Dimachkie, Mazen M

Abstract Objectives The lack of uniform terminology and abbreviations for anti-synthetase syndrome has led to significant challenges in research and clinical practice. This study aimed to establish an international consensus on a standardized nomenclature and abbreviation among a diverse group of global myositis experts and patient representatives. Methods This qualitative project was approved by the International Myositis Assessment and Clinical Studies Group (IMACS). Based on the outcomes of a literature review and preliminary survey, list of terms for nomenclature and abbreviations was finalized. Subsequently, two rounds of the Delphi survey were conducted among myositis experts and patient participants to ascertain current practices and preferences. Using Nominal Group Technique (NGT), the project steering committee developed a consensus nomenclature and abbreviation. Results A total of 241 and 132 myositis experts from six continents, 35 countries and 9 specialities participated in round 1 and round 2 of the Delphi survey, respectively. The results indicated a preference for the terms anti-synthetase syndrome, antisynthetase syndrome and anti-tRNA synthetase syndrome. The abbreviations ASS, ASyS and ASSD were most used, though ASS received notable disapproval. The steering committee, including twenty-five myositis experts and three patient representatives from diverse backgrounds and geographical locations, reached a consensus on ‘anti-synthetase syndrome’ as the preferred nomenclature and ASyS as the preferred abbreviation, with 100% and 93.1% votes, respectively. Conclusion The terms anti-synthetase syndrome and ASyS should be adopted as the standard nomenclature and abbreviation in both research and clinical practice. This standardization is expected to increase consistency within the literature.

Abstract Objectives IBM is characterized by slowly progressive muscle weakness making it challenging to detect significant changes in weakness during a clinical trial. Trial participants receiving placebo may behave differently from in natural history studies. We aimed to quantify the change in muscle strength and IBM Functional Rating Scale (IBMFRS) of IBM patients receiving placebo during clinical trials. Methods Several databases were searched. Randomized, double-blinded, placebo-controlled trials without treatment intervention on the placebo group were included. Standardized mean differences (SMD) for change in muscle strength and mean differences for IBMFRS were used to calculate pooled effects, using DerSimonian-Laird continuous random effect models. Meta-regression determined change in muscle strength. Heterogeneity was evaluated using the I2 indicator. Results Eleven eligible trials were identified with 257 participants receiving placebo and a low risk of bias per the Cochrane Collaboration Risk of Bias 2 (RoB2) tool. Participants receiving placebo on average had a measurable decline in muscle strength with a mean effect size of –0.398 (95% CI –0.652, –0.144) (P = 0.002). SMD changed by –0.009 (–0.016, –0.002) points per week (P = 0.015). Manual muscle testing was associated with higher heterogeneity (I2 = 67.68%) compared with quantitative muscle testing (I2 = 0%). Only three studies reported IBMFRS results. The pooled change in IBMFRS at 12 months was –2.189 points (–3.893, –0.485) on this 0 to 40-point scale (P = 0.012), with relatively high heterogeneity. Conclusion Participants with IBM displayed a measurable decline in their muscle strength and IBMFRS during clinical trials, in keeping with the disease’s slowly progressive nature. These estimates can inform sample size calculations in future studies.

