Tumor necrosis factor (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 diseases30,55. 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 IgG immunoglobulin, is administered as a subcutaneous injection twice weekly. Adalimumab is a human anti-TNF monoclonal antibody also administered subcutaneously. These 3 agents have been reported to be safe and effective in the treatment of rheumatoid arthritis (RA) and have recently been approved by the 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 agents6.
TNF-targeted therapies are being used for a rapidly expanding number of rheumatic and autoimmune diseases. With this increasing use and longer follow-up periods of treatment, a new spectrum of clinical and analytical adverse events are emerging. Although these agents have been studied extensively during the past decade and have demonstrated acceptable profiles of safety and tolerability27,41,43, reports of adverse events are increasing, including infections, an increased risk of cancer and lymphoma, demyelinating disorders, and cardiovascular disease. In addition, there are a growing number of reports of the development of autoimmune processes related to TNF-targeted therapies, ranging from asymptomatic immunologic alterations to life-threatening systemic autoimmune diseases31. 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. We conducted the current study to analyze the clinical characteristics, outcomes, and patterns of association with the different anti-TNF agents used in all reported cases we could find of patients developing autoimmune diseases after TNF-targeted therapy.
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 biologic agents in adult patients with systemic autoimmune diseases (see Appendix) and creating a patient registry. The information sources are cases reported by Spanish physicians treating patients with systemic autoimmune diseases and quarterly surveillance of reported cases by a MEDLINE (National Library of Medicine, Bethesda, MD) search. An additional objective of the BIOGEAS project is to collect data on systemic autoimmune diseases secondary to the use of biologic agents, with the aim of formulating a standardized, consensual protocol for these patients. The MEDLINE search included articles published between January 1990 and December 2006. Search terms included "anti-TNF," "infliximab," "etanercept," "adalimumab," "autoimmune disease," "induced," "lupus," "vasculitis," "purpura," "sarcoidosis," "pulmonary fibrosis," "granulomas," and "glomerulonephritis." Additional articles were identified through a comprehensive manual search of the references of retrieved articles.
We used the conventional chi-square and Fisher exact tests to analyze qualitative differences, the Student t-test for comparison of means in large samples of similar variance, and the nonparametric Mann-Whitney U test for small samples. Values of quantitative variables are expressed as mean ± standard deviation of the mean. A value of p < 0.05 was taken to indicate statistical significance. The statistical analysis was performed using the SPSS statistical package (Chicago, IL).
We identified 233 cases of autoimmune diseases secondary to TNF-targeted therapies in 226 patients from the literature review (Table 1). The anti-TNF agents were administered for RA in 187 (83%) patients, Crohn disease in 17, ankylosing spondylitis in 7, psoriatic arthritis in 6, juvenile RA in 5, and other diseases in 3 patients. The anti-TNF agents administered were infliximab in 105 patients, etanercept in 96, adalimumab in 21, and other anti-TNF agents in 3. The autoimmune diseases identified were classified in 4 groups: vasculitis,2,7,17,19,20,24,26,34,36,42,45-47,50,51,56,66,68,71,77,79,80,82,83,87 lupus,1,3,5,7-11,13-15,18,21,23,24,33,37,38,50,51,53,54,59,61,62,67,68,70,73-75,78,80-82,84 interstitial lung disease (ILD),24,52,74 and other autoimmune diseases.12,16,18,29,32,37,39,44,57,58,60,61,63,64,76,85,86 Epidemiologic data were available in 159 patients, of whom 129 (81%) were women and 30 (19%) were men, with a mean age of 50.4 years (range, 18-75 yr).
One hundred thirteen patients developed vasculitis after starting anti-TNF therapy (Table 2). There were 95 (84%) patients with RA, 7 with Crohn disease, 3 with ankylosing spondylitis, 5 with juvenile RA, and 3 with psoriatic arthritis. The anti-TNF agent administered was etanercept in 59 (52%) cases, infliximab in 47 (42%), adalimumab in 5 (4%), and other agents in 2 (2%) cases. Vasculitis appeared after a mean time of 38 weeks of anti-TNF therapy. Epidemiologic data were available in 98 cases (79 women and 19 men; mean age at development of vasculitis, 51 yr).
