Conducting a bayesian multi-armed trial with response adaptive randomization for comparative effectiveness of medications for CSPN.

Background: Response adaptive randomization is popular in adaptive trial designs, but the literature detailing its execution is lacking. These designs are desirable for patients/stakeholders, particularly in comparative effectiveness research, due to the potential benefits including improving participant buy-in by providing more participants with better treatment during the trial. Frequentist approaches have often been used, but adaptive designs naturally fit the Bayesian methodology; it was developed to deal with data as they come in by updating prior information. Methods: PAIN-CONTRoLS was a comparative-effectiveness trial utilizing Bayesian response adaptive randomization to four drugs, nortriptyline, duloxetine, pregabalin, or mexiline, for cryptogenic sensory polyneuropathy (CSPN) patients. The aim was to determine which treatment was most tolerable and effective in reducing pain. Quit and efficacy rates were combined into a utility function to develop a single outcome, which with treatment sample size, drove the adaptive randomization. Prespecified interim analyses allowed the study to stop for early success or update the randomization probabilities to the better-performing treatments. Results: Seven adaptations to the randomization occurred before the trial ended due to reaching the maximum sample size, with more participants receiving nortriptyline and duloxetine. At the end of the follow-up, nortriptyline and duloxetine had lower probabilities of participants that had stopped taking the study medication and higher probabilities were efficacious. Mexiletine had the highest quit rate, but had an efficacy rate higher than pregabalin. Conclusions: Response adaptive randomization has become a popular trial tool, especially for those utilizing Bayesian methods for analyses. By illustrating the execution of a Bayesian adaptive design, using the PAIN-CONTRoLS trial data, this paper continues the work to provide literature for conducting Bayesian response adaptive randomized trials.

The effect of type 2 diabetes and diabetic peripheral neuropathy on predictive grip force control.

This study investigated the impact of type 2 diabetes and diabetic peripheral neuropathy on grip force control during object manipulation. The study included three age-matched groups: type 2 diabetes alone (n = 11), type 2 diabetes with neuropathy (n = 13), and healthy controls (n = 12). Grip force control variables derived from lifting and holding an experimental cup were the ratio between grip force and load forces during lifting (GFR), latency 1 and latency 2, which represented the time between the object's grip and its lift-off from the table, and the period between object's lift-off and the grip force peak, respectively; time lag, which denoted the time difference between the grip and load force peaks during the lifting phase, and finally static force, which was the grip force average during the holding phase. Grip force control variables were compared between groups using one-way ANOVA and Kruskal-Wallis test. Post-hoc analysis was used to compare differences between groups. GFR and latency 1 showed significant differences between groups; the type 2 diabetes with neuropathy group showed larger GFR than the type 2 diabetes alone and healthy control groups. The latency 1was longer for the group with neuropathy in comparison with the health control group. There were no significant differences between groups for latency 2, time lag, and static force. Our results showed impaired GFR and latency 1 in participants with type 2 diabetes with neuropathy while the time lag was preserved. People with type 2 diabetes alone might not have any deficits in grip force control. Higher grip forces might expose people with type 2 diabetes and diabetic peripheral neuropathy to the risk of fatigue and injuring their hands. Future studies should investigate strategies to help people with type 2 diabetes with neuropathy adjust grip forces during object manipulation.

Hyaluronidase-facilitated subcutaneous immunoglobulin 10% as maintenance therapy for chronic inflammatory demyelinating polyradiculoneuropathy: The ADVANCE-CIDP 1 randomized controlled trial.

