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Recreational use of nitrous oxide (N2O) has increased rapidly in recent years and is now the second most commonly used recreational drug among young people in the UK. There has been a corresponding rise in cases of nitrous oxide-induced subacute combined degeneration of the cord (N2O-SACD), a pattern of myeloneuropathy usually associated with severe vitamin B12deficiency. This can cause serious and permanent disability in young people but, if recognised early, may be effectively treated. All neurologists should be aware of N2O-SACD and its treatment; however, there are currently no agreed guidelines. Based on our experience in East London, an area of high N2O use, we provide practical advice on its recognition, investigation and treatment.

Background: Immune-mediated necrotising myopathy is an autoimmune myopathy characterised by proximal muscle weakness, high creatine kinase concentrations, and autoantibodies recognising 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) or the signal recognition particle (SRP). No approved therapies exist for people with immune-mediated necrotising myopathy. Previous studies have suggested that complement activation might be pathogenic in immune-mediated necrotising myopathy; therefore, zilucoplan, a complement C5 (C5) inhibitor, could be a potential therapy. We aimed to evaluate the efficacy, safety, and tolerability of zilucoplan in adult participants with anti-HMGCR or anti-SRP autoantibody-positive immune-mediated necrotising myopathy. Methods: IMNM-01 was a phase 2, multicentre, randomised, double-blind, placebo-controlled study done at 15 hospital sites across the USA, the UK, France, and the Netherlands. Participants aged 18?74 years were eligible for inclusion if they had a clinically confirmed diagnosis of immune-mediated necrotising myopathy, positive serology for anti-HMGCR or anti-SRP autoantibodies, clinical evidence of weakness, serum total creatine kinase concentration of more than 1000 U/L at screening, and no change in glucocorticoids or other immunosuppressive therapies for 30 days before baseline or expected during the first 8 weeks of the study. Participants were randomly assigned (1:1) to receive daily subcutaneous zilucoplan (0?3 mg/kg) or placebo for 8 weeks by use of a computerised randomisation algorithm; with optional enrolment in the study open-label extension. Randomisation was stratified by autoantibody status. Participants and study staff were masked to treatment group assignment. Primary efficacy endpoint (in the intent-to-treat population, defined as all participants who were randomly assigned to a treatment group) was percent change from baseline to week 8 in creatine kinase concentrations. Safety analyses were performed on the safety population (participants who received at least one dose of study drug during the main study, irrespective of whether they continued to the extension period?study participants were analysed on the basis of the treatment received). This study is registered with ClinicalTrials.gov, NCT04025632. Findings: Between Nov 7, 2019, and Jan 7, 2021, we randomly assigned 27 participants (13 female and 14 male) to receive zilucoplan (n=12) or placebo (n=15). All 27 participants completed the 8-week main study. At week 8 there were no significant differences between treatment groups in median percent change of creatine kinase concentrations versus baseline (?15?1% [IQR ?31?1 to 3?2] in the zilucoplan group vs ?16?3% [?43?8 to 5?9] in the placebo group; p=0?46) and no clinically relevant improvement over time within the treatment group despite target engagement based on mode of action. There were no unexpected adverse safety or tolerability findings. Treatment-emergent adverse events were reported in nine (75%) of 12 participants in the zilucoplan group, and in 13 (87%) of 15 participants in the placebo group, and serious treatment-emergent adverse events were reported in zero participants in the zilucoplan group and three (20%) participants in the placebo group. The most frequent treatment-emergent adverse events were headache (four [33%] participants in the zilucoplan group and four [27%] participants in the placebo group) and nausea (three [25%] participants in the zilucoplan group and three [20%] participants in the placebo group). Interpretation: C5 inhibition does not appear to be an efficacious treatment modality for people with immune-mediated necrotising myopathy. Rather than being the primary driver for disease activity, complement activation might be secondary to muscle injury. Funding: Ra Pharmaceuticals (now part of UCB Pharma).

Myasthenia gravis (MG) is an antibody-mediated immune disorder of the neuromuscular junction. SARS-CoV-2 is now recognised as a trigger factor for autoimmune diseases and to cause immune-mediated dysregulation, likely due to molecular mimicry induced by viral antigens. SARS-CoV-2 vaccination, similarly, results in exposure to viral antigen. Here we report 7 cases of new-onset myasthenia gravis in timely association with SARS-CoV-2 vaccination, including the first paediatric case identified to date. We also reviewed the literature for other new-onset MG cases reported within 4 weeks of SARS-CoV-2 vaccination and discuss our findings in the context of altered (auto)immunity following SARS-CoV-2 vaccination and/or infection.

