Sarcoidosis and systemic vasculitis

Sarcoidosis and Systemic Vasculitis Sandra R.M. Fernandes, Bernhard H. Singsen, and Gary S. Hoffman Background: Systemic vasculitis is an unusual complication of sarcoidosis. Over a 10-year period, the authors have provided care for six patients who had features of both sarcoidosis and vasculitis. Vasculitis could not be attributed to other causes. Objectives: To report six patients (five children) who had sarcoidosis and systemic vasculitis and compare our experience with previous literature. To better delineate the clinical spectrum of sarcoid vasculitis and its response to therapy. Methods: Retrospective analysis and a Medline literature review of sarcoid and concurrent vasculitis from 1966. Results: Our six patients had systemic illnesses that included fever, peripheral adenopathy, hilar adenopathy, rash, pulmonary parenchymal disease, musculoskeletal symptoms, and scleritis or iridocyclitis. Biopsies revealed features compatible with the diagnosis of sarcoidosis or necrotizing sarcoid granulomata in either skin, lymph node, lung, synovium, bone, bone marrow, liver, trachea, or sclera. Arteriography showed features of large vessel vasculitis in three patients, all of whom were African American, whereas patients with small vessel vasculitis were white. Prior reports of sarcoid and vasculitis included 14 adults, of whom half had predominantly small vessel disease, and half had medium- or large-sized vessel disease. Eight previously reported children included seven with primarily large vessel sarcoid vasculitis. Racial background was noted in 15 reported cases and included whites (6), African Americans (5), and Asians (4). Among the authors’ six patients, four improved when treated with prednisone alone. However, relapses occurred when the drug was tapered or withdrawn. Conclusions: Sarcoidosis may be complicated by systemic vasculitis that can affect small- to large-caliber vessels. Sarcoid vasculitis can mimic hypersensitivity vasculitis, polyarteritis nodosa, microscopic polyangiitis, or Takayasu’s arteritis. African American and Asian patients are disproportionately represented among cases with large vessel involvement. Corticosteroid and cytotoxic therapy is palliative for all forms of sarcoid vasculitis. However, relapses and morbidity from disease and treatment is common. Semin Arthritis Rheum 30:33-46. Copyright © 2000 by W.B. Saunders Company INDEX WORDS: Sarcoidosis; vasculitis; aortitis; necrotizing sarcoid granulomatosis; treatment. From the Department of Rheumatic and Immunologic Diseases and the Center for Vasculitis Care and Research, Cleveland Clinic Foundation, Cleveland, OH. Sandra R.M. Fernandes, MD, PhD: Professor of Medicine, Department of Rheumatology, School of Medicine, State University of Campinas (UNICAMP), Brazil; Bernhard H. Singsen, MD, MPH: Senior Staff Head, Pediatric Rheumatology, Department of Rheumatic and Immunologic Diseases and the Center for Vasculitis Care and Research. Cleveland Clinic Foundation, Cleveland, OH; Gary S. Hoffman, MS, MD: Chairman, Department of Rheumatic and Immunologic Diseases, and Director, the Center for Vasculitis Care and Research, Harold C. Schott Chair for Rheumatic and Immu-

nologic Diseases, Cleveland Clinic Foundation, Cleveland, OH. Dr. Fernandes was supported by Fundac¸a˜o Amparo a` Pesquisa Estado de Sa˜o Paulo (FAPESP). The study was supported in part by The Grant Family Foundation for Vasculitis Research. Address reprint requests to Gary S. Hoffman, MD, Harold C. Schott Chair for Rheumatic and Immunologic Diseases, Cleveland Clinic Foundation/A50, 9500 Euclid Avenue, Cleveland, OH 44195. E-mail: [email protected] Copyright © 2000 by W.B. Saunders Company 0049-0172/00/3001-0004$10.00/0 doi:10.1053/sarh.2000.8364

Seminars in Arthritis and Rheumatism, Vol 30, No 1 (August), 2000: pp 33-46

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FERNANDES, SINGSEN, AND HOFFMAN

