New onset sarcoid-like granulomatosis developing during anti-TNF therapy: an under-recognised complication

Authors


  • Funding: None.

  • Conflict of interest: None.

Denise Tong, Department of Rheumatology, Westmead Hospital, Sydney, NSW 2145, Australia. Email: dwytong@yahoo.com.au

Abstract

Tumour necrosis factor-alpha (TNF-α) antagonists have advanced the treatment of inflammatory arthropathies, and are even considered for use in refractory sarcoidosis with some success. Paradoxically, cases of new onset sarcoidosis-like diseases are increasingly reported in patients receiving TNF-α antagonists. Here, we report three cases of sarcoid-like granulomatosis that developed during treatment with TNF-α antagonists. Review of the Biologics clinic data base at Westmead, Sydney, Australia identified three patients whom, during anti-TNF therapy, developed non-caseating granulomas consistent with sarcoidosis. These three cases are described with review of the literature from 2000 to 2009 using PubMed. One hundred and sixty-nine patients within our data base were reviewed for the period 2003–2009. Sarcoidosis-like granulomas developed in three patients within a period of 3 to 36 months of treatment with etanercept and/or adalimumab. All cases demonstrated non-infective, non-caseating granulomas on renal or lymph node biopsy. Improvement was seen in two cases upon cessation of TNF-α antagonist and steroid therapy. Interestingly, clinical deterioration was noted upon re-challenge with the same TNF-α antagonist in one patient. To date, a total of 37 cases of sarcoid-like granuloma development after anti-TNF therapy have been reported in the literature. Development of sarcoidosis-like granulomatosis in patients treated with TNF-α antagonists is a phenomenon previously under-recognised. All three anti-TNF agents have been observed to cause this phenomenon, suggesting a ‘class effect’ rather than being drug specific.

In the last decade tumour necrosis factor-alpha (TNF-α) antagonists have made significant therapeutic milestones in the treatment of inflammatory arthropathies, such as rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA). TNF antagonists, which impair granuloma formation, have also been utilised against granulomatous diseases, such as sarcoidosis, Crohn's disease and Wegener's granulomatosis, with variable results.1 Therefore it is paradoxical to report the onset of new sarcoidosis-like diseases in patients receiving TNF antagonists. In this paper we describe three patients with RA who developed sarcoidosis while being treated with etanercept (two) and adalimumab (one), and review the most recent literature.

Review of the Biologics clinic data base at Westmead, Sydney, Australia for the period 2003–2009 identified three patients whom during anti-TNF therapy developed sarcoid-like graulomatous disease. These three cases are described and a literature search on sarcoid-like granulomatous disease related to anti-TNF agents was performed through PubMed and Ovid databases, with the following keywords: ‘etanercept’, ‘adalimumab’, ‘infliximab’ and ‘anti-TNF’, joined by the Boolean operator ‘OR’. The result was then coupled with the keyword ‘sarcoidosis’ by the Boolean operator ‘AND’. The search was performed from January 2000 up to December 2009. All reviews, series, and case reports were evaluated, and a total of 19 papers was selected.

A 55-year-old Caucasian woman with a 9-year-history of severe PsA, on a background of essential hypertension and type-2 diabetes mellitus was unresponsive to methotrexate (MTX), leflunomide, sulphasalazine, cyclosporine and intramuscular sodium aurothiomalate. In March 2006, etanercept was commenced and sustained improvements in joint and cutaneous manifestations were achieved. In March 2009, she was found to have progressive renal deterioration on routine tests, with serum creatinine reaching 200 mmol/L (n = 45–90). Baseline creatinine measured 95 mmol/L 4 months prior. Medications at presentation were etanercept 50 mg/week, MTX 5 mg/week, nifedipine 10 mg/day, candesartan 32 mg/day, metformin 1 g t.d.s. and gliclazide 80 mg/day. The patient had not received cyclosporine for 5 years. Physical examination was unremarkable apart from hypertension (170/90 mmHg) and grade 2 hypertensive changes of the fundi. Urinary microalbumin to creatinine ratio was elevated (23.9 mg/mmol, n < 10.0 mg/mmol). No urinary sediments or casts were found. Renal biopsy demonstrated multiple non-caseating epitheloid granulomas admixed with an inflamed and mildly fibrotic interstitium consisting of lymphocytes and scattered eosinophils. Fungal and mycobacterial cultures were negative. These findings were consistent with a drug-induced sarcoid-like granulomatous interstitial nephritis. Full blood count was normal with no eosinophilia. Erythrocyte sedimentation rate (ESR) (13 mm/h, n = 0–20) and C-reactive protein (CRP) (<0.4 mg/L, n = 0–11) were normal. Angiotensin converting enzyme (ACE) level was elevated at 93 U/L (n = 22–61). Chest radiography and computed tomography (CT) did not demonstrate pulmonary infiltrate or lymphadenopathy. The tuberculin skin test (TST), both prior to etanercept, and currently, remained negative. Etanercept was ceased, and the patient given tapering doses of prednisolone (25 mg/day). Six months later, the serum creatinine and ACE levels improved to 160 mmol/L and 56 U/mL respectively. At this time, because of a flare of arthritis, etanercept was re-initiated by the patient for 3 weeks, during which serum creatinine rose to 255 mmol/L. Etanercept was ceased again, and within 3 weeks, serum creatinine improved to 165 mmol/L and urinary microalbumin to creatinine ratio improved to 41.5 mg/mmol. Six months after etanercept was ceased, her serum creatinine improved to 140 mmol/L and ACE level normalised (36 U/L).