BACKGROUND AND AIMS: ADVANCE-CIDP 1 evaluated facilitated subcutaneous immunoglobulin (fSCIG; human immunoglobulin G 10% with recombinant human hyaluronidase) efficacy and safety in preventing chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) relapse. METHODS: ADVANCE-CIDP 1 was a phase 3, double-blind, placebo-controlled trial conducted at 54 sites in 21 countries. Eligible adults had definite or probable CIDP and adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability scores of 0-7 (inclusive), and received stable intravenous immunoglobulin (IVIG) for ≥12 weeks before screening. After stopping IVIG, patients were randomized 1:1 to fSCIG 10% or placebo for 6 months or until relapse/discontinuation. fSCIG 10% was administered at the same dose (or matching placebo volume) and interval as pre-randomization IVIG. The primary outcome was patient proportion experiencing CIDP relapse (≥1-point increase in adjusted INCAT score from pre-subcutaneous treatment baseline) in the modified intention-to-treat population. Secondary outcomes included time to relapse and safety endpoints. RESULTS: Overall, 132 patients (mean age 54.4 years, 56.1% male) received fSCIG 10% (n = 62) or placebo (n = 70). CIDP relapse was reduced with fSCIG 10% versus placebo (n = 6 [9.7%; 95% confidence interval 4.5%, 19.6%] vs n = 22 [31.4%; 21.8%, 43.0%], respectively; absolute difference: -21.8% [-34.5%, -7.9%], p = .0045). Relapse probability was higher with placebo versus fSCIG 10% over time (p = .002). Adverse events (AEs) were more frequent with fSCIG 10% (79.0% of patients) than placebo (57.1%), but severe (1.6% vs 8.6%) and serious AEs (3.2% vs 7.1%) were less common. INTERPRETATION: fSCIG 10% more effectively prevented CIDP relapse than placebo, supporting its potential use as maintenance CIDP treatment.

Phase 2 trial in acetylcholine receptor antibody-positive myasthenia gravis of transition from intravenous to subcutaneous immunoglobulin: The MGSCIg study.

BACKGROUND AND PURPOSE: Data on maintenance therapy with subcutaneous immunoglobulin (SCIg) in myasthenia gravis (MG) are limited. We report on transitioning acetylcholine receptor (AChR) antibody-positive (Ab+) MG patients on stable intravenous immunoglobulin (IVIg) regimens as part of routine clinical care to SCIg 1:1.2. METHODS: This multicenter North American open-label prospective investigator-initiated study had two components: the IVIg Stabilization Period (ISP) enrolling patients already on IVIg as part of routine clinical care (Weeks -10 to -1), followed by transition of stable MG subjects to SCIg in the Experimental Treatment Period (ETP; Weeks 0 to 12). We hypothesized that >65% of patients entering the ETP would have a stable Quantitative Myasthenia Gravis (QMG) score from Week 0 to Week 12. Secondary outcome measures included other efficacy measures, safety, tolerability, IgG levels, and treatment satisfaction. RESULTS: We recruited 23 patients in the ISP, and 22 entered the ETP. A total of 12 subjects (54.5%) were female, and 18 (81.8%) were White, with mean age 51.4 ± 17 years. We obtained Week 12 ETP QMG data on 19 of 22; one subject withdrew from ETP owing to clinical deterioration, and two subjects withdrew due to dislike of needles. On primary analysis, 19 of 22 participants (86.4%, 95% confidence interval = 0.72-1.00) were treatment successes using last observation carried forward (p = 0.018). Secondary efficacy measures supported MG stability. SCIg was safe and well tolerated, and IgG levels were stable. Treatment satisfaction was comparable between ISP and ETP. CONCLUSIONS: MG patients on IVIg as part of their routine clinical care remained stable on monthly IVIg dosage, and most maintained similar disease stability on SCIg.

CIDP prognosis in patients with IVIG treatment-related fluctuations.

INTRODUCTION/AIMS: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired immune-mediated peripheral nerve disorder with variable prognosis and long-term dependence on immunotherapy. Frequent assessment of grip strength can be a useful tool to identify intravenous immunoglobulin (IVIG) treatment-related fluctuations (TRFs) and optimize IVIG treatment in real-time, but the long-term implications of TRFs are unknown. We aimed to explore the impact that real-time TRFs had on long-term CIDP prognosis, strength impairment, and disability. METHODS: This retrospective observational cohort study analyzed standard of care clinical and treatment outcomes in patients who participated in a published prospective study of intra-IVIG-cycle grip strength quantification. Patients were analyzed based upon the presence or absence of TRFs, as determined in the initial prospective study. RESULTS: Data were available for 23 CIDP patients with a mean follow-up period of 44.7 mo. There were no differences in baseline or follow-up strength, disability, or IVIG usage in patients with a low number of fluctuations compared to those with a high number of fluctuations. In both groups, drug-free remission was achieved in about one-third of patients. DISCUSSION: TRFs are important to identify in order to optimize treatment in real time, but poorly predict long-term disease activity status. The presence of minor TRFs are unlikely to result in substantial accumulation of disability over time. Periodic IVIG optimization trials using objective outcomes are encouraged in all CIDP patients receiving chronic IVIG treatment as a means to identify the lowest effective IVIG dose and frequency.