S

ARCOIDOSIS is a multisystem granulomatous disease of unknown origin. It can affect any organ, but it most commonly involves the lungs, lymph nodes, skin, and eyes (1), and is characterized histologically by noncaseating, well-formed granulomas (2). Infrequently, sarcoid granulomas may undergo necrosis (“necrotizing sarcoid”) (3, 4), a variant form of sarcoidosis that occasionally coexists with small vessel vasculitis. Prior reports have noted that vascular manifestations of sarcoidosis can be attributable to extrinsic compression of arteries and veins by enlarged lymph nodes or by direct involvement of vessel walls (5-7). Small and medium-sized vessels are frequently affected in pulmonary sarcoidosis (8), but extrapulmonary vascular involvement is uncommon. Cutaneous vascular sarcoidosis has been reported in the form of leukocytoclastic vasculitis and granulomatous vasculitis (9-15). Anecdotal reports have associated sarcoidosis with aortitis or involvement of aortic branch vessels (16-29). These cases have been severe or fatal, the diagnosis usually being established by finding sarcoid granulomas within the wall of arteries at postmortem examination. Over the past 10 years, we have cared for six patients with sarcoidosis complicated by either large, medium or small vessel vasculitis. This aspect of sarcoidosis is poorly described, and the impact of treatment has not been clearly delineated. We report our experience and compare disease presentation, course, and outcome with previously described cases.

Abbreviations ACE AIL ANCA CVID CSS CP JRA MRI MTX NSG WG

angiotensin converting enzyme angiocentric immunoproliferative lesion antineutrophil cytoplasmic antibodies common variable immunodeficiency Churg-Strauss syndrome cyclophosphamide juvenile rheumatoid arthritis magnetic resonance imaging methotrexate necrotizing sarcoid granulomatosis Wegener’s granulomatosis

MATERIALS AND METHODS

We retrospectively reviewed data from six of our patients with vascular inflammatory symptoms and biopsy-proven sarcoidosis. Four of the patients had been referred to Cleveland Clinic Foundation, and two were under the care of one of the authors (G.S.H.) at the National Institutes of Health. The diagnosis of sarcoidosis was based on histologic evidence of well-formed noncaseating granulomas and compatible clinical manifestations. The presence of vasculitis was confirmed by histologic findings on biopsy or by arteriographic features compatible with large vessel vasculitis. The histologic criteria for small vessel vasculitis as part of necrotizing sarcoid granulomatosis (NSG) includes the presence of sarcoid-like granuloma, vasculitis, and necrosis in the absence of infection or malignancy (3). Arteriographic evidence of medium or large vessel disease was shown by stenosis, occlusion, or aneurysms. A chart review was performed to retrieve demographic, clinical, laboratory, imaging and histologic features, treatment, and outcome. A Medline (National Library of Medicine, Bethesda) search was performed to identify cases of sarcoid vasculitis reported in the English literature since 1966. RESULTS

Five of six patients had the onset of sarcoidosis in childhood (22 months to 13 years). The single adult was 31 years old when she became ill. There were three male and three female patients, three blacks and three whites. The mean follow-up after diagnosis of sarcoidosis was 7.5 years (range, 2.6 to 17 years) and after vasculitis 4.0 years (range, 1.6 to 6.2 years) (Table 1). In two cases of large vessel vasculitis, sarcoidosis occurred 6 and 8 years before the clinical evidence of vasculitis (cases 4 and 5), and in the remaining case of large vessel disease, sarcoidosis and pulseleness were noted within 1 month of each other. The most frequent symptoms were fever (4 of 6) and arthralgia or arthritis (4 of 6), which were observed at presentation or during the course of illness. One patient (case 4) developed symmetrical polyarthritis, which eventually led to deformities. Two of the three patients with large vessel vasculitis had claudication of the right arm (case 6) and carotidynia (case 4). Five patients had skin lesions: maculopapular rash (n ⫽ 3), erythema nodosum (n ⫽ 1), and necrotic lesions on the face,

SARCOIDOSIS AND SYSTEMIC VASCULITIS

arms, and legs (n ⫽ 1). Half of the patients had ocular involvement, including one case each of scleritis, bilateral anterior uveitis, and bilateral iridocyclitis. Asymmetry of arterial pulses (n ⫽ 3) or vascular bruits (n ⫽ 2) were the most common clinical features in the three patients with large vessel vasculitis. Hilar adenopathy (n ⫽ 3) and pulmonary infiltrates (n ⫽ 3) were the most common chest radiograph findings (Fig 1A) (Table 1). Antineutrophil cytoplasmic antibodies was determined in two cases and was negative in both. Serum angiotensin-converting enzyme levels were measured in four patients, and were elevated in two. Biopsy proof of NSG was obtained from the lung (cases 1 and 2) (Fig 1B) and trachea and bone (case 3). Necrotizing granulomata without vasculitis were found in the lymph node, liver, skin, and sclerae. In patients with large vessel vasculitis, the diagnosis of sarcoidosis was derived from biopsy specimens of synovial tissues, bone marrow, and lymph nodes. Cultures and special stains of biopsy specimens for fungi, bacteria, and mycobacteria were negative in all cases. Arteriography performed in three patients with large vessel disease showed stenosis or aneurysms of the aorta and its main branches, a presentation that mimicked Takayasu’s arteritis. Only large vessel disease (eg, aorta and its major branches) was noted in two patients, and one patient showed both large and small vessel vasculitis (Table 1). CASE REPORTS

