Subgroup Of Idiopathic Inflammatory Myopathies Research Articles

576P High precision quantification of ICAM-1 highlights similarities and differences between subgroups of Idiopathic inflammatory myopathies

576P High precision quantification of ICAM-1 highlights similarities and differences between subgroups of Idiopathic inflammatory myopathies

Contribution of major histocompatibility complex class II immunostaining in distinguishing idiopathic inflammatory myopathy subgroups: A histopathological cohort study.

Idiopathic inflammatory myopathies (IIM) are rare, acquired muscle diseases; their diagnosis of is based on clinical, serological, and histological criteria. MHC-I-positive immunostaining, although non-specific, is used as a marker for IIM diagnosis; however, the significance of major histocompatibility complex (MHC)-II immunostaining in IIM remains debated. We investigated patterns of MHC-II immunostaining in myofibers and capillaries in muscle biopsies from 103 patients with dermatomyositis ([DM], n = 31), inclusion body myositis ([IBM], n = 24), anti-synthetase syndrome ([ASyS], n = 10), immune-mediated necrotizing myopathy ([IMNM], n = 18), or overlap myositis ([OM], n = 20). MHC-II immunostaining of myofibers was abnormal in 63/103 of patients (61%) but the patterns differed according to the IIM subgroup. They were diffuse in IBM (96%), negative in IMNM (83%), perifascicular in ASyS (70%), negative (61%) or perifascicular (32%) in DM, and either clustered (40%), perifascicular (30%), or diffuse heterogeneous (15%) in OM. Capillary MHC-II immunostaining also identified quantitative (capillary dropout, n = 47/88, 53%) and qualitative abnormalities, that is, architectural abnormalities, including dilated and leaky capillaries, (n = 79/98, 81%) in all IIM subgroups. Thus, MHC-II myofiber expression patterns allow distinguishing among IIM subgroups. We suggest the addition of MHC-II immunostaining to routine histological panels for IIM diagnosis.

Association of anti-Ro-52 antibodies with occurrence of interstitial lung disease in patients with idiopathic inflammatory myopathy

BackgroundAnti-Ro-52 antibodies have been associated with interstitial lung disease (ILD) in various autoimmune diseases. However, their role in ILD among patients with idiopathic inflammatory myopathies (IIMs) is relatively underexplored. This study aimed to investigate the association between anti-Ro-52 antibodies and the occurrence of ILD in individuals with IIMs.MethodsThis retrospective observational study included 604 patients who underwent myositis autoantibody testing between July 2018 and January 2021 at our hospital and were diagnosed with either IIMs or IIM-mimics. Comparative analyses were conducted between IIMs and IIM-mimics, as well as within the IIM group between cases with and without ILD. Logistic regression or Firth’s logistic regression analyses were employed to assess the risk of ILD development in different IIM subgroups and myositis antibody categories.ResultsThis study included 190 patients with IIM and 414 patients with IIM-mimics. Patients with IIM demonstrated higher incidence of ILD, concurrent autoimmune disease, and a greater likelihood of various myositis autoantibodies when compared to the IIM-mimics group. Within the IIM patient cohort, those with ILD exhibited a later age of onset of IIM, an increased mortality rate, and a more frequent presence of anti-aminoacyl-tRNA synthetase (ARS) antibodies compared to those without ILD. The presence of any myositis-specific antibody (MSA) was associated with a six-fold increased risk of ILD, while dual positivity for MSA and anti-Ro-52 antibodies conferred a twenty-fold risk. Anti-ARS antibodies carried a 14-fold increased risk of ILD, which escalated to 38-fold in cases of dual positivity for anti-ARS and anti-Ro-52 antibodies. Anti-Ro-52 antibodies alone increased the risk eight-fold.ConclusionsAmong patients with IIM, the presence of ILD was linked to higher mortality. Certain autoantibodies, notably anti-ARS and anti-Ro-52 antibodies, were associated with an increased risk of ILD. The greatest risk of ILD was observed in cases of dual positivity for anti-ARS and anti-Ro-52 antibodies.