Long-term safety, tolerability, and efficacy of efgartigimod (ADAPT+): interim results from a phase 3 open-label extension study in participants with generalized myasthenia gravis.

Objective: ADAPT+ assessed the long-term safety, tolerability, and efficacy of efgartigimod in adult participants with generalized myasthenia gravis (gMG). Methods: ADAPT+ was an open-label, single-arm, multicenter, up to 3-year extension of the pivotal phase 3 ADAPT study. Efgartigimod was administered in treatment cycles of 4 intravenous infusions (one 10 mg/kg infusion per week). Initiation of subsequent treatment cycles was individualized based on clinical evaluation. Safety endpoints included incidence and severity of adverse events. Efficacy endpoints assessed disease severity using Myasthenia Gravis-Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) scores. Results: As of January 2022, 151 participants had rolled over to ADAPT+ and 145 had received ≥1 dose of efgartigimod, of whom, 111 (76.6%) were AChR-Ab+ and 34 (23.4%) were AChR-Ab-. Mean study duration (treatment plus follow-up) was 548 days, and participants received up to 17 treatment cycles, corresponding to 217.6 participant-years of exposure. In the overall population, 123 (84.8%) participants reported ≥1 treatment-emergent adverse event; most frequent were headache (36 [24.8%]), COVID-19 (22 [15.2%]), and nasopharyngitis (20 [13.8%]). Clinically meaningful improvement (CMI) in mean MG-ADL and QMG scores was seen as early as 1 week following the first infusion across multiple cycles in AChR-Ab+ and AChR-Ab- participants. Maximal MG-ADL and QMG improvements aligned with onset and magnitude of total IgG and AChR-Ab reductions. For AChR-Ab+ participants at any time point in each of the first 10 treatment cycles, more than 90% had a maximum reduction of ≥2 points (CMI) in MG-ADL total score; across the 7 cycles in which QMG was measured, 69.4% to 91.3% of participants demonstrated a maximum reduction of ≥3 points (CMI) in QMG total score. Many participants demonstrated improvements well beyond CMI thresholds. In AChR-Ab+ participants with ≥1 year of combined follow-up between ADAPT and ADAPT+, mean number of annualized cycles was 4.7 per year (median [range] 5.0 [0.5-7.6]). Conclusion: Results of ADAPT+ corroborate the substantial clinical improvements seen with efgartigimod in ADAPT and support its long-term safety, tolerability, and efficacy, as well as an individualized dosing regimen for treatment of gMG. Clinical trial registration: https://classic.clinicaltrials.gov/ct2/show/NCT03770403, NCT03770403.

Non-dystrophic myotonia: 2-year clinical and patient reported outcomes.

INTRODUCTION/AIMS: Consistency of differences between non-dystrophic myotonias over time measured by standardized clinical/patient-reported outcomes is lacking. Evaluation of longitudinal data could establish clinically relevant endpoints for future research. METHODS: Data from prospective observational study of 95 definite/clinically suspected non-dystrophic myotonia participants (six sites in the United States, United Kingdom, and Canada) between March 2006 and March 2009 were analyzed. Outcomes included: standardized symptom interview/exam, Short Form-36, Individualized Neuromuscular Quality of Life (INQoL), electrophysiological short/prolonged exercise tests, manual muscle testing, quantitative grip strength, modified get-up-and-go test. Patterns were assigned as described by Fournier et al. Comparisons were restricted to confirmed sodium channelopathies (SCN4A, baseline, year 1, year 2: n = 34, 19, 13), chloride channelopathies (CLCN1, n = 32, 26, 18), and myotonic dystrophy type 2 (DM2, n = 9, 6, 2). RESULTS: Muscle stiffness was the most frequent symptom over time (54.7%-64.7%). Eyelid myotonia and paradoxical handgrip/eyelid myotonia were more frequent in SCN4A. Grip strength and combined manual muscle testing remained stable. Modified get-up-and-go showed less warm up in SCN4A but remained stable. Median post short exercise decrement was stable, except for SCN4A (baseline to year 2 decrement difference 16.6% [Q1, Q3: 9.5, 39.2]). Fournier patterns type 2 (CLCN1) and 1 (SCN4A) were most specific; 40.4% of participants had a change in pattern over time. INQoL showed higher impact for SCN4A and DM2 with scores stable over time. DISCUSSION: Symptom frequency and clinical outcome assessments were stable with defined variability in myotonia measures supporting trial designs like cross over or combined n-of-1 as important for rare disorders.

