NEW YORK — Treatment of Wegener's granulomatosis continues to challenge and evolve, as researchers investigate the complex molecular cross-talk underlying immune dysfunction, looking for new ways to target therapy, and clinicians seek new ways to balance necessarily aggressive cytotoxic treatment against the potential for serious adverse events.
Standard induction treatment for severe vasculitis associated with the presence of antineutrophil cytoplasmic antibodies (ANCA) remains cyclophosphamide plus glucocorticoids—a regimen that is lifesaving, Gary S. Hoffman, M.D., said at a rheumatology meeting sponsored by New York University.
But because of the high incidence of bladder cancer and other serious toxicities associated with long-term use of cyclophosphamide, once remission is achieved, maintenance therapy with methotrexate or azathioprine is now preferred, he said.
Relapse remains problematic, however, and a subset of patients do not respond to the most cytotoxic cyclophosphamide-based regimen.
For these patients, a potential new approach has emerged: B-cell depletion with rituximab, said Dr. Hoffman, chair of the department of rheumatic and immunologic diseases at the Cleveland Clinic Foundation.
A group of 11 patients who had active, ANCA-positive vasculitis and either did not respond to cyclophosphamide or who had contraindications to its use were given infusions of rituximab (Rituxan) plus glucocorticoids on a compassionate use basis. Ten of the patients had Wegener's granulomatosis, and one had a related ANCA-associated vasculitis, microscopic polyangiitis.
Not only did all 11 achieve remission, but they also were able to discontinue steroids, which has not been possible before, said Dr. Hoffman, who was not involved in the study.
All patients had significant decreases in ANCA, which are thought to mediate the glomerulonephritis and small vessel vasculitis, and 8 of the 11 became ANCA negative.
B-cell depletion typically persists for months following rituximab treatment; all patients remained in remission while B cells were undetectable.
Reappearance of B cells occurred in nine patients, 4–12 months after infusion. Two patients experienced disease relapse following discontinuation of glucocorticoids but recovered after resuming the rituximab/glucocorticoid regimen. Three others whose ANCA titers began to rise were retreated preemptively with rituximab alone and have remained in remission (Arthritis Rheum. 2005;52:262–8). The remaining four patients whose B cells repopulated did not revert to ANCA positivity.
Rituximab targets the CD20 receptor on the surface of B cells, and one rationale for using the drug in Wegener's granulomatosis is that it is able to deplete CD20-expressing precursors of ANCA-producing plasma cells (Arthritis Rheum. 2005;52:1–5).
A randomized, double-blind trial, Rituximab in ANCA-Associated Vasculitis (RAVE) is underway, with the goal of addressing the issue of whether targeted therapy, rather than broad-based immunosuppression, can provide enduring remission.
Many mediators other than B cells are involved in the inflammatory process of vasculitis, including dendritic cells, macrophages, and various different cytokines that interact with one another.
A previous trial evaluated the tumor necrosis factor (TNF)-α blocking agent etanercept (Enbrel), because the evidence suggested that this cytokine plays a role.
But a randomized, placebo-controlled trial that included 174 patients from eight centers found no benefit in the addition of etanercept to standard therapy. Furthermore, six patients who were taking etanercept plus cyclophosphamide developed solid tumors (N. Engl. J. Med. 2005;352:351–61).
“We didn't see this with people who were on methotrexate plus etanercept, and it's a major concern,” said Dr. Hoffman, who was coprincipal investigator for the trial.
“The new opportunities for selective targets certainly are seductive, and we hope they will work, but we cannot dismiss what we've learned from the history of this disease, which is that it carries a very high risk of morbidity and mortality, and that although our conventional therapy has risks, it is lifesaving,” he said.
Before glucocorticoids began being used for Wegener's granulomatosis, survival was only 50% at 5 months, and most patients died within 2 years of diagnosis. Even with glucocorticoids, survival increased only slightly, to 50% at 1 year.
The addition of cyclophosphamide to the regimen, first reported by the National Institutes of Health in the early 1970s, increased survival to 80% at 8 years.
“But I think we still have a long road ahead of us. I hope the future looks great, but I view it with guarded optimism,” Dr. Hoffman said.