Seminars in

ARTHRITIS

AND RHEUMATISM August 1992

VOL 22, NO 1

Sarcoidosis ByRaymond

in Autoimmune

Disease

J. Enzenauer and Sterling G. West

Sarcoidosis is a multisystem granulomatous disease of unknown etiology. Sarcoidosis coexisting with connective tissue diseases, once considered rare, complicates various such disorders, including rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, Sjiigren’s syndrome, and the spondyloarthropathies. Symptoms common to sarcoidosis and autoimmune disease include keratoconjunctivitis sicca, weight loss, fever, lymphadenopathy, pulmonary complaints, and cutaneous lesions. Consequently, the diagnosis of sarcoldosis in association with connective tissue disease is often difficult and may require biopsy of the lung, liver, skin, lymph node, muscle, or bone marrow for pathological confirmation. Abnormalities of immune function as well as autoantibody produc-

tion, including rheumatoid factor and antinuclear antibodies, are seen in sarcoidosis and in connective tissue diseases, suggesting a common immunopathogenic mechanism. The severity and course of sarcoidosis associated with autoimmune disease is variable. The incidence of sarcoidosis in association with rheumatic disease may be underestimated if new symptoms of sarcoidosis are attributed to the primary rheumatic disease and a secondary diagnosis is not pursued. This is a US government work. There are no restrictions on its use.

S

We describe six cases of sarcoidosis seen at Fitzsimons Army Medical Center (FAMC) complicating RA, SLE, SS, and dSSc and review the English-language literature of sarcoidosis associated with autoimmune disease. A common immunopathogenic mechanism between CTD and sarcoidosis is proposed.

IMILARITIES between connective tissue diseases (CTDs) and sarcoidosis have been recognized since 1946,’ and several authors have suggested a shared immunopathogenic mechanism.2-4 Although reports of coexisting sarcoidosis and CTDs have been considered rare,4 sarcoidosis has complicated rheumatoid arthritis (RA),5 diffuse systemic sclerosis (dSSc),4 limited systemic sclerosis (1SSc) or the CREST (calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome,6 Sjogren’s syndrome (SS),3 systemic lupus erythematosus (SLE),’ and the spondyloarthropathies.8-11 Cases of CTDs complicating long-standing sarcoidosis are less common, but ISSc4 and RA12 have been described. The paucity of reports of coexisting CTDs and sarcoidosis may result from the diagnostic difficulty occurring when extraarticular features develop in sites common to both disease processes.13

Seminars in Arthritis and Rheumatism,

INDEX WORDS: Sarcoidosis; disease; autoimmunity.

connective tissue

From the Rheumatology Service, Depattment of Medicine, Fitzsimons Army Medical Center, Aurora, CO. MAJ Raymond J. Enzenauer, MD: Fellow, Rheumatology Service; COL Sterling G. West, MD: Chief Rheumatology Service. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or Department of Defense. Address reprint requests to Sterling G. West, MD, Chief; Rheumatology Service, Department of Medicine, Fitzsimons Army Medical Center, Aurora, CO 80045. This is a USgovernment work. There are no restrictions on its use. 0049-0172/92/2201-OOOl$O.OO/O

Vol22, No 1 (August), 1992: pp l-l 7

2

ENZENAUER AND WEST

PATIENTS AND METHODS

Patients All patients with inflammatory CTDs seen in the rheumatology clinic at FAMC between 1981 and 1991 were followed up for the development of sarcoidosis. Of the 569 patients, 263 had RA, 144 had SLE, 82 had seronegative spondyloarthropathy, 19 had primary SS, and 61 had other miscellaneous inflammatory CTDs. All patients met established or proposed criteria for the diagnoses of their CTDs: RA,14 SLE,15 ankylosing spondylitis (AS),16 Reiter’s syndrome,17 SS,18 and polymyositis (PM).19 All patients with undifferentiated CTD and any patient with a history of sarcoidosis before the development of CTD (two SLE, one Reiter’s) were excluded from the study. Patients were evaluated for signs and symptoms suggestive of sarcoidosis, and chest roentgenograms were obtained annually. Sarcoidosis was defined as a compatible clinical presentation and the presence of noncaseating granulomas on histological examination of pathological tissue. Other causes of noncaseating granuloma were excluded, and tissue stains and cultures for mycobacterial and fungal organisms were negative. Elevation of serum angiotensin-converting enzyme (ACE) levels and/or abnormal lung gallium scans were desirable but not necessary to establish the diagnosis. A control population of 894 randomly selected patients under the age of 60 years with noninflammatory rheumatic conditions (myofascial syndromes, fibromyalgia, and osteoarthritis) seen in the rheumatology clinic during this period were also evaluated for the presence of sarcoidosis. Evaluation included workup of any clinical symptom or sign suggestive of sarcoidosis and chest roentgenography. RESULTS Six patients with inflammatory CTDs (two RA and SS, one RA, one SLE and SS, one SSc and SS, one SS) developed sarcoidosis over the lo-year study period. All were women (three black, two white, one Hispanic) with a mean age of 42 years (range, 27 to 57 years) and an average CTD duration of 8.7 years (range, 1 to 16 years). None of the 894 control patients (627 women; 692 white; mean age, 48.7 years; range, 21 to 59 years) with noninflammatory rheumatic

conditions had evidence of associated sarcoidosis. The patients with sarcoidosis and inflammatory CID had a variety of clinical presentations (Table 1). Two patients presented with asymptomatic bilateral hilar adenopathy (BHA), one with BHA associated with fatigue and night sweats, two with shortness of breath and interstitial lung disease, and one with skin lesions. Serum ACE levels were elevated in five of the six patients. Gallium lung scans were abnormal in all four patients tested. Noncaseating granuloma consistent with sarcoidosis was confirmed histologically on tissue obtained from transbronchial biopsy in three cases, mediastinal lymph node biopsy in two cases, and skin biopsy in one case. Interestingly, primary or secondary SS had been diagnosed clinically/serologically in five patients and confirmed pathologically by parotid or minor salivary gland biopsy in four patients before the development of sarcoidosis. Four of the five patients who underwent HLA typing were HLA DR3 positive. All four of these patients had SS. CASE REPORTS

Case 1 A 57-year-old white woman had SLE diagnosed 9 years before admission, manifest by hemolytic anemia, cerebritis, myositis, pneumonitis, arthritis, nephritis, oral ulceration and positive antinuclear antibody (ANA) with elevated antibodies to dsDNA. Symptoms of keratoconjunctivitis sicca (KCS) and an abnormal Schirmer’s test result prompted a minor salivary gland biopsy, which confirmed the diagnosis of secondary SS (Fig 1). The patient was admitted to FAMC for evaluation of a 5-month history of recurrent atria1 fibrillation. Symptoms of SLE were stable and controlled with nonsteroidal antiinflammatory drugs (NSAIDs) alone. She denied any cardiopulmonary symptoms. Her medical history was also remarkable for hypertension. Vital signs on admission showed an irregular pulse of 90 to 150 beats/min and a blood pressure of 150/90 mm Hg. Physical examination showed oral ulceration. Cardiac examination showed an irregularly irregular rhythym without pericardial rub. Bibasilar rales were noted without pleural rub.

