Benedetti L, Zardini E, Briani C, et al

Benedetti L, Zardini E, Briani C, et al. B-cell-activating factor in rituximab-treated patients with anti-MAG polyneuropathy. per protocol analysis at 12 months, for the number of patients with an improvement of at least 2 points in the INCAT disability scale (= 0.027), the self-evaluation scale (= 0.016), and 2 subscores of the Short FormC36 questionnaire. Conclusions: Although primary outcome measures provide no evidence to support the use of rituximab in IgM anti-MAG demyelinating neuropathy, there were improvements in several secondary outcomes in per protocol analysis. Level of evidence: This study provides Class I evidence that rituximab is ineffective in improving ISS in patients with IgM anti-MAG demyelinating neuropathy. Within the spectrum of chronic immune-mediated neuropathies, demyelinating neuropathy associated with immunoglobulin M (IgM) monoclonal gammopathy and antibodies against myelin-associated glycoprotein (MAG) is a distinct entity that typically presents with progressive sensory ataxia and painful paresthesias.1C8 Patients present with a striking immunochemical profile, suggesting the possibility of an autoimmune mechanism: monoclonal IgM recognizes a carbohydrate MAG epitope, which is shared with a number of other glycoconjugates involved in cell adhesion, including the Po glycoprotein of myelin, peripheral myelin proteinC22, sulfated sphingolipid, and other related glycolipids.9,10 The disease may progress slowly over many years in some patients, whereas others develop significant disability mostly due to dysesthesias and ataxia; thus, there is a need to develop effective treatments.11 There is insufficient evidence from most pilot studies or randomized controlled trials (RCT) on IgM anti-MAG demyelinating neuropathy to recommend any particular immunotherapy.12,13 Rituximab is a genetically engineered chimeric murine/human monoclonal antibody directed against CD20, a protein present on the surface of normal and malignant pre-B and IL-10C mature B cells until differentiation into plasma cells. Efficacy of rituximab has been supported by both uncontrolled R-121919 studies14C17 and, more recently, an RCT that concluded there was a small difference between rituximab and placebo-treated patients,18 although confirmation is needed in a larger trial. The aim of the Rituximab vs Placebo in Polyneuropathy Associated With Anti-MAG IgM Monoclonal Gammopathy (RIMAG) study was to test the hypothesis that rituximab at 375 mg/m2 is beneficial in patients with IgM anti-MAG demyelinating neuropathy. METHODS Participants. Patients, aged 18 to 82 years, were enrolled at 8 neuromuscular centers in France and one in Switzerland between March 2006 and November 2008. Inclusion and exclusion criteria are listed in table 1. Criteria for chronic demyelinating neuropathy accorded with the European Federation of Neurological Societies/Peripheral Nerve Society guidelines for chronic inflammatory demyelinating polyradiculoneuropathy.19 Table 1 Inclusion and exclusion criteria: Rituximab vs Placebo in Polyneuropathy Associated With Anti-MAG IgM Monoclonal Gammopathy (RIMAG) study Open in a separate window Using a stratified (by center) and blocked (with variable block length) randomization list (created by a statistician) to ensure that the 2 2 parallel groups were comparable at baseline, patients R-121919 were randomized by fax to one of two groups (1:1 ratio): the first group received 4 weekly infusions of 375 mg/m2 rituximab (as in regimens used in previous trials for IgM anti-MAG demyelinating neuropathy18) and the second group received placebo. Randomization was centralized and carried out independently of the clinicians. Once randomized, the patients were allowed no other immunomodulatory or immunosuppressive treatment until they reached the predefined endpoints. The study included a treatment period (weeks 1C4) and a follow-up period (week 4Cmonth 12). Patients were assessed at baseline, and at 3, 6, 9, and 12 months, but early assessment took place if clinically necessary (e.g., due to a worsening of the patient’s condition). Drug and placebo were supplied by Roche France. All investigators, assessors, evaluators, and nurses remained blinded to the randomization codes. A data and safety monitoring board was established to monitor safety. Standard protocol approvals, registrations, and patient consents. All patients provided written informed consent. The ethics committees of all participating centers approved the study protocol. This study was registered with Current Controlled Trials, under number 00259974, and was investigator-led and R-121919 cosponsored by Assistance Publique-H?pitaux de Paris (Direction de la Recherche Clinique), with financial support from a Programme Hospitalier de Recherche Clinique grant.