Efficacy and Safety of Rituximab for New-Onset Generalized Myasthenia Gravis: The RINOMAX Randomized Clinical Trial.

Importance: Rituximab is a third-line option for refractory generalized myasthenia gravis (MG) based on empirical evidence, but its effect in new-onset disease is unknown. Objective: To investigate the efficacy and safety of rituximab compared with placebo as an add-on to standard of care for MG. Design, Setting, and Participants: This 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. Interventions: Participants were randomized 1:1 without stratification to a single intravenous infusion of 500 mg of rituximab or matching placebo. Main Outcomes and Measures: Minimal 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. Results: Of 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 Relevance: A 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 Registration: ClinicalTrials.gov Identifier: NCT02950155.

Measurement of sCD27 in the cerebrospinal fluid identifies patients with neuroinflammatory disease.

BACKGROUND: Laboratory tests to assist in the diagnosis and monitoring of neuroinflammatory diseases are scarce. The soluble form of the CD27 molecule (sCD27) is shed in high concentrations by activated T cells and can be detected in the cerebrospinal fluid. The aim of this study was to investigate whether CSF quantitation of sCD27 could discriminate between inflammatory and non-inflammatory neurological diseases. METHODS: The concentration of sCD27 was measured using a commercially available ELISA in 803 well-defined subjects from a study cohort comprised of 338 patients with neuroinflammatory disease, 338 with non-inflammatory neurological disease and 127 controls without neurological disease. RESULTS: The median value of cerebrospinal fluid sCD27 was 64 pg/mL (IQR 0-200) in controls, 58 pg/mL (IQR 0-130) in patients with non-inflammatory disease and 740 pg/mL (IQR 230-1800) in patients with inflammatory disease. The likelihood ratio of having an inflammatory disease was 10 (sensitivity 74% and specificity 93%) if the sCD27 concentration was >250 pg/mL. In patients with a known inflammatory condition, the likelihood ratio of having an infection was 10 (sensitivity 40% and specificity 96%) if the sCD27 concentration was >2500 pg/mL. CONCLUSIONS: The likelihood of having an inflammatory neurological condition is increased with elevated concentrations of sCD27 in cerebrospinal fluid. Rapid tests of sCD27 should be developed to assist clinicians in diagnosis of neuroinflammatory disease.

An unusual cause of fatal rapid-onset ataxia plus syndrome.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a demyelinating disorder of the central nervous system caused by reactivation of the JC-virus and is in most cases associated with underlying immunosuppression. Acquired immune deficiency syndrome (AIDS) and hematological malignancies are well-known predisposing factors for PML. However, in the past ten years, various pharmacological agents have been associated with increased risk of PML. Based on the phenomenology PML can be divided into the cerebral form and the rare cerebellar form. CASE PRESENTATION: Here we describe a man affected by polycythemia vera (PCV) that was treated with hydroxyurea (HU) and developed PML. The initially PML presentation included ataxia as one of the main features. Brain MRI displayed widespread supratentorial and infratentorial lesions. Immunological analysis revealed absence of reactivity to a wide range of antigens. The course of disease was rapidly progressive with fatal outcome - autopsy ruled out leukemic transformation. CONCLUSION: The occurrence of PML in PCV patients is very rare and has been reported only once. Movement disorders, such as ataxia, are also less frequent. In the present case the PML was likely multifactorial.