Vasculitis presented mainly as cutaneous lesions in 98 (87%) patients, including purpura (57%), ulcerative lesions (9%), nodules (9%), digital vasculitis (6%), and maculopapular rash (5%). Visceral vasculitis was observed in 27 (24%) patients. Eighteen (16%) patients had peripheral nerve involvement, 15 (13%) had renal involvement, 5 (4%) had central nervous system (CNS) involvement, and 3 (3%) had lung involvement. Infrequent vasculitic presentations involved the gallbladder, the temporal arteries, and the heart (1 case each). Exacerbation of previous vasculitic involvement was observed in 10 (9%) cases. Eighty-three patients (73%) had histologically confirmed vasculitis. The biopsy specimen was obtained from the skin (n = 63), kidney (n = 10), muscle or sural nerve (n = 6), lung (n = 3), and temporal artery (n = 1). The main histologic finding was leukocytoclastic vasculitis in 52 (63%) cases, necrotizing vasculitis in 14 (17%), and lymphocytic vasculitis in 5 (6%) cases. Immunologic results included positive antinuclear antibodies (ANA) in 27 cases, antineutrophil cytoplasmic antibodies (ANCA) in 10 (IFI patterns were specified in 4 cases: all were pANCA), cryoglobulins in 5, anti-DNA in 4, antiphospholipid antibodies (aPL) in 3, and anti-Ro/La in 1.
Treatment of vasculitis involved withdrawing the anti-TNF therapy in 101 (89%) cases. Anti-TNF therapy was continued in the remaining 12 cases, of which 9 resolved and 3 did not. Corticosteroids were used in 28 (25%) patients, 2 of whom required intravenous methylprednisolone. Seventeen (15%) patients received immunosuppressive agents: 12 cyclophosphamide, 2 leflunomide, 2 intravenous immunoglobulins, and 1 cyclosporine A. The outcome of vasculitis was detailed in 100 cases: complete resolution was observed in 67 patients, improvement or partial resolution in 25, and no resolution in 8. Two patients died (1 with polyarteritis nodosa and the other with rapidly progressive glomerulonephritis-ANCA+).
We compared the anti-TNF agent received (infliximab vs. etanercept) in the 70 patients for whom full information was available (Table 3). Patients treated with etanercept were more frequently male (26% vs. 12%, p = 0.16) and had a higher mean age (54.6 vs. 46.7 yr, p = 0.22). In these patients, compared with patients treated with infliximab, the underlying rheumatic disease was more frequently RA (89% vs. 72%, p = 0.05), and the vasculitis more frequently involved the internal organs (29% vs. 6%, p = 0.03) and occurred later (10.8 vs. 4.5 mo, p = 0.12).
Ninety-two patients developed systemic lupus erythematosus (SLE)/lupus-like disease after starting anti-TNF therapy: 77 patients with RA, 8 with Crohn disease, 2 with ankylosing spondylitis, 2 with psoriatic arthritis, 2 with mixed connective tissue disease, and 1 with juvenile RA (Table 4). The anti-TNF agent administered was infliximab in 47 (44%) cases, etanercept in 37 (40%), and adalimumab in 15 (16%). SLE-related features appeared after a mean of 41 weeks of anti-TNF therapy. Epidemiologic data were available in 62 cases (52 women and 10 men; mean age at development of SLE-related features, 50.9 yr).