A 50-year-old Maori man with seropositive RA for 10 years was treated with MTX 20 mg/week, leflunomide 10 mg/day, prednisone 10 mg/day, hydroxychloroquine 400 mg/day and celecoxib 200 mg/day. In February 2006, etanercept 50 mg/week was added because of inadequate disease control. Baseline TST and chest radiograph were normal. The patient improved significantly, and all medications were withdrawn apart from etanercept, MTX 10 mg/week, and prednisone 5 mg/day. After 8 months, etanercept was changed to adalimumab because of suboptimal response. He became non-compliant after 2 months of adalimumab. Five months after not consuming any TNF antagonists, he was reassessed for further DMARD therapy. A chest radiograph demonstrated new soft tissue densities in the left aortopulmonary window, which were not present 1 year previously. A chest CT showed symmetrical hilar and mediastinal lymphadenopathy, 2 and 5 cm respectively. The patient was asymptomatic, with no cough, dyspnoea, fever, night sweats or cutaneous lesions noted. Clinical examination was unremarkable. Serum blood count, biochemistry and ESR (16 mm/h) were all normal. CRP (12.4 mg/L) and ACE level (82 U/L) were both elevated. TST and QuantiFERON gold assay were negative. A right paratracheal and mediastinal lymph node aspirate biopsy was performed, showing fragments of non-necrotising epitheloid granulomas with multinucleated giant cells. Flow cytometry demonstrated no evidence for lymphoproliferative disease. Fungal and mycobacterial cultures were negative. A diagnosis of sarcoidosis was reached based on the radiographic and pathologic findings. All TNF-α antagonists were ceased, prednisone was increased to 20 mg/day. His arthritis control improved, but the lymphadenopathy remained unchanged at 3 months.

A 27-year-old Caucasian woman with seropositive RA for 11 years was formerly treated with MTX 12.5 mg/week, leflunomide 20 mg/day and prednisone 2.5 mg/day. She also had type 1 diabetes mellitus, hypertension and depression. Adalimumab was introduced in September 2004, after a period of high RA disease activity. Baseline TST and chest radiograph were normal. Three months later, the patient developed progressive dyspnoea, dry cough, bilateral ankle erythematous rash, arthralgia, fever, night sweats and 8-kg weight loss. Physical examination was unremarkable except for erythema nodosum in the lower limbs, and effusions in both knees and ankles. Serum blood count and biochemistry were normal, with no hypercalcaemia. ESR (58 mm/h) and CRP (113.6 mg/L) were elevated. ACE level was normal. Repeat TST was negative. CT chest demonstrated mediastinal and bilateral hilar lymphadenopathy, the largest lymph node measuring 2 cm. A mediastinoscopy was performed, and a mediastinal lymph node biopsy demonstrated non-caseating epitheloid granulomas with lymphadenitis. Fungal and mycobacterial cultures were negative. A diagnosis of sarcoidosis was made, and prednisone was increased to 10 mg/day while adalimumab was ceased. Intramuscular sodium aurothiomalate (50 mg/week), MTX (20 mg/week), and hydroxychloroquine (400 mg/day) were prescribed to control the arthritis with good effect. One year later, she was free from any symptoms of sarcoidosis. Chest radiograph performed 18 months later revealed no evidence of hilar or mediastinal lymphadenopathy. Prednisone was gradually weaned to the current dose of 1 mg/day.