SARCOIDOSIS

IN AUTOIMMUNE

Table 1: Fittsimons

3

DISEASE

Army Medical Center Patients With Connective Tissue Disease and Sarcoidosis FAMC Case Number 1

2

3

4

5

6

57/F

45/F

45/F

42/F

27/F

37/F

W

H

W

B

B

SLE/SS

RA

ss

SSCISS

RAISS

Age (yr)/Gender Race* Diseaset Disease

duration

(yr)

Symptoms*

Laboratory

B RAISS

9

16

8

5

1

13

None

EN

Fatigue, NS

SOB, skin

None

SOB

Neg I:160

I:5120

I:640

1:1280

I:640

Neg I:320

1:5120

Neg ND

POS

POS

Neg ND

Neg ND

ND

ND

POS

ND

ND

BHA, ILD

BHA

ILD

BHA

ILD

values§

RF ANA SS-A

Neg ND

SCL-70 Chest roentgenogramli

BHA

I

I

I

NL

I

I

GalliumO

Pos

ND

ND

Pos

Pos

Pos

HLA-DR3§

Pos

ND

Pos

Pos

ND

16

ND

Neg 21

Pos

18

SS biopsy#

MSG

ND

P

ND

MSG

MSG

Sarcoid biopsy**

MLN

TB

MLN

Skin

TB

TB

ACEll

BAL fluid (% lymphs)§

25

*W, white; t-i, Hispanic; B, black. tSLE, systemic lupus erythematosus; SS, Sjijgren’s syndrome; RA, rheumatoid arthritis: SSc, systemic sclerosis. ZEN, erythema nodosum; NS, night sweats; SOB, shortness of breath. §RF, rheumatoid factor; Nag, negative; ANA, antinuclear antibody; ND, not done; Pos, positive. IIBHA, bilateral hilar adenopathy; ILD, interstitial lung disease. IACE, angiotensin-converting

enzyme; I, increased; NL, normal.

#MSG. minor salivary gland (lip); ND, not done; P, parotid.

l*MLN,

mediastinal lymph node; TB, transbronchial.

A complete blood count was normal. Routine chemistry screen was remarkable for a serum creatinine of 1.7 mg/dL (normal, < 1.5 mg/dL). Liver-associated enzymes were normal. Urinalysis showed 0 to 3 white blood cells and 3 to 10

Fig 1:

Minor salivary gland biopsy specimen

showing intense lymphocytic

infiltration

consis-

tent with SS (FAMC case 1; original magnification x 100).

red blood cells per high-power field. Twentyfour-hour urine collection showed 108 mg of protein and a calculated creatinine clearance of 33 mL/min. Serological evaluation disclosed an elevated erythrocyte sedimentation rate (47 mm/ h), positive ANA (1:160, homogeneous pattern), and negative rheumatoid factor (RF) and rapid plasma reagin (RPR). The serum did not contain antibodies to dsDNA or the nonhistone antigens Sm, nuclear RNP, SS-A, or SS-B. Complement levels were mildly depressed with a C3 of 93 mg/dL (normal, 80 to 170 mg/dL), a C4 of 12 mg/dL (normal, 15 to 45 mg/dL), and a CH50 of 35 U/mL (normal, 40 to 85 U/mL). Serum protein electrophoresis was unremarkable. The patient was HLA DR3 positive. A chest roentgenogram showed cardiomegaly with bibasilar interstitial infiltrates, a small left pleural effusion, and right hilar and paratracheal prominence. Computed tomography of the chest revealed diffuse mediastinal adenopathy. Pulmonary function testing showed restric-

A

Fig 2:

ENZENAUER AND WEST

Mediastinal

men showing tent with

lymph node biopsy speci-

noncaseating

sarcoidosis

magnification

granuloma

(FAMC

consis-

case 1; original

x 100).

tive lung disease. Transbronchial biopsy was nondiagnostic, but mediastinoscopy with mediastinal lymph node biopsy showed noncaseating granulomas (Fig 2). Cultures and special stains for fungal and acid-fast organisms were negative. Because she was asymptomatic, treatment for sarcoidosis was not initiated. Discharge diagnoses were SLE with secondary SS and pulmonary sarcoidosis. Atria1 fibrillation, probably secondary to essential hypertension, resolved. Six-year follow-up showed no progression of pulmonary sarcoidosis by chest roentgenogram or pulmonary function testing; hilar adenopathy has resolved. The SLE remains well controlled on NSAIDs. Comment. American College of Rheumatology (ACR) criteria for the classification of SLE15 were met. SS was suggested by the presence of symptoms of KCS and confirmed by minor salivary gland biopsy.18 Sarcoidosis was diagnosed on mediastinal lymph node biopsy during evaluation of an abnormal chest roentgenogram. In this case, the CTD preceded the onset of clinically overt sarcoidosis by several years. Case 2

A 45-year-old Hispanic woman received a diagnosis of erosive seronegative RA 16 years before admission. She was initially treated with NSAIDs and gold therapy for 11 years. The disease had been moderately well controlled by D-penicillamine for the previous 3 years. The patient was admitted to FAMC for evaluation

of bilateral tender lower extremity nodules and an abnormal chest roentgenogram. She complained of pain and swelling of the small joints of the hands and feet but denied systemic, pulmonary, or KCS symptoms. Physical examination revealed synovitis of the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints with ulnar deviation of the MCP joints bilaterally. Both ankles were swollen, and there was symmetric metatarsalgia. Multiple OS-cm palpable subcutaneous nodules were present over the extensor surfaces of the forearms and thighs, consistent with erythema nodosum. A mild normocytic, normochromic anemia was present. Serum chemistries, liver-associated enzymes, and urinalysis were normal. Serological examination showed an elevated erythrocyte sedimentation rate (32 mm/h), elevated C-reactive protein level (1.3 mg/dL; normal, 1:640, speckled) with anti-SS-A antibodies. Antibodies to SS-B, Sm, and dsDNA; complement levels; RPR levels; and cryoglobulin levels were normal or negative. Serum protein electrophoresis showed a total protein of 8.1 g/dL with a polyclonal gammopathy. Quantitative immunoglobulins (Ig) showed an IgG of 3,200 mg/dL (normal, 800 to 1,800 mg/dL), IgA of 222 mg/dL (normal, 90 to 450 mg/dL), and IgM of 183 mg/dL (normal, 70 to 280 mg/dL). The serum ACE level was 28 IU/L (normal, 15 to 30 IU/L). Fungal immunodiffusion analysis was negative for histoplasmin, blastomycin, coccioidin, aspergillis, and Can&da organisms. The patient was HLA-DR3 positive. Chest roentgenogram showed bilateral hilar adenopathy (Fig 5). Roentgenograms of the hands, wrists and feet were normal. Schirmer and Rose Bengal tests were positive. Parotid scanning with salivary flow study using rapid 99mtechnetium pertechnetate showed markedly decreased salivary uptake (Fig 6).

6

ENZENAUER AND WEST

Fig 5:

Posterior-anterior

(A) and lateral (B) chest roentgenograms

Pulmonary function testing showed a mild obstructive pattern without evidence of reversibility. Gallium scanning showed increased uptake in the hila and parotid glands (Fig 7). A lymphocytic infiltrate consistent with SS was seen on parotid gland biopsy (Fig 8). Mediastinal lymph node biopsy showed noncaseating granulomas (Fig 9). Cultures and special stains for fungal and acid-fast organisms were negative. Because of the lack of pulmonary symptoms, no therapy was recommended. Discharge diagnoses were SS and sarcoidosis. The patient was lost to follow-up. Comment. In this case, SS preceded the diagnosis of sarcoidosis by 8 years. Sarcoidosis was suspected when BHA was noted on chest roentgenogram and confirmed by mediastinal lymph node biopsy. Case 4

A 42-year-old black woman had a diagnosis of dSSc 5 years before evaluation. Her disease was manifest by proximal sclerodermatous skin changes, sclerodactyly, Raynaud’s phenomenon, esophageal dysmotility, keratoconjunctivitis sicca, and interstitial pulmonary fibrosis. Results of serological examination showed a positive ANA (1:320, speckled) with positive anti-SCL-70 and anti-SS-A antibodies. She

showing BHA (FAMC case 3).

underwent evaluation for new plaquelike skin lesions on the upper and lower extremities and progressive dyspnea on exertion. Sclerodermatous skin changes were seen on the face, trunk, and extremities, and plaquelike areas of hyperpigmentation were noted on both upper and lower extremities. Bibasilar rales with course rhonchi were present. A mild normocytic, normochromic anemia with a hematocrit of 38% was found. Routine chemistry screening, serum ACE levels, and urinalysis were normal. She was HLA DR3 positive. Chest roentgenograms showed diffuse interstitial lung disease. Pulmonary function testing showed a restrictive pattern, with a reduction in forced vital capacity (FVC) (1.64 L; predicted, 3.39 L) and forced expiratory volume (FEV-1) (1.59 L; predicted, 2.78 L), with a normal FEV-l/FVC ratio (97%). Lung volumes by body plethysmography showed a reduced total lung capacity (TLC) of 2.392 L (predicted, 4.82 L) and a reduction in the functional residual capacity to 2.05 L (predicted, 3.53 L). Mild increased uptake throughout both lung fields was seen on gallium scan. Lesional skin biopsy showed noncaseating granuloma, and cultures and special stains for fungal and acid-fast organ-

SARCOIDOSIS

Fig 6:

IN AUTOIMMUNE

7

DISEASE

Parotid scan with

salivary flow

study at 0

and 5 minutes-anteriorposterior view (A) and 10 minutes-lateral

view(B).

