Efficacy and Safety of Rituximab for New-Onset Generalized Myasthenia Gravis

Abstract

ImportanceRituximab is a third-line option for refractory generalized myasthenia gravis (MG) based on empirical evidence, but its effect in new-onset disease is unknown.ObjectiveTo investigate the efficacy and safety of rituximab compared with placebo as an add-on to standard of care for MG.Design, Setting, and ParticipantsThis randomized, double-blind, placebo-controlled study took place throughout 48 weeks at 7 regional clinics in Sweden. Key inclusion criteria were age older than 18 years, onset of generalized symptoms within 12 months or less, and a Quantitative Myasthenia Gravis (QMG) score of 6 or more. Patients were screened from October 20, 2016, to March 2, 2020. Key exclusion criteria included pure ocular MG, suspected thymoma, previous thymectomy, and prior noncorticosteroid immunosuppressants or high doses of corticosteroids.InterventionsParticipants were randomized 1:1 without stratification to a single intravenous infusion of 500 mg of rituximab or matching placebo.Main Outcomes and MeasuresMinimal disease manifestations at 16 weeks defined as a QMG score of 4 or less with prednisolone, 10 mg or less daily, and no rescue treatment.ResultsOf 87 potentially eligible patients, 25 were randomized to rituximab (mean [SD] age, 67.4 [13.4] years; 7 [28%] female) and 22 to placebo (mean [SD] age, 58 [18.6] years; 7 [32%] female). Compared with placebo, a greater proportion with rituximab met the primary end point; 71% (17 of 24) in the rituximab group vs 29% (6 of 21) in the placebo group (Fisher exact test P = .007; probability ratio, 2.48 [95% CI, 1.20-5.11]). Secondary end points, comparing changes in Myasthenia Gravis Activities of Daily Living and Myasthenia Gravis Quality of Life at 16 weeks with QMG at 24 weeks did not differ between groups with censoring for rescue treatment (per-protocol analysis) but were in favor of active treatment when rescue treatment was taken into account by worst rank imputation (post hoc analysis). Rescue treatments were also more frequent in the placebo arm (rituximab: 1 [4%]; placebo, 8 [36%]). One patient in the placebo arm had a myocardial infarction with cardiac arrest and 1 patient in the active arm experienced a fatal cardiac event.Conclusions and RelevanceA single dose of 500 mg of rituximab was associated with greater probability of minimal MG manifestations and reduced need of rescue medications compared with placebo. Further studies are needed to address long-term benefit-risk balance with this treatment.Trial RegistrationClinicalTrials.gov Identifier: NCT02950155

B cell depletion attenuates CD27 signaling of T helper cells in multiple sclerosis

“…The number of MG patients analyzed here is relatively small, thus limiting the statistical power. Despite the disparity in clinical efficacy of BCDTs in MS and MG (60,61), we can conclude that upregulation of CD27 in Tfh cells is a universal hallmark of the therapy.…”

New Targeted Agents in Myasthenia Gravis and Future Therapeutic Strategies

“…The only phase 2 clinical trial comparing rituximab with a placebo as an add-on treatment in AChR-MG patients recently reported disappointing results, namely, no significant differences in disease severity or corticosteroid-sparing effect over placebo [ 50 ]. More recently, results from a randomized trial using a single-dose of rituximab in AChR-positive gMG patients with a Quantitative MG (QMG) score >6 and a short disease course (<12 months) showed benefits in clinical outcomes and a reduction in the use of rescue medication [ 51 ]. Further randomized clinical trials with rituximab are needed, particularly in refractory MG patients, in whom therapeutic options are limited.…”

Rituximab in Newly Diagnosed Generalized Myasthenia Gravis

“…The RINOMAX trial suggests that rituximab may be more beneficial if started early after diagnosis of AChR gMG and that a single low dose of rituximab is clinically effective. The reason for a better clinical response in patients with new-onset AChR gMG may be related to the reduction of formation of long-lived plasma cells responsible for antibody secretion .…”

“…In this issue of the JAMA Neurology , Piehl et al report the results of the Rituximab in New-Onset Generalized Myasthenia Gravis (RINOMAX) randomized clinical trial. They included adults with new-onset gMG symptoms, QMG score of 6 or greater, and MGFA score of II to IV.…”

“…This is important because rituximab does not target plasmablasts or plasma cells (they are CD20 negative) but instead targets their precursors. However, in the current study, there was only a nonsignificant trend to reduced AChR antibody titers after rituximab treatment. Other mechanisms, such as modulation of cytokine production or elimination of CD20+ T and antigen-specific memory B cells, can also be considered …”