Idiopathic inflammatory myopathies : An interdisciplinary challenge

Idiopathic inflammatory myopathies (IIM) are rare diseases (incidence 1:100,000) with awide range of clinical symptoms and manifestations. Typical indicators of IIM are proximally emphasized muscle weakness and myalgias, which are usually accompanied by elevated creatine kinase levels and muscle atrophy. The autoantibody diagnostics separate IIM into different entities, which are each associated with atypical risk of organ manifestations and the occurrence of tumors. The IIM represents an interdisciplinary challenge and the diagnostics and treatment require the involvement of several disciplines including rheumatology, neurology, neuropathology, dermatology and pneumology. An accurate diagnosis and careful tumor screening are essential because of the association between certain subgroups of IIM and the occurrence of malignant tumors.

Gender differences inpatient experience inidiopathic inflammatory myopathies: Subanalysis from the COVAD dataset.

We aimed to investigate the gender-based differences in idiopathic inflammatory myopathies (IIMs), with a particular focus on patient-reported outcomes, utilizing the data obtained through the international COVID-19 vaccination in autoimmune disease e-survey. Patient-reported outcomes including fatigue, pain, and physical function were extracted from the COVID-19 vaccination in autoimmune disease database and compared between genders, adjusting for demographics and IIM subgroups by multivariable analysis. Inclusion body myositis (IBM) was analysed separately because of the substantial differences in outcomes. A total of 1197 complete responses from patients with IIMs as of 31 August 2021 were analysed. Seventy percent were women. Women were younger (58 [48-68] vs. 69 [58-75] years old, median [interquartile range], P < .001) and were more likely to suffer from autoimmune multimorbidity, defined as three or more autoimmune diseases in an individual patient (11.4% vs. 2.8%, P < .001). In non-IBM IIMs, fatigue visual analogue scale scores were higher in women (5 [3-7] vs. 4 [2-6], median [interquartile range], P = .004), whereas no significant gender-based differences were noted in IBM. Multivariable analysis in non-IBM IIMs revealed that women, residence in high-income countries, overlap myositis, and autoimmune multimorbidity were independently associated with increased fatigue. Women with IIMs suffer from autoimmune multimorbidity and experience increased fatigue compared to men.

A Narrative Review of Acthar Gel for the Treatment of Myositis.

Idiopathic inflammatory myopathies (IIMs) are autoimmune disorders characterized by symmetric proximal muscle weakness and chronic inflammation, with an increased risk of morbidity and mortality. The current standard of care includes traditional immunosuppressive pharmacotherapies; however, some patients cannot tolerate or do not adequately respond to these therapies, highlighting the need for alternative treatments for refractory disease. Acthar® Gel (repository corticotropin injection) is a naturally sourced mixture of adrenocorticotropic hormone analogs and other pituitary peptides that has been approved by the US Food and Drug Administration since 1952 for use in patients with two subgroups of IIMs, dermatomyositis (DM) and polymyositis (PM). However, it has not been routinely used in the treatment of IIMs. While Acthar may induce steroidogenesis, it also has a steroid-independent mechanism of action by exerting immunomodulatory effects through the activation of melanocortin receptors on immune cells, such as macrophages, B cells, and T cells. Recent clinical trials, retrospective analyses, and case reports add to the growing evidence suggesting that Acthar may be effective in patients with DM and PM. Here we review the current evidence supporting the safety and efficacy of Acthar for the treatment of refractory DM and PM.

Identification of Novel Associations and Localization of Signals in Idiopathic Inflammatory Myopathies Using Genome-Wide Imputation.

The idiopathic inflammatory myopathies (IIMs) are heterogeneous diseases thought to be initiated by immune activation in genetically predisposed individuals. We imputed variants from the ImmunoChip array using a large reference panel to fine-map associations and identify novel associations in IIM. We analyzed 2,565 Caucasian IIM patient samples collected through the Myositis Genetics Consortium (MYOGEN) and 10,260 ethnically matched control samples. We imputed 1,648,116 variants from the ImmunoChip array using the Haplotype Reference Consortium panel and conducted association analysis on IIM and clinical and serologic subgroups. The HLA locus was consistently the most significantly associated region. Four non-HLA regions reached genome-wide significance, SDK2 and LINC00924 (both novel) and STAT4 in the whole IIM cohort, with evidence of independent variants in STAT4, and NAB1 in the polymyositis (PM) subgroup. We also found suggestive evidence of association with loci previously associated with other autoimmune rheumatic diseases (TEC and LTBR). We identified more significant associations than those previously reported in IIM for STAT4 and DGKQ in the total cohort, for NAB1 and FAM167A-BLK loci in PM, and for CCR5 in inclusion body myositis. We found enrichment of variants among DNase I hypersensitivity sites and histone marks associated with active transcription within blood cells. We found novel and strong associations in IIM and PM and localized signals to single genes and immune cell types.

