This study will test the safety and effectiveness of the drug Rituximab in treating a nerve
disease called MGUS (also known as neuropathy with anti-MAG antibodies). Patients with MGUS
have an abnormal protein called monoclonal IgM immunoglobulin that attacks the myelin sheath
(protective coating) of nerves, causing them to not function properly. The disease affects
the nerves in the legs or arms, and patients have numbness, tingling, muscle weakness, and
unsteady gait. There are no adequate treatments. Immunosuppressive drugs or human
immunoglobulin infusions can produce mild and transient improvement, but the benefits of
these therapies are not significant.
The abnormal immunoglobulin protein in MGUS is produced by white cells called B lymphocytes.
Rituximab is approved to treat B cell lymphomas. Also, the drug showed promise in a recent
study of patients with demyelinating neuropathy associated with production of antibodies
from B lymphocytes directed against certain nerve proteins. Although the number of patients
treated with Rituximab was small, the drug was well tolerated and caused significant
improvement in several of the patients.
Patients 25 years of age and older with MGUS may be eligible for this 2-year study.
Candidates will be screened with a medical history, physical and neurological examinations,
and blood tests.
Participants will be randomly assigned to receive intravenous (through a vein) infusions of
either Rituximab or placebo (a solution that looks like Rituximab but has no active
ingredient) once a week for 4 consecutive weeks. In addition, they will undergo the
following tests and procedures:
- Monthly follow-up visits following Rituximab treatment for repeat physical and
neurological examinations, blood tests, muscle strength measurements, and review of
signs and symptoms.
- Two sessions of lymphapheresis, one at the beginning of the study and one a year
later-to collect lymphocytes. For this procedure, whole blood is drawn through a needle
in an arm vein, much like donating a unit of blood. The blood then flows through a
catheter (plastic tube) into a cell separating machine, where the white blood cells are
extracted and removed. The red cells and plasma are then returned to the body through a
needle in the other arm. The procedure takes about 60 to 90 minutes.
- Electrophysiologic studies (electromyography and nerve conduction testing) are done
once at the beginning of the study and again one year later. For electromyography, a
small needle is inserted into a few muscles and the patient is asked to relax or to
contract the muscles. The electrical activity of the muscle cells is recorded and
analyzed by a computer. For nerve conduction testing, nerves are stimulated through
small wire electrodes attached to the skin and the response is recorded and analyzed.
If this study indicates that Rituximab is beneficial against MGUS, patients who were
assigned to receive placebo during the trial will be offered treatment with Rituximab (four
weekly infusions) at the end of the study.
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
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.
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
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.