[Immune-Mediated Necrotizing Myopathy].

Immune-mediated necrotizing myopathy (IMNM) is a form of autoimmune myositis characterized by the presence of necrotic and regenerating process as a major finding in the muscle. Anti-SRP and anti-HMGCR have been identified as IMNM-specific autoantibodies. Patients with this disease often present with severe muscle weakness and markedly elevated serum creatine kinase (CK) levels. Differentiation from muscular dystrophy is challenging in certain cases. When patients meet the condition "subacute onset", "hyperCKemia over 1000 IU/L", and "clinical diagnosis of muscular dystrophy lacking molecular diagnosis", the possibility of IMNM should be considered. Autoantibody measurement, including of anti-SRP and HMGCR antibodies, is recommended. Treatment with corticosteroid in combination with immunosuppressants, intravenous immunoglobulin, and rituximab can be performed.

Pathologic Features of Anti-Ku Myositis.

OBJECTIVE: Characteristics of myositis with anti-Ku antibodies are poorly understood. The purpose of this study was to elucidate the pathologic features of myositis associated with anti-Ku antibodies, compared with immune-mediated necrotizing myopathy (IMNM) with anti-signal recognition particle (SRP) and anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies, in muscle biopsy-oriented registration cohorts in Japan and Germany. METHODS: We performed a retrospective pathology review of patients with anti-Ku myositis samples diagnosed in the Japanese and German cohorts. We evaluated histologic features and performed HLA phenotyping. RESULTS: Fifty biopsied muscle samples in the Japanese cohort and 10 in the German cohort were obtained. After exclusion of myositis-specific autoantibodies or other autoimmune connective tissue diseases, 26 samples (43%) of anti-Ku antibody-positive myositis were analyzed. All the samples shared some common features with IMNM, whereas they showed expression of MHC class II and clusters of perivascular inflammatory cells more frequently than the anti-SRP/HMGCR IMNM samples (71% vs 7%/16%; p < 0.005/<0.005; 64% vs 0%/0%; p < 0.005/<0.005). Anti-Ku myositis biopsies could be divided into 2 subgroups based on the extent of necrosis and regeneration. The group with more abundant necrosis and regeneration showed a higher frequency of MHC class II expression and perivascular inflammatory cell clusters. HLA phenotyping in the 44 available patients showed possible associations of HLA-DRB1*03:01, HLA-DRB1*11:01, and HLA-DQB1*03:01 (p = 0.0045, 0.019, and 0.027; odds ratio [OR] 50.2, 4.6, and 2.8; 95% CI 2.6-2942.1, 1.1-14.5, and 1.0-7.0) in the group with less conspicuous necrosis and regeneration. On the contrary, in the group of more abundant necrosis and regeneration, the allele frequencies of HLA-A*24:02, HLA-B*52:01, HLA-C*12:02, and HLA-DRB1*15:02 were lower than those of healthy controls (p = 0.0036, 0.027, 0.016, and 0.026; OR = 0.27, 0, 0, and 0; 95% CI 0.1-0.7, 0-0.8, 0-0.8, and 0-0.8). However, these HLA associations did not remain significant after statistical correction for multiple testing. DISCUSSION: While anti-Ku myositis shows necrotizing myopathy features, they can be distinguished from anti-SRP/HMGCR IMNM by their MHC class II expression and clusters of perivascular inflammatory cells. The HLA analyses suggest that anti-Ku myositis may have different subsets associated with myopathologic subgroups.

"Amyopathic" MDA5-positive dermatomyositis with severe lung involvement presenting with net myositic morphological features - insights from an autopsy study.

Anti-MDA5-positive dermatomyositis (MDA5-DM) often presents with extramuscular, especially pulmonary and skin manifestations, and apparent clinical signs of frank myositis can be missing (so called amyopathic DM). We hereby present two male patients who died from respiratory failure during the course of MDA5-DM. While overt signs of myositis or any skin involvement were absent at admission to hospital we noticed conspicuous inflammatory alterations in various skeletal muscles morphologically, showing different degrees of affection. Furthermore, pathological changes of the lungs compatible with rapid progressive interstitial lung disease and characteristic cutaneous vasculoocclusive features were identified at autopsy. This observation shows that muscles and skin are subclinically affected in a widespread fashion, hence subtle signs of muscle involvement should be sought after in anti-MDA5-positive patients with predominant lung affection to ensure adequate treatment.

