5Autoimmune diseases induced by TNF-targeted therapies
Introduction
Tumor necrosis factor-α (TNF-α) is a cytokine that plays a crucial role in causing inflammation by means of predominantly T-cell-mediated tissue damage. Inhibition of TNF-α has recently emerged as an effective therapy for treating rheumatic diseases.1, 2 Three anti-TNF agents are currently approved by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMEA). Infliximab is a chimeric monoclonal antibody against TNF-α administered as an intravenous infusion. Etanercept, a p75 TNF-receptor fusion protein conjugated to the Fc region of human immunoglobulin G (IgG), is administered as a subcutaneous injection twice weekly. Adalimumab – a human anti-TNF monoclonal antibody – is also administered subcutaneously. These three agents have been reported to be safe and effective in the treatment of rheumatoid arthritis (RA) and have recently been approved by FDA and EMEA for the treatment of other rheumatic, digestive, and cutaneous diseases. More than 1 million patients with these diseases have been treated with anti-TNF agents.3
With the increasing use and longer follow-up periods of TNF-targeted therapies, a new spectrum of clinical and analytical adverse events is emerging. Although these agents have been studied extensively during the past decade and have demonstrated acceptable profiles of safety and tolerability4, 5, *6, reports of adverse events are increasing, including infections, an increased risk of cancer and lymphoma, demyelinating disorders, and cardiovascular disease. In addition, there is a growing number of reports of the development of autoimmune processes related to TNF-targeted therapies, ranging from asymptomatic immunological alterations to life-threatening systemic autoimmune diseases.7 The available safety data on autoimmune diseases induced by TNF-targeted agents rely mainly on case reports, and information regarding their management and clinical significance is very limited. The purpose of this review was to analyze the clinical characteristics, outcomes, and patterns of association with the different anti-TNF agents used in all reported cases of patients developing autoimmune diseases after TNF-targeted therapy.
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The BIOGEAS project
In 2006, the Study Group on Autoimmune Diseases (GEAS) of the Spanish Society of Internal Medicine created the BIOGEAS project (www.biogeas.org), a multicenter study devoted to collecting data on the use of biological agents in adult patients with systemic autoimmune diseases (SAD). The information sources are cases reported by Spanish physicians treating SAD and quarterly surveillance of reported cases by a Medline search. An additional objective of the BIOGEAS project is to collect data on
Lupus induced by anti-TNF agents
One-hundred-and-five patients developed systemic lupus erythematosus (SLE)/lupus-like disease after starting anti-TNF therapy (Table 2). Eighty-seven patients had rheumatoid arthritis (RA), ten had Crohn's disease (CD), two had ankylosing spondylitis (AS), two had psoriatic arthritis (PsA), two had mixed connective tissue disease (MCTD), one had Still disease and one had juvenile RA (JRA). The anti-TNF agent administered was infliximab in 45 (43%) cases, etanercept in 38 (36%) and adalimumab in
Vasculitis induced by anti-TNF agents
One-hundred-and-eighteen patients developed vasculitis after starting anti-TNF therapy (Table 3). Ninety-nine patients had RA, eight had CD, five had JRA, three had AS, and three had PsA. The anti-TNF agent administered was etanercept in sixty (51%) cases, infliximab in fifty-one (43%), adalimumab in five (4%), and other agents in two (2%). Vasculitis appeared after a mean time of 38 weeks of anti-TNF therapy. Epidemiological data were available in 103 cases (eighty-two females and twenty-one
Interstitial lung disease induced by anti-TNF agents
Thirty four patients developed interstitial lung disease (ILD) after starting anti-TNF therapy (interstitial pneumonitis in thirty-one patients, pulmonary hemorrhage in two, and bronchiolitis obliterans organizing pneumonia in one). Thirty patients had RA, two had CD, one had AS, and one had adult-onset Still disease. The anti-TNF agent administered was infliximab in twenty (59%) cases, etanercept in eleven (32%), and adalimumab in three (9%). Twenty (65%) out of thirty-one patients had
Antiphospholipid features induced by anti-TNF agents
Thirty-two patients developed antiphospholipid syndrome (APS)-related features after starting anti-TNF therapy (Table 4). There were eighteen patients with Wegener granulomatosis, five with CD, four with RA, two with AS, one with SLE, one with sarcoidosis, and one with systemic sclerosis. The anti-TNF agent administered was infliximab in fourteen (44%) cases, etanercept in sixteen (50%) cases, and adalimumab in two (6%) cases. The APS-related features included deep vein thrombosis (DVT) in
Sarcoidosis induced by anti-TNF agents
Ten patients (five females and five males, with a mean age at development of sarcoidosis of 48.9 years) developed sarcoidosis after starting anti-TNF therapy. Five patients had RA, three had AS, and two had PsA. The anti-TNF agent administered was infliximab in two cases and etanercept in eight. Sarcoidosis involved the lungs in the ten cases, together with the skin in three cases, and the parotid glands in one case. Treatment of ILD involved the withdrawal of anti-TNF therapy in eight cases,
Psoriasis induced by anti-TNF agents
Grinblat and Scheinberg20 have recently reviewed fifty patients who developed psoriasis after starting anti-TNF therapy (twenty-eight patients with RA, eleven with AS, six with CD, two with Behçet disease, and three with other diseases). The anti-TNF agent administered was infliximab in thirty-three cases, etanercept in seventeen, and adalimumab in ten (ten patients received two or three anti-TNF agents). Exacerbation of previous psoriasis was reported in 7/37 (19%) patients. Treatment of
Ocular autoimmune disease induced by anti-TNF agents
Nineteen patients developed ocular autoimmune disease (OAD) after starting anti-TNF therapy (uveitis in seven cases, optic neuritis in six, scleritis in four, orbital myositis in one, and endogenous endophthalmitis in one). Twelve patients had RA, three had PsA, two had AS, one had JRA, and one had adult Still disease. The anti-TNF agent administered was infliximab in seven cases and etanercept in twelve.
Autoimmune hepatitis induced by anti-TNF agents
Seven patients developed autoimmune hepatitis after starting anti-TNF therapy. There were three patients with RA, one with CD, one with AS, one with PsA, and one with ulcerative colitis. The anti-TNF agent administered was infliximab in all cases.
Myopathies induced by anti-TNF agents
Four patients with RA developed inflammatory myopathies after starting anti-TNF therapy. There were two cases of polymyositis related to infliximab and two cases of dermatomyositis (one related to etanercept and one with lenercept).
Conclusion
More than one million patients have been treated with the three currently available anti-TNF agents (adalimumab, etanercept, and infliximab) for a variety of rheumatic, digestive, and dermatological diseases.3 Etanercept and infliximab have been studied extensively during the past decade and have demonstrated acceptable safety and tolerability profiles.4, 5, 18 However, due to the seriousness and unexpected nature of certain adverse events (AEs) that have been seen with all three agents, safety
Acknowledgments
The authors thank David Buss for his editorial assistance.
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