Arthritis & Rheumatism (Arthritis Care & Research) Vol. 55, No. 5, October 15, 2006, pp 817– 820 DOI 10.1002/art.22238 © 2006, American College of Rheumatology CASE REPORT Development of Sarcoidosis During Etanercept Therapy MARCOS A. GONZÁLEZ-LÓPEZ, RICARDO BLANCO, M. CARMEN GONZÁLEZ-VELA, HÉCTOR FERNÁNDEZ-LLACA, AND VICENTE RODRÍGUEZ-VALVERDE Introduction The 3 currently available tumor necrosis factor ␣ (TNF␣) blocking agents are a soluble receptor fusion protein (etanercept), a humanized mouse monoclonal antibody (inﬂiximab), and a fully human monoclonal antibody (adalimumab). All of these agents are highly effective in the treatment of rheumatoid arthritis and other inﬂammatory diseases, including ankylosing spondylitis (AS), psoriatic arthritis, and psoriasis vulgaris (1). They have been used in refractory sarcoidosis, with different results. Whereas inﬂiximab, the more widely used agent in this entity, has demonstrated clear efﬁcacy in this disease (2,3), the results with etanercept were generally disappointing (2,4), although in isolated cases etanercept was shown to be effective (5,6). Reported experiences with adalimumab in sarcoidosis, although encouraging, are very scarce. Recently, the development of several syndromes characterized by granuloma formation has been reported in patients receiving TNF␣ blocking therapy for a variety of diseases. Except for one patient treated with adalimumab (7), the remaining patients were treated with etanercept (8 –14). We describe a patient diagnosed with AS who developed a granulomatous syndrome consistent with sarcoidosis while being treated with etanercept. Case Report A 70-year-old man was diagnosed with AS in our rheumatology clinic in 1995. He reported having inﬂammatory low spinal pain for several years as well as arthritis of Marcos A. González-López, MD, Ricardo Blanco, MD, M. Carmen González-Vela, MD, Héctor Fernández-Llaca, MD, Vicente Rodrı́guez-Valverde, MD: Hospital Universitario Marqués de Valdecilla, Universidad de Cantabria, Santander, Spain. Address correspondence to Vicente Rodrı́guez-Valverde, MD, Professor of Medicine and Chief, Rheumatology Service, Hospital Universitario Marqués de Valdecilla, Facultad de Medicina, Universidad de Cantabria, Avda, Valdecilla s/n, 39008, Santander, Spain. E-mail: rodriguv@ unican.es. Submitted for publication October 24, 2005; accepted in revised form February 14, 2006. the wrists, knees, ankles, and several metacarpophalangeal, interphalangeal, and metatarsophalangeal joints. In addition, he had grade III bilateral sacroiliitis and was HLA–B27 positive; rheumatoid factor and antinuclear antibodies were negative. He was treated with various nonsteroidal antiinﬂammatory drugs (NSAIDs) and lowdose prednisone (10 mg/day) in addition to sulfasalazine (up to 3 gm/day) followed by methotrexate (up to 20 mg/ week). After initial improvement, the patient repeatedly had a relapse of AS symptoms with increased low back pain, peripheral arthritis, and raised acute-phase reactant levels. In August 2002, due to persistent clinical activity with increased acute-phase reactant levels (erythrocyte sedimentation rate [ESR] of 62 mm/hour [Westergren] and C-reactive protein level of 2.8 mg/dl [normal value ⬍0.5 mg/dl]), treatment with etanercept (25 mg twice weekly) was started. Following our national guidelines to exclude latent tuberculous infection (15), a puriﬁed protein derivative (PPD) skin test and a chest radiograph performed prior to etanercept therapy were negative and normal, respectively. Two months later the patient was clinically asymptomatic and acute-phase reactant levels were normal. In June 2004, after 21 months of etanercept therapy and while asymptomatic, the patient reported a 6-week history of skin lesions on his face. Physical examination disclosed 3 ﬁrm, nontender, red-brown nodular lesions ranging in size from 1 cm to 1.5 cm, located on the forehead, right eyebrow, and the nasolabial area (Figure 1). Diascopy of the nodules showed the appearance of an apple-jelly color. No other lesions were present on the skin or mucosa. There were no superﬁcial lymphadenopathies or hepatosplenomegaly. A skin biopsy was performed. The histopathologic study demonstrated numerous noncaseating granuloma of the sarcoidal type extending through the entire thickness of the dermis (Figure 2). Polarizing microscopy for foreign body evaluation; tissue stains; and bacteria, fungus, and mycobacterium cultures, as well as polymerase chain reaction for Mycobacterium tuberculosis were all negative. A chest radiograph and a computed tomography of the thorax revealed bilateral hilar and paratracheal adenopathies. 