Normal thyroid gland uptake

and

markedly

de-

creased salivary gland uptake consistent

with

SS

are seen (FAMC case 3).

isms were negative. Transbronchial biopsy was nondiagnostic. A trial of high-dose corticosteroids (prednisone, 60 mg/d) for 2 months with a gradual taper was undertaken. Subjective improvement of pulmonary symptoms followed, but symptoms recurred with lower doses of medication. Final diagnoses were dSSc with secondary SS and sarcoidosis. High-dose corticosteroids diminished cutaneous lesions but did not change pulmonary symptoms. Interstitial lung disease progressed to require continuous home oxygen therapy, and pulmonary hypertension developed. Comment. This patient had well-documented dSSc when sarcoidosis was diagnosed. Clinical and serological data were consistent with dSSc (anti-SCL-70 positive) and SS (antiSS-A positive). Pulmonary symptoms could be attributed to progression of pulmonary fibrosis because of dSSc or to the development of sarcoidosis. Skin biopsy of the new plaquelike, hyperpigmented extremity lesions showed non-

caseating granuloma osis.

consistent

with sarcoid-

Cases 5 and 6

FAMC patients 5 and 6 were first described in a report by Kucera in 1989.” In summary, both patients were black women, age 27 and 37 years, and had secondary SS in association with seropositive RA. Disease duration was 1 and 13 years, respectively, before the diagnosis of sarcoidosis. Symptoms of KCS were confirmed by a positive Schirmer’s test and Rose Bengal staining. Minor salivary gland biopsy showed lymphocytic infiltration consistent with secondary SS. Chest roentgenograms showed BHA in one case and interstitial lung disease in the other. One patient developed symptoms of shortness of breath; the other had asymptomatic BHA which prompted further pulmonary evaluation. Both patients had elevated serum ACE levels and positive pulmonary uptake on gallium scanning. Noncaseating granuloma consistent with sarcoidosis was documented on transbronchial biopsy.

8

ENZENAUER AND WEST

Fig 9:

Mediastinal

lymph node biopsy showing

noncaseating granuloma consistent with sarcoidFig 7:

Gallium scan showing increased uptake

osis (FAMC case 3; original magnification

x 100).

in the parotid gland and hila (FAMC case 3).

DISCUSSION

One of the two patients was HLA-DR3 positive. Neither patient required systemic corticosteroid treatment for pulmonary sarcoidosis. Comment. These patients met criteria for seropositive RA. l4 Secondary SS was suggested by positive Schirmer and Rose Bengal tests and confirmed by minor salivary gland biopsy. Pulmonary symptoms and chest roentgenogram abnormalities prompted further evaluation, and the diagnosis of sarcoidosis was established by transbronchial biopsy. Patient 5 was lost to followup, and patient 6 has had no progression of pulmonary disease after a 6-year follow-up.

Sarcoidosis is a multisystem granulomatous disease that commonly affects the hilar lymph nodes, lung parenchyma, skin, and eyes, although almost any organ or tissue can be involved.4 The criteria for establishing the diagnosis of sarcoidosis include (1) compatible clinical and/or radiological findings, (2) histological evidence of noncaseating granuloma, and (3) negative cultures and the absence of other agents that can cause epitheliod granuloma.4 The possibility that sarcoidosis represents a hypersensitivity response to a single agent or multiple inciting agents has been considered.4 A relationship between sarcoidosis and autoimmune disorders has been suggested since the 1960s2 and a common immunopathogenesis has been proposed. 3,4Initially considered rare, sarcoidosis coexisting with other autoimmune diseases is being reported with increasing frequency. SLE and Sarcoidosis

Fig 8: Parotid gland biopsy showing lymphocytic infiltrate consistent with SS (FAMC case 3; original magnification

x 100).

The majority of cases of sarcoidosis associated with a CTD have involved SLE4,7,20-24 (Table 2). The first description of sarcoidosis and SLE was in 1945 by Teilum,25 who reported two patients with SLE who had disseminated noncaseating granulomas at autopsy. Teilum was the first to suggest that sarcoidosis and SLE might be expressions of the same underlying disease.2s

SARCOIDOSIS

IN AUTOIMMUNE

9

DISEASE

Table 2: Systemic Lupus Erythematosus

Patients With Sarcoidosis Reference

Age (yr)/Gender

4

7

20

21

22

23

24

20/F

55/F

62/F

52/F

47/F

43/F

B

W

W

W

W

82/M -

4.5

1.3

29

6

0.3

0

1

FUO

Cough,

Cough,

DOE

None

Rash,

Nodules,

papules

DOE

weakness

plaques

Pos

Neg 1:512

1:80

1:20

1:40

1:80

Neg I:160

Neg 1:256

BHA, RNI

BHA

BHA

NL

Hilar prom,

Race* Disease duration (yr) Symptomst

6

Laboratory values* -

RF

1:160

ANA Chest roentgenogramg

Cardiomegaly

Pos BHA,RNI

inter mark

lB, black;

-

I

ACEll BiopsyY

Liver, BM

W, white; -,

Liver, - skin

-

LN, OLB

TBB

NL TBB, BM

Muscle, skin

I TBB, skin

not reported.

origin; DOE, dyspnea exertion. *RF, rheumatoid factor; Pos, positive; Neg, negative; ANA, antinuclear

tFU0, fever of unknown §BHA, bilateral

hilar adenopathy;

RNI, reticulonodular

infiltrates;

antibody. hilar prom,

hilar prominence;

inter mark, increased

interstitial

markings. JIACE, angiotensin-converting BM, bone marrow;

enzyme;

I, increased;

NL, normal: -,

not reported.

LN, lymph node; OLB, open lung biopsy.

There have been seven subsequent welldescribed cases of sarcoidosis occurring in patients with SLE4,7,20-24 in addition to FAMC case 1. All cases except one were in women, consistent with the female predominance observed in SLE, although not in sarcoidosis, in genera1.26,27 Patients ranged in age from 20 to 82 years, with only one patient less than 40 years old.4 Duration of SLE before the diagnosis of sarcoidosis ranged from 0 and 4 months22,23to as long as 29 yearszO Pulmonary symptoms were the most common presenting complaints, seen in three of eight cases7,20,21;sarcoidosis was an incidental finding in three patients who were otherwise asymptomatic (FAMC case 1 and references 22 and 23). Other presenting symptoms include fever of unknown origin4 and cutaneous lesions.7J3x24 Chest roentgenograms showed BHA in six of eight cases, but a normal roentgenogram has been reported in an asymptomatic patient.23 Serum ACE was elevated in two of three cases for whom results were reported,4,24 and in the case seen at FAMC (FAMC case 1). Sarcoidosis was confirmed by transbronchial,21,22,24skin,7J3,24 muscle,23 lymph node ( FAMC case 1 and reference ZO), bone marrow,4,22 liver,4,7 and open lung20 biopsies. SLE and sarcoidosis share several similarities

of altered immune function. All reported patients with SLE and sarcoidosis had positive ANA, and 25% had positive RF. ANA and RF positivity can be features of both SLE and sarcoidosis.28,29Additionally, altered T-lymphocyte function and circulating immune complexes are seen in both diseases.30-33 Cellular and humoral immune abnormalities seen in sarcoidosis include hypergammaglobulinemia, defective cell-mediated immune function, loss of tolerance to self-antigens, depression of antibody-dependent cell-mediated cytotoxicity, and an increased number of circulating monocyteG and are similar to the immunologic abnormalities found in SLE. RA and Sarcoidosis FL4 is the second most common CTD reported in association with sarcoidosis with six cases reported in the literaturesJ3,34s36(Table 3) and one additional case seen at FAMC (FAMC case 2). Six of the seven cases were women, consistent with the strong female predominance in RA. Three patients (43%) were black, consistent with the racial prediliction for sarcoidosis in the United States. Two of the FAMC patients with RA/SS and sarcoidosis were also black. The majority of patients had long-standing rheumatic disease from 7 to 16 years, but two

