Placebo-controlled trial of rituximab in IgM anti-myelin-associated glycoprotein antibody demyelinating neuropathy. A randomised controlled trial of intravenous immunoglobulin in IgM paraprotein associated demyelinating neuropathy. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. Intravenous immune globulin (10% caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomised placebo-controlled trial. A controlled study of intravenous immunoglobulin in demyelinating neuropathy with IgM gammopathy. A randomised clinical trial comparing interferon-alpha and intravenous immunoglobulin in polyneuropathy associated with monoclonal IgM. The IgM-associated Polyneuropathy Study Group. Is combination rituximab with cyclophosphamide better than rituximab alone in the treatment of lupus nephritis? Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. A phase 1 trial of riluzole in spinal muscular atrophy.
Report a double-blind, placebo-controlled study of rituximab in patients with anti-MAG demyelinating polyneuropathy (A-MAG-DP).
                Twenty-six patients were randomized to four weekly infusions of 375 mg/m(2) rituximab or placebo. Sample size was calculated to detect changes of > or = 1 Inflammatory Neuropathy Course and Treatment (INCAT) leg disability scores at month 8. IgM levels, anti-MAG titers, B cells, antigen-presenting cells, and immunoregulatory T cells were monitored every 2 months.
                Thirteen A-MAG-DP patients were randomized to rituximab and 13 to placebo. Randomization was balanced for age, electrophysiology, disease duration, disability scores, and baseline B cells. After 8 months, by intention to treat, 4 of 13 rituximab-treated patients improved by > or = 1 INCAT score compared with 0 of 13 patients taking placebo (p = 0.096). Excluding one rituximab-randomized patient who had normal INCAT score at entry, and thus could not improve, the results were significant (p = 0.036). The time to 10m walk was significantly reduced in the rituximab group (p = 0.042) (intention to treat). Clinically, walking improved in 7 of 13 rituximab-treated patients. At month 8, IgM was reduced by 34% and anti-MAG titers by 50%. CD25+CD4+Foxp3+ regulatory cells significantly increased by month 8. The most improved patients were those with high anti-MAG titers and most severe sensory deficits at baseline.
                Rituximab is the first drug that improves some patients with A-MAG-DP in a controlled study. The benefit may be exerted by reducing the putative pathogenic antibodies or by inducing immunoregulatory T cells. The results warrant confirmation with a larger trial. This multicentre randomised double blind crossover trial tested the short term efficacy of intravenous immunoglobulin (IVIg) 2.0 g/kg given over 24 or 48 hours in patients with paraproteinaemic demyelinating neuropathy (PDN). Twenty-two patients were randomised and completed the trial. After 2 weeks, the overall disability grade decreased during both IVIg treatment and placebo but neither change was significant nor was the mean difference between the treatment effects. After 4 weeks the overall disability decreased by a mean of 0.55 [0.67] grades during the IVIg period (p = 0.001) while it was substantially unmodified during the placebo period. The mean difference between the treatment effects was significant (p = 0.05). Overall during the IVIg period 10 patients improved and 11 were stable and one got worse. During the placebo period 4 patients improved, 4 deteriorated and 14 were stable. Many secondary outcome measures, including Rankin scale, time to walk 10 metres, grip strength, sensory symptoms score were significantly better during IVIg treatment. Two serious adverse events occurred during the trial, both during placebo treatment. In conclusion the trial showed some short-term benefit of IVIg in about half of the patients confirming previous observation. There is increasing evidence that B lymphocytes are involved in the pathogenesis of multiple sclerosis, and they may be a therapeutic target. Rituximab, a monoclonal antibody, selectively targets and depletes CD20+ B lymphocytes.
                In a phase 2, double-blind, 48-week trial involving 104 patients with relapsing-remitting multiple sclerosis, we assigned 69 patients to receive 1000 mg of intravenous rituximab and 35 patients to receive placebo on days 1 and 15. The primary end point was the total count of gadolinium-enhancing lesions detected on magnetic resonance imaging scans of the brain at weeks 12, 16, 20, and 24. Clinical outcomes included safety, the proportion of patients who had relapses, and the annualized rate of relapse.
                As compared with patients who received placebo, patients who received rituximab had reduced counts of total gadolinium-enhancing lesions at weeks 12, 16, 20, and 24 (P<0.001) and of total new gadolinium-enhancing lesions over the same period (P<0.001); these results were sustained for 48 weeks (P<0.001). As compared with patients in the placebo group, the proportion of patients in the rituximab group with relapses was significantly reduced at week 24 (14.5% vs. 34.3%, P=0.02) and week 48 (20.3% vs. 40.0%, P=0.04). More patients in the rituximab group than in the placebo group had adverse events within 24 hours after the first infusion, most of which were mild-to-moderate events; after the second infusion, the numbers of events were similar in the two groups.
