negative as compared with
those demonstrating the RBAF in serum and/or
synovial fluid. However, the RBAF positive group
had greater evidence of articular destructive
changes, both clinically and radiologically; other
evidence of increased disease activity in this
group was indicated by the presence of more
pronounced constitutional symptoms, a higher
Lansbury index, an increased frequency of synovial effusions, and a greater prevalence of nodules, splenomegaly and other extra-articular
manifestations of rheumatoid disease. AIthough
these findings suggested that the RBAF was related to the level of disease activity in RA,
they did not clarify the sequence of this relationship.
DIAGNOSIS
OF EARLYARTHRITIS
AND OUTPATIENTS)
( A 1-8 YEAR FOLLOW-UPSTUDYOF INPATIENTS
Sidney S. Berkowitz, Edwmdo Guariglia, Samuel Laurian,
and Otto Steinbrocker, New York, N. Y.
Sixty-eight patients whose original diagnoses
were acute or initial arthritis were reexamined 1
to 7 years later. The diagnoses were confinned in
33 (48.5per cent) and had to be revised in 11
(16.2 per cent) patients. The origin of the arthritis could not be determined in 7 other patients,
and there no longer was evidence of arthritis in
the remaining 18 patients. Thirteen of the latter
were probably instances of rheumatic fever that
were no longer active.
Fifty-five outpatients whose original diagnoses
were possible or probable rheumatoid arthritis,
based on the criteria of the American Rheumatism Association, were reexamined 3-8 years later.
Approximately 1/3 of the patients originally diag-
nosed as possible rheumatoid arthritis and 36 of
those diagnosed as probable rheumatoid arthritis
eventually progressed to definite rheumatoid disease. Twenty-seven per cent were found to have
musculoskeIeta1 diseases other than rheumatoid
arthritis, and 22 per cent on reexamination showed
no evidence of any musculoskeletal disease.
These findings emphasize that clinical and laboratory diagnostic features are often inadequate
to make a reliable diagnosis in early or acute
arthritis. The “test of time” frequently is needed
to arrive at a final diagnosis. Care should be exercised in the use of potent drugs until a definite
diagnosis is established.
AS THE PRINCIPAL
AORTICINSUFFICIENCY
OF SYSTEMIC
LUPUSERYTHEMATOSUS
MANIFESTATION
G. C. Bernhard, R. L. Lung and G. T . Hensley, Milwaukee, Wisc.
Aortic insufficiency is uncommon in systemic
lupus erythematosus (SLE ) and has not been de-
scribed as the presenting or principal manifestation of this disease.
267
ABSTRACTS
Three patients are reported with this clinical
problem. Two women had intractable congestive
heart failure, auscultatory, hemodynamic and
cinema-angiocardiographic evidence of severe
aortic regurgitation. Other features of SLE included non-deforming arthritis, fever, skin rash,
nephrotic syndrome, hyperglobulinemia, and
either positive LE phenomenon or antinuclear
factor. Multiple blood cultures were negative.
Postmortem examination showed pericarditis and
myocarditis with fibrinoid necrosis. There was
aortic valve dilatation. Aortic valves were incompetent due to dilatation of the aortic ring, and the
valves were markedly thinned with central perforations and areas of fibrinoid necrosis, There
were no verrucae and no features of bacterial
endocarditis. The kidneys showed evidence of
lupus nephritis, and there was periarteriolar fibro-
sis in the spleen. The third patient is a 59-yearold man who had arthralgias, autohemolytic
anemia, hypergammaglobulinemia and LE phenomenon. H e developed clinical features of aortic
incompetence and recurrent congestive heart failure. Several blood cultures have been negative,
and he has been afebrile.
Marked valve leaflet thinning and fenestrations
seen in the autopsy cases occurred after corticosteroid therapy. While the role of corticosteroids
should be considered in the production of the
aortic valve changes, it is difficult to implicate
this medication since one of the autopsied patients had been on corticosteroids only during the
last month of her life. The primary reason for
this report is to point out that SLE should be
added to the list of causes of severe and progressive aortic insufficiency.
“AMYOPATHIC”
DERMATOMYOS~TIS
Yale B. Bickel, Lauren Reager, J . B. Peter and Carl M . Pearson, Los Angeles, Calif.
Polymyositis is a pleomorphic syndrome characterized by diffuse inflammatory and degenerative
involvement of skeletal muscle, often associated
with varying dermal and systemic features. The
term dermatomyositis describes a syndrome wherein dermal and myopathic involvement coexist.
Ten patients were encountered in whom muscle
disease was minimal or absent, despite the presence of rash indistinguishable from dermatomyositis. The group consisted of 8 women and 2 men,
ranging in age from 3 to 65 years. Evidence of
muscle weakness was absent in 4, minimal in 3,
and moderate, but rapidly regressed, in 3 cases.
EMG was normal in 6 cases, and revealed fibrillation potentials in 3, 2 of whom h i d moderate
weakness. Muscle enzymes were normal in 7 and
only transiently elevated in 3 cases, Muscle biopsies from 5 patients were normal or minimally
abnormal and none were diagnostic of myositis.
Time from onset to diagnosis, in months, varied
from 1.5 to 12, with a mean of 6.5. Associated
conditions included rheumatoid arthritis, salmonella enteritis, pulmonary “fibrosis”, thyroid disease, pregnancy and invasive epidermoid carcinoma of the cervix. Skin biopsies obtained in 7
of 10 patients revealed varying degrees of hyperkeratosis, follicular plugging, edema of dermal
collagen, and perivascular inflammation. Necrotizing angiitis and basal cell degeneration were
absent. These data suggest that dermatomyositis represents a disease spectrum wherein muscle
and dermal features may coexist to varying degrees. Polymyositis may occur without skin involvement, and the dermal features may be seen
in the absence of detectable muscle disease.
“Amyopathic” dermatomyositis represents another
variant in the clinical spectrum of myositis.
FUNCTION
AND INTERMITTENT STEROID THERAPY
ADRENOCORTICAL
IN RHEUMATOID
ARTHRITIS
Paul J . Bilka, Minneapolis, Minn.
Adrenocortical function was studied through
the use of the oral metyrapone (“metopirone”)
test in 15 patients who had been on no ( 2 patients) or various cortisol derivatives (13 patients) and were then placed on a single cortisol
derivative-dexamethasone. All patients had at
least a %month trial of dexamethasone given
every other day, and 11 patients had a t least a 2month trial of dexamethasone given two times
a day. Nine patients were further studied after a
change to prednisone or prednisolone given once
a day or every other day for about 3 months; 6
of these patients were still further studied after
an additional 10 to 12 months of their intermittent
schedule.
Dexamethasone, a long-acting steroid analog,
failed to improve 17-hydroxy-corticosteroid excretion despite the alternate day dosage administration in 13 of the 15 patients, and actually
caused suppression in 6 of these patients. Still
268
ABsTRAms
greater suppression, however, was evident with
the twice a day dexamethasone dosage.
When 9 patients were changed to the shortacting steroids, prednisone or prednisolone, given
every other day or a once a day (AM), 17OHCS excretion improved in 6 and was unchanged in 3 patients after an average of 3
months therapy. And when 6 of these 9 patients
were continued on this same intermittent schedule
for an additional 10 to 12 months, 17-OHCS
excretion improved or remained unchanged in 5
and showed a modest fall in only one patient.
These data point to a definite preference for
the use of the short acting adrenocorticosteroids
every AM or every other day as a means of
minimizing adrenocortical suppression, The clinical
control of the patients’ symptoms was more difficult on intermittent steroid therapy, but most patients developed a tolerance to the initial “swings”
in their arthritis symptoms, and in only one patient was it necessary to go back to the two-timesa-day dosage schedule in order to regain adequate
symptomatic control. The data did not indicate
significant differences in the clinical signs of
steroid toxicity when patients were on the different
dosage schedules.
ANKYLOSING
SPONDYLITIS
WITHCHILDHOODONSET
Samson Bitnun, Jane Schaller and Ralph J . Wedgwood,
Nelson, British Columbia and Seattle, Wash.
Ankylosing spondylitis is rarely recognized before puberty. We have seen 7 males with ankylosing spondylitis beginning between ages 7 and
12 years (current ages 15 to 38 years). Three
presented with pain in low back, hip, or groin.
Four presented with asymmetric peripheral arthritis (knees, ankles, feet, MCP); 3 of these developed low back symptoms within 4 years of
disease onset. Six now have stiffness of the entire
spine; 1 has stiffness limited to lumbar spine. Six
have decreased chest expansion. All have bilateral sacroiliac destruction or fusion radiologically;
6 have radiologic findings consistent with ankylosing spondylitis in lumbar spine, and 4 in thoracic
or cervical spine. Four have destructive hip disease; only 2 have had persistent peripheral arthritis with radiologic changes.
None has had bowel disease, urethritis, psoriasis, rheumatoid nodules, rheumatoid factor, or
iritis. Three have had low-grade fevers; 3, growth
retardation; 3, duodenal ulcers; and 5, consistly
elevated sedimentation rates. Function has remained good in 5, but is poor in 2.
Although 6 of these patients had early symptoms referable to the low back, only 2 were
recognized as having ankylosing spondylitis during childhood (other diagnoses: juvenile rheumatoid arthritis, acute rheumatic fever, pelvic
chondrodysplasia ) . Ankylosing spondylitis should
be considered in the differential diagnosis of
childhood arthritis, particularly in children with
low back, hip, or groin pain.
This disease is to be distinguished from juvenile
rheumatoid arthritis which predominantly involves
peripheral joints and frequently involves the cervical spine, but almost uniformly spares the lumbodorsal spine and is associated with radiologic
sacroiliitis without prominent low-back symptoms.
HEMIARTHRITIS
HEMIPLEGIAAND RHEUMATOID
John H . Bland and Winston M . Eddy, Burlington, Vt.
Hemiplegia protects against both rheumatoid
arthritis and osteoarthritis on the paralyzed side.
The mechanism is unknown. Both upper and lower
motor neuron lesions confer protection. Clinical,
radiologic and histologic evidence of hemiarthritis
in hemiplegia has been described. Twelve cases
supporting this general concept have been reported.
The present report is of a patient with left
ASEPTIC NECROSIS
OF
THE
hemiparesis occurring in 1951, followed by development of severe rheumatoid arthritis within 4
months. The disease did not involve the paralyzed side, while gross destructive disease developed on the non-paralyzed side. The patient
was observed over a 13-year period. Clinical and
radiologic evidence of unilateral disease will be
presented. Proposed protective mechanisms and
their biologic importance are discussed.
FEMORAL
HEADS
IN SICKLE
A HEMOGLOBIN
DISEASE
Sheldon Blau and David Hamemnan, New York, N. Y.
Heterozygous sickle cell disease (SA or sickle
trait) is generally regarded as a benign disease,
although a number of serious complications can
occur, such as splenic infarcts, hyposthenuria,
ABSTRACTS
hematuria, and infarctions of other organs, all
presumably secondary to vascular occlusions.
Avascular necrosis of the femoral heads is a fairly
well known occurrence in the homozygous variety (SS) of the disease, as well as in other
heterozygous combinations of abnormal hemoglobins, but it is apparently rare in SA disease.
The following apparently consititutes the third
report in the American literature. The patient is
a 43-year-old Negro laundry worker whose complaints were entirely confined to low back pain
for several years. There were no previous illnesses.
The only medication taken was Zactirin. Physical
examination, including the gait, was normaI. Laboratory studies were normal except for hemoglobin electrophoresis, which revealed SA. X-rays
of the hips were available from 1960. At that
time only a lucent area in the left femoral head
was observed. In 1961 there were multi-loculated
defects in the right femoral head as well. In 1966
reactive sclerosis had filled in the lucent areas in
both hips. Apparently, avascular necrosis of the
femoral heads progressed without symptoms in
this patient for many years. A review of possible
predisposing factors other than SA disease was
made, and none was thought to be contributory:
trauma, alcoholism, ionizing radiation, Caisson disease, vascular insufficiency, systemic connective
tissue disease, steroid therapy, and many others.
Hemoglobin SA disease would seem to be the
predisposing condition for aseptic necrosis of the
femoral heads in this patient.
THEINCIDENCE
AND SIGNIFICANCE
OF THE LUPUSERYTHEMATOSUS
( L E ) PHENOMENON
IN 45 RHEUMATOID
ARTHRITISPATIENTSOBSERVED
FOR 10 YEARS
Gilbert B. Bluhm, John W. Sigler, Dwight C . Ensign and John W. Rebuck, Detroit, Mich.
This report summarizes the clinical findings and
laboratory data of 45 patients with rheumatoid
arthritis (RA) observed in a prospective study for
a 1 0 year period. Fourteen of the 45 patients (31
per cent) exhibited LE cells. Three patients had
4 or more LE cells in a single test. One of these
patients developed clinical signs of systemic lupus
erythematosus (SLE) after 2 years of observation and is excluded from this summary. Nine
patients have died. Histologic changes of SLE
were absent in 4 patients autopsied.
After 10 years, 32 patients remained available
for clinical assessment. Twenty-two were in the
LE cell negative (LEN ) group and 10 in the LE
cell forming ( L E F ) group. None of the patients
exhibited a positive serological test for syphilis.
Nodules were present in 44 per cent, rheumatoid
factor ( R F ) in 60 per cent, antinuclear factor
(ANF) in 70 per cent, and 17 per cent exhibited
Stage IV rheumatoid progression. All 11 patients
in Functional Class 3 and 4 exhibited RF and 8
had subcutaneous nodules; whereas, of those patients in Functional Class l and 2, only 9 of 21
had R F and 6 of 21 had nodules. The average
duration of disease was the same in both groups.
Comparisons were made between the LEN and
L E F patients.
LEN
(Median
Disease
Duration )
16 Yrs.)
LEF
(Median
Disease
Duration)
17 Yrs.)
~-
Stage I11 & IV
Functional
Class 3 & 4
RF
Nodules
Positive ANF
17/22
10/10
5/22
12/22
7/22
13/21
6/10
8/10
7/10
8/9
Our findings suggest that the transient occurrence
of the LE cell in RA is associated frequently
with progression to a more advanced stage of
rheumatoid disease but infrequently with the development of SLE.
THEPROCAINE
AMIDE-INDUCED
LUPUSERYTHEMATOSUS
SYNDROME
Stephen F. Bodman, Marvin J . Hoflman and John J. Condemi, Rochester, N. Y.
Over a 6-month period, we have observed 13
cases of the procaine amide-induced lupus erythematosus syndrome. Our group includes 8 women
and 5 men, all Caucasian. The mean age was 62
years. Symptoms began onIy after substantial
amounts of the drug had been taken (mean total
dose approx. 1 kg.; mean duration of therapy
one and one-half years). Seven of 13 patients
developed arthralgias and arthritis without x-ray
changes, myalgias, pleurisy, pericarditis, fever,
lymphadenopathy, hepatomegaly, splenomegaly,
or weight loss. Six of 13 complained only of insidious malaise, weakness, anorexia, and mild
musculoskeletal symptoms.
ABSTRACTS
Hematocrits were normal in 12/13. Leukopenia was found in 5/13 and absolute lymphopenia in 8/13. Renal function was normal. Five
of 11 patients had positive non-gamma Coomb's
test, indicating complement on the red cells. LE
cell tests were positive in 12/13 patients. Antinuclear antibodies ( ANA ), determined by immunofluorescence and Hyland Lab latex nucleoprotein tests, were present in all 13 patients. High
titers of IgG and lower titers of IgA and JgM
ANA were noted by immunofluorescence. Two
patients who were evaluated early in their illness
were found to have negative LE cell tests and
absent ANA but were found to develop positive
tests later. Five of 13 patients had positive latex
fixation ( antiglobulin) tests. Serum complement
levels were within normal range. Hyperglobulinemia was present in 4/13, but the mean IgG
value was at the upper extreme of the normal
range.
Five-month follow-up reveals that symptoms often persist for several months after drug cessation,
requiring corticosteroids in 8/13 of our patients.
ANA have disappeared from the sera of 3 patients. The non-gamma Coomb's test has become
negative in all 5 patients. Latex fixation tests
have become negative in 3/5 and have decreased in titer in 2/5. Significant decrease in
IgG levels after drug cessation has occurred in
all patients.
RHEUMATOID
ARTHRITIS,
STEROID
THERAPY,
AND THE CRYPTOCOCCUS
C. W. Brandt and E . C. Toone, Richmond, Va.
The prolonged use of immunosuppressive
agents, such as a corticosteroid, in a disease in
which the immune mechanism is probably already
deranged, such as rheumatoid arthritis, raises concern about potential infectious complications. Our
attention has recently been diverted to the
cryptococcus.
A 56-year-old white man with advanced
rheumatoid arthritis of 15 years duration, receiving 10 to 15 mg of prednisone daily, presented
with the complaints of vertigo, headaches, weakness, and fever, and was found to have pyuria
with azotemia (BUN 70 mg per cent). Initial
urine cultures were negative for the routine pyogenic bacteria, hut cryptoccocus neoformanS was
suspected in the urine sediment and confirmed
by culture. Further studies, including needle
biopsy of the kidney, demonstrated pyelonephritis with necrotising papillitis, and showed the
cryptococcus in the renal parenchyma. Examination of the cerebrospinal fluid revealed the
cryptococcus associated with pleocytosis, elevated
proteins, and decreased sugar. Both the renal and
central nervous system infections responded well
to 1000 mg. of intravenous Amphotericin B, administered over 35 days. The records of the
Medical College of Virginia Hospitals from 1956
to 1966 revealed a second case of steroid-treated
rheumatoid arthritis complicated by cryptococcal
infection, in this instance involving the lung and
meninges.
A third case of cryptococcal meningitis complicating corticosteroid treated rheumatoid arthritis
was seen in another local hospital.
Three cases of disseminated cryptococcosis occurring in steroid-treated rheumatoid arthritis
serves to call attention to this as an infectious
complication. Diagnosis may be difficult due to
the variable clinical factors, often obscured by
pre-existing disease. Alertness is demanded, however, since effective therapy is available.
XANTHINEAND HYPOXANTHINE
LEVELSDURING
DRUGTHERAPY
IN GOUT
URINARY
W. G. Briney, F . J . Baehnk, and B. A. Bartholomew, Denver, Colo.
The use of the xanthine oxidase inhibitor, 4hydroxypyrazolo (3,4-d) pyrimidine ( HPP), in
the treatment of gout results in increased levels of
the urinary oxypurines, hypoxanthine and xanthine. The present study deals with urinary hypoxanthine and xanthine levels as determined in patients with gout during therapy with HPP,
uricosuric agents, and anti-inflammatory agents
alone and in combination.
A paper chromatography method was used to
separate xanthine and hypoxanthine. The individ-
ual components were determined b y a coupled
enzymatic reaction employing xanthine oxidase
and uricase. Values for serum urate and 24-hour
urinary uric acid, xanthine, and hypoxanthine
levels will be presented. Single determinations on
control patients (including 7 patients with renal
transplants and three patients with untreated
gout ) showed urinary xanthine and hypoxanthine
levels from 1.5 to 32 and 2.0 to 28 mgm/24
hours respectively. Two patients evaluated on a
metabolic ward for one-month periods had 1 ) in-
271
ABSTRACTS
creased xanthine and hypoxanthine levels during
HPP therapy, with the major rise in xanthine and
2 ) a relative decrease in both oxypurines when
HPP and sulfinpyrazone were used concomitantly.
Five patients studied weekly for 4 to 6 months
showed prompt elevations of urinary oxypurines.
The major rise was in xanthine in 4 patients and
hypoxanthine in one patient. One patient receiving
HPP showed a decrease in both oxypurines with
the addition of indomethacin, and a return to
pretreatment levels upon its discontinuation. These
results, suggesting an individual variability in response to combination drug therapy in gout, will
be discussed in detail.
OCCURRENCE
OF RHEUMATOID
ARTHRITIS
( RA) AND RHEUMATOID
FACTOR( R F )
IN LARGEFAMILIES
T . A. Burch and P . H . Bennett, Phoenix, Ariz.
I n previously reported studies no evidence was
found to support the hypothesis that rheumatoid
arthritis (RA) or rheumatoid factor ( R F ) in the
Blackfeet and Pima Indians were determined by
any presently demonstrable genetic mechanisms.
These studies were based on epidemiological data
from 1101 Blackfeet and 969 Pima Indians, aged
30 years and over, living on their respective reservations. Further analysis has shown that rheumatoid factor, detected by the bentonite flocculation
test and the sheep cell agglutination test, occurred
one and a half times as frequently among the
larger sibships of the Pima tribe than among the
smaller sibships. Rheumatoid arthritis, probable and
definite, was found more than twice as frequently
among the larger sibships of the same tribe
(P<0.01).
The relationship of RA to sibship size appeared
to be independent of age, but that of RF was
most marked when the eldest sibling was at least
55 years old. No definite evidence of an increased risk to the spouse of affected subjects
was found.
These data provide strong evidence that RA
and RF are the result of environmental influences,
perhaps infections, which probably operated during infancy, childhood or adolescence. The detailed findings will be presented.
ABRUPTCHANGES
IN TARGET
ORGANENCOUNTERED
AMONGPATIENTSWITH AUTOIMMUNE
DISEASE
E. M . Caperton, Jr., R. C . Williams, Jr., P . J. B i l k and M . J. Murray, Minneapolis, Minn.
Some predictable pattern of clinical progression of the various so-called autoimmune diseases
is well known. However, frequently a considerable degree of overlap of clinical or pathologic
findings occurs.
We have recently encountered 6 patients exhibiting evidence for abrupt transitions of involvement of multiple organ systems during their disease. These patients showed little in the way of
concurrent overlap, but rather a clinical course
that was marked by abrupt changes in the target
organs involved. Included in this study were patients with:
1 ) Lupus erythematosus, manifested as polyarthritis. Complete remission followed 12 years of
symptoms. Following a traumatic episode, patient
developed classical ulcerative colitis.
2 ) Rheumatoid arthritis complicated by ulcerative colitis. Colectomy led to complete remission
of gastrointestinal disease whille the rheumatoid
arthritis progressed unabated.
3 ) Remission of multiple sclerosis followed by
typical lupus erythematosus. Remission of the lupus
was prompted by steroid therapy; symptoms of
multiple sclerosis promptly returned.
4) Severe ulcerative colitis requiring colectomy
for control. Six days later arthritis, which progressed to typical rheumatoid arthritis, ensued.
5 ) A patient showing evidence of multiple disease states, each appearing independently of the
other. In order of appearance they were asthma,
bloody diarrhea, lupoid hepatitis, thyrotoxicosis,
nephrosis, skin ulceration, and terminally brain
and pancreatic necrosis.
6 ) Chronic glomerulonephritis requiring kidney
transplantation, followed by ulcerative colitis.
The association of multiple concurrent organ
involvement is a familiar clinical entity; however,
abrupt transitions notable among these patients
present unique situations. It is possible that target
organ shift is secondary to exhaustion of the
antigenic capacities of the original organ.
272
ABSTRACTS
RHEUMATOID KNEE
SOFTTISSUE
STABILIZATION
OF THE UNSTABLE
Peter A. Casagrande, Buffalo, N. Y.
The problem of the unstable, painful knee is a
vexing one that occurs in 20 per cent of rheumatoid patients. In over 75 per cent of these knees,
the instability is due to capsular-ligamentous laxity
secondary to chronic hypertrophic synovitis. The
laxity is most pronounced in the weight-bearing
posture with the knee usually assuming a valgus
deformity.
How can the knee be stabilized? The method
herein described produces adequate stability together with a functional range of motion. Our criteria for the selection of surgical candidates are
two-fold: 1) the instability must be primarily due
to capsular-ligamentous laxity, and 2 ) abduction
(or varus) of the knee must exceed 30 degrees
on stress (weight-bearing or passive manipulation). The surgical procedure consists of using 2
long strips of quadriceps fascia to re-enforce the
cruciate and lateral ligaments (modified Jones
procedure), in conjunction with a thorough joint
debridement, i.e., synovectomy, partial patellectomy, and removal of osteophytes, deranged
menisci and loose bodies.
Post-operative care is most important. The leg
cast is removed in 48 hours. Passive manipulations of the joint is then done on a sedated patient. A cylinder cast is applied which is bivalved
the next day. Thereafter, passive and active joint
motion including quadriceps muscle exercises is
done two or three times daily. Isometric exercises are done every hour. Ninety degrees of flexion can be obtained in most knees within 7 to 14
days. Ambulation is permitted with crutches and
the bivalved cylinder cast 3 to 4 days postdperatively. The cylinder halves are dispensed
with as soon as the knee can be extended against
moderate resistance.
This soft tissue stabilization of the knee has
been most gratifying. I t produces stability adequate for the stresses that may be applied by
such a patient, In addition the knee is comfortable
and allows motion adequate for activities of daily
living.
ISOLATED
IGA DEFICIENCY
IN JUVENILE RHEUMATOID
ARTHRITIS
Jam’es T. Cassidy and Ann Burt, Ann Arbor, Mich.
Patients with congenital agammaglobulinemia
or primary acquired hypogammaglobulinemia exhibit an increased incidence of chronic arthritis.
Arthritis has not been associated, however, with
Type I11 dysgammaglobulinemia. Immunoelectrophoresis of sera from 100 patients with juvenile
rheumatoid arthritis identified 8 with no IgA
precipitin arc. The current age range of this latter
group was 5 to 23 years. Six were females. Serial
determinations over 4 to 6 years in 6 of these individuals confirmed the persistence of this abnormality. Immunoassay indicated that 5/8 had no
detectable IgA, and 3 /8 had decreased levels
( 0.07-0.52 mg/ml) . The concentrations of IgG
and M were normal to increased. There was no
IgA by electro-immunodiffusion in the parotid
saliva, tears, or synovial fluid of 2 with agammaglobulinemia-A, and 0.04 mg/ml in the saliva of
one with hypogammaglobulinemia-A. This same
girl had positive rheumatoid factor tests.
Antisera were prepared in rabbits to 2 immunodeficient sera, and cross-adsorption studies indicated that no antibody was induced to IgA. There
was no correlation of IgA deficiency with clinical
features of the arthritis. Family members had normal serum IeveIs of this immunoglobulin, except
for one mother with low IgG, A and M. One of
146 randomly selected, non-hospitalized control
subjects 1 to 20 years of age had no IgA. In retrospect this was a 14-year-old boy who had had
transient arthritis at age 6.
It was concluded that juvenile rheumatoid
arthritis was associated with selective IgA deficiency in addition to the known increased occurrence of arthritis in classical, complete forms of
hypo- and agammaglobulinemia.
CHARACTERIZATION
OF A TISSUE
ANTIGENREACTIVEWITH LUPUSERYTHEMATOSUS
( L E ) SERA
Geoffrey Clark, Morris Reichlin and Thomas B . Tom& Jr., Buffalo, N.
The serum of a patient with a connective tissue
syndrome closely resembling disseminated lupus,
but with negative antinuclear antibody, was
found to react with extracts of human tissue in
Y.
complement fixation and precipitin reactions. The
antigen was purified IW-fold by DEAE chromatography followed by gel filtration. The antigen
was present in only small amounts and precipitin
273
ABSTRACTS
reactions required 10-fold concentration of the
complement fixing activity in the original extract. It was not destroyed by trypsin, chymotrypsin, pepsin, papain, RNAase or DNAase. It was
destroyed by heating at 70 ' for 30 minutes, periodate oxidation and . O M parahydroxy mercuribenzoate; the latter effect being partially reversible with cysteine. Gel filtration studies indicated
a macromolecule of approximately 100,000 in
molecular weight. The antigen gave a single precipitin arc in the a1 globulin region in immunoelectrophoresis when developed with LE sera. The
serum factor was demonstrated to be a gamma
globulin. Cell fractionation by a modified Chauveau method revealed that the activity was primarily in the soluble cytoplasmic high speed
supernatant. A nuclear extract had little activity.
It is distinct from known nuclear antigens including the system recently described by Tan and
Kunkel (J. Immun. 96:464, 1966). The antibody
was found in 40 per cent of unselected LE sera.
This system is of interest because, unlike most of
the previously described antigens reactive with
LE sera, it appears to be cytoplasmic in origin
and the antibody is present in certain sera in large
amounts.
AND SYNOVIAL
ALTERATIONS
IN SCLERODERMA
SEROLOGIC
J . A. Clark, R. K . Winkelmann, F. C . McDufie and L. E . Ward, Rochester, Minn.
Rheumatoid factor was present in serum of 35
per cent of 265 patients with scleroderma. Sedimentation rate was normal in one-third, increased
up to 40 mm. (Westergren) in one-third, and
over 40 mm. in one-third of 401 cases. Lupus
erythematosus cells were found in 4 of 230
sclerodermatous females but none of the 58 males;
nucleolysis were found in 10 additional patients
( 2 males, 8 females). Serologic test for syphilis
was positive in 5 per cent of 363 patients. Serum
protein electrophoretic patterns (313 patients)
generally were normal; gamma globulin was
mildly increased in 26 per cent, rarely decreased.
Synovial biopsies were performed in 36 patients.
In 14 with negative rheumatoid factor (RF), generally there was much hyaline sclerosis and deposition of fibrin; in 22 with positive RF there
was a tendency for somewhat less fibrin and
sclerosis, and lymphocytic infiltration was somewhat more prominent. Five sclerodermatous patients with articular changes like those of rheum-
DYNAMIC
SPLINTINGOF
atoid arthritis exhibited rheumatoid-like lymphocytic and plasma cell infiltrates in the synovial
membrane.
