Rituximab shows promise for autoimmune disorders

November 1, 2007

A small, phase 1 study found that rituximab can safely be added to the regimen of patients with pemphigus vulgaris that is refractory to other autoimmune therapies. However, the role of this drug independent of adjunctive therapy still requires further study.

National report - Results of a recent phase 1 study of rituximab for the treatment of pemphigus vulgaris (PV) demonstrated that it was safe and well-tolerated by all patients, but its direct effect independent of adjunctive therapy is unclear.

"Rituximab (Rituxan, Genentech) may be a promising treatment for PV, but further studies are warranted to determine the proper dosing regimen for this disease," says Joshua Zeichner, M.D., Mount Sinai Medical Center, New York.

The disease

Since many patients never achieve complete remission, there is an ongoing need for new medications to treat refractory PV, Dr. Zeichner tells Dermatology Times.

"Rituximab is a monoclonal antibody that targets the CD20 antigen on the surface of B-cells, but not stem cells or plasma cells. It is comprised of a murine variable region and human constant region, and binding of rituximab to CD20 leads to lysis of the target B-cell through complement-dependent cytotoxicity," he explains.

Rituximab is approved by the Food and Drug Administration (FDA) for treatment of relapsed or refractory low-grade or follicular, CD20+, B-cell non-Hodgkin's lymphoma (NHL) and rheumatoid arthritis. The mechanism of action of rituximab and subsequent depletion of B-cells suggest that it could be an effective treatment for autoimmune disorders. Rituximab also has been studied in a variety of non-malignant autoimmune disorders, including systemic lupus erythematosus, idiopathic thrombocytopenic purpura and hemolytic anemia.

"There are several case reports confirming the successful use of rituximab in treating pemphigus vulgaris. Therefore, based on its mechanism of action and previously reported cases, we propose that rituximab may serve as an adjuvant or alternative therapy for patients with PV," Dr. Zeichner says.

The study

Dr. Zeichner and colleagues set out to assess the safety of rituximab for the treatment of PV in a phase 1, single-center, open-label study. The safety endpoint was drawn from adverse events and disease progression during the study.

In addition, evaluating clinical efficacy in treating PV was a secondary objective of the trial. Efficacy was determined from the change in baseline of the total blister lesion severity index (BLSI), defined as the total surface area of all active lesions. Another secondary objective was the assessment of patient quality of life through the use of patient surveys.

Subjects were followed for 12 months. They visited the study center at weekly intervals for the first month, then monthly intervals until month six, and then every three months until month 12. All patients received doses of rituximab (1,000 mg) through an intravenous infusion on days one and 15. They were pre-medicated with 1,000 mg acetaminophen and 50 mg diphenhydramine.

Five patients enrolled in the study. All were older than 18 years and had active PV despite traditional therapies. Average patient age was 45 years, with a range of 28 to 55 years. Average duration of PV prior to enrollment was 6.15 years, with a range of 3 months to 25 years.

"In analyzing the results of this study, there were some confounding factors. For example, all patients were on concurrent immunosuppressive regimens including prednisone, dapsone, azathioprine, methotrexate, intravenous immunoglobulin (IVIG) and gold. Patients were not required to discontinue concurrent medications," Dr. Zeichner says.

Results

"Rituximab was found to be safe in all patients. One patient reported subjective fever lasting several hours during the evening after the first rituximab infusion," he says, noting that there were no other adverse events related to rituximab during the study.

"One patient was hospitalized for PV exacerbation after screening, but prior to receiving the first infusion of rituximab, so it was not related to the drug."

The most common side effects of rituximab are transient, infusion-related reactions. However, serious events including appearance of Stevens-Johnson syndrome, bacterial and viral infections and hematologic abnormalities have been reported. These were not experienced by patients in this study.