Serum antibodies to muscle specific kinase (MuSK) are present in a proportion of patients with acetylcholine receptor antibody seronegative myasthenia gravis (SNMG), but their reported frequencies in different populations vary. From 2002, serum samples were sent to Oxford for MuSK antibody testing from 35 centres in 6 continents. MuSK antibodies were identified in 143/465 (30.8%) previously untested SNMG sera. They were not identified in 147 adult acetylcholine receptor antibody positive patients or in 63 adult ocular MG patients. As expected from subsequent reports, the MuSK antibody positive patients differed in gender, clinical severity, bulbar predominance and treatment requirements from the 322/465 (69.2%) MuSK antibody negative SNMG patients, but they were improved following the more aggressive treatments received, although still showing bulbar predominance. Similar features were seen in the 42 childhood cases tested (17/42 (40%) MuSK-Ab positive from 18 centres); although numbers were small there was bulbar predominance that persisted after the treatments that were more extensive than those given to the juvenile SNMG patients. Although found in each continent, MuSK-MG showed an unexpected and surprising distribution. The frequency of MuSK-Abs within individual centres varied in the Northern Hemisphere with a clear north-south gradient from 0% to 47% in Europe and North America. There were fewer cohorts from Asia but data from 11 publications, including five from East and South East Asia, confirmed a latitudinal distribution of MuSK-Ab frequency consistent with a Gaussian curve peaking at 40 degrees North, and trending towards very low frequencies above this latitude in Europe and below this latitude in South East Asia. Thus, MuSK-Abs, that are predominantly IgG4 rather than IgG1 subclass, show a striking and unexpected relationship with latitude in the Northern Hemisphere. The results raise interesting questions regarding the environmental and genetic factors involved, with possible relevance also for the increasing number of IgG4 antibody-mediated neurological disorders, including forms of neuropathy and autoimmune encephalitis.

Background: AChR antibodies (Abs) in Myasthnia Gravis (MG) are detected in approximately 50% of ocular and 85% of generalized MG by the current gold standard radioimmunoprecipitation assay (RIPA). Recently, fixed and lived Cell-Based assays (L-CBA) are developed. We clinically validated our in-house L-CBA in detecting AChR Ab in clinically suspected MG patients. Methods: Between January 2020 and April 2022, we assayed 10167 sera for AChR Ab by RIPA. We also assayed 4349 of AChR Ab seronegative sera of the above suspected MG samples for anti-MuSK Ab by RIPA. Then 1228 sera of double seronegative and/or borderline AChR Ab was assessed by L-CBA for AChR Ab. For clinical validation, we obtained clinical information on 36 seropositive cases for AChR Ab by L-CBA. Results: We found additional eighty-four cases seropositive for AChR Ab by L-CBA. The clinical information was obtained for 36 cases and based on their final diagnosis, twenty had generalized MG, thirteen had ocular MG, 2 not yet diagnosed and 1 case was of not-MG. Conclusions: The L- CBA has demonstrated improved sensitivity and higher diagnostics performance than RIPA. The L-CBA allowed improved clinical diagnosis and increased seropositivity (by 7%) in clinically suspected MG patients who were earlier seronegative/borderline for AChR Ab by RIPA.

Background: MOG-IgG is associated with non-MS demyelinating disease of the optic nerves, spinal cord and brain. Specificity has been issue so we validated the live and fixed MOG-IgG CBAs against the Oxford Autoimmune Neurology Diagnostic Laboratory (OANG) live CBA as a comparator with high specificity. Methods: At BC Neuroimmunology lab (BCNI), 54 MOG-IgG serum samples previously positive by live-CBA at OANG and BCNI were blindly tested by commercial fixed CBA. All 54 MOG IgG positives came from MOG-IgG positive patients. In addition, 256 samples from healthy people and other neurolgic disease were tested. Results: The live MOG-IgG CBA performed at BCNI was 100% concordant (54/54) with OANG live CBA. In contrast, only 49/54 samples were found seropositive by the commercial fixed CBA. The BCNI live-CBA identified 3/256 control samples as positive while 6/256 controls were positive on the fixed commercial CBA. On this cohort the live CBA is 100% sensitive, 98.8% specific and has PPV of 95%. The commercial fixed MOG test is 91% sensitive, 97.6% specific and has PPV of 87.5%. Conclusions: BCNI live MOG-IgG CBAs are in 100% agreement with MOG-IgG. Three positive results in non-MOGAD associated clinical phenotype require further investigation. These data confirm the superiority of the live MOG CBA.

