Severe Vasculitis Yields to Rituximab

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By Nancy Walsh, Staff Writer, MedPage TodayPublished: March 01, 2012
Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Action Points

• One small study documented that rituximab was very effective and well-tolerated therapy for HCV-associated cryoglobulinemic vasculitis in patients in whom antiviral therapy had failed to induce remission.
• In a second, larger study, rituximab monotherapy was again very effective and safe for a longer duration in patients with severe manifestations of mixed cryoglobulinemia or cryoglobulinemic vasculitis.

The B-cell depleting agent rituximab (Rituxan) effectively alleviates serious manifestations of cryoglobulinemic vasculitis, two groups of researchers found.
In one trial that included 24 patients, 83% of patients randomized to rituximab were in remission at six months compared with 8% of those on conventional therapy (P<0.001), according to Michael C. Sneller, MD, of the National Institute of Allergy and Infectious Diseases in Bethesda, Md., and colleagues.
In a second study that enrolled 59 patients, 64.3% of those receiving rituximab remained on therapy at one year -- an endpoint implying that the treatment was both safe and effective -- compared with 3.5% of those on standard treatment. This represented a between-group difference of 60.8% (95% CI 43.5 to 63.9, P<0.0001), according to Salvatore De Vita, MD, of University Santa Maria della Misericordia, in Udine, Italy, and colleagues.
In both trials, the high rate of response to rituximab led to early study termination. The studies appeared in the March issue of Arthritis & Rheumatism.
New Agents Needed
The lymphoproliferative disorder cryoglobulinic vasculitis most often is a complication of chronic hepatitis C virus (HCV) infection, and is characterized by skin ulceration, glomerulonephritis, and peripheral neuropathy.
Patients who respond to antiviral treatment with interferon-alpha and ribavirin typically also have resolution of the vasculitis, but more than half of patients do not experience a sustained virologic response.
Furthermore, conventional immunosuppressive therapies, such as glucocorticoids, can worsen the underlying HCV infection, so newer therapeutic options clearly are needed.
Rituximab has been considered a possible candidate because an important initiating event in this type of vasculitis is clonal expansion of B cells, which then go on to secrete rheumatoid factor (RF) that contributes to the formation of pathogenic immune complexes.
To examine rituximab's effects in HCV-related cryoglobulinemic vasculitis, Sneller and colleagues tested a regimen of 375 mg/m² once weekly for four weeks.
Patients randomized to rituximab also could continue stable doses of immunosuppressants. Controls could receive "best available therapy," including immunosuppressants or plasmapharesis.
At baseline, disease activity was similar in the rituximab and control groups, with median scores of 8 and 8.5, respectively. By the fourth month, however, scores had fallen significantly in the rituximab group (P<0.02).
Three patients who were in remission at six months subsequently relapsed, but responded to a second course of rituximab. Six patients in the rituximab group were also on prednisone, but in five the glucocorticoid was tapered and then withdrawn.
None of the controls were able to discontinue prednisone.
One patient receiving rituximab had a severe infusion reaction that promptly resolved. There were no serious infections in either group.
Limitations of this study included its lack of blinding and exclusion of patients with potentially lethal vasculitis involvement, such as of the heart or central nervous system.
The investigators also cautioned that antiviral treatment remains the primary approach to the management of HCV-related vasculitis, noting that rituximab could be used for patients who do not respond to first-line treatment or in whom antivirals are contraindicated.
Early Response Noted
In the second study, patients with vasculitis -- either with or without evidence of HCV infection -- were randomized to receive two infusions of rituximab, each 1 gram, plus prednisone, while controls were treated with the glucocorticoid, azathioprine or cyclophosphamide, or plasmapheresis.
Aside from the primary endpoint of remaining on treatment at one year, remaining on treatment at other time points also favored rituximab:

• Month 24, 60.7% of the rituximab patients versus 3.5% of controls (P<0.0001)
• Month 6, 71.4% versus 3.5% (P<0.0001)
• Month 3, 92.9% versus 13.8% (P<0.0001)

Finding a response at that earliest time point was important, according to the investigators, because this could be a crucial time for deciding whether to continue treatment or change to a different approach.
Disease scores in the rituximab group fell from a baseline of 11.9 to 7.1 at two months, 6.9 at six months, 5.4 at 12 months, and 4.4 at 24 months (P<0.0001).
Patients in the control group who did not respond could switch to rituximab. Among the 82.1% who did so, 60.9% then responded by six months. Duration of response was 18 months in the original rituximab group and 12 months in those who switched.
A total of 15 patients had a second course of rituximab, with a good response being seen in 11. One patient in the control group died, as did two in the rituximab group and three who switched treatments.
There were four serious infections, one each in the rituximab and control groups, and two in the group who switched. There also were six cardiovascular events -- three in the rituximab group, two in the group who switched, and one in the control group.
Rituximab was not associated with changes in liver enzymes or IgG levels.
Full B-cell depletion was seen by week four in all patients receiving rituximab, accompanied by a rise in serum C4 levels by six months, but these laboratory values did not correlate with relapse. Nor was restoration of the B-cell population associated with relapse, which suggested that the treatment resulted in a "possible immune reset," according to the Italian investigators.
"Besides B cell depletion, a decrease in RF levels and an increase in C4 levels was noted, which is consistent with the biologic effects of [rituximab] on this RF-positive immune complex-mediated condition," they explained.
Like the U.S. trial, this study was limited by not being blinded.

The U.S. study was supported by the National Institutes of Health. One of the U.S. investigators has received support from Genentech.
Three of the Italian investigators reported receiving funding from sources including Bristol-Myers Squibb, Pfizer, Roche, and Glaxo.

Primary source: Arthritis & Rheumatism
Source reference:
Sneller M, et al "A randomized controlled trial of rituximab following failure of antiviral therapy for hepatitis C virus-associated cryoglobulinemic vasculitis" Arthritis Rheum 2012; 64: 835-842.
Additional source: Arthritis & Rheumatism
Source reference:
De Vita S, et al "A randomized controlled trial of rituximab for the treatment of severe cryoglobulinemic vasculitis" Arthritis Rheum 2012; 64: 843-853.