A secondary analysis of PAIN-CONTRoLS: Pain's impact on sleep, fatigue, and activities of daily living.

INTRODUCTION/AIMS: Peripheral neuropathies commonly affect quality of life of patients due to pain, sleep disturbances, and fatigue, although trials have not adequately explored these domains of care. The aim of this study was to assess the impact of nortriptyline, duloxetine, pregabalin, and mexiletine on pain, sleep, and fatigue in patients diagnosed with cryptogenic sensory polyneuropathy (CSPN). METHODS: We implemented a Bayesian adaptive design to perform a 12-wk multisite, randomized, prospective, open-label comparative effectiveness study in 402 CSPN patients. Participants received either nortriptyline (n = 134), duloxetine (n = 126), pregabalin (n = 73), or mexiletine (n = 69). At prespecified analysis timepoints, secondary outcomes, Patient Reported Outcomes Measurement Information System (PROMIS) surveys including Short Form (SF)-12, pain interference, fatigue, and sleep disturbance, were collected. RESULTS: Mexiletine had the highest quit rate (58%) due to gastrointestinal side effects, while nortriptyline (38%) and duloxetine (38%) had the lowest quit rates. If tolerated for the full 12 wk of the study, mexiletine had the highest probability (>90%) of positive outcomes for improvements in pain interference and fatigue. There was no significant difference among the medications for sleep disturbance or SF-12 scores. Adverse events and lack of efficacy were the two most common reasons for cessation of therapy. DISCUSSION: Physicians caring for patients with CSPN should consider mexiletine to address pain and fatigue, although nortriptyline and duloxetine are better medications to trial first since they are better tolerated. Future research should compare other commonly used medications for CSPN to determine evidence-based treatment strategies.

Open-label pilot study of ranolazine for cramps in amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Neuronal hyperexcitability (manifested by cramps) plays a pathological role in amyotrophic lateral sclerosis (ALS), and drugs affecting it may help symptomatic management and slow disease progression. We aimed to determine safety and tolerability of two doses of ranolazine in patients with ALS and evaluate for preliminary evidence of drug-target engagement by assessing muscle cramp characteristics. METHODS: We performed an open-label dose-ascending study of ranolazine in 14 individuals with ALS in two sequential cohorts: 500 mg (cohort 1) and 1000 mg (cohort 2) orally twice daily. Each had a 2-week run-in period, 4-week drug administration, and 6-week safety follow-up. Primary outcome was safety and tolerability. Exploratory measures included cramp frequency and severity, fasciculation frequency, cramp potential duration, ALS Functional Rating Scale---Revised score, and forced vital capacity. RESULTS: Six and eight participants were enrolled in cohorts 1 and 2, respectively. There were no serious adverse events. Two subjects in cohort 2 discontinued the drug due to constipation. The most frequent drug-related adverse event was gastrointestinal (40%). Cramp frequency decreased by 54.8% (95% confidence interval [CI], 39%-70.8%) and severity decreased by 46.3% (95% CI, 29.5-63.3%), which appeared to be dose-dependent, with decreased awakening due to cramps. Other outcomes showed no change. DISCUSSION: Ranolazine was well tolerated in ALS up to 2000 mg/day, with gastrointestinal side effects being the most frequent. Ranolazine reduced cramp frequency and severity, supporting its investigation for muscle cramps in a future placebo-controlled trial.

IgG regulation through FcRn blocking: A novel mechanism for the treatment of myasthenia gravis.

