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Objective:To evaluate the efficacy of rituximab in treatment of anti-muscle-specific kinase (MuSK) myasthenia gravis (MG).Methods:This was a multicenter, blinded, prospective review, comparing anti-MuSK-positive patients with MG treated with rituximab to those not treated with rituximab. The primary clinical endpoint was the Myasthenia Gravis Status and Treatment Intensity (MGSTI), a novel outcome that combines the Myasthenia Gravis Foundation of America (MGFA) postintervention status (PIS) and the number and dosages of other immunosuppressant therapies used. A priori, an MGSTI of level ≤2 was used to define a favorable outcome. Secondary outcomes included modified MGFA PIS of minimal manifestations or better, mean/median prednisone dose, and mean/median doses of other immunosuppressant drugs.Results:Seventy-seven of 119 patients with anti-MuSK MG evaluated between January 1, 2005, and January 1, 2015, at 10 neuromuscular centers were selected for analysis after review of limited clinical data by a blinded expert panel. An additional 22 patients were excluded due to insufficient follow-up. Baseline characteristics were similar between the rituximab-treated patients (n = 24) and the controls (n = 31). Median follow-up duration was >3.5 years. At last visit, 58% (14/24) of rituximab-treated patients reached the primary outcome compared to 16% (5/31) of controls (p = 0.002). Number needed to treat for the primary outcome is 2.4. At last visit, 29% of rituximab-treated patients were taking prednisone (mean dose 4.5 mg/day) compared to 74% of controls (mean dose 13 mg/day) (p = 0.001 and p = 0.005).Classification of evidence:This study provides Class IV evidence that for patients with anti-MuSK MG, rituximab increased the probability of a favorable outcome.

Background: Plectin crosslinks intermediate filaments to their targets in different tissues. Defects in plectin cause epidermolysis bullosa simplex (EBS), muscular dystrophy (MD), and sometimes pyloric atresia. Association of EBS with a myasthenic syndrome (MyS) was documented in a single patient in 1999. Objectives: To analyze the clinical, structural, and genetic aspects of a second and fatal case of EBS associated with a MyS and search for the genetic basis of the disease in a previously reported patient with EBS-MD-MyS. Methods: Clinical observations; histochemical, immunocytochemical, and electron microscopy studies of skeletal muscle and neuromuscular junction; and mutation analysis. Results: An African American man had EBS since early infancy, and progressive muscle weakness, hyperCKemia, and myasthenic symptoms refractory to therapy since age 3 years. Eventually he became motionless and died at age 42 years. At age 15 years, he had a marked EMG decrement, and a reduced miniature endplate potential amplitude. The myopathy was associated with dislocated muscle fiber organelles, structurally abnormal nuclei, focal plasmalemmal defects, and focal calcium ingress into muscle fibers. The neuromuscular junctions showed destruction of the junctional folds, and remodeling. Mutation analysis demonstrated a known p.Arg2319X and a novel c.12043dupG mutation in PLEC1 . The EBS-MD-MyS patient reported in 1999 also carried c.12043dupG and a novel p.Gln2057X mutation. The novel mutations were absent in 200 Caucasian and 100 African American subjects. Conclusions: The MyS in plectinopathy is attributed to destruction of the junctional folds and the myopathy to defective anchoring of muscle fiber organelles and defects in sarcolemmal integrity.

Myasthenia gravis (MG) with antibodies to muscle-specific tyrosine kinase (MuSK) receptors is characterized by prominent weakness of facial and bulbar muscles. MuSK MG often requires aggressive immunosuppression, and inadequate treatment may leave patients with permanent, fixed weakness due to structural changes in the neuromuscular junction. Even with appropriate therapy, only 50% of patients reach minimal manifestations of disease or remission.1

Objective: To determine if mycophenolate mofetil (MMF) can be tapered without worsening in patients with myasthenia gravis (MG). Background MMF is frequently used in the treatment of MG, but no studies address long term management. Design/Methods: The Duke MG Patient Database was reviewed to identify all patients who were prescribed MMF from 1999-2011. Two hundred fifty-seven patients with adequate data were identified and 147 reached Minimal Manifestation Status (MMS) or Pharmacologic Remission (PR) after starting MMF. Their records were reviewed to determine if a taper of MMF had been attempted and were analyzed for factors including initial and worst MGFA scores, duration of MG prior to starting MMF, MMF dose, and concurrent therapies. If MG symptoms recurred after the dose of MMF was tapered, the dose at which relapse occurred and the subsequent clinical course were recorded. Patients were required to be on a stable lower dose of MMF for 6 months for a taper to be deemed successful. Results: MMF taper or discontinuation was attempted in 60 of 147 patients. Forty-four attempts (73%) were successful. No significant differences were found between the taper success and failure groups, other than an increased rate of prednisone use in the relapsing group (42% vs 14%). In the sixteen patients who failed attempts at an MMF taper, most developed only ocular symptoms and 69% again achieved MMS or PR after the prior dose was restored. The mean dose at which relapse occurred was 1066 mg/day (mean starting dose 2375 mg/day). Only one patient required addition of therapy (prednisone). Conclusions: In this retrospective analysis, 73% of MG patients tolerated MMF dose reduction without worsening. Concurrent prednisone use was associated with a higher rate of taper failure. In patients who did relapse, their symptoms were minor and most improved after the prior dose was restored. Disclosure: Dr. Hobson-Webb has received personal compensation for activities with Frederick O9Connor Medical Consultants as a consultant.Dr. Hobson-Webb has received research support from Genzyme Corporation. Dr. Juel has nothing to disclose. Dr. Guptill has nothing to disclose. Dr. Massey has nothing to disclose. Dr. Sanders has received personal compensation for activities with Athena Diagnostics, Accordant Health Services, Jacobus Pharmaceuticals, CytoKinetics, Bayhill Therapeutics, and GlaxoSmithKline, Inc.