Introduction

TNF-α inhibitors are efficacious for treating rheumatoid arthritis (RA) and various other chronic inflammatory diseases. Their side effects and complications have been documented for over 10 years. It was therefore somewhat unexpected that a few recent case reports described granuloma formation and complete sarcoidosis in patients treated with these drugs. Etanercept has been the culprit in most of these cases, although some have been ascribed to infliximab and adalimumab treatment [1–18]. TNF-α is thought to play a central role in the pathogenesis of sarcoidosis [19] and monoclonal antibodies against, such as infliximab, have shown promising results in the treatment of sarcoidosis [20, 21]. Paradoxically, etanercept, a TNF-α p75 soluble receptor fusion protein, has not proven to be effective [22, 23]. Because TNF-α antibody therapies differ in action compared with the soluble TNF-α receptor, questions have been raised regarding etanercept’s possible unique role in promoting sarcoidosis, or whether this is a class effect for all TNF-α inhibitors. Here we present the cases of three patients who developed sarcoidosis while being treated with etanercept for ankylosing spondylitis, juvenile chronic arthritis, and RA, respectively.

Patient 1

A 42-year-old male presented with flu-like symptoms in November 2007. He complained of swelling in the throat and parotid area associated with a runny nose, dry eyes, and dry mouth. His past medical history consisted of 30 years of ankylosing spondylitis with peripheral arthritis for which he had been treated with different DMARDs, NSAIDs, and for the last year, etanercept.

On clinical examination, his parotid glands and submandibular lymph nodes were enlarged and tender. An eye examination revealed keratoconjunctivitis sicca and a posterior uveitis. Laboratory tests showed a moderate leukocytosis, moderately raised C-reactive protein (CRP), and increased levels of angiotensin converting enzyme (ACE). Comprehensive immunological and viral serology tests did not show any abnormality. Routine cerebrospinal fluid investigations and microbiological tests, including screening for tuberculosis, were negative. A salivary gland biopsy from the lower lip revealed necrotizing granulomas. A CT scan showed swelling of the parotid and submandibular glands bilaterally, and multiple, moderately enlarged lymph nodes in the anterior cervical chain, and in the para-aortic and mesenteric regions. Liver biopsy demonstrated granulomatous inflammatory changes and staining for tuberculosis was negative. A diagnosis of extrapulmonary sarcoidosis was made, involving the salivary and lacrimal glands, posterior uvea, liver, and lymph nodes.

Suspecting an association between the use of etanercept and the clinical syndrome, the medication was discontinued and the patient was started on azathioprine and corticosteroids. Follow-up in the outpatient clinic 2 weeks later showed resolution of the lymphadenopathy. Five months later, the patient was started on adalimumab for arthritis flare-ups with a rapid and favorable response. One month later, methotrexate was reintroduced. Six months after the diagnosis of sarcoidosis, the patient shows no signs of recurrence.

Patient 2

A 29-year-old female with juvenile chronic arthritis since the age of 6 presented with a 2-week history of bilateral parotid swelling and dryness of the eyes and mouth. She had been treated with etanercept for the last 2 years for poorly controlled arthritis. A lower lip biopsy revealed multiple granulomas consisting of epitheloid cells and some giant cells and lymphoid cells. Areas of necrosis and fibrosis were also noted (Fig. 1). A chest X-ray and Pirque-test were normal. Routine blood tests showed mildly deranged liver function tests and raised ACE. She continued with etanercept because it provided good control of the arthritis. The sicca symptoms gradually resolved. After some time, etanercept was discontinued for conception but was reintroduced 3 years later. One year after reintroduction, dryness of the mouth, eyes, and cervical lymphadenopathy recurred. A biopsy of the salivary glands at this stage did not show any abnormality.

Fig. 1
figure 1

Biopsy from a small salivary gland showing non-necrotizing epitheloid granulomas with a small occurrence of lymphocytes, consistent with sarcoidosis

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Patient 3

A 48-year-old female with RA for 20 years presented with a 2-month history of dyspnea upon exercise and a dry cough. She was treated with methotrexate and, for the last 3 years prior to presentation, with etanercept. Her chest X-ray showed bilateral hilar adenopathy and a transbronchial biopsy showed non-caseating granulomas consistent with sarcoidosis (Fig. 2). Bronchoalveolar lavage showed a predominance of CD4 cells compared with CD8 cells. There were no malignant cells, and all microbiological tests, including tbc, were negative. Routine blood tests, including ACE and CRP, were normal. A diagnosis of sarcoidosis was made and etanercept discontinued. The patient was treated with oral prednisolone and had a favorable response and resolution of symptoms and signs. A chest X-ray 3 months later was normal.

