Durham, N.C. — Dermatologists at Duke University using rituximab (Rituxan, Genentech) for the management of patients with treatment-resistant bullous pemphigoid (BP) have found that this anti-CD20 monoclonal antibody allows corticosteroid-dependent patients to successfully taper their immunosuppressive therapy.
They are hopeful their research may lead to a new understanding of disease pathogenesis and better approaches to its treatment.
Russell P. Hall III, M.D., and colleagues have reported on a series of six patients with BP who could not be tapered off a relatively high dose of prednisone (mean ~30 mg/day). Two infusions of rituximab 1 gm were administered at an interval of two weeks. After about 100 days, all patients were able to decrease their prednisone dose to about 10 mg, and during continued follow-up, some patients were able to discontinue prednisone completely, while others could be maintained at a dose as low as 5 mg/day.
Serology studies showed IgG anti-BP180 titers decreased gradually in all patients, falling significantly below the baseline level after nine months, but never disappearing. Thereafter, IgG anti-BP180 antibody levels slowly increased, although the rise occurred without any worsening of disease activity, reports Dr. Hall, J. Lamar Callaway Professor of Dermatology, Duke University Medical Center, Durham, N.C.
“These observations suggest to us there may be pathogenic and nonpathogenic populations of anti-BP180 antibodies. Therefore, we are also speculating there may be two populations of antibody-producing plasma B cells, a short-lived subtype that produces disease-causing autoantibodies, and a long-lived subtype that produces antibodies against the same antigen, but yet are not pathogenic,” he says.
“We hope that further research will lead us to understand the pathogenesis of BP, because, ultimately, that might enable us to develop therapy targeting the B cells important in disease etiology, while hopefully minimizing any impact on production of antibodies responsible for natural immune function.”
When it first became commercially available, rituximab was only approved for the treatment of non-Hodgkin’s (B cell) lymphoma. However, there had been reports of its efficacy in treating other autoimmune diseases, and, more recently, evidence indicates that rituximab is very effective in treating other autoimmune blistering diseases, particularly pemphigus, Dr. Hall says.
Serology studies performed to elucidate the mechanism of action of rituximab indicated it did not affect memory plasma cells responsible for antibody production against naturally occurring antigens, as there were no significant changes in total IgG or IgG anti-varicella zoster virus antibody levels. Other investigators using rituximab to treat pemphigus have reported a similar finding, Dr. Hall says.
“This finding suggests production of the autoantibodies and long-lived antibodies are controlled by different mechanisms, and this is encouraging, because it suggests it may be possible to find a treatment able to control the disease without causing general immunosuppression,” he says.
While rituximab initially depleted the circulation of B cells, flow cytometry studies performed to type B cell subsets showed that when the B cell population was reconstituted, it comprised a lower proportion of memory B cells (CD38-/IgD-) and an increase in the proportion of naïve/transitional B cells (CD38++/IgD+) relative to before rituximab treatment.
Dr. Hall notes that the observation that rituximab treatment was associated with a change in the B cell population provides evidence that circulating B cells are important in the pathogenesis of BP. Going forward, Dr. Hall and colleagues will be investigating whether features of the B cell response and reconstitution might be prognostic variables.
“Undoubtedly, as we treat more patients, we will find variations in response to rituximab. One hypothesis we will be exploring is whether treatment response and its longevity can be predicted by the nature of the B cell population and the speed of repopulation,” he explains.
Disclosure: Genentech funded this research, but Dr. Hall reports no relevant financial interest in the company.