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OBJECTIVE: ACTN2, encoding alpha-actinin-2, is essential for cardiac and skeletal muscle sarcomeric function. ACTN2 variants are a known cause of cardiomyopathy without skeletal muscle involvement. Recently, specific dominant monoallelic variants were reported as a rare cause of core myopathy of variable clinical onset, although the pathomechanism remains to be elucidated. The possibility of a recessively inherited ACTN2-myopathy has also been proposed in a single series. METHODS: We provide clinical, imaging, and histological characterization of a series of patients with a novel biallelic ACTN2 variant. RESULTS: We report seven patients from five families with a recurring biallelic variant in ACTN2: c.1516A>G (p.Arg506Gly), all manifesting with a consistent phenotype of asymmetric, progressive, proximal, and distal lower extremity predominant muscle weakness. None of the patients have cardiomyopathy or respiratory insufficiency. Notably, all patients report Palestinian ethnicity, suggesting a possible founder ACTN2 variant, which was confirmed through haplotype analysis in two families. Muscle biopsies reveal an underlying myopathic process with disruption of the intermyofibrillar architecture, Type I fiber predominance and atrophy. MRI of the lower extremities demonstrate a distinct pattern of asymmetric muscle involvement with selective involvement of the hamstrings and adductors in the thigh, and anterior tibial group and soleus in the lower leg. Using an in vitro splicing assay, we show that c.1516A>G ACTN2 does not impair normal splicing. INTERPRETATION: This series further establishes ACTN2 as a muscle disease gene, now also including variants with a recessive inheritance mode, and expands the clinical spectrum of actinopathies to adult-onset progressive muscle disease.

BACKGROUND: Immune-mediated necrotizing myopathy (IMNM) is an autoimmune myopathy characterised by proximal muscle weakness, high creatine kinase (CK) values, and autoantibodies recognizing 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) or the signal recognition particle (SRP). There are currently no approved therapies for IMNM and many patients experience active disease despite off-label treatment with intravenous immunoglobulin, glucocorticoids, and immunosuppressants. Detection of complement-activating anti-HMGCR and anti-SRP autoantibodies and the presence of complement deposition on the sarcolemma of non-necrotic myofibers led to the hypothesis that complement activation may be pathogenic in IMNM, therefore zilucoplan, a complement component 5 (C5) inhibitor, could be a potential therapy. METHODS: IMNM01, a phase 2, multicenter, randomised, double-blind, placebo-controlled study (NCT04025632) at 15 sites (four countries) evaluated efficacy, safety, and tolerability of zilucoplan in adult participants with anti-HMGCR or anti-SRP autoantibody-positive IMNM. Participants were randomised 1:1 to receive daily subcutaneous zilucoplan (0·3mg/kg) or placebo for eight weeks; with optional enrolment in the study open-label extension. Primary efficacy endpoint was percent change from baseline to Week 8 in CK levels. Secondary endpoints included safety. FINDINGS: Between 07 November 2019 and 07 January 2021, 27 participants (13 female and 14 male) received zilucoplan (n=12) or placebo (n=15) and completed the 8-week main study. At Week 8 there were no clinically relevant or statistically significant differences, despite target engagement based on mode of action, between treatment arms in mean percent change (standard deviation) of CK levels versus baseline (-9·86% [26·06] versus -20·72% [31·22] in zilucoplan [n=10] and placebo arms [n=14], p=0·46, respectively) and no clinically relevant improvement over time within the treatment arm. There were no unexpected adverse safety or tolerability findings. Treatment emergent adverse events (TEAEs) and serious TEAEs were reported in n=9 (75·0%) vs n=13 (86·7%) and n=0 (0%) and n=3 (20·0%) participants, respectively. The most frequent TEAEs were headache (n=4 in both groups [33·3% and 26·7%, respectively]) and nausea (n=3 in both groups [25·0% and 20·0%, respectively]). INTERPRETATION: C5 inhibition does not appear to be an effective treatment modality for IMNM. Rather than driving myofiber necrosis, complement activation may be secondary to muscle injury. FUNDING: Study funded by Ra Pharmaceuticals (now part of UCB Pharma).

Precision Medicine is an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle. Autoimmune diseases are those in which the body's natural defense system loses discriminating power between its own cells and foreign cells, causing the body to mistakenly attack healthy tissues. These conditions are very heterogeneous in their presentation and therefore difficult to diagnose and treat. Achieving precision medicine in autoimmune diseases has been challenging due to the complex etiologies of these conditions, involving an interplay between genetic, epigenetic, and environmental factors. However, recent technological and computational advances in molecular profiling have helped identify patient subtypes and molecular pathways which can be used to improve diagnostics and therapeutics. This review discusses the current understanding of the disease mechanisms, heterogeneity, and pathogenic autoantigens in autoimmune diseases gained from genomic and transcriptomic studies and highlights how these findings can be applied to better understand disease heterogeneity in the context of disease diagnostics and therapeutics.