Immunopathological features of myopathy associated with small-to-medium-sized vessel vasculitis and differences from autoimmune myositis.

OBJECTIVES: Patients with systemic vasculitis may develop myalgia as an initial symptom. However, the immunopathology of vasculitic myopathy remains unclear. We investigated the immunopathological features of skeletal muscle in small-to-medium-sized vessel vasculitis. METHODS: We analysed muscle tissue biopsies from 15 patients with vasculitis, including antineutrophil cytoplasmic antibodyassociated vasculitis and polyarteritis nodosa, and 15 patients with autoimmune myositis (AIM), including polymyositis and immune-mediated necrotising myopathy, as comparison disease controls. Immunohistochemical staining for CD56/neural cell adhesion molecule (NCAM), major histocompatibility complex class I, C5b-9/membrane attack complex (MAC), and CD31 was performed. The vascularity score was defined as the total number of CD31-expressing blood vessels. The association between CD56/NCAM-expressing myofibers and clinical findings was evaluated in patients with vasculitis. RESULTS: Patients with vasculitis had a significantly lower frequency of CD56/NCAM-expressing myofibers than those with AIM and a positive correlation between the frequency of CD56/NCAM-expressing myofibers and serum aldolase levels. Patients with vasculitis had significantly fewer major histocompatibility complex class I-expressing myofibers and C5b-9/MAC deposits on the sarcolemma than those with AIM. C5b-9/MAC deposits in blood vessels were observed in >70% of patients with vasculitis. Patients with vasculitis had significantly higher vascularity scores in the endomysium than those with AIM. CONCLUSIONS: Patients with vasculitis demonstrated mild myofiber damage based on the lower involvement of CD56/NCAM-expressing myofibers compared to those with AIM. Complement component deposits on the vessel walls and hypervascularity in the endomysium areas may be immunopathological features of vasculitic myopathy.

[Antisynthetase Syndrome-Associated Myositis].

Antisynthetase syndrome-associated myositis is a major form of autoimmune myositis defined by the presence of anti-aminoacyl tRNA synthetase autoantibodies. It involves the skeletal muscle as well as the lungs, joints, and skin. Severity of each symptom varies by autoantibody subtype; anti-OJ is associated with severe muscle involvement. Pathological changes from the perimysium to the adjacent perifascicular area, including perifascicular necrosis, is a distinctive feature. The skeletal muscle provides an immunological micro-milieu for specific plasma cells. Therapies against plasma cells or factors defining B cell/plasma cell niche may be a more effective mechanism-specific treatment.

Association Between HLA Alleles and Autoantibodies in Dermatomyositis Defined by Sarcoplasmic Expression of Myxovirus Resistance Protein A.

OBJECTIVE: The diagnosis in the studies analyzing HLA of dermatomyositis (DM) was based on a combined clinical category of polymyositis/DM. This retrospective study investigated the associations of HLA with 5 DM-specific autoantibodies in Japanese patients diagnosed by muscle pathology. METHODS: We diagnosed Japanese patients with DM based on sarcoplasmic expression of myxovirus resistance protein A. These patients underwent investigation for 5 DM-specific autoantibodies and HLA genotyping. RESULTS: Of 175 patients (83 males and 92 females; range 1-86 yrs; mean 46 yrs), 173 (98.9%) had 1 of the 5 autoantibodies. Seven alleles-A*02:07, B*46:01, DRB1*04:07, DRB1*07:01, DRB1*08:03, DQB1*06:01, and DPB1*02:02-were more frequently detected in the patients with DM than healthy controls, but these associations were not significant after multiple testing correction. Stratifying by DM-specific autoantibodies, we found the associations of 6 already known and 7 new alleles-B*48:01, B*52:01, C*12:02, DRB1*04:05, DRB1*15:02, DPB1*05:01, and DPB1*09:01-with subsets of DM. Moreover, significant associations of 5 alleles with antinucleosome remodeling deacetylase complex (Mi-2) remained after multiple testing correction. In particular, the DRB1*04:07 (odds ratio [OR 28.9]; corrected P = 2.7 × 10-6) and DQB1*06:01 (OR 4.0; corrected P = 1.6 × 10-4) alleles were significantly more prevalent in patients with anti-Mi-2 antibody than in controls. CONCLUSION: This study demonstrates DM-specific autoantibodies defined immunogenetic subsets of DM.

