VIENNA, Austria - Emerging research in vasculitis is paving the way toward less toxic treatments, according to experts speaking Wednesday at the Annual European Congress of Rheumatology of the European League Against Rheumatism (EULAR) in Vienna, Austria.1
Today, doctors are taking a second look at tumor necrosis factor-alpha (TNF-α) inhibitors as induction therapy in vasculitis and are also excited about the possibilities of deoxyspergualin and rituximab.
TNF-α blockade in vasculitis fell out of favor to a degree when a study showed that etanercept was no better than placebo at inducing or maintaining remission in Wegener's granulomatosis (WG) and may increase risk of solid malignancy. This study, the WG Etanercept Trial (WGET), was presented at the American College of Rheumatology 2004 meeting in San Antonio, Texas.2
In the trial, 90% or more of patients in both groups achieved remission, 69.7% in the etanercept group achieved sustained remission, as did 75.3% of patients in the control group. While the difference was not statistically significant, the control group did at least as well, if not better than the etanercept group, according to this study.
Add-on therapies may improve efficacy, reduce toxicity
In the Infliximab in ANCA-associated Vasculitis (ACTIVE) trial, in which infliximab was given as an add-on to patients, most went into remission within 2 to 3 weeks, and were able to reduce their steroid dose by 50%. However, beyond the 3-month induction period, there was a 30% increase in severe infection rates, points out David Jayne, MD, head of the vasculitis and SLE service at the University of Cambridge in the UK.
"Long-term use of TNF-α inhibitors on top of immunosuppressants is very toxic," he says, adding that "vasculitis escapes from TNF-α blockade if it is used for a long time." The infliximab data suggest that the findings from the WGET trial "are not surprising, as these agents do not have a sustained effect."
That said, "There is a revisiting of the TNF-α inhibitors and I think infliximab may be superior to etanercept," Dr. Jayne says. "I don't think you should forget about TNF-α inhibition in vasculitis; it warrants further study as induction therapy but not as remission maintenance."
"The books are not closed on etanercept and WG," says Wolfgang L. Gross, MD, PhD, professor of medicine, Medical University of Lübeck and Rheumaklinik Bad Bramstedt GmbH in Germany.
Rituximab plays big role in future
"Rituximab will be the big thing in the next 10 years," Dr. Jayne tells CIAOMed. "It is the drug of the future for vasculitis."
"In a multicenter study of rituximab in refractory WG, there was a good response," he continues, adding that, in data from 25 patients, "provided we induce B-cell depletion, it does work." But, he says, "these are the early days and we need more studies."
Preliminary studies suggest that the immunosuppressive deoxyspergualin can induce high rates of remission, decreases in the Birmingham Vasculitis Activity Scale (BVAS) scores for WG, and decreases in prednisone doses, according to Dr. Jayne.
Prior to the use of steroids, vasculitis was fatal in 80% of patients within one year. And while the use of cyclophosphamide was considered "breakthrough" in the late 1970s, this agent shows signs of early and late toxicity. Oral cyclophosphamide for 12 months was the standard of care, but now doctors can switch patients over to less toxic therapies such as azathioprine.
"A current debate is whether to give cyclophosphamide intravenously, as in lupus, or as a daily oral," Dr. Jayne says. "In terms of primary endpoints, time to remission and time to flare, there is no difference between IV and daily oral cyclophosphamide, but I am happier using IV because you expose patients to much less cyclophosphamide."
References:
- Jayne, D. Induction and maintenance of remission in systemic vasculitis: available options and optimal selection of patients. The Annual European Congress of Rheumatology of EULAR. Vienna, Austria, June 8-11, 2005.
- Stone JH and the WGET Research Group. The Wegener's Granulomatosis Etanercept Trial (WGET): randomized, double-masked, placebo-controlled trial of etanercept for the induction and maintenance of remission. Presented at: the Annual Meeting of the American College of Rheumatology; October 16-21, 2004; San Antonio, Texas.