Tumor Necrosis Factor-a Blockade and the Risk of Vasculitis
LOÏC GUILLEVIN, MD;
LUC MOUTHON, MD,
Department of Internal Medicine,
AP–HP and Université Paris 5,
Address reprint requests to Dr. L. Guillevin, Department of Internal Medicine, Hôpital Cochin, 27 rue du Faubourg Saint-Jacques, 75679 Paris Cedex 14, France. E-mail: firstname.lastname@example.org
Tumor necrosis factor-a (TNF-a) blockade is the reference treatment for patients with moderate to severe rheumatoid arthritis (RA) who respond poorly to conventional disease modifying antirheumatic drugs. The impressive antiinflammatory effects of TNF blockers etanercept, infliximab, and adalimumab have led to their use in numerous other inflammatory diseases. Notably, some TNF-a antagonists have been approved to treat Crohn's disease, ankylosing spondylitis, juvenile chronic arthritis, adult Still's disease, and psoriasis.
In recent years, infliximab has also been used to treat systemic vasculitides, particularly Wegener's granulomatosis (WG) refractory to corticosteroids and immunosuppressants1,2. Complete or partial remission was obtained in all 13 patients with WG included in the 2 published series, while the corticosteroid dose was maintained or lowered1,2. The infliximab dose infused to induce remission was not standardized, and 3 mg/kg2 to 5 mg/kg were administered per session1. We empirically recommended the latter, but remission may be obtained with lower doses. In our experience, the daily steroid dose could be dramatically lowered, from 20 to 8 mg, at 6 months. Every patient treated obtained a partial or complete remission, and infliximab discontinuation was sometimes possible.
Arbach, et al3 also obtained partial to complete remissions in 3 patients with Churg–Strauss syndrome who had had severe relapses refractory to cyclophosphamide and corticosteroids. Anti-TNF-a agents were also prescribed to patients with giant cell arteritis, including patients with Takayasu's arteritis whose disease could not be controlled with corticosteroids or other immunosuppressants. Granulomatous inflammation is a typical feature of Takayasu's arteritis, and TNF-a contributes to the formation of granulomas. Among 15 patients with active, relapsing Takayasu's arteritis who received anti-TNF-a agents4, 10 achieved complete remission that was sustained for 1–3.3 years without corticosteroids, 4 achieved partial remission with > 50% reduction in their corticosteroid requirement, and one failed therapy. For 9 of the 14 responders, the anti-TNF-a dose had to be increased to sustain remission; 2 of them relapsed during periods when therapy (etanercept) was interrupted, but remissions were again obtained upon its reinstitution4.
TNF-a blockers have also been used successfully in several patients with RA-associated vasculitis1, those with refractory vasculitis secondary to mixed cryoglobulinemia associated or not with hepatitis C virus infection1,5, and in a child with refractory Kawasaki disease6. Finally, TNF-a blockade has also been described in case reports and in small series of patients with Behçet's disease, particularly in the presence of severe refractory uveitis, central nervous system involvement, gastrointestinal involvement, or severe orogenital ulcers7.
Although anti-TNF-a agents are usually well tolerated, it is now well documented that they can induce side effects. Infectious complications have been noted, mainly Mycobacterium tuberculosis and other granulomatous infections8, and thorough medical history-taking in terms of tuberculosis, including tuberculin testing and radiographic examination, is an essential component of anti-TNF-a therapy.
The development of autoantibodies under anti-TNF-a agents has been well described, with 5%–8% IgM anti-dsDNA in patients receiving infliximab in combination with methotrexate, and 5% anti-dsDNA in patients treated with etanercept9. New autoantibody synthesis was associated with both a higher number of infusions and a higher total dose of infliximab infused. More recently, new antinuclear, anti-DNA, anti-Sm, and anti-RNP antibodies were detected in the absence of signs of connective tissue diseases in about 25%–50% of patients with RA treated with infliximab, depending on the antibody specificity10. Rare patients with RA developing etanercept- or infliximab-induced systemic lupus erythematosus (SLE) have been described11,12. Lastly, demyelination has also been reported as an adverse effect of TNF-a antagonism13.
In this issue of The Journal, Mohan and colleagues describe 35 patients who developed leukocytoclastic vasculitis [biopsy-proven in 17 (48.5%)] during treatment with TNF-a-blocking agents14. In the first such case reported, a patient with RA treated with etanercept15, drug discontinuation led to complete resolution of the vasculitis. Recently, Jarrett, et al16 described the same reversal of vasculitis and/or vasculitic rash that had developed in 8 additional RA patients taking anti-TNF-a blockers; 7 of them received infliximab and one etanercept.