The neonatal Fc receptor (FcRn) is an MHC class I-like molecule that is widely distributed in mammalian organs, tissues, and cells. FcRn is critical to maintaining immunoglobulin G (IgG) and albumin levels through rescuing these molecules from lysosomal degradation. IgG autoantibodies are associated with many autoimmune diseases, including myasthenia gravis (MG), a rare neuromuscular autoimmune disease that causes debilitating and, in its generalized form (gMG), potentially life-threatening muscle weakness. IgG autoantibodies are directly pathogenic in MG and target neuromuscular junction proteins, causing neuromuscular transmission failure. Treatment approaches that reduce autoantibody levels, such as therapeutic plasma exchange and intravenous immunoglobulin, have been shown to be effective for gMG patients but are not indicated as ongoing maintenance therapies and can be associated with burdensome side effects. Agents that block FcRn-mediated recycling of IgG represent a rational and promising approach for the treatment of gMG. Blocking FcRn allows targeted reduction of all IgG subtypes without decreasing concentrations of other Ig isotypes; therefore, FcRn blocking could be a safe and effective treatment strategy for a broad population of gMG patients. Several FcRn-blocking antibodies and one antibody Fc fragment have been developed and are currently in various stages of clinical development. This article describes the mechanism of FcRn blockade as a novel approach for IgG-mediated disease therapy and reviews promising clinical data using such FcRn blockers for the treatment of gMG.

Quantifying Treatment-Related Fluctuations in CIDP: Results of the GRIPPER Study.

OBJECTIVE: The objective of this study was to explore the extent of IV immunoglobulin (IVIG) treatment-related fluctuations (TRFs) by using home collection of daily grip strength in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and to use that information to develop evidence-based treatment optimization strategies. METHODS: This prospective observational study included 25 patients with well-defined CIDP. Participants recorded grip strength daily for 6 months. Disability and gait metrics were collected weekly. Serum immunoglobulin G levels were obtained at peak, trough, and midcycle IVIG intervals. Day-to-day grip strength changes <10% were considered random. To identify patients with TRFs, 3-day averaged grip strength was calculated on each consecutive day after an IVIG infusion. TRFs were defined as ≥10% 3-day averaged grip strength difference compared to the pre-IVIG baseline. RESULTS: Participants successfully recorded grip strength on all but 9% of recordable days. Twelve patients (48%) were classified as low/no fluctuaters and 13 (52%) as frequent fluctuaters. In the frequent fluctuating group, grip strength improved over 1 week and thereafter was relatively stable until the third week after infusion. Grip strength was significantly correlated with measures of disability. CONCLUSIONS: Grip strength collection by patients at home is reliable, valid, and feasible. A change in grip strength by ≥10% is a useful, practical, and evidence-based approach that may be used to identify clinically meaningful TRFs. From these data, we propose a treatment optimization strategy for patients with CIDP on chronic IVIG that may be applied to routine clinic care during both face-to-face and virtual video or telephone patient encounters. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT02414490.

Patient Assisted Intervention for Neuropathy: Comparison of Treatment in Real Life Situations (PAIN-CONTRoLS): Bayesian Adaptive Comparative Effectiveness Randomized Trial.

Importance: Cryptogenic sensory polyneuropathy (CSPN) is a common generalized slowly progressive neuropathy, second in prevalence only to diabetic neuropathy. Most patients with CSPN have significant pain. Many medications have been tried for pain reduction in CSPN, including antiepileptics, antidepressants, and sodium channel blockers. There are no comparative studies that identify the most effective medication for pain reduction in CSPN. Objective: To determine which medication (pregabalin, duloxetine, nortriptyline, or mexiletine) is most effective for reducing neuropathic pain and best tolerated in patients with CSPN. Design, Setting, and Participants: From December 1, 2014, through October 20, 2017, a bayesian adaptive, open-label randomized clinical comparative effectiveness study of pain in 402 participants with CSPN was conducted at 40 neurology care clinics. The trial included response adaptive randomization. Participants were patients with CSPN who were 30 years or older, with a pain score of 4 or greater on a numerical rating scale (range, 0-10, with higher scores indicating a higher level of pain). Participant allocation to 1 of 4 drug groups used the utility function and treatment's sample size for response adaptation randomization. At each interim analysis, a decision was made to continue enrolling (up to 400 participants) or stop the whole trial for success (80% power). Patient engagement was maintained throughout the trial, which helped guide the study and identify ways to communicate and disseminate information. Analysis was performed from December 11, 2015, to January 19, 2018. Interventions: Participants were randomized to receive nortriptyline (n = 134), duloxetine (n = 126), pregabalin (n = 73), or mexiletine (n = 69). Main Outcomes and Measures: The primary outcome was a utility function that was a composite of the efficacy (participant reported pain reduction of ≥50% from baseline to week 12) and quit (participants who discontinued medication) rates. Results: Among the 402 participants (213 men [53.0%]; mean [SD] age, 60.1 [13.4] years; 343 White [85.3%]), the utility function of nortriptyline was 0.81 (95% bayesian credible interval [CrI], 0.69-0.93; 34 of 134 [25.4%] efficacious; and 51 of 134 [38.1%] quit), of duloxetine was 0.80 (95% CrI, 0.68-0.92; 29 of 126 [23.0%] efficacious; and 47 of 126 [37.3%] quit), pregabalin was 0.69 (95% CrI, 0.55-0.84; 11 of 73 [15.1%] efficacious; and 31 of 73 [42.5%] quit), and mexiletine was 0.58 (95% CrI, 0.42-0.75; 14 of 69 [20.3%] efficacious; and 40 of 69 [58.0%] quit). The probability each medication yielded the highest utility was 0.52 for nortriptyline, 0.43 for duloxetine, 0.05 for pregabalin, and 0.00 for mexiletine. Conclusions and Relevance: This study found that, although there was no clearly superior medication, nortriptyline and duloxetine outperformed pregabalin and mexiletine when pain reduction and undesirable adverse effects are combined to a single end point. Trial Registration: ClinicalTrials.gov Identifier: NCT02260388.