Objectives The assessment of physical function is fundamental in the management of patients with idiopathic inflammatory myopathies (IIMs). We aimed to investigate the physical function of patients with IIMs compared with those with non-IIM autoimmune rheumatic diseases (AIRDs) utilizing Patient-Reported Outcome Measurement Information System (PROMIS) Physical Function (PF) data obtained in the COVAD study, an international self-reported e-survey assessing the safety of COVID-19 vaccines in AIRDs. Methods Demographics, AIRD diagnosis, disease activity, and PROMIS PF short form-10a data were extracted from the COVAD database. PROMIS PF-10a scores were compared between disease categories and stratified by disease activity. Factors affecting PROMIS PF-10a scores other than disease activity were identified by multivariable regression analysis in patients with inactive disease. Results A total of 1057 IIM patients, 3635 non-IIM AIRD patients and 3981 healthy controls (HCs) responded to the COVAD e-survey from April to August 2021. Using a binomial regression model, the predicted mean of PROMIS PF-10a scores was significantly lower in IIM patients compared with non-IIM AIRD patients or HCs [36.3 (95% CI 35.5, 37.1) vs 41.3 (95% CI 40.2, 42.5) vs 46.2 (95% CI 45.8, 46.6), P Conclusion Physical function is significantly impaired in IIMs compared with non-IIM AIRDs or HCs, even in patients with inactive disease. Our study highlights a critical need for better strategies to minimize functional disability in patients with IIMs.

ObjectivesThis is a protocol for a Cochrane Review (intervention). The objectives are as follows:To assess:the safety and efficacy, as assessed by the effect on disease severity or functional ability and the burden of alternative treatment, of rituximab (including biosimilar variants) for the treatment of myasthenia gravis in adults; andoutcomes and adverse effects between different patient subgroups, and treatment strategies, in order to aid treatment choice for individuals, and to inform policymakers about those most likely to benefit.

Objectives The COVID-19 vaccination in autoimmune diseases (COVAD) study aimed to assess short-term COVID-19 vaccination-related adverse events (AEs) in RA patients. Methods An online self-reported questionnaire (March–December 2021) was used to capture data related to COVID-19 vaccination-related AEs in RA, other autoimmune rheumatic diseases (AIRDs) (excluding RA and inflammatory myositis), non-rheumatic autoimmune diseases (nrAIDs) and healthy controls (HCs). Descriptive and multivariable regression analyses were performed. Results Of the 9462 complete respondents, 14.2% (n = 1347) had been diagnosed with RA; they had a mean (s.d.) age of 50.7 (13.7) years, 74.2% were women and 49.3% were Caucasian. In total, 76.9% and 4.2% of patients with RA reported minor and major AEs, respectively. Patients with active and inactive RA had similar AE and hospitalization frequencies. Overall, AEs were reported more frequently by BNT162b2 and mRNA-1273 recipients and less frequently by BBV152 recipients compared with the rest. Major AE and hospitalization frequencies were similar across recipients of different vaccines. Patients receiving methotrexate and hydroxychloroquine reported fewer minor AEs than those patients not on them. Compared with HCs and patients with other AIRDs, patients with RA reported similar total AEs, overall minor AEs, and hospitalizations. Compared with nrAIDs, patients with RA reported lower frequencies of overall AEs, minor AEs (both odds ratio [OR] = 0.7; 95% CI: 0.5, 0.9), and injection site pain (OR = 0.6; 95% CI: 0.5, 0.8) with similar major AE and hospitalization frequencies. Conclusion Despite the differences in AE frequency across different COVID-19 vaccines, all were well tolerated in patients with RA and were comparable to HCs, providing reassurance as to the safety of COVID-19 vaccination.

In clinical neurology practice, there are few sensitive, specific and responsive serological biomarkers reflecting pathological processes affecting the peripheral nervous system. Instead, we rely on surrogate multimodality biomarkers for diagnosis and management. Correct use and interpretation of the available tests is essential to ensure that appropriate treatments are used and adjusted in a timely fashion. The incorrect application or interpretation of biomarkers can result in misdiagnosis and delays in appropriate treatment. Here, we discuss the uses and limitations of such biomarkers and discuss possible future developments.

Purpose of review No clinical trial in sporadic inclusion body myositis (IBM) thus far has shown a clear and sustained therapeutic effect. We review previous trial methodology, explore why results have not translated into clinical practice, and suggest improvements for future IBM trials. Recent findings Early trials primarily assessed immunosuppressive medications, with no significant clinical responses observed. Many of these studies had methodological issues, including small participant numbers, nonspecific diagnostic criteria, short treatment and/or assessment periods and insensitive outcome measures. Most recent IBM trials have instead focused on nonimmunosuppressive therapies, but there is mounting evidence supporting a primary autoimmune aetiology, including the discovery of immunosuppression-resistant clones of cytotoxic T cells and anti-CN-1A autoantibodies which could potentially be used to stratify patients into different cohorts. The latest trials have had mixed results. For example, bimagrumab, a myostatin blocker, did not affect the 6-min timed walk distance, whereas sirolimus, a promotor of autophagy, did. Larger studies are planned to evaluate the efficacy of sirolimus and arimoclomol. Summary Thus far, no treatment for IBM has demonstrated a definite therapeutic effect, and effective treatment options in clinical practice are lacking. Trial design and ineffective therapies are likely to have contributed to these failures. Identification of potential therapeutic targets should be followed by future studies using a stratified approach and sensitive and relevant outcome measures.

