Blood, 15 May 2003, Vol. 101, No. 10, pp. 3759-3759
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/m2
weekly 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.
Howard A. Liebman
University of Southern California- Keck School of
Medicine