Importance The etiology of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, is unknown. However, neuroinflammation and complement activation may play a role in disease progression. Objective To determine the effects of zilucoplan, an inhibitor of complement C5, in individuals with ALS. Design, Setting, and Participants Zilucoplan was tested as regimen A of the HEALEY ALS Platform Trial, a phase 2 to 3 multicenter, randomized, double-blind, placebo-controlled perpetual platform clinical trial with sharing of trial infrastructure and placebo data across multiple regimens. Regimen A was conducted from August 17, 2020, to May 4, 2022. A total of 162 participants were randomized to receive zilucoplan (122 [75.3%]) or regimen-specific placebo (40 [24.7%]). An additional 124 concurrently randomized participants were randomized to receive placebo in other regimens. Interventions Eligible participants were randomized in a 3:1 ratio to receive zilucoplan or matching placebo within strata of edaravone and/or riluzole use for a planned duration of 24 weeks. Active drug (zilucoplan, 0.3 mg/kg) and placebo were provided for daily subcutaneous dosing. Main Outcomes and Measures The primary end point was change in disease severity from baseline through 24 weeks as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) total score and survival, analyzed using a bayesian shared-parameter model and reported as disease rate ratio (DRR; <1 indicating treatment benefit). The study included prespecified rules for early stopping for futility. Outcome analyses were performed in the full analysis set comparing the zilucoplan group with the total shared placebo group (n = 164). Results Among the 162 participants who were randomized (mean [SD] age, 59.6 [11.3]; 99 [61.1%] male), 115 (71.0%) completed the trial. The estimated DRR common to ALSFRS-R and survival was 1.08 (95% credible interval, 0.87-1.31; posterior probability of superiority, 0.24). The trial was stopped early for futility. No unexpected treatment-related risks were identified. Conclusions and Relevance In this randomized clinical trial of zilucoplan in ALS, treatment did not alter disease progression. The adaptive platform design of the HEALEY ALS Platform Trial made it possible to test a new investigational product with efficient use of time and resources. Trial Registration ClinicalTrials.gov Identifier: NCT04297683

Objective To assess the efficacy and tolerability of tocilizumab in a multicenter, randomized, double‐blind, placebo‐controlled trial in refractory adult patients with dermatomyositis (DM) and polymyositis (PM). Methods Thirty‐six subjects with probable or definite DM/PM were enrolled in a 6‐month phase 2B clinical trial and randomized 1:1 to receive tocilizumab (8 mg/kg intravenously) or placebo every 4 weeks for 24 weeks. Eligible subjects had either a DM rash, a myositis‐associated autoantibody or an adjudicated PM diagnosis. Active disease was defined by at least three of six abnormal core set measures (CSMs), including a manual muscle testing (MMT)‐8 score of less than 136/150. If the MMT‐8 score was greater than 136, then a cutaneous score of 3 or more (10 cm visual analogue scale) was required along with three additional abnormal CSMs indicating disease activity. The primary endpoint compared the Total Improvement Score (TIS) between both arms from week 4 to 24. Secondary outcomes included time to meeting minimal TIS improvement, changes in CSMs, time to worsening, steroid‐sparing effect, proportion of subjects meeting more stringent improvement criteria, and safety outcomes. Results There was no significant difference ( P = 0.86) in the TIS over 24 weeks between tocilizumab and placebo arms. The secondary endpoints of time to improvement (minimal, moderate, or major), time to worsening, CSM changes, safety outcomes, and steroid‐sparing effect were also not significantly different between arms. Conclusion Tocilizumab was safe and well tolerated but did not meet the primary or secondary efficacy outcomes in refractory DM and PM in this 24‐week phase 2B study.

ABSTRACT Introduction : A randomized trial demonstrated benefit from thymectomy in nonthymomatous acetylcholine receptor (AChR)‐antibody positive myasthenia gravis (MG). Uncontrolled observational and histologic studies suggest thymectomy may not be efficacious in anti–muscle‐specific kinase (MuSK)‐MG. Methods : The therapeutic impact of thymectomy was evaluated from data collected for a multicenter, retrospective blinded review of rituximab in MuSK‐MG. Results : Baseline characteristics were similar between thymectomy ( n = 26) and nonthymectomy ( n = 29) groups, including treatment with rituximab (42% vs. 45%). At last visit, 35% of thymectomy subjects reached the primary endpoint, a Myasthenia Gravis Foundation of America (MGFA) post‐intervention status (PIS) score of minimal manifestations (MM) or better, compared with 55% of controls ( P = 0.17). After controlling for age at onset of MG, rituximab, prednisone, and intravenous immunoglobulin/plasma exchange treatment, thymectomy was not associated with greater likelihood of favorable clinical outcome (odds ratio = 0.43, 95% confidence interval 0.12–1.53, P = 0.19). Discussion : Thymectomy was not associated with additional clinical improvement in this multicenter cohort of MuSK‐MG patients. Muscle Nerve 59:404–410, 2019