Synovial fluid in patients with negative serum
rheumatoid factor tests generally was RF negative,
mucin clot test was type 2 and ragocyte count
was low, whereas in those with RF in serum the
synovial fluid was RF positive, mucin clot was
type 2 or 3, and ragocyte count tended to be
slightly higher.
Articular symptoms or signs were found in 77
per cent of 446 cases, mainly fibrositic stiffness
of finger and medium sized joints, arthralgia,
Iimited motion, tenderness, slight swelling and
crepitation. Well-defined synovitis was less commonly detected clinically. Clinically-detectable
synovitis tended to be more prominent in those
with positive RF. Definite sclerodermatous x-ray
changes were found in 25 per cent, suggestive
changes in 36 per cent, rheumatoid-like changes
in 3 per cent.
THE
RHEUMATOIDHAND
F. Richard Conuery, 3. Pierce Conuty and Vernon L. Nickel, Downey, Calif.
For the past 7 years, a dynamic hand splint
designed to maintain motion, improve function,
relieve pain and prevent the progression of deformity has been used on the arthritis service at
Rancho Los Amigos Hospital. During the period
1959 to 1965, 61 patients with rheumatoid arthritis were fitted with this splint. Twenty-seven
hands in 17 patients, who used the splints for
more than one year with a mean duration of 34
months, are available for review. Thirteen hands
in 8 patients, who were fitted but did not use the
splints, and were followed for more than one
year with a mean follow-up of 32 months, are
available for comparison.
The splints adversely affected wrist motion in
those wrists that had had good extension. Wrist
extension was not maintained, total range was
reduced with a mean loss of 47 degrees, and
significant wrist deformities developed in 3 wrists
out of 13 that had had an essentially normal
range. In the wrists with pre-existing deformity,
the adverse effects were not so apparent. The
wrists in the comparison group showed a mean
loss of extension of 5 degrees and of total range
of only 7 degrees. Twenty per cent of the MCP
joints developed flexion deformities. Flexion
range was lost in 39 per cent. Nineteen MCP
joints had a passive flexion deformity at the onset
of splinting. Of these, 8 improved, 8 were worse,
and 3 did not change. The mean loss of total
274
ABSTRACTS
range was 15 degrees. In the comparison group,
there was no significant loss of total range, but
flexion deformity developed in 12 per cent of the
MCP joints. Splinting of the metacarpophalangeal
joint seemed to adversely affect the proximal
interphalangeal joint. There was a mean loss of
motion of 17 degrees, which can be compared to
7 degrees in the nonsplinted group.
Dynamic splinting of the rheumatoid hand does
not prevent the progression of deformities, does
not effectively correct pre-existing deformities, and
in addition, probably results in limitation of motion that is greater than would be expected if the
hand had not been splinted.
ATYPICALSIGNSOF RHEUMATOIDARTHRITIS
Joseph D. Croft, Jr. and Ralph F . Jacox, Rochester, N. Y.
When unusual clinical and radiological signs
of rheumatoid arthritis precede clinically apparent disease by several years, they may provide
insight into the natural history of this disorder.
Three such patients have been seen in our clinic.
Two women developed a “ganglion” of the wrist,
and the histologic appearance of these lesions was
identical to the chronic synovitis seen in rheumatoid arthritis. Several years later both patients
developed sero-positive rheumatoid arthritis. A
third patient had a large bone cyst in the distal
end of the right tibia. This lesion, when surgically
removed, was, on pathologic examination, iudistinguishable from rheumatoid granulation tissue.
RETENTION
OF CRYOPRECIPITAUILITY I N
THE
During the subsequent 17 years, this patient has
gone on to develop severe, erosive, and crippling
arthritis with notable absence of advanced radiological changes in the ankle adjacent to the surgically excised cyst.
The pathology and clinical aspects of these
cases will be discussed. The above observations
suggest that: 1) when “rheumatoid” ganglia are
diagnosed, such patients should be closely followed for the development of rheumatoid arthritis and 2 ) rheumatoid disease should be included in the differential diagnosis of a large
bone cyst even when no radiological evidence of
adjacent joint disease exists.
5s PEPTIC FRAGMENT
OF A CRYOGLOBULIN
Norman A. Cummings, Houston, Tex.
Cryoglobulins, serum globulins which reversibly
precipitate in the cold, are found in a variety of
connective tissue disorders and other disease5.
The present project investigates the site on the
molecule which is necessary for cryoprecipitation.
A “7s” cryoglobulin was isolated from serum by
of 6.61s at inficold precipitation. It had an, ,S
nite dilution, gave a single homodisperse peak in
the ultracentrifuge, a single symmetrical peak on
gel filtration, and a single band against rabbit
anti-human serum by immunoelectrophoresis. In a
defined system, 30 per cent of the protein reversibly precipitated a t 0” C .
The cryoglobulin was dige5ted with pepsin. The
of 5.3s and a
remaining fragment had an S,
molecular weight of ahout 106,000. Under the
same conditions used for the whole cryoglobulin,
15 per cent of the 5.3s protein reversibly precipitated at 0” C. Neither normal pooled fraction 11
(IgG) nor its 5s peptic fragment showed cryo-
precipitability .
Since heavy chains are generally less soluble
than the native molecule, one might suspect a
heavy chain site as being responsible for cryoprecipitability. However, it was observed that
conditions needed to keep unaggregated heavy
chains in solution inhibit cryoprecipitability even
in the whole cryoglobulin. Heavy chains probably consist of a variable, and a relatively invariant, portion in terms of amino acid sequence.
I t is the C-terminal, or invariant, portion of the
heavy chain which hydrolyzed by pepsin and
which is not needed for cryoprecipitation, although cryoprecipitability is enhanced by its
presence.
Further studies of structural alterations related
to cryoprecipitation may be simplified by the use
of the 5s peptic fragment rather than the whole
molecule.
THEEFFECTOF HEATWITH AND WITHOUTADDEDDIETARY
SALT,ON
S35 FIXATION
BY CARTILAGE
AND OTHERTISSUE
Charles W. Denko, Columbus, Ohio
Despite the climatologic universality of connective tissue disorders, arthritis patients, with or
without medical advice, still seek benefits in
warmer climates. Heat is frequently recommended
275
ABSTRACTS
in treating arthritis in conservative programs. Localized and generalized heat, including baths,
showers, packs, paraffin dips and heat lamps is
used. Yet little information is available on the
effects of heat on metabolism of cartilage and
connective tissue,
To determine whether or not generalized heat
had any effect on connective tissues in the rat,
animals were kept in incubators at 37°C for varying periods. Some received sodium chloride
freely, while others were restricted during exposure to heat. The longest exposure was 8 hours
daily, 5 days per week, for 3 weeks. S36 was injected as the metabolic tracer.
Animals that were restricted in their salt intake
had augmented levels of S35 incorporation in the
aorta, adrenals, heart muscle, liver and kidney,
This increase was about 50 per cent. No significant change was found in radioactive sulfate uptake by costal cartilage, tibia1 cap, stomach,
spleen, colon and lung. When salt was freely
available to the young rats, nearly all their tissues had normal levels of radiosulfur. Only lung
and kidney had elevated uptakes. However, the
level in costal cartilage was diminished, being one
fourth less than in controls.
Interpretation of these changes remains speculative. The lung and kidney are excretory organs
that may be stimulated by heat. The inhibition
of radiosulfur fixation in costal cartilage is similar
to the effects produced by anti-inflammatory drugs.
A CLINICOPATHOLOGIC
STUDYOF THREEPATIENTS
DYINGWITH THE SICCA (SJ~GREN’S)
SYNDROME
C . W. Denko, K . P. Clausen, C . Boesel, G . Penn and J . W. Old, Columbus, Ohio
Few autopsies have been reported on patients
dying with the sicca ( Sjogren’s) syndrome. Three
such patients were studied recently to correlate
ante-mortem clinical and biochemical abnormalities with histopathological changes. In addition to
the sicca syndrome, several features were common to all: namely, polyclonal dysproteinemia,
diffuse plasma cell infiltration of reticulo-endothelial organs, myopathy, and arthritis. The myopathy was manifest by weakness, myalgia, and
wasting. All patients had taken steroids but the
muscular lesion, fatty degeneration, was clearly
not that usually reported with steroid therapy.
After 6 years of therapy, one patient had clinical
and autopsy evidence of improvement of her
severe myopathy. A second had biopsy diagnosis
of sicca myopathy and electromyographic evidence of diffuse myopathy. The third had clinical
myopathy and myopathic lesions at autopsy iclentical to the first 2.
The non-specificity of the lupus erythematosus
(LE ) cell was illustrated in 2 of these patients
with positive LE tests, macular skin rash, nodular
colloid goiters and splenomegaly. Both were
women who had clinical systemic lupus erythematosus, but had no histologic lesions diagnostic of
lupus at autopsy. The male patient had a nonspecific collagen disorder most consistent with
rheumatoid arthritis. All, however, had negative
latex fixation tests.
This study correlates the sicca syndrome with
a specific myopathic lesion and demonstrates other
common features of this connective tissue disease
which are not typical of any classically defined
rheumatic disorder.
GLYCOSAMINOGLYCANS
OF REGENERATING
TENDON
Robert W. Dorner, St. Louis, Mo.
The connective tissue which forms following
surgical excision of rabbit calcaneal tendon is
suitable for study at various stages of maturity
and eventually approximates mature tendon histologically. Pooled regeneration tissues from groups
of 4 rabbits were obtained after regeneration
periods of 4 days to 4 months. Aliquots of the
pooled samples were used for the following
studies: 1 ) cetyl pyridinium chloride (CPC)
cellulose column methods for determillation of
hyaluronate, chondroitin-4-sulfate, chondroitin-6sulfate, dermatan sulfate, and CPC complex solubility profiles; 2 ) Ecteola cellulose chromatography, mainly to determine keratosulfate; 3 ) total
hexosamine determinations; 4 ) collagen solubility
studies and disk electrophoretic determinations of
collagen alpha/beta peptide ratios.
The most pronounced changes in composition
of the connective tissue took place during the
first 3 weeks: hyaluronate decreased from about
50 per cent at 4 days to 20 per cent, and dermatan sulfate increased from about 10 per cent to
over 40 per cent of the total CPC precipitahle
glycosaminoglycans. Further, less rapid increases
in dermatan sulfate and decreases in hyaluronate
took place during the following 100 days. Chonclroitin-4-sulfate was found in variable concentrations in most of the regeneration tissues, but
276
ABSTRAtTS
very little, if any, was found in 4-month regeneration tissue and in mature tendon. Chondroitin6-sulfate represented a relatively constant portion
of the glycosaminoglycans of all regeneration tis-
sues, as well as mature tendon. Four-month regeneration tissue had a composition approximating
that of mature tendon.
OF THE LOWERLIMBS
REGIONAL
MIGRATORY
OSTEOPOROSIS
Howard Duncan, Boy Frame, Harold Frost and A. Robert Arnstein, Detroit, Mich.
A syndrome characterized by regional and
migratory osteoporosis in the lower extremities occurred in 3 patients, either spontaneously or after
mild trauma. Initially, there was pain and tenderness in the general region of the knee, ankle or
foot, associated with a rapid progression of a
spotty demineralization in the bones of the affected area. The pain was severe on weight bearing. There was edema, warmth, and evidence of
increased vascularity of the overlying soft tissue.
The clinical findings subsided in 6 to 9 months
followed by improved mineralization of the involved bones.
In all subjects, identical and sequential episodes
of pain and spotty osteoporosis occurred over a
period of 2 years in other areas of the same or
opposite lower extremity without initiating cause.
The same area was never involved with a second
episode. Various forms of arthritis and general
metabolic bone disease could readily be ruled
out.
The syndrome resembles Sudek‘s atrophy (reflex osteodystrophy) but is unique in that there is
subsequent migratory and regional osteoporosis
and soft tissue swelling of other areas in the same
or opposite lower extremity.
THECOMPARATIVE
EFFECTSOF A DEXAMETHASONE
AND A DEXAMETHASONE-ASPIRIN
COMBINATION
IN THE TREATMENT
OF RHEUMATIC
DISEASE
DeWitt W. Englund and Sanford H. Roth, Phoenix, Ariz.
This study was an attempt to conduct a clinical
evaluation in order to show the relative benefits of dexamethasone and a dexamethasone-buffered-aspirin combination.
Twenty nine patients were seen at the
Phoenix Arihritis Center in this double blind
study. Of these, 21 patients had rheumatoid arthritis. The remaining patients had osteoarthritis or
other musculoskeletal conditions. Patients were
given dexamethasone in a total daily dose of
0.75 or 1.5 mgs. as plain steroid, or in combina-
tion with aspirin and aluminum hydroxide in the
same relative amounts of dexamethasone.
Following each 2-week course of therapy, patients were interviewed and examined. The severity of symptoms and physical findings was evaluated relative to the daily dose of dexamethasone, or dexamethasone-aspirin combination, and
was recorded. Statistical analysis of the results
shows the results shows the “steroid sparing”
effect of the dexamethasone-aspirin combination
compared to dexamethasone alone.
INVITROEFFECTOF GOLDON LYSOSOMAL
HYDROLASES
R. S. Ennis, J . L. Granda and A. S. Posner, New York, N. Y.
Recent evidence suggests that an important
mechanism in the pathogenesis of rheumatoid
joint disease is the labilization of lysosomes, with
subsequent digestion and necrosis of joint cartilage.
Persellin and Ziff postulate that the therapeutic
effect of gold compounds in rheumatoid arthritis
may be related to their effect on lysosomal enzymes.
In the present series of experiments, intact lysosoma1 granules were obtained from rabbit liver by
differential ultracentrifugation. Lysosomal stability was measured by incubation at p H 5.0, 37” C
for 40 minutes. The addition of gold compounds
( thiomalate, thioglucose, chloride) did not protect lysosomes from disruption.
Lysosomal acid phosphatase, ,8-glucuronidase
and cathepsin were assayed in aliquots of liver
lysosome fractions and in samples of human
rheumatoid synovial fluid. I t was found that the
gold compounds in concentrations ranging from
0.01-1.0 mg/ml inhibited the three enzymes by
50 per cent, 60 per cent, 50 per cent respectively.
This inhibition is shown to be independent of pH,
precipitation and chelation effects. Sulfhydrylbinding compounds ( iodoacetate, p-chloromercurybenzoic acid, mercuric acetate) are able to
reproduce these inhibitory effects. In addition, it
is shown that the gold inhibition of acid phosphatase and cathepsin can be diminished or reversed
by the addition of a sulfhydryl compound (10
277
ABSTRACTS
mmJL cysteine) to the system.
Michaelis-Menton kinetics were determined for
acid phosphatase and P-glucuronidase, including
inhibition constants of the various gold compounds
and sulfhydryl-binding
agents. Gold com-
pounds and sulfhydryl-binding agents act by a
mechanism of non-competitive inhibition,
Results suggest that one mechanism of action
of gold in rheumatoid joint disease may be its ability to inhibit lysosomal hydrolases.
EFFECTOF ADRENOCORTICOSTEROID
THERAPY
ON THE L-CHAINABNORMALITIES
OF PATIENTS
WITH SYSTEMICLUPUSERYTHEMATOSUS
Wallace V. Epstein and Margaret Tan, San Francisco, Calif.
The concentration of free L-polypeptide chains
of immunoglobulins is strikingly elevated in the
serum and urine of most patients with systemic
lupus erythematosus ( SLE). Present evidence
suggests that L-chain degradation is predominantly through kidney mediated catabolism. In
all forms of renal insufficiency studied (120 patients), serum and urine concentrations of Lchain rise as the creatinine clearance falls. Some
SLE patients without renal insufficiency have Lchain elevations as great as do patients with advanced renal insufficiency. Administration of
adrenocorticosteroids to patients with SLE results in a fall in both serum and urine L-chain
concentrations. 1125-labelled L-chain protein has
been administered t o three patients with SLE
having creatinine clearances over 77 ml/min.
Despite elevations of endogenous L-chain pro-
tein concentration, the time required to reduce
protein bound radioactivity in serum to 5 per
cent of the administered L-chain protein was only
6 hours. In contrast, a patient with SLE and a
creatinine clearance of 44 ml/min required 19
hours to effect the same reduction while patients
with advanced renal insufficiency or anephric individuals require approximately 78 hours. The administration of prednisone to patients in advanced
renal failure fails to accelerate the rate of clearance of labelled exogenous L-chain protein; however, the endogenous light chain level is lowered.
These results suggest that the elevated L-chain
concentration seen in SLE reflects augmented
production of L-chain protein either cle novo or
by gamma globulin breakdown. In either case,
the process appears responsive to adrenocorticosteroid administration.
CHARACTERIZATION
OF A COLLAGENOLYTIC
ENZYME
FROM
CULTURES
OF RHEUMATOID
SYNOVIUM
John M . Evanson, John J . Jeffrey and Stephen M . Krane, Boston, Mass.
Although collagen degradation accompanies the
chronic synovitis of rheumatoid arthritis (RA),
previous attempts to identify enzymatic activity in
extracts of synovial tissue and leukocytes which
can break down native collagen fibrils have been
unsuccessful. In the present study, this problem
was approached by cultivating fragments of
rheumatoid synovium obtained at operation on
gels of reconstituted 14C-glycine labeled collagen,
at neutral pIi, for 3 to 5 days, and measuring
release of soluble radioactivity. Lysis of gels
greater than trypsin controls was observed in
synovial cultures from 8 of 10 subjects with RA.
In positive experiments, explants contained abundant proliferating cells, similar morphologically to
synovial cells, as well as lymphocytes; viable cells
were scanty in cultures in which no collagenolytic activity was detected. Soluble enzyme was
harvested from cultures of synovial tissue in modi-
fied Eagle's medium. This enzyme had maximal
activity at neutral pH (none at p H 5 ) and reduced the viscosity of collagen solutions at 27" C
by approximately 60 per cent. Caseinolytic activity was negligible. Activity was linear with time
and proportional to concentration of enzyme protein and was abolished by prior heating or treatment with EDTA. Reaction products at 27" C
when examined by disc electrophoresis, electron
microscopy and optical rotation showed that at
this temperature the enzyme attacked the collagen
molecule yielding 92 length fragments which retained helical structure. Thus, the reaction products resemble those produced by amphibian collagenase but are distinct from those produced by
clostridial enzyme. Production of this collagenase
by synovium may be important in the tissue
destruction of RA.
278
ABSTRACTS
INTRA-ARTICULAR
RADIOACTIVE
GOLD( 1DRAu) IN THE TREATMENT
OF RHEUMATOID
SYNOVITIS
OF THE KNEE
Paul H. Fine, Paul A, Farrer, Manfred Albrecht and Ralph F. Jacox, Rochester, N. Y.
Surgical synovectomy may be a useful procedure in the treatment of persistent rheumatoid
synovitis of the knee, but surgical removal of
synovium is usually not complete and recurrences
may occur. This technique may also be contraindicated in poor risk patients. The use of colloidal
intra-articular radioactive gold (1QSAu)in the management of chronic synovial effusions has been
reported by Ansell (1963) and Makin (1964).
This study is designed to evaluate the effect of
intra-articular colloidal 198Au on persistent rheumatoid synovitis with effusion of the knee.
A total of 11 knees in 10 patients were treated.
All patients had definite or classical rheumatoid
arthritis with synovitis and effusion of the knee
joint(s), persisting for a minimum of 6 months
prior to treatment and not controlled by usual
measures including systemic steroids in 8 of 1 0
patients. After aspiration of the effusion, 10 millicuries of lQ8Au in 10 cc. volume was injected.
Serial scintillation scans revealed striking localization of radioactive material in both regional and
distant lymph nodes and in the liver. The detectable levels of radioactivity in blood and 24-hour
urine collections were small. The shape and size
of the knee cavity were well defined on 24 hour
joint scans. Additional data regarding joint fluid
changes during the followup period will be presented.
Four of 11 treated knees developed increased
pain and swelling 7 to 12 days after injection.
This rapidly subsided after rest and aspiration.
Eight of 11 treated knees followed for 5 to 24
months have shown improvement in regard to
pain and/or effusion.
PLASMAGROWTHHORMONEAND URINARYHYDROXYPROLINE
IN JUVENILE
RHEUMATOID
ARTHRITIS
Chester W. Fink, Hugo Jasin, Roger Unger and Morris Ziff, Dallas, Tex.
Growth arrest is common in juvenile rheumatoid arthritis. In an attempt to evaluate factors
involved, a group of 13 affected children were
studied. Growth rates were determined by sequential measurements of height, and disease activity assessed by clinical and laboratory evaluation. In addition, total urinary hydroxyproline was
measured as a parameter of growth rate. In most
cases, concomitant determinations of plasma
growth hormone ( G H ) levels using a radioimmunoassay technique were obtained both in the
basal state and during insulin induced hypoglycemia.
Nine of 13 patients were growing actively;
their urinary hydroxyproline levels were those of
actively growing children and their maximum
plasma GH levels were normal when compared
with those of a group of 20 control children. None
were receiving corticosteroids. Four patients were
not growing and the urinary hydroxyproline levels
were correspondingly low in 3.
I n spite of lack of growth, 3 of 4 patients had
normal GH levels. Two were receiving corticosteroid and one not. The failure to grow in the
presence of adequate GH levels suggests a
peripheral interference with growth.
These results indicate that normal plasma
growth hormone levels are found in most patients
with juvenile rheumatoid arthritis whether growing or not. Absence of growth in the presence of
adequate growth hormone levels suggests either
a deficiency of “sulfation factor” or a lack of
responsiveness of the “end-organ” involved in
growth, due either to disease activity, corticosteroid effect, or both.
ISOLATION
OF BEDSONIA
AGENTSFROM PATIENTS
WITH
UNCOMPLICATED
NON-GONOCOCCAL
URETHRITIS
Denys K . Ford, Vancouver, British Columbia
Urethral scrapings were obtained with a Dunlop-Jones curette from 30 patients with uncomplicated non-gonococcal urethritis attending the
Vancouver Venereal Disease Control Clinic.
These scrapings were inoculated into the yolk
sacs of 6- to 8-day-old embryonated eggs, which
were subsequently incubated at 35” C until the
day prior to hatching. The eggs were then opened
and the yolk sacs removed. Smears were made of
the yolk sac material, and these were stained
279
ABSTRACTS
with Gimenez modification of Machiavello’s stain.
In 3 cases, one or more of the inoculated eggs
showed elementary particles suggestive of Bedsonia agents, and on subsequent yolk-sac passages profuse growth of typical Bedsonia agents
was obtained from each case. These agents have
been assumed to be of the Trachoma-Inclusion
Conjunctivitis type ( TRIC agents ).
Employing a psittacosis antigen, complement-
fixing antibody was demonstrable in the serum of
35 per cent of male patients attending the Venereal Disease Clinic and in 30 per cent of patients
with Reiter’s syndrome. Attempts to isolate Bedsonia agents from 10 patients with Reiter’s syndrome have been fruitless up to the present, although in no case were optimal clinical specimens
studied under optimal laboratory conditions.
OF IGM ANTI-IGGFACTOFS
USINGINDIRECT
IMMUNOFLUORESCENCE
DEMONSTRATION
George J. Friou, Mita Ehn, Ronald Hill and Cecilia Gonzales, Los Angeles, Calif.
In vitro inhibition of C‘ fixation by rheumatoid
factor ( R F ) suggests function of RF or other
anti-IgG antibodies in in vivo mechanisms modifying antigen-antibody induced inflammation.
Antibody to autologous IgG altered by reaction
with antigen appears more likely to function in
such a mechanism than classical RF which reacts
with more grossly altered IgG. We have investigated existence of antibody to autologous IgG
bound to antigen using, as a model, immunofluorescent tests for antinuclear antibodies ( ANA),
whole serum, and corresponding IgG and IgM
fractions.
Serums showing apparent IgG and IgM ANA
were fractionated and tested further using 3 step
immunofluorescence, rat liver sections or DNA
or DNP spots, immunoglobulin specific rabbit
serum and goat anti-rabbit conjugate. The studies
(table) indicated anti-IgG activity in 9 of 27
serums, although only 4 of the 9 serums or IgM
fractions yielded positive latex fixation tests.
Conclusions: Results indicate that IgM antiIgG-factors may simulate IgM ANA. Studies of
whole serum IgM ANA, and other IgM anti-tissue
IgM ANA
Anti IgG
apparently IgM ANA
activity
Antigen present ( 1) confirmed ( 2 ) detected ( 3 )
spots:
DNA
7
DNP
8
Liver speckled
antigen 12
2
1
3
3
8
3
( 1) Whole serum positive for IgM ANA
( 2 ) IgM fraction positive
(3) IgM fraction negative alone, but positive
when incubated on antigen, following
IgG.
antibodies, are therefore open to question. Occurrence of classical R F and antibody t o autologous
IgG bound to antigen do not correspond. Study
of this type of anti-IgG, rather than RF, may
provide a useful approach to investigation of the
in vivo role of anti-IgG in modifying complex
induced inflammation.
DECREASED
CONCENTRATION
OF HISTIDINE
IN THE SERUM
OF PATIENTS
WITH
RHEUMATOID
ARTHRITIS-A NEW DIAGNOSTIC
AID
Donald A. Gerber and Marcia G . Gerber, Brooklyn, N. Y.
Measurements have been made of the concentration of the amino acid histidine in the serum
of patients with rheumatoid arthritis and control
subjects by a simple new spectrophotofluorometric
method which depends on the fact that histidine
forms a fluorescent compound with o-phthaldialdehyde. The average concentration of histidine in
serum from 57 patients with rheumatoid arthritis
was 1.28 mg per 100 ml (S.D. = 0.4, S.E. =
0.05). The average concentration of histidine in
the serum from 178 control subjects was 1.82 mg
S.E. = 0.03). The difper 100 ml (S.D. ~0.4,
ference between these 2 groups of patients is
highly significant ( p
10-4). Stated in another
<
way, 71 per cent of the patients with rheumatoid
arthritis, but only 5 per cent of the patients with
other diseases, had a serum histidine concentration of less than 1.42 mg per 100 ml. In the control subjects there was no correlation between the
concentration of histidine in serum and age, sex,
sedimentation rate, or the presence of debilitating or chronic inflammatory disease. In patients
with rheumatoid arthritis and in control subjects
the administration of aspirin was not associatewith a decrease in the concentration of histidine
in serum. No patients were studied who were receiving anti-inflammatory steroids or gold compounds, This study indicates that the concentra-
280
ABSTRACTS
tion of histidine, as measured with o-phthaldialdehyde, is uniquely low in the serum of patients
with rheumatoid arthritis, and is not related to
inflammation per se or the administration of any
drug. It is hoped that this measurement may help
in diagnosing and understanding rheumatoid
arthritis.
ARTHROSCOPY
AS A DIAGNOSTIC
AND RESEARCH
METHODIN
THE
RWEUMATIC DISEASES
Jauier Robles Gil, Mexico City, Mexico
Arthroscopy was performed in 30 patients: 13
with degenerative joint disease, 10 with rheumatoid arthritis, 2 with Jaccoud syndrome, and 5
with gout.
The aim of the study was:
1) To learn more about the anatomo-pathological picture, as well as changes at the different
stages of each disease. 2 ) To compare their
similarities and differences. 3 ) To obtain a selected biopsy of the synovial membrane or cartilage guided by visual observation. 4 ) To study
the macroscopic modification of the joint tissue
lesions after the use of different drugs, as well as
by histopathological studies. 5 ) To try t o elucidate
the beneficial effects of the arthroscopy observed
almost in every instance, through p H and enzymatic studies.
The results, observation and conclusions are
presented in different charts. Several pictures
taken while the arthroscopy was performed illustrate the different subjects above mentioned.
It was concluded that:
1) Arthroscopy can help in the differential diagnosis of some rheumatic diseases. 2 ) In some
cases the arthroscopy can explain the lack of
therapeutic response and even be helpful to
establish better treatment. 3 ) Experimental work
on joint tissue metabolism, as well as on the etiopathogenesis of rheumatic diseases, can be helped
by arthroscopy. 4 ) Effectiveness of anti-inflammatory drugs or other therapeutic procedures can be
evaluated with arthroscopy studies. 5 ) Various
other observations and conclusions were withdrawn.
CLINICALAND LABORATORY
STUDIES
OF HYPOPHYSO-ADRENAL
RESERVE
IN PROLONGED
CORTICOTHERAPY
Jauier Robtes Gil, Mexico City, Mexico
The correct function of the hypophysis and
suprarenal glands is essential to homeostasis. It
has been stated that such function is seriously
disturbed with prolonged corticotherapy.
Two studies were undertaken. The first was designed to discover the incidence of clinical manifestations of adrenal insufficiency in 220 patients
with rheumatoid arthritis ( R A ) , 35 with disseminated lupus erythematosus and 5 with progressive systemic sclerosis treated over more than
2 years with steroids.
The second was an investigation of the hypophyso-suprarenal reserve through the ACTH and
SU-4885 (Metopirone) tests in 20 RA patients
with steroid therapy of 11 to 4?i years’ duration. After knowing the results of this investigation, the daily fractional steroid doses were
changed to a single intermittent dose every 48
hours, for 12 weeks; the previous laboratory
studies were also done in this group, always with
a basal determination of ketogenic-steroid excretion (KCS) in the urine (Norymberski method).
