Expanding use of rituximab in immunopathic disorders

This issue of Blood contains 2 independent reports on the treatment of refractory mixed cryoglobulinemia with the anti-CD20 humanized monoclonal antibody rituximab. Cryoglobulins, first reported by Maxwell Wintrobe in 1933, are serum immunoglobulins that undergo reversible precipitation in cold. The presence of a serum cryoglobulin can be associated with a spectrum of clinical findings including cutaneous vascular purpura, skin necrosis, urticaria, Raynaud phenomenon, sensory and motor neuropathies, glomerulonephritis, and arthralgias/arthritis. Cryoglobulins have been classified by Brouet and colleagues (Am J Med. 1974;57:775-778) as a monoclonal immunoglobulin (type I), a mixed polyclonal IgG immunoglobulin and a monoclonal IgM immunoglobulin (type II), or 2 or more mixed polyclonal immunoglobulins (type III). It has now been clearly demonstrated that the majority of type II and III mixed cryoglobulinemias (MC) are associated the chronic hepatitis C virus infection (HCV).

Mixed cryoglobulinemia is the most common extrahepatic manifestation of HCV infection. More than 50% of chronically infected patients will have detectable MC, and half of these patients will have clinical manifestations related to the MC. Because HCV is the primary antigen driving the production of the cryoglobulin, optimal therapy has been directed toward suppression of virus. Treatment with interferon alpha alone or in combination with ribavirin can suppress HCV RNA in 50% to 60% of patients with a subsequent decrease in the cryoglobulins. However, many patients fail to respond to interferon therapy, and half the responders will relapse.

The reports by Sansonno and colleagues (page 3818) and Zaja and colleagues (page 3827) provide strong clinical data supporting the use of rituximab in the treatment of refractory HCV–related cryoglobulinemia. The selection of rituximab is clearly a logical choice. Rituximab has documented efficacy in the treatment of follicular B-cell lymphomas and can rapidly deplete circulating and tissue B lymphocytes. Therefore, rituximab should effectively reduce or eliminate rheumatoid factor–producing B lymphocytes, resulting in reduction in the cryoglobulin. In addition, rituximab is reported to be effective in a number of refractory IgG–mediated autoimmune disorders including immune thrombocytopenic purpura, autoimmune hemolytic anemia, and acquired factor VIII inhibitors.

Sansonno and colleagues treated 20 HCV-positive MC patients, who were refractory to interferon therapy, with rituximab 375 mg/m²weekly for 4 weeks. Sixteen patients (80%) had a complete response defined as a 75% or greater reduction in cryoglobulins and resolution of at least 2 major clinical signs and symptoms. In responding patients, rituximab treatment resulted in a reduction in both the IgM and IgG components of the cryoglobulin. At the time of this report, only 4 patients had relapsed and the median duration of response had not been reached. The 15 MC patients treated by Zaja and colleagues were a more diverse patient population, with 12 HCV-infected patients and 3 patients with MC unrelated to HCV. Responses were mixed: all patients had early improvement in their cutaneous manifestations, but only 1 patient had complete resolution of the cryoglobulin at 6 months, and only 3 patients lost their rheumatoid factor. In 7 of 8 patients, maintenance corticosteroids were withdrawn by the second posttreatment month.

A number of important questions remain unanswered by these 2 reports. These include the following: What is the duration of the remissions induced by rituximab? Is retreatment of relapsed patients equally effective? Is the increase in serum viral load reported by Sansonno and colleagues associated with aggravation of liver disease? Although the answers to these important questions will require longer follow-up and larger trials, it is apparent from these 2 reports that rituximab is highly effective in the management of the acute clinical manifestations of refractory HCV–associated MC.