Association of immune-mediated necrotizing myopathy with HLA polymorphisms.

Immune-mediated necrotizing myopathy (IMNM) is a type of autoimmune myositis typically characterized clinically by proximal muscle weakness with elevated creatine kinase levels, pathologically by myofiber necrosis and regeneration with paucity of lymphocytic cell infiltration, and serologically by the presence of either of two myositis-specific autoantibodies, anti-SRP, and anti-HMGCR antibodies. However, the HLA loci and alleles associated with IMNM are still not fully understood at least partly because IMNM was a relatively recently established condition. In this study, we genotyped the six HLA loci (HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1) in 250 patients (237 patients over age 18 years and 13 juvenile patients) diagnosed with IMNM based on clinicopathological features and autoantibody information and performed a case control study with Japanese healthy subjects. In the adult patients, specific HLA alleles associated with IMNM were identified at all HLA loci, with DRB1*08:03 showing the strongest association (OR = 2.5; p = 0.00000017). Furthermore, subgroup analysis with various clinical information showed that C*03:04 (OR = 3.7; p = 0.00012) was a higher risk allele for collagen disease in adult patients, and B*13:01 (OR = 23.2; p = 0.021) and C*03:04 (OR = 5.8; p = 0.0074) were higher risk for juvenile patients with anti-HMGCR antibody-positive IMNM. These findings will help to better understand the HLA genetic background and features of IMNM in designing future studies.

Morphologic and Molecular Patterns of Polymyositis With Mitochondrial Pathology and Inclusion Body Myositis.

BACKGROUND AND OBJECTIVE: To characterize morphological and molecular underpinnings of polymyositis with mitochondrial pathology (PM-Mito) in comparison with sporadic inclusion body myositis (IBM) and to define common and distinct pathophysiologic features with a focus on interferon (IFN)-associated inflammation and T-cell response. METHODS: In this cross-sectional study, skeletal muscle biopsy samples and clinical and laboratory data from patients with PM-Mito and IBM were analyzed at Charité university hospital in Berlin, Germany. All available PM-Mito biopsy samples, an equal number of randomly selected IBM biopsy samples, and randomly selected nondiseased controls (NDCs) were included in the study. Biopsy samples were studied by histopathology, immunohistochemistry, and quantitative PCR (qPCR) and compared with biopsies derived from NDCs. Primary outcomes included cell counts for immunohistochemistry and gene expression (fold-change values compared with those in NDCs) for qPCR. RESULTS: Twenty-five skeletal muscle biopsy samples of patients with PM-Mito and IBM were included in the study and compared with 5 biopsy samples from NDCs. PM-Mito and IBM qualitatively harbored a strikingly similar molecular signature and shared important histopathologic features. Expression of IFN-induced guanylate-binding protein (GBP)6 and T-cell function-related KLRG1 distinguished IBM from PM-Mito biopsies with IBM patients showing significantly higher expression of GBP6 and KLRG1. Cryptic exon expression was detected in both patient groups with IBM patients showing higher expression levels. Skeletal muscle biopsies from IBM patients showed significantly more GBP6+ cells and KLRG1+ lymphocytes in comparison with biopsies from patients with PM-Mito. CD45+, CD68+, CD57+, PD1+, and CD8+ cytotoxic T cells were also significantly more abundant in patients with IBM. Clinically, patients with PM-Mito presented with a spectrum of muscle-related symptoms including myalgia, proximal paraparesis, proximal tetraparesis, and incomplete IBM-like patterns. Thirteen of 14 (93%) patients with PM-Mito for whom clinical follow-up was available later developed clinically defined IBM. Notably, 2 follow-up biopsies obtained 5 and 7 years after the first ones were available in this cohort, both showing histopathologic progress to net IBM including GBP6 and KLRG1 upregulation. DISCUSSION: Our combined data suggest that specific IFN-mediated inflammation plays a key role in both IBM and PM-Mito. GBP6 was identified as a new molecule of type II IFN-induced inflammation distinguishing IBM from PM-Mito. Skeletal muscles from both groups harbor dysfunctional T cells of similar type, albeit in different quantity. T-cell senescence exemplified by KLRG1 positivity does not play a significant role in PM-Mito. Based on these findings, we propose to include PM-Mito in the spectrum of IBM (IBM-spectrum disease [IBM-SD]) as a possible early form of this disease. The establishment of IBM-SD as a larger entity could potentially have a significant effect on the design of trials and therapeutic interventions.