The clinical and immunologic features suggestive of SLE were detailed in 72 patients and included positive autoantibodies in 68 (94%) patients, cutaneous features in 64 (89%), musculoskeletal manifestations in 28 (39%), and general symptoms (fever, malaise, asthenia) in 21 (29%). According to the 1997 SLE criteria33a, the following features were observed: positive ANA in 57 (79%) patients, anti-dsDNA in 52 (72%), SLE cutaneous features (malar rash, photosensitivity and/or discoid lupus) in 48 (67%) patients, arthritis in 22 (31%), cytopenia in 16 (22%), serositis in 9 (12%), aPL in 8 (11%), anti-Sm in 7 (10%), nephropathy in 5 (7%), oral ulcers in 3 (4%), and CNS involvement in 2 (3%). Other immunologic features included low complement levels in 16 (22%), anti-Ro/La antibodies in 9 (12%), and anti-RNP in 5 (7%). Only 37 (51%) patients fulfilled 4 or more classification criteria for SLE, 17 (24%) fulfilled 3 criteria, and the remaining 18 (25%) fulfilled 1 or 2 criteria. After discarding clinical or analytical features present before the initiation of anti-TNF therapy, only 25 (35%) patients fulfilled SLE criteria.
Treatment of SLE-related features involved the withdrawal of anti-TNF therapy in 72/77 (94%) cases. Corticosteroids were used in 31 (40%) patients, and 7 (12%) patients received immunosuppressive agents (3 methotrexate, 1 cyclophosphamide, 1 leflunomide, 1 mycophenolate, and 1 azathioprine). Improvement was observed in all but 1 case, and no death was reported.
We compared the anti-TNF agent received (infliximab vs. etanercept) in the 74 patients for whom full information was available (Table 5). Patients treated with etanercept were more frequently female (91% vs. 74%, p = 0.082) and more frequently had RA (95% vs. 68%, p = 0.003) compared with those treated with infliximab. Clinically, subacute/chronic SLE-specific cutaneous features were more frequently observed in patients who received etanercept (44% vs. 12%, p = 0.01), while serositis was more frequently observed in those treated with infliximab (24% vs. 3%, p = 0.008). A trend to a significantly higher frequency of the development of vasculitis was observed in the etanercept group (13% vs. 3%, p = 0.127). A higher percentage of patients receiving infliximab fulfilled 4 or more SLE criteria than of those treated with etanercept (51% vs. 37%, p = 0.218), especially when SLE features appearing after the initiation of anti-TNF therapy were considered (32% vs. 7%, p = 0.075).
Interstitial Lung Disease
Twenty-four patients developed ILD after starting anti-TNF therapy (interstitial pneumonitis in 18 patients, sarcoidosis in 3, pulmonary hemorrhage in 2, and bronchiolitis obliterans organizing pneumonia in 1). There were 17 (71%) patients with RA, 2 with Crohn disease, 1 with ankylosing spondylitis, 1 with psoriatic arthritis, and 1 with adult Still disease. The anti-TNF agent administered in the development of vasculitis was infliximab in 19 (79%) cases, etanercept in 4 (17%), and adalimumab in 1 (4%). ILD appeared after a mean of 42 weeks of anti-TNF therapy. Twelve (50%) patients had received methotrexate. Exacerbation of a previous ILD was observed in 4 (17%) patients. Epidemiologic data were available in 21 cases (14 women and 7 men; mean age at development of vasculitis, 63.9 yr).
The clinical presentation of ILD was detailed in 19 cases and included dyspnea in 17 (89%), fever in 13 (68%), cough in 10 (53%), and pleuritic pain in 2 (10%). Treatment of ILD involved the withdrawal of anti-TNF therapy in all cases. Corticosteroids were used in 15 patients and immunosuppressive agents in 4. The outcome of anti-TNF-induced ILD was detailed in 19 cases: resolution was observed in 9 (47%) patients and no resolution in 10 (53%). Death occurred in 6 (32%) patients (4 had a previous diagnosis of ILD).
Other Autoimmune Diseases
Four patients developed other autoimmune diseases after starting anti-TNF therapy. There were 2 cases of inflammatory myopathies (1 related to infliximab and 1 with lenercept) and 2 cases of antiphospholipid syndrome after treatment with adalimumab.