10

ENZENAUER AND WEST

Table 3: Rheumatoid Arthritis Patients With Sarcoidosis Reference 5

Age (yr)/Gender Race* Disease duration

(yr)

Symptomst

13

34

35

36

65/M

24/F

37/F

27/F

57/F

30/F

6

B

W

I3

13

0.8

8

8

7

1.5

DOE

DOE

DOE

Wt loss;

DOE

Rash

W

fever/S; fatigue Laboratory

values*

RF ANA Chest roentgenogramg

1:1280

1:5120

1:5120

1:320

Neg BHA

I

I

Neg -

TB

TB

TB

RNIP

ACEll BIOPSY7

I:160 -

1:128

-

BVI -

PIN

BHA/N -

Liver, LN/BM

-

LN/Liver,

TB, skin

spleen *B, black; W, white; -,

not reported.

tDOE, dyspnea on exertion; S, splenomegaly. *RF, rheumatoid factor; ANA, antinuclear antibody; Neg, negative; -, §RNIP, reticulonodular

interstitial pattern:

not reported.

BHA, bilateral hilar adenopathy;

involvement; N, nodules; -,

not reported.

/IACE, angiotensin-converting

enzyme; I, increased; -,

BVI, bilateral vascular involvement;

PI,

pulmonary

not reported.

llTB, transbronchial; LN, lymph node; BM, bone marrow.

patient@j had disease less than 2 years at the time sarcoidosis was diagnosed. Unlike SLE, all the patients with sarcoidosis and RA were symptomatic with pulmonary symptoms seen in 57% of cases (four of seven) and skin lesions in 29% (two of seven). All patients had positive RF, often high titer (> 1:1280). Low-titer RF ( < 1:80) can be seen in up to 38% of patients with sarcoidosis, but titers of > 1:1,280 are rare.37 Seropositive RA patients with high titers of serum RF have an increased frequency of extraarticular manifestations. Pleuropulmonary disease is not uncommon with many clinical presentations, including pleurisy, interstitial lung disease, pulmonary nodules, and pulmonary vasculitis.3* Patients with RA may have interstitial fibrosis, a manifestation of their CTD.5 In most cases, further evaluation is not pursued, which may explain the low prevalence of sarcoidosis in association with RA.j Chest roentgenogram findings were abnormal in all the RA cases with coexistent sarcoidosis; however, BHA characteristic of sarcoidosis was seen in only four cases (FAMC cases 2 and 5 and references 5 and 36). Sarcoidosis was suggested in three cases by elevated serum ACE levels (FAMC case 2 and reference 5) and in one case by

increased pulmonary uptake on gallium scan.13 The diagnosis was established by transbronchial biopsy in the majority of cases (five of seven; FAMC cases 2,5, and 6), but in two cases it was confirmed by liver biopsy.34,35 SS and Sarcoidosis Primary SS has preceded sarcoidosis in six reported cases3,39-42 (Table 4) and one case seen at FAMC (FAMC case 3). Secondary SS was seen in association with sarcoidosis in four cases seen at FAMC (FAMC cases 1, 4, 5, and 6).5 Age at diagnosis of sarcoidosis ranged from 34 to 57 years in primary SS and 27 to 57 years in secondary SS. All patients except one43 were women. Forty percent of the patients were black, which is consistent with the increased prevalence of sarcoidosis in black Americans.26 The duration of CTD was 0 to 25 years in primary SS and 1 to 13 years in secondary SS. Forty percent of the patients were asymptomatic at the time of diagnosis; others presented with shortness of breath (FAMC case 4 and reference 5), dyspnea on exertion,42 cough,42 myalgias,39 weight 10ss,~”fatigue (FAMC case 3), or arthralgias.40 Chest roentgenograms showed BHA in 45% of cases, interstitial disease in 27%, and no

11

SARCOIDOSIS IN AUTOIMMUNE DISEASE

Table 4: Primary Sjiigren’s Syndrome Patients With Sarcoidosis Reference

Age (yr)/Gender

3

39

40

41

42

43

34/F

55/F -

57/F

60/F

57/F

B

w

w

37/M -

B

Race* Disease duration

(yr)

Symptomst

6

0.4

0

25

10

1

None

Myalgias

wt loss,

None

DOE,

IPF

knee pain Laboratory

cough

values*

RF

Neg -

ANA

Neg I:160

Neg

1:40

1:256

-

Neg

1:320

1:400

SS-A

-

Neg

Neg

SS-B

-

Neg NL

Neg NL

I

I

NL

Chest roentgenogramg ACE/I Gallium*

-

PFTS

-

Biopsyll

TB

*W, white; B, black; -,

-

Pos

-

-

Pos

-

BHA/MA

-

NL

NL -

NL

Pos

-

-

NL

NL

NL

NL

-

Buccal

LN

MLN

OL

-

not reported.

tDOE, dyspnea on exertion; IPF, interstitial

pulmonaryfibrosis.

SRF, rheumatoid factor; ANA, antinuclear antibody: PFT, pulmonary function testing; Neg. negative;Pos, positive; NL, normal: -,

not

reported. INL, normal; BHA, bilateral hilar adenopathy: MA, mediastinal adenopathy. IlACE, angiotensin-converting

enzyme; I, increased; NL, normal; -,

not reported.

llTB, transbronchial; LN, lymph node; MLN, mediastinal lymph node; OL, open lung; -,

abnormality in 36%. All patients with normal chest roentgenograms had primary SS.3,39,40,42 Serum ACE levels were elevated in the majority of cases,5,39,40but normal levels may be seen.41 Gallium scans showed increased pulmonary uptake in the majority,5,42 but negative scans were seen.41 SS was most often confirmed by minor salivary gland biopsy.5,40,42Sarcoid granuloma was documented by transbronchial,3J bucca1,j9 lymph node (FAMC case 3 and references 40 and 41) and open lung44 biopsies. When the diagnosis of SS precedes that of sarcoidosis, systemic symptoms of sarcoidosis are often overlooked or not pursued. The prevalence of KCS in sarcoidosis is as high as 70% with subclinical involvement of the salivary glands seen in 50% of patients with pulmonary sarcoidosis who had minor salivary gland biop~y.~~ Bilateral salivary and lacrimal gland enlargement with symptoms of KCS has also been reported in sarcoidosis, mimicking SS and necessitating diagnosis on histological grounds.44 In sarcoidosis, the underlying process is a granulomatous infiltration of the lacrimal and salivary glands. Biopsy of labial minor salivary glands is a highly discriminatory method of

not reported.