Development of new non-infective granulomata during therapy with TNF-α antagonist is a phenomenon not as uncommon as previously thought. In our case series, out of 165 patients on TNF-α antagonist from January 2003 to August 2009, three patients (1.82%) were found to have new onset sarcoid-like granulomas. In 2008, the national French incidence of post-anti-TNF therapy sarcoid-like granulomatosis in patients was estimated to be 0.04% (1/2800).2 In Australia, only one case of etanercept related pulmonary sarcoidosis has been officially reported to the Australian Drug Reactions Advisory Committee (ADRAC).3

New onset sarcoidosis in RA patients not on TNF-α antagonist has been reported in only 8 cases.4 However, between January 2000 and December 2009, our literature search revealed 37 reports of new sarcoid-like granulomatous disease in arthritic patients on TNF-α antagonist (see Table 1). In all these cases, non-caseating granuloma was confirmed on tissue biopsy, with the exception of one case by Sturfelt et al.18 The median age of affected patients was 50 years (range 7–73), with a male to female ratio 3:5. The underlying diagnoses were: RA (21), AS (nine), PsA (five) and juvenile idiopathic arthritis (one). Most patients had more than one organ involved, including: lungs (23 patients, 62.2%), lymph nodes (22, 59.5%), skin (9, 24.3%), eye (4, 10.8%), liver (1, 2.7%), kidney (1, 2.7%) and central nervous system (1, 2.7%). The median time to onset of granulomatous disease was 21 months, but this ranged from 1 to 69 months. All cases but one improved upon TNF-α antagonist withdrawal, although three patients had clinical but not radiological improvements, and the outcome of one case was not specified. Additional steroid therapy was given in 17 cases; one case required synergistic MTX therapy; and anti-tuberculosis therapy was co-administered in two cases although mycobacterial cultures were negative. After resolution of the granulomatous lesions, six patients were successfully switched to an alternative biological DMARD: adalimumab (four), etanercept (one), rituximab (one).

Table 1.  Literature review: development of sarcoidosis-like illness during TNF antagonist therapy
Authors (year)Age (years)/sex/diseaseDrugs/duration of therapy at onset of sarcoidosis (months)Clinical features of sarcoidosisTreatment/outcome
  • All cases of sarcoidosis proven histologically by evidence of non-caseating granuloma on biopsy. AS, ankylosing spondylitis; F, female; JIA, juvenile idiopathic arthritis; M, male; MTX, methotrexate; PsA, psoriatic arthritis; RA, rheumatoid arthritis; SAPHO, synovitis, acne, pustulosis, hyperostosis, osteitis