Course of Illness Case 1 In December 1992, a 3-year-old boy presented with a 20-month history of NSG. Initial findings included fever, hepatosplenomegaly, lymphadenopathy, and pulmonary infiltrates. Evaluation for infectious causes was unrewarding. Biopsies of lymph node, liver, and lung all showed necrotizing sarcoid granulomas. Prednisone (2 mg/kg/d) was started, which led to improvement, but relapse occurred (fever, cough, and worsening of pulmonary infiltrates) when prednisone was tapered to 1 mg/kg/d 2 months later. Prednisone was again increased (2 mg/kg/d), but fever and shortness of breath persisted. Cyclophosphamide (CP) (2 mg/ kg/d) was added. Improvement followed, but relapses again occurred when prednisone was tapered to less than 0.6 to 1.5 mg/kg every other day.

35

After 1 year, because of possible CP-induced cystitis, CP was replaced by methotrexate (MTX). While receiving MTX (0.3 mg/kg/wk) and prednisone (1.4 mg/kg every other day), he again developed hepatosplenomegaly, fever, cough, and rash. Increased doses of both MTX (0.40 mg/kg/ wk) and prednisone (1 mg/ kg/d) again led to improvement. He remained stable while receiving MTX and prednisone (0.3 mg/kg/d), until inferior vena cava occlusion (Budd-Chiari syndrome) occurred about 1 year later. Despite long-term prednisone therapy, he experienced five additional relapses, each time prednisone was tapered. He was last seen in February 1999. Case 2 An 8-year-old boy was first evaluated in December 1992. Common variable immunodeficiency was recognized at 19 months, 6 1⁄2 years before the diagnosis of NSG. In October 1989, his initial presentation included recurrent upper airway infections (otitis media and sinusitis). Immunologic evaluation indicated the absence of immunoglobulin A (IgA) and reduction of IgG subclass 2 (5 mg/dL). Circulating total T cells (CD3) were markedly reduced (117 cells/␮L). The CD4/CD8 ratio was 1.82. At age 6 years, he presented with cervical adenopathy, and 6 months later a cough developed. In May 1992, at the age of 8 years, he developed pulmonary infiltrates, which on biopsy indicated NSG. He was also experiencing fever, maculopapular rash, scleritis, sinusitis, lymphadenopathy, and hepatosplenomegaly. In July 1992, prednisone (2 mg/kg/d) was started and led to improvement. The liver was reduced in size, and the spleen was no longer palpable. Six months later, he presented with hypertension and new conjunctival lesions, and MTX (0.15 mg/kg/wk) was started. In the following year, disease flare (fever, skin lesions, and arthritis) occurred despite treatment with intravenous gammaglobulin, prednisone, and MTX (0.9 mg/kg/wk). MTX was stopped in November 1993. Over the next 11⁄2 years, he had persistent hepatosplenomegaly and lymphadenopathy. He had three separate hospital admissions for Pneumocystis carinii pneumonia, chronic parvovirus B19 infection, and Listeria sepsis with concurrent pancreatitis. He died of overwhelming pulmonary infection in July 1995.

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FERNANDES, SINGSEN, AND HOFFMAN

Table 1: Systemic Vasculitis in Sarcoidosis—Features of Our 6 Cases Sarcoidosis Case

Age* at Onset (yr)

Gender/ Race

1

1.8

M/C

Fever, adenopathy, maculopapular rash, lung infiltrates, hepatosplenomegaly, ascites, arthralgia

LN/liver (NG)

2

6

M/C

Fever, sinusitis, scleritis, hilar adenopathy, lung infiltrates, hepatosplenomegaly, maculopapular rash

LN, skin, sclerae (NG)

3

7

F/C

4†

3

F/AA

Weight loss, fever, skin lesions, dyspnea, cough, hearing deficit, tracheal narrowing, lung infiltrates, arthalgia, myalgia Cervical adenopathy, fever, maculopapular rash, polyarthritis/deformities, anterior bilateral uveitis

5

13

M/AA

Symmetric polyarthritis, erythema nodosum, Bell’s palsy

BM: (G)

6

31

F/AA

Weight loss, hilar adenopathy, bilateral iridocyclitis, leukopenia

LN: (G)

Clinical Features

Biopsy

Synovium: (G)

Abbreviations: ND, not done; CVID, common variable immunodeficiency; C, Caucasian; AA, African American; L, left; R, right; RCC, right common carotid artery; REC, right external carotid; LSC, left subclavian artery; RSC, right subclavian artery; RA, renal artery; Il, iliac artery; NSG, necrotizing sarcoid granulomatosis; NG, necrotizing granulomatous inflammation; G, granulomatous inflammation; BM, bone marrow; LN, lymph node; FSGN, focal segmental crescentic glomerulonephritis; BP, blood pressure; (A), aneurysm; (S), stenosis; (O), occlusion; P, prednisone; CP, cyclophosphamide; D, dexamethasone; MTX, methotrexate. * Age at sarcoidosis onset. † Previously reported (reference 26).