distinguishing between sarcoidosis and SS.46 However, if minor salivary gland biopsy is negative and the diagnosis of sarcoidosis is still considered, transbronchial or open lung biopsy may be required.3%42 Bronchoalveolar lavage findings in SS4’ and sarcoidosis48,49are strikingly similar, showing an increase in the proportion and number of lymphocytes. The lymphocytosis seen in sarcoidosis and SS was present in all four FAMC patients undergoing bronchoalveolar lavage (FAMC cases 1, 3, 5, and 6) and mainly reflects an increase in T lymphocytes of the OKT4iLeu3 T-helper cell phenotype.50 Some authors suggest that persistent bronchoalveolar lavage lymphocytosis on serial measurements is a reliable indicator of disease activity in sarcoidosis51; others dispute the prognostic value of lavage lymphocytosis when conclusions are drawn from a single lavage sample.52 Serological evaluation was variable in the cases of primary SS associated with sarcoidosis. A positive ANA was seen in more than 50% of patients (FAMC case 3 and references 39, 41, and 42) and SS-A antibodies were seen in three of six cases (FAMC cases 3, and 4 and reference

12

ENZENAUER AND WEST

42). RF was positive in 50% of cases (FAMC cases 3,5, and 6 and references 41 and 42). The cases of secondary SS associated with sarcoidosis all had at least one abnormal autoantibody; a positive ANA was seen in 50% (FAMC cases 1 and 4), a positive RF was seen in 50% (FAMC cases 5 and 6), and a positive SS-A was seen in one case (FAMC case 4). HLA associations with SS have been studied extensively.53 SS is associated with the HLADR3 alloantigen, 53which was present in four of five cases of SS associated with sarcoidosis at FAMC (FAMC cases 1, 3, 4, and 6). HLA associations with sarcoidosis have also been studied, but definite conclusions are lacking. Brewerton et a154reported that HLA-B8 was associated with sarcoid arthropathy. HLA-DR3 has been associated with a good prognosis in British patients with sarcoidosis.55 SSc and Sarcoidosis Four cases of scleroderma have preceded sarcoidosis, including two cases of ~SSC~,~~ and two cases of dSSc (FAMC case 4 and reference 4) (Table 5). All were women ranging in age from 42 to 68 years. Although three of four patients had symptoms of SSc for at least 5 years before sarcoidosis was diagnosed, (FAMC case 4 and references 6 and 56), Wisenhutter reported a 46-year-old woman with simultaneous Table 5: Systemic Sclerosis Patients With Sarcoidosis

v W-

Race* Disease

duration

(yr)

12

0

10

Symptomst

None

URI

Chest roentgenogramS

BHA -

RNI

Nod shad

I

-

ACE§

-

Galliumll

MLN

Biopsy7 *W, white; -,

Dyspnea/cough

Pos

-

OL

TB/liver

tURI, upper respiratory infections. RNI, reticulonodular

infil-

trates; Nod shad, nodular shadows. §ACE, angiotensin-converting

enzyme;

I, increased; -,

not

reported. I(Pos, positive; -,

not reported.

llMLN, mediastinal lymph node; OL, open lung; TB, transbronchial.

Spondyloatihropathy and Sarcoidosis

Sarcoidosis has not been reported in association with an established seronegative spondyloarthropathy in the English-language literature but has been associated with ankylosing spondylitis in Europe.*-lo Heel pain similar to that seen in enthesopathies may be a presenting symptom of sarcoidosis.11,57-59 Achilles tendonitis57,58and sacroiliac tenderness59 also have been noted. Nine cases of enthesitis, primarily heel pain, mimicking spondylarthopathy have been reported. Ages range from 27 to 54 years, with no gender preference (four women, five men). Fever, malaise, weight loss, and anorexia are not uncommon.57-59 Erythema nodosum was present in seven cases,57-59suggesting Lofgren’s syndrome in association with spondyloarthropathy. The erythrocyte sedimentation rate was elevated in seven patients (78%), and BHA was present on chest roentgenograms in every case.57-59 Gout and Sarcoidosis

not reported.

SBHA, bilateral hilar adenopathy;

onset of dSSc and sarcoidosis.4 Serological data were reported in three cases (FAMC case 4 and references 6 and 57), all of whom were ANA positive; one patient had a positive extractable nuclear antigen (“ENA”) and another a positive SCL-70 antibody (FAMC case 4). Three of four patients had pulmonary symptoms. All four had abnormal chest roentgenograms, but only one had BI+Y4 Because interstitial lung disease is not uncommon in SSc, the diagnosis of sarcoidosis may not be considered unless the characteristic findings of BHA are present. Therefore, the prevalence of sarcoidosis in SSc may be underestimated if the diagnosis is not considered and actively pursued. In the cases reported, tissue diagnosis showing noncaseating granuloma was obtained by lesional skin (FAMC case 2), mediastinal lymph node,4 transbronchial,56 liver,56 and open lung6 biopsies.

Gout is rarely associated with sarcoidosis,60-62 although the first report of cutaneous sarcoidosis described by Jonathan Hutchinson in 1877 occurred in an elderly man with gout.61 Hyperuricemia is seen in up to 20% of patients with sarcoidosis.61 The coexistence of a common disorder such as gout with sarcoidosis cannot be considered evidence of a relationship between

SARCOIDOSIS IN AUTOIMMUNE

13

DISEASE

the diseases. Nevertheless, Kaplan and Klatskin suggest that similarities or radiographic bone changes and clinical presentation make underreporting likely. 61The occurrence of psoriasis in some of these patient$O@ is another potential source of confusion. Patients with gout and sarcoidosis are predisposed to nephrolithiasis from both sarcoid-induced hypercalciuria and gout-associated hyperuricosuria.“2 Dennatomyositis and Sarcoidosis

Three cases of concomitant dermatomyositis and sarcoidosis have been reported.‘j3-@ In 1980, Itoh et al first reported a patient with classic dermatomyositis preceding sarcoid myopathy.63 A 46-year-old Japanese woman with a lo-year history of a typical heliotrope rash noted progressive proximal muscle weakness with the onset of a new pruritic rash involving the face, neck, chest, shoulders, elbows, and the dorsum of the hands. Muscle enzyme (lactate dehydrogenase and aldolase) levels were elevated, and an electromyogram showed a myopathic pattern. Biopsy of the elbow rash was compatible with dermatomyositis, whereas muscle biopsy showed numerous granulomatous lesions typical of sarcoidosis. Chest roentgenograms did not show hilar adenopathy, and serum ACE levels were normal. She was treated with high-dose prednisone with improvement of cutaneous symptoms and muscle weakness. Hart et alh4 reported a 56-year-old Japanese man with arthritis of the hands and an erythematous rash of the lower legs, forehead, and back with associated periorbital edema. Creatinine kinase was elevated at 384 IU/L (normal, < 240 IU/L). Symptoms fluctuated over the next 5 years until a disease flare that coincided with the development of moderately differentiated adenocarcinoma of the colon (Duke’s B). Repeat laboratory evaluation showed an elevated creatinine kinase of 2,464 IU/L and a normal serum ACE level. Nerve-conduction studies were consistent with a mild sensorimotor peripheral neuropathy, and electromyography showed fibrillation potentials and low-amplitude polyphasic motor unit action potentials consistent with active polymyositis. Muscle biopsy showed focal inflammation and necrosis as well as prominent noncaseating granuloma formation consistent with sarcoid myopathy. He was