Muscle-specific kinase (MuSK) myasthenia gravis (MG) is often a more severe form of MG that presents with a rapid onset and prominent bulbar symptoms. Today, the diagnosis of MuSK MG is heavily reliant on the antibody (Ab) status of the patient. In most laboratories worldwide, the Abs are measured by radio immune precipitation assay (RIPA). We have developed another testing platform using surface plasmon resonance (SPR) technology. Our aim was to measure the clinical sensitivity and specificity for two different MuSK Ab assays.

Myasthenia gravis (MG) is a heterogeneous condition, characterized by autoantibodies (Abs) that target functionally important structures within neuromuscular junctions (NMJ), thus affecting nerve-to-muscle transmission. MG patients are more often now subgrouped based on the profile of serum autoantibodies, which segregate with clinical presentation, immunopathology, and their response to therapies. The serological testing plays an essential role in confirming MG diagnosis and guiding disease management, although a small percentage of MG patients remain negative for antibodies. With the advancements in new highly effective pathophysiologically-specific immunotherapeutic options, it has become increasingly important to identify the specific Abs responsible for the pathogenicity in individual MG patients. There are several new assays and protocols being developed for the improved detection of Abs in MG patients. This review focuses on the divergent immunopathological mechanisms in MG, and discusses their relevance to improved diagnostic and treatment. We propose a comprehensive “reflex testing,” algorithm for the presence of MG autoantibodies, and foresee that in the near future, the convenience and specificity of novel assays will permit the clinicians to consider them into routine systematic testing, thus stimulating laboratories to make these tests available. Moreover, adopting treatment driven testing algorithms will be crucial to identify subgroups of patients potentially benefiting from novel immunotherapies for MG.

Myasthenia gravis (MG) is a heterogeneous condition, characterized by autoantibodies (Abs) that target functionally important structures within neuromuscular junctions (NMJ), thus affecting nerve-to-muscle transmission. MG patients are more often now subgrouped based on the profile of serum autoantibodies, which segregate with clinical presentation, immunopathology, and their response to therapies. The serological testing plays an essential role in confirming MG diagnosis and guiding disease management, although a small percentage of MG patients remain negative for antibodies. With the advancements in new highly effective pathophysiologically-specific immunotherapeutic options, it has become increasingly important to identify the specific Abs responsible for the pathogenicity in individual MG patients. There are several new assays and protocols being developed for the improved detection of Abs in MG patients. This review focuses on the divergent immunopathological mechanisms in MG, and discusses their relevance to improved diagnostic and treatment. We propose a comprehensive "reflex testing," algorithm for the presence of MG autoantibodies, and foresee that in the near future, the convenience and specificity of novel assays will permit the clinicians to consider them into routine systematic testing, thus stimulating laboratories to make these tests available. Moreover, adopting treatment driven testing algorithms will be crucial to identify subgroups of patients potentially benefiting from novel immunotherapies for MG.

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.

Worldwide, the beta interferons remain the most commonly prescribed disease-modifying drugs for multiple sclerosis. However, it is unclear if they alter survival. We investigated the association between beta interferon and mortality in the 'real-world' setting. This was a multi-centre population-based observational study of patients with relapsing-onset multiple sclerosis who were initially registered at a clinic in British Columbia, Canada (1980-2004) or Rennes, France (1976-2013). Data on this cohort were accessed from the clinical multiple sclerosis databases and from individually linked health administrative data; all data were collected prospectively. Participants were followed from the latter of their first multiple sclerosis clinic visit, 18th birthday or 1 January 1996; until death, emigration or 31 December 2013. Only those who were naïve to disease-modifying therapy and immunosuppressant treatment of multiple sclerosis at the start of their follow-up were included in the analysis. A nested case-control approach was used. Up to 20 controls, matched to cases (deaths) by country, sex, age ± 5 years, year and disability level at study entry, were randomly selected from the cohort by incidence density sampling. The associations between all-cause mortality and at least 6 months beta interferon exposure, and also cumulative exposure ('low', 6 months to 3 years; and 'high', >3 years), were estimated by conditional logistic regression adjusting for treatment with other disease-modifying therapies and age in years. Further analyses included separate analyses by sex and country, additional adjustment for comorbidity burden in the Canadian cohort, and estimation of the association between beta interferon and multiple sclerosis-related death in both countries. Among 5989 participants (75% female) with a mean age of 42 (standard deviation, SD 11) years at study entry, there were 742 deaths (70% female) and the mean age at death was 61 (SD 13) years. Of these cases, 649 were matched to between one and 20 controls. Results of the conditional logistic regression analyses are expressed as adjusted odds ratios with 95% confidence intervals. The odds of beta interferon exposure were 32% lower among cases than controls (0.68; 0.53-0.89). Increased survival was associated with >3 years beta interferon exposure (0.44; 0.30-0.66), but not between 6 months and 3 years exposure (1.00; 0.73-1.38). Findings were similar within sex and country, and for multiple sclerosis-related death. Beta interferon treatment was associated with a lower mortality risk among people with relapsing-onset multiple sclerosis. Findings were consistent between two geographically distinct regions in North America and Europe.

