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The kidney in rheumatoid arthritisStudies by renal biopsy.

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Arthritis and Rheumatism
O$cial Journal of- the gmeuican Rheumatismassociation
VOL. V, NO. 1
The Kidney in Rheumatoid Arthritis :
Studies by Renal Biopsy
Renal biospsies and renal function tests
were done on 41 rheumatoid arthritis
patients. Histologically, vascular disease was found in 14, amyloidosis in
4, and lupus nephritis in 2. The kidney
was‘ normal in 21. “Rheumatoid glomerulitis was not found in any biopsy,
but occurred in 6 of 16 autopsies. The
significance of these results is discussed
with particular reference to the effect
of gold salts on the kidney and the interrelationships of cortisone treatment
and amyloidosis.
Biopsias renal e tests de function renal
esseva effectuate in 41 patientes de arthritis rheumatoide. Histologicamente,
morbo vascular esseva trovate in 14,
amyloidosis in 4, e nephritis a lupus
in 2. Le ren esseva normal in 21. Glomerulitis “rheumatoide” non esseva trovate
in ulle biopsia sed Occurreva in 6 inter
16 necropsias. Le signification de iste
resultatos es discutite con referentias
particular a1 effect0 de sales de auro
in le ren e a1 relation inter therapia a
cortisona e amyloidosis.
LOMERULITIS has been observed relatively frequently in postmortem
studies on the kidneys of patients dying with rheumatoid arthritis.1*9
During life, however, proteinuria, abnormalities of the urinary sediment, and
decompensation of renal function have been reported to be relatively uncomWhen clinical evidence of reiial
mon in patients with rheumatoid
abnormalities has been found, unrelated intrinsic renal disease or amyloidosis
secondary to rheumatoid arthritis have often been implicated to sxplain the
proteinuria or a z ~ t e m i a . ~Clearly,
v ~ * ~ further studies on the kidney in patients
with rheumatoid arthritis are needed, as emphasized by Short, Bauer, and
They considered ( 1) that more “histologic observations on the
kidney in rheumatoid arthritis derived from autopsy and biopsy material”
were important, and ( 2 ) that “quantitative measurements of the excretion of
of albumin, cellular elements, and casts in this disease along with tests of
renal function by modern techniques,” were necessary.
From the Departments of Medicine, Presbyterian-St. Luke’s, Cook County, and Research
and Educational Hospitals, and from the Departments of Medicine and Pathology, University of Illinois College of Medicine, Chicago, 111.
Presented in part at the Annual Meeting of the American Rheumatism Association, June
90-21, 1958, San Francisco, Calif.
Supported by grants from tlxd Illinois Chapter of the Arthritis and Rheumatism Foundution, and from the U . S . Public Health Seruice, Bethesda, Md. (H-2253 and A-968).
In this communication we will report on clinical findings and rend biopsy
studies in 41 patients with rheumatoid arthritis. In studying the renal biopsies,
particular attention was paid to the glomerulitis reported by others in necropsy
studies,lS2J’ to the diagnosis of lupus nephritis,1° to renal amyloidosis, and to
possible histologic evidence of toxic effects in the nephron due to treatment
with gold salts.
Clinical. Most patients were admitted to hospital for study from the Arthritis Clinic of
the University of Illinois Hospitals; a few were studied in other hospitals. In all, 41 patients
were investigated. The diagnosis of rheumatoid arthritis was made using the criteria of the
American Rheumatism Association.11 None had ankylosing spondylitis. The patients were
not selected a t random. Many were selected because of long-standing severe rheumatoid
arthritis with marked deformities. Some patients were chosen for study because proteinuria
liad been found on routine urinalysis in the outpatient clinic, and others because they had
been treated with gold salts. In fact, the patients were selected for renal biopsy because
it was thought that they were the patients most likely to have renal abnormalities.
Tha average duration of rheumatoid arthritis was over 8 years (range: 2 months to
25 years). Eighteen patients had been treated with gold salts for periods of 12 weeks to
more than 4 years; thirteen had received at least one Gm. of Myochrisine. Twenty-one
had received ACTH or cortisol and its analogs. Most patients had been treated with 37.5
to 75 mg. of cortisol daily or its equivalent. Eight had been treated with both gold salts
and ACTH or cortisol. Eleven had received neither drug.