treated with prednisone, 40 mgld, with marked symptomatic improvement over the next 4 weeks and normalization of the creatinine kinase level to 130 IU/L. Lipton et a165reported a 21-year-old woman with myalgias, weakness, malar rash, erythematous plaques over the extensor surfaces of the elbows and knees, and classic Gottron’s papules over the knuckles. Creatinine kinase and serum lactate dehydrogenase levels were elevated at 760 IU/L and 297 U/L, respectively. Chest roentgenograms showed BHA. Electromyography showed myopathic units with fibrillations. Muscle biopsy showed perifascicular inflammation, increased numbers of internal nuclei, and regenerating fibers consistent with dermatomyositis as well as several granulomata. Subsequent mediastinal lymph node biopsy showed multiple noncaseating granulomata. Serum ACE levels were twice normal. The patient’s clinical symptoms resolved spontaneously without treatment with considerable regression of pulmonary lymphadenopathy. Hart et al note that two of the reported cases of dermatomyositis associated with sarcoidosis have been in Japanese patients, suggesting the possibility of a genetic predisposition.@ Two of the cases were similar, with prominent cutaneous manifestations of dermatomyositis and sarcoid granuloma documented on muscle biopsy.m4 - Although symptomatic muscle weakness is uncommon in sarcoidosis, up to 50% of muscle biopsies in asymptomatic patients show granulomas.66 Primary Biliary Cirrhosis and Sarcoidosis Six patients with sarcoidosis and primary biliary cirrhosis (PBC) have been described.56,67-69. All were women ranging in age from 32 to 56 years, consistent with the strong female predominance observed in PBC but not in sarcoidosis.‘O Four of six patients had PBC for at least 3 yearW7 before the diagnosis of sarcoidosis, but one had simultaneous onset of pruritus and hilar adenopathy .‘j* Four patients presented with pulmonary symptoms of dyspnea on exertion, pleurisy, or cough,56,67prompting further evaluation. Chest roentgenograms were abnormal in five cases,56s67,68but a normal chest roentgenogram has also been reported.69 Two patients had “fine nodular shadows,“67 two had

14

“mid- and lower-zone confluent shadows,“56 and one had hilar and paratracheal lymph node enlargement.68 Decreased diffusion capacity for carbon dioxide was seen in both patients whose pulmonary function tests were reported.56,67 All six patients were positive for antimitochondrial antibodies consistent with PBC.56,67-69 Serum ACE levels are elevated in up to 50% of patients with active sarcoidosis, but elevated levels may also be seen in up to 14% of patients with PBC alone.70 Consequently, elevated serum ACE levels are of little value in diagnosing sarcoidosis associated with PBC. PBC was confirmed by liver biopsy in the four patients with PBC preceding the onset of sarcoidosis.56v67 Noncaseating granuloma consistent with sarcoidosis was documented by transbronchial biopsy in two patients, 56by liver biopsy in two,56,68and by skin biopsy in one.G9 In the two patients reported by Stanley et a1,67 the presence of multiple pulmonary and mediastinal lymph node granulomas was confirmed at postmortem examination. Because approximately half of the patients with PBC have granulomas on liver biop~y,~l extrahepatic granulomatous involvement should be sought when pursuing the diagnosis of sarcoidosis and PBC. The presence of hepatic granulomas and depression of cell-mediated immune reactions in both PBC and sarcoidosis suggests a potential common pathogenesis for these two systemic diseases and involvement of multiple organ systems.72 The rarity of lung involvement in PBC should prompt the clinician to consider the additional diagnosis of sarcoidosis in PBC patients with pulmonary signs and symptoms7* Juvenile RA and Sarcoidosis No cases of sarcoidosis associated with juvenile RA (JRA) have been reported, although the arthropathy and uveitis of childhood sarcoidosis may mimic JRA. In 1946, Castellanos and Galan described a 6-year-old Cuban boy with fever, polyarthritis, lymphadenopathy, and splenomegaly consistent with Still’s disease.73 Bone marrow biopsy showed multinucleated giant cells similar to those found in sarcoid granuloma.73 Sarcoid granuloma was documented in a deltoid muscle biopsy, and a diffuse infiltration of epithelioid cells was noted in a biopsied inguinal lymph node.73 Synovial biopsy

ENZENAUER AND WEST

showed only a chronic nonspecific inflammatory process without sarcoid granuloma. In 1985, Lindsley and Godfrey reported two patients with symmetrical polyarthritis beginning at 19 to 24 months of age who subsequently developed iritis and had JRA diagnosed.74 Both patients initially responded to prednisone therapy. The diagnosis of sarcoidosis was made after 7 to 10 years of disease, when noncaseating granulomas were found on conjunctival and supraclavicular lymph node biopsies.74 Serum ACE levels were normal in both patients, and neither had evidence of pulmonary disease.74 Similar to JRA, sarcoid uveitis may be the initial and/or dominant manifestation of disease, may produce few symptoms, and does not necessarily parallel joint disease activity.73,74 Joint and eye disease of both sarcoidosis and JRA respond well to corticosteroids and may delay the proper diagnosis for prolonged periods.74 The presence of pulmonary disease and elevated serum ACE levels may not be helpful in diagnosing childhood sarcoidosis.73,74 Autoimmune Thrombocytopenia and Sarcoidosis

Thrombocytopenia in patients with sarcoidosis is rare, with a prevalence of 1.9%.75 Four patients with autoimmune thrombocytopenic purpura as the initial manifestation of sarcoidosis have been reported.76,79 All were male, ranging in age from 13 to 27 years. Symptoms at presentation included gingival bleeding,77g79epistaxis,77,78and migratory arthralgia.“j Physical examination was remarkable for petechiae involving the abdomen, lower extremities, trunk, face, and mucous membranes,76-79 purpura,“j generalized ecchymoses,78 lymphadenopathy,77 and splenomegaly. 77,79Platelet counts ranged from 2,000 to 7,000/mm3. Chest roentgenograms showed BHA in three cases76,77,79 and a diffuse reticulonodular infiltrate in one case.78 Serum ACE levels were elevated in two patients.76,79Bone marrow biopsy showed normal celullarity76v79with an increased number of megakaryocytes.76-79Noncaseating granuloma consistent with sarcoidosis were confirmed on biopsy of mediastina176 and cervical77 lymph nodes or transbronchial biopsy. 78,79All patients were treated with high-dose corticosteroids, with improvement in platelet counts,76-79although one patient required a single dose of intravenous

SARCOIDOSIS

IN AUTOIMMUNE

15

DISEASE

vincristine’” and another who developed steroidinduced psychosis required splenectomy.78 Thrombocytopenia associated with sarcoidosis may be a consequence of hypersplenism77,78 and generally improves with splenectomy.76 Bone marrow biopsy results suggest increased consumption and peripheral destruction.74,77 The presence of platelet antibodies78,80 and improvement after corticosteroid therapy76 also support an immunological origin of thrombocytopenia in sarcoidosis. Lawrence and Greenbergso propose that the polyclonal proliferation of B lymphocytes and the associated synthesis of immunoglobulins seen in active sarcoidosissl may result in the occasional production of antibodies with affinity for platelet antigens causing autoimmune thrombocytopenia. Sarcoidosis Preceding Autoimmune Disease

Sarcoidosis rarely precedes a variety of autoimmune diseases, including RA,12 SLE,82 SSC,~J~ PBC,6Rx72 and the spondyloarthropathies.83,84 Two cases of SLE and one case of Reiter’s syndrome were seen at FAMC in patients with preexisting sarcoidosis. SUMMARY Six cases of sarcoidosis in patients with previously well-documented CTD are described: three patients had RA, and one each had primary SS, SLE, and scleroderma. The frequency of sarcoidosis associated with CTD at FAMC was 6 of 569 patients, or 1%. Five patients had primary (FAMC case 3) or secondary (FAMC cases 1, 4, 5, and 6) SS. Patients with SS may be at increased risk for developing sarcoidosis compared with patients with other rheumatic diseases. Additionally, there may be an increased risk of sarcoidosis in patients with HLA-DR3 (FAMC cases 1, 3, 4, and 6), an

alloantigen commonly associated with both SS and sarcoidosis.39,41The English-language literature of sarcoidosis complicating a variety of autoimmune diseases or other CTDs has been reviewed. The severity and course of sarcoidosis associated with autoimmune disease is variable. Spontaneous resolution of pulmonary symptoms59 and lymphadenopathy45 has been reported. Although some patients respond to low-dose corticosteroids (prednisone, 5 to 15 mg/d43J7), others do not improve even with high-dose corticosteroids.20 The majority of patients at FAMC received no systemic corticosteroid therapy for asymptomatic pulmonary sarcoidosis and suffered no adverse sequelae. The one FAMC patient (FAMC case 4) in whom a trial of corticosteroids failed had severe dSSc with truncal skin involvement. Progression of pulmonary disease despite corticosteroid therapy suggests her symptoms were due to scleroderma lung disease rather than pulmonary sarcoidosis. In the majority of patients, sarcoidosis in association with rheumatic disease does not adversely affect the long-term morbidity and mortality associated with underlying CTD alone. Sarcoidosis is an uncommon complication of a variety of autoimmune diseases. Immunologic abnormalities associated with sarcoidosis and autoimmune disease suggest a possible common etiopathogenesis. The prevalence of sarcoidosis in association with rheumatic disease may be underestimated if new pulmonary symptoms caused by sarcoidosis are attributed to the primary rheumatic disease and not pursued. ACKNOWLEDGMENT The authors thank Dr Vishnu Reddy for his assistance in the review and production of the photomicrographs of pathological specimens provided in the manuscript.

