Anti-TNF-alpha-induced anti-phospholipid syndrome manifested as necrotizing vasculitis

Tumour necrosis factor-alpha (TNFa) plays an important role in the pathogenesis of rheumatoid arthritis (RA). In recent years new biological drugs have been developed, including anti-TNFa antibodies. The use of TNFa inhibitors has been a great advance in the treatment of patients with RA (1), especially in patients with high and persistent disease activity and unresponsiveness to other disease-modifying anti-rheumatic drugs (DMARDs). However, TNFa inhibitors may stimulate the production of different autoantibodies, such as anti-nuclear antibodies (ANA), anti-doublestranded DNA antibodies (anti-dsDNA), anti-cardiolipin antibodies (aCL) and human anti-chimeric antibodies (HACA). In this letter we describe the case of a patient with RA in whom anti-TNF therapy induced aCL with severe clinical consequences. In 1987 a 52-year-old woman presented with deep-vein thrombosis (DVT) complicated with pulmonary embolism and anticoagulant therapy was administered for 6 months. The patient was aCL negative, the activated partial thromboplastin time (aPTT) was within the normal range, and lupus anticoagulant (LA) was also negative. She was not tested exclusively for isolated anti-beta 2-glycoprotein (anti-beta2GPI), but as the aCL enzyme-linked immunosorbent assay (ELISA) was beta2GPI dependent, indirectly we knew that the patient was negative to anti-beta2GPI. Other known and frequent reasons for thrombophilia, such as high lipoprotein (a) [Lp(a)] and homocysteine concentration, FV Leiden mutation and FII polymorphism, were carefully excluded in the case of this patient. RA was diagnosed in 2002, methotrexate (MTX; 7.5– 20 mg/week) was initiated, and later due to permanent disease activity leflunomide (20 mg/day) was administered. From 2005 the patient received continuous lowdose steroid therapy (5–15 mg/day prednisolone equivalent dose). Because of the permanent disease activity, anti-TNF therapy was started in November 2006. At baseline, the Disease Activity Score using 28 joint counts (DAS28) was 6.01 and ANA, aCL, and antiDNA antibodies were negative. After the third infusion the DAS28 scorewas reduced to 3.1. However, high-level immunoglobulin M (IgM)-type aCL was detected in March 2007. A month later, soft-tissue streptococcus infection developed on the heel. The patient received local therapy and antibiotics according to the antibiotic sensitivity. First anti-TNF therapy and a few weeks later MTX and leflunomide were discontinued. Immune serology indicated a high persistently IgM aCL titre, monitored every 12 weeks, and in November necrotizing vasculitis was manifested in the toes and fingers of the patient. ANCA, cryoglobulin, and also virus serology were negative. Despite a preventive dose of low molecular weight heparin (LMWH) treatment, DVT developed in her lower right extremity in January 2008. She was treated with a therapeutic dose of LMWH and coumarin. From December 2007, pulse methylprednisolone was given to the patient, but due to response failure, plasmapheresis synchronized with intravenous Ig (0.4 g/bwkg) and cyclophosphamidewas subsequently administered (Table 1, Figure 1). As a consequence of this therapy, the vasculitis and necrosis went into remission. In some patients TNFa blocker therapy leads to autoantibody formation, yet these ANA and anti-phospholipid autoantibodies can present without autoimmune clinical manifestations (2–5). The prominent ANA and anti-dsDNA autoantibody response is not a pure class effect of TNFa blockers, it is largely restricted to short-term IgM responses, and is not associated with other serological or clinical signs of lupus. Similar findings with aCL suggest that the modulation of humoral immunity may be a more general feature of infliximab treatment and this phenomenon is not disease specific; besides RA patients, individuals with spondyloarthritis (SpA) can experience similar side-effects (6). Comparison of infliximab plus MTX and MTX plus placebo treatment has shown that the IgG and IgM aCL positivity at baseline of infliximab therapy was similar in all treatment groups. A slightly higher proportion of patients were identified who received infliximab plus MTX and although they were negative for IgM aCL at baseline, subsequently became positive for IgM aCL (7).