Measurements of renu2 functions. The methods used for the measurement of renal functions and for urinalysis have been described elsewhere.10
Renal biopsies. The methods used to obtain specimens of renal tissue by percutaneous
needle biopsy have been described, as have the methods of handling the renal tissue.10
Where indicated, sections stained with Congo red and Crystal violet were examined for
ainyloid deposits.12
Histologic (Table 1).No histologic abnormality was detected in the kidneys
of 21 patients. Arterio- and arteriolosclerosis or arteriolar nephrosclerosis were
the most common histologic abnormalities, and were observed in 14 biopsies.
In most patients these lesions were relatively mild. The average age of the
patients with vascular changes was 50 years; that of those with normal kidneys
was 37 years.
Amyloidosis was found in the kidneys of four patients, three of whom were
being treated with cortisol. Lupus nephritis was diagnosed in two. Other evidence of systemic lupus erythematosus was subsequently demonstrated in both
patients with lupus nephritis.* Glomerulitis of the type described in rhcumatoid
arthritis by Baggenstoss and Rosenbergl and by Fingerman and Andrus2 was
not observed.
*Both of these patients were admitted to hospital for study from the Arthritis Clinic
where the diagnosis of rheumatoid arthritis had been made according to the. criteria of the
American Rheumatism Association. The finding of lesions consistent with lupus nephritis
and the subsequent clinical evolution and laboratory findings led us to conclude that thc
correct diagnosis was systemic lupus erythematosus.
Table 1.-Histologic
Diagnoses in Patieiits with Rheumatoid Arthritis on
Whom Renal Riovsies Were Made
Histologic diagnosis
Normal kidney
Arterio- & arteriolosclerosis
Arteriolar nephrosclerosis
Lupus nephritis
“Rheumatoid” glomerulitis
Patients with
Patients with
no proteinuria
CZinical. Thirteen patients had persistent proteinuria ( table I). I: was associated with amyloidosis in four patients, lupus nephritis in two, and arteriolar
nephrosclerosis in two. Proteinuria also occurred in two patients with rrnal
arterial and arteriolar sclerosis but no interstitial or glomerular fibrosis. It is
uncertain whether or not the vascular disease was the cause of the proteinuria.
In three patients with normal kidneys, no underlying histologic abnormality
was found which might explain the proteinuria.
Tests of renal function were within normal limits in almost all the patients.
After dehydration overnight for 14 hours, the average urinary specific gravity
was 1.026; the average serum creatinine and urea nitrogen levels were 0.8
mg./100 ml. and 12.0 mg./100 ml. respectively. The average creatinine clearance
was 100 ml./min., and the average urea clearance was 85 per cent of average
normal renal function. Only five patients had a slight elevation of the serum
urea nitrogen level. Two had arteriolar nephrosclerosis and two had renal
amyloidosis. No renal lesion was found in the fifth patient.
The &ect of gold salts o n the kidnay. One patient first became ill with
rheumatoid arthritis in the summer of 1955. When she first attended the
Arthritis Clinic one year later, her urine contained no protein. Shcrtly after
treatment with Myochrisine was started, protein was noted in her urine, and
proteinuria persisted thereafter. A renal biopsy was done in February 1958.
Arteriosclerosis was diagnosed but, in addition, there was some degeneration
and fatty metamorphosis of the convoluted tubules. Whether or not these nonspecific degenerative changes in the tubules were due to gold treatment must
remain an open question at present. We found no histologic evidence for a
toxic effect of gold salts on the kidney in the other 17 patients who had received this drug. Proteinuria was noted in only 4 of the 18 patients treated
with gold salts and in 3 of 17 patients who had never received gold salts (excluding from consideration patients with lupus nephritis and renal amyloidosis ) .