REFERENCES 1. Teilum G: Pathogenetic studies on lupus erythematosus disseminatus and related diseases. Acta Med Stand 123:126-142,1946 2. Teilum G: Morphogenesis and development of sarcoid lesions. Similarities to the group of collagenosis, in Lofgrens, Rungl, Boktryckeriet (eds): The 3rd International Conference on Sarcoidosis. Stockholm, Sweden, Norstedt and Soner, 1964, pp 14-18 3. Turiaf J, Battesti JP: Gougerot-Sjogren syndrome and sarcoidosis. Ann NY Acad Sci 278:401-405, 1976 4. Wisenhutter CW, Sharma OP: Is sarcoidosis an auto-

immune disease? Report of four cases and review of the literature. Semin Arthritis Rheum 9:124-144, 1979 5. Kucera RF: A possible association of rheumatoid arthritis and sarcoidosis. Chest 95:604-606,1989 6. Sharma OP, Ahamad I: The CREST syndrome and sarcoidosis: Another example of an overlap syndrome. Sarcoidosis. 5:71-73, 1988 7. Harrison GN, Lipham M, Elguindi AS, Loebl DH: Acute sarcoidosis occuring during the course of systemic lupus erythematosus. South Med J 72:1387-1388,1979

16

8. Vestratten JM, Bekaert J: Association de spondylite ankylosante et de sarcoidose. ActaTub Belg 2:149-151,195l 9. Martin E, Fallet GH: Pneumopathies chroniques et rhumatisme. Schweiz Med Wochenschr 34:776-796,1953 10. Deshayes P, Desseauve J, Hubert J, et al: Un cas de polyarthrite au tours d’une sarcoidose: Un cas de spondylarthrite ankylosante au tours d’une sarcoidose. Rev Rhum 32:671-674,1965 11. Shaw RA, Holt PA, Stevens MB: Heel enthesopathy in sarcoidosis. Arthritis Rheum 3O:S41,1987 (abstr) 12. Hillerdal 0, Hultquist G, Linder L: A case of sarcoidosis, syphilis, and rheumatoid arthritis. An unusual combination of systemic diseases. Acta Tub Pneum Stand 46:65-70,1965 13. Fallahi S, Collins RD, Miller RK, Halla JT: Coexistence of rheumatoid arthritis and sarcoidosis: difficulties encountered in the differential diagnosis of common manifestations. J Rheumatol11:526-529, 1984 14. Arnett FC, Edworthy SM, Bloch DA, et al: The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315-324,1988 15. Tan FM, Cohen AS, Fries JF, et al: The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25:1271-1277,1982 16. Van Der Linden S, Valkenburg HA, Cats A: Evaluation of the diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum 27:361-368, 1984 17. Wilkens RF, Arnett FC, Bitter T, et al: Reiter’s syndrome: evaluation of preliminary criteria for definite disease. Arthritis Rheum 24:844-849, 1981 18. Fox RI, Robinson CA, Curd JG, et al: Sjogren’s syndrome. Proposed criteria for classification. Arthritis Rheum 29:577-585, 1986 19. Bohan A, Peter JB: Polymyositis and dermatomyositis. N Engl J Med 292:344-347,403-407, 1975 20. Hunter T, Arnott JE, McCarthy DS: Features of systemic lupus etythematosus and sarcoidosis occuring together. Arthritis Rheum 23:364-366, 1980 21. Askari A, Thompson P, Barnes C: Sarcoidosis: Atypical presentation associated with features of systemic lupus erythematosus. J Rheumatol15:1578-1579,1988 22. Needleman SW, Silber RA, Von Brecht JH, et al: Systemic lupus erythematosus complicated by disseminated sarcoidosis: Report of a case associated with circulating immune complexes. Am J Clin Path01 78:105-107,1982 23. Aronson PJ, Fretzin DF, Morgan NE: A unique case of sarcoidosis with coexistent collagen vascular disease. J Am Acad Dermatol138:886-891,1985 24. Soto-Aguilar MC, Boulware DW: Sarcoidosis presenting as antinuclear antibody positive glomerulonephritis. Ann Rheum Dis 47:337-339,1988 25. Teilum G: Miliary epitheliod-cell granulomas in lupus erythematosus disseminatus. Acta Path01 Microbial Stand 22:73-79,1945 26. Sharma OP: Sarcoidosis: Clinical, laboratory, and immunologic aspects. Semin Roentgen01 20:340-355, 1985 27. Schur PH: Clinical features of SLE, in Kelley WN, Harris ED, Ruddy S, et al (eds): Textbook of Rheumatology (ed 3). Philadelphia, PA, Saunders, 1989, pp 1101-1129

ENZENAUER AND WEST

28. Veien NK, Hardt F, Bendixen G, et al: Immunological studies in sarcoidosis: a comparison of disease activity and various immunologic parameters. Ann NY Acad Sci 278~47-51,1976 29. Kunkel HG, Simon HJ, Fudenberg H: Observations concerning positive serologic reactions for rheumatoid factor in certain patients with sarcoidosis and other hyperglobulinemic states. Arthritis Rheum 1:289-296, 1958 30. Williams RC, Bankhurst AD: Clinical immunologic studies in systemic lupus eyrthematosus. Arthritis Rheum 21:S202-209,1978 (suppl) 31. Hamilton ME, Winfield JB: T cells in systemic lupus erythematosus. Arthritis Rheum 22:1-6,1979 32. Gupta RC, Kueppers F, DeRemee RA, et al: Pulmonary and extrapulmonary sarcoidosis in relation to circulating immune complexes. Am Rev Respir Dis 116:261-266, 1977 33. Goodwin JS, DeHoratius R, Israel H, et al: Suppressor cell function in sarcoidosis. Ann Intern Med 90:169-173, 1979 34. Thompson WR, Ferenzi GW: Sarcoidosis and rheumatoid arthritis. Ill Med J 129:239-242,1966 35. Putkonen T, Virkkunen M, Wager 0: Joint involvement in sarcoidosis with special reference to the coexistence of sarcoidosis and rheumatoid arthritis. Acta Rheum Stand 11:53-61,1965 36. Davis MW, Crotty RQ: Sarcoidosis associated with polyarthritis. Ann Intern Med 36:1098-1106,1952 37. Oreskes I, Siltzbach LE: Changes in rheumatoid factor activity during the course of sarcoidosis. Am J Med 44:60-67,1968 38. Shiel WC, Prete PE: Pleuropulmonary manifestations of rheumatoid arthritis. Semin Arthritis Rheum 13:235243,1984 39. Seinfeld ED, Sharma OP: TASS syndrome: Unusual association with thyroiditis, Addison’s disease, Sjogren’s syndrome and sarcoidosis. J R Sot Med 76:883-885,1983 40. Melson RD, Speight PM, Ryan J, et al: Sarcoidosis in a patient presenting with clinical and histological features of primary Sjogren’s syndrome. Ann Rheum Dis 47:166-168, 1988 41. Justiniani FR: Sarcoidosis complicating primary Sjogren’s syndrome. Mt Sinai J Med 56:59-61,1989 42. Deheinzelin D, Carvalho CRR, Tomazini ME, et al: Association of Sjogren’s syndrome and sarcoidosis. Report of a case. Sarcoidosis 5:68-70, 1988 43. Johnson CD: Obstructive jaundice in a patient with ulcerative colitis, Sjogren’s syndrome and sarcoidosis. J R Sot Med 82:362,1989 44. Greenberg G, Anderson R, Sharpstone P, et al: Enlargement of the parotid gland due to sarcoidosis. Br Med J 2:861-862, 1964 45. Crick RP, Hoyle C, Smellie H: The eyes in sarcoidosis. Br J Ophthalmol45:461-481, 1961 46. Giotaki H, Constantopoulous SH, Papadimitriou CS, et al: Labial minor salivary gland biopsy: a highly discriminatory diagnostic method between sarcoidosis and Sjogren’s syndrome. Respiration 50:102-107, 1986 47. Bariffi F, Pesci A, Bertorelli G, et al: Pulmonary involvement in Sjogren’s syndrome. Respiration 46:82-87, 1984