Case 3 In October 1995, a 7-year-old girl presented with arthralgia, myalgia, and weight loss. Three months later, she developed shortness of breath, cough, and hearing deficit. A chest radiograph was normal. Subglottic tracheal narrowing was detected by endoscopy. A tracheal biopsy showed a nonspecific chronic inflammatory cell infiltrate. She was treated with antibiotics and experienced some improvement. In June 1996, she was admitted because of increasing stridor. At this juncture, bronchoscopy showed a tracheal mass, which on biopsy indicated NSG. She experienced improvement with oral prednisone (2 mg/kg/d), which was gradually tapered over 3 months. In December 1996, she complained of left hip pain, and a radio-

graph showed a lucent defect of the left iliac crest. A bone biopsy showed NSG. The patient improved with prednisone therapy but continued to have intermittent fever and rash. In 1998, she developed multinodular lung infiltrates during prednisone tapering. In April 1998, she developed multiple small necrotic cutaneous lesions on her face, arms, and legs. She again improved with steroid therapy (dexamethasone 20 mg every other day). She was last seen in May 1998. Case 4 In March 1987, a 15-year-old African American girl was referred for possible Takayasu’s arteritis. Her initial presentation at age 3 consisted of a maculopapular rash, fever, and symmetric polyar-

SARCOIDOSIS AND SYSTEMIC VASCULITIS

37

Table 1: Systemic Vasculitis in Sarcoidosis—Features of Our 6 Cases (Cont’d) Vascular Disease Clinical Features Hepatic venous thrombosis (Budd-Chiari syndrome)

Necrotic lesions on face, arms, and legs Carotidynia, 2 radial and carotid pulses, cardiac murmurs, absent BP L arm Abdominal bruit, asymmetry of lower extremity pulses and BP Claudication of R arm, absent pulse and BP of R arm

Vascular Histopathology

Arteriography

Lung (NSG)

ND

Lung (NSG)

ND

Trachea/Bone (NSG)

ND

ND

Synovium: small vessels, aortitis, FSGN ND

RCC (A), REC (A), Innominate artery (A), LSC (O) Aorta (A), bilateral RA(A) and Il(A), LSC(O), RSC(O) RSC (S), splenic (S)

thritis. She developed bilateral uveitis approximately 1 year later. Arthritis and uveitis persisted despite treatment with aspirin, topical ophthalmic corticosteroids, and D-penicillamine, which were provided for what was first considered to be juvenile rheumatoid arthritis. In 1981, a synovial biopsy (wrist) was performed, which showed noncaseating granulomas. In 1984, she was first noted to have a diminished left radial pulse and multiple cardiac murmurs. She later developed fever, pain, and tenderness of the left side of the neck. Left carotid, brachial, and radial pulses were diminished. Prednisone therapy was started (60 mg/d), gradually tapered, and discontinued over the next 8 months. She experienced three episodes of transient loss of vision during this period. At the time

Treatment/ Follow-up (yr) P CP MTX 6.2 P MTX IV Ig 2.5 D 2.6 P 5.7

P Surgical repair for dissection 1.6 P 5.5

Outcome Alive at age 10. Portal hypertension Died at age 11 of infection (CVID) Alive at age 10; some improvement Alive at age 20; arthritis

Alive at age 22; some improvement Alive at age 36; stable

of referral, blood pressure was not recordable in the left arm. Bruits were heard over right carotid artery and abdominal aorta. A systolic murmur was present over the sternum. She had synovial thickening and deformities of small joints of hands, feet, and wrists. Echocardiogram showed mitral regurgitation. Angiography showed fusiform aneurysms of the right subclavian, innominate and right common carotid arteries, and left subclavian artery occlusion (Fig 2). No additional symptoms were noted until the age of 19 years, when she presented with carotidynia and arthralgia. She received increased therapy with corticosteroids over 4 months but relapsed (arthritis and uveitis) when prednisone was tapered. Prednisone was increased (40 mg/d) and again gradually tapered over the next 10

38

FERNANDES, SINGSEN, AND HOFFMAN

Fig 1 (case 2). (A) Chest radiograph showing diffuse pulmonary infiltrates. (B) Lung biopsy shows necrotizing sarcoid granulomata and granulomas with foci of tissue necrosis. Special stains and cultures for infectious agents were negative. (Hematoxylin & eosin stain, original magnification ⴛ10).