Skeletal muscle provides the immunological micro-milieu for specific plasma cells in anti-synthetase syndrome-associated myositis.

Anti-synthetase syndrome (ASyS)-associated myositis is a major subgroup of the idiopathic inflammatory myopathies (IIM) and is characterized by disease chronicity with musculoskeletal, dermatological and pulmonary manifestations. One of eight autoantibodies against the aminoacyl-transferase RNA synthetases (ARS) is detectable in the serum of affected patients. However, disease-specific therapeutic approaches have not yet been established.To obtain a deeper understanding of the underlying pathogenesis and to identify putative therapeutic targets, we comparatively investigated the most common forms of ASyS associated with anti-PL-7, anti-PL-12 and anti-Jo-1. Our cohort consisted of 80 ASyS patients as well as healthy controls (n = 40), diseased controls (n = 40) and non-diseased controls (n = 20). We detected a reduced extent of necrosis and regeneration in muscle biopsies from PL-12+ patients compared to Jo-1+ patients, while PL-7+ patients had higher capillary dropout in biopsies of skeletal muscle. Aside from these subtle alterations, no significant differences between ASyS subgroups were observed. Interestingly, a tissue-specific subpopulation of CD138+ plasma cells and CXCL12+/CXCL13+CD20+ B cells common to ASyS myositis were identified. These cells were localized in the endomysium associated with alkaline phosphatase+ activated mesenchymal fibroblasts and CD68+MHC-II+CD169+ macrophages. An MHC-I+ and MHC-II+ MxA negative type II interferon-driven milieu of myofiber activation, topographically restricted to the perifascicular area and the adjacent perimysium, as well as perimysial clusters of T follicular helper cells defined an extra-medullary immunological niche for plasma cells and activated B cells. Consistent with this, proteomic analyses of muscle tissues from ASyS patients demonstrated alterations in antigen processing and presentation. In-depth immunological analyses of peripheral blood supported a B-cell/plasma-cell-driven pathology with a shift towards immature B cells, an increase of B-cell-related cytokines and chemokines, and activation of the complement system. We hypothesize that a B-cell-driven pathology with the presence and persistence of a specific subtype of plasma cells in the skeletal muscle is crucially involved in the self-perpetuating chronicity of ASyS myositis. This work provides the conceptual framework for the application of plasma-cell-targeting therapies in ASyS myositis.

SIGLEC1 enables straightforward assessment of type I interferon activity in idiopathic inflammatory myopathies.