OBJECTIVE To examine whether sustained minimal manifestation status (MMS) with complete withdrawal of prednisone is better achieved in thymectomized myasthenia gravis (MG) patients. METHODS This study is a post hoc analysis of data from the randomized trial of thymectomy in myasthenia gravis (MGTX). MGTX was a multicenter, randomized, rater-blinded 3-year trial that was followed by a voluntary 2-year extension for patients with acetylcholine receptor (AChR) antibody positive MG without thymoma. Patients were randomized 1:1 to thymectomy plus prednisone versus prednisone alone. Participants were age 18-65 years at enrollment with disease duration less than 5 years. All patients received oral prednisone titrated up to 100mg on alternate-days until they achieved MMS, which prompted a standardized prednisone taper as long as MMS was maintained. The achievement rate of sustained MMS (no symptoms of MG for 6 months) with complete withdrawal of prednisone, was compared between the thymectomy plus prednisone and prednisone alone groups. RESULTS MG patients in the thymectomy plus prednisone group achieved sustained MMS with complete withdrawal of prednisone more frequently (64% vs 38%) and quickly compared to the prednisone alone group (median time 30 months vs no median time achieved, P<0.001) over the 5-year study period. Prednisone associated adverse symptoms were more frequent in the prednisone alone group and distress level increased with higher doses of prednisone. CONCLUSIONS Thymectomy benefits MG patients by increasing the likelihood of achieving sustained MMS with complete withdrawal of prednisone. TRIAL REGISTRATION The trial was registered on clinicaltrials.gov, number NCT00294658Classification of Evidence: This study provides Class II evidence that for generalized MG patients with AChR antibody, those receiving thymectomy plus prednisone are more likely to attain sustained MMS and complete prednisone withdrawal than those on prednisone alone.

Background Because multiple sclerosis (MS) is a chronic disease causing disability over decades, it is crucial to know if the short-term effects of disease-modifying therapies reported in randomised controlled trials reduce long-term disability. This 10-year prospective observational study of disability outcomes (Expanded Disability Status Scale (EDSS) and utility) was set up, in conjunction with a risk-sharing agreement between payers and producers, to investigate this issue. Methods The outcomes of the UK treated patients were compared with a modelled untreated control based on the British Columbia MS data set to assess the long-term effectiveness of these treatments. Two complementary analysis models were used: a multilevel model (MLM) and a continuous Markov model. Results 4862 patients with MS were eligible for the primary analysis (mean and median follow-up times 8.7 and 10 years). EDSS worsening was reduced by 28% (MLM), 7% (Markov) and 24% time-adjusted Markov in the total cohort, and by 31% (MLM) and 14% (Markov) for relapsing remitting patients. The utility worsening was reduced by 23%–24% in the total cohort and by 24%–31% in the RR patients depending on the model used. All sensitivity analyses showed a treatment effect. There was a 4-year (CI 2.7 to 5.3) delay to EDSS 6.0. An apparent waning of treatment effect with time was seen. Subgroup analyses suggested better treatment effects in those treated earlier and with lower EDSS scores. Conclusions This study supports a beneficial effect on long-term disability with first-line MS disease-modifying treatments, which is clinically meaningful. However the waning effect noted requires further study.