The results showed:
1) 50 per cent of the patients with continuous
steroid treatment for less than 2?1 to 3 years had
abnormally low KCS determinations after ACTH.
2 ) 62.5 per cent of the SU-4885 tests were low
but as before a smaller percentage was observed
after 2%to 3 years ( 2 8 per cent). 3 ) Considering the results of the combination of the two
tests as the hypophyso-adrenal reserve, 75 per
cent were negative in the patients with less than
3 years duration of therapy and only 28 per cent
after. 4) The results of the tests after the intermittent treatment showed better hypophyso-adrenal function. The average KCS determination
was 3.90 mg to 5.48 mg in the previous group.
5 ) The clinical incidence of hypophyso-adrenal
dysfunction was rather low. The various manifeatations are shown in different charts.
All the results are described in detail and illustrated, with slides. Some conclu4ions are withdrawn.
281
ABSTRACTS
MEASUREMENT
OF yG GLOBULIN
ON COMPLEMENT
COATEDREDCELLS
Bruce C . cilliland, John P. Leddy and John H . Vaughan, Rochester, N. Y.
RBC showing positive agglutination reactions
with anti-complement sera and negative reactions
with anti-y globulin sera have often been described
in patients with connective tissue disorders, idiopathic acquired hemolytic disease or lymphomas.
This has promoted the concept that there may be
processes that lead to the attachment of complement components to the red cell surface without
the participation of antibody protein. Alternatively,
very small amounts of complement-hing antibodies may be involved.
To investigate this further, a more sensitive
method for the detection and quantification of
yG globulin on the RBC was developed. Combining quantitative complement fixation with the
antiglobulin consumption technique has made possible the detection of as few as 50 molecules of yG
globulin per RBC, as evidenced by analysis with
measured quantities of yG anti-A isoantibodies.
This level of detection represents at least a 10fold increase in sensitivity over the direct antiglobulin test.
Using this method, the complement-coated
RBC's of 6 patients showing negative antiglobulin agglutination reactions with a potent anti-yG
serum were investigated. In 4 patients, the quantities of yG globulin found were 75 to 200 or
more molecules per cell. The other 2 patients, like
normals, had RBC's with less than 35 molecules
of yG per red cell.
The increased quantity of yG globulin on the
RBC's of 4 patients may represent complementfixing antibody. This possibility needs to be tested
by attempts to recover specific antibody in concentrated eluates of such cells. The possibility
that some complement-coated RBC's have present
small quantities of yM antibody also merits investigation.
OF
UNILATERAL
OSTEOARTHRITIS
THE
HIP
J. P. Gofton, Vancouver, British Columbia
Degenerative disease of the hip may be primary (idiopathic) or secondary to some predisposing cause. About N of idiopathic cases are, and
remain, unilateral. No current hypothesis satisfactorily explains this condition. It is self-evident
that a worn hip foreshortens the affected leg. I t is
usually stated that the leg on the side affected is
shorter than the contra-lateral one for this reason.
Clinical observations of idiopathic unilateral osteoarthritis of the hip suggest that this is not always so.
A series of cases has been measured for true
leg length by an x-ray method with the patient
standing. Unilateral osteoarthritis of a specific type
( superolateral) has a striking correlation with a
long leg on the affected side; this is more impressive if allowance is made for some loss of leg
length through degeneration and deformity of the
hip joint on that side.
Evidence will be presented upon which the
following conclusions are based: 1 ) A significant
number of cases of unilateral osteoarthritis of the
hip, otherwise idiopathic, are associated with and
presumably provoked by weight-bearing on a long
leg. The greatly increased stress on the hip due to
the mechanical disadvantage of this mild deformity will be discussed. 2 ) Degenerative osteoarthritis of the hip so produced differs in its pattern
of onset and progression from other cases of degenerative hip disease. 3 ) The success or failure
of osteotomy procedures should be reassessed with
these foregoing considerations in mind. A rationale for the surgical procedure might be related to simple shortening of the affected leg, in
some cases. 4) Theoretically, at least, this form of
unilateral idiopathic osteoarthritis of the hip is
preventable.
INCREASED
LYSOSOMES
IN RHEUMATOID
SYNOVUL
CELLSIN TISSUE
CULTURE
Sidney Goldftscher, Carol Smith and David Hamerman, New York, N. Y.
Earlier cytochemical studies of normal and
rheumatoid synovial membranes showed markedly
increased acid phosphatase activity in the lining
cells of the rheumatoid membranes. Acid phosphatase activity, visualized in cytoplasmic granules, serves as a marker for lysosomes. The possi-
bility was investigated that rheumatoid synovial
cells maintain in culture the increased lysosomal
enzyme activity they show in tissue sections. Cells
from normal and rheumatoid synovial membranes
were grown in nutrient medium with 10 per cent
calf serum added, on cover slips in disposable
282
ABSTRACTS
plastic petri dishes at 37” C in an atmosphere of
1 0 per cent CO,. Cells from 3 normal and 4
rheumatoid cultures were compared. Both normal
and rheumatoid cells were studied as early as the
second subculture, and as late as the seventh,
after 5 months in continuous culture. The cells
were washed in normal saline, fixed for 3 minutes
in cold 2.5 per cent gluteraldehyde, and rinsed
in distilled water. Acid phosphatase activity was
visualized with Gomori’s lead medium, or Barka
and Anderson’s azo-dye medium. Activity of another lysosomal enzyme, glucosaminidase, was visualized by Hayashi’s method. Rheumatoid cells
from 4 different membranes displayed much more
activity of these lysosomal hydrolases than cells
from 3 normal membranes, and could readily be
distinguished from the normal by this increased
staining. Why increased lysosomal enzyme activity persists in the rheumatoid synovial cells
through prolonged subculture is not known. In
the rheumatoid synovial membrane enhanced
phagocytosis of products from joint fluid was
thought to explain the findings of large numbers
of lysosomes of the residual body type. In tissue
culture, the phagocytic capacity of the synovial
cells appears quite limited, as judged by the failure of the normal and rheumatoid cells to take up
from the medium the heme protein horse radish
peroxidase. The elevated levels of lysosomal enzyme activities in the rheumatoid cells may possibly be due to the increased breakdown of intracellular constituents ( autophagic activity).
OF THE KNEEWITH GOUTAND RHEUMATOID
ARTHRITIS
CHONDROCALCINOSIS
Armin E . Good and Robert Rapp, Ann Arbor, Mich.
A recent uncontrolled study reported radiographic evidence of meniscal calcification in 10 of
31 patients with gout (New Eng. J. Med. 275:
754, 1966). Although the calcium deposits were
not noted to be as heavy as those reported in
cases of pseudogout, this study has cast some
doubt upon the value of this sign in the differentiation between gout and pseudogout.
Using a “blind’ technique, we examined for
the presence of soft tissue calcification knee films
of 43 patients with proven gout intermingled
with a control series of films from 38 patients
with classical rheumatoid arthritis.
Five cases were found with definite, extensive
calcification of menisci, 2 from the gout series and
3 from the rheumatoid. In addition, 2 gout and
one rheumatoid case were found with faint, focal,
meniscal calcification.
The prevalences of definite chondrocalcinosis
in the gout series (5 per cent) and the rheumatoid ( 8 per cent) are nearly the same as those
reported elsewhere among unselected nursing
home inmates and from a large cadaver population. We could not confirm an increased association of gout with either definite or faint chondrocalcinosis.
THE PHARMACOLOGY
OF MYOCHRYSINE
( SODIUMAUROTHIOMALATE
) INJECTED
BY THE INTRA-ARTICULAR
ROUTEIN PATIENTSWITH RHEUMATOID
ARTHRITIS
Norman L. Gottlieb and Edward M . Smith, Miami, Fla.
Based on the work of Lewis and Ziff (Arthritis
Hheum. Y:682, 1966), we have instituted a longterm prospective study to investigate the pharmacology and efficacy of intra-articular injections of
hlyochrysine. This material has been labeled with
radioactive gold-195 and combined with the nonradioactive pharmaceutical substance. The labeled
material has been shown to behave biologically in
the same manner as the nonradioactive drug.
Subacutely inflamed knees of patients with classical rhcumatoid arthritis (as defined by ARA
criteria) were injected with a single 50 mg. dose
o f labeled Myochrysinc (25 mg. of gold). These
patients had not received any form of gold therapy
in the past, a n d the only anti-inflammatory medication they were receiving was salicylates. Thc
contralateral knees were used as controls. The
rate of disappearance of the radionuclide from the
knees and concurrent rate of appearance in snmples of blood, urine, and synovial fluid were determined. In addition, kidneys and other joints and
organs were monitored for their level of radioactivity. Also the spatial distribution of the radioactive gold in the region of the knee at various
intervals of time was evaluated using a multicrystal rectilinear scanner. The rate of disappearance of gold from the knee joint was represented
by a curve with at least three components; 50 to
70 per cent disappeared with a half-time of less
than 4 hours, 15 to 25 per cent with a half-time of
approximatcly 1 day and the remaining with a
half-time of greater than 20 days. Soon after injection, thc radioactive gold could be measured in
the blood, and reached a maximum at 4 to 6
283
ABSTRACTS
hours. The disappearance curve consisted of one
component with a half-time of between one and
two days comprising 30 per cent of the maximum
activity and the remaining disappeared with an
8- to 10-day half-time. The kidneys contained
between 10 and 20 per cent of the injected activity, which was slowly eliminated. The major route
of excretion appears to be urinary. Synovial fluid
aspirated from the injected joint contained radioactive gold. When the fluid was allowed to clot,
no significant amount of activity was detected in
the clot. No significant amounts of gold could be
detected in the organs or joints.
OF SEPTICARTHRITIS
CALFCYSTABSCESS-AN UNRECOGNIZED
COMPLICATION
Anthony P . Hall and L. A . Healey, Seattle, Wash.
The causes of calf swelling in patients with
rheumatoid arthritis have been delineated by Hall
and Scott (Ann. Rheum. Dis. 25:32, 1966).
Hench described dissecting popliteal cyst simulating thrombophlebitis at this meeting in June,
1966.
We have seen 4 patients with infection in a
synovial cyst of the calf as a complication of
septic arthritis of the adjacent knee. Two of these
patients had rheumatoid arthritis and 2 had diabetes mellitus. In all 4, the painful swollen calf
was initially interpreted as thrombophlebitis.
In one patient, the abscess was demonstrated by
needle aspiration of the calf swelling and positive
contrast arthrography outlined a large cyst communicating with the knee joint. This patient also
had a huge infected cyst of the upper arm which
was shown by arthrography to connect with the
olecranon bursa.
One of the 4 patients had an infection due to
an unusual organism, Serratia marcescens, that did
not respond to antibiotics. The calf cyst abscess
was not detected until his leg had been amputated above the infected knee.
In all of these patients, fever and other signs of
infection were not controlled until the infected
cyst was recognized and drained.
ABNORMAL RENALFUNCTION
IN RHEUMATOID
ARTHRITIS
L. A. Healey and Roger 1. Bulger, Seattle, Wash.
Renal function tests were performed in 42 ambulatory patients with definite rheumatoid arthritis. None of the patients had diabetes mellitus
or systemic lupus erythematosus.
Abnormalities were found in 22 patients. Sixteen of them had a 24-hour creatinine clearance
of less than 80 cc/min. Inability to concentrate
the urine after a 12-hour fast (specific gravity
<1.018) was present in 19. Two patients had
red cell casts and 11 had granular and white cell
casts. Only 2 had proteinuria and none showed
nitrogen retention.
Eleven patients were diagnosed as interstitial
nephritis, 2 as glomerulonephritis, and 9 were
unclassificd. No evidence of infection, amyloidosis
or papillary necrosis was present.
The 22 patients with abnormal tests did not
differ from the 20 patients with normal function
as to age, sex, duration or severity of arthritis,
presence of rheumatoid factor or the type of medication. Only 2 patients, both with normal tests, had
taken any phenacetin. All had taken aspirin. The
estimated total aspirin intake was greater in the
patients with abnormal tests, 93 vs. 66 tablet/
years (p<0.05).
In this study, abnormal renal function tests
were found in 22 of 42 patients with definite
rheumatoid arthritis. An association with prolonged
aspirin intake is suggested but not proven.
THE ALTERATIONOF SERUMALBUMINn Y ACETYLSALICYLIC
ACID
P . Kahler Hench and Richard 5’. Farr, La Jolla, Calif.
Previous studies employing equilibrium dialysis
and anion exchange chromatography have demonstrated that sera from patients with rheumatoid
arthritis (RA) have a greater affinity for low
concentrations of 1131-labeled sodium acetrizoate
than do normal sera. The factor responsible for
increased acetrizoate binding has been char-
acterized as an altered albumin. Although no correlation exists between acetrizoate binding and
salicylate levels in randomly selected sera from
patients with RA, it has been found that albumin
from normal individuals binds significantly more
acetrizoate following: 1) the ingestion of 2.4
grams of acetylsalicylic acid ( A S A ) per day for
284
ABSTRACTS
21 days; or 2 ) dialysis against ASA in vitro.
Albumin thus altered by ASA does not revert to
normal after dialysis against saline. Many other
medications tested, including sodium salicylate,
do not enhance acetrizoate binding.
To learn if all in vivo increases in acetrizoate
binding are due to the ingestion of ASA, 13
patients with RA taking 3 to 5 grams of ASA per
day were changed to an equivalent dose of sodium
salicylate. The acetrizoate binding fell significantly
in 11 and remained unchanged in 2. Serial deter-
minations in 4 patients indicate that the half-life
of the albumin responsible for increased acetrizoate binding is 15-22 days. The observation that
the acetrizoate binding did not decrease in 2
patients after changing from ASA to sodium
salicylate suggests the possibility that a metabolite
associated with RA may structurally alter albumin
in a manner similar to ASA. It remains to be
learned whether alteration of albumin during
treatment with ASA is beneficial or detrimental to
the patient.
TREATMENT
OF ALKAPTONURIA
AND OCHRONOTIC
ARTHRITIS
WITH A Low PHENYLALANINE-LOW
TYROSINE
DIET
Donald E. Holdsworth, Margaret L. Barry and Judith L. Swyter, Boston, Mass.
Alkaptonuria is a rare metabolic error which
results in the disease ochronosis. Previous attempts at treating this disease by limiting protein
intake have been unsuccessful.
This paper reports the successful application of
a low phenylalanine-low
tyrosine diet to a
brother and sister afflicted with alkaptonuria and
ochronotic arthritis.
The basic diet was a low phenylalanine-low
tyrosine food powder based on a specially processed enzymatic hydrolysate of casein. Except for
phenylalanine and tyrosine the food powder was
nutritionally adequate. The formula was supplemented with selected foods low in phenylalanine
to add variety and provide bulk. The final composition diet was 1700 calories, 227 gms. carbohydrate, 65 gms. fat and 56 gms. protein. The
formula supplied 8 per cent of the protein and
75 per cent of the calories. The total phenylala-
nine content was 772 mgs.
In both patients there has been clinical improvement characterized by decrease in joint pain
and stiffness. In one patient, recurrent joint effusions are no longer apparent and distressful
bouts of atrial fibrillation are now a rarity.
Twenty-four hour urinary excretion of homogentisic acid in the 2 patients has been lowered
from pre-treatment levels of 1540 mgs. to 700
mgs. and from 2000 mgs. to 850 mgs. respectively.
Observation over a 9- and 18-month period has
revealed maintenance of normal nutrititon and
continued improvement in their arthritic status.
Case summaries and metabolic data will be
presented.
I t is believed that this may be the first report
of a diet which can be of benefit to patients
afflicted with this disease.
RATEOF DNA SYNTHESIS
BY BLoon MONONUCLEAR
CELLSIN INFLAMMATORY
DISEASE
D. A. Horwitz, P. Stastny and M . Z i f f , Dallas, Tex.
Since mononuclear cells of the blood are known
to incorporate tritiated thymidine (H3Tdr)
actively in tissue culture under certain conditions, experiments were carried out to examine
the rate of such incorporation in human buffy
coat cells of patients with inflammatory disease.
Ten million washed buffy coat leukocytes
were cultured for 5 hours in minimal essential
medium containing 15 per cent human serum
and 1 pc/ml. tritiated thymidine. The radioactivity incorporated was determined by scintillation counting and the results expressed as counts
per total mononuclear cells in the sample (100
x C.P.M./per cent mononuclear cells). The mean
H3Tdr uptake of 11 healthy volunteers was 51
( 15-72). Four patients with miscellaneous non-
inflammatory disease (aseptic necrosis of the hip,
arteriosclerotic heart disease, cerebrovascular disease and hyperthyroidism) had a mean uptake
of 66 (20-88).
The mean H3Tdr incorporation of 15 patients
with systemic lupus erythematosus was 445 (681580). In 2 patients with acute rheumatic fever,
uptakes were 99 and 116 respectively; one patient with mixed collagen disease had a value of
465. The mean uptake of 5 patients with hepatitis
was 232 (73-372) and 4 patients with tuberculosis, 186 ( 1 0 0 3 7 0 ) .
When the buffy coat cells of 4 patients with
inflammatory disease (SLE 2; exfoliative dermatitis, l; and acute rheumatoid arthritis, l ) were
cultured on admission, mean H3Tdr uptake was
ABSTRACTS
880 (408-1415).With the onset of clinical improvement, this decreased to 270 C.P.M. (44575).
There was no correlation of H3Tdr incorporation
with the erythrocyte sedimentation rate or the
levels of total globulin, a2 globulin, or y globulin
when these were measured at the same time.
These preliminary findings of
increased
DNA synthesis by blood mononuclear cells in inALTERATIONS
flammatory states are of interest in view of a
previous observation that a large fraction of
mononuclear cells which localize in inflammatory sites are of hematogenous origin and
have recently synthesized DNA.
Studies are in progress to determine whether
the technique described may serve as an index
of inflammatory activity in disease.
COMPOSITION
OF GROWTH CARTILAGE
SEPTA DURINGCALCIFICATION
BY MICROSCOPIC
X-RAY ELEMENTAL
ANALYSIS-IN
STUDIED
CORRELATIONWITH BIOCHEMICALSTUDIES
IN THE
D. S . Howell, L. Carlson and E . Deldiamps, Miami, Fla. and Stockholm, Sweden
Distribution of total mass, S and P measured by
x-ray elemental analysis in microscopic sites at the
zone of provisional calcification and adjacent to
uncalcified cartilage septa permitted a quantitative estimation of changes in sulfated glycosaminoglycans, as well as organic and mineral
phases. Onset of calcification within the cartilage
septa was identified by a sharp increase in concentration of P and total mass per unit area of
histologic sections in measurements progressing
from the proliferating cell zone to the metaphysis.
P concentration was 2 to 3 per cent within
proliferating and hypertrophic cartilage cells and
4 to 5 per cent at proliferating cell margins with
elevated total dry mass. Despite negative Von
Kossa stains in this zone, the findings are strongly
suggestive of a mineral phase. The concentration
of P was 1.7 per cent in hypertrophic cell septa,
and 0.4 per cent in the central regions of the
proliferating cell septa. Results of biochemical
study of phosphate, partitioned in these tissues,
as well as a comprehensive electrolyte profile
measured on similar cartilages previously were
entirely consistent with the current x-ray elemental analysis.
There was a slight decrease of S and a larger
decrease of organic per-unit area of intact histologic section in progression of measurements
from uncalcified to calcified cartilage septa1
matrix. The abrupt changes in the organic composition at the boundary of the calcification front
at the margins of proliferating cells are believed
to be related to biochemical steps in calcification.
A working hypothesis concerning biochemical
pathways of endochondral calcification will be
presented and their close relationship to similar
processes in remodeling of articular cartilage explained.
TRANSIENT
UNILATERAL
OSTEOPOROSIS
OF
THE
HIP: A CLINICALSYNDROME?
Gene G. Hunder and Patrick I. Kelly, Rochester, Minn.
Existence of a relatively unrecognized clinical
syndrome is suggested by the association, in 8
patients, of 1) osteoporosis involving only one hip,
2 ) pain during weight bearing, 3 ) absence of apparent local or systemic cause, and 4) recovery
after a period of bed rest. In 6 men and 2 women,
ages 35 to 52, pain developed in one hip and
persisted 2 to 6 months. Pain was most noticeable
during or after weight bearing. Limitation of
motion of the affected hip was the only pertinent
physical finding.
Roentgenograms of all painful hips showed
marked osteoporosis of the femoral head and often
the femoral neck and acetabular bones. Joint
space and contour of the femoral head remained
normal. Half the patients had increased erythrocyte sedimentation rates. Other laboratory results were normal. Arthrotomy was done in all
cases. Grossly, joint capsules were thickened or
synovia were injected in 5 of 8 cases, but
microscopically the synovial membrane appeared
normal or showed only minimal chronic inflammation in all cases. Bone biopsies obtained in 4
cases showed necrosis, resorption, and new hone
formation. Cultures of synovial tissue and fluid
were negative.
Functional recovery of the hip and disappearance of pain were complete in all cases after
convalescence following arthrotomy ( 2 to 12 year
follow-up ) . Osseous recalcification occurred in all
7 cases with available follow-up roentgenograms.
Similar episodes of osteoporosis later developed in
one patient’s shoulder and another patient’s foot.
Recognition and study of more cases of this
syndrome may amplify and explain these unusual
findings.
286
ABSTRACTS
RENAL INVOLVEMENT
IN SYSTEMICLUPUS ERYTHEMATOSUS:
CLINICALAND BIOPSYFINDINGS
Eric R. Hurd, Stanley W. Strunk and Morris Zifl, Dallas, Tex.
Of 37 patients with systemic lupus erythematosus (SLE ), 24 (64 per cent) initially demonstrated clinical evidence of renal disease. Of the
13 patients with negative findings, 7 continued
negative for an average of 5.9 years (3.0-10).
However, 6 ( 1 6 per cent of the overall group)
developed clinical renal disease after an average
of 2.2 years (0.8 to 3.8). This late development
of renal disease is significant in view of previous
reports that nephritis in SLE, if not present at
onset, is not likely to develop later.
When clinical data and renal biopsy at onset
of SLE were correlated, 11 of 14 patients with
positive clinical findings showed definite histologic
abnormalities and 3 showed minimal changes: i.e.,
none was normal. In 8 patients with negative
clinical findings, the biopsy was normal in 6 and
showed minimal glomerular changes in 2.
Electron microscopic examination of biopsies
taken at onset in all of 10 patients with positive
clinical findings and 7 of 8 with negative clinical
findings showed electron-dense deposits in the
glomerulus. I n the same group, 10 of 10 biopsies
with positive histology and 4 of 6 with negative
histology also showed electron dense deposits.
Serologic studies were performed. In view of
the suggestion that rheumatoid factor protects
against nephritis in SLE, it is of interest that
latex fixation tests were negative in all 6 patients
with persistently negative renal findings.
The results described demonstrate 1) the uniform presence of histologic abnormalities in patients with clinical renal disease; 2 ) absence of
histologic changes but presence of ultrastructural
abnormality in most patients with negative clinical
findings; and 3 ) an impressive correlation between
the results of clinical and histologic evidence of
nephritis.
SYNOVIAL
LININGCELLSYNTHESIS
OF A SUBSTANCE
IMMUNOLOGICALLY
RELATEDTO CARTILAGE
PROTEINPOLYSACCHARIDE
Rosamond Janis, John Sandson, Carol Smith and David Hanzerman, New York, N. Y.
The proteinpolysaccharides (PP ) of cartilage
matrix have at least two antigenic determinants.
One is shared by PP from human, pig, and bovine
cartilages, and has been called the common site.
The other determinant is found only in cartilage
PP from the particular species, and is called the
species-specific site. When rabbits are immunized
with human cartilage PP, the antiserum obtained
forms 2 lines on agar diffusion against human
cartilage PP, indicating reactions with both the
specific and common site. If the antiserum is absorbed with bovine cartilage PP and tested against
human cartilage PP, only a single precipitin
line is observed, for the antiserum now reacts only
with the species-specific site. Synovial fluids contain a component immunologically identical with
the species-specific site of cartilage. This component is present in normal and many pathological
fluids, but is diminished in chronic rheumatoid
effusions. It can be separated from hyaluronate
by zone electrophoresis and migrates in the ,8
globulin zone. An immunofluorescent study of
human synovial membrane sections was performed using the specific antiserum and a fluorescein-labeled goat anti-rabbit globulin. Bright
fluorescence, indicating a component reactive with
antiserum to the species-specific site, was localized
in the lining cells of the normal synovial membrane, but staining was diminished in rheumatoid
membrane lining cells. To exclude the possibility
that the lining cells merely phagocytize the
species-specific component from the joint fluid,
the same immunofluorescent study was carried out
with synovial cells in tissue culture. These cells,
too, showed bright fluorescence. Furthermore, the
species-specific component was identified in the
culture medium by agar diffusion studies. Thus,
the synovial membrane lining cells secrete a substance immunologically identical to the speciesspecific site of cartilage PP, and for reasons not
yet understood, this function is diminished in
rheumatoid arthritis.
THE CARDIOVASCULAR
AND PLASMA
CORTISOL
RESPONSE
TO SYNOVECTOMY
OF THE KNEE IN CORTICOSTEROID-TREATED
RHEUMATOID
PATIENTS
M . K . Jasani, P. A. Freeman, J . A. Boyle, M . J . Diver, A. I . M . Reid
and W . W . Buchanun, Glasgow, Scotland
Understanding of the prevalence and site of
involvement of the hypothalamo-pituitary-adre-
nal (HPA) axis in patients with rheumatoid iirthritis receiving oral corticosteroid drugs has
287
ABSTRACTS
increased recently with the availability of several
methods of testing the functional integrity of this
axis, such as the Synacthen (tetraicosapeptide
P I - 2 4 ) , lysines-vasopressin, insulin-induced hypoglycemia, and metyrapone tests.
The purpose of the study was to determine the
effect of surgical stress in corticosteroid-treated
rheumatoid patients on their plasma cortisol and
cardiovascular responses, and to correlate these
responses with the results of tests of the HPA
axis.
Measurements of plasma cortisol, pulse rate,
and blood pressure were carried out before,
during, and after anterior synovectomy of the
knee in 40 rheumatoid patients, 20 of whom were
receiving long-term oral corticosteroid therapy;
the remainder, who had never received corticosteroid therapy, served as controls. The anaesthetic
procedure and the operation time was the same in
both groups: the synovectomies were performed
by one surgeon. The corticosteroid-treated patients
received their last dose of corticosteroid 18 hours
before operation, and therapy was resumed 6
hours after operation.
The results show that as a group the corticosteroid-treated patients had significantly poorer
plasma cortisol responses, and had slightly lower
blood pressure responses. Ten of the corticosteroid-treated patients with definite adrenal suppression as tested by Synacthen had plasma
responses which lay below the lower limit of the
95 per cent confidence limits of the plasma cortisol
responses in the control patients; and one developed hypotension which required treatment with
intravenous hydrocortisone. The remaining 10
corticosteroid-treated patients with normal Synacthen tests, and with either normal or abnormal
lysines-vasopressin, insulin hypoglycemia and
metyrapone tests, were found to have normal
plasma cortisol responses to surgery.
The practical and theoretical implications of
these studies will be discussed.
SJOGHEN’S
SYNDROME,
MONOCLONAL
MACHOGLOBULINEMIA
AND ACCELERATED
IGG CATABOLISM
John S. Johnson, Thomas A. Waldmann and Norman Talal, Bethesda, Md.
Reports from this institute have described the
development of malignant lymphoma and pseudolymphoma in certain patients with Sjogren’s syndrome. Patients with pseudolymphoma have
unusual extraparotid lymphoproliferative infiltrates
and, frequently, elevated serum IgM concentrations.
A patient is reported with Sjogren’s syndrome,
pulmonary lymphocytic-plasmacytic infiltrates,
cryogelglobulinemia, elevated serum IgM, reduced total hemolytic complement (C’H,,) and a
clinical course characterized by repeated infections. Her “cryogelglobulin” consists of 18s IgM
and 7s IgG. The isolated IgM component was
shown to possess light polypeptide chains of a
single antigenic type ( K ) and to be highly
homogenous by other techniques. Specificity of
the isolated IgM for IgG was demonstrated, as
well as its failure to interact with IgA and other
non-immunoglobulin serum proteins.
This IgM thus behaves like a “monoclonal”
Waldenstrom-type macroglobulin with rheumatoid factor specificity. Serum protein metabolic
studies revealed a normal survival of IgM, IgA
and albumin, but a markedly reduced survival of
IgG. It is suggested that the catabolism of IgG
complexed with IgM is a significant factor in the
reduced serum IgG concentration.
AVASCULAR
NECROSISOF BONEIN ALCOHOLISM
John Paul Jones, Jr. and Ephraim P. Engleman, San Francisco, Calif.
Osseous avascular necrosis was discovered in 25
patients with alcoholism. Avascular necrosis was
diagnosed roentgenographically in all cases and
confirmed histologically in 16 patients. The triad
of alcoholism, fat embolism and avascular necrosis
may represent a new syndrome, since in no instance was there major antecedent trauma or
known systemic condition( s ) associated with nontraumatic avascular necrosis. Necrosis was found
in 37 femoral heads and in 6 humeral heads.