Background/Aims Anti-synthetase syndrome (ASS) represents a distinct entity within myositis spectrum disorders; however, correct classification of patients with anti-tRNA synthetase autoantibodies and skin manifestations akin to dermatomyositis (DM) remains uncertain. Our aim was to compare clinical characteristics, skin involvement, and malignancy, between patients with ASS and DM, classified by disease-specific autoantibodies. Methods Data from 05/2009-03/2016 from 9 countries from the prospective, myositis EuroMyositis registry were downloaded. Those with anti-tRNA synthetase autoantibodies (Jo-1/PL-7/PL-12/OJ/EJ/KS) were classified as ASS, and those with Mi-2/TIF1-γ/NXP2/SAE/MDA5 autoantibodies as DM. Clinical phenotypes including malignancies (except skin malignancies) were tabulated. Characteristics of patients with skin involvement (excluding mechanic’s hands and Raynaud’s phenomenon) were compared using Fisher’s exact test with Bonferroni corrected p-values. Results Of 3,067 patients, 2,028 had autoantibody profiling results (66.1%), of which 783 (38.6%) were positive for at least one of the autoantibodies being considered. Five patients with dual autoantibody specificities were excluded. Of the remaining 778, 320 (41.1%) were classified as DM, and 458 (58.9%) as ASS. Median age at diagnosis was 48.2 years (interquartile range [IQR] 37.5 to 57.8) in the DM cohort and 49 (IQR 38.3 to 62.2) in the ASS cohort. Skin involvement was present in 277 (86.6%) DM patients (DM skin) vs 204 (44.5%) ASS patients (ASS skin) (pcorr Conclusion Patients with ASS have frequent skin involvement but also a distinct clinical phenotype compared to DM. These findings may inform the development of future classification criteria for ASS. Disclosure R.M. Hum: None. J.B. Lilleker: None. J.A. Lamb: None. W.E. Ollier: None. G. Wang: None. L.R. Wedderburn: None. L.P. Diederichsen: None. J. Schmidt: None. P. Oakley: None. O. Benveniste: None. M.G. Danieli: None. K. Danko: None. N.T.P. Thuy: None. M.V.D. Mercado: None. H. Andersson: None. B.D. Paepe: None. J.L.D. Bleecker: None. B. Maurer: None. L.J. McCann: None. N. Pipitone: None. N. McHugh: None. P. New: None. J. Vencovsky: None. I.E. Lundberg: None. H. Chinoy: None.

BackgroundNitrous oxide (N2O) is the second most common recreational drug used by 16- to 24-year-olds in the UK. Neurological symptoms can occur in some people that use N2O recreationally, but most information comes from small case series.MethodsWe describe 119 patients with N2O-myeloneuropathy seen at NHS teaching hospitals in three of the UK’s largest cities: London, Birmingham and Manchester. This work summarises the clinical and investigative findings in the largest case series to date.ResultsParaesthesia was the presenting complaint in 85% of cases, with the lower limbs more commonly affected than the upper limbs. Gait ataxia was common, and bladder and bowel disturbance were frequent additional symptoms. The mid-cervical region of the spinal cord (C3–C5) was most often affected on MRI T2-weighted imaging. The number of N2O canisters consumed per week correlated with methylmalonic acid levels in the blood as a measure of functional B12deficiency (rho (ρ)=0.44, p=0.04).ConclusionsPreventable neurological harm from N2O abuse is increasingly seen worldwide. Ease of access to canisters and larger cylinders of N2O has led to an apparent rise in cases of N2O-myeloneuropathy in several areas of the UK. Our results highlight the range of clinical manifestations in a large group of patients to improve awareness of risk, aid early recognition, and promote timely treatment.

Objectives COVID-19 vaccines have been proven to be safe in the healthy population. However, gaps remain in the evidence of their safety in patients with systemic autoimmune and inflammatory disorders (SAIDs). COVID-19 vaccination-related adverse events (AEs) in patients with SAIDs and healthy controls (HC) seven days post-vaccination were assessed in the COVAD study, a patient self-reported cross-sectional survey. Methods The survey was circulated in early 2021 by >110 collaborators (94 countries) to collect SAID details, COVID-19 vaccination details and 7-day vaccine AEs, irrespective of respondent vaccination status. Analysis was performed based on data distribution and variable type. Results Ten thousand nine hundred respondents [median (interquartile range) age 42 (30–55) years, 74% females and 45% Caucasians] were analysed; 5867 patients (54%) with SAIDs were compared with 5033 HCs. Seventy-nine percent had minor and only 3% had major vaccine AEs requiring urgent medical attention (but not hospital admission) overall. Headache [SAIDs = 26%, HCs = 24%; odds ratio (OR) = 1.1 (95% CI: 1.03, 1.3); P = 0.014], abdominal pain [SAIDs = 2.6%, HCs = 1.4%; OR = 1.5 (95% CI: 1.1, 2.3); P = 0.011], and dizziness [SAIDs = 6%, HCs = 4%; OR = 1.3 (95% CI: 1.07, 1.6); P = 0.011], were slightly more frequent in SAIDs. Overall, major AEs [SAIDs = 4%, HCs = 2%; OR = 1.9 (95% CI: 1.6, 2.2); P Conclusion Vaccination against COVID-19 is safe in SAID patients. SAIDs were at a higher risk of major AEs than HCs, though absolute risk was small. There are small differences in minor AEs between vaccine types in SAID patients.