The incidence and cause of proteinicrin in rheunzatoid arthritis. In the second
edition of Osler’s Modern Medicine, McCrae reported that proteinuria occurred in 20 per cent of 500 patients with arthritis deformans, including those
with spondylitis. Cylinduria occurred in over one-half of those with protein~ r i a Eaton
. ~ and Cocheu found albumin in the urine in 48 of 111 cases with
“hypertrophic arthritis” and in 48 of 170 cases of “atrophic arthritis,” but the
criteria used by these authors for the diagnosis of these disorders were not
clearly delineated in their paper.13
In 1943 Fingerman and Andrus reported on a retrospective study of 61 ca5es
of rheumatoid arthritis from the autopsy files of the University of Minnesota
Hospitals. Protein had been observed in the urine during life in IS of these
patients, at least 9 of whom were shown to have renal amyloidosis.2
In 1955 Fearnley and Lackner5 attempted to assess the incidence and significance of proteinuria in rheumatoid arthritis. They studied all 183 patients attending an arthritis clinic during a one year period, and tested the urine for
protein at each visit to the clinic. Persistent proteinuria was found in 24. The
proteinuria appeared to be associated with some obvious renal disease such as
glomerulonephritis or pyelcnephritis or with congestive cardiac failure in 15
patients. Amyloidosis was demonstrated by retention of Congo red or by liver
bic;psy in 8 cf the remaiaing 12 patients; the other 4 could not be investigated
for the underlying cause of proteinuria. Short, Bauer and Reynolds havc reported detailed cbjervations cn 293 patients with rheumatoid arthritis. They
attempted to exclude frcm consideration those patients with primary urinary
tract disorders, and noted that seven per cent of their patients had proteinuria
not associated with primary urinary tract disease.3
Our observations on a selected group of patients suggest that when proteinuria occurs in patients with rheumatoid arthritis, it is usually not attributable
directly to rheumatoid involvement of the kidney; it may result from complicating amyloidosis, cr from other diseases such as lupus nephritis, or frcm renal
vascula; disease.
The incidence of amyloidosis in rheumntoid arthritis. Secondary arriyloidosis
in patients with rheumatoid arthritis may cause the nephrotic syndrome or death
in renal failure.7.R~1~*’~
We found amybid deposits in the renal biopsies of
four patients, but this does not reflect the incidence of amyloidosis in rheumatoid arthritis as the patients were selected. The best available estimate of the
incidence of amyloidosis appears to be that of Fearnley and Lackner. They
studied 183 unselected patients with rheumatoid arthritis attending an arthritis
clinic in a one year period, and found amyloidosis in eight.5 All had proteinuria,
and the diagnosis of amyloidosis was made by liver biopsy, by necropsy, or by
the Congo red test. Unger and his colleagues examined 56 patients with rheumatoid arthritis and found evidence of amyloidosis in six.l6 These clinical observations indicate that amyloidosis is the most common cause of serious renal disease in patients with rheumatoid arthritis.
In postmortem studies, amyloid disease has also been found frequently. In
a careful review of the literature, Missen and Taylor found 42 acceptable cases
of amyloidosis complicating rheumatoid arthritis in reports by others of small
series or isolated cases1? They also reviewed the incidence of amyloidosis in
several larger postmortem series of patients with rheumatoid arthritis. A total
of 66 instances of amyloidosis was found among 353 cases studied at autopsy
Table 2.--Incidence of Amyloidosis in Rheumatoid Arthritis (Autopsy Studies!
Teilum & Lindahl ( 19-54)?
Gedda (1955)s
Fingerman & Andrus ( 1943)2
Missen & Taylor (1956)17
Solomon (1943)lS
Bayles ( 1943) 19
Sinclair & Cruickshank (1956)e
Young & Schwedel (1944)zO
Unger et al. (1948)lO
Baggenstoss & Rosenberg (1943)l
Number of
Per cent
(table 2) .' No other cause of amyloidosis was present in 57, whereas in 9
there was another possible cause such as tuberculosis in addition to rheumatoid
arthritis. In most of the series the reported incidence of amyloidosis was less
than 20 per cent (table 2),2l but Teilum and Lindahl found a much higher
incidence of amyloidosis.7 They restudied the autopsies on 28 patients and
found severe amyloid disease in 10 and lesser deposits of amyloid h i 7. All 10
patients with severe disease had had proteinuria, and 7 had died in uremia.