817 818 González-López et al of the patient’s AS with an increase in low back pain and peripheral arthritis was then observed, which was treated with intravenous pamidronate (60 mg monthly during 6 months) with a good clinical response. A new chest radiograph in November 2004 showed the disappearance of the intrathoracic lymph nodes, and the ACE levels reverted to normal; a whole-body scintigraphy with 67Ga performed in March 2005 was normal. When the patient was last seen in December 2005, his AS remained controlled with NSAIDs and he did not have any signs or symptoms of sarcoidosis. Figure 1. Nodular lesion in the nasolabial region. 67 A scintigraphy with Ga showed increased uptake in the paratracheal and hilar lymph nodes, in both parotid glands, and in the right lachrymal gland. Pulmonary function tests were normal and a new PPD skin test was again negative; the angiotensin-converting enzyme (ACE) level was mildly elevated at 76 units/ml (reference range 8 –52 units/ml) and the ESR was 30 mm/hour. These ﬁndings were consistent with the diagnosis of sarcoidosis with skin involvement. A possible relationship between the development of sarcoidosis and treatment with etanercept was suspected, and etanercept was stopped in August 2004. A rapid improvement of the cutaneous lesions was evident 2 weeks after discontinuation of etanercept, and the lesions spontaneously and completely resolved in 2 months. A reactivation Figure 2. Noncaseating sarcoid granuloma in the dermis (hematoxylin and eosin stained; original magniﬁcation ⫻ 200). Discussion Sarcoidosis is a multisystemic disease characterized by noncaseating granulomatous inﬁltration primarily of the lungs and lymphatic system, although it may affect multiple organ systems. Sarcoidosis often presents as bilateral hilar lymphadenopathy and pulmonary inﬁltrates, and less frequently with skin, ocular, or joint manifestations. Skin involvement usually manifests either acutely with erythema nodosum or chronically as lupus pernio, nodular lesions, or plaque lesions (5). The etiology of sarcoidosis remains unknown, although current evidence supports the concept that inﬂammation and granuloma formation are the result of an antigendriven immune response mediated by the T cell CD4⫹ phenotype 1 (Th1) and activated alveolar macrophages, with increased secretion of several cytokines such as interleukin-2, interferon-␥ (IFN␥), and TNF␣ (16). To this respect, the cytokine most extensively studied is TNF␣, and there is wide evidence of its pivotal role in the induction and maintenance of both inﬂammation and granuloma (16). Based on these data, TNF␣ blocking therapy has been used in the treatment of refractory sarcoidosis with mixed results. Even though a good response has been reported with etanercept in isolated cases (5,6), the results of an open-label study in stages II and III of progressive pulmonary sarcoidosis were generally disappointing, with worsening of the disease observed in 11 of 16 patients (4). In contrast, more than 30 cases of successful results with inﬂiximab have been reported (2,3). Here, we report the development of a granulomatous process consistent with sarcoidosis in a patient with AS after 21 months of etanercept therapy. Although we cannot rule out the rare association between sarcoidosis and AS (17), the rapid improvement of the skin lesions and other manifestations of sarcoidosis after suspension of etanercept support the inducing