Sporadic inclusion body myositis (IBM) is the most common acquired muscle disease in adults over age 50, yet it remains unclear whether the disease is primarily driven by T cell–mediated autoimmunity. IBM muscle biopsies display nuclear clearance and cytoplasmic aggregation of TDP-43 in muscle cells, a pathologic finding observed initially in neurodegenerative diseases, where nuclear loss of TDP-43 in neurons causes aberrant RNA splicing. Here, we show that loss of TDP-43–mediated splicing repression, as determined by inclusion of cryptic exons, occurs in skeletal muscle of subjects with IBM. Of 119 muscle biopsies tested, RT-PCR–mediated detection of cryptic exon inclusion was able to diagnose IBM with 84% sensitivity and 99% specificity. To determine the role of T cells in pathogenesis, we generated a xenograft model by transplanting human IBM muscle into the hindlimb of immunodeficient mice. Xenografts from subjects with IBM displayed robust regeneration of human myofibers and recapitulated both inflammatory and degenerative features of the disease. Myofibers in IBM xenografts showed invasion by human, oligoclonal CD8+ T cells and exhibited MHC-I up-regulation, rimmed vacuoles, mitochondrial pathology, p62-positive inclusions, and nuclear clearance and cytoplasmic aggregation of TDP-43, associated with cryptic exon inclusion. Reduction of human T cells within IBM xenografts by treating mice intraperitoneally with anti-CD3 (OKT3) suppressed MHC-I up-regulation. However, rimmed vacuoles and loss of TDP-43 function persisted. These data suggest that T cell depletion does not alter muscle degenerative pathology in IBM.

BACKGROUND: Immune checkpoint inhibitors (ICI) produce durable antitumor responses but provoke autoimmune toxicities, including uncommon but potentially devastating neurologic toxicities. The clinical features, including the spectrum, timing, and outcomes, of ICI-induced neurologic toxicities are not well characterized. METHODS: We performed disproportionality analysis using Vigibase, the World Health Organization pharmacovigilance database, comparing neurologic adverse event (AE) reporting in patients receiving ICIs vs. the full database. Neurologic AEs were classified by group queries using Medical Dictionary for Regulatory Activities, between database inception to September 28, 2018. Associations between ICIs and neurologic AEs were assessed using reporting odds ratios (ROR) and information component (IC). IC compares observed and expected values to find associations between drugs and AEs using disproportionate Bayesian reporting; IC025 (lower end of the IC 95% credibility interval) > 0 is considered statistically significant. RESULTS: Among the full database, 18,518,994 AEs were reported, including 48,653 with ICIs. ICIs were associated with higher incidence of myasthenia gravis (0.47% of ICI reports vs. 0.04% of the full database, ROR 16.5 [95% CI 14.5-18.9]; IC025 3.31), encephalitis (0.51% vs. 0.05%, ROR 10.4 [95% CI 9.2-11.8]; IC025 3.15), peripheral neuropathy (1.16% vs. 0.67%, IC025 0.68), and meningitis (0.15% vs. 0.06%, ROR 3.1 [95% CI 2.5-3.9]; IC025 1.01). Myasthenia gravis and encephalitis were associated with anti-PD-1 whereas other neurologic AEs were associated with anti-CTLA-4. Myasthenia gravis was characterized by high fatality rates (~ 20%), early onset (median 29 days), and frequent concurrent myocarditis and myositis; whereas other neurologic AEs had lower fatality rates (6-12%), later onset (median 61-80 days), and were non-overlapping. CONCLUSIONS: ICIs produce a spectrum of distinct classes of neurologic AEs that can cause significant morbidity and mortality and tend to occur early and with class-specific associations.

Autoantibodies are important for the diagnosis of autoimmune interstitial lung disease (ILD). Standard immunoassays have limitations, including their qualitative nature and/or a narrow dynamic range of detection, hindering the usefulness of autoantibodies as biomarkers of disease activity. Here, the luciferase immunoprecipitation system (LIPS) was evaluated for measuring myositis-specific and other lung-related autoantibodies in 25 subjects with idiopathic inflammatory myopathies (IIM), 26 with Sjögren's disease (SjD), and 10 healthy volunteers. LIPS detected a broad dynamic range of autoantibodies, to MDA5, Jo-1, PL12, KS, U1-70K, and Ro52, and matched seropositivity status with established immunoassays. Robust anti-MDA5 autoantibodies in four IIM-ILD patients had a median value of 1,134,000 LU (IQR 473,000-2,317,000), which was 500 times higher than in 21 seronegative IIM patients. Markedly elevated anti-Jo-1 autoantibodies in five IIM-ILD patients demonstrated a median value of 1,177,000 LU (IQR: 604,000-2,520,000), which was 1000-fold higher than in seronegative patients. Robust anti-Ro52 and other anti-tRNA-synthetase autoantibodies were detected in a subset of IIM-ILD subjects. In SjD, only anti-U1-70K and KS autoantibodies were identified in ILD patients with a prevalence of 30% and 20%, respectively. In longitudinal samples of five IIM-ILD patients, anti-Jo-1 autoantibody levels paralleled clinical improvement of lung function. LIPS can accurately quantify autoantibody levels as biomarkers for treatment response in patients with autoimmune ILD. [ABSTRACT FROM AUTHOR]