They had been ill with rheumatoid arthritis for an average of 28 years. Four
of those with less severe disease had deposits of amyloid in the kidney, but
none died in uremia. They had had rheumatoid arthritis for an average of 12
years. These observations re-emphasize the importance of searching liistologic
sections diligently for evidence of amyloidosis. Of the 17 cases of ainyloiciosis
diagnosed by these authors, only 2 had been diagnosed when the init;al routine
postmortem examination was made. The other 15 were brought to light by the
systematic study of the renal and other tissues after staining for amyloid with
both Congo red and methyl violet.
Possible effects of treatment with cortbol and its analogs on the imclmce
of amyloidosis. Teilum has demonstrated that when mice were trtated for
several weeks with injections of casein in amounts insufficient to produce
amyloidosis, a few injections of cortisone resulted in the prompt appearance
of amyloid in the spleenJ2 These observations were confirmed by Christenset~~3
On the other hand, cortisone administration started prior to and continued
during casein treatment was found either to reduce the incidence or to pre'In their paper, Missen and Taylor include one series of patients with rheumatoid
arthritis which has been excluded from table 2. This was the series of Bennett.31 Missen
and Taylor quote Bennett as having found no case of amyloidosis among 48 autopsies on
patients with rheumatoid arthritis. However, it is clear from the discussion which follows
Bennett's paper that Bennett found 11 cases of amyloid infiltration. Although it seems
likely that these were among the patients with rheumatoid arthritis studied by him, it is
not clear from this discussion whether the 11 cases of amyloid infiltration were found only
among patients with rheumatoid arthritis or among patients with both rheumatoid arthritis
and rheumatic fever. For this reason Bennett's series have been omitted from table 2.
vent the formation of a m y l ~ i d .An
~ ~analogous
situation might conceivably
apply to cortisol treatment of rheumatoid arthritis in man, and a few observations have been reported which suggest a possible precipitating effect of
ACTH or cortisol on amyloid formation.25vz6The possibility that amyloidosis
results from cortisol treatment in our patients cannot be excluded, but it is
pertinent to recall that amyloidosis was found frequently in patients with
rheumatoid arthritis before the introduction of treatment with ACTH and
cortisol (table 2 ) . Certainly there is as yet no proof of an amyloid-promoting
effect of cortisol therapy in man. Well controlled serial biopsy studies will be
necessary to prove this point.
Glomerulitis in rheumatoid arthritis. The incidence of glornerulitis in three
series of postmortem studies is given in table 3. Glomerulitis was fouiid in
28 of 107 autopsies on patients with rheumatoid arthritis; we h w e found
glomerulitis in 8 of lG autopsies."7 The lesions were characterized by mild
endothelial hyperplasia without significant epithelial cell changes and without exudative features. There was little or no evidence of titbular degeneration
nor of interstitial fibrosis and inflammation. In striking contrast with these
findings was the complete absence of glomerulitis in the tissues studied by
renal biopsy. It is unlikely that the absence of glomerulitis in biopsy specimens
was due to sampling error, as the endothelial hyperplasia seen in postmortem
specimens was diffuse and involved all or almost all glomeruli.
The highest incidence (63 per cent) of glomerulitis was found by Baggenstoss and R0senberg.l Nine of their 19 patients with glomerulitis had acute
or chronic pulmonary infections when they died. Bell has demonstrated a
proliferative glomerulitis in patients dying of pneumonia and other bacterial
but Baggenstoss and Rosenberg pointed out that the pdmonary
infection could not account per se for the high incidence of glomerulitis. T!iey
concluded that these lesions were probably due to or associated with the
rheumatoid disease. If they are indeed a manifestation of rheumatoid disease,
the failure to find such lesions in renal biopsies suggests that glomerulitis may
be a late or preterminal manifestation, and that it has little clinical significance.
This view is supported by the observations of Duihie and his colleagues, who
restudied 283 patients with rheumatoid arthritis an average of six ycars after
their discharge from hospital for active rheumatoid diseaseGAt this time the
average duration of the disease was about 12 years. Of the 36 patients who
died, 4 died of renal disease, 3 of pyelonephritis, and 1of amyloidosis.
