Rituximab for the treatment of type II mixed cryoglobulinemia

Rituximab is a human/mouse chimeric monoclonal antibody (IgG1κ) that reacts specifically with CD20 antigen (a transmembrane protein present during different steps in the maturation of B lymphocytes, from early pre B to mature lymphocyte), inducing complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity. The marked and systemic B cell depletion observed in non-Hodgkin's lymphoma patients treated with rituximab has recently led to use of this agent in autoimmune diseases, with the aim of inhibiting production of antibodies reacting against normal cells and tissues. Preliminary published results appeared encouraging, because rituximab showed activity in some cases of cold agglutinin disease (1-3), warm antibody hemolytic anemia (2), idiopathic thrombocytopenic purpura (4-6), paraproteinemic polyneuropathy (7), and myasthenia gravis (8). Type II mixed cryoglobulinemia (MC) is a systemic vasculitis strictly associated with hepatitis C virus (HCV) infection and is generally sustained by proliferation of non-neoplastic oligoclonal B cells (9, 10). Based on the hypothesis that rituximab could act on proliferating B cells and thus on systemic autoimmune manifestations, we used the drug in 4 patients with symptomatic type II MC who were unresponsive to previous treatments. The main clinical features of these patients, before treatment with rituximab, are described below. Patient 1 (previously described; see ref. 11) was a 58-year-old man who had formerly been treated with interferon-α (IFNα), cyclophosphamide, prednisone, danazol, and plasmapheresis. Forty-six months after the diagnosis of type II MC, the patient still had diffuse purpura, arthralgias, fever, moderate anemia, and chronic renal failure. Patient 2 was a 67-year-old woman previously treated with prednisone and plasmapheresis. One hundred eight months after the diagnosis of type II MC, despite mildly positive cryoglobulins and rheumatoid factor (RF), she had purpura, diffuse bullous lesions, and urticaria. Patient 3 was a 68-year-old woman who was HCV negative and had been unresponsive to plasmapheresis and prednisone. Five months after the diagnosis of type II MC, she presented with diffuse purpura, ulcerative skin lesions on her lower limbs, and a severe, primarily sensorial polyneuropathy. Patient 4, a 68-year-old woman, had previously been treated with prednisone. Forty-eight months after the diagnosis of type II MC, her clinical picture was characterized by development of a CD20+ B cell non-Hodgkin's lymphoma (small lymphocytic lymphoma according to the revised European-American lymphoma classification), with superficial lymphadenopathies and bone marrow involvement (<10% of marrow infiltrated), Coombs-negative hemolytic anemia, and grade IV neutropenia (according to World Health Organization grading). Rituximab was administered intravenously in a dose of 375 mg/m2 on days 1, 8, 15, and 22. No other cytotoxic, immunosuppressive, or steroid drugs were allowed in association with use of rituximab. Response was evaluated by assessing the modifications of clinical signs, symptoms, and the main immunologic pattern. Each patient's clinical and laboratory features before and after rituximab treatment are summarized in Tables 1–4. Patient 4 had a complete remission of the clinical manifestations and normalization of laboratory values. Patients 1, 2, and 3 demonstrated good partial responses, as defined by >50% reduction in clinical and laboratory signs of disease. The duration of response ranged from 3 to 13 months. Depletion of CD20+ B cells and reduction of serum IgG and RF levels were observed in all 4 patients. In patients 3 and 4, the disappearance of the serum monoclonal component IgMκ was shown by immunofixation. Normalization of complement levels was inconsistent, and disappearance of cryoglobulins was seen in patients 1 (transient disappearance only) and 4. In patient 1, the therapeutic regimen was interrupted after the second infusion of rituximab because of the development of acute left-sided amaurosis with a documented thrombosis of the retinal artery. A symmetric panniculitis at the elbows and knees, which spontaneously resolved after 1 month, was recorded for patient 2 on day 60. No other acute or delayed relevant side effects or infectious complications occurred. In this preliminary experience, rituximab treatment proved effective in all 4 type II MC patients whose clinical manifestations had been unresponsive to conventional treatments. Clinical improvement was accompanied by improvement in disease-related laboratory values. In particular, the reduction in the levels of IgM and RF and the disappearance of the monoclonal component of IgMκ in 2 patients, in conjunction with the concomitant depletion of B cells from the peripheral blood, indicate that rituximab inhibited type II MC–related B cell proliferation and pathogenic autoantibody production. Rituximab therapy, although not targeted to the key infectious trigger of type II MC, effectively treated manifestations of the disease, presumably by blocking the crucial pathobiologic events (RF and immunocomplex production) linked to the infection. This fact may be relevant in type II MC patients, in whom HCV eradication may not be achieved because of inefficacy of or contraindications to treatment with antiviral agents. Data for patients with non-Hodgkin's lymphomas and autoimmune diseases indicate that use of rituximab is associated with low toxicity and, in particular, absence of infectious complications. This is important, because infection, the most common cause of death in type II MC, is commonly associated with use of steroids and cytotoxic drugs. Administration of rituximab was not associated with arterial or venous thrombosis in a large series of patients (12). However, the thrombotic event observed in patient 1 could have been related to factors predisposing to type II MC (e.g., vasculitis, hyperviscosity). Thus, use of rituximab should be carefully supervised in patients with type II MC, especially if additional risk factors for vascular events are present. In conclusion, these preliminary results suggest that rituximab may represent an important alternative for the treatment of patients with type II MC. Rituximab could be the ideal replacement for corticosteroids and conventional cytotoxic drugs, which increase the risk of infection and oncogenic events. Moreover, rituximab could also be the ideal drug for use in association with classic antiviral therapy (i.e., IFNα, ribavirin). We wish to thank Roche Diagnostics S.p.A. (Monza, Italy) for kindly supplying rituximab and Professor Angelo Giumanini for editing. Francesco Zaja MD*, Salvatore De Vita MD*, Domenico Russo MD*, Angela Michelutti*, Renato Fanin MD*, Gianfranco Ferraccioli MD*, Michele Baccarani MD , * Policlinico Universitario, Udine, Italy, Policlinico S.