Objective: The pathogenesis of inflammatory myopathies is poorly understood and there is a need to dissect the transcriptome in more granular ways beyond gene expression. Methods: We used a set of muscle RNA‐sequencing data from different myositis subtypes grouped by their specific autoantibodies (n = 152). We quantified annotated RNA transcripts for each myositis subtype and identified uniquely expressed RNA as well as transcriptional similarities among myositis types. In addition, we quantified event‐based alternative splicing with predicted protein changes. And finally, we searched for cryptic exons. Results: We saw considerable overlap in RNA expression among subtypes. In addition, MADCAM1 was previously shown to be uniquely expressed in Mi‐2 myositis; we discovered it was two noncanonical transcripts that predominantly contributed to the observed increased expression. At the transcriptional level, dermatomyositis subtypes were least similar to inclusion body myositis (IBM) or Jo1, followed by HMGCR, then SRP and other dermatomyositis subtype. Additionally, we discovered many alternative splicing events that were unique by myositis subgroup, including events in muscle dystrophy genes and one event in SRP72, which was seen uniquely in SRP myositis. Finally, we looked for previously reported cryptic exons in IBM and did not find them. Conclusion: The large degree of transcriptional overlap among myositis subtypes reinforces the need to use disease (in addition to healthy) controls to find unique features of autoimmune disease. Unique alterations in the transcriptome that are seen in one myositis subtype and not others advance our understanding of distinct disease pathology. [ABSTRACT FROM AUTHOR]

Objective: Myositis‐associated autoantibodies (MAAs) have been associated with overlap myositis, certain disease manifestations such as interstitial lung disease (ILD), and worse prognosis in the idiopathic inflammatory myopathies. MAAs overall remain largely uncharacterized in patients with juvenile‐onset myositis. Moreover, it is unknown whether the number of MAAs is associated with disease severity. Methods: Patients with juvenile myositis in cross‐sectional natural history studies who underwent testing for myositis autoantibodies were included. Demographics, myositis autoantibodies, clinical characteristics, medications received, and outcomes of those with and without MAAs were compared. Multivariable logistic regression was performed to determine whether the number of MAAs detected was associated with severe disease features. Results: Among 551 patients, 36% had an MAA and 13% had more than one MAA. Among those who were MAA positive, there was a higher frequency of overlap myositis (18% vs 5.9%, P < 0.001). MAA positivity was associated with certain clinical features, including Raynaud phenomenon (odds ratio [OR] 2.44, 95% confidence interval [CI] 1.41–4.28) and ILD (OR 3.43, 95% CI 1.75–6.96), as well as a chronic disease course (OR 1.72, 95% CI 1.10–2.72) and mortality (OR 3.76, 95% CI 1.72–8.43). The number of MAAs was also associated with mortality (OR 1.83, 95% CI 1.16–2.86). Conclusion: MAAs were prevalent in a large cohort of patients with juvenile myositis. ILD, refractory disease, and mortality were associated with MAA positivity. Prospective studies are needed to determine whether early detection of MAAs may lead to improved outcomes for patients with juvenile myositis. [ABSTRACT FROM AUTHOR]

Objective: Novel autoantibody specificities including anti‐CCAR1 were recently discovered in adult patients with anti‐transcriptional intermediary factor (TIF1)–positive dermatomyositis (DM) and were associated with attenuated cancer emergence. The aims of the present study were to examine whether these autoantibodies occur in patients with juvenile‐onset DM (JDM) and to determine their associated features. Methods: Sera from 150 patients with anti‐TIF1γ autoantibody‐positive JDM in a cross‐sectional cohort and 90 juvenile healthy controls were assayed for anti‐CCAR1, anti‐C1Z1, anti‐IMMT, anti‐TBL1XR1, and anti‐Sp4 autoantibodies. Demographics, myositis autoantibodies, clinical features, medications, outcomes, and HLA‐DRB1 and HLA‐DQA1 alleles were compared between those with and without these autoantibodies. Results: Any one of the anti‐TIF1γ‐associated autoantibodies was present in 44 patients (29%) overall, including 25 (17%) with anti‐Sp4, 22 (15%) with anti‐TBL1XR1, 14 (9%) with anti‐CCAR1, 2 (1%) with anti‐C1Z1, and 2 (1%) with anti‐IMMT autoantibodies. These anti‐TIF1γ‐associated autoantibodies frequently co‐occurred. Patients with any of the anti‐TIF1γ‐associated autoantibodies had less frequent falling (34% [15] vs. 53% [56], P = 0.032) and lower peak muscle enzymes. None of the patients had cancer. Among White patients, HLA‐DRB1*03 was protective against an anti‐TIF1γ‐associated autoantibody (odds ratio 0.20, 95% confidence interval 0.07–0.52). Conclusion: Autoantibodies associated with anti‐TIF1γ were found in isolation and in combination among a subset of patients with JDM. Patients with these autoantibodies had less severe muscle disease and were not enriched for HLA‐DRB1*03. Additional autoantibodies among patients with positive anti‐TIF1γ with JDM likely contribute to the heterogeneity of the anti‐TIF1γ serologic subgroup. [ABSTRACT FROM AUTHOR]