LONDON, UK—Serious adverse events (AEs) forced early termination of a small study¹ of infliximab (Remicade®) for systemic vasculitis and will likely close the book on the use of TNF-inhibitors in treating systemic vasculitides. In the new infliximab study, one of nine patients treated died and adverse effects with other TNF-blockers included increased risk of solid tumors in the Wegener's Granulomatosis Etanercept Trial (WGET).²

"[T]he adverse effects and lack of benefit experienced in our series raises concerns about the role of anti-TNFα in patients with systemic vasculitides," writes lead author Shirish R. Sangle, MD, with the lupus research unit at The Rayne Institute of St. Thomas Hospital London, in the UK. "Other biological treatments such as B-cell depletion and/or intravenous immunoglobulin in antineutrophil cystoplasmic antibodies associated vasculitides may be more fruitful."

AEs force early termination of study

Dr. Sangle et al studied nine patients with systemic vasculitides who failed to respond to one or more immunosuppressives including cyclophosphamide, methotrexate, azathioprine, or mycophenolate mofetil. All patients required more than 15 mg/day of prednisolone. Three patients had Wegener's granulomatosis (WG), two had Behçet's disease, one had Churg Strauss vasculitis, one had adult-onset Still's disease, one had Henoch Schonlein purpora, and one had relapsing polychondritis.

All patients were to receive five infusions of infliximab at a dose of 5 mg/kg over a 6-month period. Only five patients completed the full treatment course; four patients discontinued therapy because of AEs, including hearing and vision deterioration, lupus-like reaction, flares, leucopenia, and anemia. The adult-onset Still's disease patient died after 6 months from cardiac failure. Her inflammatory markers were abnormal throughout the study period. The researchers could not definitively tie infliximab therapy to her death, but an autopsy found no evidence of heart disease; nonetheless, researchers terminated the study and notified the authorities. Four patients were admitted to the hospital for a severe flare and lupus-like reaction and required rescue with 500 mg of methyl prednisolone pulses and intravenous immunoglobulin. Four patients in the study developed new autoantibodies which became negative 3 months after discontinuing therapy.

No improvements seen

There was no improvement in the median Birmingham Vasculitis Activity Score, Vascular Damage Index, and short form (SF) 36 scores.

Some studies have shown improved endothelial function after TNF-blockade, but "our findings do not support previous observations that infliximab helps to achieve remission in patients with systemic vasculitides that is difficult to treat," the authors conclude.

TNF-inhibitors as a class show risk but no benefit for vasculitis

WGET found that etanercept (Enbrel®) was no better than placebo at inducing or maintaining remission in WG and may increase risk of solid malignancy.

In the WGET cohort, 56% of patients taking etanercept and 57% of controls sustained at least one severe, life-threatening, or fatal AE. Six patients receiving etanercept developed solid tumors compared with none in the placebo group. During the 6-month follow-up, three more malignancies were found.

"The WGET demonstrated that etanercept is not effective for the treatment of Wegener's granulomatosis," Philip Seo, MD, MHS, assistant professor of medicine at The Johns Hopkins University School of Medicine, and Co-Director of The Johns Hopkins Vasculitis Center in Baltimore, Maryland, told CIAOMed. "What has been less clear, however, is whether these findings could be extended to other TNF inhibitors."

In some parts of the world, infliximab is considered to be standard therapy for refractory WG, Dr. Seo said. "Because we know that not all autoimmune diseases (eg, Crohn's disease) respond to TNF-inhibitors equally, it is reasonable to ask if infliximab might succeed where etanercept had failed [in WGET]."

"Although small, this study supports the hypothesis that TNF-inhibitors as a class are not effective for the treatment of Wegener's granulomatosis. We know from other studies that the use of infliximab for the treatment of Wegener's granulomatosis is associated with a high rate of infectious complications."

In addition, analysis of the WGET data demonstrates a link between the use of etanercept and the development of malignancy in patients with WG, he said. "Taken in sum, it seems increasingly less likely that TNF-inhibitors will play an important role in the treatment of this disease."

Is B-cell depletion the solution?

There are multiple cases demonstrating the efficacy of rituximab (Rituxan®) for the treatment of WG, Dr. Seo said. Johns Hopkins is participating in Rituximab in ANCA-associated Vasculitis (RAVE), a multicenter, randomized, placebo-controlled trial comparing the efficacy of rituximab to cyclophosphamide for the treatment of severe WG and microscopic polyangiitis.

"Although it is difficult to recommend rituximab as a first-line therapy at this time, we are all hopeful that rituximab may succeed where the TNF inhibitors seem to have failed," he said.

References

1. Sangle SR, Hughes GRV, D'Cruz DP. Infliximab in patients with systemic vasculitis that is difficult to treat: poor outcome and significant adverse effects. Ann Rheum Dis. 2007;66:564-565.
2. The WGET Research Group. Etanercept plus standard therapy for Wegener's granulomatosis. N Engl J Med. 2005;352:351-361.