Earliest roentgen abnormalities appeared within
12 months after joint pain and stiffness were reported. Metadiaphyseal lesions were generally
asymptomatic and appeared in the distal femur
( 6 ) and proximal tibia (8).
We have previously shown experimentally that
fat emboli occlude terminal intraosseous capillaries with resultant micro-infarctions. Several
patients experienced unexplained pneumonitis,
hypertension and hypertriglyceridemia. Of 15 patients studied, probable systemic fat embolism
was established by detecting lipuria in 7, of whom
288
ABSTRACTS
2 had intravascular fat within resected femoral
heads.
The alcohol-induced fatty liver is probably the
commonest source of continuous or intermittent
low-grade showers of systemic fat emboli. Twenty
patients showed significant hepatomegaly and
bromsulphalein retention. Five of 7 livers demonstrated fatty metamorphosis histologically. One
patient with a biopsy-proven fatty liver, hypertriglyceridemia and lipuria spontaneously devel-
oped unilateral groin pain and the earliest
tomographic manifestations of necrosis. Intraosseous phlebography and intramedullary manometry suggested avascularity, and biopsy revealed
avascular necrosis of the femoral head. Another
patient with alcoholism, who had prior metadiaphyseal bone infarctions, suddenly expired. Autopsy demonstrated marked hepatic steatosis, fat
embolism and early avascular necrosis of a femoral
head.
UNEXPECTED
RADIOGRAPHIC
CHANGES
OF THE HIP JOINTFOLLOWING
LUMBARSYMPATHECTOMY
FOR ARTHRITIS
W . H . Kammerer and T . I . Hoen, New York, N. Y.
Since 1927 sporadic reports have appeared in
the medical literature regarding the beneficial
effects of lumbar sympathectomy in the relief of
pain of arthritis of the weight-bearing joints. From
1960 to the present 16 patients with severe painful
arthritis of the lower extremities have had lumbar
sympathectomy at The Hospital for Special Surgery. All were women ranging in age from 25 to
80 years. Nine had rheumatoid arthritis, 7 had
degenerative joint disease. Fourteen remain under
observation or have been contacted. Hip joint
pain was relieved completely or almost so in 6
patients, in 6 there was no benefit, in 2 the immediate result was excellent but they have been
lost to observation, and in 2 the immediate result
has been excellent but follow-up is less than 6
months.
In 1966 a patient with classical rheumatoid
arthritis was admitted to hospital for a synovectomy of the elbow. She had had a right lumbar
sympathectomy in 1962 for severe right hip pain
which resulted in relief of pain and increased
functional ability in this joint. An x-ray of the
pelvis, done at the time of the second admission,
revealed a startling improvement in the radiographic appearance of the right hip consisting of
remolding of the joint, improvement in the texture
of the bone and increase in joint space. Following
this unexpected finding, x-rays of other patients
who had had successful outcome of sympathectomy were obtained and these will be presented.
THEINHIBITION
OF ADJUVANT
ARTHRITISBY STATOLON
M . A. Kapusta and J. Mendelson, Montreal, Canada
An immunological basis for adjuvant induced
arthritis is commonly accepted, although the role
of viral and/or Bedsonia organisms as etiological
agents in this model has not been excluded.
Statolon is a broad spectrum antiviral-antibedsonia agent which probably acts through the mediation of interferon produced in the recipient
animal. In the present study an attempt has been
made to alter the course of adjuvant arthritis with
statolon to provide insight into pathogenetic mechanisms in this experimental model of arthritis.
Sprague Dawley and Charles River strains of
rat were used in all studies. Arthritis-producing
doses of modified Freund’s adjuvant ( M . F . A . )
were administered to 4 groups of rats and their
clinical course followed. Statolon was given intraperitoneally in 10 mgm. doses.
1 ) Controls-no
statolon. 2 ) One injection of
statolon 24 hours prior to the administration of
M.F.A. 3) Pre M.F.A. statolon plus a second dose
one week later. 4) Pre M.F.A. statolon plus 2
further doses one week apart.
The severity of arthritis was graded in all rats,
21 days post-induction, on an arbitrary scale of
1 to 20 by “third party” observers. The average
scale results were: Group 1, 15.3, Group 2, 16.9,
Group 3, 11.7, and Group 4, 1.7. Group 4 did not
develop increased acute joint involvement or deformities for 2 months following the last dose of
statolon. Gross and histological comparisons will
be presented.
These results indicate the protective effect of
statolon on adjuvant arthritis, and suggest a possible role for a true virus or Bedsonia group of
organism in the pathogenesis of this experimental
disease, and indirectly a possible role of interferon
in its modification.
289
ABSTRACTS
LONG-TERM
CAREOF
THE
ARTHRITIC
lrving Karten, A. Oscar Koatz and Currier McEwen, New York, N. Y.
Rehabilitation of the patient with advanced
rheumatoid arthritis is exceptionally difficult because of the severe mechanical limitation produced
by joint deformities and the uncertain course of
the disease activity. Pain and limited tolerance
for exercise further contribute to an unpredictable
prognosis. Rehabilitation becomes a life-long process in which goals are determined by a changing
disease. Early cases may respond well to treatment in outpatient centers or in acute hospitals,
but the severely deformed patient is exhausted by
the time he dresses and travels to a clinic, and
when hospitalized he needs long-term care at a
tempo that will permit optimum rehabilitation.
Nursing homes, chronic care institutions and other
extended-care facilities would be suitable for the
arthritic if properly staffed and if the atmosphere
of custodial care could be replaced by one of
active treatment with patients in whom some improvement could reasonably be expected.
In the past 2% years we have organized a pro-
gram for older arthritics with longstanding disease
on a 30-bed ward of a chronic care hospital.
Fifty-eight patients with rheumatoid arthritis have
completed treatment, lasting a mean of 3%
months and consisting of medical supervision as
well as occupational and physical therapy provided on the ward. As a group the patients showed
advanced deformities and could perform few of
the activities of self care or were restricted to a
wheelchair.
Functional improvement on an Activities of
Daily Living scale was obtained in approximately
half of the most severely disabled patients. Seventeen of 31 wheelchair patients accomplished at
least partial ambulation. Of the 58 patients, 3 died
while under treatment and 6 died during the
follow-up period extending from 2 months to 2
years. Rehospitalization was required for 7 additional patients, and 6 additional patients eventually required custodial care.
THEARTHRITISOF ABORTIVESARCOLDOSIS
Warren A. Katz, Hubert I . Caplan and Mayer Rubinstein, Philadelphia, Pa. and Boston, Mass.
The syndrome of bilateral hilar adenopathy,
erythema nodosum, and polyarthritis is well established. Although the etiology is uncertain,
evidence has accumulated indicating that this disorder is probably a hypersensitivity reaction presenting as an abortive form of sarcoidosis. The
presence of the characteristic nodose lesions in a
young adult with joint disease strongly suggests
the diagnosis, while the finding of hilar adenopathy on chest x-ray confirms it.
I t is the purpose of this report to discuss a
similar group of 19 patients who presented primarily with articular manifestations, The key
feature of erythema nodosum, however, was absent. An incorrect initial diagnosis, therefore, resulted in almost every case. Subsequent chest
x-ray in all patients and biopsy material in 80 per
cent confirmed the existence of sarcoidosis.
Clinically the patients formed a fairly homog-
enous group with regard to age, onset of symptoms, generalized manifestations, and polyarthritis.
The ankle, the most commonly involved joint,
usually presented with characteristic clues pointing to the correct diagnosis. These included
marked periarticular inflammation with striking
tenderness despite the absence of pain on motion.
The erythrocyte sedimentation rates and serum
globulins were usually elevated, but the antistreptolysin titers were normal. The disease ran
its course in several months, and almost all patients were asymptomatic and free of hilar
adenopathy within one year.
Because of the tendency of this syndrome to
mimic other rheumatic diseases, particularly acute
rheumatic fever and rheumatoid arthritis, and because of its favorable prognosis, early diagnosis
and conservative therapy are important.
URINARYACID MUCOPOLYSACCHARIDES
AS A MEASURE
OF ACTIVITYIN RHEUMATOID
ARTHRITIS
Ronald L . Kaye, L. Emmerson Ward and John V . Roseoear,
Palo Alto, Calif. and Rochester, Minn.
A modified method of determining the urinary
acid mucopolysaccharide (AMPS) excretion is
defined. The quantitative measurement is ex-
pressed on the basis of urinary creatinine, so that
the test can be done on a random urine sample.
Normal upper limits for this value are presented
290
ABSTRACTS
from study of control groups of 27 men and 21
women. The control groups were studied for age
and sex influence, daily excretion variations, and
influence of the time of daily collection. The
method was found to be reproducible and not
significantly affected by these variables or diet.
Fifty-three patients with classic or definite rheumatoid arthritis were examined clinically and by
various laboratory parameters. The patients were
assessed as clinically active or inactive by experienced rheumatologists on the basis of fibrositis,
synovitis and other objective signs of inflammation. I n only 3 of the 53 patients with rheumatoid
arthritis did the urinary AMPS values disagree
with this clinical assessment, whereas the erythrocyte sedimentation rate disagreed in 22 of the 53
cases.
There appeared to be no influence upon the
relevancy of AMPS values by the presence of
subcutaneous rheumatoid nodules, anemia, abnormal serum protein electrophoresis, x-ray evidence
of rheumatoid arthritis, the presence of rheumatoid factor or lupus erythematosus cells. This lack
of influence appeared also to be true of associated
conditions noted and certain drugs, including
most of the usual anti-inflammatory drugs prescribed for rheumatoid arthritis.
It is felt that this simple reproducible test of
urinary AMPS excretion should be helpful to the
clinician as an additional determinant of the
presence of disease activity in patients with rheumatoid arthritis. ..
DEFECTS
IN AN ENZYME
OF PURINE METABOLISM ASSOCIATED
WITH
EXCESSIVE
PRODUCTION
OF URICACIDIN GOUT
William N . Kelley, Frederick M . Rosenbloom, J. Frank Henderson
and J. Edwin Seegmiller, Bethesda, Md.
Accelerated purine synthesis de novo with excessive uric acid production is a characteristic
feature of a large segment of the gouty population. The greatest purine production and uric acid
excretion is found in patients with the familial
syndrome characterized by hyperuricemia, choreoathetosis, compulsive self-mutilation, mental retardation, and spasticity, which was first described
by Lesch and Nyhan.
A deficit in an enzyme of purine metabolism,
phosphoribosyltransferase
hypoxanthine-guanine
(HGPRT), was found in dialyzed lysates of erythrocytes, fibroblasts or leukocytes of 9 patients who
had in common excessive production of uric acid.
They segregate into 3 groups on the basis of
neurological function and enzyme activity, using
guanine as substrate. 1) Three brothers showing
0.6 to 0.8 per cent of normal activity had typical
gouty arthritis with onset in adult life and no
obvious neurological dysfunction. 2 ) Two brothers
showing 0.5 per cent of normal activity showed a
mild to moderate dysfunction of the spinocerebellar type. Both patients developed uric acid nephrolithiasis in childhood and one developed gout at
age 13. 3 ) Four unrelated patients with the
complete syndrome as described by Lesch and
Nyhan showed a complete absence (<0.004 per
cent of normal) of enzyme activity. The activity
of a closely related enzyme, adenine phosphoribosyltransferase, was not diminished in these patients.
The finding of normal HGPKT activity in 10
additional patients exhibiting excessive production
of uric acid suggests 1) that the decrease in
cnzyme activity observed is not a secondary phenomenon, and 2 ) that excessive production of
uric acid represents the phenotypic expression of
a heterogeneous group of genetic clisorders.
FURTHER
OBSERVATIONS
ON SOURCE01- SYNOVIAL
FLUIDENZYMES
G. P. Kerby and S . M . Taylor, Durham, N. C.
Synovial fluid enzymes have been re-explored
for source. Lysosomal enzymes acid phosphatase
( AcP) and lysozyme (LZ), glycolytic enzymes
lactic dehydrogenasc ( LDII ) and pyruvate kinase
(PK), and potential muscle enzymes adenylic
kinase ( AK) and ATP-crcatine transphorylase
( CPK ) were measured in promptly-separated,
centrifuged, washed cellular sediment resuspended in buffer to original volume and sonicated
( I ) , in supernatant fluid (11), and in wliole
sonicated fluid (111). Theoretically the sum of I
plus I1 should equal 111. hleasured protein content
of each fraction established the validity of this
point in each fluid.
Data were scattered. In the small number of
oxalated fluids studied thus far, enzyme activity
and levels of protein, leukocytes and erythrocytes
were greater in rheumatoids ( R A ) than in non-
291
ABSTRACTS
rheumatoids ( N ) . Protein increase was overwhelmingly predominant in 11, indicating probable
plasma and cellular enzyme leakage. AcP activity
increased predominantly in I, indicating little
lysosomal cellular leakage prior to sonication. LZ
activity in contrast increased about equally in I
and 11, indicating also a plasma or perhaps connective tissue source, since AcP increase did not
suggest major intra-articular lysosomal release
from cells. LDH and PK increased variably in I
and 11, indicating possible multiple source and
certainly significant cellular source. AK increased
more in I than in 11, again indicating cellular
source, quite possibly platelets, with some cellular
and possibly connective tissue leakage. CPK increase, like that of LZ, was about equal in I and
11, again suggesting possible connective tissue
leakage in addition to possible other source.
Levels of LZ and CPK activity in both RA and
N fluids and of LDH in RA fluids were lesy in I11
than in I plus 11, suggesting presence of an inhibitor effective on release of these enzymes into
the fluid.
IN SALIVA
OF RHEUMATOID
AND NON-RHEUMATOID
INDIVIDUALS
KALLIKREINS
G. P. Kerby and S. M . Taylor, Durham, N. C.
Kallikrein levels in human saliva have been
determined in rheumatoid and non-rheumatoid
individuals. Saliva was selected because it is secreted by a tissue usually not overtly inflamed in
rheumatoid disease. All saliva samples were frozen
1 to 5 days before use. The enzyme was then
partially purified by initial acetone precipitation
at pH 6.0, absorption of the crude acetone powder
in water on Cellex D at pH 7.0, elution, dialysis
and concentration of the sample. In vitro assay
used TAME as substrate. Esterase activity was not
inhibited by soybean trypsin inhibitor, in contrast
to trypsin which was used as a control. In a few
random samples tested, biological activity ( increased blood flow and decreased blood pressure
in a dog) was confirmed.
Esterase activity is expressed as units ( E U )
equal to 1 FU for a preparation of human urinary
kallikrein ( 5.7 FU/mg ) kindIy furnished by Web-
ster. Results are given as E U per 100 mg. protein
in the original saliva. The kallikrein content in
saliva from non-rheumatoid controls averaged
194 ? 87 (S.D.) EU per 100 mg. in 10 individuals
assayed to the time of this abstract. A single
individual averaged 193 ? 18 EU per 100 mg in
9 samples prepared after saliva collected on different days was frozen for 1 to 10 days. In 15
rheumatoid patients assayed thus far, kallikrein
content averaged 283 2 117 E U per 100 mg. The
difference between rheumatoid and non-rheumatoid levels is not significant to date ( t = 2.00,
p
0.05).
Of interest was the demonstration of a positive
rheumatoid latex agglutination with some samples,
using commercial slide reagents. Positivity was not
limited to samples derived from rheumatoid patients. This finding is being explored further.
>
IDENTIFICATION
OF COLLAGEN
IN SYNOVIAL
FLUID
Rodanthi Kitridou, Darwin J. Prockop and Daniel J. McCarty, Jr., Philadelphia, Pa.
Phase contrast microscopic examination of wet
smears of synovial fluid aspirated from arthritic
joints frequently shows fibrous structures. These
vary greatly in number and in length and their
presence does not appear to correlate with a particular type of arthritis. Buttons of particulate
matter obtained by centrifugation of synovial fluid
samples which had been treated by freeze-thawing and with hyaluronidase were washed with
distilled water and dried over anhydrous calcium
chloride. The dry weight, hydroxyproline content
( after acid hydrolysis ), and alpha amino nitrogen
content (Ninhydrin) of each sample were determined. Thirteen of 15 samples from 11 patients
with a variety of joint diseases contained significant amounts of hydroxyproline. The collagen
content of each sample based on dry weight
ranged from 0.14 to 4.0 per cent with an average
of 1.7 per cent. The collagen content based on the
alpha amino containing nitrogen fraction ranged
from 0.5 to 8.0 per cent. Articular cartilage obtained at necropsy, homogenized and treated like
the joint fluid samples, contained 80 per cent
collagen based on dry weight.
Electron microscopic examination of two synovial fluid buttons and of the articular cartilage
material showed typical collagen fibers with a
periodicity of 640 A.
The total collagen content of the joint fluid
correlated poorly with the number of fibrils in the
wet preparations as estimated by phase microscopy. A tentative correlation with joint instability
was evident in this preliminary study.
292
ABSTRAmS
COMPARATNE
EFFECTSOF SCURVY
AND PENIC~LLAMINE
ON THE CONSERVATNE
REUTILIZATIONOF MAH3-COLLAGEN IN VIVO
LeRoy Klein and Bhagwan D. Garg, Cleveland, Ohio
We have shown in chronically labeled animals
that a significant amount of radioactive collagen
can accumulate in granulation tissue that was
newly induced by polyvinyl sponges or carrageenin. This suggested that mature collagen
could be depolymerized to a soluble state and
reaggregated during new collagen formation, The
suggestion was tested in previously labeled animals by comparing the effects of scurvy ( a condition that decreases neutral-salt-soluble collagens)
and penicillamine treatment ( one that increases
neutral-salt-soluble collagens) on the specific
radioactivities of soluble collagens.
Ten young female guinea pigs and twelve
weanling male rats were injected (8 to 10 times)
with H3-proline over 4 to 5 weeks. Two months
after labeling, guinea pigs were placed on scorbutic diets for 21 days and rats were fed 60 to
100 mgs of D-penicillamine per day for 8 to 15
days. Neutral-salt-soluble collagens ( 0.15 and
0.45 M NaCl) and citrate-soluble collagen were
extracted from 5 gms of skin. The hydroxyproline
from the extracted and insoluble collagens was
separated chromatographically and their specific
activities were compared. In the scorbutic state
the amount of neutral-salt-soluble collagens decreased 75-85 per cent while in penicillaminetreated rats it increased 7 to 8 times over the
control values. There were small increases of
citrate-soluble collagen under both conditions. In
the scorbutic state the relative specific activities
of hydroxyproline from neutral-salt-soluble collagens were 3 to 4 times higher than the controls
and almost equal to that of citrate-soluble collagen. No difference in the relative specific activities
of neutral-salt-soluble collagens was observed in
the penicillamine-treated rats. The relative specific
activities of citrate-soluble collagen was slightly
higher than the controls under both experimental
conditions and was 75 per cent of that in the
residual insoluble collagen.
The higher specific activities of hydroxyproline
in neutral-salt-soluble collagens from scorbutic
guinea pigs and the lack of change of specific
activities in neutral-salt-soluble collagens from
penicillamine-treated rats support our earlier postulate for a conservative reutilization of fibrous
collagen.
EFFECTOF JWENILE RHEUMATOID
A R ~ R ~ON
~ IDENTAL
S
MATURITY
AND DEVELOPMENT
OF THE DENTO-FACIAL
COMPLEX
R. N . Kramer, D . F. Bowers, T . R. Frye and W. M . Gibson, Columbus, Ohio
Reported studies on mandibular growth in juvenile rheumatoid arthritis have been based on
small numbers of children with obvious destruction of the temperomandibular joint. Arthritic
involvement leading to destruction of the growth
center and the impact of systemic illness on
growth both need to be assessed. As part of a
longitudinal study on 60 children with juvenile
rheumatoid arthritis, measurements have been carried out to determine dental age in relation to
chronologic age. A comparison has been made of
dental maturity, bone age at the wrist and hand,
and height and weight, in identifying the effect of
this illness on somatic age. Lateral cephalometric
roentgenograms have been traced and measured
to show serial evidence of growth patterns of the
dento-facial complex. Study casts have been made
on 20 children for evahation of occlusion. Documentation has been made of the degree and duration of activity of the disease as well as the dose
and duration of steroids where it has been used.
The results of these measurements are compared
with normals and demonstrate the effect of this
chronic disease on dental maturity, mandibular
outline, and occlusal relationships.
INTRA-ARTICULAR
TREATMENT
OF RHEUMATOID
ARTHRITISWITH GOLD,
AND LIWCAINEHYDROCHLORIDE
TRIAMCINOLONE,
Wm. C . Kuzell, Donald L . Bittner, Lydia M . Seebach
and Richard P . Glouer, San Francisco, Calif.
Gold sodium thiomalate, triamcinolone, and
lidocaine hydrochloride have been used in combination for the intra-articular injection of joints
in 30 patients with rheumatoid arthritis. Injections
have been given into the small joints of the hands
and wrists as well as into the knees, ankles, elbows,
293
ABSTRACTS
and shoulders. The study includes patients who
have previously received gold intramuscularly as well as others who have only received intra-articular injections. Generally, it has
been possible to discontinue intramuscular injections during the treatment with intra-articular injections. The duration of treatment has varied
between 2 and 10 months. The response to
treatment has been uniformly good both with
respect to marked improvement in the joints injected and in the general status of the patients.
Cytological studies of the joint fluids prior to and
during treatment have demonstrated striking diminution in cell counts, and there has been an
increase in viscosity of the synovial fluid coincident
with improvement. Reactions to treatment have
been minimal as well as infrequent and have not
necessitated termination of treatment. The results
of this study suggest that in chrysotherapy of
“new” patients with rheumatoid arthritis the intraarticular rather than the intramuscular route of
administration be tried.
REMISSIONS
IN RHEUMATOID
ARTHRITISWITH A VARIETYOF SKININFLAMMATIONS
John Lansbury, Philadelphia, Pa.
We have observed 10 striking remissions in
rheumatoid arthritis following various quite unrelated types of skin infl,ammation. The remissions
lasted from 1 to 18 or more months (average 6
months). The degree of benefit was unrelated
to the cause of the inflammation. The remissions
were complete or excellent in 9 instances and
gratifying in the remaining case. Causes of the
acute dermatitis were: scalding of skin, moderately
severe sunburn, ivy poisoning, contact dermatitis,
two cases of seborrheic dermatitis, drug reactions to Atabrine and Camoquin, and two cases of
gold dermatitis.
STUDIESON
THE
The variety of unrelated inciting agents suggests
that the benefit may be due to a common
mechanism which is simply skin inflammation, irrespective of cause. Both the beneficial effect
of heat and the deleterious effect of chilling
might be similarly mediated, also the ancient and
unconfirmed reports of benefit from skin blistering.
These observations are only suggestive as they
were not controlled. Nevertheless, like the earlier
observations of the beneficial effects of pregnancy
and jaundice, they point to a neglected area of
investigation.
SPECIFICITY
OF ERYTHROCYTE
AUTOANTIBODIES
IN MAN
John P . Lacldy and Richard F. Bakemeier, Rochester, N. Y.
The autologous proteins sensitizing human RBC
and causing positive direct Coombs tests ( D C T )
fall into three patterns: a ) yG-globulin alone;
b ) yG-globulin plus complement ( C ) ; c ) C‘
alone. From the work of others some RBC autoantibodies show specificity for Rh or other blood
group antigens. We now wish to report evidence
for a correlation of DCT pattern with autoantibody specificity. Eluted yG autoantibodies from
31 patients (patterns a and b ) were tested against
Rh..11 RBC, i.e., human RBC lacking detectable
Rh antigens but possessing a normal representation of other known RBC antigens. In 11 of 17
cases with positive DCT of pattern a), autoantibodies failed to react with Rh,,,, RBC wbile
reacting strongly with RBC of various “normal”
phenotypes. Conversely, in 13 of 14 cases with
positive DCT of pattern b ) , autoantibodies reacted equally well with Rh
and “normal”
RBC. These results suggest that: 1) yG autoantibodies with potential for C’ fixation are generally reactive with RBC antigens outside the Rh
system, in keeping with experience with blood
group isoantibodies; 2 ) that non-C‘-fixing yG
autoantibodies may be divided into a major group
which has specificity for antigen(s) of the Rh
complex, and a smaller group which does not.
In further studies, autoantibodies isolated from
seven patients’ RBC during active disease reacted
strongly with autologous Coombs-negative RBC
obtained during remission. Thus, transition from
active autoantibody formation to remission was
not associated with a serologically detectable
change in the RBC antigens involved. To test
the idea that autoantibodies might arise against
antigens that develop late in ontogeny, autoantibody eluates were tested against human fetal
RBC of 10 to 14 weeks of age. Reactions were
comparable, however, to those with adult RBC.
Finally, a test was made of the hypothesis that
RBC autoantibodies might arise from a maternal
lymphoid graft reacting against paternally inherited antigens on the patient’s RBC. Such a
maternal graft might be expected to be tolerant
of maternal RBC antigens. However, the autoantibodies of 6 patients reacted vigorously with
RBC from their mothers.
294
ABSTRACTS
JAUNDICE WITH THE
USE OF ~-HYDROXYPYRAZOLO(
3,4-D)PYRIMIDINE( 4-HPP)
Martin D. Lidsky and John T. Sharp, Houston, Tex.
4-HPP has been given to 14 patients with
primary gout, selected because of the presence
of renal impairment and/or severe arthritis. Daily
doses of 300 to 900 mg. were employed. The
endogenous creatinine clearance ranged from 32
to 64 ml./min. in 6 of the 7 patients with renal
impairment.
Two patients with renal impairment developed
intrahepatic obstructive jaundice and another developed elevation of serum alkaline phospbatase
and transaminase activities without jaundice. In
2 other patients with renal disease, only the serum
alkaline phosphatase activity became elevated.
The 2 patients with jaundice received 600 and
900 mg 4-HPP daily for 3 weeks and had initial
creatinine clearances of 32 and 52 ml./min.
respectively. Liver dysfunction disappeared after
4-HPP was discontinued. Examination of liver
tissue from one patient disclosed periportal in-
flammatory infiltrates containing eosinophils. Readministration of 4-HPP to this patient 2 years
after the episode of jaundice, when the creatinine
clearance had fallen to 20 ml./min. did not
produce liver dysfunction. The dose (300 m g )
was half that previously used.
Six of 7 patients without renal impairment have
been followed for 2 to 30 months. Elevation of
serum alkaline phosphatase and transaminase activities has occured in one patient with an initial
creatinine clearance of 96 ml./min. on a daily
dose of 400 mg.
The data suggest an increased susceptibility of
patients with renal insufficiency to the hepatotoxic
effect of 4-HPP. In such patients, the dose must
be carefully monitored to achieve desirable reduction of serum urate concentration without inducing serious liver dysfunction.
PERCUTANEOUS BIOPSY
INTRA-ARTICULAR
STRUCTURES UNDER D~RECT
VISION
ARTHROSCOPY: EXPERIENCE WITH
OF
Richard L. Lipson, Jackson J . Clemmons and John W. Frymoyer, Burlington, Vermont
Marked variations in the histopathologic appearance of synovial tissue taken from different
areas of the same joint have been well-documented. Because of the patchy distribution of the
pathologic lesions, synovial membrane biopsies are
usually done by open exploration or by percutaneous needle biopsy with multiple blind samplings.
Several instruments and techniques have been
devised to improve the yield obtained by percutaneous biopsy, but the incidence of failure to
obtain adequate tissue for histologic evaluation
continues to vary from 5 to 23 per cent.
.An arthroscope that permits percutaneous biopsy
under direct vision has been reported previously.
It is the purpose of this report to relate our experience with this biopsy technique in 17 patients.
Adequate synovial tissue was obtained for histologic examination in 100 per cent of the cases.
The biopsy site could be picked at will and
photographs obtained of the tissue to be biopsied.
In addition, biopsies of articular cartilage, pannus,
erosions and joint mice were obtained.
The technique will be described and in vivo
photographs of the tissue selected for biopsy as
well as photomicrographs of the specimens obtained will be shown.
COMPARISON OF THE VAPOR PRESSURE AND CRYOSCOPIC METHODS
FOR DETERMINING THE TOTAL
OSMOTIC PRESSURES
OF SYNOVIAL
FLUIDAND PLASMA
Richard L. Lipson and A. Frances Johnson, Burlington, Vermont
Accurate measurements of the total osmotic
pressures of synovial fluid and plasma are of
fundamental importance for understanding the
pathophysiology of joint effusions. Most laboratories measure total osmolality of biological fluids
by cryoscopic methods. In our laboratory, vapor
pressure osmometry is used because it permits
determinations under physiologic conditions, i.e.,
in an atmosphere of 5 per cent CO, at 37" C,
and eliminates possible errors due to temperaturedependent molecular interactions and solute solubility. Cryoscopic measurements on synovial
fluid present additional problems because of the
effect viscosity has on heat conductivity and the
foaming that frequently occurs during the procedure.
Because of theoretical and practical problems
inherent in the cryoscopic method, a study was
295
ABSTRACTS
undertaken to compare the freezing point depression and vapor pressure methods. The total
osmolality of 17 paired samples of synovial fluid
and plasma from patients with various rheumatic
diseases was measured by both methods.
