Marked clinical and jitter improvement after eculizumab in refractory myasthenia.

TL;DR: There was virtually complete resolution of all myasthenic symptoms and signs, with marked improvement of all clinical measures and jitter in a 55-year-old, male, phase II trial participant with a 30-year history of MG.

Abstract: Eculizumab, a humanized monoclonal antibody inhibiting terminal complement complex formation, has been evaluated in prospective phase II and phase III trials in refractory, generalized myasthenia gravis (MG). Changes in clinical measures, jitter and antibody levels were examined before and after eculizumab treatment in a 55-year-old, male, phase II trial participant with a 30-year history of MG. Bulbar symptoms began at age 25 and became generalized within 2 months. Pyridostigmine initially produced transient improvement. Prednisone up to 80 mg/day for 18 years produced limited improvement. Transsternal thymectomy (month 8) revealed thymic hyperplasia. Intravenous immunoglobulin 2 g/kg 3 2 (year 9), azathioprine 200 mg/day for 6 months (year 13), and mycophenolate mofetil 2 g/day for 7 months (year 20) produced no improvement. Cyclosporine 400 mg/day (year 14) produced some improvement, but the dose was reduced because of azotemia. Marked temporary improvement followed therapeutic plasma exchange (TPE) performed approximately every 12 months (years 25–29). Before eculizumab treatment (year 30), he had mild, generalized weakness (MGFA class 2A) and was receiving cyclosporine 100 mg/day, pyridostigmine 240 mg/day, and periodic TPE. During the clinical trial, he received eculizumab 600 mg/week for 4 weeks, 900 mg 1 week later, then maintenance eculizumab 900 mg every 2 weeks for 12 weeks. MG manual muscle testing (MG-MMT) and quantitative MG (QMG) scores and jitter and acetylcholine receptor (AChR)–binding antibody levels were assessed periodically for 18 years before and 4 years after eculizumab administration. Jitter was measured in the extensor digitorum muscle with single-fiber electromyography (SFEMG) electrodes using conventional techniques. MG–Activities of Daily Living (MG-ADL) data were assessed before and after eculizumab administration. Pyridostigmine was held for at least 12 hours before SFEMG and QMG assessments. Before eculizumab treatment, these various measures reflected stable, generalized MG: MG-ADL (mean 4.5, range 3–6); MGMMT (mean 8.9, range 5–22); QMG (mean 11.6, range 9–16); jitter [mean consecutive difference (MCD): mean 183 ls, range 140–203 ls]; and % blocking pairs (mean 80%, range 65%–90%). AChR antibodies were persistently elevated (mean 77.1, range 43.8–133 nmol/L; normal <0.02 nmol/L). Although clinical endpoint improvements in the placebo treatment period suggested a placebo effect (Fig. 1A), no significant change in jitter was observed between studies performed at the beginning (MCD: mean 182 ls; % blocking 85%) or at the end of the placebo treatment period (MCD: mean 184 ls; % blocking 90%) (Fig. 1B). One week after initial administration of eculizumab 600 mg, there was virtually complete resolution of all myasthenic symptoms and signs, with marked improvement of all clinical measures and jitter (Fig. 1) for the remainder of the 16-week study period: MG-MMT (mean 1.8, range 1–4); QMG (mean 1.2, range 1–2); jitter (MCD: mean 47 ls; % blocking 5%), MG-ADL (mean 0, range 0). AChR antibody levels were essentially unchanged (72.1 nmol/L). Hemolysis assays for complement activity were normal before eculizumab dosing, and confirmed complete complement inhibition 1 week after the initial dose. Diplopia and limb weakness recurred 5 weeks after the last eculizumab infusion and there was full relapse to pre-eculizumab baseline 4 years later, with increased MG-MMT (18) and jitter (MCD: mean 204 ls; % blocking 90%), but without a significant change in AChR antibody level (64.7 nmol/L). In conclusion, eculizumab administration in a man with chronic, refractory, generalized MG was followed by rapid, marked, temporary clinical improvement with dramatic, parallel improvement in validated clinical outcome and electrophysiological measures. These observations demonstrate the potential for rapid, robust improvement in refractory MG treated with complement inhibition. Although a phase II trial demonstrated significantly greater improvement in QMG with eculizumab treatment compared with placebo, the present report provides provided additional useful information regarding the performance of jitter as a biomarker in the VC 2017 Wiley Periodicals, Inc.