Rituximab Shows Promise in Scleroderma PDF Print E-mail
Monday, 08 February 2010 16:25
Rituximab (Rituxan) improved lung function in patients with Scleroderma, a small proof-of-principle study found.

At one year, patients randomized to receive rituximab had a median 10.25% increase in forced vital capacity (FVC) compared with baseline, while those who received standard treatment had a deterioration of 5.04% (P=0.002), according to Dimitrios Daoussis, MD, and colleagues from the University of Patras in Greece. There also was a significant 19.46% increase in diffusing capacity of carbon monoxide (DLco) in the rituximab-treated patients, while the controls showed deterioration of 7.5% (P=0.023), the researchers reported in the February issue of Rheumatology.

Interstitial lung disease is a common manifestation of diffuse Scleroderma and represents the disease component that dictates prognosis because it can be progressive and typically responds poorly to treatment. Animal and human studies have suggested a possible pathogenic role for B cells in the disease. There have been a few reports of clinical and histologic improvements in Scleroderma and in graft-versus-host disease (which shares some features with Scleroderma) after treatment with the B-cell depleting monoclonal antibody rituximab.

These encouraging early findings led Daoussis and colleagues to undertake an open-label, controlled study that included 14 patients with diffuse disease. Median age was 55 and mean disease duration was seven years. All patients continued their standard medications, which included various agents such as prednisone, bosentan (Tracleer), mycophenolate mofetil (CellCept), and cyclophosphamide.

Those randomized to rituximab treatment also underwent four weekly pulses of the drug (375 mg/m2) at baseline and six months later.

By one year, the mean FVC in the rituximab group had risen from 68.13% of normal predicted value based on age, sex, and height, to 75.63% (P=0.0018), while FVC in the control group fell nonsignificantly from 86% of normal to 81.67%. In the rituximab group, DLco increased from a mean of 52.25% of normal at baseline to 62% (P=0.017) at one year, while the controls decreased nonsignificantly from 65.33% to 60.17%.

None of the patients treated with rituximab experienced worsening of FVC or DLco, whereas lung function deteriorated in five controls.

"We should note, however, that patients in the control group tended to have more early disease and better lung function parameters (although not statistically different from the [rituximab] group) making them more likely to deteriorate over the time of the study," the investigators commented.

Skin manifestations of the disease also showed improvements in the rituximab group. Skin thickening, as measured by the Modified Rodnan Skin Score, improved by 39.25% in the rituximab group and by 20.80% in the control group, a difference that was not statistically significant. Skin fibrosis also improved by a median of 38.33%, while it worsened by 5.23% in controls.

Histologic improvement was seen in four of the rituximab-treated patients, corresponding with clinical benefits. One patient in the active treatment group had a significant reduction of fibrosis in both the papillary and reticular dermis, accompanied by an almost complete resolution of skin lesions. Improvement in skin fibrosis was most common in patients who had evidence of B-cell depletion in the skin.

Overall function, as evaluated by the Health Assessment Questionnaire, improved from a median baseline score of 0.687 to 0.312 at one year (P=0.03), while no change was seen in controls.

The pathogenesis of Scleroderma is poorly understood, according to the authors, but this study adds support to a possible role for B cells. In addition, rituximab indirectly targets T cells, which also are thought to be implicated.

The authors noted potential limitations, including the study's small size and the fact that most patients had longstanding disease, had been treated with multiple immunosuppressive agents in the past, and were receiving concurrent therapies during the study.

"This is a proof-of-principle study that was performed in order to obtain preliminary data regarding the effect of [rituximab] on a limited number of patients," the authors wrote. "Our data could serve as a good starting point for the design of larger scale, multicenter studies with longer evaluation periods and especially in earlier stages of the disease," they concluded.

In an accompanying editorial, Robert W. Simms, MD, and Robert Lafyatis, MD, of Boston University, echoed concerns about the small number of patients and the lack of blinding in the study. "One cannot...on the basis of this study, recommend rituximab in the routine clinical care of patients with Scleroderma," the editorialists wrote.

The findings will need to be replicated in a multicenter randomized trial, but "do provide some hope that B-cell depletion might enhance the currently restricted therapeutic armamentarium of this disease."

Source: Medpage Today
 
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