Epidemiological evidence for a hereditary contribution to myasthenia gravis: a retrospective cohort study of patients from North America.

OBJECTIVES: To approximate the rate of familial myasthenia gravis and the coexistence of other autoimmune disorders in the patients and their families. DESIGN: Retrospective cohort study. SETTING: Clinics across North America. PARTICIPANTS: The study included 1032 patients diagnosed with acetylcholine receptor antibody (AChR)-positive myasthenia gravis. METHODS: Phenotype information of 1032 patients diagnosed with AChR-positive myasthenia gravis was obtained from clinics at 14 centres across North America between January 2010 and January 2011. A critical review of the epidemiological literature on the familial rate of myasthenia gravis was also performed. RESULTS: Among 1032 patients, 58 (5.6%) reported a family history of myasthenia gravis. A history of autoimmune diseases was present in 26.6% of patients and in 28.4% of their family members. DISCUSSION: The familial rate of myasthenia gravis was higher than would be expected for a sporadic disease. Furthermore, a high proportion of patients had a personal or family history of autoimmune disease. Taken together, these findings suggest a genetic contribution to the pathogenesis of myasthenia gravis.

Clinical features of LRP4/agrin-antibody-positive myasthenia gravis: A multicenter study.

INTRODUCTION: Our aim in this study was to identify the prevalence and clinical characteristics of LRP4/agrin-antibody-positive double-seronegative myasthenia gravis (DNMG). METHODS: DNMG patients at 16 sites in the United States were tested for LRP4 and agrin antibodies, and the clinical data were collected. RESULTS: Of 181 DNMG patients, 27 (14.9%) were positive for either low-density lipoprotein receptor-related protein 4 (LRP4) or agrin antibodies. Twenty-three DNMG patients (12.7%) were positive for both antibodies. More antibody-positive patients presented with generalized symptoms (69%) compared with antibody-negative patients (43%) (P ≤ .02). Antibody-positive patients' maximum classification on the Myasthenia Gravis Foundation of America (MGFA) scale was significantly higher than that for antibody-negative patients (P ≤ .005). Seventy percent of antibody-positive patients were classified as MGFA class III, IV, or V compared with 39% of antibody-negative patients. Most LRP4- and agrin-antibody-positive patients (24 of 27, 89%) developed generalized myathenia gravis (MG), but with standard MG treatment 81.5% (22 of 27) improved to MGFA class I or II during a mean follow-up of 11 years. DISCUSSION: Antibody-positive patients had more severe clinical disease than antibody-negative patients. Most DNMG patients responded to standard therapy regardless of antibody status.

Methotrexate Polyglutamation in a Myasthenia Gravis Clinical Trial.