Peno-Green et al. (2002)550/F/RAEtanercept/2Reticulonodular pulmonary infiltrates + cutaneous nodulesEtanercept withdrawn, steroid/resolution
Vavricka et al. (2003)673/M/RAAdalimumab/6Bilateral nodular pulmonary infiltratesAdalimumab withdrawn + anti-TB therapy/persistent disease
Hubscher et al. (2003)741/F/RAEtanercept/19Subpleural nodule and cavitated lung lesionEtanercept withdrawn/outcome not specified
Hashkes et al. (2003)87/M/JIAEtanercept/10Cutaneous/panuveitis/liver granulomasEtanercept withdrawn, steroid/resolution
Philips et al. (2005)937/M/PsAEtanercept/19Bilateral pulmonary reticulonodular infiltratesEtanercept withdrawn/resolution
O'Shea et al. (2006)1034/M/ASInfliximab/58Mediastinal/hilar lymphadenopathy + pleural effusionEtanercept withdrawn, steroid/clinical but not radiological improvement
González-López et al. (2006)1170/M/ASEtanercept/21Cutaneous nodules, bilateral hilar and paratracheal lymphadenopathyEtanercept withdrawn/resolution
Kudrin et al. (2007)1252/F/RAEtanercept/18Nodular pulmonary infiltratesEtanercept withdrawn, steroid/resolution
Farah et al. (2007)1340/M/PsAEtanercept/10Pulmonary non-caseating granulomasEtanercept withdrawn, steroid/resolution
Almodovar et al. (2007)1434/M/ASInfliximab/24Bilateral pulmonary infiltrates, hilar and mediastinal lymphadenopathyInfliximab withdrawn/resolution
Louie et al. (2007)1535/F/ASEtanercept/1Bilateral pulmonary infiltrates, hilar and mediastinal lymphadenopathy/UveitisEtanercept withdrawn, steroid/resolution
Verschueren et al. (2007)1653/F/RAInfliximab + MTX/12Bilateral pulmonary reticulonodular infiltrates, hilar and mediastinal lymphadenopathyEtanercept withdrawn, steroids/resolution
Verschueren et al. (2007)1646/F/RAEtanercept/6Mediastinal lymphadenopathy + cutaneous plaquesEtanercept withdrawn/resolution
Ishiguro et al.17 (2008)65/F/RAEtanercept/21Bilateral pulmonary nodular infiltrate, mediastinal and hilar lymphadenopathyEtanercept withdrawn/resolution
Sturfelt et al. (2008)1841/F/RAInfliximab + MTX/69Meningoencephalitis, bilateral granulomatous iridocyclitisInfliximab withdrawn, steroid, MTX, ventriculo-peritoneal shunt/resolution
Toussirot et al. (2008)1927/M/ASInfliximab/22Bilateral pulmonary infiltrates/hilar lymphadenopathyInfliximab withdrawn/resolution
Toussirot et al. (2008)1949/F/RAEtanercept/26Bilateral pulmonary reticulonodular infiltrates, hilar lymphadenopathyEtanercept withdrawn/resolution
Ognenovski et al. (2008)2060/M/RAEtanercept/9Bilateral pulmonary nodulesEtanercept withdrawn, steroid/resolution, now stable on adalimumab
Ognenovski et al. (2008)2060/F/RAEtanercept + MTX/48Bibasilar interstitial pulmonary changesEtanercept withdrawn, steroid/resolution, now stable on adalimumab
Ognenovski et al. (2008)2065/F/RAEtanercept/48Bilateral pulmonary nodules/mediastinal lymphadenopathyEtanercept withdrawn, steroid/resolution, now stable on adalimumab
Ognenovski et al. (2008)2050/F/RAEtanercept/60Bilateral interstitial pulmonary changes/mediastinal lymphadenopathyEtanercept withdrawn/resolution, stable on adalimumab
Josse et al. (2009)2161/F/RAInfliximab/33Cutaneous/mediastinal lymphadenopathyInfliximab withdrawn/resolution, stable on rituximab
Daïen et al. (2009)246/M/PsAEtanercept/2Cutaneous nodulesEtanercept withdrawn/resolution
Daïen et al. (2009)272/F/RAEtanercept + MTX/18Inflammatory scarsEtanercept withdrawn/resolution
Daïen et al. (2009)269/F/RAEtanercept/27Erythema nodosum, bilateral anterior uveitis, mediastinal lymphadenopathy, apex lobes infiltrateEtanercept withdrawn, steroid/resolution except uveitis relapsed
Daïen et al. (2009)238/F/ASEtanercept/18Bilateral basal pulmonary infiltrateEtanercept withdrawn, steroid/resolution
Daïen et al. (2009)249/F/RAEtanercept/26Bilateral pulmonary reticulonodular infiltrates, hilar lymphadenopathyEtanercept withdrawn, anti-TB therapy/resolution
Daïen et al. (2009)254/F/ASInfliximab/14Cutaneous nodules, basal pulmonary infiltrate, mediastinal lymphadenopathyInfliximab withdrawn/resolution/commenced on etanercept for 12 months – no events.
Daïen et al. (2009)250/M/ASInfliximab/51Mediastinal/hilar lymphadenopathyInfliximab withdrawn/clinical but not radiological improvement
Daïen et al. (2009)227/M/ASInfliximab/17Bilateral pulmonary nodular infiltrates, mediastinal lymphadenopathyInfliximab withdrawn/resolution
Daïen et al. (2009)253/F/RAAdalimumab/21Erythema nodosum, cutaneous nodules, mediastinal lymphadenopathyAdalimumab withdrawn/clinical but not radiological improvement
Daïen et al. (2009)251/F/SAPHOAdalimumab/1Fever, hypercalcaemia, mediastinal/hilar lymphadenopathyAdalimumab withdrawn/resolution
Massara et al. (2009)2245/M/PsAInfliximab/25Bilateral pulmonary reticulonodular infiltrates, hilar lymphadenopathyInfliximab withdrawn, steroid/resolution
Massara et al. (2009)2230/F/RAAdalimumab + MTX/27Bilateral pulmonary infiltratesAdalimumab withdrawn/resolution
Present case 155/F/PsAEtanercept/36 + MTX 60Interstitial nephritisEtanercept withdrawn, steroid/not resolved
Present case 250/M/RAEtanercept/8 + adalimumab/3 + MTX 36Mediastinal/hilar lymphadenopathyEtanercept withdrawn, steroid/await response
Present case 327/F/RAAdalimumab/3 + MTX 72Mediastinal/hilar lymphadenopathy/cutaneous/feverAdalimumab withdrawn, steroid/resolution