                A single course of rituximab reduced inflammatory brain lesions and clinical relapses for 48 weeks. This trial was not designed to assess long-term safety or to detect uncommon adverse events. The data provide evidence of B-cell involvement in the pathophysiology of relapsing-remitting multiple sclerosis. (ClinicalTrials.gov number, NCT00097188 [ClinicalTrials.gov].).
                Copyright 2008 Massachusetts Medical Society. Short-term studies suggest that intravenous immunoglobulin might reduce disability caused by chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) but long-term effects have not been shown. We aimed to establish whether 10% caprylate-chromatography purified immune globulin intravenous (IGIV-C) has short-term and long-term benefit in patients with CIDP.
                117 patients with CIDP who met specific neurophysiological inflammatory neuropathy cause and treatment (INCAT) criteria participated in a randomised, double-blind, placebo-controlled, response-conditional crossover trial. IGIV-C (Gamunex) or placebo was given every 3 weeks for up to 24 weeks in an initial treatment period, and patients who did not show an improvement in INCAT disability score of 1 point or more received the alternate treatment in a crossover period. The primary outcome was the percentage of patients who had maintained an improvement from baseline in adjusted INCAT disability score of 1 point or more through to week 24. Patients who showed an improvement and completed 24 weeks of treatment were eligible to be randomly re-assigned in a blinded 24-week extension phase. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00220740.
                During the first period, 32 of 59 (54%) patients treated with IGIV-C and 12 of 58 (21%) patients who received placebo had an improvement in adjusted INCAT disability score that was maintained through to week 24 (treatment difference 33.5%, 95% CI 15.4-51.7; p=0.0002). Improvements from baseline to endpoint were also recorded for grip strength in the dominant hand (treatment difference 10.9 kPa, 4.6-17.2; p=0.0008) and the non-dominant hand (8.6 kPa, 2.6-14.6; p=0.005). Results were similar during the crossover period. During the extension phase, participants who continued to receive IGIV-C had a longer time to relapse than did patients treated with placebo (p=0.011). The incidence of serious adverse events per infusion was 0.8% (9/1096) with IGIV-C versus 1.9% (11/575) with placebo. The most common adverse events with IGIV-C were headache, pyrexia, and hypertension.
                This study, the largest reported trial of any CIDP treatment, shows the short-term and long-term efficacy and safety of IGIV-C and supports use of IGIV-C as a therapy for CIDP. Eleven patients with demyelinating polyneuropathy associated with monoclonal IgM antibodies were randomized to receive IVIg or placebo, monthly, for 3 months in a double-blind study. After a washout period, they crossed over to the alternate therapy. Response was gauged by evaluating muscle strength, sensation, and neuromuscular symptoms at baseline, after 3 months, and at treatment's end. After IVIg therapy, the strength improved in only 2 of 11 patients, by 28 and 38.5 points from baseline, and declined after placebo. In 1 other patient, the sensory score improved by 13 points. Antibody titers to MAG/SGPG or gangliosides did not appreciably change. We conclude that IVIg has only a modest benefit to not more than 18% of patients with IgM paraproteinemic demyelinating neuropathy. The polyneuropathy associated with a monoclonal IgM directed to the myelin associated glycoprotein (MAG) is a specific entity with a putative causal link between the IgM and the neuropathy. The small benefit offered by alkylating agents or plasma exchanges in these patients justifies the search for alternative treatments.
                A 12 month multicentre, prospective, randomised, open clinical trial was carried out comparing intravenous immunoglobulin (IVIg; 2g/kg and then 1 g/kg every three weeks) and recombinant interferon-alpha (IFN-alpha; 3 MU/m2 subcutaneously three times weekly). The main end point was a clinical neuropathy disability score (CNDS) after six months of treatment. Twenty patients were enrolled; 10 were assigned to IVIg and 10 to IFN-alpha.
                At six months, one out of 10 patients treated with IVIg had a CNDS improvement of more than 20% whereas eight out of 10 patients treated with IFN-alpha had such an improvement (P=0.005). The mean CNDS worsened by 2.3 (SD 7.6) (8%) in the IVIg group whereas it improved by 7.5 (SD 11.1) (31%) in the IFN-alpha group (P=0.02). This improvement persisted after 12 months and was mainly related to an improvement of the sensory component (P=0.02) whereas the motor component was unchanged (P=0.39). Electrophysiological data did not show improvement of motor nerve conduction velocities whereas sensory nerve conduction velocities improved in the upper limbs. A decrease in the level of the monoclonal IgM was seen in two patients treated with IFN-alpha. At the end of the treatment, antibody activity to MAG was still detected in the serum of all patients.
                IVIg, as used in this study, did not improve patients with polyneuropathy and monoclonal IgM. By contrast, although its mechanism of action remains to be fully elucidated, IFN-alpha was effective in eight out of 10 patients at six months. To assess if combination rituximab and cyclophosphamide is more effective than rituximab monotherapy as an induction therapy for proliferative lupus nephritis.