There is e~perirnental~~
and clinical evidence30 to suggest that either the
Table 3.--Incidence
Glomerulitis in Rheumatoid Arthritis (Autopsy Studies)
Baggenstoss & Rosenberg (1943)l
Fingerman & Andrus ( 1943)z
Sinclair & Cruickshank (1956)9
Number of
pathcgenic stimulus to the glomerular endothelial cells or their reactivity to
such a stimulus may be controlled by adequate treatment with cortisone. Thus,
it is conceivable but unlikely that the absence of glomerulitis might be explained in part by the fact that cne-half of the patients studied had been
treated with ACTH or cortisol and its analogs.
1. Renal biopsies and tests of renal function were made on 41 selected
patients with rheumatoid arthritis. The patients were chosen for studv because it was thought that these patients were most likely to have renal abnormalities.
2. No histologic abnormality was found in 21 cases. Arterio- and arteriolosclerosis or arteriolar nephrosclerosis was found in 14 biopsies. Amyloidosis
occurred in 4 biopsies, and lupus nephritis was diagnosed in 2. Glomerulitis of
the type described by others in postmcrtem studies was not observed.
3. Proteinuria was observed persistently in 13 patients. It was associated
with amyloidosis in 4, with lupus nephritis in 2, and with renal vascular disease in 4.In 3 patients no underlying histolcgic abnormality was found. Tests
of renal function were within normal limits in almost all the patients. Slight
elevation of the serum urea nitrogen level was found in only 5, 2 of whom had
renal amyloidosis and 2 had arteriolar nephrosclerosis.
4. Eighteen patients had been treated with gold salts. Although proteinuria
first appeared in one patient after treatment with gold salts was started, in
the series as a whole proteinuria occurred as frequently in those who had
never received gold therapy as in thcse who were being treated with gold. We
found no histologic evidence for a toxic effect of gold salts on the kidney except for the presence of slight fatty metamorphosis in the convoluted tubules
of one patient.
l. Bsggenstoss, A. H., and Rosmnberg, E.
F.: Visceral lesions associated with
chronic infectious (rheumatoid) arthritis. Arch. Path. 35:503, 1943.
Fiqgerman, D. L., and Andrus, F. C.:
Visceral lesions associated with rheumatoid arthritis. Ann. Rhemat. Dis.
3:168, 1943.
Short, C. L., Bauer, W., and Reynolds,
W. E.: Rheumatoid Arthritis. Cambridge, Mass., Harvard University
Press, 1957.
McCrae, T.: Arthritis Deformans. In
Modern Medicine, 2nd ed., Osler,
W. and McCrae, T., eds.: Philadelphia, Lea & Febiger, 1913-1915.
Fearnley, G. R., and Lackner, R.:
Amyloidosis in rheumatoid arthritis,
and significance of “unexplainsd” albuminuria. A report of eight cases.
Brit. Med. J. 1:1129, 1955.
Duthie, J. J. R., Brown, P. E., Knox, J.
D. E., and Thompson, M.: Course
and prognosis in rheumatoid arthritis. Ann Rheumat. Dis. 16:411, 1957.
Teilum, G., and Lindahl, A.: Frequency
and significance of amyIoid changes
in rheumatoid arthritis. Acta. med.
scandinav. 149:449, 1954.
Gedda, P. 0.: On amyloidosis and other
causes of death in rheumatoid arthritis. Acta med scandinav. 150:443,
1955. .
Sinclair, R. J. G., and Cruickshank, B.
A.: Clinical and pathological study
of sixteen cases of rheumatoid arthri-
tis with extensive visceral involvement 20. Young, D., and Schwedel, J. B.: The
(“rheumatoid disease”). Quart. J.
heart in rheumatoid arthritis: A study
Med. 25:313, 1956.
of thirty-eight autopsy cases. Am.
10. Muehrcke, R. C., Kark, R. M., Pirani,
Heart J. 28:1, 1944.
C. L., and Pollak, V. E.: Lupus 21. Ropes, M. W.: Massachusetts General
nephritis: a clinical and pathologic
Hospital Case No. 31212. New England J. Med. 232:632, 1945.
study based on renal biopsies. Medi- .