Transcriptome analysis of skeletal muscle in dermatomyositis, polymyositis, and dysferlinopathy, using a bioinformatics approach.

Polymyositis (PM) and dermatomyositis (DM) are two distinct subgroups of idiopathic inflammatory myopathies. Dysferlinopathy, caused by a dysferlin gene mutation, usually presents in late adolescence with muscle weakness, degenerative muscle changes are often accompanied by inflammatory infiltrates, often resulting in a misdiagnosis as polymyositis. To identify differential biological pathways and hub genes related to polymyositis, dermatomyositis and dysferlinopathy using bioinformatics analysis for understanding the pathomechanisms and providing guidance for therapy development. We analyzed intramuscular ribonucleic acid (RNA) sequencing data from seven dermatomyositis, eight polymyositis, eight dysferlinopathy and five control subjects. Differentially expressed genes (DEGs) were identified by using DESeq2. Enrichment analyses were performed to understand the functions and enriched pathways of DEGs. A protein-protein interaction (PPI) network was constructed, and clarified the gene cluster using the molecular complex detection tool (MCODE) analysis to identify hub genes. A total of 1,048, 179 and 3,807 DEGs were detected in DM, PM and dysferlinopathy, respectively. Enrichment analyses revealed that upregulated DEGs were involved in type 1 interferon (IFN1) signaling pathway in DM, antigen processing and presentation of peptide antigen in PM, and cellular response to stimuli in dysferlinopathy. The PPI network and MCODE cluster identified 23 genes related to type 1 interferon signaling pathway in DM, 4 genes (PDIA3, HLA-C, B2M, and TAP1) related to MHC class 1 formation and quality control in PM, and 7 genes (HSPA9, RPTOR, MTOR, LAMTOR1, LAMTOR5, ATP6V0D1, and ATP6V0B) related to cellular response to stress in dysferliniopathy. Overexpression of genes related to the IFN1 signaling pathway and major histocompatibility complex (MHC) class I formation was identified in DM and PM, respectively. In dysferlinopathy, overexpression of HSPA9 and the mTORC1 signaling pathway genes was detected.

Identification of feature genes and key biological pathways in immune-mediated necrotizing myopathy: High-throughput sequencing and bioinformatics analysis

BackgroundImmune-mediated necrotizing myopathy (IMNM), a subgroup of idiopathic inflammatory myopathies (IIMs), is characterized by severe proximal muscle weakness and prominent necrotic fibers but no infiltration of inflammatory cells. IMNM pathogenesis is unclear. This study investigated key biomarkers and potential pathways for IMNM using high-throughput sequencing and bioinformatics technology. MethodsRNA sequencing was conducted in 18 IMNM patients and 10 controls. A combination of weighted gene coexpression network analysis (WGCNA) and differentially expressed gene (DEG) analysis was conducted to identify IMNM-related DEGs. Feature genes were screened out by employing the proteinprotein interaction (PPI) network, support vector machine-recursive feature elimination (SVM-RFE), and least absolute shrinkage selection operator (LASSO). Quantitative real-time polymerase chain reaction (qRTPCR) was performed to verify their differential expression, and the receiver operating characteristic curve (ROC) was used to evaluate their diagnostic efficiency. Functional enrichment analysis was applied to reveal the hidden functions of feature genes. Furthermore, 28 immune cell abundance patterns in IMNM samples were measured. ResultsWe identified 193 IMNM-related DEGs that were aberrantly upregulated in the IMNM population and were closely associated with immune-inflammatory responses, regulation of skeletal and cardiac muscle contraction, and lipoprotein metabolism. With the help of the PPI network and the LASSO and SVM-RFE algorithms, three feature genes, LTK, MYBPH, and MYL4, were identified and further confirmed by qRTPCR. ROC curves among IMNM, dermatomyositis (DM), inclusion body myositis (IBM), and polymyositis (PM) samples validated the LTK and MYL4 genes as IMNM-specific feature markers. In addition, all three genes had a notable association with the autophagylysosome pathway and immune-inflammatory responses. Ultimately, IMNM displayed a marked immune-cell infiltrative microenvironment. The most significant correlation was found between CD4 T cells, CD8 T cells, macrophages, natural killer (NK) cells, and dendritic cells (DCs). ConclusionsLTK, MYBPH, and MYL4 were identified as potential key molecules for IMNM and are believed to play a role in the autophagylysosome pathway and muscle inflammation.