OBJECTIVE: To evaluate sialic acid binding Ig-like lectin 1 (SIGLEC1) expression on monocytes by flow cytometry as a type I interferon biomarker in idiopathic inflammatory myopathies (IIM). METHODS: We performed a retrospective analysis of adult and paediatric patients with the diagnosis of IIM. SIGLEC1 expression was assessed by flow cytometry and was compared with Physician Global Assessment or Childhood Myositis Assessment Scale disease activity scores. Mann Whitney U test and receiver operating characteristic curves were used for cross-sectional data analysis (n=96), two-level mixed-effects linear regression model for longitudinal analyses (n=26, 110 visits). Response to treatment was analysed in 14 patients within 12 months, using Wilcoxon test. SIGLEC1 was compared with interferon-stimulated gene 15/MxA status by immunohistochemical staining of muscle biopsies (n=17). RESULTS: 96 patients with adult (a) and juvenile (j) dermatomyositis (DM, n=38), antisynthetase syndrome (AS, n=19), immune-mediated necrotising myopathy (IMNM, n=8), inclusion body myositis (IBM, n=9) and overlap myositis (n=22) were included. SIGLEC1 distinguished significantly between active and inactive disease with an area under the curve of 0.92 (95% CI 0.83 to 1) in DM and correlated with disease activity longitudinally (aDM: standardised beta=0.54, p<0.001; jDM: standardised beta=-0.70, p<0.001). Response to treatment in DM was associated with a decreasing SIGLEC1 (p<0.01, Wilcoxon test). SIGLEC1 was found upregulated in 8 of 19 patients with AS, 2 of 9 patients with IBM but not in IMNM. CONCLUSION: SIGLEC1 is a candidate biomarker to assess type I interferon activity in IIM and proved useful for monitoring disease activity and response to treatment in juvenile and adult DM.

Successful plasmapheresis and immunoglobulin treatment for severe lipid storage myopathy: Doing the right thing for the wrong reason.

Three consecutive skeletal muscle biopsies during a several months time-frame, showing different degrees of neutral lipid storage. This is highlighted by Oil-red-O stains (D, E, F) and electron microscopy (G, H, I). Note the impact on mitochondrial morphology with so called 'parking lots (K, L). Zooming 'in and out' into the ultrastructure, using the nanotomy platform provides interesting detailled information (http://nanotomy.org). ​.

Myoclonic Epilepsy with Ragged-red Fibers with Intranuclear Inclusions.

We herein report a case of myoclonic epilepsy with ragged-red fibers (MERRF) harboring a novel variant in mitochondrial cysteine transfer RNA (MT-TC). A 68-year-old woman presented with progressive myoclonic epilepsy with optic atrophy and peripheral neuropathy. A skin biopsy revealed p62-positive intranuclear inclusions. No mutations were found in the causative genes for diseases known to be related to intranuclear inclusions; however, a novel variant in MT-TC was found. The association between intranuclear inclusions and this newly identified MERRF-associated variant is unclear; however, the rare complication of intranuclear inclusions in a patient with typical MERRF symptoms should be noted for future studies.

Mild form of Danon disease: two case reports.

Danon disease is typically lethal by the mid-twenties in male patients due to cardiomyopathy. This report aims to describe two unrelated male patients showing mild manifestations of the disease. A 39-year-old man presented with a 10-year history of elevated serum creatine kinase levels with slowly progressive muscle weakness. Muscle pathology showed autophagic vacuoles with sarcolemmal features. Genetic testing revealed a hemizygous mutation in exon 9b, an alternatively spliced exon, of lysosome-associated membrane protein-2 (LAMP-2) (c.1097_1098delAA). Cardiac testing showed asymptomatic mild left ventricular hypertrophy. He had borderline intelligence. Early stage of retinopathy was detected. Another male patient, currently 53-year-old, had asymptomatic supraventricular extrasystole and muscle weakness but no intellectual disability, harboring the same mutation. He also had retinopathy. The present patients commonly carry a mutation in exon 9b of LAMP-2, suggesting that mutations in the exon are associated with a mild form of Danon disease.

Updates on the Immunopathology in Idiopathic Inflammatory Myopathies.