INTRODUCTION: Methotrexate (MTX) is an immunosuppressive and anti-inflammatory drug used to treat rheumatoid arthritis (RA) and other autoimmune conditions. MTX is transported into cells, where glutamate moieties are added and is retained as methotrexate polyglutamates (MTXPGs). In the RA literature, it has been reported that the degree of polyglutamation correlates with the anti-inflammatory effect of MTX in RA. There are no prior studies evaluating the relationship between MTXPGs and myasthenia gravis (MG) outcome measures. The objective of this study was to assess the correlation between methotrexate (MTX) polyglutamates (MTXPGs) with Myasthenia Gravis (MG) outcome measures. METHODS: An analysis was done of blood drawn from patients enrolled in the 12-month randomized, placebo-controlled study of MTX in MG study. Red blood cell MTXPGs were measured via ultra-performance liquid chromatography and tandem mass spectrometry. MTXPG was correlated to MG outcome measures using Spearman Correlation Coefficient. A two-group t-test was used to determine the difference in MTXPG based on clinical outcome responder definitions. RESULTS: Twenty-one polyglutamate samples were analyzed of subjects on MTX while eight samples were analyzed from subjects on placebo. Pentaglutamate had the strongest correlation with the MG-ADL (0.99), while tetraglutamate had the strongest correlation with the QMG (0.54). Triglutamate had the strongest correlation with MGC (0.76). CONCLUSION: There were variable correlations between MTXPG1-5 and MG outcomes (rho range: 0.08 to 0.99). There are strong correlations between MTXPG and the MG-ADL, QMG, and MGC. Long chain methotrexate polyglutamates correlate better with MG outcomes.

Clinical Effects of the Self-administered Subcutaneous Complement Inhibitor Zilucoplan in Patients With Moderate to Severe Generalized Myasthenia Gravis: Results of a Phase 2 Randomized, Double-Blind, Placebo-Controlled, Multicenter Clinical Trial.

Importance: Many patients with generalized myasthenia gravis (gMG) have substantial clinical disability, persistent disease burden, and adverse effects attributable to chronic immunosuppression. Therefore, there is a significant need for targeted, well-tolerated therapies with the potential to improve disease control and enhance quality of life. Objective: To evaluate the clinical effects of zilucoplan, a subcutaneously (SC) self-administered macrocyclic peptide inhibitor of complement component 5, in a broad population of patients with moderate to severe gMG. Design, Setting, and Participants: This randomized, double-blind, placebo-controlled phase 2 clinical trial at 25 study sites across North America recruited participants between December 2017 and August 2018. Fifty-seven patients were screened, of whom 12 did not meet inclusion criteria and 1 was lost to follow-up after randomization but before receiving study drug, resulting in a total of 44 acetylcholine receptor autoantibody (AChR-Ab)-positive patients with gMG with baseline Quantitative Myasthenia Gravis (QMG) scores of at least 12, regardless of treatment history. Interventions: Patients were randomized 1:1:1 to a daily SC self-injection of placebo, 0.1-mg/kg zilucoplan, or 0.3-mg/kg zilucoplan for 12 weeks. Main Outcomes and Measures: The primary and key secondary end points were the change from baseline to week 12 in QMG and MG Activities of Daily Living scores, respectively. Significance testing was prespecified at a 1-sided α of .10. Safety and tolerability were also assessed. Results: The study of 44 patients was well balanced across the 3 treatment arms with respect to key demographic and disease-specific variables. The mean age of patients across all 3 treatment groups ranged from 45.5 to 54.6 years and most patients were white (average proportions across 3 treatment groups: 78.6%-86.7%). Clinically meaningful and statistically significant improvements in primary and key secondary efficacy end points were observed. Zilucoplan at a dose of 0.3 mg/kg SC daily resulted in a mean reduction from baseline of 6.0 points in the QMG score (placebo-corrected change, -2.8; P = .05) and 3.4 points in the MG Activities of Daily Living score (placebo-corrected change, -2.3; P = .04). Clinically meaningful and statistically significant improvements were also observed in other secondary end points, the MG Composite and MG Quality-of-Life scores. Outcomes for the 0.1-mg/kg SC daily dose were also statistically significant but slower in onset and less pronounced than with the 0.3-mg/kg dose. Rescue therapy (intravenous immunoglobulin or plasma exchange) was required in 3 of 15, 1 of 15, and 0 of 14 participants in the placebo, 0.1-mg/kg zilucoplan, and 0.3-mg/kg zilucoplan arms, respectively. Zilucoplan was observed to have a favorable safety and tolerability profile. Conclusions and Relevance: Zilucoplan yielded rapid, meaningful, and sustained improvements over 12 weeks in a broad population of patients with moderate to severe AChR-Ab-positive gMG. Near-complete complement inhibition appeared superior to submaximal inhibition. The observed safety and tolerability profile of zilucoplan was favorable. Trial Registration: ClinicalTrials.gov Identifier: NCT03315130.