Inclusion body myositis (IBM) is characterised by infiltration of CD8+ T-cells and signs of protein aggregation such as rimmed vacuoles and inclusion bodies. Aggregated proteins include those present in neurodegenerative diseases, and also those involved in protein homeostasis. The aim of this review is to discuss the pathological effects of protein aggregates and the process of aggregation following immune attack in IBM. Immune attack is likely to cause protein aggregation by impairing endoplasmic reticulum (ER) and mitochondrial function. Apoptotic and necrotic pathways are activated, possibly leading to nucleo-cytoplasmic coagulation. Overexpression of nuclear and ribosomal proteins in rimmed vacuoles suggests that the vacuoles develop from the collapse of myonuclei and the surrounding ER. Aggregated proteins can activate the NLR family pyrin domain containing 3 (NLRP3) inflammasome or provoke a humoral immune response. Heat shock proteins, ribosomal proteins and protein fragments may provoke interferon-gamma and cytotoxic T-cell responses in a similar manner to Mycobacterium tuberculosis antigens. Persistent provocation can lead to T-cell large granular lymphocytic leukaemia which is resistant to immunosuppression, and would explain the progression from polymyositis to IBM. Protein aggregates may impair the cellular machinery, and proteins may propagate along a myocyte in a prion-like manner. These pathological mechanisms may prevent myocyte regeneration following damage from eccentric muscle contraction, causing weakness and atrophy in a characteristic pattern. Further understanding of the mechanisms of protein aggregation in IBM may lead to additional therapies as well as novel muscle and blood biomarkers. Earlier diagnosis and treatment may result in improved outcomes when effective therapies are available.

Immunoglobulin (Ig) is used to treat chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy with conduction block (MMNCB). Regular infusions may be used for symptom control. Disease activity is monitored with clinical outcome measurements. We examined outcome measure variation during clinically stable periods in Ig-treated CIDP and MMNCB patients. We explored utility of serial outcome measurement in long-term outcome prediction. Retrospective longitudinal analysis of a single neuroscience centre's Ig-treated CIDP and MMNCB patients, 2009-2020, was performed. Mean and percentage change for grip strength, Rasch-built overall disability scales (RODS) and MRC sum scores (MRC-SS) during periods of clinical stability were compared to score-specific minimal clinically important differences (MCID). Latent class mixed modelling (LCMM) was used to identify longitudinal trends and factors influencing long-term outcome. We identified 85 CIDP and 23 MMNCB patients (1423 datapoints; 5635 treatment-months). Group-averaged outcome measures varied little over time. Intra-individual variation exceeded MCID for RODS in 44.2% CIDP and 16.7% MMNCB datapoints, grip strength in 10.6% (CIDP) and 8.8%/27.2% (MMNCB right/left hand) and MRC-SS in 43.5% (CIDP) and 20% (MMNCB). Multivariate LCMM identified subclinical trends towards improvement (32 patients) and deterioration (73 patients) in both cohorts. At baseline, CIDP 'deteriorators' were older than 'improvers' (66.2 vs 57 years, P = .025). No other individual factors predicted categorisation. The best model for 'deteriorator' identification was contiguous sub-MCID decline in more than one outcome measure (CIDP: sensitivity 74%, specificity 59%; MMNCB: sensitivity 73%, specificity 88%). Outcome measure interpretation determines therapeutic decision-making in Ig-dependent neuropathy patients, but intra-individual variation is common, often exceeding MCID. Here we show sub-MCID contiguous changes in more than one outcome measurement are a better predictor of long-term outcome.

The idiopathic inflammatory myopathies represent a rare group of diseases characterized by autoimmune inflammation of skeletal muscle and other organs. There has been significant recent progress in understanding pathogenesis, phenotyping disease subtypes and investigating effective therapeutic options. Patients typically present with progressive, proximal weakness and elevated muscle enzymes, and often have additional extramuscular manifestations, including skin, respiratory, articular, gastrointestinal and cardiovascular involvement. These extramuscular manifestations can precede or occur in the absence of clinically detectable muscle involvement. There are a multitude of potential differential diagnoses to consider and a careful initial evaluation supported by structured investigations remains critical for accurate diagnosis and timely commencement of appropriate treatment.

Objective The current classification criteria for idiopathic inflammatory myopathy (IIM) retain PM as a major disease subgroup. However, evolution in the understanding of IIM has suggested that many of these patients could be better described as having an alternative diagnosis. In the present study, we apply the latest understanding of IIM subtyping to retrospectively review PM diagnoses in a large cohort of IIM patients. Methods Within a previously reported cohort of 255 patients from a UK tertiary myositis clinic, 37 patients classified as PM according to both the EULAR/ACR IIM criteria and expert opinion were identified. Clinical data and complementary tests were reviewed, and consensus decisions regarding final classification were reached in each case. Results Nine (9/37, 24.3%) patients remained classified as PM, 3.5% (9/255) of the original cohort; these PM patients were seronegative for myositis antibodies, responsive to immunosuppression, and in 4/7 (57.1%) patients where muscle biopsy was performed had HLA-1 upregulation and endomysial inflammatory infiltrates. Immune-mediated necrotizing myopathy (5/37, 13.5%) and connective tissue disease overlap myositis (7/37, 19%) were the main alternative diagnoses. The remaining patients were diagnosed as: unspecified myopathy (6/37, 16%), dermatomyositis (2/37, 5%), cancer-associated myopathy (3/37, 8.1%), and non-inflammatory myopathy (1/37, 3%, myofibrillar myopathy). Four patients (4/37, 10%) had insufficient data available to confidently reclassify. Conclusion Our study confirms that PM can now be considered a rare IIM subgroup. A thorough examination, complete myositis autoantibody panel, and careful interpretation of the biopsy results is recommended to confirm the correct IIM sub-type.

