The 3 currently available tumor necrosis factor α (TNFα) 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 TNFα 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.
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 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 low-dose 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. A scintigraphy with 67Ga 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 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.
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 antigen-driven 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-γ (IFNγ), and TNFα (16). To this respect, the cytokine most extensively studied is TNFα, and there is wide evidence of its pivotal role in the induction and maintenance of both inflammation and granuloma (16). Based on these data, TNFα 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 TNFα 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 TNFα blocking agent were variable (Table 1). Except for 1 patient, all were being treated with etanercept.
Table 1. Granulomatous reactions associated with TNFα blocking therapy*
TNFα blocking agent/time to reaction, months
TNFα = tumor necrosis factor α; RA = rheumatoid arthritis; PsA = psoriatic arthritis; AS = ankylosing spondylitis.
Crohn's-like disease with abdominal pain, diarrhea, and bloody stools
Acute and chronic inflammation with crypt destruction
Etanercept continued/controlled with mesalamine
Cutaneous nodules, bilateral hilar and paratracheal adenopathies
Noncaseating sarcoid granulomas
Resolution 2 months after etanercept withdrawal
Taking into account the pivotal role of TNFα in the pathogenesis of sarcoidosis and granuloma formation, the development of these granulomatous reactions while receiving TNFα 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 IFNγ 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-TNFα 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 TNFα on their membranes and preferentially neutralizes soluble TNFα, leaving TNF receptor p75 (TNFR p75) signaling largely intact. In addition, the binding of etanercept to TNFα has both high-on and high-off kinetics, shedding ∼50% of soluble and 90% of transmembrane TNFα only 10 minutes after binding, thus allowing redistribution of bioactive TNFα from sites of production, such as the inflamed joints, into other tissues where overall TNFα concentrations are low. Moreover, in patients with AS treated with etanercept, a significant increase in the percentage of T cells expressing TNFα and INFγ has been reported, suggesting that neutralization of peripheral TNFα 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 TNFα and INFγ, by preserving the TNFR p75–mediated immunoregulatory functions, and by its incomplete blockade of TNFα 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 TNFα blocking agent leaves, at least in some patients, sufficient cytokine activity to support granuloma formation.