SARCOIDOSIS

IN AUTOIMMUNE

DISEASE

48. Daniele RP, Elias JA, Epstein PE, et al: Bronchoafveolar lavage: Role in pathogenesis, diagnosis, and management of interstitial lung disease. Ann Intern Med 102:93108,1985 49. Bjermer L, Rosenhalf L, Angstrom T, et al: Predictive value of bronchoalveofar cell favage analysis in sarcoidosis. Thorax 43:284-288,1988 50. Hunninghake GW, Crystal RG: Pulmonary sarcoidosis: A disorder mediated by excess helper T lymphocyte activity at sites of disease activity. N Engf J Med 305:429434,198l 51. Israel-Biet D, Venet A, Chretien J: Persistent high alveolar fymphocytosis as a predictive criterion of chronic pulmonary sarcoidosis. Ann NY Acad Sci 465:395-406, 1986 52. Buchalter W, App W, Jackson L, Chandler D, et al: Bronchoalveolar favage cell analysis in sarcoidosis: a comparison of lymphocyte counts and clinical course. Ann NY Acad Sci 465:678-684,1986 53. Wilson R, Provost IT, Bias WB, et al: Sjogren’s syndrome: Influence of multiple HLA-D region affoantigem on clinical and serologic expression. Arthritis Rheum 27:1245-1253, 1984 54. Brewerton DA, Cockburn C, James DCO, et al: HLA antigens in sarcoidosis. Cfin Exp Immunol 27:227-229, 1977 55. Gardner J, Kennedy HG, Hamblin A, et al: HLA associations in sarcoidosis: A study of two ethnic groups. Thorax 39:19-22, 1984 56. Fagen EA, Moore-Giflon JC, Turner-Wanvick M: Multiorgan granufomas and mitochondriaf antibodies. N Engf J Med 308:572-575, 1983 57. Shaw RA, Holt PA, Stevens MB: Heel pain in sarcoidosis. Ann Intern Med 109:675-677, 1988 58. Ott H, Van Linthoudt D: Heel pain in sarcoidosis-Is sarcoid a cause of spondarthropathy? Br J Rheumatol 26:468, 1987 (fetter) 59. Kirkham B, Jobanputra P: Sarcoidosis and spondarthritis. Br J Rheumatof 27:241, 1988 60. Bunin JJ, Kimberg DV, Thomas LB, et al: The syndrome of sarcoidosis, psoriasis and gout. Ann Intern Med 57:1018-1040, 1962 61. Kaplan H, Kfatskin G: Sarcoidosis, psoriasis, and gout: Syndrome or coincidence? Yale J Biof Med 32:335352,196O 62. Harvey JA, Pak CYC: Gouty diathesis and sarcoidosis in a patient with recurrent calcium nephrofithiasis. J Ural 139:1287-1289,1988 63. Itoh J, Akiguchi I, Midorikawa R, et al: Sarcoid myopathy with typical rash of dermatomyositis. Neurology 30:1118-1121. 1980 64. Hart Y, Schwartz MS, Bruckner F, et al: Relapsing dermatomyositis associated with sarcoidosis. J Neurof Neurosurg Psych 51:311-313, 1988 65. Lipton JH, McLeod BD, Brownell KW: Dermatomyositis and granulomatous myopathy associated with sarcoidosis. Can J Neurof Sci 15:426-429, 1988 66. Stjernberg N, Cajander S, Truedsson H, et al: Muscle

17

involvement in sarcoidosis. Acta Med Stand 209:213-216, 1981 67. Stanley NN, Fox RA, Whimster WF, et al: Primary biliary cirrhosis or sarcoidosis-or both. N Engl J Med 287:1282-1284,1972 68. Karfish AJ, Thompson RPH, Williams R: A case of sarcoidosis in primary biliaty cirrhosis. Lancet 297:559, 1969 (letter) 69. Sherman S, Nieland NS, Van Thiel DH: Sarcoidosis and primary bifiary cirrhosis. Coexistence in a single patient. Dig Dis Sci 33:368-374, 1988 70. Studdy P, Bird R, James DG, Sherlock S: Serum angiotensin-converting enzyme (SACE) in sarcoidosis and other granulomatous disorders. Lancet 2:1331-1333, 1978 71. Lee RG, Epstein 0, Jauregui H, et al: Granulomas in primary biliary cirrhosis: A prognostic feature. Gastroenterofogy 81:983-986,198l 72. Keefe EB: Sarcoidosis and primary biliary cirrhosis: Literature review and illustrative case. Am J Med 83:977980,1987 73. Casteflanos A, Gafan E: Sarcoidosis (Besnier-BoeckSchaumann’s disease). Report of a case in a child simulating Still’s disease. Am J Dis Child 71:513-529, 1946 74. Lindsley CB, Godfrey WA: Childhood sarcoidosis manifesting as juvenile rheumatoid arthritis. Pediatrics 76:765-768,1985 75. Mayock RL, Bertrand P, Morrison CE, et al: Manifestations of sarcoidosis: Analysis of 145 patients, with a review of nine series selected from the literature. Am J Med 35:67-89, 1963 76. Beris P, Laficata M, Miescher P: Autoimmune thrombocytopenia and sarcoidosis. Stand J Haematof 35:456-457, 1985 77. Dickerman JD, Holbrook PR, Zinkham WH: Etiology and therapy of thrombocytopenia associated with sarcoidosis. J Pediatr 81:758-764,1972 78. Thomas LLM, Afberts C, Pegefs JG, et al: Sarcoidosis associated with autoimmune thrombocytopenia and selective IgA deficiency. Stand J Haematol28:357-359, 1982 79. Larner AJ, Doffery CT, Cox TM, et al: Life threatening thrombocytopenia in sarcoidosis. Br Med J 300:317-319, 1990 80. Lawrence HJ, Greenberg BR: Autoimmune thrombocytopenia in sarcoidosis. Am J Med 79:761-764, 1985 81. Hunninghake GW, Crystal RG: Mechanismsof hypergfobulinemia in pulmonary sarcoidosis: site of increased antibody production and role of T-lymphocytes. J Clin Invest 67:86-92, 1981 82. Fivenson DP, Crump G, Scheefe P, et al: Systemic lupus erythematosus developing in a patient with longstanding pulmonary sarcoidosis. J Rheumatol 16:1116-f 119, 1989 83. Perfman SG, Damergis J, Witorsch P, et al: Vertebral sarcoidosis with paravertebral ossification. Arthritis Rheum 21:271-276, 1978 84. Curran JJ, Dennis GJ, Bofing EP: Sarcoidosis and spondyloarthropathy. Arthritis Rheum 3O:S42, 1987 (abstr)