This study aims to describe the patient perspective on glucocorticoid (GC) treatment and adverse effects (AEs) in idiopathic inflammatory myopathy (IIM). An online survey was distributed to patients with adult-onset IIM using the Myositis UK page on Healthunlocked.com, an online social network for health. Respondents were asked to rate the severity of AEs they attributed to GCs on a Likert scale (0-5), and to report concerns and overall experience of GC treatment. The survey was completed by 122 respondents. The median reported current daily dose of prednisolone was 15 mg (interquartile range [IQR] 8, 25) and median treatment duration 5.3 years (IQR 3.4, 8.0) at the time of survey completion. Only 54% of respondents "agreed" or "strongly agreed" that the information provided to them about GC treatment was adequate. AEs rated most severe by respondents were weight gain, moon face, sleep disturbances and increased hunger. The duration of GC treatment weakly correlated with the mean number of reported AEs (p = 0.004) and mean severity of AEs (p = 0.017). There was an inverse relationship between age and acne, stretch marks, hair loss, facial hair, nausea and heartburn (p 0.05). In this first study of patient-reported experiences of GCs specifically in IIM, we describe the burden of treatment and highlight the unmet need for safe and well-tolerated treatments. We report that patients with IIM often remain on long-term GC treatment at moderate doses, and that AEs are common. The reported data will be useful in planning discussions with patients regarding adherence to their treatment options. Key Points • Glucocorticoids (GC) are the first-line treatment in patients with idiopathic inflammatory myopathies (IIM), and are associated with a wide range of adverse effects • The adverse effects related to GC are very common, and those reported most severe by patients included weight gain, moon face, increased hunger or sleep disturbance, which may differ from the primary concerns of their treating clinician • Understanding the patient perspective and concerns about treatment is necessary to maintain a good physician-patient relationship and may help with treatment adherence.

BackgroundRisdiplam is the first oral spinal muscular atrophy (SMA) treatment and was made available in the UK through an Early Access to Medicines Scheme (EAMS), which enrolled patients between September 2020–July 2021.MethodsRisdiplam’s EAMS indication was for patients with Type 1/2 SMA, ≥2 months old and not suitable for authorised SMA treatments. Patient characteristics and risdiplam-provision data from treating physi- cians, and patient/caregiver feedback, were collected.ResultsOf 242 patients enrolled, 92 were children (ConclusionsRisdiplam was made available to a varied SMA population through the EAMS, targeting patients otherwise unable to access disease-modifying treatment. Many patients received disease- modifying treatment for the first time, addressing a significant unmet need.

Myotonic Dystrophy Type 1 (DM1) is the most common muscular dystrophy in adults. Structured multi- disciplinary care is required to manage the multi-system involvement, to improve patient safety, and to reduce mortality and morbidity. Previous audits based on the 2018 consensus-based care recommenda- tions have been conducted at individual UK centres. In this study a standardised audit tool was created and deployed to 3 tertiary UK neuroscience centres.In total, data regarding 375 patients (197 (53%) female, mean age 47 years (range 1-84)) with DM1 were analysed. 62% had adult-onset disease. Neurology teams reviewed 64% of patients at least once a year. Key findings included: Cardiology review was performed annually for only 30%; of patients with respiratory needs, only 12% were reviewed six-monthly by specialist teams; Swallowing function was assessed in only 44% of those required; Clinical assessment for cognitive impairment was conducted in 12%.In conclusion, this multi-centre UK audit identifies several significant areas of care that need to be optimised in DM1, even within dedicated neuromuscular clinics. This highlights the need for a national initiative to establish minimum care standards. Such initiative can help drive resource allocation resulting in positive change.

The coronavirus disease-2019 (COVID-19) pandemic continues to be a cause of unprecedented global morbidity and mortality. Whilst COVID-19 vaccination has emerged as the only tangible solution to reducing poor clinical outcomes, vaccine hesitancy continues to be an obstacle to achieving high levels of vaccine uptake. This represents particular risk to patients with autoimmune diseases, a group already at increased risk of hospitalization and poor clinical outcomes related to COVID-19 infection. Whilst there is a paucity of long-term safety and efficacy data of COVID-19 vaccination in patients with autoimmune diseases, the current evidence strongly suggests that the benefits of vaccination outweigh the risks of adverse effects and disease flares. Herein, we report the protocol of the COVID-19 Vaccination in Autoimmune Diseases (COVAD) study, an ongoing international collaborative study involving 29 countries and over 110 investigators. Supplementary Information The online version contains supplementary material available at 10.1007/s00296-021-05046-4.