Before discussing the potential mechanisms underlying the role of TNF-a blockade in inducing leukocytoclastic vasculitis, it must be emphasized that, in the absence of any relationship with a therapeutic agent, it has long been accepted that RA is associated with or may evolve into vasculitis16. Notably, in their earlier study17, Mohan, et al reported the occurrence of leukocytoclastic vasculitis in patients, the majority with RA, who had been treated with TNF-a blockers, and observed that 22/35 of them experienced total or marked regression of skin lesions upon treatment withdrawal. Indeed, the number of patients with RA purported to have developed leukocytoclastic vasculitis while taking anti-TNF-a agents is small compared to the large number of patients treated with them. It is, nonetheless, possible that TNF-a blockers induce leukocytoclastic vasculitis. Pertinently, in the current study, 9 patients were rechallenged, 6 of them experiencing leukocytoclastic vasculitis recurrences, while the remaining 3 fared well.
It is worth mentioning that infliximab was well tolerated in our 10 patients with systemic vasculitis during short term followup1; the only adverse effect observed was a cutaneous eruption that developed in 2 patients: one corresponded to an erythematous macular rash (no skin biopsy was obtained), and the other was considered an allergic reaction to the partially humanized antibody.
The mechanisms that might participate in the induction of leukocytoclastic vasculitis in patients receiving TNF-a blockers are not completely understood. Humoral mechanisms involving autoantibodies and/or immune complexes deposited in vessel walls might play a role or cause a shift in T cell responses. It has been suggested that anti-TNF-a–TNF-a immune complexes could be deposited in small capillaries, where they activate complement, and thereby trigger a type III hypersensitivity reaction. A further analysis of the infliximab effect on B cell activation in patients with RA demonstrated that this anti-TNF-a agent downregulates CD23 expression on T cell-activated B cells18. This downregulation is associated with the presence of circulating immune complexes containing TNF-a. It has been hypothesized that Fcg-RIIb1 endows IgG-containing immune complexes, e.g., TNF-a–anti-TNF-a, with the capacity to regulate B cells and inflammatory reactions17.
Since etanercept- or infliximab-induced SLE has been reported, albeit rarely, and because leukocytoclastic vasculitis is encountered relatively frequently in SLE, possible SLE induction by these drugs should be kept in mind. Another possible mechanism is a switch from the predominant T helper type 1 (Th1) cytokine response to a Th2 response. TNF-a blockers are prescribed for diseases characterized as Th1-lymphocyte-driven, with the major T cell cytokines involved being TNF-a, interleukin 2 (IL-2), IL-12, and interferon-g. Th2 responses are associated with enhanced activities of IL-4, IL-5, IL-6, IL-10, and IL-13, responsible for upregulation of antibody production. Thus, TNF-a antagonists, by inhibiting Th1 lymphocyte functions, might break their control of Th2 clones, thereby favoring the activation of antibody-mediated immune mechanisms.
The prescription of anti-TNF-a antibodies, as for any drug, should take into account the risk of side effects. Vasculitis is one of them. But these drugs are so beneficial that the risk of developing easily reversible vasculitis should not prevent the physician, and in turn deprive the patient, from using them. However, for special indications, like vasculitis, anti-TNF-a antibody use should be restricted to those patients with vasculitis refractory to steroids and immunosuppressants who have relapsed.
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7. Ohno S, Nakamura S, Hori S, et al. Efficacy, safety, and pharmacokinetics of multiple administration of infliximab in Behcet's disease with refractory uveoretinitis. J Rheumatol 2004;31:1362-8. [MEDLINE]
9. Weinblatt M, Kremer J, Bankhurst A, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 1999;340:253-9. [MEDLINE]
12. Charles P, Smeenk R, De Jong J, Feldmann M, Maini R. Assessment of antibodies to double-stranded DNA induced in rheumatoid arthritis patients following treatment with infliximab, a monoclonal antibody to tumor necrosis factor alpha. Findings in open-label and randomized placebo-controlled trials. Arthritis Rheum 2000;43:2383-90. [MEDLINE]
14. Mohan N, Edwards ET, Cupps TR, et al. Leukocytoclastic vasculitis associated with tumor necrosis factor-alpha blocking agents. J Rheumatol 2004;31:1955-8.
18. De Miguel S, Jover J, Vadillo C, Judez E, Loza E, Fernandez-Gutierrez B. B cell activation in rheumatoid arthritis patients under infliximab treatment. Clin Exp Rheumatol 2003;21:726-32. [MEDLINE]