This study will examine the safety, tolerability, and efficacy of the humanized monoclonal antibody Rituximab to induce a clinical and serological remission in patients with IgM-anti-glycoconjugate antibody-mediated demyelinating neuropathy. Rituximab is a monoclonal antibody specific for the common B cell antigen CD20. Its administration depletes pre-B and mature B lymphocytes without altering neutrophils or hematopoietic stem cells. In humans with indolent B cell lymphomas, Rituximab can be safely administered, is well tolerated, promotes selective B cell depletion and lowers the serum IgM levels. Preliminary experience in some patients with demyelinating polyneuropathy and IgM-anti-glycolipid antibodies has shown that Rituximab was beneficial in improving the patient's symptoms and reducing the anti IgM antibody levels. In the present study we will examine in a placebo randomized trial the efficacy of Rituximab in patients with polyneuropathy related to IgM-anti-glycolipid antibodies. Twenty-six patients will be randomized to receive placebo or Rituximab given at four weekly intravenous infusions of 375 mg/M(2). The primary outcome will be based on changes in the monthly measurements of the neuropathy scores. The fine specificities of the IgM antibodies to various glycoconjugates or differences in the affinity binding to various antigens in neural membranes will be explored before and after treatment. It is anticipated that the study will: a) provide a new, immune-based and target-oriented therapy for patients with this neuropathy and b) examine the pathogenic role of these antibodies in the cause of the disease.
- INCLUSION CRITERIA: Research subjects will have documented disability of IgM anti-glycoconjugate antibody-mediated demyelinating neuropathy. Neuropathy associated with IgM monoclonal immunoglobulins reactivate to MAG or other glycoconjugates. Willingness and legal ability to give and sign informed study consent. Willingness to travel to NIH for scheduled protocol studies and treatment. Men and women of reproductive potential must agree to use an acceptable method of birth control during treatment and for six months after completion of treatment. Adequate bone marrow, renal, and liver function: ANC greater than 1000/mm3, BUN/Cr with normal range for age, AST or ALT less than 2 x of upper limit of normal. EXCLUSION CRITERIA: Immunosuppressive drug therapy at the time of or 6 months prior to enrollment. Specifically, candidates may not be taking prednisone, cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil, anti-lymphocyte agents, cyclophosphamide, methotrexate, or other agents whose therapeutic effect is immunosuppressive or could provoke neuropathy as undesirable secondary effect. Any medical or social condition that precludes follow-up visits. Any active malignancy or any history of a hematogenous malignancy or lymphoma. Patients with melanoma will be excluded. Patients with primary, cutaneous basal cell or squamous cell cancers may be enrolled providing the lesions are treated prior to enrollment. Coagulopathy or requirement for anticoagulation therapy that would contraindicate protocol. Platelet count less than 100,000/mm(3). Hemoglobin less than 7.0 mg/dl. Any known immunodeficiency syndrome included HIV infection. Any history of cardiac insufficiency, major vascular disease, or symptomatic coronary artery disease. Patients with cardiomyopathy grade III or IV by the New York Heart Classification will be excluded from this study. Systemic edema or pulmonary edema. Chronic hypotension (SBP less than 100 mm Hg). Any condition that would likely increase the risk of protocol participation or confound the interpretation of the data including active infections. Pregnancy. Serum pregnancy test will be performed and must be negative in all women of childbearing potential enrolled in the study. History of active psychiatric disorder that may interfere with participation in the study. Patients below the age of 25 because this neuropathy does not occur in such age groups.