SARCOIDOSIS AND SYSTEMIC VASCULITIS

Fig 2. Angiogram of large vessel vasculitis in sarcoidosis (case 4): left subclavian occlusion, irregular fusiform aneurysms of the right carotid, innominate and subclavian arteries.

months. She was last seen in December 1992, at age of 20 years. On this occasion, the patient had been off prednisone over 3 months and had no objective findings of active disease. Comment. In this patient, persistent polyarthritis, rash, and uveitis, and the finding of noncaseating granulomas in the synovial biopsy, suggested the diagnosis of childhood sarcoidosis. She subsequently developed clinical and angiographic features of large-vessel vasculitis 9 years after the disease onset. Case 5 A 13-year-old African American boy presented with fever, symmetric polyarthritis, and a selflimited Bell’s palsy. A diagnosis of sarcoidosis was made by the finding of noncaseating granulomas on bone marrow biopsy. Over the ensuing years he had one episode of erythema nodosum. At the age of 19 years, an abdominal bruit and asymmetry of lower extremity pulses was detected.

39

Arteriography showed aneurysms of the aorta and the iliac and renal arteries and occlusion of both subclavian arteries (Fig 3). He improved with prednisone therapy (60 mg/d). One month after prednisone was withdrawn, fever and polyarthritis recurred. Progressive illness included renal impairment (creatinine, 3.2 mg/dL; proteinuria, 24 g/d). A renal biopsy indicated focal segmental crescentic glomerulonephritis, and a synovial biopsy showed small vessel vasculitis with giant cells. Magnetic resonance imaging (MRI) did not show any morphologic change of the aortic aneurysm. The serum creatinine level normalized, and proteinuria decreased (9.9 g/d) after 1 week of intravenous methylprednisolone (40 mg twice daily). One week later, he developed extensive dissection of the thoracic and abdominal aortic aneurysm. An aortic root to bilateral iliac artery reconstruction was successfully performed. The aortic pathology disclosed diffuse inflammatory changes with extensive calcification and atheromatous disease of the aorta. Six months later, he was stable while receiving prednisone 35 mg every other day. Serum creatinine was normal, and proteinuria was 2 g/d.Three months later, he presented with severe occipital headache, confusion, and stiff neck. MRI showed a questionable right occipital infarct. He improved with increased prednisone therapy (100 mg for 5 days and then 50 mg/d).The last follow-up was 1 month later, at which time he was stable and his vascular examination was unchanged. Serum creatinine was normal, and urinalysis showed 2 ⫹ protein. Comment. This patient had evidence of both large and small vessel vasculitis and sarcoidosis. Cases 5 and 6 illustrate that large-vessel involvement may occur later in the course of previously apparent sarcoidosis, whereas in case 6, both large vessel vasculitis and extravascular sarcoid occurred during the same period. Case 6 In January 1990, a 31-year-old African American woman presented with a 3-month history of bilateral iridocyclitis, weight loss (18 pounds), and hilar adenopathy. She complained of right arm claudication over the prior 4 months. The physical examination was remarkable for absence of the right radial pulse and unobtainable blood pressure by cuff in the right arm. A transbronchial lymph node biopsy showed noncaseating granuloma. Ar-

40

FERNANDES, SINGSEN, AND HOFFMAN

Fig 3. Angiogram of large vessel vasculitis in sarcoidosis (case 5). (A) Abdominal aortic aneurysm. (B) Aneurysms of the distal aorta and iliac arteries. (C) Occlusion of left and right subclavian arteries. Note the thoracic aneurysm of the descending aorta.

teriography indicated right subclavian and splenic artery stenoses. In March 1990, prednisone 60 mg/d was begun and improvement followed, so that treatment could be gradually tapered and stopped over 5 months. There was no evidence of disease activity until December 1993, when she developed transient facial paresthesia which resolved after prednisone therapy (40 mg/d) over 2 weeks. She remained well and has not required

prednisone over an additional 30 months of followup. She was last seen in June 1996. DISCUSSION

Systemic vasculitis is an uncommon complication of sarcoidosis. We have observed small or large vessel vasculitis in six cases of sarcoidosis. Clinical manifestations have ranged from mild cutaneous vasculitis to glomerulonephritis with renal

SARCOIDOSIS AND SYSTEMIC VASCULITIS

41

Table 2: Small Vessel Vasculitis of the Skin in Sarcoidosis—Adult Onset Disease (Literature Review) Skin Biopsy Age (yrs)/ Vasculitis Ref Sex Race Lung LN Other Manifestations Lung LCV GV Involvement