PURPOSE OF REVIEW: To review recent advances in immunopathology for idiopathic inflammatory myopathies, focusing on widely available immunohistochemical analyses. RECENT FINDINGS: Sarcoplasmic expression of myxovirus resistance protein A (MxA) is specifically observed in all types of dermatomyositis and informs that type I interferons are crucially involved in its pathogenesis. It is a more sensitive diagnostic marker than perifascicular atrophy. Diffuse tiny dots in the sarcoplasm highlighted by p62 immunostaining are characteristically seen in immune-mediated necrotizing myopathy. This feature is linked to a chaperone-assisted selective autophagy pathway. Myofiber invasion by highly differentiated T cells, a marker of which is KLRG1, is specific to inclusion body myositis and has a crucial role in its pathogenesis. The recent advances in immunopathology contribute to increased diagnostic accuracy and a better understanding of the underlying pathophysiology in different types of idiopathic inflammatory myopathies.

Inflammatory features in sporadic late-onset nemaline myopathy are independent from monoclonal gammopathy.

Sporadic late-onset nemaline myopathy (SLONM) is a rare adult-onset non-hereditary disease with subacute proximal muscle and often axial muscle weakness, characterized by the presence of nemaline bodies in skeletal muscle biopsies. Considering its association with concurrent monoclonal gammopathy of undetermined significance (MGUS), the disease is classified into two major subtypes (1) SLONM without MGUS (SLONM-noMGUS) and (2) with MGUS (SLONM-MGUS) association. SLONM associated with HIV infection (SLONM-HIV) is also reported. SLONM-MGUS has been shown to be associated with poorer prognosis and required aggressive treatment including high-dose melphalan and autologous stem cell transplantation. The approach is currently debatable as recent reports suggested effectiveness of intravenous immunoglobulin as initial treatment with indifference of overall survival despite the presence of MGUS. Our study aimed to find an underlying basis by review of pathological features in 49 muscle biopsy proven-SLONM from two large tertiary centers in Japan and Germany (n = 49: SLONM-noMGUS = 34, SLONM-MGUS = 13, SLONM-HIV = 2). We compared pathological findings in SLONM-noMGUS and SLONM-MGUS and focused on the presence of any detectable inflammatory features by immunohistochemistry. The clinical and histological features in SLONM-noMGUS and SLONM-MGUS were not distinctively different except for more common regenerating fibers (>5% of myofibers) present in SLONM-MGUS (p < 0.01). HLA-ABC expression and fine granular p62 were observed in 66.7% and 78.3% of SLONM, respectively. The predominant inflammatory cells were CD68+ cells. The inflammatory cells showed positive correlations with the percentage of nemaline-containing fibers (p < 0.001). In conclusion, inflammatory features are present although rather mild in SLONM. This finding contributes to the hypothesis of an acquired inflammatory disease pathogenesis and opens the possibility to offer immunotherapy in SLONM with inflammatory features regardless of the monoclonal gammopathy status.

Systemic sclerosis-associated myositis features minimal inflammation and characteristic capillary pathology.

Systemic sclerosis represents a chronic connective tissue disease featuring fibrosis, vasculopathy and autoimmunity, affecting skin, multiple internal organs, and skeletal muscles. The vasculopathy is considered obliterative, but its pathogenesis is still poorly understood. This may partially be due to limitations of conventional transmission electron microscopy previously being conducted only in single patients. The aim of our study was therefore to precisely characterize immune inflammatory features and capillary morphology of systemic sclerosis patients suffering from muscle weakness. In this study, we identified 18 individuals who underwent muscle biopsy because of muscle weakness and myalgia in a cohort of 367 systemic sclerosis patients. We performed detailed conventional and immunohistochemical analysis and large-scale electron microscopy by digitizing entire sections for in-depth ultrastructural analysis. Muscle biopsies of 12 of these 18 patients (67%) presented minimal features of myositis but clear capillary alteration, which we termed minimal myositis with capillary pathology (MMCP). Our study provides novel findings in systemic sclerosis-associated myositis. First, we identified a characteristic and specific morphological pattern termed MMCP in 67% of the cases, while the other 33% feature alterations characteristic of other overlap syndromes. This is also reflected by a relatively homogeneous clinical picture among MMCP patients. They have milder disease with little muscle weakness and a low prevalence of interstitial lung disease (20%) and diffuse skin involvement (10%) and no cases of either pulmonary arterial hypertension or renal crisis. Second, large-scale electron microscopy, introducing a new level of precision in ultrastructural analysis, revealed a characteristic capillary morphology with basement membrane thickening and reduplications, endothelial activation and pericyte proliferation. We provide open-access pan-and-zoom analysis to our datasets, enabling critical discussion and data mining. We clearly highlight characteristic capillary pathology in skeletal muscles of systemic sclerosis patients.