                A randomized open-label pilot study in which 9 patients received rituximab alone and 10 patients received two doses rituximab + intravenous cyclophosphamide. The clinical, laboratory and renal histological changes were assessed after 48 weeks of treatment.
                At week 48, four patients had a complete response, 11 patients achieved partial response, 2 patients remained the same or stable and 2 worsened. There were no statistical differences in the proportion of patients with complete or partial response between the two groups. None of the variables was an independent predictor of response at week 48. Nine patients had significant improvement in activity indices in renal biopsies, but there were no significant differences between the two groups. Overall, 18 out of 19 patients were found to have effective B-cell depletion. The median duration of complete B-cell depletion in all patients was 22 weeks. There were no statistically significant differences in the proportion of patients with complete depletion at weeks 4, 8, 24 and 48 between the two groups except at week 2.
                Rituximab monotherapy appears to be effective as induction therapy in lupus nephritis. The addition of cyclophosphamide offers no additional improvement in clinical, laboratory and renal histological assessment or the duration of B-cell depletion at 48 weeks. Large-scale studies with longer duration are needed to confirm these findings. Rituximab, a monoclonal antibody that targets the CD20 cell surface antigen, has clinical activity in patients with non-Hodgkin's lymphoma and other B-lymphocyte disorders when administered alone or in combination with chemotherapy. Promising results have previously been reported in nonrandomized studies in patients with chronic lymphocytic leukemia (CLL). This trial was designed to compare chemoimmunotherapy with chemotherapy alone in patients with previously treated CLL.
                This international, multicenter, randomized trial compared six cycles of rituximab plus fludarabine and cyclophosphamide (R-FC) with six cycles of fludarabine and cyclophosphamide alone (FC) in patients with previously treated CLL. A total of 552 patients with Binet stage A (1%), B (59%), or C (31%) disease entered the study and were randomly assigned to receive R-FC (n = 276) or FC (n = 276).
                After a median follow-up time of 25 months, rituximab significantly improved progression-free survival in patients with previously treated CLL (hazard ratio = 0.65; P < .001; median, 30.6 months for R-FC v 20.6 months for FC). Event-free survival, response rate, complete response rate, duration of response, and time to new CLL treatment or death were also significantly improved. Although the rates of adverse events, grade 3 or 4 events, and serious adverse events were slightly higher in the R-FC arm, R-FC was generally well tolerated, with no new safety findings and no detrimental effect on quality of life.
                R-FC significantly improved the outcome of patients with previously treated CLL. Severe spinal muscular atrophy (SMA) (Werdnig-Hoffmann disease, acute SMA, and SMA I) is a disease of the motor neuron characterized by onset before 6 months of age, failure ever to achieve sitting without support, and a life expectancy of 2 years or less. There is no known treatment for SMA, and, until recently, no therapeutic trials have been attempted. There is reason to believe that glutamate, an excitatory neurotransmitter, enhances programmed cell death of anterior horn cells. Riluzole, a glutamate inhibitor, has been shown to slow the rate of decline in patients with amyotrophic lateral sclerosis, another form of motor neuron disease.
                To determine whether a glutamate inhibitor might be tolerated by infants with SMA and, furthermore, whether this medication could have a positive effect on life expectancy.
                Subjects with homozygous deletions of the survival motor neuron gene were recruited from pediatric neuromuscular clinics and randomized in a 2:1 ratio, 2 riluzole to 1 placebo. Neurologic examination was performed at the first visit by one of the investigators. Complete blood count, hepatic and renal screens, and urinalysis were performed at baseline, 2 weeks, 1 month, 2 months, 3 months, 6 months, and 9 months after drug or placebo was started. An electrocardiogram was done at baseline, 3 months, 6 months, and 12 months. Treatment was stopped after 9 months, and blood work was repeated at 12 months. Treatment was reinstituted at 1 year if requested by the parents. The enrollment goal was 30 patients; however, support from the pharmaceutical company was withdrawn when Rhone-Poulenc Rorer was taken over by Aventis. The investigational review boards of the participating centers approved the protocol and consent forms.
                Seven patients received riluzole and 3 received placebo medication. All 3 patients in the placebo group died (mean age, 9 months). Three of 7 who received active drug are still living at ages 513 years, 4 years, and 30 months. None of the 10 subjects experienced adverse effects or changes in laboratory test results. None showed any change in motor abilities.
                Riluzole appears to be safe in young children. This was a limited study with insufficient power to show a difference between the 2 groups. Because there is a suggestion of possible benefit in treated subjects, we recommend further study of riluzole in pediatric patients with SMA.
There is inadequate reliable evidence from trials of immunotherapies in anti-myelin-associated glycoprotein paraproteinaemic neuropathy to form an evidence base supporting any particular immunotherapy treatment. There is very low quality evidence of benefit from rituximab. Large well designed randomised trials of at least six to 12 months duration are required to assess existing or novel therapies, preferably employing unified, consistent, well designed, responsive and valid outcome measures.