22. Teilum, G. : Cortisone-ascorbic acid
cine 36:1, 1957.
11. Ropes, M. W., Bennett, G. A,, Cobb,
interaction and the pathogenesis of
S., Jacox, R., and Jessar, R. A.:
amyloidosis. Mechanism of action of
Diagnostic criteria for rheumatoid
cortisone on mesenchymal tissue.
arthritis. Bull. Rheumat. Dis. 7 :121,
Ann. Rheumat. Dis. 11:119, 1952.
1956, and Ann. Rheumat. Dis. 16: 23. Christensen, H. E.: Effects of cortisone
in experimental mouse amyloidosis.
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12. Lillie, R. D.: Histopathologic Terhnic
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matology, Rome, 1961.
24. Bestetti, A., Pirani, C. L., and CatchYork, Blakiston, 1954.
13. Eaton, E. R., and Cocheu, L. F.:
pole, H. R.: Studies on experimental
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literature. J. Am. Inst. Homeop. 25: 25. West, H. F., and Newns, C. R.: Some
effects of long-continued cortisone
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therapy in rheumatoid arthritis. Lan14. Trasoff, A., Schneeberg, N., and Scarf,
M.: Recovery from multiple rheumncet 2:515, 1952.
toid arthritis complicated by amy- 26. Frenkel, M., and Groen, J.: Amyloidosis
na behandeling met ACTH. Nederl.
loidosis in a child. Report of a case
tijdschr. geneesk. 98:2352, 1954.
and review of the literature. Arch.
27. Pirani, C. L., and Pollak, V. E.: UnInt. Med. 74:4, 1944.
published observations.
15. Reece, J. M., and Reynolds, T. B.:
Amyloidosis complicating rheumatoid 28. Bell, E. T.: Renal Diseases, ed. 2.
Philadelphia, Lea & Febiger, 1950.
arthritis. Am. J. Med. Sc. 228:554,
29. Teilum, G., Engbaek, H. C., Harboe,
16. Unger, P. N., Zuckerbrod, M., Beck, G.
N., and Simonsen, M.: Effects of
J., and Steele, J. M.: Amyloidosis in
cortisone on experimental glomerulonephritis. J. Clin. Path. 4:301, 1951.
rheumatoid arthritis. A report of ten
cases. Am. J. Med. Sc. 216:51, 1948. 30. Pollak, V. E., Pirani, C. L., and Kark,
R. M.: The effect of large doses of
17. Missen, G. A. K., and Taylor, J. D.:
Amyloidosis in rheumatoid arthritis.
prednisone on the renal lesions and
life span of patients with lupus
J. Path. & Bact. 71:179, 1956.
glomerulonephritis. J. Lab. & Clin.
18. Solomon, W. M.: Amyloidosis in chronic
atrophic arthritis. Ann. Int. Med. 18:
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846, 1943.
31. Bennett, G. A.: Comparison of the
19. Bayles, T. B.: Rheumatoid arthritis and
pathology of rheumatic fever and
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rheumatoid arthritis. Ann. Int. Med.
19:111, 1943.
cases. Am. J. Med. Sc. 205:42, 1943.
Vidor E. Pollak, M.B., M.R.C.P.E., Research Assistant Professor of Medicine, University of Illinois College of Medicine;
Attending Physiciiin, Research and Edlicaiional Hospiials;
Assistant Attending Physician, Presbyterian-St. Luke‘s Eioupital, Chicago, 111. Established Investigator of the Americari
Heart Association, supported by the Illinois Heart Association.
Conrad L. Pirnni, M.D., Professor of Putthology, Unioersity of
Illinois College of Medicine, Chicago, 111.
Irving E . Steck, M.D., Clinical Associate Professor of Medicine, University of Illinois College of Medicine, and Director,
Arthritis Clinic, Research and Educaiional Hospitals, Chicago,
Robert M . Kark, F.R.C.P., F.A.C.P., Profexor of Medicine,
University of Illinois College of Medicine; Attending Physician, Presbytcrian-St. Luke’s Hospita!, Cook Counly Hospital, and Researoh and Educational Hospitals, C h i a g o , Ill.
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biopsy, renar, kidney, arthritisstudies, rheumatoid
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