In our case series, it is intriguing to find that Case 1, upon rechallenge with the same TNF antagonist, developed worsening renal function, which promptly resolved after cessation of etanercept. Prior to the rechallenge, etanercept, which has a half-life of 70 h,23 was ceased for 6 months, which is sufficient for complete drug elimination. The temporal relationship of the original granulomata onset, as well as this positive rechallenge, would suggest that etanercept causing this non-caseating granulomatosis is biologically plausible. To date, there are no other reports of sarcoidosis associated with rechallenge of the same TNF antagonist.

Sarcoidosis is a diagnosis of systemic inflammation characterised by non-caseating granulomas, made after other causes of granulomatoses are excluded. It principally affects the lungs and lymph nodes, but may involve any organs.24 While its exact aetiology remains unknown, sarcoidosis is thought to be driven by antigen-activated CD4+ T cells, especially of type 1 helper (Th-1) variety. The main cytokines responsible for initiation and function of granulomas are TNF-α, interferon-gamma (IFN-γ) and interleukin-2.23 Indeed, TNF-α antagonists have been used effectively to treat refractory sarcoidosis in 30 case reports.25 It is therefore surprising and somewhat paradoxical that anti-TNF therapy would cause granulomatosis. Nonetheless, several observations would suggest TNF-α antagonist is the likely culprit: (i) there is a temporal relationship between introduction of TNF-α antagonists and onset of granulomatosis, (ii) the granulomatosis improves after TNF-α antagonists are ceased and (iii) the clinical manifestation of granulomatosis would deteriorate upon re-challenge with the same TNF-α antagonist (as observed in our first patient).

Of the three currently available TNF-α antagonists, there is one soluble TNF-α receptor antagonist (etanercept), and two anti-TNF monoclonal antibodies (adalimumab and infliximab). All three TNF-α antagonists have been reported to cause sarcoidosis-like granulomatous reactions. Of the 37 cases, the implicated agents were: etanercept 22 cases (59.5%), infliximab 10 cases (27.0%) and adalimumab five cases (13.5%). This suggests that soluble TNF-α receptor antagonist has a higher risk of new granulomatosis compared with anti-TNF monoclonal antibodies. Several reasons might account for this observation. While infliximab increases lysis of CD4 and CD8 cells, hence reducing IFN-γ expression, etanercept increases production of IFN-γ, which is vital in granuloma formation, and indeed found in higher concentration in patients with sarcoidosis.1 Etanercept also preserves the function of the p75-mediated TNF-α receptor, so some degree of TNF-α function persists, compared with infliximab that completely inhibits both p55- and p75-mediated TNF-α receptors.1

As part of the criteria for prescribing TNF-α antagonist in Australia, MTX was maintained during anti-TNF therapy in all three of our cases. MTX was co-administered with TNF-α antagonist in 7 of the 37 described cases, and its contributory role towards granuloma development could not be excluded. Although rare, granuolma development can be seen in MTX-induced lung injury, usually as an early complication of MTX26. Of the seven cases, five of which had MTX concurrently with TNF-α antagonist, MTX was consumed between 18 and 72 months prior to granuloma development.

The simultaneous occurrence of RA and sarcoidosis is extremely rare. Since 1950, there have only been four case reports of co-existence of RA and sarcoidosis.27–30 On the contrary, since 2002, there have been 34 other histologically-proven cases describing TNF antagonist related onset of non-infectious granulomata in various organs. This, along with the biological plausibility of TNF antagonists causing sarcoid-like lesions discussed earlier, increases the likelihood that TNF antagonist related sarcoid-like granulomatosis is a real phenomenon.

In summary, we report the development of sarcoidosis-like granulomatosis in 3 patients during TNF-α antagonist therapy. There are increasing reports of this phenomenon among all three anti-TNF agents, suggestive of a ‘class effect’ that was previously under-recognised. Granuloma development should be considered when unexplained extra-articular manifestations develop in a patient whose joint disease is otherwise well controlled on anti-TNF therapy.

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