9 13

31/M 44/F

NS C

⫺ ⫺

10

41/M

NS

⫺

14

54/F

NS

⫺

11

24/F

AA

⫹

12

49/M

NS

⫺

15

28/F

NS

⫹

⫹ Annular lesions ⫺ ⫺ Palpable purpura, ⫺ hepatosplenomegaly ⫹ Fever, arthritis, cough, ⫺ conjunctivitis, erythema nodosum ⫹ Nodules, purpuric and ⫺ bullous lesions, fever, rhinorrhea, polyarthritis, conjunctivitis ⫹ Uveitis, peripheral Small neuropathy, vessels hepatosplenomegaly, leg ulcer ⫺ Fever, arthralgia, ⫺ papilladema, maculopapular lesions ⫺ ⫹ Uveitis, cough, hepatosplenomegaly, retinal vasculitis, macular and erythematous lesions

Treatment/ Follow-Up

Outcome

⫹ ⫹

None/NS P/2 yrs

Recovery Recovery

⫹

P/NS

Recovery

⫹

Diclofenac/ 2 yrs

Recovery

⫹ P CP-1 Mo/2 yrs

Recovery; ulcer recurred

⫹ P/few weeks

Recovery

⫹ P/NS

Recovery; flare (cranial neuropathy)

Abbreviations: Ref, references; ⫺, not involved; ⫹, involved; NS, not specified; AA, African American; C, Caucasian; GV, granulomatous vasculitis; LCV, leukocytoclastic vasculitis; LN, lymph node; P, prednisone; CP, cyclophosphamide.

failure, transient cerebral ischemia, and Takayasulike disease with aortitis, aortic dissection, and involvement of primary branches of the aorta (eg, aneurysms and stenosis). In our patients, the diagnosis of sarcoidosis was well established by the presence of typical clinical features and histopathologic findings. In three cases, evidence of NSG was present. NSG was first described by Liebow (3) in 1973 as a mild disorder with sarcoid-like granuloma, vasculitis of smallsized vessels, and necrosis. It has been reported that pulmonary parenchymal involvement in NSG is common, whereas lymph node disease is very unusual (3,4,30). However, two of our three cases of NSG with pulmonary involvement had hilar or cervical lymph node enlargement. Our patients

with NSG were younger than 8 years old at disease onset. Among 44 previously reported cases of NSG (3,4,30,31), only two occurred in children (32,33). Because NSG principally affects the lung, the differential diagnosis includes indolent granulomatous infections (eg, tuberculosis and fungi), pneumoconioses, Churg Strauss syndrome (CSS), lymphomatoid granulomatosis, and Wegener’s granulomatosis (WG) (30). In NSG, WG and CSS hilar lymph node enlargement is uncommon. George et al (34) observed mediastinal or hilar adenopathy in only 2% of 302 patients with WG (34). In a study of 22 children with WG, no cases presented with lymph node enlargement, whereas tracheal narrowing (subglottic stenosis)

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FERNANDES, SINGSEN, AND HOFFMAN

Table 3: Medium/Large Vessel Vasculitis in Sarcoidosis—Adult-Onset Disease (Literature Review)

Ref

Age (yrs)/ Sex

21 16

58/F 55/F

22

Involvement Race

Lung

LN

Other Manifestations

NS NS

⫹ ⫺

⫹ NS

31/F

AA

⫹

⫹

Pulmonary hypertension Fever, arthritis, abdominal pain, hypertension, renal impairment, asthma Fever, dyspnea, uveitis, erythema nodosum, stroke, hand and feet gangrene, hypertension

19

56/F

Asian

⫹

⫹

Sudden abdominal pain

17 18

51/M 52/M

AA Asian

⫹ ⫹

⫹ ⫹

Fever, cough, weigh loss, congestive heart failure Palpitations, dyspnea, absent peripheral pulse

20

19/F

Asian

⫹

⫹

Fever, cough, proteinuria, pulmonary hemorrhage

Abbreviations: Ref, references; ⫺, not involved; ⫹, involved; NS, not specified; AA, African American; C, Caucasian; GV, granulomatous vasculitis; PA, pulmonary artery; (A), aneurysm; (D), dissection; (R), rupture; (S), stenosis; (T), wall thickening; P, prednisone; LN, Lymph node; CP, cyclophosphamide.