The results reveal that the total osmotic pressure of synovial fluid was always significantly
higher when measured by freezing point depression than by the vapor pressure method with an
average difference of 19 milliosmoles or 323 millimeters of mercury, and that of the plasma was
higher by the freezing point method in all but
one instance, with an average difference of 14
milliosmoles or 238 millimeters of mercury. Thus,
our results indicate that a more accurate picture
of in vivo osmolality of synovial fluid and plasma
is obtained with the vapor pressure method rather
than by freezing point depression.
N-ACETYLCYSTEINE
( NAC ) THERAPY
IN RHEUMATOID
ARTHRITIS
Arthur Lorber, Howard J . Weinberger and James Meriwether, Los Angeles, Calif.
Thiols have theoretical therapeutic value in
rheumatoid arthritis because they exert a protective antioxidant effect on sulfhydryl ( S H )
groups of enzymes, structural proteins, and depolymerize rheumatoid factor ( R F ) in vitro. Furthermore, the administration of thiols i.e.,
alpha-mercaptopropionyl glycine and d-penicillamine, has been reported to be beneficial in
rheumatoid arthritis (RA). Our experience with
d-penicillamine supports these observations. Nevertheless, occurrence of serious adverse reactions
prompted us to investigate the therapeutic possibilities of another thiol compound, NAC. The
medication was administered in doses of 2.5 to 4
grams daily. No serious adverse reactions were
observed in 17 patients receiving oral and one
intravenous NAC.
Six patients with peripheral RA received the
medication for nearly a year. Five showed improvement in grip strength; 4 showed reduced
circumference of PIP joints, increased range of
motion, and improved Steinbrocker functional
index. Three patients with pulmonary involve-
ment (biopsy-confirmed) manifested increased
exercise tolerance and in 2 patients considerable
resolution of radiographic pulmonary lesions. Four
patients with extensive necrobiotic cutaneous lesions and evidence of visceral vasculitis manifested
cutaneous healing and a halt in the progression
of vascular lesions on therapy.
S35-labeled NAC administered orally was excreted largely via the kidneys; some labeling of
serum proteins and expectorated bronchial secretions was also observed.
I n vitro incubation of rheumatoid sera with
0.025 molar NAC caused dissociation of IgM
similar to that observed with other thiols. Decline
in RF titer, however, was not achieved with NAC
therapy though this has been observed with d-penicillamine. Serum protein SH content was noted
to increase in several patients receiving NAC.
Preliminary therapeutic evaluation of NAC in
RA appears sufficiently encouraging to warrant
further clinical and pharmacological studies of
this agent and related thiol compounds.
AND ASEPTICNECROSISOF
GOUT, HYPERURICEMIA
THE
FEMORAL
HEAD
Donald E. McCollum, Robert S. Mathews and Phillip T . Pickett, Durham, N.C.
In a group of 152 patients with aseptic necrosis
of the femoral head, the authors found significant
trauma in 62, sickle cell trait or disease in 18,
and other diseases known to be associated with
aseptic necrosis in 7 patients. In the remaining
65 patients no etiology could be established, and
they were considered to be idiopathic.
In the idiopathic group the average age of
onset was 39 years, and in 34 per cent both hips
were involved. Five patients had diabetes mellitus
and 5 had significant hypertension. Twenty-six of
40 patients either had findings of cirrhosis or
admitted excessive alcohol intake.
At the time of reevaluation, 14 patients had
developed definite gouty arthritis involving other
joints. An additional 9 patients had hyperuricemia
without gouty attacks. Routine study of synovium
obtained at surgery revealed only nonspecific
synovitis. When the synovium was fixed in absolute
alcohol and examined using polarized light, we
found uric acid crystals in the tissue of 3 patients
with gout, three with hyperuricemia, and in m e
patient who had aseptic necrosis without gout or
hyperuricemia. Identity of the crystals was confirmed by use of a red compensating lens and
methenamine silver stain.
The x-ray changes in the hip of patients with
gout and aseptic necrosis are similar to those
produced by other diseases. The occurence of
gout or hyperuricemia in 23 of 65 patients with
idiopathic aseptic necrosis suggests that gout must
be considered as an etiologic agent.
296
ABSTRACTS
PRIMARILY
NON-INFLAMMATORY
ANKYLOSING
ARTHRITISOF
THE
FINGERS
Currier McEwen, New York, N. Y.
It is generally believed that osteoarthritis does
not lead to ankylosis. It is therefore considered to
be of interest to report 4 examples of what apparently is straightforward, though severe, osteoarthritis of the hands which has progressed to
solid bony fusion of distal ( D I P ) and proximal
interphalangeal (PIP) joints of the fingers. In
each patient Heberden’s nodes appeared first and
early changes in PIP joints were typically those
of osteoarthritis. The only other joints significantly
involved were the first carpo-metacarpals in 2 of
the patients. Although pain occurred in PIP joints,
especially with change of weather, frank clinical
evidence of inflammation was lacking and the
erythrocyte sedimentation rate was little, if any,
increased. Tests for rheumatoid factors were repeatedly negative. The sister of one patient had
advanced osteoarthritis involving DIPS and PIPS
with marked limitation of motion but without
ankylosis.
ANTI-INFLAMMATORY
EFFECTOF Low DOSES
COLCHICINE:
IN A SENSITIVE
BACTERIAL
SYSTEM
Stephen E. Malawista and Vincent T . Andriole,
New Haven, Conn.
Low doses of colchicine have not previously
been thought to alter bacterial infections. However, because of various inhibitory effects on
granulocytes, colchicine might be expected to
have a general anti-inflammatory effect, which, in
a bacterial system, would enhance the spread of
infection. To test this hypothesis, we used a
system sensitive enough to detect small differences
in inflammation: the response of guinea pig skin
to the intradermal injection of hemolytic, coagulase
positive Staphylococcus aureus ( Giorgio).
Bacteria ( 2 to 4 x 1 0 8 ) were placed at 0, 2, 4,
6 and 8 hours after single, intraperitoneal injections of saline or colchicine (13, 27 or 80pg/
200 g ) . The mean diameters of erythema-induration and of necrosis were measured at 24 and 48
hours.
Significant increases in erythema-induration
andfor necrosis were seen with all the doses of
colchicine used. The most prominent anti-inflammatory effects were found in the lesions placed
from 4 to 8 hours after colchicine. These doses of
colchicine did not produce neutropenia at 4, 8
or 24 hours.
Although these results do not imply that small
amounts of colchicine have any significant clinical
effect in human infection, our findings do exemplify a general anti-inflammatory effect of colchicine, and tell us where to look next; namely,
for the specific attribute( s ) of gouty inflammation
that make colchicine clinically effective in acute
gouty arthritis, but ineffective in most other inflammatory conditions.
IN RHEUMATOID
SYNOVIAL
FLUID
CRYOPRECIPITINS
Robert L. Marcus and Alexander S . Totunes, Baltimore, Md.
A previous report from our laboratory described
the occurrence of anticomplementary activity in
the synovial fluid of patients with rheumatoid
arthritis. We have now found that this complement-fixing property of rheumatoid synovial fluid
is invariably associated with the presence of cold
precipitable proteins. To our knowledge cryoproteins in rheumatoid synovial fluid have not
been previously reported.
Cryoproteins have been found in 10 of 11
rheumatoid synovial fluids appropriately collected
and processed at 37°C to prevent the loss of
cryoprecipitins. Analysis of washed cryoprecipitates from these fluids indicate that they contained
from 75 to 410 micrograms of cryoprecipitable
protein per ml. Removal of cryoprecipitins by
centrifugation after 18 hours of incubation at 0°C
resulted in loss of all or a major portion of the
original complement fixing activity of the synovial
fluid, and this activity could he recovered in the
precipitate. Further studies of these precipitates
are in progress. Preliminary immuno-electrophoretic analysis with potent antihuman serum indicates the presence of several precipitin bands
which include gamma G globulin in all, and
gamma M globulin in some of the cryoprecipitates
examined thus far.
The association of cryoprecipitins with reduced
complement levels and anticomplementary activity in rheumatoid synovial fluid is analogous to
ABSTRACTS
similar findings in the serum of patients with
systemic lupus erythematosus previously reported
by Christian and his coworkers. These findings
support the hypothesis that aggregates (or com-
plexes) containing immunoglobulin may be responsible for the anticomplementary activity and
the reduced complement observed in rheumatoid
synovial fluids.
ON 34 CHRONIC ( HASHIMOTO’S
)
SERIALCLINICAL-HISTOPATHOLOGIC
OBSERVATIONS
THYROIDITIS
PATIENTS,
WITH IMPLICATIONS
CONCERNING
THE PATHOGENESIS
OF THIS LESION
Alfonse T . Masi, William H . Hartmann, and Richard C . Reba, Baltimore, Md.
The literature reviewed by Vickery and Hamlin
(New Eng. J. Med. 264: 226, 1961) contains
reports of 36 patients with Hashimoto’s thyroiditis
who had multiple thyroid operations. We have
observed 34 additional patients, including 9 with
a thyroid operation antedating their first histopathologic diagnosis of thyroiditis.
The patients were classified into three clinical
categories: 1) thyrotoxic at any time, 2 ) euthyroid
continuously, 3 ) hypothyroid without previous
toxicity. The thyroid slides were reviewed
( W H H ) without knowledge of patient identity,
clinical status, or sequence of thyroid operation,
on 2 independent occasions one year apart. Reviewer variability as well as the evolution of the
lesions were analyzed and clinical-histopathologic
correlations were made.
Eight patients who had clinical hyperthyroidism
with epithelial hyperplasia typical of Graves’
disease at the first operation progressed to chronic
thyroiditis with euthyroid or hypothyroid status.
Seventeen patients who were initially euthyroid
remained so with Hiirthle epithelial cells and
prominent lymphocytes typical of Hashimoto’s
thyroiditis at both operations. Nine patients with
euthyroid-chronic thyroiditis progressed to hypothyroidism with epithelial atrophy and fibrosis.
The most impressive histologic phenomenon observed between operations was a change in the
thyroid epithelium. Hyperplasia, when prominent
initially, was followed by the eosinophilic Hiirthle
cell alteration and finally by atrophy. Round cell
infiltration and germinal centers were seen mainly
in the Hiirthle cell stage.
These clinical-histopathologic observations and
other recent data suggest that in Hashimoto’s
thyroiditis the primary lesion is a chronic epithelial
alteration allowing thyroglobulin to escape into
the thyroid interstitium and draining lymph. The
infiltration of lymphocytes with humoral antibody
formation to thyroglobulin appear to follow a
sustained release of thyroglobulin from colloid
stores due to epithelial alteration.
THE IMMUNOSEROLOGY
OF RHEUMATOID
ARTHRITIS(RA)
R. S . Mathews, C . R. Lincoln and C . E. Buckley, KII, Durham, N. C.
We did quantitative radial diffusion studies of
immunoglobulin ( I g ) and ,GlC/plA concentrations, rheumatoid factor ( R F ) activity and
antinuclear factor (ANF) in 56 patients with RA
in comparison to 76 normal controls. We also
examined synovial fluid (SF) in 24 patients and
9 non-rheumatoid patients and did simultaneous
synovial biopsies. Statistical analyses of the percentile distribution of Ig concentrations in RA
patients revealed a difference of -71 mg. (p<.5)
For IgG at the 50th percentile, 84 mg (p<.Ol)
for IgA and 153 mg (p<.OOl) for IgM. Ninetyfive per cent of RA patients had serum IgM concentrations above the 99.9 percentile of controls.
The ratio of specific activity of RF (log titer/
[IgM]) in SF to serum ranged up to 4.8 in some
patients. Differential counts of pyroninophilic
plasma cells and lymphocytes were highest (86
per cent) in synovial biopsies of patients with
high synovial fluid RF titers. IgM concentration
and RF specific activity ratio paralled the activity
of rheumatoid joint disease and was highest in
patients with thickened proliferative synovia. All
ANF assays were negative. The concentration of
synovial fluid plC/plA was inversely related
to the serum concentration and decreased in
active rheumatoid disease. These studies document
the kind of reactive hyperglobulinemia in RA and
relate the local occurrence of RF and IgM in the
joint to synovial pyronin positive mononuclear cells
and ,81C/PlA depletion.
298
ABSTRACTS
SYSTEMIC
LUPUSERYTHEMATOSUS
IN CHILDHOOD
Aaron G. Meislin and Naomi Rothfield, New York, N.Y.
Clinical and laboratory findings in 25 of 40
children with systemic lupus erythematosus have
been analyzed to date and compared to the data
from 200 adult patients with the disease.
Of the 25 children with SLE thus far analyzed,
the median age of onset was 11 years with 12 per
cent at 3 years of age. The median age at diagnosis was 13 years. The diagnosis was not made
in some patients until 8 to 11 years later, The
most common symptoms prior to diagnosis were
fever, joint pains and rash. Weakness was the
principal complaint at time of diagnosis in 8 per
cent and dramatic neurologic abnormalities in 8
per cent. The reticuloendothelial and hematopoetic systems were involved at the time of diagnosis in 56 per cent of patients and 48 per cent
had renal involvement. At the present time 60 per
cent of the patients are alive and 40 per cent
have died. Of the 15 survivors, 3 are asymptomatic, 8 have minor symptoms and 4 are severely
ill. The median survival time is 3 3/4 years from
time of diagnosis and 7 years from the time of
onset of symptoms. The median survival time in
the 10 dead children was 1 1/2 years from the
time of diagnosis and 3 years from the time of
onset. The prognosis was directly related to the
number of systems involved at the time of diagnosis.
The incidence of renal disease and prognosis
will be compared to the group of adult patients.
The data suggest that although the disease is
similar in children and adults, there is a longer
period between onset of symptoms and time of
diagnosis in the children. The delay in diagnosis
may be related to the poorer prognosis in this
group. The data also indicate that childhood
lupus is not uncommon, since 20 per cent of 240
patients with SLE developed symptoms of their
disease during childhood.
THE RENALVASCULAR
LESIONIN RHEUMATOID
DISEASE
James H . Meriwether, Jr., Howard J. Weinberger and Irene 0. Gleason,
Los Angeles, Calif.
Large autopsy series and 3 renal biopsy studies
have not demonstrated arteritis in the rheumatoid
kidney. Vascular lesions, when present, were
those of arteriosclerosis and arteriolar nephrosclerosis. However, in those rheumatoids who
develop the “malignant vascular syndrome,” renal
lesions do occur and have been previously,
sporadically reported. This renal vascular lesion
has not been widely recognized, and this study
reports an additional 8 such cases.
Disseminated visceral vasculitis is unusual, occurring in 6 per cent of those patients with
rheumatoid arthritis who came to autopsy at
Wadsworth General Hospital, Los Angeles, from
1950-1965. Of the 11 patients who had evidence
of active or chronic vasculitis in 3 or more visceral
organs, 8 had renal arteritis. The lesions involved
primarily the medium size (arcuate) to larger
arteriolar vessels and varied in age from acute
necrotizing injury to intimal scarring with organized thrombosis. Glomerular involvement was
minimal, primarily mesangial thickening, with
only one instance of diffuse glomerulonephritis.
Tubular and interstitial changes were predominantly those of ischemic atrophy. The spectrum
of vascular pathology is discussed and differences
from other renal vascular diseases noted. The
pathologic similarity to periarteritis nodosa is emphasized.
Diffuse vasculitis was suspected in only 4 of
the 8 cases premortem, confirmed by muscle
biopsy in 3, and obtained several years before
death in 2. There was minimal evidence of clinical
renal disease and death was not attributable to
renal involvement in any of the cases. Relevant
clinical information including the incidence of
hypertension and the use of steroids is included.
PHYSIOLOGIC
EFFECTSOF RHEUMATOID
FACTORS:
STUDIESOF PHAGOCYTOSIS
IN SUBACUTE
BACTERIAL
ENJIIOCARDITIS
R. P. Messner, T . Laxdal, P . G. Quie and R. C . Williams, Jr., Minneapolis, Minn.
The physiologic consequences or in vivo effects
of rheumatoid factors (RF ) remain controversial.
Their possible role in the synovial inflammatory
cycle or in competing with complement components, thereby sparing renal injury, has received
recent attention. This study was directed at quan-
ABSTRACTS
titative in vitro estimation of the effect of both
autologous and heterologous RF on phagocytic
mechanisms using well-defined opsonins derived
from patients with subacute bacterial endocarditis
(SBE). A group of 32 patients with SBE were
studied. In most instances highest opsonic activity
for infecting bacteria occurred in 7s serum fractions isolated by gel filtration or gradient ultracentrifugations. 7s yG opsonins from DEAE
cellulose chromatograms were added to human
leukocytes in the presence of autologous or heterologous 19s RF. Titrations of both 7s opsonin and
RF confirmed the sensitivity of phagocytosis assay,
where end-point constituted killing of bacteria.
Direct bacterial agglutination titers of SBE
patient whole serum, 7 s yG, and combinations
of 7 s yG with isolated rheumatoid factors indicated R F potentiation of agglutination in most
instances. However, the results of such combinations on phagocytosis were more diverse. In one
instance definite facilitation of phagocytosis was
noted when heterologous R F was added to
bacteria and 7s SBE patient opsonin. In others,
no RF potentiation of phagocytosis was observed.
In several experiments, various heterologous RF
preparations showed almost complete inhibition of
phagocytic effectiveness. Clearcut R F facilitation
or inhibition of bacterial phagocytosis by human
leukocytes varied depending on the combinations
of 7 s opsonin and RF employed.
COLLAGEN I N HUMAN
ARTICULAR
AND COSTAL CARTILAGE
Edward 1. Miller, Jan K. van dm Korst and Leon Sokolof, Bethesda, Md.
Disruption of collagen, the major protein constituent of articular cartilage, is an integral part
of the osteoarthritic process. To determine whether
alterations of collagen at the molecular level are
associated with aging and/or osteoarthritis, costal
and articular cartilage were studied in 25 necropsied individuals, 1 to 70 years of age. Collagen
in both types of cartilage is insoluble in aqueous
solvents which do not denature the protein. A
denaturing solvent, such as 5 M guanidine hydrochloride ( 5 M G ) at neutral pH, is capable of
solubilizing only 3 per cent of the total collagen
in articular cartilage samples whereas somewhat
less (about 1 per cent) of the collagen in costal
cartilage is extractable. This was true for cartilage
from infants as well as from aged individuals,
suggesting that the collagen in these tissues is
rapidly stabilized through the formation of intraand intermolecular crosslinks. The presence of
gross osteoarthritic fibrillation had no effect upon
the solubility of articular cartilage collagen in 5
MG.
In all age groups, approximately 65 per cent
of dried articular cartilage is protein, and collagen
constitutes 90 per cent of the protein. Costal
cartilage from patients in the first decade is similar to articular cartilage with regard to protein
content and the proportion of collagen in the
total protein. However, the proportion of collagen
in the total protein of costal cartilage gradually
decreases in older age groups, reaching a minimum value of 55 per cent in the seventh decade.
Amino acid analyses of purified collagen from
costal and articular cartilages indicate that it is
aimilar to human skin collagen in amino acid
composition, but contains more hydroxylysine and
less lysine.
HUMANANTIBODIES
AGAINST
ACETYLSALICYLIC
ACID-ALTERED
HUMANSERUMALBUMIN
Percy Minden and Richard S. Farr, La Jolla, Calif.
Normal human serum albumin (HSA) is altered
following in vitro exposure to acetylsalicylic acid
( ASA ), as evidenced by an increased capacity
to bind 1131-labeled sodium acetrizoate. Similar
enhancement of the capacity of albumin to bind
acetrizoate has been observed in patients with
rheumatoid arthritis (RA) and has been induced
in normal persons after prolonged oral ingestion
of ASA. Sodium salicylate does not alter acetrizoate binding. To learn if the suggested structural
change in ASA altered albumin (ASA-HSA)
could be detected immunologically, rabbits were
immunized with HSA or ASA-HSA in complete
Freund's adjuvant. The capacities of these antisera
to bind P I - H S A or 1131-HSA-ASA were studied by
precipitating antigen-antibody complexes with 50
per cent saturated ammonium sulfate. No differences in the specificities of the antibodies produced against HSA or ASA-HSA were detected
by means of either direct binding tests or by
inhibition studies.
However, since the rabbit immune mechanism
sometimes fails to distinguish between subtle
structural differences in human proteins such as
the sub-groups of IgG, experiments were carried
out to determine if the human immune mech-
300
ABSTRACXS
anism could distinguish between these 2 antigens.
Accordingly, radioimmunoelectrophoresis was employed in an attempt to detect antibodies against
HSA and ASA-HSA in sera from patients with
RA and aspirin disease and from normal human
controls. Specific antibodies with capacity to bind
ASA-HSA were present in the IgG fractions from
all groups. Occasional sera also contained ASAHSA binding in IgA, and IgM. No anti-HSA was
detected. I t remains to be determined if these
frequently occurring antibodies against altered
albumin may sometimes play a significant protective or pathogenic role in human disease states.
POLYARTHRITIS
AND ERYTHEMA-NODOSUM-LIKE
LESIONSOCCURRING
WITH
SUBACUTE
PANCREATITIS
Gerald T. Mullins, ]r. and Ralph C. Williams, Jr., Minneapolis, Minn.
During the past year, 2 patients have been
encountered whose initial manifestations of illness
included multiple pretibial erythema-nodosnm-like
lesions. In one instance joint pain, stiffness, and
multiple synovial effusions were also present. Only
later did the presence of subacute pancreatitis
become apparent. In one patient the initial clinical
picture, skin lesions, and synovial swelling produced a tentative diagnosis of erythema nodosum
alone.
In both instances, the underlying pancreatic
pathology was subacute obstructive pancreatitisin one case from a steering wheel injury and in the
other pancreatitis secondary to cholelithiasis and
common duct obstruction. Elevation of sedimentation rate, left pleural effusion, negative tests for
rheumatoid factors, and gradual subsidence of
nodular pretibial skin lesions were characteristic
clinical features in both patients. Serum, ascitic,
or urinary amylase and lipase values were markedly elevated during acute onset of skin lesions
or synovitis. When obstructive pancreatic lesions
were alleviated following definitive surgical therapy, prompt subsidence of both skin lesions and
synovitis occurred. In both instances exploratory
laparotomy showed massive focal peritoneal and
omental fat necrosis. The skin and synovial space
manifestations in such patients have generally
been presumed to be due to generalized fat
necrosis and peripheral effects of released circulating pancreatic enzymes.
These cases are presented in detail as an unusual syndrome at times closely resembling erythema nodosum, but associated with severe, active
pancreatitis. It now seems important to study
intrinsic plasma or tissue proteolytic mechanisms
in other patients with erythema nodosum of uncertain etiology.
THEPROBLEM
OF INFECTION
IN SYSTEMICLUPUS
ERYTHEMATOSUS
Allen R. Myers, Iohn A. Milk and Marian W. Ropes, Boston, Mass.
It is generally accepted that patients with systemic lupus erythematosus (SLE) are more susceptible to infectious complications than are
healthy subjects or persons afflicted with a variety
of other chronic diseases. Corticosteroid therapy
is felt to be a major factor in predisposing such
patients to infection. The frequency of infections
in several reports of patients with SLE varies from
10 to 30 per cent. The relationship of infections to
the course of the disease and in particular to the
administration of corticosteroid therapy has not
been previously studied in a large series of patients.
The occurrence of a number of unexpected
serious and even fatal systemic infections in patients with SLE prompted this study of our experience at the Massachusetts General Hospital.
In a series of 89 patients with well-defined
systemic lupus erythematosus, a total of 32 had
one or more major infectious complications during the course of their disease. These infections
have included salmonella, pneumococcal and
meningococcal septicemias, pneumonia and a
variety of localized septic processes. Nineteen of
the 33 patients with infections had received
steroid therapy for a total of 563 months. Infections were not a problem in 18 other patients who
had received steroid therapy for 572 months.
Urinary tract infections were also found in 36 of
82 patients who had urine cultures performed,
approximately one half of whom had received
steroid therapy.
It is concluded that patients with SLE have
an unusual incidence of infection, but that steroid
therapy per se may not be a major factor in this
respect. The relationship of infections to other
features of SLE will be discussed.
301
ABSTRACTS
RECOGNITION
OF FEELING
IN THE TREATMENT
OF PSYCHOGENIC
MUSCULAR
RHEUMATISM
W. Edward Naugler, San Francisco, Calif.
There is a group of people with muscular
“rheumatism” who tend not to recognize feeling
as feeling but to project it (as a physical symptom) to a muscle group which has symbolic
significance. Daily conversation attests to this
universal, almost conscious equating of feeling
and physical symptom, “This is going to be another headache,” “He is a pain in the neck,” “I
feel pushed,” “Oh, my aching back,” etc.-these
phrases refer to muscular response to an unpleasant feeling of which the person is not fully aware.
If the physician considers that the symptoms are
an expression of blocked awareness of feeling,
then the clinical picture will be seen to have
meaning.
Three case presentations will be made. The
case presentations illustrate that the patient actually has strong feelings which he is not fully
aware of and that pain is often associated with
sighing or a feeling of breathlessness at rest.
Muscle spasm and areas tender to firm digital
pressure are found on physical examination.
Treatment is directed along the following lines:
1) Establishment of a good patient-physician relationship by allowing the patient to talk about
what is most meaningful to him. When a relationship is thus established the patient’s feelings are
more available to him and he feels safe in expressing them. 2 ) Teaching, if indicated, the
technique of conscious breathing control when
he feels emotionally uncomfortable. This is slow,
quiet, abdominal breathing with the mouth
closed. 3 ) Diazepam, 2.5-5.0 mg. 4 times daily.
4) Hot, moist packs followed by massage. 5 )
Injections of tender areas with xylocaine-steroid.
DERMALATHYRISM:
A DEFECTIN THE INTRAMOLECULAR
AND INTERMOLECULAR
CROSSLINKING
OF COLLAGEN
IN SOFT TISSUES
CAUSEDBY PENICILLAMINE
Marcel Nimni, Los Angeles, Calif.
Administration of D-penicillamine to animals
and humans causes a marked accumulation of
soluble collagen in skin. Rats weighing 150 grams
were given equimolar amounts of either D-penicillamine or BAPN fumarate (0.58 mM/day)
for a period of 45 days. The penicillamine-treated
animals grew as well as the controls and exhibited
no visible abnormalities except for subcutaneous
hemorrhages. The BAPN-treated showed a pronounced growth retardation and acute signs of
osteolathyrism (thickening and deformation of
the long bones, spinal curvature in the thoracic
region, disruption of the epiphyseal plates ). Those
receiving penicillamine did not show osseous
changes but had about twice the amount of
soluble collagen in their skin and tail tendon than
the BAPN-treated and almost 8 times more than
the controls. The tensile strength of the skin of
the penicillamine animals was 15 per cent that
of the controls. Shrinkage of the skin of BAPN
rats occurred in the normal range (TS=63”C),
but was undetectable in the penicillamine-treated.
Crosslinking the penicillamine treated collagen
with bifunctional aldehydes ( IO-3M) restored the
T, to normal. Soluble collagen from the penicillamine and BATN- treated animals behaved normally ( thermal aggregation, viscosity, optical rotation). Penicillamine in the media ( lO-3M), or added after collagen gelation at 37°C caused the gel
to dissolve rapidly upon cooling. Analysis of the
collagen subunits in dermalathyrism induced by
penicillamine ( 97% ) and those isolated from
tissue collagen solubilized by thiols (66%8, 34
per cent p ) would seem to indicate that penicillamine disrupts and inhibits the formation of intermolecular bonds, and that the intramolecular defect
described previously is a sequelae of the intermolecular abnormality.
IN SKELETAL
MUSCLEOF PATIENTS
WITH SYSTEMIC
MICROVASCULAR
ABNORMALITIES
LUPUSERYTHEMATOSUS
Walter L . Norton, Eric Hurd, David Lewis and Morris Zi%,Dallas, Tex.
Muscle biopsies have been performed in 22
patients with systemic lupus erythematosus
(SLE ). Measurements of the frequency of blood
vessels per cross sectional area, blood vessel diameter, and vascular basement membrane thickness were made by electron microscopic examination. The values differed from those in an equal
number of clinically well subjects.
Basement membrane thickness was also increased, though to a lesser degree, in groups of
patients with rheumatoid arthritis and pulmonary
tuberculosis ( 140 mp in both). The changes in
blood vessel frequency and blood vessel diameter
in SLE were similar to those previously noted in
302
ABSTRACTS
Blood Vessels
SLE
Control
per mm2
Blood Vessel
Diameter (&)
Basement
Membrane
Thickness (mp)
125 f 50
170 & 30
5.6 i 1.2
4.6 f 0.6
160 f 60
125 2 30
p<o.o1
p<o.o1
muscle biopsies of patients with scleroderma.
Correlation with other parameters of SLE were
sought. No correlation was found between vascular parameters and sex, age, race or duration of
disease. Statistically significant relationships ( p
<0.05) were found between blood vessel diameter and corticosteroid dosage, and between
blood vessel diameter and serum gamma globulin
concentration. Basement membrane thickness was
found to be significantly smaller in patients receiving corticosteroids than in those not receiving
steroid therapy (p<o.o1). Serum gamma globulin
p<o.o5
concentration and steroid therapy were inversely
related.
The multiplicity of factors in these patients does
not permit unambiguous conclusions, but the findings have been interpreted as evidence of significant peripheral microvascular injury in SLE.