Purpose of review To examine recent developments relating to cardiac involvement in the adult idiopathic inflammatory myopathies (IIM) and those inherited muscle diseases which may present in adulthood and mimic IIM.Recent findings Cardiac involvement is a common feature of IIM and inherited muscle diseases. Frequency according to disease subtype varies, with serotype having particular influence in IIM, and genotype in the inherited muscle diseases. Innovative techniques for examining cardiac function have been investigated further, including speckle-tracking echocardiography and cardiac magnetic resonance tomography. The present work has highlighted a likely underestimate of the burden of cardiac disease to date. The complex relationship between IIM, atherosclerosis, and traditional cardiovascular risk factors has been further elucidated. Consensus recommendations for managing patients with inherited muscle diseases and prominent cardiac involvement have been recently published. In addition to supportive care, disease modifying treatments are increasingly becoming available for inherited muscle diseases which may also improve cardiac outcomes.Summary Cardiac involvement is associated with significant morbidity and mortality. We suggest having a low threshold for considering the possibility of cardiac involvement in all patients with muscle disease.

The idiopathic inflammatory myopathies (IIM) are heterogeneous and lead to high morbidity and mortality. Knowledge deficits among healthcare professionals could be detrimental to clinical care. Identifying areas of deficient Knowledge, Attitude and Practice (KAP) of IIM can improve physician education and patient outcomes. To assess the proportion of physicians treating IIM with poor KAP and identify the key areas of deficit. An anonymised and validated e-survey (57 questions) was circulated among physicians treating IIM (purposive sampling). Responses were evaluated using the Likert scale for good (> 70% correct response), poor (> 20% chose > 2 answers) and the rest as intermediate consensus. Descriptive statistics were used. Intergroup comparisons were done using non-parametric tests. Of 80 (9.1% of 883) respondents, 90% were rheumatologists and 37.5% academicians. The knowledge base of treating physicians was good in specific domains such as triggers (80–90%), clinical presentation (MDA5, statin myositis, steroid myopathy, anti-synthetase syndrome) (82–92%), IIM mimics (41–89%), investigations (23–92%) and risk of osteoporosis in IIM (79%). There is also an intermediate knowledge base/consensus for outcome measures (30–56%) and response criteria (30–53%). There was poor knowledge and consensus on trials (27–34%), EULAR/ACR criteria (31%) and exercise-based interventions (17–62%). While 90% agree on the need for muscle biopsy to diagnose polymyositis, only one-third advocated it for juvenile and adult DM. Physicians have a good understanding of the triggers, clinical presentation and mimics of IIM. Poor to intermediate knowledge and consensus exists regarding muscle biopsy, outcome measures, response criteria and exercise-based interventions, which could be addressed through future focussed educational initiatives.

A 63-year-old woman was referred to neurology with bilateral severe progressive pain and stiffness in her thighs. The patient had a 3-year history of injecting intramuscular cyclizine into the anterior thigh to treat nausea associated with a longstanding pan-enteric dysmotility syndrome. MRI of the thighs demonstrated fibrotic appearances. A biopsy of the left vastus lateralis and surrounding fascia identified pathology consistent with a fibrous myopathy. The patient was advised to stop intramuscular injections of cyclizine and undergo physiotherapy but she still remained in considerable pain. Although fibrous myopathy occurring as a consequence of recurrent intramuscular drug injections, particularly heroin, has been previously described, this is the first report of fibrous myopathy associated with the use of intramuscular cyclizine. We highlight this rare association and suggest that the long-term use of intramuscular cyclizine be avoided.

Background Sporadic inclusion body myositis (IBM) is a muscle wasting disorder usually affecting those aged over 50 years, characterised by slowly progressive weakness of the distal upper limbs and proximal lower limbs. Particular weakness of pinch, knee extension and ankle dorsiflexion result in functional decline and disability. Weakness-associated functional decline differences between genders has not previously been investigated. This study aimed to investigate for differences of functional decline in men and women with IBM. Methods A cohort of verified adult IBM patients were followed at a single specialist neuromuscular clinic (Royal Victoria Infirmary, Newcastle-upon-Tyne, UK) between 2004-15, with data collected at each clinic visit. Strength of 11 movements was measured via dynamometry at each clinic visit. Patient-reported function was measured via the Neuromuscular Symptom Score (NSS). Generalised linear modelling, adjusted for disease duration, was carried out to identify associations between strength and function (NSS). Pinch, knee extension and ankle dorsiflexion strength measurements were analysed. Modelling was carried out separately for male and female cohorts. Results Data of 75 participants (47% female) was analysed. A total of 591 measurements were taken. Median age at time of IBM diagnosis was 68.8 years. Median baseline NSS score was 45 (IQR 37, 54) for the male cohort and 40 (IQR 29, 45) for the female cohort. The median disease duration of the study cohort was 2.6 years. Reduced function (NSS) was significantly associated with reduced pinch, knee extension and ankle dorsiflexion strength in the male cohort only (Table 1). No significant associations were observed in the female cohort. Conclusion This is the first study to demonstrate that the progression of weakness, in the characteristic muscle groups affected in IBM, impacts on function differently in men and women. These results illustrate the importance of functional assessment in patients with IBM and the importance of focused physiotherapy upon function-dependent muscle groups. Further, potential gender-based differences of weakness-related function in IBM should be considered when designing clinical trials. Disclosures J. Williams None. A. Oldroyd None. J. Lilleker None. H. Chinoy None. J. Miller None.