Table 4: Systemic Vasculitis in Sarcoidosis—Childhood Onset Disease (Literature Review) Age at Onset (yrs)

Sex/ Race

Involvement

Ref

Sarcoid

Vasculitis

Lung

LN

24

0.7

5

F/C

⫺

⫺

24

F/C

⫺

⫹

F/C

⫺

⫺

Other Manifestations

25

0.7

4

26*

3.5

11.5

F/AA

⫺

⫺

Arthritis, iritis, seizures, hypertension, erythematous rash Fever, iritis, hepatomegaly, arthritis, hypertension Arthritis, uveitis, erythematous rash, hypertension Arthritis, uveitis, papular rash, carotidynia

27

7

7

M/AA

⫺

⫺

Iritis, leg pain, fever

28

1

4

F/Asian

⫺

⫹

23

0.4

0.4

F/C

⫺

⫹

Arthritis, iridocyclitis, purple papules, hypertension, leg infarction Fever, rash, foot drop, hepatosplenomegaly, digital ischemia

29

0.8

M/C

⫹

⫹

8

10

Arthritis, deformities, uveitis (blindness), papular rash, seizures, hypertension

Abbreviations: Ref, reference; ⫺, not involved; ⫹, involved; NS, not specified; C, Caucasian; AA, African American; A, arteriography; H, histopathology; MRI, magnetic resonance imaging; GV, granulomatous vasculitis; LCV, leukocytoclastic vasculitis; (S), stenosis; (A), aneurysm; AZA, azathioprine; P, prednisone; CP, cyclophosphamide; LN, lymph node; MTX, methotrexate. * (Case 4).

SARCOIDOSIS AND SYSTEMIC VASCULITIS

43

Table 3: Medium/Large Vessel Vasculitis in Sarcoidosis—Adult-Onset Disease (Cont’d)

Lung PA(A) PA(GV)

Vasculitis Extrapulmonary Mesenteric arteries (GV)

⫺

Brachial, radial and ulnar arteries (S)

Medium-sized vessels

Aorta (GV)(T)(D), coronary/renal arteries (GV) Aorta (GV)(T) Aorta (GV)(A), iliac (GV), subclavian arteries-(GV)(S) Aorta (GV)(T)

⫺ PA(GV) Small/medium-sized vessels PA (GV)

Treatment/ Follow-up

Outcome/Duration of Illness

None/NS None/NS

Died/NS Died/8 yrs

P CP IVIg/5 yrs None/NS

Remission; legs amputed at 13 yrs Died/NS

None/NS None/NS

Died/5 mos Died/6 mos

None/NS

Died/2 mos

Table 4: Systemic Vasculitis in Sarcoidosis—Childhood Onset Disease (Cont’d)

Extra-Pulmonary Vasculitis

Evidence of Vasculitis

Renal arteries (S), iliacs arteries (S) Aorta (GV)

A

Renal arteries (S), superior mesenteric artery (S) Left carotid artery (S), left subclavian artery (S) Aorta (A), myxoid degeneration

A

H

A MRI

Popliteal artery (GV), renal arteries (S) Skin (LCV)

H, A

Aorta (GV)

H

H

Treatment/Follow-up

Outcome

P CP/1 yr P/NS

Alive, asymptomatic

P angioplasty/NS P/4 yrs Surgical repair P/3 yrs P/2 yrs P CP MTX/3.5 yrs P CP AZA/NS

Died at age 24 yrs Alive Alive, asymptomatic Alive, asymptomatic Alive at age 24 yrs, renal failure Alive, asymptomatic

Died at age 10 yrs

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was common (48%) (35). One child in our group of three with NSG had lung involvement and subglottic stenosis, without lymph node enlargement. These clinical features were more suggestive of WG than sarcoidosis, but the histologic findings were more compatible with NSG, that is, well-formed granulomas, in the absence of geographic necrosis (36). CSS is distinguished from NSG and WG by the presence of asthma, eosinophilia, and eosinophilic infiltrates (4), whereas lymphomatoid granulomatosis, part of the spectrum of extranodal lymphoma, is characterized histologicaly by an angiocentric immunoproliferative lesion (AIL). The spectrum of AIL includes lymphocyte atypia, clonal expansion, and frank lymphoma. True granuloma formation is not present (37). Despite prior suggestions that NSG only affects the lungs (3,4), other reports indicate that central nervous system, ocular, and other forms of extrapulmonary disease also may occur (11,38-40). Our three patients with NSG had involvement of the skin, eyes, liver, and spleen, which confirms observations about NSG being a systemic disease. Hepatic venous thrombosis was associated with hepatosplenomegaly in one of two cases with these findings. Our experience with childhood NSG indicates that the course of disease is one of frequent relapses and severe morbidity despite palliation with high-dose corticosteroid and cytotoxic therapy. Two of our three patients with NSG received MTX, and one of these patients had also failed to achieve remission with cyclophosphamide therapy. In one child, MTX appeared to be partially efficacious and allowed more successful tapering of prednisone. However, none of our patients with NSG achieved complete disease remission, independent of prednisone therapy. The single patient with adult-onset sarcoidosis in our series (case 6) was treated with prednisone (60 mg/d) alone, improved, and later had a flare of disease when the drug was tapered. She subsequently achieved remission, which was sustained over the next 21⁄2 years, without further treatment. Each of our three patients with large vessel vasculitis, two children and one adult, all improved with corticosteroid therapy. Our two children with sarcoid–large vessel vasculitis had similar clinical manifestations to those previously described. Arthritis, skin lesions, and eye involvement were the