or triggering role of etanercept. In our review of the literature (7–14), we found 10 patients who developed different syndromes characterized by granuloma formation while receiving TNF␣ blocking therapy. The most frequent clinical presentations were lung involvement with nodular or reticulonodular inﬁltrates (6 patients) and rheumatoid nodulosis (2 patients). The outcomes after withdrawal of the TNF␣ blocking agent were variable (Table 1). Except for 1 patient, all were being treated with etanercept. Taking into account the pivotal role of TNF␣ in the pathogenesis of sarcoidosis and granuloma formation, the development of these granulomatous reactions while re- 73/M/RA 50/F/RA 37/M/PsA 41/F/RA 53/F/RA 67/M/RA 52/M/RA 50/M/RA 79/F/RA 21/M/PsA 70/M/AS (7) (8) (9) (10) (11) (12) (12) (12) (13) (14) Current report Etanercept/21 Etanercept/35 Etanercept/24 Etanercept/3 Etanercept/2 Etanercept/2 Etanercept/4 Etanercept/19 Etanercept/19 Etanercept/2 Adalimumab/6 Rheumatoid nodules in lungs, ﬁngers, and elbows Cough, dyspnea, pleural effusions, and cavitating lung lesions Rheumatoid nodulosis in ﬁngers and elbows Rheumatoid nodulosis in ﬁngers; nailfold infarcts Giant cell arteritis, with temporal headache and jaw pain Crohn’s-like disease with abdominal pain, diarrhea, and bloody stools Cutaneous nodules, bilateral hilar and paratracheal adenopathies Cough, weight loss, bilateral nodular lung inﬁltrates Cough, dyspnea, reticulonodular lung inﬁltrates, and skin lesions Fever, cough, dyspnea, and bilateral reticulonodular lung inﬁltrates Subpleural nodule and cavitated lung lesion Clinical manifestations * TNF␣ ⫽ tumor necrosis factor ␣; RA ⫽ rheumatoid arthritis; PsA ⫽ psoriatic arthritis; AS ⫽ ankylosing spondylitis. Age/sex/disease Reference TNF␣ blocking agent/time to reaction, months Acute and chronic inﬂammation with crypt destruction Noncaseating sarcoid granulomas Giant cell arteritis Not performed Not performed Necrotizing pulmonary nodules and vasculitis Necrotizing area surrounded by a palisade of histiocytes and chronic inﬂammatory cells Rheumatoid nodules Noncaseating granulomas Noncaseating granulomas in lungs and skin Necrotizing granulomas Biopsy results Granulomatous reaction Table 1. Granulomatous reactions associated with TNF␣ blocking therapy* Resolution 2 months after etanercept withdrawal Etanercept continued/controlled with mesalamine Slight improvement after adding leﬂunomide to etanercept No data Improvement after etanercept withdrawal Resolution after etanercept withdrawal and treatment with azathioprine and steroids Stable despite continuing etanercept Etanercept withdrawn/outcome not speciﬁed Adalimumab withdrawn/persistence despite antituberculous therapy Stabilization after etanercept withdrawal/resolution with prednisone Resolution 9 months after etanercept withdrawal Treatment/outcome Etanercept Therapy and Sarcoidosis 819 820 ceiving TNF␣ blocking therapy, mainly with etanercept, seems paradoxical. This might indicate that other cytokines could play a crucial role in granuloma formation. In this respect, it is known that IFN␥ is able to activate macrophages and to transform them into giant cells, which are important building blocks of the granuloma (18). In contrast, the mechanisms of action of etanercept differ in several respects from those of the monoclonal anti-TNF␣ antibodies (reviewed in references 19 and 20). These differences could account for the limited efﬁcacy of etanercept in sarcoidosis and Crohn’s disease, and for allowing the development of the reported granulomatous reactions. To this respect, it is known that etanercept does not lyse CD4⫹ T cells expressing TNF␣ on their membranes and preferentially neutralizes soluble TNF␣, leaving TNF receptor p75 (TNFR p75) signaling largely intact. In addition, the binding of etanercept to TNF␣ has both high-on and high-off kinetics, shedding ⬃50% of soluble and 90% of transmembrane TNF␣ only 10 minutes after binding, thus allowing redistribution of bioactive TNF␣ from sites of production, such as the inﬂamed