More than 1 million patients have been treated with the 3 currently available anti-TNF agents (adalimumab, etanercept, and infliximab) for a variety of rheumatic, digestive, and dermatologic diseases6. Etanercept and infliximab have been studied extensively during the past decade and have demonstrated acceptable safety and tolerability profiles27,41,43. However, due to the seriousness and unexpected nature of certain adverse events that have been seen with all 3 agents, safety concerns persist. These adverse events include serious infections40, opportunistic infections including tuberculosis4, demyelinating disorders49, and lympho-proliferative processes88. More recently, the use of anti-TNF agents has been associated with an increasing number of reports of autoimmune features, both clinical and analytical31. In the current review, we describe the main characteristics of the autoimmune diseases associated with the use of anti-TNF agents reported to date (mainly lupus, vasculitis, and ILD).
At the last update of the registry, there were 92 reported cases of lupus following anti-TNF therapy (infliximab in 40 cases, etanercept in 37, and adalimumab in 15). Nearly half the cases fulfilled 4 or more classification criteria for SLE33a, although this figure fell to one-third after discarding preexisting lupus-like features. The most typical features of these patients were general symptoms, musculoskeletal manifestations, lupus-like cutaneous features, and positive autoantibodies. Since 199970, reported manifestations of lupus in patients treated with anti-TNF agents have included articular involvement, serositis, and skin rashes. The induction of autoantibodies in patients with RA treated with these agents has also been well documented. Eriksson et al22 found that the prevalence of ANA at dilution >1:100 increased from 24% at baseline to 77% at 30 weeks and 69% at 54 weeks in 53 patients treated with infliximab for RA, while in a series of 156 patients with RA also treated with infliximab, 22 (14%) patients developed anti-dsDNA antibodies11. Other studies have confirmed the frequent induction of ANA and anti-dsDNA after the use of anti-TNF agents8,23.
In the current review, more than half the reported cases of lupus after anti-TNF therapy presented clinical and serologic features that, taken together, met the 1997 ACR revised criteria for SLE33a. However, while the frequency of certain SLE criteria was high (ANA in 79%, anti-dsDNA in 72%, cutaneous features in 67%, and arthritis in 31%), other criteria were described in less than 10% of cases (anti-Sm antibodies, oral ulcers, CNS involvement, or renal involvement). Most cases of lupus related to anti-TNF agents are characterized by general symptoms, cutaneous features, and articular involvement (Table 6), a clinical presentation highly suggestive of a drug-induced lupus-like syndrome72. However, some patients developed a clinical presentation indistinguishable from idiopathic SLE. In these patients, it is possible that biologic agents may act as a triggering factor of a possible underlying or subclinical SLE, resembling the lupus flares triggered by exposure to sunlight, exercise, or pregnancy.
Some of the reported cases with RA had lupus features before the initiation of anti-TNF therapy. This suggests a preexisting overlap between RA and an underlying SLE in these patients, in whom the use of the anti-TNF drug triggered new SLE features leading to the fulfillment of SLE criteria. Of the 92 reviewed cases of lupus developing after anti-TNF therapy, only 25 (35%) fulfilled the classification criteria of SLE after discarding clinical and analytical criteria present before the initiation of anti-TNF therapy. In these patients, the biologic agent seems to exacerbate an underlying SLE rather than triggering or inducing SLE. Unfortunately, not all the reported cases of lupus related to anti-TNF therapies had a baseline immunologic study before use of the biologic agent. In these cases, a preexisting overlap between RA and SLE cannot be discarded.
We describe the clinical characteristics of 113 patients who developed vasculitis after receiving anti-TNF agents (etanercept in 59 cases, infliximab in 47, adalimumab in 5, and other agents in 2). The most frequent type of vasculitis was leukocytoclastic vasculitis, also named leukocytoclastic angiitis69, in which a drug-based etiology is implicated in approximately 10%-24% of cases28. Purpura was the most frequent cutaneous feature, although other lesions, such as ulcers, nodules, or rash, were also described. Some patients developed digital vasculitis, a cutaneous manifestation typically described in patients with SLE48. A significant finding was that one-quarter of patients with vasculitis related to anti-TNF agents had extracutaneous involvement. Peripheral neuropathy and renal vasculitis were the most frequent type of visceral vasculitis in these patients, although other sites of vasculitic involvement included the lungs, CNS, gallbladder, and coronary arteries. Four cases fulfilled ACR classification criteria for a defined systemic vasculitis65. It is not clear why some patients developed benign limited cutaneous vasculitis, others developed vasculitic involvement of internal organs, and others developed a defined systemic vasculitis; this suggests a possible role for individual genetic susceptibility.