Background: Lifespan is 6–10 years shorter in multiple sclerosis (MS), but the reasons remain unclear. Using linked clinical- and population-based administrative health databases, we compared cause-specific mortality in an MS cohort to the general population. Methods: MS patients in British Columbia (BC), Canada, were followed from the later of first MS clinic visit or January 1, 1986, to the earlier of death, emigration, or December 31, 2013. Comprehensive mortality information was obtained by linkage to BC’s multiple-cause-of-death mortality data. Causes were grouped using International Classification of Disease codes. Standardized mortality ratios (SMRs) were calculated for underlying cause, and relative mortality ratios (RMRs) for any mention cause, by comparison to mortality rates in the age-, sex-, and calendar year-matched general population. Cause-specific relative mortality was explored by sex and disease course (relapsing onset and primary progressive). Results: Among 6,629 MS patients with 104,236 patient-years of follow-up, 1,416 died. The all-cause mortality risk was increased relative to the general population (SMR 2.71; 95% CI 2.55–2.87). MS was the underlying cause in 50.4%, and a mentioned cause in 77.9%, of deaths. Mortality by underlying cause was higher than expected for genitourinary disorders/infections (SMR 3.55; 95% CI 2.25–5.32), respiratory diseases/infections (SMR 2.69; 95% CI 2.17–3.28), suicide (SMR 2.40; 95% CI 1.61–3.45), cardiovascular disease (SMR 1.57; 95% CI 1.36–1.81), and other infections/septicemia (SMR 1.83; 95% CI 1.15–2.78). Risks of death due to overall cancer, accidents, digestive system disorders, and endocrine/nutritional diseases as underlying causes were similar to the general population. However, mortality with any mention of accidents (RMR 2.71; 95% CI 2.22–3.29) or endocrine/nutritional diseases (RMR 1.75; 95% CI 1.46–2.09) was greater. Bladder cancer mortality was increased in women (SMR 3.87; 95% CI 1.42–8.42) but not men. No notable differences were observed by disease course. Conclusions: MS itself was the most frequent underlying cause of death. Infections (genitourinary, respiratory, and septicemia), suicides, cardiovascular disease, and accidents contributed significantly to the increased risk of death. Some findings differed by sex, but not disease course. Multiple-cause death data offer advantages over “traditional” use of underlying cause only.

Background The Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone (MGTX) showed that thymectomy combined with prednisone was superior to prednisone alone in improving clinical status as measured by the Quantitative Myasthenia Gravis (QMG) score in patients with generalised non-thymomatous myasthenia gravis at 3 years. We investigated the long-term effects of thymectomy up to 5 years on clinical status, medication requirements, and adverse events. Methods We did a rater-blinded 2-year extension study at 36 centres in 15 countries for all patients who completed the randomised controlled MGTX and were willing to participate. MGTX patients were aged 18 to 65 years at enrolment, had generalised non-thymomatous myasthenia gravis of less than 5 years' duration, had acetylcholine receptor antibody titres of 1.00 nmol/L or higher (or concentrations of 0.50-0.99 nmol/L if diagnosis was confirmed by positive edrophonium or abnormal repetitive nerve stimulation, or abnormal single fibre electromyography), had Myasthenia Gravis Foundation of America Clinical Classification Class II-IV disease, and were on optimal anticholinesterase therapy with or without oral corticosteroids. In MGTX, patients were randomly assigned (1: 1) to either thymectomy plus prednisone or prednisone alone. All patients in both groups received oral prednisone at doses titrated up to 100 mg on alternate days until they achieved minimal manifestation status. The primary endpoints of the extension phase were the time-weighted means of the QMG score and alternate-day prednisone dose from month 0 to month 60. Analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00294658. It is closed to new participants, with follow-up completed. Findings Of the 111 patients who completed the 3-year MGTX, 68 (61%) entered the extension study between Sept 1, 2009, and Aug 26, 2015 (33 in the prednisone alone group and 35 in the prednisone plus thymectomy group). 50 (74%) patients completed the 60-month assessment, 24 in the prednisone alone group and 26 in the prednisone plus thymectomy group. At 5 years, patients in the thymectomy plus prednisone group had significantly lower time-weighted mean QMG scores (5.47 [SD 3.87] vs 9.34 [5.08]; p=0.0007) and mean alternate-day prednisone doses (24 mg [SD 21] vs 48 mg [29]; p=0.0002) than did those in the prednisone alone group. 14 (42%) of 33 patients in the prednisone group, and 12 (34%) of 35 in the thymectomy plus prednisone group, had at least one adverse event by month 60. No treatment-related deaths were reported during the extension phase. Interpretation At 5 years, thymectomy plus prednisone continues to confer benefits in patients with generalised non-thymomatous myasthenia gravis compared with prednisone alone. Although caution is appropriate when generalising our findings because of the small sample size of our study, they nevertheless provide further support for the benefits of thymectomy in patients with generalised non-thymomatous myasthenia gravis. Copyright (C) 2019 Elsevier Ltd. All rights reserved.