Fig. 2
figure 2

Transbronchial lung biopsy showing non-necrotizing granulomas with only a small occurrence of lymphocytes, consistent with sarcoidosis

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Discussion

These case histories are consistent with previous reports of granulomatous reactions as well as frank sarcoidosis observed in patients on TNF-α antagonists [1–18]. It is intriguing that etanercept seems more commonly associated with this phenomenon than the other TNF-α antibody drugs, and also fails to be efficacious in sarcoidosis treatment [22, 23]. Notably, our first patient did not relapse when adalimumab was introduced after etanercept. Etanercept has failed in treatment of sarcoidosis and Crohn’s disease [22–24], while infliximab and adalimumab have demonstrated effect in both diseases [20, 21, 25–27]. Also the risk of reactivation of latent Mycobacterium tuberculosis is significantly higher for infliximab than for etanercept [28, 29]. Several explanations for these discrepancies may exist and for the possible predominance of promoting sarcoidosis during etanercept treatment.

Infliximab and etanercept differ with respect to dosing, pharmacokinetics, and binding avidity. Infliximab and adalimumab are monoclonal TNF-α antibodies whereas etanercept is a TNF-α p75 soluble receptor that binds mainly to soluble TNF-α molecules and interacts with transmembrane TNF with reduced avidity compared with infliximab. Infliximab binds both transmembrane TNF and soluble TNF. Clearance of etanercept is about 13 times greater than that of infliximab and adalimumab. Therefore, suppression of TNF-α is greater and more prolonged with infliximab and adalimumab [30]. Infliximab tend to achieve higher peak dose and it has been proposed that higher immediate dosing leads to intracellular suppression of TNF [31].

The granulomas in sarcoidosis consist of epitheloid-like macrophages and giant cells, surrounded by mostly CD4+ T cells [32]. Cytokines, such as TNF-α, IL-2, and especially IFN-γ, appear to be of crucial importance for the formation and continuation of the granulomas [33].

T regulatory (Treg) cells are important in preventing autoimmunity and are capable of suppressing proliferation and cytokine production of activated CD4+ and CD8+ T cells, and are found in close contact to these cells. TNF-α inhibits the suppressive function of Treg cells [34]. Recent studies in RA patients suggest impaired Treg cell function, and treatment with anti-TNF-α antibodies appears to restore the number and function of Treg cells [35]. In sarcoidosis Treg cells are down-regulated [36]. Treatment with etanercept maintains low levels of TNF-α, hence Treg cells remain down-regulated to some extent and can lead to an augmented Th1 immune response, important in the pathophysiology of sarcoidosis. In contrast, treatment with infliximab inhibits TNF-α activity to a much greater extent, so Treg cells are not down-regulated, leading to a more pronounced inflammatory suppression.

In addition, infliximab and adalimumab suppress IFN-γ production, whereas etanercept does not [37]. In light of the role of IFN-γ for granuloma formation these differences may be of vital importance. While infliximab more or less completely inhibits both TNF-α and IFN-γ, patients on etanercept maintain higher levels of IFN-γ as well as an incomplete elimination of TNF.

Few other observations add to the evidence for the role of IFN-γ and TNF-α in granuloma formation. IFN-α treatment, commonly used for chronic viral hepatitis and some malignant disorders, can induce sarcoidosis and a variety of other autoimmune conditions [38]. Although the exact mechanism is unknown, administration of IFN-α increase IFN-γ and interleukin-2 production by CD4+ T cells and may promote granuloma formation [39]. Furthermore, infections with M. tuberculosis, Listeria monocytogenes, and Histoplasma capsulatum, occur with 2- to 10-fold greater frequencies in patients treated with infliximab than in those treated with etanercept [37]. Both IFN-γ and TNF-α are essential in protecting against tuberculosis. The inability to produce IFN-γ strongly predisposes patients to tuberculosis [40]. The risk that infliximab poses with regard to reactivation of latent M. tuberculosis infection is therefore possibly due to the simultaneous suppression of TNF-α and IFN-γ, and may as well explain why it is effective in treatment of sarcoidosis, where the presence of both IFN-γ and TNF-α is necessary.

The effects of TNF-α antagonists for inhibition or induction of the granulomatous process is complex and unclear. If there is an increased frequency of sarcoidosis on etanercept treatment, this could be due to different cytokine profiles induced by the two groups of anti-TNF agents. On the other hand there also exist reports on granuloma formation on adalimumab and infliximab treatment. This could point to a possible class effect of all TNF-α inhibitors. However, if one considers exposure to these agents, patient years (PTY) for infliximab was 4,294,729, adalimumab 877,885, and etanercept 1,952,000 PTY per September 2009 (numbers according to companies representatives). Since etanercept accounts for 27% of PTY of all anti-TNF treatment, and 61% (20/33) of case reports are on etanercept (Table 1), this indicates some predilection for granuloma formation with this drug. Further observations will clarify this matter and will also shed light on the pathophysiology of sarcoidosis and other granulomatous disorders.

Table 1 Reported cases of sarcoidosis developing during TNF-α blocking therapy
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