PURPOSE OF REVIEW: To describe recent advancements in diagnostic and therapeutic approaches to inclusion body myositis (IBM).RECENT FINDINGS: Our understanding of the implications of anti-cytosolic 5'-nucleotidase 1A autoantibody status in IBM and other diseases is increasing. Muscle imaging using magnetic resonance techniques and ultrasound is increasingly being performed and characteristic patterns of muscle involvement may help with diagnosis. Longitudinal imaging studies are likely to help with monitoring and as an outcome measure in clinical trials. Recent small-scale studies of Arimoclomol and Rapamycin have shown promising results and further investigation of these medications is ongoing. Exercise is likely to form an increasingly important facet of management of patients with IBM, but the optimal type of exercise programme to enrol patients in is not yet determined.SUMMARY: Antibody testing and muscle imaging results may improve our ability to diagnose IBM and the availability of effective disease modifying treatments targeting novel non-inflammatory pathways could soon become a reality. It remains the duty of those involved in the management of patients with IBM to facilitate involvement in clinical trials and other research studies.

Spinal muscular atrophy (SMA) is a hereditary neuromuscular disorder, which causes progressive muscle weakness and in severe cases respiratory failure and death. Although the majority of the SMA cases are autosomal recessive, there is an autosomal dominant variant of SMA that primarily affects the lower extremities, known as 'spinal muscular atrophy - lower extremity, dominant' (SMALED). Mutations in the Dynein Cytoplasmic 1 Heavy Chain 1 (DYNC1H1) gene were the first to be associated with SMALED. Here we report a family with SMALED caused by a pathogenic heterozygous missense c.1809 A>T, p.glu603Asp mutation in DYNC1H1. The main clinical features were congenital hip displacement, talipes, delayed motor development, wasting and weakness in lower limbs with relative sparing of upper extremities and very slow disease progression. SMALED is extremely rare and only a handful of families have been reported. Over the years other phenotypes including Charcot Marie Tooth type 2 and hereditary mental retardation with cortical neural migration defects have also been reported to be caused by DYNC1H1 mutations. This report aims to increase our awareness of SMALED and various other phenotypes associated with mutations in this gene.

Idiopathic inflammatory myopathies represent a rare group of diseases characterized by a central role of autoimmune processes and the inflammation of skeletal muscle. There has been significant recent progress in understanding disease pathogenesis, phenotyping subtypes of disease and investigating effective therapeutic options. Patients typically present with progressive, proximal weakness and functional impairment, and elevated muscle enzymes. There can also have extramuscular manifestations, including skin, respiratory, articular, gastrointestinal and cardiovascular involvement, which can precede or occur in the absence of clinically detectable muscle involvement. There are therefore a multitude of potential differential diagnoses to consider. A conscientious initial evaluation supported by pragmatically structured investigations remains critical to accurate diagnosis and appropriate management of these complex conditions.

Metabolic myopathies are a diverse group of rare genetic disorders and their associated muscle symptoms may be subtle. Patients may present with indolent myopathic features, exercise intolerance or recurrent rhabdomyolysis. Diagnostic delays are common and clinicians need a high index of suspicion to recognise and differentiate metabolic myopathies from other conditions that present in a similar fashion. Standard laboratory tests may be normal or non-specific, particularly between symptomatic episodes. Targeted enzyme activity measurement and next-generation genetic sequencing are increasingly used. There are now specific enzyme replacement therapies available, and other metabolic strategies and gene therapies are undergoing clinical trials. Here, we discuss our approach to the adult patient with suspected metabolic myopathy. We outline key features in the history and examination and discuss some mimics of metabolic myopathies. We highlight some disorders of glycogen and fatty acid utilisation that present in adulthood and outline current recommendations on management.

The inositol 1,4,5-triphosphate receptor type 1 (ITPR1) gene on chromosome 3 belongs to a family of genes encoding intracellular calcium channel proteins. Such channels are located primarily within the endoplasmic reticular membrane and release Ca2+, an intracellular messenger, which governs numerous intracellular and extracellular functions. We report a family with infantile-onset cerebellar ataxia with delayed motor development and intellectual disability caused by a heterozygous c.805C>T, p.Arg269Trp missense mutation in ITPR1. Both affected family members had postural tremor, hypotonia and dysarthria, but neither had pyramidal signs. Their neuroimaging revealed cerebellar atrophy. Several neurological conditions have been associated with ITPR1 mutations, such as spinocerebellar ataxia type 15 and Gillespie syndrome, and the phenotype may vary according to the location and type of mutations. Spinocerebellar ataxia type 15 is an autosomal dominant disorder, which causes late onset pure cerebellar ataxia. Gillespie syndrome is characterised by bilateral iris hypoplasia, congenital hypotonia, non-progressive ataxia and cerebellar atrophy. In this report, we provide a detailed phenotypic description of a family with a missense mutation in ITPR1. This mutation has only been reported once before. We also provide a literature review of the various phenotypes associated with ITPR1 gene.

The idiopathic inflammatory myopathies are a group of conditions characterised by inflammation of muscles (myositis) and other body systems. The diagnosis can be challenging because of the many potential clinical features and extra-muscular manifestations, which may be seemingly unrelated. An accurate diagnosis requires up-to-date understanding of the clinical manifestations, different clinical subtypes and appropriate interpretation of investigations, including newly described serological subtypes.This review will detail the approach to the diagnosis of an idiopathic inflammatory myopathy, based on up-to-date knowledge. The recently updated classification criteria and treatment options will also be described.