joints, into other tissues where overall TNF␣ concentrations are low. Moreover, in patients with AS treated with etanercept, a significant increase in the percentage of T cells expressing TNF␣ and INF␥ has been reported, suggesting that neutralization of peripheral TNF␣ is able to up-regulate the ability of T cells to produce these cytokines. Therefore, treatment with etanercept would preserve, at least to some degree, the mechanisms leading to granuloma formation and integrity by increasing the proportion of T cells expressing TNF␣ and INF␥, by preserving the TNFR p75–mediated immunoregulatory functions, and by its incomplete blockade of TNF␣ bioactivity. In summary, we report a patient with AS who developed a granulomatous syndrome consistent with sarcoidosis while receiving etanercept therapy. This observation, along with the reported cases of other granulomatous reactions in relation almost exclusively to etanercept therapy and the rather poor results obtained with this agent in Crohn’s disease and refractory sarcoidosis would suggest that by its mechanism of action, this TNF␣ blocking agent leaves, at least in some patients, sufﬁcient cytokine activity to support granuloma formation. REFERENCES 1. Haraoui B. Differentiating the efﬁcacy of the tumor necrosis factor inhibitors. Semin Arthritis Rheum 2005;34 Suppl 1:7– 11. González-López et al 2. Keystone EC. The utility of tumour necrosis factor blockade in orphan diseases. Ann Rheum Dis 2004;63 Suppl 2:ii79 – 83. 3. Doty JD, Mazur JE, Judson MA. Treatment of sarcoidosis with inﬂiximab. Chest 2005;127:1064 –71. 4. Utz JP, Limper AH, Kalra S, Specks U, Scott JP, VukPavlovic Z, et al. Etanercept for the treatment of stage II and III progressive pulmonary sarcoidosis. Chest 2003;124: 177– 85. 5. Khanna D, Liebling MR, Louie JS. Etanercept ameliorates sarcoidosis arthritis and skin disease. J Rheumatol 2003;30: 1864 –7. 6. Hobbs K. Chronic sarcoid arthritis treated with intraarticular etanercept [letter]. Arthritis Rheum 2005;52:987– 8. 7. Vavricka SR, Wettstein T, Speich R, Gaspert A, Bachli EB. Pulmonary granulomas after tumour necrosis factor ␣ antagonist therapy. Thorax 2003;58:278 –9. 8. Peno-Green L, Lluberas G, Kingsley T, Brantley S. Lung injury linked to etanercept therapy. Chest 2002;122:1858 – 60. 9. Phillips K, Weinblatt M. Granulomatous lung disease occurring during etanercept treatment. Arthritis Rheum 2005;53: 618 –20. 10. Hubscher O, Re R, Iotti R. Pulmonary rheumatoid nodules in an etanercept-treated patient [letter]. Arthritis Rheum 2003; 48:2077– 8. 11. Kekow J, Welte T, Kellner U, Pap T. Development of rheumatoid nodules during anti–tumor necrosis factor ␣ therapy with etanercept [letter]. Arthritis Rheum 2002;46:843– 4. 12. Cunnane G, Warnock M, Fye KH, Daikh DI. Accelerated nodulosis and vasculitis following etanercept therapy for rheumatoid arthritis. Arthritis Rheum 2002;47:445–9. 13. Seton M. Giant cell arteritis in a patient taking etanercept and methotrexate [letter]. J Rheumatol 2004;31:1467. 14. Oh J, Arkfeld DG, Horwitz DA. Development of Crohn’s disease in a patient taking etanercept. J Rheumatol 2005;32: 752–3. 15. Comité de Expertos de la SER. Actualización de la Conferencia de Consenso de la Sociedad Española de Reumatologı́a sobre terapia anti-TNF en Artritis Reumatoide. Rev Esp Reumatol 2002;29:51–5. 16. Ziegenhagen MW, Muller-Quernheim J. The cytokine network in sarcoidosis and its clinical relevance. J Intern Med 2003;253:18 –30. 17. Stucki G, von Felten A, Speich R, Michel BA. Ankylosing spondylitis and sarcoidosis: coincidence or association? Case report and review of the literature. Clin Rheumatol 1992;11: 436 –9. 18. Judson MA. The etiologic agent of sarcoidosis: what if there isn’t one? Chest 2003;124:6 – 8. 19. Ehlers S. Why does tumor necrosis factor targeted therapy reactivate tuberculosis? J Rheumatol Suppl 2005;74: 35–9. 20. Dinarello CA. Differences between anti-tumor necrosis factor-␣ monoclonal antibodies and soluble TNF receptors in host defense impairment. J Rheumatol Suppl 2005;74: 40 –7.