Prospective Study of TNFα Blockade with Infliximab in Anti-Neutrophil Cytoplasmic Antibody-Associated Systemic Vasculitis

Abstract

Abstract. Tumor necrosis factor ␣ (TNF␣) plays an important role in the pathogenesis of anti-neutrophil cytoplasmic antibody-associated systemic vasculitis. TNF␣ blockade is a potential therapy for these disorders. Methods: An open-label, multi-center, prospective clinical trial in two subgroups was performed. Study I examined acute disease, either first presentation or relapse (Birmingham Vasculitis Activity Score [BVAS] Ն 10; n ϭ 16); study II examined persistent disease (BVAS Ն 4; n ϭ 16). Patients received infliximab (5 mg/kg) at 0, 2, 6, and 10 wk. Concomitant therapy in study I included prednisolone and cyclophosphamide. Study II patients continued their existing treatment regimens, with prednisolone tapered according to clinical status. Results: Mean age was 52.4 yr, 53% of the patients were female, and follow-up was 16.8 mo. Twenty-eight patients (88%) achieved remission (14 per study group). BVAS decreased from 12.3 (confidence interval [CI] ϭ 10.5 to 14.0) at entry to 0.3 (CI ϭ 0.2 to 0.9) at wk 14 (P Ͻ 0.001). C-reactive protein (mg/L) decreased from 29.4 (CI ϭ 16.8 to 42.0) at entry to 7.0 (CI ϭ 3.3 to 10.9) by wk 14 (P ϭ 0.001). Mean prednisolone dose (mg/d) in study II decreased from 23.8 (CI ϭ 15.0 to 32.5) at entry to 8.8 (CI ϭ 5.9 to 11.7) at wk 14 (P ϭ 0.002). There were two deaths and seven serious infections. Relapse occurred in five patients (three in study II) after a mean of 27 wk. Conclusion: TNF␣ blockade with infliximab was effective at inducing remission in 88% of patients with antibody-associated systemic vasculitis and permitted reduction in steroid doses. Severe infections were seen in 21% of patients, and despite continued infliximab, 20% of initial responders experienced disease flares. Infliximab is a promising new therapy for vasculitis both as a component of initial therapy and in the management of refractory disease. These results need confirmation in larger randomized trials.The primary systemic necrotizing vasculitides are a group of life-threatening diseases that, untreated, have an 85% 2-yr mortality. The best defined and most studied subgroup of these diseases are the anti-neutrophil cytoplasmic antibody (ANCA)-related small vessel vasculitides (AASV), which are characterized by a pauci-immune microscopic vasculitis and focal, necrotizing glomerulonephritis (1).The introduction of steroids and cyclophosphamide results in disease remission in 80% of patients by 3 mo and in 95% by 6 mo (15). However, there is considerable morbidity related to current regimens, on which at least 25% of patients experience severe drug-related adverse effects. Furthermore, 50% of patients experience disease relapse, resulting in accumulating damage from disease scars and treatment (2,3,16). The addition of plasma exchange or pulsed methylprednisolone improves rates of renal recovery but increases the risk of side effects. There is a clear need to achieve more effective remission induction and to reduce therapy-related toxicity in AASV.Evidence suggests that tumor necrosis factor ␣ (TNF␣) plays...

Infliximab Improves Endothelial Dysfunction in Systemic Vasculitis

“…Ten of 14 patients with active disease agreed to enter an established clinical pilot study, 20 in which patients received 5 infusions of the human-mouse chimeric monoclonal antibody infliximab, directed against TNF-␣ (5 mg/kg) at 0, 2, 6, and 10 weeks. Infliximab was given either alone (nϭ6) to patients receiving stable prednisolone doses (unchanged for a month) and mycophenolate mofetil or in addition to standard induction therapy of prednisolone and cyclophosphamide (nϭ4).…”

The Role of Biological Therapies in the Management of Systemic Vasculitis

“…In different dosage (3mg/kg in 2 patients and 5 mg/kg in 4 patients), the addition of infliximab to standard therapy achieved remission in five out six patients, being discontinued in the remaining one due to a non-confirmed infection. In another study (Booth et al, 2004), an open-labelled multicenter non-controlled trial, infliximab was associated with a high rate of remission (88% patients in about 6 weeks) in 28 patients with Wegener granulomatosis and microscopic polyangiitis. Disease activity scores, inflammatory markers and prednisolone but high rate of relapses after discontinuation and intolerable severe adverse events (especially infections and increased risk of malignancies -found with etanercept) make anti-TNF agents not formally recommended for the management of ANCA-associated vasculitis.…”

Novel Strategy for the Treatment of Refractory Vasculitis Syndrome

“…In addition to conventional immunosuppressants, infliximab was administered at 3-5 mg/kg at intervals of 4-8 weeks, resulting in induction of remission in 43 (81%). Booth, et al, 9) reviewing 32 cases, reported that remission could be achieved very early, i.e., a mean of 6.4 weeks after the introduction of infliximab. In the 33 cases followed up for 1 year or longer, remission could be maintained for 6 months or longer in 28 (85%), and reactivation after remission was observed in 5 (12%).…”

“…However, 4 open pilot studies have been reported along with case reports suggestive of its usefulness. [6][7][8][9] Of the 54 cases included in the 4 reports, 35 had Wegener's granulomatosis, and 16 had microscopic polyangiitis. Thirty-seven of the 54 cases were refractory cases in which remission could not be induced by a standard immunosuppressive therapy.…”