Background:Since first described, our understanding of polymyositis (PM) has evolved substantially. Patients previously diagnosed with PM may now be better described as having an alternative diagnosis, including immune-mediated necrotizing myopathy (IMNM), connective tissue disease overlap myositis (CTD-OM), anti-synthetase syndrome (ASS) or inclusion body myositis (IBM).Objectives:To apply the current understanding of IIM subtypes to retrospectively review the diagnosis of patients classified as PM at our centre.Methods:We reviewed a cohort of 255 patients from a UK tertiary myositis clinic, with 37 patients classified as PM according to the EULAR/ACR IIM criteria and expert opinion (1). Consensus decisions made as to whether reclassification as an alternative IIM subtype would be appropriate in each case.Results:Thirty-seven patients with PM diagnosis according to EULAR/ACR IIM criteria and expert opinion were included in the analysis. Twenty-six patients (26/37, 68.4%) were female. The mean age at diagnosis was 57 years (SD 16.25) and mean follow up was 5.2 years (SD 4.8).After consensus discussions, ten patients (27%) retained classification as PM, representing 3.9% (10/255) of the original cohort of 255 patients. The remaining 27 were reclassified as follows: 7 CTD-OM (18.9%), 6 IMNM (16.2%), 6 unspecified myopathy (16.2%), 2 DM (5.4%), 1 IBM (2.7%), and 1 non-inflammatory myopathy (2.7%, myofibrillar myopathy). Four patients (10%) had insufficient data available to allow for a defined diagnosis.Of the 10 patients retaining classification as PM, 7 (70%) were female and mean age at diagnosis was 58.9 years. Clinical characteristics are represented in table 1. Mean CK at diagnosis was 2321 IU/L. Four patients (40%) were ANA positive, 8 patients (80%) were tested for the complete myositis antibody panel and 8 (80%) were specifically tested for the presence of HMGCR antibodies (figure 1). EMG revealed a myopathic pattern in 6/7 patients tested, while MRI demonstrated muscle oedema compatible with myositis in 3/5 of the patients that were tested. A complete muscle biopsy report was available in 8/10 PM-classified patients (80%), diffuse HLA-1 upregulation was present in 5 patients (50%), endomysial inflammatory infiltrates in 5 (50%) and perimysial infiltrates (in conjunction with endomysial infiltrates) in 3 (30%). No other specific features were found.Table 1.Clinical features.PM (n=10)CTD-OM (n=7)IMNM (n=6)All (n=37)Pyrexia0001 (2.7 %)Weight loss2 (20%)2 (28.6%)2 (33.3%)6 (16.2 %)Cutaneous rash01 (14.3%)02 (5.4 %)Mechanic’s hands1 (10%)2 (28.6%)04 (10.8 %)Sclerodactyly01 (14.3%)01 (2.7 %)Periungual erythema01 (14.3%)02 (5.3 %)Raynaud’s05 (71.4%)08 (21.6 %)Arthralgia05 (71.4%)08 (21.6 %)Arthritis02 (28.6%)05 (13.5 %)Muscle weakness10 (100%)7 (100%)6 (100%)36 (97.2%)Myalgia3 (30%)5 (71.4%)3 (50%)20 (54 %)Dysphagia3 (30%)5 (71.4%)1 (16.7%)13 (35.1 %)Interstitial lung disease (ILD)03 (42.9%)04 (10.5 %)Malignancy1 (9.1%)02 (33.3%)3 (8.1%)Conclusion:This study confirms that PM can now be considered a rare IIM subtype. A thorough examination, complete myositis antibody panel including HMGCR testing and careful interpretation of the biopsy results is recommended to accurately classify these patients.References:[1]Parker MJS, Oldroyd A, Roberts ME, Lilleker JB, Betteridge ZE, McHugh NJ, et al. The performance of the European League Against Rheumatism/American College of Rheumatology idiopathic inflammatory myopathies classification criteria in an expert-defined 10 year incident cohort. Rheumatol (United Kingdom). 2019 Mar 1;58(3):468–75Disclosure of Interests:None declared

Idiopathic inflammatory myopathies (IIMs) are heterogeneous conditions, and the optimal way to classify patients and divide them into subgroups remains unclear. Could machine learning techniques be the answer to the problem of defining homogeneous disease phenotypes, enabling stratified treatment approaches and the formulation of future IIM classification criteria?

The idiopathic inflammatory myopathies are a group of heterogeneous autoimmune connective tissue diseases. Despite increase in the understanding of these conditions, securing a timely diagnosis and accurate subtype classification remains difficult in some cases. This has important implications for patients, where delayed or inappropriate treatments can have a negative effect on outcomes.Several conditions can mimic myositis, including metabolic myopathies, genetic myopathies and neurological disease. In addition, the heterogeneity within the idiopathic inflammatory myopathy spectrum can also create diagnostic confusion, referred to here as ‘myositis chameleons’. This includes inclusion body myositis, immune-mediated necrotizing myopathy, hypomyopathic variants of anti-synthetase syndrome and overlap disease.We highlight the importance of a thorough diagnostic workup, refer to updated classification criteria and emphasize the importance of myositis autoantibody testing. Where diagnostic doubt exists, the involvement of a specialist centre and a multidisciplinary team is vital.