The relationship of microvascular abnormalities
to serum gamma globulin concentration and the
effect of steroid therapy on these abnormalities
gives indirect support to a relationship between
disease activity and the peripheral microvascular
changes.
CHANGES
IN RHEUMATOIDFACTOR
ACTIVITY DURING
THE COURSE
OF S ARCOIWSIS
Irwin Oreskes and Louis Siltzbach, New York, N. Y.
Rheumatoid factor (RF) has been found in
patients with sarcoidosis in different investigations
with varying frequency ranging from 10 per cent
to as high as 47 per cent. I t is not clear whether
these disparate results reflected technical variations in test procedures or differences in the patient populations studied.
In the present study, among 64 patients with a
tissue-confirmed diagnosis of sarcoidosis examined
for RF in their serum, 38 per cent were positive
on initial testing, with the tanned sheep cell test.
Titers tended to be low with a median value of
1:80. By comparison, among 37 cases of definite
or classical rheumatoid arthritis a median titer
value of 1:5120 was found. The tanned sheep
cell test proved to be considerably more sensitive
than slide or tube latex tests in detecting RF
activity in sarcoidosis.
Presence of RF was unrelated to the presence
or absence of joint symptoms. RF was far more
prevalent in active disease processes than in inactive disease, and in patients with later stages of
pulmonary involvement than with hilar node enlargement alone. Patients with RF were ill with
sarcoidosis approximately twice as long as patients
without RF. RF was found nearly twice as often
in females as in males.
Initial presence of R F was of little prognostic
significance, but disappearance or reduction of
RF titers upon later retesting was associated with
an improving clinical course. Conversely, appearance of R F for the first time or increase in RF
titer on retesting was associated with continued
disease activity and with a relatively poorer clinical outcome.
It appears that the finding of RF activity in
sarcoidosis depends not only on the sensitivity of
the test procedure employed, but on such factors
as sex of the patients and the duration and severity of the disease.
RHEUMATOIDDISEASEAND MALIGNANCY
Duncan S. Owen, Jr., Marion Waller and Elam Toone, Richmond, Va.
In view of the fact that rheumatoid disease is
now considered by most observers to be a disturbance of the immune mechanism, it seems reasonable to direct some study toward the relationship
between it and malignancy, which also may be
related to disturbances of the immune mechanism.
As a secondary consideration, it would seem of
value to see if immuno-suppressive agents, particularly steroids, used often in the treatment of
rheumatoid disease, would cause further change
in the immune mechanism and increase the incidence of malignancy.
In order to initiate this study, we have reviewed the charts of 196 patients with either
303
ABSTRACTS
classic or definite rheumatoid disease and the
charts of 125 patients with some type of arthritis
other than rheumatoid-degenerative joint disease, gout, psoriatic arthritis, and tendinitis. The
patients were all private, mainly Caucasian, in the
middle or upper classes and were between 50 and
74 years of age. Each patient had a complete
history and physical examination and those followed longer than one month had periodic complete examinations. The observation period ranged
from 1 to 288 months with a mean of 49.5 months.
The results were as follows:
Nan-rheumatoid arthritis
Total patients: 125
Malignancies : 5
1 colon carcinoma
1 renal carcinoma
1 prostatic carcinoma
1 breast & colon carcinoma
1chronic granulocytic leukemia
Per cent malignancy: 4
Rheumatoid mthritis
Total patients: 196
Malignancies : 8
2 breast carcinoma
1carcinoma urinary bladder
2 acute leukemia
1 carcinoma endometrium
2 carcinoma lung
Per cent malignancy: 4.1
From the above data, it is concluded that there
is no statistical difference in the incidence of
malignancies in the two groups of patients.
DERIVED
FROM BACTERIAL
CULTURES
MYCOPLASMA
( P P L 0 ) - L m COLONIES
Willy N . Puchas, Boston, Mass.
Mycoplasma-like colonies apparently derived
from bacterial cultures have been occasionally
seen in this laboratory. More recently we have
reported the isolation of PPLO-like colonies from
a number of bacterial cultures-in
2 strains of
salmonella, and in one each of diphtheroid and
H. Influenza (Pachas and Dienes, 67th Meeting,
American Society of Microbiology).
The production of PPLO-like colonies was accomplished by exposing the bacteria to penicillin
after they had been passed several times through
cell-free tissue culture medium without antibiotics.
Preliminary fermentation studies indicate differences between the 3 strains of PPLO-like colonies.
The fermentation pattern was also different from
that of the parent bacteria. Methylene Blue (0.002
per cent concentration) inhibited only the growth
of the mycoplasma-like colonies derived from the
salmonella.
Antigenic studies are presently in progress and
will b e reported later.
The diphtheroid, strain NMI, produced 3 different bacterial phenotypes, each producing
PPLO-like colonies. Reversion from the PPLOlike form to the diphtheroid was observed in one
instance.
Diphtheroids and PPLOs have long been considered to have a possible role in the pathogenesis
of some rheumatic disorders. Recently others have
reported the isolation of diphtheroids and PPLOs
from rheumatoid and lupus materials. However,
the origin of these isolates is still a controversial
matter and awaits further evidence. The various
microbiological findings, if genuine, may be due
to differences in the cultural methods. On the
other hand, if the diphtheroids are contaminants,
their counterpart PPLO’s may be the result of
their exposure to antibiotics.
THEORETICAL
CONSIDERATIONS CONCERNING THE ROLEO F RHEUMATOID FACTOR
AND THE
MACROPHAGE
IN FIBROSING
ALVEOLITIS
H . Rowland Pearsall, Kenneth Ray Wilske and Edward H . Morgan, Seattle, Wash.
There is an unexplained high incidence of
fibrosing alveolitis (pulmonary fibrosis) in patients
with rheumatoid arthritis (RA). This has been
confirmed in our laboratory in a study of 108
patients selected solely on the basis of serum
rheumatoid factor ( R F ) titer. Previous work
(Caplan) has shown that there is an even higher
incidence of this complication in patients exposed
to silica particles.
This paper will analyze the findings in our
series of patients and review current theories
concerning the pathophysiology of rheumatoid
lung disease and silicosis.
I t is proposed that the slowing of capillary
circulation secondary to increased serum viscosity,
known to occur in RA, favors the deposition in the
lung of RF and other macroglobulins necessary
for the formation of RA inclusion bodies. Subsequent phagocytosis of these inclusion bodies by
lung macrophages results in fibrosis in a manner
similar to that thought to occur in silicosis.
304
ABSTRACTS
RENALEVALUATION
IN DISCOIDLUPUSERYTHEMATOSUS
(DLE )
T. I. Pekin, J . F. Maher, N . J . Zuaifler, T . Antonovich and P. N . Horvath, Washington, D.C.
Many studies have tried to relate chronic DLE
and systemic lupus erythematosus (SLE) but
none have included systematic renal evaluation.
This study was designed to determine if renal
abnormalities occur in DLE and, if they are
present, their relationship to other clinical or immunologic features of DLE. Twenty-one patients
with typical skin lesions and biopsies were chosen
by a dermatologist as examples of uncomplicated
DLE. Their histories and physical examinations
were evaluated for evidence of systemic diseases.
Laboratory studies included L E cell preparation,
sedimentation rate, globulin level, serum complement, rheumatoid factor, antinuclear, anticytoplasmic and anti-DNA antibodies. Renal studies
showed proteinuria, present in half, exceeding
300 mg/day in 2. Urine sediment was abnormal in
6; none had blood casts. Creatinine clearance
was low in 4 and PSP excretion decreased in one.
Bacilluria was present in 2 and pyelography abnormal in 2 . Six had no clinical renal findings, 6
only trace proteinuria, and 4 multiple but minimal
findings. Renal disease was strongly suspected in
5. Biopsy showed glomerular changes consistent
with mild lupus nephritis in 5 and vascular lesions
in 3 others. Renal abnormalities did not correlate
with extrarenal laboratory findings. It is concluded
that minor renal abnormalities occur frequently in
DLE; therefore, SLE cannot be distinguished by
renal evaluation.
THESIGNIFICANCE
OF IMMUNO-CONGLUTININ
IN RHEUMATOID
ARTHRITIS
J. S . Percy, Denver, Colo.
Immuno-conglutinin is an antibody to adsorbed
complement, i.e., it is produced in man in response to the fixation of complement on an
antigen/antibody complex. It is probable that the
titer of immuno-conglutinin reflects the amount of
complement fixed, and therefore the magnitude
of the antigen/antibody reaction.
In 100 patients with rheumatoid arthritis, the
immuno-conglutinin titer has been shown to correlate directly with a clinical assessment of the
degree of disease activity. Levels of this antibody
have also been compared with the titer of rheumatoid factor, erythrocyte sedimentation rate,
white cell count, hemoglobin and the course of
the disease.
Since it is conceivable that the results obtained
in rheumatoid arthritis simply reflect non-specific
tissue damage, conditions involving aseptic tissue
necrosis [myocardial infarction ( 3 0 ) , closed fractures and dislocations ( 2 2 ) and uninfected skin
abrasions (18)] were studied. The levels of
immuno-conglutinin found in these conditions did
not differ from those of the normal population.
This work is thought to show that an etiologically significant antigen/antibody reaction, involving complement, occurs in rheumatoid arthritis.
THEAPPEARANCE
OF A LYSOSOME
STABILIZER I N
ADJUVANT
ARTHRITIS
THE
COURSE OF
Robert H . Persellin, Portland, Ore.
There is substantial evidence relating lysosomes
to the development of the inflammatory reaction.
Once initiated, the inflammatory process would
tend to be self-perpetuating, since lysosome contents are autolytic following release from the
organelle. If substances capable of impeding this
release appeared as a consequence of tissue degradation, they could interrupt the inflammatory
process. Using adjuvant arthritis in rats as a model
of self-limited inflammation, the occurrence of a
lysosomal stabilizer was investigated.
Sera obtained at various stages of polyarthritis
were studied for their effect on the stability of a
rat liver lysosome suspension, stressed by incubation at 37" C. Enzyme activities liberated into the
supernate were assayed. The activities of 2 lyso-
soma1 enzymes, acid phosphatase and /3-glucuronidase, released from the organelles in the presence
of a 1 : l O dilution of arthritis serum, were 47 and
41 per cent of control values, respectively. A
mitochondria1 enzyme, isocitric dehydrogenase,
was not affected. Enzyme activities were not inhibited by arthritis sera. The lysosome-protecting
effect reached a maximum soon after the peak of
inflammation and was not detectable when the
arthritis had completely subsided. The serum factor was not related to levels of circulating corticosteroids. Neither heating at 56" C., for 30 min.,
nor repeated absorption with antigen-antibody
complexes altered the level of activity. The stabilizer was non-dialyzable, could be totally removed by absorption with washed lysosomal
305
ABSTRACTS
membranes, but was not found in the gamma
globulin fraction of serum. Activity appeared to be
in the alpha-2 globulin fraction, suggesting the
serum factor may be an acute-phase protein.
I t is concluded that the membrane-reactive
OSTEOARTHRITISOF
THE
lysosome stabilizer appearing in the course of
adjuvant arthritis is a consequence of tissue destruction and may represent a homeostatic response to inflammation.
FIRSTCARPOMETACARPAL
JOINT
I . B. Peter and Leonard Marmor, Los Angeles, Calif.
Osteoarthritis of the first carpometacarpal (trapezio-metacarpal ) joint frequently accompanies
Heberden’s and Bouchard’s nodes in postmenopausal women in whom there is no generalized
osteoarthritis. Our recent experience shows a fema1e:male incidence of about 1 O : l . Careful
clinical and roentgenographic examination typically shows the disease to be bilateral, but
symptoms are sometimes unilateral. In this case,
and especially when other joints are asymptomatic,
the diagnosis may be confused with De Quervain’s
disease or flexor tenosynovitis or the swelling at
the thumb base may be mistaken for a ganglion.
Rheumatoid arthritis commonly spares this joint
unless wrist involvement is severe.
Grasping, pinching and wringing movements
cause pain which is especially severe with abduction of the metacarpal. Occasionally the origin of
the pain may not be clear to the patient, or may
seem to arise in the metacarpophalangeal joint,
but crepitus and pain can be reproduced on rotation of the metacarpal with the wrist fixed. Because the base of the metacarpal tends to sublux
proximally and radially, the hand assumes a
“squared” appearance. X-rays show loss of joint
space, osteophytes and sometimes para-articular
ossicles and subluxation of the first metacarpal.
An excellent view for demonstrating the entire
trapezio-metacarpal joint is obtained by an A-P
view of the hand and forearm in full internal
rotation. Illustrative examples of this disease will
be presented and its treatment discussed.
THERAPY
IN TWENTY-FIVE
PATIENTS
WITH RHEUMATOID
ARTHRITIS ( RA )
AZATHIOPRINE
VoZ K . Philips, W a l d a a r Bergen and Norman 0. Rothenich, Columbus, Ohio
Nineteen patients with classical RA and 6 with
definite RA were treated with azathioprine as
primary or supporting treatment for periods of 3
to 4 months, interspersed with varying placebo
trial periods. All patients, 22 of whom were female, had disease established for more than one
year, and had proven unresponsive to adequate
therapy including salicylates, steroids, gold, indomethacin or combinations of these.
Clinical observation, made at 2- to 4-week
intervals, consisted of the Systemic Index, the
Articular Index of Lansbury, and questions concerning symptoms of drug toxicity. Hematologic
and biologic evaluations included erythrocyte
sedimentation rate, reticulocyte count, quantitative latex fixation test, and serum electrophoretic
pattern. Anti-DNA titers were determined by
bentonite flocculation, immunofluorescent study,
and using 1131 tagged DNA antigen. Anti-RNA was
detected by ,bentonite flocculation method. ,
Salicylate was usually maintained at a daily
dosage of 2.4 to 3.6 grams per day. Attempts at
reduction of steroid rarely exceeded 1 mg. prednisone or equivalent per day per visit. Where
appropriate, gold therapy was discontinued.
Although some patients reported subjective improvement, serial evaluation of Systemic Index
remained essentially unchanged during the treatment. The Articular Index showed a definite decline in the number of joints actively involved
in synovitis with relapse during placebo trials.
Anti-RNA antibody was found present in 23.
It was not altered by treatment. Anti-DNA antibody was found in only 5 patients’ serums by
bentonite flocculation method, but in 15 by the
immunofluorescent method. In no patient was the
presence of anti-RNA or anti-DNA antibody altered by the dosage of azathioprine given (100150 mg./day). Neither the titer of rheumatoid
factor (latex fixation), nor quantity of gamma
globulin present in the sera of these patients
were altered by azathioprine therapy.
Toxicity was limited to some degree of anorexia
or nausea in 22 of the 25 patients. Three patients
demonstrated temporary granulocytopenia, disappearing on reduction or discontinuance of the
drug, it being resumed in lower dosage without
subsequent effect. Azathioprine may have mild
anti-inflammatory effects rather than immunosuppressive effects in the dosages given.
306
ABSTRACTS
THEANTINUCLEOLAR
ANTIBODIES:CLINICALINCIDENCE,
IMMUNOFLUORESCENCE
PATTERNS
AND A DESCRIPTIONOF A NEW ANTIBODY
TO AN INTRANUCLEOLAR
STRUCTURE
R. F . Ritchie, Portland, Maine
In conventional immunofluorescent techniques
antinucleolar antibodies ( ANoA) are frequently
masked by coexistent antinuclear antibodies
(ANA). The clinical incidence and immunofluorescent morphology of this group of immunoglobulins was investigated by examination of
Disease
SLE
ss
liA
JRA
#Pts. #ANAS-> 1:16
55
22
184
49
53
17
58
11
% Total
fluorescence photomicrographs ( 1250X ) produced
by a method which yields sharp resolution.
In the group of patients with definite rheumatic
diseases the following distribution of ANA and
ANoA were found:
ANoA+
( 96% )
15
(77%)
(31%)
(22%)
9
Examination of ANoA immunofluorescent patterns indicates that, as also occurs with antinuclear
antibodies, several types exist. Five fluorescence
patterns have been observed: a ) the whole nucleolus, b ) a lobnlated intra-nucleolar structure
which resembles the nucleolema, c ) very small,
usually single, round intra-nuclear structures, d )
a rim of bright fluorescence around the nucleolus,
e ) combinations of the above. The lobulated pattern ( b ) is most frequently observed. Using a
fluorescein-labeled preparation of this yG antibody in the ANA inhibition technique previously
described, the clinical incidence in 139 rheumatic
sera was as shown in the table to the right.
14
4
% Total
%ANA+ > 1 :I6
(27%)
(41%)
( 8%)
( 8%)
28%
53%
24 %
36%
Disease
SLE
ss
RA
JRA
Total
%+
7% (4/55)
9% (2/22)
3% (5/184)
0
(0/49)
4% (11/309)
The data indicate that antinucleolar antibodies
are common in rheumatic patients-particularly
those with systemic sclerosis. Identification of a
new factor reacting with only a portion of the
nucleolus, perhaps the nucleolema, is further evidence for the fine specificity of these antibodies.
FUNCTION
IN THE SURGICAL
RHEUMATOID
HAND
H . S . Robinson, Patricia MacBain and F. P. Patterson, Vancouver, British Columbia
A prospective study of hand function following
a uniform surgical procedure on the rheumatoid
hand has been carried out.
The surgical procedure consisted of metacarpophalangeal ( M P ) joint arthroplasty ( M P head
resection), realignment of fingers with Kirschner
wires and reposition of extensor tendons on the
radial side.
The procedure was carried out by a single surgical team in the Department of Orthopaedic
Surgery at the University of British Columbia.
Patients selected had severe MP joint involvement with subluxation and associated ulnar drift.
All had extensor tendon displacement. Care was
taken to screen out those with marked proximal
interphalangeal joint limitation.
Hand function tests measuring some aspects of
function have been established, including stand-
ardized tests of power grip; applied strength;
dexterity; pinch strength; and hook strength.
These were carried out in the Canadian Arthritis
and Rheumatism Society Arthritis Unit in Vancouver.
The present study is concerned with 14 hands
in 12 consecutive patients who have been followed
from 6 months to 1 year post-operatively by a
team consisting of surgeon, occupational therapist
and rheumatologist. In this group of patients the
battery of functional tests were applied preoperatively and post-operatively at 6-month and
1-year intervals.
I n the overall picture 8 of 14 hands have significantly improved function, 4 are unchanged
functionally, and 2 are worse. One of the latter
developed a complicating infection.
Improvement occurred in the majority of cases
307
ABSTRACTS
in the areas of pinch strength, dexterity and hook
strength with lesser gains in power grip and its
application.
With one exception, realignment of the fingers
has been maintained. From the patients’ point of
view, there has been less pain, improved function
and a desirable cosmetic result.
FAMILIAL
NEPHROPATHY
AND GOUT IN
A
KINDRED
Frederick M . Rosenbloom, William N . Kelley, Albert A. Carr and J . Edwin Seegmiller,
Bethesda, Md.
The renal disease associated with gout is clas- Among 4 sons of 2 affected fathers, the oldest 3
(ages 14, 16 and 17) have hyperuricemia and
sically of late onset; morbidity is low and early
mortality is rare. The presence of gout and renal diminished inulin clearances. The eldest has had
disease with early death in 4 brothers stimulated one attack of gout. Audiograms on all are normal.
investigation of 3 generations of their kindred. In Evaluation of uric acid metabolism by balance
the first generation 3 brothers died with renal and isotope techniques revealed normal production. Renal biopsies on 2 showed no distinctive
disease and gout before age 37. Another brother
died at age 60; his serum uric acid was normal. pathology. Karyotypes on 2 were unremarkable.
The high concordance of gout and renal disease
An only sister has asymptomatic hyperuricemia.
In the second generation, 4 sons of an affected in this family suggests that the 2 conditions are
brother developed gout around age 20 and died both manifestations of the same genetic defect.
with renal disease before age 35. Two other sons The transmission from father to son over 3 generain this sibship have normal serum uric acid. The tions is compatible with an autosomal dominant
only son of a second affected brother has asymp- form of inheritance. Clinical and pathologic featomatic hyperuricemia. We have studied 9 of 13 tures of this disease distinguish it from previously
members of the third generation. Three sons of described forms of hereditary nephritis.
unaffected fathers have normal serum uric acid.
IN RESPONSE
TO ALLOPURINOL
AN ENZYMATIC
BIOCHEMICAL
BASISFOR VARIATION
Frederick M . Rosenbloom, William N . Kelley, John M . Miller and J. Edwin Seegmiller
Bethesda, Md.
Treatment with allopurinol produces interruption of uric acid formation by inhibition of
xanthine oxidase, and inhibition of total purine
production. Although the first effect is consistently
observed in all patients, the magnitude of the
latter varies greatly among individuals. A group
of 5 patients with nontophaceous gout showed a
decrease in total purine excretion (-19 to -75 per
cent) when treated with allopurinol, while 8 additional patients showed no significant decrease
(-8per cent to +23 per cent). A marked deficiency
of the enzyme hypoxanthineguanine phosphoribosyltransferase (HGPRT) was found in 7 of
these 8 patients who failed to show a response.
The enzyme activity in dialyzed erythrocyte lysates, using hypoxanthine as a substrate, was
<0.02 per cent of normal in 2 children with the
familial neurological syndrome described by Lesch
and Nyhan, 2 per cent of normal in 3 brothers
with adult gout, and 1 0 per cent of normal in
2 brothers in a different family, one of whom had
gout. Since the enzyme HGPRT is responsible
for the conversion of hypoxanthine, guanine, or
allopurinol to their respective nucleotides, the
forms necessary for their actions as feedback inhibitors of purine synthesis, the observed deficiency readily explains the failure of allopurinol
to reduce total purine excretion in this group.
HGPRT deficiency was associated with a 5-fold
increase over normal in cerebrospinal fluid oxypurine concentrations. This was further increased
2- to 3-fold by treatment with allopurinol. The
possible role of oxypurines in the generation of the
neurological dysfunction found in some of these
patients will be discussed.
INWMETHACIN
IN THE TREATMENT
OF JUVENILE
RHEUMATOID
ARTHRITIS
Sanford H . Roth and DeWitt W . Englund, Phoenix, Ariz.
Indomethacin has enjoyed widespread clinical
usage as an anti-rheumatic drug. To date, how-
ever, reported data has been insufficient to allow
its application on other than an investigative
308
ABSTRACTS
basis in the treatment of juvenile rheumatoid arthritis. This report concludes a four-year study of
indomethacin in the treatment of 24 patients seen
at the Phoenix Arthritis Center with the diagnosis
of juvenile rheumatoid arthritis. The ages of the
patients ranged from 3 to 15 years. Dosages of
indomethacin were from 12.5 to 100 mgms. per
day, depending on the surface area of the child.
By A.R.A. Therapeutic Criteria, 9 of the 24
patients showed Grade I improvement, 9 showed
Grade I1 improvement, and 6 showed Grade I11
improvement. In all instances there was improvement when indomethacin was added to the patient’s existing therapeutic regimen. In 5 of the
above cases, however, a subsequent recrudescence
of disease activity necessitated addition of other
antiphlogistic medications. Side effects were minor
although not uncommon and ranged from headaches to mild vertigo and nausea. An exception to
this was one patient who developed an active
duodenal ulcer necessitating the withdrawal of
indomethacin and her other antiphlogistic drugs.
I n this study, all 24 children demonstrated
some degree of salutory effect from indomethacin.
The drug was found to be relatively safe with the
exception of one child who developed duodenal
ulcer. I t is our conclusion that indomethacin has
merit in the treatment of juvenile rheumatoid
arthritis when used with proper care and caution
in the overall management of the patient.
THE USE OF PLASMAGOLDLEVELSIN DETERMINING
DOSE, FREQUENCY,
TYPEOF COLD
SALT,AND IMPENDING
TOXICITY
IN CHRYSOTHERAPY
FOR RHEUMATOID
ARTHRITIS
Norman 0. Rothermich, Wuldemar Bergen and Vol I<. Philips, Columbus, Ohio
Freyberg’s findings ( 1941 ), that the concentration of gold in plasma reaches a maximum within
one hour after injection, remains constant for a
few hours and then declines, is reconfirmed. Soluble gold salts injected at 7-day intervals ( 2 5 mg.
elemental gold) result usually in stairstep increases in the average plasma gold level to 400
mcg% ( & 100 mcg.% ). Increasing the frequency
of gold injections to twice a week results in a
more rapid rise in average plasma gold level,
without a resultant increase in urinary excretion
rate. Reduction of the frequency of injection of
intramuscular gold to 2- or 3-week intervals
results in a negligible plasma gold level, no incremental increase being noted upon each subsequent injection.
Doubling the dose ( 50 mg. of elemental
gold ), but not the frequency of gold injection
doubles the average plasma gold level. Decrease
of frequency of such gold injections to 2- to 3-
week intervals results in negligible plasma gold
levels.
After initial 20-week “classical” soluble-salt
chrysotherapy, attempted “maintenance” at 2, 3,
and 4 week intervals results in rapid decline in
average plasma gold levels, regardless of the dosage. If initial treatment with soluble gold salt is
supplanted by “maintenance” with an oil-depot
preparation, this decline may be avoided.
Our early studies would indicate that measurement of plasma gold values and individualization
of intramuscular gold injection frequency, dosage
and type may be valuable in achieving maximum
results from chrysotherapy.
Our early studies ( 3 instances ) would indicate no definite relationship between average
plasma gold level achieved or maintained and the
appearance of muco-cutaneous lesions of gold
toxicity.
SERUMANTINUCLEAR
FACTORS
I N PROGRESSIVE SYSTEMIC SCLEROSIS ( SCLERODERMA
)
Naomi F . Rothfield and Gerald P . Rodnan, New York, N. Y. and Pittsburgh, Pa.
The sera of 48 patients with progressive systemic sclerosis were studied for antinuclear factors
( ANF) by the indirect fluorescent antibody technique, using mouse liver sections as a source of
nuclei. Sera from 28 patients had a positive test
for ANF at a titer of 1:16 or greater; 4 patients
had titers of 1:256 or greater. The most common
pattern of nuclear fluorescence observed, using
undiluted sera, was that of fine speckles which
formed a reticular network (14 patients.) Large
discreet speckles were present in 13 sera. A dif-
fuse pattern without speckles was present in only
2 sera. The peripheral pattern was not observed.
There was no correlation between rapidity of progression of disease or disease duration and titer or
pattern of ANF. Of the 28 sera which gave a
titer of 1:16 or more using antihuman y-globulin,
18 had both IgM and IgG ANF, when specific
anti-IgG and anti-IgM were used. Four patients
had only IgM ANF and 6 patients had only IgG.
The large speckles were most commonly seen
using the anti-IgM. There was no correlation be-
309
ABSTRACTS
tween the presence of IgM ANF and rheumatoid
factor. There was no correlation between the
presence of any immunoglobulin class of ANF
and severity of disease progression or duration of
disease.
None of 84 first-degree relatives of 24 patients
had a titer of greater than 1:8. Titers of 1:8 or
less were present in 13 relatives. One of 18
spouses had a titer of 1:128.
The data indicate that the ANF present in
scleroderma patients occur less frequently, are of
a lower titer and, in general, give a different pattern of nuclear fluorescence than the ANF in sera
of patients with systemic lupus erythematosus.
HEREDITARY
PERIODIC EDEMA
TREATED
BY SYMPATHECTOMY
Jerome Rotstein, Stanley C . Fell and Francis F. Foldes, Bronx, N. Y.
A 17-year-old white woman presented with
increasingly frequent episodes of intermittent
elephantine non-pitting blanching erythematous
edema of the right hand and left foot for 3%
years and 25 years respectively. The only other
physical abnormality was dermatographia and the
only laboratory abnormality was a persistently
elevated eosinophil count. Lymphangiograms of
the lower extremities during periods of remission
were normal. A diagnosis of juvenile rheumatoid
arthritis was made by many observers prior to
admission to our facility. The physical findings
and laboratory abnormality suggested to us a disorder of the wheal-and-erythema type or triple
response of Lewis reaction. This results from
excessive sympathetic activity which leads to
constriction of the post-capillary venule and precapillary arteriole, based on a disorder of histamine release or a defect in the z o n a l reflex.
Sympathetic nerve blocks relieved pain completely and edema partially. A right transthoracic
sympathectomy completely relieved the upper
extremity edema in 72 hours, followed by the
longest continuous remission in 3% years. A left
lumbar sympathectomy produced even more dramatic relief of signs and symptoms in the lower
extremity. A discussion of periodic edema and the
rationale of therapy of this disorder will be pre.
sented in this paper.
EARLY
SYNOVECTOMY
IN THE JWENILERHEUMATOID
ARTHRITIC
John L . Sburburo, Jr., Albert0 Bosch, Peter Vunace and Evan Owens, Philadelphia, Pa.
and Atlantic City, N. J.
There have been only sporadic reports concerning the efficacy of early synovectomy in the
rheumatoid arthritic child. Very little is known
about the subsequent course of the disease or the
local response of the surgically treated joint. Of
great importance is the effect of synovectomy on
the developing epiphysis.
This report will describe our experience with
early synovectomy in the systemic form of rheumatoid arthritis. Over the past two years, 10 patients have been treated with selective synovec-
tomy. Where feasible, the opposite joint has been
utilized as a clinical control. The ankles, knees,
hips, wrists and finger joints have been evaluated
with 15 surgical procedures. The average age was
9.7 years, with the youngest being 6 years and the
oldest 17 years.