Several factors support an etiologic role for anti-TNF agents in the development of vasculitis. First, the occurrence of vasculitis was temporally associated with the initiation of therapy. Second, in some patients treated with etanercept, the skin lesions started at the injection site and spread to involve other areas of the body, supporting a role for a direct antigen-mediated hypersensitivity vasculitis. Third, even though patients were reported to be on concomitant medications that have been associated with vasculitis, the cutaneous lesions resolved in more than 90% of patients after discontinuation of anti-TNF agents. Fourth, a positive rechallenge phenomenon (reappearance or worsening of symptoms on reexposure to the agent) was seen in 75% of reported cases.
In addition to the association between anti-TNF agents and the development of lupus and vasculitis, recent data suggest that these agents may be associated with the development of ILD. We analyzed 24 cases of ILD associated with the use of anti-TNF agents, including interstitial pneumonitis in 18 patients, sarcoidosis in 3, pulmonary hemorrhage in 2, and bronchiolitis obliterans organizing pneumonia in 1. Two specific characteristics of the ILD associated with anti-TNF therapy should be highlighted: the poor prognosis in spite of cessation of anti-TNF therapy, and the possible adjuvant role of receiving methotrexate concomitantly.
Of the 19 cases in whom the outcome was detailed, more than half showed no resolution of pulmonary involvement after cessation of anti-TNF therapy and initiation of corticosteroids and immunosuppressive agents. One-third of patients died, most of whom had a preexisting pulmonary disease. This poor prognosis clearly contrasts with the benign outcome of the majority of cases of lupus and vasculitis associated with anti-TNF agents. Data from the British Society for Rheumatology Biologics Register (BSRBR), which prospectively collects data on all patients with RA receiving biologic therapy in the United Kingdom, reveal that after treatment with any anti-TNF agent, patients with a preexisting pulmonary disease (n = 184) had a mortality rate of 90 per 1000 person-years of follow-up compared with those without pulmonary disease (n = 6061), who had a mortality rate of 14 per 1000 person-years of follow-up. This represented a 6.4-fold higher mortality rate among patients treated with anti-TNF agents with previous pulmonary diseases (BSRBR May-August 2004 Newsletter data). This suggests that anti-TNF agents should be used with extreme caution in patients with a preexisting or underlying lung disease, especially those who have severe disease. Heightened vigilance for pulmonary complications during postmarketing surveillance of anti-TNF therapies is also recommended.
Half the ILD cases associated with anti-TNF agents occurred in patients receiving methotrexate, which has been associated with the development of drug-induced alveolitis/pulmonary fibrosis. It may be hypothesized that, in some patients, anti-TNF agents might potentiate the pulmonary toxicity of methotrexate through deficient apoptosis of infiltrating inflammatory cells. Thus, the use of anti-TNF agents might facilitate the development of interstitial pneumonitis, and the longer half-life of these agents could also be responsible for the slow clearance of pulmonary infiltrates. Screening of candidates for anti-TNF agents with chest radiograph and spirometry is recommended to discard an underlying ILD, especially if the patient is receiving methotrexate35.
Some concerns remain, including the incidence of these autoimmune diseases, the possible effect of the dosage of anti-TNF agents, and the etiopathogenic link between these autoimmune diseases and TNF blockade. Few data are available on the incidence of these autoimmune processes in large series of patients treated with anti-TNF agents. Thus, the prevalence of lupus is lower than 0.5% of treated patients (0.10% in the study by Schiff et al74, 0.22% in the study by Charles et al11, and 0.39% in the study by Shakoor et al78), while the prevalence of vasculitis was 3.9% in the study by Flendrie et al24. With respect to the dosage of anti-TNF agents, in most available cases the standard dosage was used. Finally, the descriptive design of the current study did not allow us to ascertain a direct association between anti-TNF agents and the etiopathogenesis of these autoimmune diseases. More than 80% of reported cases have RA, a disease that may be associated with lupus-like features (coexisting in some patients with SLE) and that may also induce vasculitis or ILD (due to the RA itself or associated with the use of methotrexate). Large, prospective, postmarketing studies, using patients treated with conventional therapies as controls, are required to evaluate the risk of developing autoimmune diseases in patients receiving TNF-targeted therapies.
