PATRAS, Greece—The search for scleroderma treatments less toxic and immunosuppressive than cyclophosphamide has moved to drugs targeting B cells.

Dimitrios Daoussis, MD, and colleagues at the University of Patras, Greece, report pilot data from a 1-year study which showed significant improvement in forced vital capacity (FVC) and in the diffusing capacity of carbon monoxide (DL_CO) in patients receiving rituximab plus standard treatment, compared with decreases in both functions in similar patients treated with standard therapy alone.¹

”This study establishes proof-of-principal that rituximab can improve lung function in SSc and strongly suggests that rituximab may have disease-altering effects on skin thickening. One should bear in mind though that this is a pilot study that does not have the statistical power to prove efficacy,” Dr. Daoussis told Musculoskeletal Report.

Dr. Daoussis said that the next step should be a randomized, controlled, large-scale multicenter study with enough patients to prove efficacy.

Lung function improved with rituximab, declined with standard treatment

The study included 14 patients with scleroderma (SSc, systemic sclerosis), 8 of whom were randomized to 2 cycles of rituximab at baseline and at 24 weeks in addition to standard treatment, and 6 of whom were randomized to standard treatment alone. Each rituximab cycles consisted of 4 weekly infusions (375 mg/m2). Four patients in the rituximab group and 2 in the control group were on mycophenolate mofetil (MMF) during the study and had been on MMF for at least 4 year prior to study enrollment. Three patients in the rituximab group and 1 in the control group had received cyclophosphamide (CYC) in the past but were off that therapy for at least 3 years prior to study enrollment. Patients in the control group continued their previously administered treatment unchanged throughout the study.

At the 1-year evaluation, FVC had increased significantly in the rituximab group compared with baseline, but there was no change in FVC in the control group. Median upper and lower quartile FVC improvement was 10.25% in the rituximab group vs. a deterioration of 5.04% in the control group.

“Direct comparison of FVC changes recorded at 1 year revealed that the RTX-treated group improved significantly (P=0.002) compared with the standard treatment (control) group,” the authors reported.

DL_CO values similarly improved in the rituximab group while deteriorating in the control group.

Lung function improvements in the rituximab-treated patients were apparent by 24 weeks.

Rituximab may also reverse skin damage in SSc

The researchers used skin biopsies to evaluate rituximab effects on SSc skin involvement. Skin thickening, collagen deposition, and skin infiltrating B cells all improved with rituximab treatment, as did HAQ scores.

The authors report that one rituximab-treatment patient “displayed a significant reduction of skin fibrosis not only in the papillary but in the reticular dermis as well, and had clinically an almost complete resolution of sclerodermatous skin lesions.”

High-resolution CT (HRCT) of the chest suggested “that rituximab treatment may stabilize pulmonary lesions apparent on imaging in diffuse SSc,” the authors write. They note that this contrasts with lack of improvement in imaging systems and suggest that this may reflect methodological differences.

Next step: determine rituximab mechanism of action in SSc

According to Dr. Daoussis, establishing the mechanism of action of rituximab in SSc is important, particularly in view of clinical reports suggesting that RTX has beneficial effects in SSc.

Long-term efficacy of rituximab in SSc is another unknown. “Our study is still active—we are still recruiting and treating patients,” Dr. Daoussis said. “Results so far are promising with a gradual improvement of lung function over time under continuous rituximab treatment given every 6 months. We have just published a case report [Seminars in Arthritis and Rheumatism, in press] regarding a patient who received 4 consecutive courses of RTX. In the 2-year follow up the patient showed an impressive improvement of lung function and evidence of skin remodeling,” he said.

If these findings are confirmed, they would indicate that B cells play a more central role in SSc pathogenesis than previously appreciated. “There is also the possibility that rituximab has an indirect effect on other immune cells such as T cells,” Dr. Daoussis said.

Translating research into practice: time to move ahead with new SSc studies

Robert Lafyatis, MD, who has also studied B cell depletion with rituximab in SSc, told Musculoskeletal Report that this data is “hopeful” but that the study is too small to be considered convincing. However, Dr. Lafyatis said that this study, added to his own earlier studies, would justify moving to larger clinical trials.

“The results are consistent with our earlier results showing a trend toward improvement in the FVC in rituximab treated patients, and our other study showing dense B cell infiltrates in the lungs of many patients with systemic sclerosis,” said Dr. Lafyatis, who is Professor of Medicine at Boston University School of Medicine.

In view of the urgent need for better SSc treatments, Dr. Lafyatis urged trials of rituximab, mycophenolate, stem cell transplant, c-abl inhibitors (imatinib and dasatinib), anti-IL13, and anti-IFNAR go ahead in parallel as funding is available. “It is key that the community not focus on just one therapeutic alternative at a time,” he said.

Reference

1. Daoussis D, Liossis S-NC, Tsamandas AC, et al. Experience with rituximab in scleroderma: results from a 1-year, proof-of-principle study. Rheumatology. 2009; [epub ahead of print] September 15, 2009. doi:10.1093/rheumatology/kep093.