This is an on-going project and it will not be
possible to state any definite conclusions for a
number of years; however, the early results have
been quite encouraging. Our indications, contraindications and results thus far will be discussed.
IN PATIENTSWITH GENERALIZED
SCLERODERMA
(PROGRESSIVE
COLLAGENALTERATIONS
) TREATED
WITH DIMETHYL
SULFOXIDE
( DMSO )
SYSTEMIC
SCLEROSIS
Arthur L. Scherbel and Lawrence J . McCormack, Cleveland, Ohio
The effect of dimethyl sulfoxide administered
for 3 to 30 months to 61 patients with progressive
systemic sclerosis is reported. Criteria for classification of disease severity and also for evaluating
objective clinical improvement are included. Good
to excellent cutaneous improvement occurred in
40 of the patients including the healing of ischemic ulcers in 30 of 33 patients. No significant
effect was noted on visceral manifestations of the
disease.
During the study, 8 patients with advanced
disease died of renal, cardiac or pulmonary complications. Histochemically, serial skin biopsies
showed an increase in acid mucopolysaccharides
and a decrease in collagen bundles. Simultaneously, urinary hydroxyproline levels increased.
310
ABSTRACTS
Certain patients also shqwed a decrease in interstitial calcinosis. To our knowledge these changes
GAMMAGLOBULIN TURNOVER
have never been reported with other methods of
therapy.
IN
RHEUMATOID ARTHRITIS
Frank R. Schrnid, Chicago, Ill.
Gamma globulin derived from healthy donors
is metabolized normally in recipients with rheumatoid arthritis. The present study suggests that
gamma globulin derived from patients with
rheumatoid arthritis acts similarly when its turnover is determined in either rheumatoid or nonrheumatoid recipients.
Gamma globulin from 7 individual donors was
isolated from either whole serum or its ammonium
sulfate fraction in the first elution peak off DEAE
cellulose and trace-labeled with iodine-131. Each
preparation usually was given to 2 or 3 recipients.
In every case, one of the recipients was also the
donor of the globulin. A total of 17 studies were
performed in 12 subjects, including persons with
hyper- and hypogammaglobulinemia and one
with rheumatoid factor but without rheumatoid
arthritis. Five subjects were studied twice. Serum
and urine concentrations of the label were followed for usually 3 weeks. The data were calcnlated as described by Cohen and Freeman
(Biochem. J. 76:475, 1960).
No correlation could be established between
the presence of rheumatoid factor and rate of
removal of the label as determined by the fractional catabolic rate or serum half life. However,
a correlation was found between the total intravascular pool of gamma globulin and its rate of
removal, hypergammaglobulinemia being associated with accelerated removal and hypogammaglobulinemia with decreased removal. Four of the
globulin preparations were partially denatured as
indicated by reduced half lives (Z = 11 days,
normal 20 days) and by a faster catabolic rate
early in each study. Although rheumatoid factor
might have been expected to bind more effectively to such preparations and hasten its removal,
no differences could be discerned between rheumatoid and non-rheumatoid recipients.
These results suggest that the turnover of
gamma globulin in the patient with rheumatoid
arthritis is governed by the amount of globulin
in the intravascular space as has been shown for
normal individuals. Rheumatoid factor does not
appear to influence this function. Its possible effect
upon the elimination of aggregated globulin or
globulin in immune complexes has not been excluded.
THESYNOVIAL
MEMBRANE
IN PSEUDOGOUT:
ELECTRON
MICROSCOPIC
OBSERVATIONS
H . Ralph Schumacher, Boston, Mass.
Many studies have reported joint fluid findings
in pseudogout ( chondrocalcinosis articularis ) . Although the histopathology of the synovial membrane has been briefly described (McCarty and
Gatter, Bull. Rheum. Dis. 14:331, 1964) its ultrastructure has not been investigated. Therefore,
needle biopsies from knees of 2 patients during
acute episodes of pseudogout were studied by
light and electron microscopy.
Calcium pyrophosphate crystals were found in
the interstitium, in hyperplastic type A and B
synovial lining cells, and in neutrophils and
macrophages. They were rodlike, acicular, rhombic or irregular with a lacelike internal structure.
The crystals were best retained in alcohol-fixed
specimens, but these gave poor preservation of
tissue ultrastructure. Frequently, after glutaraldehyde fixation for electron microscopy only
electron-lucent crystal-shaped spaces remained.
Intracellular crystals or residual clefts were gen-
erally membrane-bounded and appeared to be in
phagosomes which also contained fibrin and cellular debris. A number of crystals were located
adjacent to the Golgi apparatus of type B lining
cells. Many of these cells also contained focal
lipid deposits. Phagocytosis of degenerating neutrophils by macrophages was common. Fibrin and
extracellular dense bodies were seen in the interstitium.
Many small venules demonstrated endothelial
gaps, some of which were occupied by erythrocytes and emigrating neutrophils. Basement membranes were often laminated. Crystals were not
found in the vascular wall, and there was no
evidence of thrombosis or necrosis of blood vessels. The vascular changes were therefore considered compatible with the effects of a chemical
mediator.
These findings will be discussed and compared
with ultrastructural studies in other joint diseases.
311
ABSTRACTS
THEMICROVASCULATURE
OF THE SYNOVIAL
MEMBRANE:
ULTRASTRUCTURE
AND RESPONSE
TO ISCHEMIA
AND JOINT MOTION
H . Ralph Schumacher and Guido Majno, Boston, Mass.
Recently there have been several reports of
ultrastructural alterations in the blood vessels in
rheumatic diseases; however, there has been no
systematic investigation of the fine structure of
normal synovial vessels or of vessels responding
to relatively simple forms of injury. Therefore,
we have studied the synovial membrane of the
Cebus Albifrons monkey by whole mounts and
light and electron microscopy after intravenous
injection of tracer particles (carbon, ferritin ) ,
Synovium was examined from 3 areas of the
knee joint: capsule, fatty villi and fibrous synovium overlying the femoral condyles. Electron
microscopy of normal superficial capillaries and
venules showed many endothelial fenestrations
closed by thin diaphragms. Deeper vessels had
strikingly high endothelium with cytoplasm unusually rich in organelles including many pinocytic vesicles, dense bodies, fibrils, rod-like
Weibel-Palade bodies, abundant rough endoplas-
mic reticulum, and phagosomes containing lipid
and other materials. Numerous pericytes were
prominent even around the smallest vessels. Capillaries between lobules of fat consistently had
thinner, darker endothelium. Tracers occasionally
leaked through gaps between endothelial cells.
In order to ascertain whether joint motion was
responsible for these “physiologic leaks”, knees
were subjected to passive flexion and extension
for periods up to one and one half hours; in some
animals significant increases in leakage were
noted, but in others none were demonstrable. The
basis for these discrepancies is under investigation.
Two and one half hours of tourniquet-induced
ischemia caused minor, focal increases in leakage,
but no other morphologic lesions.
These observations will be discussed in relation
to the possible role of microvascular changes in
joint disease.
IMMUNOCHEMICAL
OBSERVATIONS
ON SERAOF PATIENTSWITH SYSTEMIC
LUPUS
AND DURINGCLINICALACTIVITY,
AND IN REMISSION
ERYTHEMATOSUS
(SLE), PRECEDING
Peter H . Schur and John Sandson, New York, N. Y.
Serum antibodies to nuclear components and
low levels of hemolytic complement (C’H50) are
thought to occur primarily in patients with active
rather than inactive SLE. Relatively few patients
have been observed on whom similar studies
were performed prior to the development of
clinical activity. The present investigation was
undertaken to determine what immunochemical
parameters would correlate with or precede clinical activity. Ninety-two patients with definite SLE
were studied. Most of the patients were seen
during both clinically active and inactive phases.
There was no difference in the incidence of
antibodies to calf thymus, soluble nuclear antigen,
or nucleoprotein ( N P ) in patients with active or
inactive disease. Serum C‘H50 was normal at
some time in only 10 per cent of patients with
active renal disease, 50 per cent with inactive
renal disease, and 88 per cent without renal disease. Serum C‘H50 was low at some time in over
90 per cent of all patients. Therefore a normal
level of serum C‘H50 strongly argues against active renal disease. Similar analyses indicated that
precipitating antibodies to ribosomes ( R b ) occurred only in renal disease and that precipitating
antibodies to deoxyribonucleic acid (DNA) and
heat-denatured DNA (HDNA) favored the presence of (active) renal disease. Some patients
were seen in whom exacerbations were preceded
by a fall in serum C’H50, others by a simultaneous fall in C’H50 and rise in antibody titers to
NP and Rh. Of particular interest were a number
of patients in whom exacerbation of disease was
preceded by increasing titers of antibodies to
DNA (and Rb), followed by hypocomplementemia. These studies suggest that therapy based
on immuno-chemical parameters may be utilized
in certain patients with SLE in order to prevent
clinical exacerbation.
ACIDOSISIN RHEUMATICDISEASES
LATENTRENAL TUBULAR
Martin A. Shewn, and Wu-Hao Tu, San Francisco, Calif.
Because hyperchloremic acidosis with inadequate acidification of urine (renal tubular acidosis ) has been reported in hyperglobulinemic states,
investigation of renal acidification in rheumatic
diseases was undertaken with the purpose of detecting subclinical (latent) cases of renal tubular
312
ABSTRACTS
acidosis. Ten patients with Sjogren’s syndrome
( S S ) , 12 with systemic lupus erythematosus
(SLE), and 18 with rheumatoid arthritis (RA),
were studied and compared to 21 healthy subjects.
All patients had normal values for 24-hour endogenous creatinine clearance and serum electrolytes, and in each the urine was sterile. Renal
acid excretion was assessed before and after
administration of an acute acid load (0.1G.
NH,Cl/kg. weight). Renal concentration was assessed by measuring urine osmolality after 14
hours of fluid deprivation. Three of 10 patients
with SS, 2 of 12 with SLE, but none with RA,
were found to have a n impairment of urinary
acidification in that their urine p H failed to de-
crease below 5.5 (>mean $3SD) after NH,C1
loading in spite of increased blood hydrogen ion
concentrations. Also, a subnormal response was
observed in the excretion of titratable acid and
ammonium per unit of glomerular filtration rate
in patients with SS and SLE but not in the RA
group. No correlation was detected between the
acidification abnormality observed and the duration of disease, drug history, gamma globulin
concentration or renal biopsy findings. It is concluded that patients with SS and SLE without
overt evidence of acid base imbalance may have
a functional defect in renal acidification (latent
renal tubular acidosis) of obscure cause.
PHARMACOKINETIC STUDIES OF ACETYLSALICYLIC
ACD
RHEUMATOIDARTHRITIS
IN
PATIENTS WITH
Stephen D. Sholkofl, Malcolm Rowland, Edward J. Eyring and Sidney Riegelman,
San Francisco, Calif.
Observations in this and other laboratories have
suggested an alteration in acetylsalicylic acid
( ASA) metabolism in patients with rheumatoid
arthritis. This report describes pharmacokinetic
studies of ASA performed to determine whether
a difference exists because of an abnormal absorption, chronic ingestion of the drug, or concomitant
corticosteroid administration. We are currently
investigating the effects of these factors on salicylic acid.
The study groups consisted of rheumatoid patients on long-term ASA and corticosteroid therapy
(Group I ) , rheumatoid patients on chronic ASA
ingestion alone (Group I1 ), and normal volunteers
( Group I11 ) . A gas-liquid chromatography technique was used to measure the concentrations of
ASA.
The biological half-life of ASA in whole blood
in vitro averaged 28 minutes for Group I, 26
minutes for Group 11, and 32 minutes for Group
111.
ASA in solution was given to the subjects to
study the kinetics in vivo. For Group I the peak
plasma concentration averaged approximately 8
pg/ml and was reached between 15 and 21 minutes after administration. The half-life was 17.5
minutes. In Group I1 the peak plasma level was
also approximately 8 #g/rnl and was reached between 15 and 21 minutes after administration. The
half-life was 16.5 minutes. The peak ASA level
in normal was approximately 10 /g,uml, attained in
the range of 15 to 25 minutes after drug administration. The half-life for normal was 17.4 minutes.
The results of these studies demonstrated no
evidence for a significant alteration in the pharmacokinetics of ASA in rheumatoid patients
caused by drug-induced tolerance, concomitant
corticosteroid administration, or by abnormal drug
absorption.
THEEPIDEMIOLOGY
OF DRUG-INDUCED
SYSTEMIC
LUPUSERYTHEMATOSUS
( SLE ) :
COMPARATIVE
DATA ON IDIOPATHIC
SLE
M . Siegel, S. L. Lee, and N . S . Peress, Brooklyn, N. Y.
The epidemiology of drug-induced systemic
lupus erythematosus has been investigated in New
York City for the years 1957 to 1966. The study is
based on a critical review of cases following
prolonged use of four commonly implicated drugs,
diphenylhydantoin, isoniazid, hydralazine and
procainamide. The results on host factors and
time trends obtained in 54 cases are compared
with data on 101 cases of idiopathic SLE.
An increase in the incidence of drug-induced
lupus was observed, which was not apparent for
idiopathic SLE. The increase was due to a sharp
rise in cases attributed to procainamide in 1965
and 1966. This apparently is related to more
widespread use of the drug as evident in the twofold increase in its sales.
Comparative data on host characteristics are
available for sex, age and race. 1) The prepon-
313
ABSTRACTS
derance of females so typical of SLE was also years for drug-induced lupus and 35.8 years for
observed for drug-induced lupus, although the SLE. 3) Unlike idiopathic SLE, there was no
difference is less marked, particularly for isoniazid evidence of an increase in cases of drug-induced
and procainamide. 2 ) The age groups affected Iupus among Negroes.
varied with the population treated from an averThus, comparative epidemiological data on
age of 33.4 years for epileptic subjects on drug-induced SLE and idiopathic SLE were rediphenylhydantoin to 60.7 years for patients with vealing of similarities and differences which may
coronary occlusion and arrythmia treated with be of etiological significance.
procainamide. The over-all mean age was 47.4
THEEFFECTOF AGGREGATION
ON THE REMOVAL
OF GAMMAGLOBULINFROM
RHEUMATOID
JOINTS
Anthony 1. Sliwinski and Nnthan J . Zvaifler, Washington, D. C.
Recent studies suggest that autologous gamma
globulin and rheumatoid factor combine in the
joint cavity causing the articular inflammation of
rheumatoid arthritis. It has been proposed that
rheumatoid factor retains aggregated gamma
globulin in the joint, thereby localizing the injury.
Heat aggregated gamma globulin treated with
2-mercaptoethanol reacts with rheumatoid factor
but is not complement fixing or phlogistic.
Autologous gamma globulin from sera of 6
patients with seropositive rheumatoid arthritis and
one with osteoarthritis was mercaptoethanol
treated. As much as 7.9 mgm. of autologous
mercaptoethanol gamma globulin and 1.0 mgm of
heat aggregated mercaptoethanol gamma globulin
were introduced without producing joint inflammation. Autologous gamma globulin, mercaptoethanol gamma globulin, and heat aggregated
mercaptoethanol gamma globulin were labeled
with 1131 or 1125. The simultaneous disappearance
of any two labeled proteins was followed by
external counting over the knee. Autologous
gamma globulin and autologous mercaptoethanol
gamma globulin disappeared at similar rates (1.1
to 1.5 day half-life). Aggregation of autologous
mercaptoethanol gamma globulin did not retard
its disappearance from the knee 1.4 to 1.3 day
half-life); the greater the aggregation the faster
its disappearance. Similar results were obtained
in osteoarthritis. Blood levels of heat aggregated
mercaptoethanol gamma globulin were 2- to 200fold less than non-aggregated mercaptoethanol
gamma globulin. The greater the alteration of
the protein, the greater the difference noted.
Radioactivity was non-dialyzable in the blood,
but was dialyzable in the urine.
These studies show that: 1) No joint inflammation was produced with autologous mercaptoethanol gamma globulin. 2 ) Aggregation of mercaptoethanol gamma globulin enhances rather
than retards its removal from the joint. 3) No
difference was noted between rheumatoid arthritis
and osteoarthritis joints. 4) These findings do not
support the proposed theories of joint inflammation.
ON PULMONARY
FUNCTION
IN PATIENTS
WITHPROGRESSIVE
EFFECTOF D-PENICILLAMINE
SYSTEMICSCLEROSIS
J . Donald Smiley, Robert L. Johnson,
Evaluation of drug effectiveness in progressive
systemic sclerosis (PSS) is difficult because of the
lack of objective criteria for improvement during
JT.
and Morris Zif, Dallas, Tex.
short-term therapy. However, pulmonary function,
particularly gas diffusion measurements, which
may be repeated in the same patient with highly
~
Mean Values As % of Normal
Pre-treatment
Post-treatment
Forced Vital Capacity
Forced Expiratory Volume (1 sec.)
Total Lung Diffusing Capacity (DL)
Membrane Diffusing Capacity (U,)
Total Lung Capacity
72.2%
70.2
59.3
51.4
82.5
71.2%
72.7
57.2
44.8
not done
314
ABSTRACTS
reproducible results, offer an opportunity for controlled quantitative evaluation of response to
therapeutic agents in PSS. Such pulmonary function was moderately to severly impaired in 11
patients treated with D-penicillamine ( Cuprimine), a drug which has been found to increase
the soluble collagen content of the skin. Detailed
tests were carried out before and after 4 to 5
months of treatment with one to 2 grams daily of
this agent. Seven patients tolerated the drug for
the complete treatment period. Results in these
patients are shown.
No objective clinical changes in other organ
systems were noted following treatment. Two patients, not included above, who were treated with
penicillamine without pulmonary function tests
also showed no evidence of clinical improvement
during the treatment period.
Four patients showed gastrointestinal or allergic
reactions requiring cessation of treatment after a
few days. However, these were also re-evaluated
and will be presented for comparison with the
treated group.
It is concluded that, in addition to producing
severe toxic reactions in some patients, penicillamine failed to induce significant improvement
in pulmonary function of patients with PSS during the time period studied in the dosage range
utilized.
CAPILLAROSCOPY
AND BIOPSYSTUDY
OF CUTANEOUS
MICROANGIOPATHY
IN SYSTEMIC
LUPUSERYTHEMATOSUS
N . M . Smukler, W. Redisch, E . J . Messinu, G. Hughes and J . P . Kulka, Boston, Mass.
and New York, N. Y.
Widespread distortion of the microvasculature
in normal-appearing skin of patients with systemic
lupus erythematosus has previously been demonstrated by in vivo capillaroscopy or alkaline phosphatase staining of tissue sections. The present
investigation was designed to correlate the in vivo
observations of this microangiopathy with the
findings in quick-frozen biopsy specimens which
permitted both three-dimensional visualization of
the microvasculature and subsequent histologic
study of paraffin sections.
In 10 patients with systemic lupus erythematosus, rotary punch biopsies were obtained without
use of anesthesia from nailfold, forearm or malleolar skin at sites which in all but one instance
showed capillaroscopic evidence of microangiopathy. Abnormalities of the capillary loops included,
in order of incidence, dilatation, a meandering
course and pericapillary densities. Comparable
changes were noted in 4 of the frozen-cleared
preparations, even though these specimens failed
to show evidence of inflammation or other histologic changes. I n 2 of the remaining 6 biopsies
there was minimal focal inflammation and in 2
others slight focal erythrocyte extravasation. Although 6 patients were under steroid therapy at
the time of biopsy, the occurrence of microangiopathy without associated inflammation was not
dependent on steroid treatment, since it was also
found in 2 patients who had received no such
therapy.
The finding of a distorted microvascular pattern, even without associated inflammation, in the
skin of patients with systemic lupus erythematosus
indicates that the microangiopathy is a basic manifestation of the disease. It is suggested that this
underlying abnormality may predispose to the
development of the clinical lesions.
CLINICALSIGNIFICANCE
OF
THE
“RA CELL”
D. A. Sones, F. C . hlcDufie and G . G. Hu,ncler, Rochester, Minn.
The diagnostic value of the presence of “RA
cells” in synovinl fluid remains controversial. In an
effort to evaluatc the significance of such leukocytic inclusions as an aid to early diagnosis of
rheumatoid arthritis, fluids from 47 patients were
studied. Twenty-nine patients had classic, definite or probable rheumatoid arthritis, 5 were
classified as possible rheumatoid, G had nonrheumatoid inflammatory conditions and 7 represented non-inflammatory arthritis.
Eighty-five per cent (25/29) of rheumatoid
fluids demonstrated intraleukocytic inclusions but
the lysed cell extracts of only 5 fluids contained
demonstrable rheumatoid factor by the SingerPlotz latex and Ripley anti-Rh methods, and in
each of these rheumatoid factor ( K F ) was also
present in the synovial fluid and serum, urnally
in high titer. Inclusions were aIso present in the
leukocytes of 8 of the remaining 11 fluids (73
per cent) from patients regarded as having “inflammatory” arthritis ( 5 “poaaible” rheumatoids
and G non-rheumatoid) but in none was rlieuma-
315
ABSTRACTS
toid factor detected in the cell extracts. Only one
of 7 “non-inflammatory” fluids revealed the presence of inclusions.
Eight patients with monarticular arthritis suspected of having RA (one definite, 5 probable,
2 possible) were examined critically in the hope
that the presence of RA cells might be of significant diagnostic help at an early stage. Though
fluids from all 8 contained significant numbers of
POLYMYALGIA
RHEUMATICA
WITHOUT
THE
these cells, the disrupted leukocytes of only one
contained demonstrable rheumatoid factor, and in
this patient RF was also present in serum and
synovial fluid as well.
Morphologically identifiable “RA cells” are a
helpful index of inflammatory synovitis but are
not of any specific diagnostic significance. Perhaps
to avoid the implication of specificity the term
“RA cell” should be avoided.
CONSEQUENCES
OF
TEMPORAL
ARTERITIS
Harry Spiera, Charles M . Plotz and Sehan Dauison, New York, N. Y.
Polymyalgia rheumatica is a clinical syndrome
of unknown etiology and pathogenesis. It has
been reported that biopsy of the temporal artery
in some patients with this syndrome shows pathologic changes consistent with temporal arteritis
even in the absence of clinical evidence of temporal arteritis. This has led to the suggestion that
polymyalgia rheumatica is a variant of temporal
arteritis.
The authors have studied a series of 28 patients
with the typical features of polymyalgia rheumatica
for periods ranging from 6 months to 4 years.
All patients were treated either with high doses
of salicylates, or prednisone with a maximum
dose of 10 milligrams a day. In no case did signs
of a generalized arteritis appear nor was there
any occurrence of visual impairment or blindness.
One patient has died of an atherosclerotic mesenteric thrombosis. Sixteen patients have recovered
completely and are in remission without medication. The rest are still under treatment.
It would appear therefore on the basis of this
experience that polymyalgia rheumatica is a benign syndrome with excellent prognosis in which
symptoms can be effectively suppressed with salicylates or small doses of corticosteroids. Temporal
arteritis, on the other hand, may be a serious
disease, with blindness occurring in a substantial
percentage of patients unless treated with large
doses of corticosteroids.
The benign natural history of polymyalgia
rheumatica is such that when there is no clinical
evidence of temporal arteritis, patients should be
spared the potential hazards of high-dose steroid
therapy. Further study is necessary to define the
significance of vascular histopathologic changes in
the elderly and to determine whether the mere
presence of histopathologic changes in the temporal artery is sufficient to diagnose the clinical
syndrome of temporal arteritis with its ominous
prognostic implications.
DEGRADATION
OF PROTEINPOLYSACCHARIDE
( PP-L )
BY
PUIUFIEDLYSOSOMES
Isaias Spilberg and Gerald Weissmann, New York, N. Y.
Although indirect evidence points to lysosomes
as sources for enzymes which degrade cartilage
matrix in arthritis, no direct proof has yet been
obtained with purified subcellular fractions. Using
discontinuous sucrose density gradients ( 1.8-1.4
M ), fractions of lysosomes rich in aryl sulfatase,
beta-glucuronidase and acid phosphatase, but free
of mitochondria1 enzymes, have been isolated
from rabbit liver. Breakdown of bovine nasal
cartilage PP-L was determined by measuring diffusion of uronic acid across millipore filters separating lucite chambers filled either with PP-L and
bcffer, or buffer alone. Purified lysosomes (300
pg/piotein/ml) caused uronic acid to diffuse across
filters ( 0 . 2 2 p ) from solutions of PP-L, to 10 per
cent of the total uronic acid. After 2 to 3 hours’
incubation, negligible amounts of uronic acid
(representing degradation of PP-L) diffused from
PP-L alone, or from PP-L treated with boiled
lysosomal extracts. Release of uronic acid from
non-diffusable PP-L was time-and-temperaturedependent, and proportional to lysosoma1 enzyme
concentration. In 0.1M acetate buffer, pH optimum for liver lysosomes was 4.6 to 5.0. Whole
leucocytes disrupted by freezing and thawing also
contained PP-L degrading activity, but such fractions were less active than pure lysosomal
fractions, and released similar amounts of uronic
acid at p H 4.6 and 7.4. Their activity was also
abolished by boiling. Since these results could be
duplicated by treatment of PP-L with trypsin, the
effects of several protease inhibitors was tested
and will be presented.
These experiments demonstrate that highly
316
ABSTRA(;TS
purified lysosomal fractions can degrade purified
PP-L, and that this attack is proteolytic. Therefore, measures designed to stabilize lysosomes or
to inhibit their enzymes might prevent breakdown
of cartilage matrix in joint disease.
THE“REACTED”LYMPHOCYTE-A CINERECORDING
A. B. Stanfield, C . A. L. Stephens, IT., J . L. Parsons and J . B. Cubberly, Tucson, Ariz.
Lymphocytes occurring in primary explants of
synovialis in Rose chambers are observed to react
characteristically but without agglutination when
challenged with phytohemagglutinin.
In addition to an increased mitotic rate, marked
enlargement of many cells is observed. Large
smooth nuclei with prominent nucleoli and a forerunner of clear cytoplasm are observed in the
“reacted” lymphocytes. Pronounced pseudopods,
frequently ending in fine cytoplasmic streamers,
trail 2 to 3 times the length of the main body of
the cells. A peculiar rolling motion of the nucleus
occurs within the cells.
Cinerecordings of cultures of rheumatoid lymphocytes challenged with sonicated synovial fluid
also display an increase in mitotic rate and an
enlargement of cells. For comparative purposes
reacted peripheral lymphocytes transferred onto
fibroblasts in chambers are included in the cinerecording.
This experiment further emphasized the usefulness of this method for the long-term study
and recording of both primary explant and peripheral lymphocytes and their response to a variety
of immunologic, physiologic, and metabolic
stimuli.
A STRAINOF SYNOVIAL
CELLSMITOGENIC
FOR LYMPHOCYTES
OF PATIENTS
WITH
RHEUMATOID
ARTHRITIS
Peter Stastny and Morris Ziff, Dallas, Tex.
In the course of experiments in which rheumatoid synovium was cultured with buffy coat lymphocytes, a strain of cells was encountered which
appeared to exert a selective mitogenic effect on
lymphocytes from rheumatoid patients.
Cell line D F was isolated from a 9-year-old
juvenile rheumatoid patient undergoing synovectomy, and carried by weekly trypsinization and
twice-weekly renewal of medium. Cultures containing 10 million buffy coat cells from
rheumatoid patients and controls were set up in
Eagle’s medium with 15 per cent fetal calf serum.
Monolayer cells of D F were washed twice and
added to the buffy coat cultures at concentrations of 20 X 103 and 100 X lo3 cells per flask.
After 6 days, tritiated thymidine (HaTdr) was
added and the cells allowed to incorporate label
for 6 hours. Incorporation of H3Tdr into DNA
was determined by liquid-gel scintillation counting.
The HSTdr incorporation of D F cells alone was
negligible, but when they were added to buffy
coat cells from 10 rheumatoid patients, a 2.1 to
7.3-fold increase in HsTdr incorporation resulted,
mean increase 4.6t 1.8. The mean of 13 nonrheumatoid controls of miscellaneous type was
1.8 2 0.6 (p<O.Ol).
Twelve other rheumatoid and 6 non-rheumatoid
synovial cell lines as well as several lines of
fibroblasts from skin have not shown a difference
in response on the part of rheumatoid patients
and controls.
Cell line D F did not exert a significant mitogenic effect on allogeneic buffy coat cells of
control individuals, whereas 6 other rheumatoid
cell lines tested did so. This would suggest that
the selective ability of D F cells to stimulate lymphocytes from rheumatoid patients may represent
an unmasking of an effect not ordinarily detectable in allogeneic cell mixtures. It appears
possible that strain D F may be deficient in one or
more of the usual complement of surface antigens
of the transplantation type. The nature of the
apparent rheumatoid specific reaction observed is
at present not known.
EFFECTSOF INTRA-ARTICULAR
ANTI-METABOLITES
Marvin E. Steinberg, Richard W. Cohen and Frederick C . Cogen, Philadelphia, Pa.
Although the intra-articular injection of antimetabolites in the treatment of rheumatoid arthritis has recently received considerable atten-
tion, almost no basic animal investigation has been
reported. Thus, little evidence of gross or histological change within the injected joints has been
317
ABSTFiACTS
presented and neither potential effectiveness nor
safety has been directly established.