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most common extrapulmonary clinical features, similar to the profile found in early childhood sarcoidosis without vasculitis (39,41). All three of our patients (two children, one young adult) with large vessel disease were African American. The treatments and clinical outcomes of previously reported cases of sarcoidosis with systemic vasculitis are quite varied. Outcomes have ranged from complete recovery after prednisone therapy, to severe morbidity, including blindness, digital infarction, leg amputation, and death caused by dissection of an aortic aneurysm. Adults with small vessel disease usually have recovered completely with corticosteroid, corticosteroid plus cytotoxic therapy, or no treatment (Table 2). Bottcher (16; 1959) was the first to observe abnormalities of large arteries due to sarcoidosis in adult patients. Since that report, seven additional cases of sarcoidosis and large vessel vasculitis have been reported in adults in the English literature (Table 3). These patients had involvement of large vessels, including the aorta, subclavian, iliac, mesenteric, renal, coronary, or pulmonary arteries. Six patients with this pattern who were not treated with corticosteroids or cytotoxic agents died. The only surviving patient was treated with prednisone plus cyclophosphamide. Over 1 month, this patient developed infarction of fingers and feet while taking prednisone (20 mg/daily) and later intravenous methylprednisolone (125 mg every 8 hours). The addition of cyclophosphamide was followed by a remission that was sustained over 5 years. To the best of our knowledge, only eight cases of extrapulmonary vasculitis in childhood sarcoidosis have been described in the English literature, which includes one of our pediatric patients (Table 4) (26). Seventy-five percent were female. Five of eight were white, two were African American, and one was Asian. Pulmonary parenchymal involvement occurred in one case and hilar lymph node involvement occurred in half of the cases. All children had medium and large-sized vessel vasculitis. Two of eight previously described children with sarcoid vasculitis died. One was treated with prednisone only (24) and the other with prednisone plus cytotoxic agents (29). Six surviving children received treatment with prednisone alone (25-28) or prednisone plus cytotoxic therapies (23,24) (Table 4).

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In one patient (Case 5) in our series, long-term treatment with prednisone did not prevent aortic aneurysm dissection. He required extensive aortic reconstruction, which was successfully accomplished. Sarcoidosis and aortic disease has been described previously in three children and four adults (note cases in Tables 3 and 4). The only patient similar to ours, who survived, also was treated chronically with corticosteroids and had a surgical repair (27). Two other previously reported children with aortitis died as a consequence of aneurysm dissection; neither received medical or surgical treatment (18,19). There appears to be an ethnic predisposition to developing large vessel vasculitis as a complication of sarcoidosis. Although none of our patients with large vessel vasculitis were Asian, among 12 previously reported adults and children in this subset in which race was reported, four were Asian (33% v 2.9% of the American population during this time).42 In addition, four other patients in the large vessel disease subset were African American (33% v 11.7% of all Americans).42 All three of our patients with large vessel-sarcoidosis were African American. CONCLUSIONS

The cumulative literature regarding sarcoidosis and systemic vasculitis describes a small number of cases, treated in a highly variable

manner. Comparisons of reports are difficult at best. Nonetheless, among patients with large vessel disease, African Americans and Asians appear to be overrepresented compared with their proportionate populations in the United States. All of our patients with large vessel disease were African American. Our series, and others, indicate that untreated sarcoid vasculitis has a poor prognosis. Treatment with prednisone alone may be palliative and even life-saving. However, such therapy rarely leads to complete remission that permits subsequent withdrawal of treatment. Cytotoxic agents have been added to corticosteroid therapy in many cases. In some instances this strategy has allowed for remission-maintenance, using lower doses of corticosteroids and even their discontinuation. However, permanent remission appears to be uncommon. In selected cases with large vessel aneurysms, surgical therapy may be life-saving Both children and adults with sarcoidosis should be evaluated for features of small and large vessel disease. Small vessel involvement is most often apparent in the skin but also can involve numerous other sites. Large vessel disease should be assessed by careful evaluation of pulses and blood pressures for asymmetry, large vessel bruits, and signs of aortic regurgitation. Sarcoidosis and systemic vasculitis is almost certainly more common than reported and recognized in clinical practice.

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