A novel mutation in NEB causing foetal nemaline myopathy with arthrogryposis during early gestation.

Nemaline myopathies are a clinically and genetically heterogeneous group of congenital myopathies, mainly characterized by muscle weakness, hypotonia and respiratory insufficiency. Here, we report a male foetus of consanguineous parents with a severe congenital syndrome characterized by arthrogryposis detected at 13 weeks of gestation. We describe severe complex dysmorphic facial and musculoskeletal features by post mortem fetal examination confirming the prenatal diagnosis. Histomorphological and ultrastructural studies of skeletal muscle reveal mini-rods in myotubes caused by a novel homozygous splice-site mutation in NEB (NM_001164508, chr2:g.152,417,623C>A GRCh37.p11 | c.19,102-1G>T ENST00000397345.3). No rods were seen in the myocardium. We discuss the relevance of this mutation in the context of nemaline myopathies associated with early developmental musculoskeletal disorders.

Sirolimus for treatment of patients with inclusion body myositis: a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2b trial.

BACKGROUND: Inclusion body myositis is the most frequent myositis in patients older than 50 years. Classical immunosuppressants are ineffective in treating inclusion body myositis, and to date there are no recommendations for pharmacological approaches to treatment. When used after organ transplantation, sirolimus can block the proliferation of effector T cells, while preserving T regulatory cells, and induce autophagy, all of which are processes that are impaired in inclusion body myositis. In this pilot study, we aimed to test the efficacy of sirolimus in patients with inclusion body myositis. METHODS: This randomised, double-blind, placebo-controlled, proof-of-concept, phase 2b trial was done at a single hospital in Paris, France. The study included men and women (aged 45-80 years) who had a defined diagnosis of inclusion body myositis according to established criteria. Eligible participants were randomly assigned (1:1) to receive once-daily oral sirolimus 2 mg or placebo. Centralised balanced block randomisation (blocks of four) was computer generated without stratification. The study comprised a 15-day screening period (days -15 to 0) and a 52-week treatment period (day 0 to month 12). The primary endpoint was the relative percentage change from baseline to month 12 in maximal voluntary isometric knee extension strength. Secondary endpoints included the following assessments at months 6 and 12: 6-min walking distance, isometric muscle strength for hand grip (finger flexors), knee flexion and elbow flexion and extension, forced vital capacity, muscle replacement with fat measured by quantitative nuclear MRI, Inclusion Body Myositis Weakness Composite Index (IBMWCI), Inclusion Body Myositis Functional Rating Scale (IBMFRS), Health Assessment Questionnaire without Disability Index (HAQ-DI), and analyses of T-cell subpopulations by mass cytometry. The primary analysis was done on the intention-to-treat population. The trial is registered at ClinicalTrials.gov, NCT02481453. FINDINGS: Between July 15, 2015, and May 13, 2016, we screened 285 patients, 44 of whom were randomly allocated to sirolimus (22 patients) or placebo (22 patients). We observed no difference in the primary outcome of relative percentage change from baseline to month 12 of the maximal voluntary isometric knee extension strength (median difference 3·78, 95% CI -10·61 to 17·31; p=0·85). For secondary outcomes, differences between the groups were not significant for changes in strength of other muscle groups (grip, elbow flexion and extension, or knee flexion), IBMWCI, IBMFRS, and lower limb muscle fat fraction. However, we observed significant differences in favour of sirolimus between the study groups for HAQ-DI, forced vital capacity, thigh fat fraction, and 6-min walking distance. Ten (45%) of 22 patients in the sirolimus group had a serious adverse event compared with six (27%) of 22 patients in the placebo group. Four (18%) patients in the sirolimus group stopped their treatment because of adverse events (severe mouth ulcers, aseptic pneumonia, renal insufficiency, and peripheral lower limb oedema), which resolved after treatment discontinuation. Canker sores were the most frequent side-effect and were mainly mild or moderate in ten patients. INTERPRETATION: We found no evidence for efficacy of sirolimus for treating inclusion body myositis based on maximal voluntary isometric knee extension strength and other muscle strength measures, and the side-effects of treatment were substantial for some patients. However, we believe there was enough evidence of benefit in certain secondary outcomes to pursue a multicentre phase 3 trial to further assess the safety and efficacy of sirolimus. FUNDING: Institut national de la santé et de la recherche médicale, Direction générale de l'offre de soins, and Association Française contre les Myopathies.