One hundred thirty-three young and adult
rabbits received injections of either Nitrogen Mustard, Thio-tepa or Methotrexate into the left knee
and sterile saline into the right. Doses were
varied and were given either singly or at 3 weekly
intervals. Animals were sacrificed at intervals
ranging from one day to 12 weeks. Clinical effects, gross appearance of joints and histological
changes were noted.
After Nitrogen Mustard injection changes were
moderate to marked in virtually all joints. Gross
and histologic destruction of articular cartilage,
epiphyseal plates and adjacent bone was noted.
There was no evidence of synovial obliteration,
although inflammatory changes and fibrosis in
sub-synovial layers occurred. After Thio-tepa or
Methotrexate injection no severe reactions occurred,
even with high doses. Articular cartilage, epiphyseal line and adjacent bone were unaffected.
Synovium generally was unaltered or showed only
minimal reaction, although in a few cases mild
fibrosis occurred.
Thus Nitrogen Mustard showed no selective
synovial obliteration, and caused such severe and
generalized joint damage that its clinical use
would be hazardous. Thio-tepa and Methotrexate,
although showing little selective synovial effect in
the normal knee, would appear relatively safe to
other intra-articular structures. Their potential
value in the treatment of rheumatoid arthritis is
being investigated experimentally and clinically.
RESPONSETO IMMUNIZATION
IN SLE
May Betty Stevens, Murray B . Urowitz, Lawrence M . Mulhern and
Lawrence E . Shulman, Baltimore, Md.
Efforts to demonstrate abnormal antibody responses to foreign antigens in patients with SLE
have yielded conflicting results.
In the present study, the response to Vi antigen
was evaluated in 12 patients with SLE and 12
normal controls matched for age, sex, and race.
By design, 6 patients with SLE had nephritis.
Forty gamma of the antigen were administered
subcutaneously and anti-Vi titers determined by a
hemagglutination technique using .%fold serum
dilutions. Serial serum specimens obtained during
the immunization period were also examined for
change in serologic activity.
The kinetics of the antibody response was the
same for all patients and all controls, with an
induction time of 7 to 10 days. In 9 of 12
patients with SLE,the anti-Vi titer increased by 5
or more tube dilutions. Only 2 of the 12 controls
showed a response of this magnitude. Furthermore,
the increment in anti-Vi titer was greater in
patients with lupus nephritis than in the lupus
patients without nephritis.
The degree of reactivity to Vi antigen did not
correlate with any of the serologic abnormalities
of SLE. Moreover, in no patient did immunization
with Vi evoke an “anamnestic” response with respect to the autoantibodies of SLE or increase
their titer.
These data indicate that patients with SLE tend
to respond more vigorously than do normals to
immunization. It is further suggested that there
may be significant immunologic differences between lupus patients with nephritis and those
without renal disease.
MOVEMENT
ON THE DEVELOPMENT
OF LESIONS
IN
EFFECTOF EXAGGERATED
ADJLWANT
DISEASEOF RATS
Michael S. Stulbarg, L. Peter Einstein, Yves Van Schoote and J. Peter Kulka,
Boston, Mass.
Immobilization or denervation of a limb has
been observed to influence the severity and localization of peripheral lesions in patients with
rheumatoid arthritis. We investigated the role of
tissue movement in a comparable systemic disorder by studying the effect of exaggerated tail
bending on the development of local connective
tissue lesions in rats with mycobacterial adjuvant
disease.
The middle half of the tail was braced, forcing
the animal to bend excessively the segment proxi-
mal to the brace. Braces, made of metal rods
held together by Elastoplast bands, were applied
to 25 animals before or after adjuvant injection,
for periods of 4 or more days. Control animals
with weighted Elastoplast bands were used to
rule out the effect of possible constriction by the
bands and of extra weight on the tail.
The proximal portion of the tails of all braced
animals developed a large fusiform lesion which
was in contrast with scattered maculo-papules and
subcutaneous nodules of the controls. This result
318
ABSTRACTS
was obtained even when bracing extended only
to the eighth day of the latent period, 2 or more
days before the onset of arthritis. The tail lesions
usually appeared earlier in braced animals than
in controls, and were more commonly associated
with limitation of motion.
These findings indicate that the mechanical
stress resulting from excessive motion of an extremity may localize and intensify connective
tissue lesions in systemic inflammatory disease.
The ability to produce such lesions consistently at
a specified site will facilitate study of the pathogenetic mechanism and possible therapeutic measures.
DEFICIENCY
RHEUMATICMANIFESTATIONS
ASSOCIATEDWITH IMMUNOGLOBUIN
Stanley Tobias, Eugene V. Barnett and Carl M . Pearson, Los Angeles, Calif.
A high incidence of “auto-immune” disorders
and lymphoreticular neoplasms has been noted in
hypo-y-globulinemia. Reported here are 2 cases
of hypo-y-globulinemia and 2 cases of dys-yglobulinemia, each with one or more associated
rheumatic manifestations or neoplasms. M.G. is a
49-year-old white female with recurrent infections since age 12. At age 43 she noted progressive weakness. Muscle biopsy revealed focal
interstitial myositis and vasculitis. Muscle enzymes
were normal. There was persistent mild leukopenia. yG was 200 mgm per cent; yA<20 mgm
per cent; yM, 22 mgm per cent. S.L. is a 70-yearold white female, well until age 61 when she
presented with diarrhea which totally remitted in
10 months. This was followed by recurrent otitis,
sinusitis and bronchitis. At age 65 a benign thymoma was removed. At age 66, there was
migratory polyarthralgia. An adenocarcinoma of
the uterus was resected. yG was <lo0 mgm per
cent; yA, <20 mgm per cent, yM, <10 mgm
per cent. M.P. is a 25-year-old white female with
a 21-year history of recurrent superficial vasculitis and skin ulcers. Biopsy revealed obliterative
vasculitis. Cryoglobulins were present, but there
were negative ANA, LE tests. yG was 600 mgm
per cent; yA, 30 mgm per cent; yM, 142 mgm
per cent (Type I dys-y-globulinemia). B.T. is a
51-year-old white female with no prior history of
infections. At age 50 she had acute onset of
febrile illness characterized by purpura, peripheral
neuritis, nephritis, hypertension, myocarditis, splenomegaly, thrombocytopenia, hemolytic anemia
and polyserositis. ANA, negative; latex, 1 :20,000;
and complement depressed. yG was 200 mgm
per cent; yA, 64 mgm per cent; yM, 420 mgm
per cent (Type I dys-y-globulinemia). A high
incidence of rheumatic disorders with immunoglobulin deficiency may imply an infectious etiology. A pathogenetic role for small amounts of
auto-antibodies in these disorders is not excluded.
COMPARISON
OF SERUMURATECLEARANCE
BY DALMATIAN
DOG, A NON-DALMATIAN
AND A DALMATIAN
WITH A TRANSPLANTED
NON-DALMATIAN
LIVER
Richard 3. Tompkins, Paul H . Andreini, John T . McCall and L. Emmerson W a r d ,
Rochester, Minn.
The significantly higher urinary uric acid excretion in Dalmatian dogs compared to nonDalmatians has not been satisfactorily explained.
Although it has been proposed that the difference
is primarily due to defective renal tubular reabsorption of urate, non-Dalmatian kidneys transplanted into nephrectomized Dalmatians have
been reported to excrete as much uric acid as do
Dalmatian kidneys. Other data suggest that defective hepatic conversion of uric acid to allantoin
in the Dalmatian may be important. Serum uric
acid levels following intravenous uric acid loads
remain elevated significantly longer in Dalmatians
than in non-Dalmatians. Since the Dalmatians
have been found to possess at least as much liver
uricase activity as other breeds, it has been proposed that an intrahepatic defect sequesters the
uric acid from the uricase.
In the present study 30 mg. of uric acid per
kgm. body weight was injected into the leg vein
of a Dalmatian, a non-Dalmatian and a Dalmatian
with a non-Dalmatian liver transplant ( 4 months
post-transplantation with no evidence of hepatic
dysfunction). Serum uric acid was measured in
blood drawn from the jugular vein. The results
showed nearly identical serum uric acid clearances in the non-Dalmatian and the Dalmatian
with the liver transplant, both being significantly
greater than in the intact Dalmatian. This, as
well as the urinary uric acid excretion data from
these dogs, indicates that the altered metabolism
of urate in the Dalmatian can be almost entirely
explained by an hepatic defect.
319
ABSTRACTS
LONG-TERM
FOLLOW-UP
OF NORMAL
INDIVIDUALS
WITH POSITIVE
TESTS
FOR
RHEUMATOID
FACTOR
Elam Toone and Marion Waller, Richmond, Va.
Positive tests for rheumatoid factor have been
associated with a variety of diseases other than
rheumatoid arthritis, and an increased incidence
of positive tests have been observed in elderly
individuals without evidence of rheumatoid disease. Moreover, it has been recognized that rheumatoid arthritis need not coexist with, antedate, or
even follow the demonstration of positive tests for
rheumatoid factor. Nevertheless, the prognostic
implication of high titers of rheumatoid factor in
normal individuals allow for considerable conjecture; and consequently, the observation of these
individuals over a period of several years has
been attempted.
In a survey for rheumatoid factor in 5461 presumably normal individuals, 12 individuals were
found to have SHC titers in excess of 1:320.
However, on physical examination, 3 had possible
or probable rheumatoid arthritis. One individual
was not examined, and the other 8 individuals
were entirely normal.
This report will deal with the follow-up study
of 3 of these normal individuals who have been
under observation from 6 to 9 years. Each demonstrated positive tests with high titers when they
first came under study and have maintained positive tests for rheumatoid factor over the entire
period. Each has undergone complete physical
evaluation, x-ray study, and laboratory tests, and
none shows evidence of rheumatoid arthritis.
The implications of these studies, embracing
certain minor laboratory and physical changes,
will be discussed.
SCLERODERMA
AND HEREDO-FAMILIAL
DISEASE:
STUDIESOF THREE
FAMILIES
D. L . Tuflanelli, San Francisco, Calif.
In the present study the families of 3 probands
with scleroderma, all demonstrating unusual aggregations of immunological and genetic aberrations, are presented.
In the first family the mother of the propositus
was an XO/XX Turner mosaic. Two siblings had
mental retardation, spastic diplegia and congenital
ichthyosiform erythroderma. In the second family
the proband’s mother had both rheumatic fever
and rheumatoid arthritis, a sister had multiple
sclerosis and her son was a Trisomy 21 mongol.
In the third family the mother had lupus erythematosus and a sister had died of glomerulonephritis.
The proband with scleroderma also had a monoclonal IgG gammopathy.
Chromosomal and serological studies, including
serum electrophoresis, fluorescent antinuclear antibodies, LE factor, antibody to gamma globulin,
and quantitative immunoglobulin levels have been
done on 21 first-degree relatives and have demonstrated a familial clustering of abnormalities.
The incidence of chromosomal abnormalities,
other connective tissue disorders, and immunological abnormalities in these unusual families
supports the hypothesis that scleroderma may be
genetically predetermined.
THEINFLUENCE
OF AGEON THE CLINICAL
PATTERNOF SYSTEMIC
LUPUSERYTHEMATOSUS
Murray B. Urowitz, Mary Betty Stevens and Lawrence E. Shulman, Baltimore, Md.
The influence of age on the clinical expression
of systemic lupus erythematosus (SLE) has not
been evaluated. It has been our impression that
the pattern of SLE emerging in the older age
groups differs from the clinical picture seen in the
young. The present study was undertaken to test
the validity of this impression.
Of 106 cases indexed as “lupus erythematosus”
at The Johns Hopkins Hospital during 1963-1965,
82 fulfilled predetermined criteria for the diag-
nosis of SLE. All clinical and serologic manifestations of SLE in these patients were recorded, and
analyzed according to decade of age.
As seen in the table below, certain features of
SLE, namely cutaneous lesions, articular involvement and lymphadenopathy, were more common
in the young and decreased progressively with
age. In contrast, the pneumonitis of SLE was
more frequent in the older age groups.
320
ABSTRACTS
Age at Dx
(years)
10-19
20-29
30-39
4-49
50 and over
Total
NO.
Pts.
Skin
21
15
23
14
9
16(76%)
12(80%)
14(61%)
8(57%)
3(33%)
There were no correlations between age and the
prevalence of other features of SLE, including
nephritis.
Moreover, there was evidence that SLE in the
elderly was a milder disorder than that in the
young. The average duration of symptoms before
diagnosis in those under 20 years of age was 14
months; it increased progressively to 50 months
Manifestations of SLE
Joint
Lymph
Nodes
21 (100%)
15 (100%)
22 (96%)
12 (86%)
5 (56%)
14(67%)
14(93%)
10(44%)
4(29%)
2(22%)
Lungs
4(19%)
3(20%)
10(44%)
5(36%)
5(56%)
in the oldest age group, suggesting a more subtle
disease in the latter. In addition, the corticosteroid dosage requirement was lower in the older
patients than in the younger ones.
These data, therefore, indicate that age does
exert a modifying influence on the clinical expression of systemic lupus erythematosus both in its
individual manifestations and its severity.
SENESCENT
PIGMENTATION
OF CARTILAGE
Jan K . tlan deT
KOTSt,
Leon Sokoloff and Edward J. Miller, Bethesda, Md.
The pathologic significance of progressive pigmentation in the aging of animal tissues is the
subject of current interest. Lipofuscins are inert,
but it has been suggested that they may, by occupying sufficient cytoplasmic space, embarrass
the vital activities of cells. Another group of
pigments, less well characterized chemically, affects connective tissues; there have been some
recent speculations that they may be involved in
cross-linking of fibrous proteins. Analogy of the
pigmentation of old cartilage to ochronosis was
drawn by Virchow in his original description of
this entity. So far as we know, no systematic description of non-alkaptonuric pigmentation of cartilage in relation to the aging and degenerative
disease of joints has been made.
For this reason, the pigmentation of patellar
and costal cartilages, quadriceps tendon and intervertebral discs was studied in 55 necropsies on
patients 1 to 70 years of age. The pigment first
appeared in rib cartilage in the last half of the
third decade, and increased in degree thereafter.
The color of the costal cartilage and tendon
generally paralleled each other within each individual. The pigment was bleached slowly by 30
per cent hydrogen peroxide, but resisted extraction by 5 M guanidine, acid, alkali or fat solvents.
By various histochemical procedures, ultraviolet
microscopy and low temperature emission spectroscopy, it could be distinguished from lipfuscin,
ceroid, melanin, hemosiderin or lipchromes. It
likely represents one or more polymeric derivatives of aromatic amino acids. Although the surface
of articular cartilage in old or osteoarthritic persons frequently appears slightly brown, this
apparently is the result of staining by synovial
fluid. The relative sparing of articular cartilage
from senescent pigmentation is one more property
in which this tissue differs biologically from other
cartilages and connective tissues. No association
was found between the severity of degenerative
joint disease and the pigmentation of the various
connective tissues.
MANIFESTATIONS
OF RHEUMATOID
ARTHRITIS
FOLLOWING
STROKE
Edward E. Velayos and B. Stanley Cohen, Baltimore, Md.
Rheumatoid arthritis and hemiplegia are relatively common conditions, but their coexistence in
the same patient has been described infrequently.
In 6 cases previously reported, hemiplegia present
at the onset of rheumatoid arthritis has been
shown to exert a protective effect on the joints of
the paretic side. The statement has been made
that pre-existing rheumatoid arthritis is not amel-
iorated by subsequent hemiplegia, and, in fact,
a single case report in the literature suggests the
converse.
The present report is concerned with a patient
with long standing rheumatoid arthritis who developed hemiplegia. Over the next several years,
changes were noted in the subcutaneous nodules,
in the degree of ulnar deviation, and in the
321
ABSTRACTS
relative severity of radiographic findings on the
2 sides. In each instance the paretic side showed
less involvement. In addition symptoms were
largely confined to the uninvolved extremities.
The previously reported cases are reviewed and
the possible mechanisms and avenues for future
investigation are discussed.
OF ERYTHROCYTES
SENSITIZED
WITH THE RIPLEYANTI-RK
AUTOLOGOUS
AGGLUTINATORS
WITH 14 DIFFERENT
PROTEOLYTIC
ENZYMES
ANTIBODY
DIGESTED
Marion Waller, Richmond, Va.
Erythrocytes sensitized with Ripley anti-Rh antibodies digested with 14 different proteolytic
enzymes have revealed an astonishing array of
autoagglutinators to his own enzymatically degraded anti-Rh antibodies. These autoagglutinators
have comparable counterparts ( isologous agglutinators) in most human sera. They were found to
be IgG globulins, were serologically distinguishable from the IgM rheumatoid factors and were
unrelated to his anti-Rh antibodies.
The enzymes could be arbitrarily divided into
3 groups in respect to the serologic manifestations
of the enzymatic degradation. The characteristics
of each group of enzymes will be discussed. The
gamma globulins digested for various lengths of
time revealed relationships between agglutinator
titers, anti-Fc titers and bivalency and univalency
of the anti-Rh antibodies.
Heterologous anti-Fc antisera absorbed with
Fab fragments prepared with a variety of proteolytic enzymes have revealed differences heretofore undetected.
AORTICANEURYSM
AND RHEUMATOID
ARTHRITIS
Howard J. Weinberger and Harry Sacks, Los Angeles, Calif.
Rheumatoid heart disease with aortitis and
aortic valvulitis is a generally accepted clinical
entity. Aortic aneurysm in rheumatoid arthritis
(RA) has been reported previously in one patient.
Three females with RA and aortic aneurysm have
been observed by us.
The first patient, age 67, had the onset of stage
IV, class IV, RA in 1946. Progressive aneurysmal
dilatation of the sub-clavian, ascending and transverse aorta was noted in 1951, and aortic insufficiency in 1953. Hypertension, coronary artery and
peripheral vascular disease also were present.
Anti-luetic therapy for a benign false positive
serology was given in 1941 and 1953. Autopsy in
1961 showed aortic histopathologic alterations
consistent with syphilis, although a rheumatoid
basis could not be excluded. Obliterative pericarditis was also present.
The second patient, age 57 years, developed
arthritis in 1962. Pericarditis, mediastinal mass,
transient aortic insufficiency, and paroxysmal arrhythmias were noted in 1964. The patient was
normotensive. Aortography was inconclusive. At
thoracotomy, aneurysm of the ascending aorta
with intra-luminal clot and totally adherent pericardium were found. Biopsy of the aorta showed
a chronic mononuclear cell inflammatory reaction.
Blood and spinal fluid serologic tests for syphilis
(STS) were negative. Aortic insufficiency and
cardiomegaly have been progressive.
The third woman, age 67, had low-grade polyarthritis for 15 years with acute exacerbation in
the knees one year ago. History and STS were
negative for lues. Blood pressure was 120/80.
Aortic aneurysm was found 6 months ago. Biopsy
of the knee and synovial fluid examination were
consistent with RA. Sudden death occurred 2
months ago, presumably related to aneurysmal
rupture.
The clinical and histopathological findings,
though inconclusive, suggest an association between RA and aortic aneurysm rather than ail
unusual coincidence.
RHEUMATOID
NODULESIMULATING
BASALCELL CARCINOMA
K . R. Wilske and L. A. Healey, Seattle, Wash.
Rheumatoid nodules are known to occur at sites
of pressure, and thus they usually appear about
the elbows and over the occiput and sacrum.
We have seen 6 patients, each with a rheumatoid nodule in an unusual location, the bridge of
the nose. All had classic rheumatoid arthritis. Five
had high titers of rheumatoid factor and many
nodules in the customary locations. In addition,
three had a nodule on the ear.
All 6 patients wore glasses, and it is postulated
322
ABSTRACTS
that the pressure from the nose piece of the eye
glass frame led to the formation of the nodule
in this area. These nodules tended to drain and
form eschars. Both their location and their appearance with a central ulcer surrounded by a
raised rolled border suggested basal cell carcinoma. I n 2 patients, the lesion was excised and
showed the characteristic histology of a rheumatoid nodule. In the others, it gradually cleared
spontaneously.
URIC ACID LITHIASISIN PRIMARYGOUT: ANALYSISOF 280 CASES
Ts’ui-fan Yii and Alexander B. Gutmun, New York, N.Y.
Of our 1258 cases of primary gout, 280 (22
per cent) gave a history of uric acid lithiasis.
Two factors were found to predispose to stone
formation: 1 ) increased uric acid concentration
in the urine; 2 ) low urine pH. With increasing
urinary uric acid excretion the incidence of calculi
rises, reaching 50 per cent of the cases when the
output exceeds 1 gm/day. The urine in primary
gout tends to be unduly acid, pH<5.0 in about a
third of the cases (early morning specimens),
5.1 to 5.3 in another third. There is also minimal
diurnal fluctuation in urine pH; the alkaline tide
is diminished or absent in many cases. This persistent undue acidity of the urine is attributable
to deficient urinary ammonium excretion. In 111
cases of primary gout (with or without stone),
free of detectable renal impairment, the mean
urinary NH,+ excretion was 25 to 30 per cent
lower than that in the nongouty; in the pH range
4.8 to 5.6, 24.2 2 6.4 pEq/min in the gouty, 33.0
2 7.3 pEq/min in the nongouty ( p < O . O O l ) . No
difference in titratable acid was detected in early
morning urine specimens.
Seventy cases of uric acid lithiasis in gout who
did not respond to conventional alkali and hydration therapy were treated with allopurinol. The
results were sufficiently satisfactory to indicate
that allopurinol is the drug of choice in the
management of uric acid lithiasis in gout.
THE ROLE OF ANAEROBIC
BACTERIAIN BONE AND JOINT INFECTIOKS
Irwin Ziment, Luwrence G. Miller, Alvin Duuis and Sydney M . Finegold,
Los Angeles, Calif.
A review of the literature reveals a paucity of
reports on anaerobic infections of bones and joints.
No report has been found of any systematic
investigation into the prevalence of anaerobes in
these conditions, and their incidence and pathogenic role still remain undetermined.
Since 1959 we have found 14 cases of osteomyelitis at Wadsworth Veterans Administration
Hospital in which anaerobes have been cultured
from pus and/or resected bone; in addition, we
report one case of anaerobic arthritis. Anaerobic
cultures were not made routinely in these types
of cases but only in selected instances.
The cases fall into four categories: 1 ) Osteomyelitis of the foot, mainly in diabetics-6 cases;
2 ) Osteomyelitis associated with mastoid or sinus
disease-5 cases; 3 ) Osteomyelitis of long b o n e 4
cases (one diabetic, also in Category 1);4 ) Acute
pyogenic arthritis-1 case.
Isolates included B. frugilk-11 strains; B. melaninogenicus-7; B. funduliformis4; Fusobacterium-2; Bifidobucterium-1 ; and anaerobic cocci
-9. In only 2 instances were anaerobes (Bacteroides) present in pure culture; in the mixed
infections aerobes were present also.
Clues to the possible presence of anaerobes in
these patients were 1 ) failure to isolate a potential pathogen on routine culture of frank pus-6
patients, 2 ) foul odor to purulent discharge-10
patients, 3 ) presence of gas in t i s s u e s 3 patients,
4 ) necrosis in soft tissues-3 patients, 5 ) presence
of pleomorphic organisms resembling Bucteroides
on direct gram stain of p u s 4 cases, and 6 )
black discharge due to presence of B. melaninogenicus-1 patient.
D-PENICILLAMINE
THERAPY
IN RHEUMATOID
ARTHRITIS
lack Zicckner, Robert H . Ramsey, Robert W. Dorner and George E . Ganfncr, Jr.,
St. Louis, Mo.
The u5e of penicillamine offers a new approach
to the treatment of patients with rheumatoid
arthritis. Its effect on macroglobulins, copper, sulf-
hydryl levels, pyridoxine metabolirm and collagen poses interesting speculation about basic
mechani5ms of action in its relationship to results
323
ABSTRACTS
obtained in rheumatoid arthritis.
Fifteen rheumatoid patients received d-penicillamine for a period of approximately one
year. The daily dosage was 1 to 2 grams, usually
given in 4 divided doses. Improvement graded as
good or excellent was obtained in 7 patients; 2
others derived benefit which questionably fell
into this group. Improvement was first noted after
1-1/2 to 2-1/2 months of therapy in G patients;
after 3 to 4 months of therapy in 2 ; and after
6 months in one case. Toxicity appeared in 9
patients, including bad taste in 4, canker sores in
2, agranulocytosis in 1, skin odor in 1, and
epigastric distress and nausea in 1 each.
Rheumatoid factor titre diminished in all of 14
patients who had elevated values at the onset of
therapy. The sedimentation rate decreased in 9
patients. By immunodiffusion techniques using
Hyland plates, it was shown that gamma M levels
decreased in 8 cases; gamma G levels diminished
in G patients, but also increased in 1; and gamma
A levels were not significantly changed. Serum
ceruloplasmin levels (Hyland plates) were lowered in 5 patients, and possibly in 2 others.
Cultures for lymphocyte transformation were performed 228 times at varying periods during the
study; penicillamine caused no significant inhibition of this reaction. Correlation of these laboratory results with the clinical status was not demonstrated.
CORRELATIONS
IN LUPUSNEPHRITIS
SERIALCLINICAL-PATHOLOGIC
Burton Zuieiman, Joan Kornblum, John Cornog and Eugene A. Hildreth, Philadelphia, Pa.
Increasing attention is being directed to renal
involvement in the morbidity and mortality of
systemic lupus erythematosus. Some observers
cIassify lupus nephritis into several pathologic
patterns differing in prognosis and therapeutic
consideration. They have noted little progression
from the milder to the more severe histologic
picture over a follow-up period. They also found
certain urinary findings highly suggestive of severe histologic patterns. In the situation where
renal biopsy was not feasible or available to the
clinician, such urinary findings might imply prolonged use of high-dosage steroid therapy.
A study comparing the clinical and histologic
findings at initial renal biopsy has been made in
39 lupus patients. These correlations have then
been evaluated in light of subsequent clinical and
histologic courses ( mean duration of follow-up4 yearr ), including antinuclear factor determinations.
A frequent lack of correlation between renal
clinical and histologic findings was found. Ten
patients exhibited one or more urinary abnormalities in the absence of significant histopathology or
evidence of infection. These patients generally
showed no clinical progression of renal disease.
Two of them showed some histologic worsening.
Five subjects showed histologic abnormalities
in the absence of any clinical evidence of renal
disease. None of these patients have shown gross
clinical evidence of renal disease and the serial
histologic patterns have been stable.
Twenty patients initially had both significant
clinical and histologic renal abnormalities. Three
of them with the severe initial histologic pictures
died in renal failure. Clinical and/or histologic
progression of renal disease has occurred in four
of the survivors.
Conclusions at this time are: 1 ) There is a
frequent lack of correIation between clinical and
pathologic findings. Urinary abnormalities without
pathologic change have not been commonly associated with progression of renal disease. Therefore, in the absence of biopsy data, one cannot
accurately predict the nature of the pathoIogic
process with therapeutic and prognostic implications. 2 ) Although patients with both clinical and
histologic renal abnormalities have fared worst,
14 of 19 such patients are alive (mean duration3 years ) after initial study. Relationships between
clinical course and treatment in these patients
will be discussed.
MEDIUMCHAIN TRIGLYCERIDES IN THE TREATMENT
OF
INTESTINAL
PROGRESSIVE
SYSTEMIC
SCLEROSIS
E . S. Rfongan, M . S. Kleinman, and I. M . Samloff, Rochester, N . 1’.
A female patient, age 58, with proven small-intestinal involvement caused by progressive systemic
sclerosis (PSS ) developed severe malabsorption associated with abdominal distension, borborygmi
after meals, a 6-kilogram weight loss, anemia and
frequent periods of diarrhea. Two periods of tetra-
cyline therapy of one month duration produced no
therapeutic effect.
The patient was studied on a metabolic ward
where dietary fat intake and fecal fat excretion
were measured. On a low fat diet supplemented by
65 grams of medium chain triglycerides (MCT)
324
per day, the daily fecal fat excretion fell from 38.2
g/d to 16.0 g/day in 2 weeks and the patient’s
symptoms improved markedly. She maintained the
clinical improvement on MCT dietary supplements
at home for the next month.
The patient was re-studied by placing her on a
normal diet. Her symptoms promptly recurred.
Quantitative cultures from the jejunum revealed
4 x 10 8 colonies of E. coli per milliliter sensitive to
kanamycin. A 12-day course of 4 grams of kanamycin per day produced a significant change in the
bacterial flora of the jejunum and in fecal fat
excretion, but did not affect her symptoms.
Peroral intestinal biopsies of the jejunum before,
ABSTRAmS
during and after MCT and kanamycin therapy
showed no significant- change. All the biopsies
showed patchy villous atrophy similar in appearance to the changes found much more extensively
in non-tropical sprue. A gluten-free diet resulted
in reversal of the villous changes toward normal
but did not alter fat excretion or the patient’s
symptoms.
These results suggest that a marked curtailment
of the amount of long-chain fatty acids usually
found in American diets and the substitution of
MCT may have a beneficial effect in patients with
severe malabsorption due to intestinal PSS.
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june, paper, 1516, proceedings, new, 1967, abstract, meeting, york, associations, annual, submitted, rheumatic, american
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