Rituximab in refractory chronic inflammatory demyelinating polyneuropathy.

INTRODUCTION: Chronic inflammatory demyelinating polyneuropathy (CIDP) is a disorder in which early effective treatment is important to minimize disability from axonal degeneration. It has been suggested that some patients with CIDP may benefit from rituximab therapy, but there is no definitive evidence for this. METHODS: Baseline and post-rituximab-therapy neuromuscular Medical Research Council (MRC) sum scores, Inflammatory Neuropathy Cause and Treatment (INCAT) disability score, and functional status were assessed in 11 patients with refactory CIDP. RESULTS: The MRC sum score, INCAT disability score, and functional status improved in all patients after rituximab therapy. DISCUSSION: Our study provides evidence of the efficacy of rituximab therapy in at least some patients with CIDP. A placebo-controlled study to assess the effectiveness of rituximab therapy in CIDP with and without nodal antibodies is required to identify disease markers that predict responsiveness.

Immunosuppressive and immunomodulatory therapies for neuromuscular diseases. Part I: Traditional agents.

Immunosuppressive and immunomodulatory therapies have had a major effect on the treatment of immune-mediated neuromuscular diseases. After the landmark introduction of synthetic corticosteroids, other therapies have become available, including plasma exchange (PLEX), immunoglobulin G (IgG), and steroid-sparing immunosuppressive drugs. More recently, novel biologically derived and antigen-specific pharmaceuticals have entered neuromuscular practice. Various levels of evidence guide the use of these treatments. This article reviews current immune-based therapies in neuromuscular diseases and is divided into two parts. Part I provides an update on the evidence and use of traditional therapies, such as corticosteroids, PLEX, intravenously delivered IgG (IVIG), and steroid-sparing immunosuppressive drugs. Part II focuses on the recently US Food and Drug Administration-approved therapies eculizumab and subcutaneous IgG (SCIG), the current indications for rituximab in neuromuscular disease, and on novel immunosuppressive therapeutic approaches under development.

Immunosuppressive and immunomodulatory therapies for neuromuscular diseases. Part II: New and novel agents.

While traditional immunosuppressive and immunomodulatory therapies remain the cornerstone of immune-mediated neuromuscular disease management, new and novel agents including antigen-specific, monoclonal antibody drugs, have emerged as important treatment options. This article is the second of a two-part series that reviews immune-based therapies in neuromuscular diseases. The first article provides an update on the use of traditional immune-based therapies such as corticosteroids, plasma exchange, steroid-sparing immunosuppressive drugs, and intravenous immunoglobulin G. This second article focuses on new and novel immune-based therapies, including eculizumab, a complement inhibitor approved for acetylcholine receptor antibody-positive myasthenia gravis; rituximab, a B-cell depletion therapy with evolving indications in neuromuscular diseases; and the subcutaneous formulation of immunoglobulin G that gained approval for use in chronic inflammatory demyelinating polyradiculoneuropathy in 2018. Finally, several novel antigen-specific drugs at different stages of investigation in neuromuscular disease are also reviewed.

Approach to Muscle and Neuromuscular Junction Disorders.

PURPOSE OF REVIEW: Muscle and neuromuscular junction disorders are a diverse group of disorders that can be difficult to diagnose. This article provides a diagnostic approach based on clinical history and neurologic examination leading to a narrow set of diagnostic tests. RECENT FINDINGS: Numerous discoveries in recent years have facilitated clinician access to more advanced laboratory and genetic testing to pinpoint the exact diagnosis in patients with muscle or neuromuscular junction disorders. Large-scale genetic testing has become much less expensive, and free testing has become available for many of the rare conditions because of increased research and the availability of effective therapies for these rare disorders. SUMMARY: The approach to muscle and neuromuscular junction disorders depends on the clinical pattern of muscle weakness. By classifying patients into one of 10 muscle patterns, diagnostic testing can be targeted and gene testing yield will be optimized. With the increased accessibility and reduced cost of genetic testing (eg, gene panels, whole-exome sequencing, whole-genome sequencing, and chromosomal microarray), this clinical approach to muscle weakness and targeted gene testing will ensure a cost-effective investigational plan. This clinical approach should also assist clinicians in making a timely and accurate diagnosis.