HLA-DRB1 allele and autoantibody profiles in Japanese patients with inclusion body myositis.

INTRODUCTION: Inclusion body myositis (IBM) is an idiopathic inflammatory myopathy, characterized by unique clinical features including finger flexor and quadriceps muscle weakness and a lack of any reliable treatment. The human leukocyte antigen (HLA)-DRB1 allele and autoantibody profiles in Japanese IBM patients have not been fully elucidated. METHODS: We studied 83 Japanese IBM patients with a mean age of 69 years (49 males and 34 females) who participated in the 'Integrated Diagnosis Project for Inflammatory Myopathies' from January 2011 to September 2016. IBM was diagnosed by histological diagnosis. Various autoantibodies were screened by RNA immunoprecipitation and enzyme-linked immunosorbent assays. HLA-DRB1 genotyping was performed using polymerase chain reaction-sequence based typing. A total of 460 unrelated healthy Japanese controls were also studied. RESULTS: The allele frequencies of DRB1*01:01, DRB1*04:10, and DRB1*15:02 were significantly higher in the IBM group than in the healthy control group (Corrected P = 0.00078, 0.00038 and 0.0046). There was a weak association between the DRB1*01:01 allele and severe leg muscle weakness and muscle atrophy. While hepatitis type C virus infection and autoantibodies to cytosolic 5'-nucleotidase 1A were found in 18 and 28 patients, respectively, no significant association with HLA-DRB1 alleles was observed. CONCLUSION: Japanese IBM patients had the specific HLA-DRB1 allele and autoantibody profiles.

Where are we moving in the classification of idiopathic inflammatory myopathies?

PURPOSE OF REVIEW: Discoveries of myositis-specific antibodies, transcriptomic signatures, and clinicoseropathological correlation support classification of idiopathic inflammatory myopathies (IIM) into four major subgroups: dermatomyositis, immune-mediated necrotizing myopathy (IMNM), antisynthetase syndrome (ASS), and inclusion body myositis (IBM) whereas leaving polymyositis as a historical nonspecific diagnosis of exclusion. This review summarizes and comments on recent knowledge regarding the major subgroup of IIM. RECENT FINDINGS: Type 1 interferon (IFN1) pathway activation is the most prominent in dermatomyositis whereas type 2 interferon (IFN2) pathway activation is high in IBM and ASS; neither pathway is distinct in IMNM. Myxovirus-resistant protein A, IFN1 surrogate marker, is now one of definite dermatomyositis muscle biopsy criteria in the new 2018 European Neuromuscular Centre classification of dermatomyositis; the classification emphasizes on different categorization with and without dermatomyositis-specific antibody result. Novel HLA loci associated with anti-TIF1-γ, anti-Mi-2, and anti-Jo-1 antibodies in Caucasian population are identified. Associations of chaperon-assisted selective autophagy (CASA) and complement-mediated autoimmunity in IMNM as well as highly differentiated T cells in IBM are discovered. SUMMARY: Current IIM classification requires integrated clinicoseropathological approaches. Additional information, such as transcriptomics, HLA haplotyping, and potential biomarkers help tailoring categorization that may have future diagnostic and therapeutic implications.