In conclusion, the use of anti-TNF agents has been associated with an increasing number of cases of autoimmune diseases, principally cutaneous vasculitis, lupus-like syndrome, SLE, and ILD. At the last update of the registry (December 31, 2006), there were 233 cases of autoimmune diseases associated with TNF-targeted therapies identified in 226 reported patients. In spite of the retrospective, observational design of the current study, we suggest some recommendations for the management of patients with autoimmune disease triggered by anti-TNF agents (Table 7). First, we suggest a careful clinical and immunologic evaluation upon starting anti-TNF therapy, discarding preexisting features suggestive of an underlying autoimmune disease. Second, a baseline immunologic study (ANA, anti-dsDNA, aPL, and ANCA) and chest X-ray should be obtained before initiating anti-TNF treatment. Third, a differentiated therapeutic approach should be considered according to the severity of the anti-TNF-related autoimmune disease. In patients with mild features (cutaneous, articular, and/or general involvement), cessation of anti-TNF therapy will probably be sufficient, although continuation might be considered under close follow-up (especially in patients with isolated cutaneous lesions or immunologic alterations). In patients with severe involvement (pulmonary, renal, or neurologic), cessation of anti-TNF therapy is mandatory, together with initiation of oral corticosteroids and adding immunosuppressive agents according to the clinical evolution. Finally, with respect to the use of anti-TNF therapy in patients with preexisting autoimmune diseases, anti-TNF agents should be used with caution in patients with preexisting SLE (especially when renal, pulmonary, or neurologic involvement is demonstrated) and should not be used in patients with preexisting interstitial pulmonary disorders.
The authors thank David Buss for his editorial assistance.
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APPENDIX: THE BIOGEAS STUDY GROUP
The members of the Spanish Study Group of Biological Agents in Autoimmune Diseases (BIOGEAS) are as follows:
M. Ramos-Casals (Coordinator, Hospital Clinic, Barcelona), P. Brito-Zerón (Hospital Clinic, Barcelona), J. L. Callejas (Hospital San Cecilio, Granada), L. Caminal (Hospital Central Asturias), M. T. Camps (Hospital Carlos Haya, Málaga), A. Colodro (Complejo Hospitalario de Jaen), M. V. Egurbide (Hospital Cruces, Barakaldo), D. Galiana (Hospital de Cabueñes, Gijón), F. J. García Hernández (Hospital Virgen del Rocío, Sevilla), A. Gil (Hospital La Paz, Madrid), J. Jiménez-Alonso (Hospital Virgen de las Nieves, Granada), A. Martínez-Berriotxoa (Hospital Cruces, Barakaldo), F. Medrano (Hospital Universitario de Albacete), M. L. Micó (Hospital La Fe, Valencia), S. Muñoz (Hospital Clinic, Barcelona), C. Ocaña (Hospital Virgen del Rocío, Sevilla), J. Oristrell (Hospital Parc Taulí, Sabadell), N. Ortego (Hospital San Cecilio, Granada), L. Pallarés (Hospital Son Dureta, Mallorca), E. de Ramón (Hospital Carlos Haya, Málaga), G. Ruiz-Irastorza (Hospital Cruces, Barakaldo), G. Salvador (Hospital La Fe, Valencia), J. Sánchez-Roman (Hospital Virgen del Rocío, Sevilla), A. Selva-O'Callaghan (Hospital Vall d'Hebron, Barcelona), N. Soria (Hospital Clinic, Barcelona), and C. Tolosa (Hospital Parc Taulí, Sabadell).