Myostatin in idiopathic inflammatory myopathies: Serum assessment and disease activity.

In idiopathic inflammatory myopathies (IIM), disease activity is difficult to assess, and IIM may induce severe muscle damage, especially in immune-mediated necrotising myopathies (IMNM) and inclusion body myositis (IBM). We hypothesise that myostatin, a negative regulator of muscle mass, could be a new biomarker of disease activity and/or muscle damage. Prospective assessment of myostatin protein level in 447 IIM serum samples (dermatomyositis [DM], n= 157; IBM, n= 72; IMNM, n= 125; and antisynthetase syndrome [ASyS], n= 93) and 59 healthy donors (HD) was performed by ELISA. A gene transcript analysis was also carried out on 18 IIM muscle biopsies and six controls to analyse myostatin and myostatin pathway-related gene expression. IIM patients had lower myostatin circulating protein levels and gene expression compared to HD (2379 [1490; 3678] pg/ml vs 4281 [3169; 5787] pg/ml; p< 0.0001 and log2FC = -1.83; p= 0.0005, respectively). Myostatin-related gene expression varied accordingly. Based on the Physician Global Assessment, inactive IIM patients showed higher myostatin levels than active ones. This was the case for all IIM subgroups, except IMNM where low myostatin levels were maintained (2186 [1235; 3815] vs 2349 [1518; 3922] pg/ml; p= 0.4). Myostatin protein and RNA levels are decreased in all IIM patients, and protein levels correlate with disease activity. Inactive ASyS and DM patients have higher myostatin levels than active patients. Myostatin could be a marker of disease activity in these subgroups. However, IMNM patients do not have significant increase in myostatin levels after disease remission. This may highlight a new pathological disease mechanism in IMNM patients.

Dengue infection triggered immune mediated necrotizing myopathy in children: a case report and literature review

BackgroundImmune-mediated necrotizing myopathy (IMNM) is a subgroup of idiopathic inflammatory myopathies manifesting with progressive weakness, elevated serum creatine kinase (CK) levels, and necrotizing myopathic features on muscle biopsy. There is a paucity of data on the clinical presentation of IMNM in children. We report a paediatric patient who developed anti-3-hydroxy-3-methylglutaryl-CoA reductase (anti-HMGCR)-positive necrotizing myopathy after recent dengue infection.Case presentationA previously healthy 9-year-old boy presented with acute proximal muscle weakness after recovery from dengue infection. Five days after the fever subsided, he could not stand from a squatting position. He denied having skin rash, arthritis, or other systemic features. He had marked elevation of CK level of 30,833 mg/dL and was put on steroid therapy. The patient initially responded to oral prednisolone, however the weakness persisted and muscle enzymes increased as steroids were decreased. He was then referred to our hospital for further assessment. Subsequent investigation revealed anti-HMGCR positivity along with specific histopathological findings consistent with IMNM. The patient was treated with six cycles of intravenous immunoglobulin (IVIG) monthly, then followed by a gradual taper of prednisolone and oral methotrexate weekly with complete recovery in motor power.ConclusionsOur report presents a child with clinical manifestations of IMNM which can be categorized as acute onset of muscle weakness following dengue infection. Two key points supporting a diagnosis in this case are clinical response after immunosuppressive therapy and absence of rashes found in juvenile dermatomyositis.

The Genetics of Autoimmune Myositis.

The idiopathic inflammatory myopathies (IIM) are rare, heterogeneous systemic autoimmune disorders, characterized by inflammation of skeletal muscle and multi-organ involvement. Studies to identify genetic risk factors and dysregulated gene expression in IIM aim to increase our understanding of disease pathogenesis. Genome-wide association studies have confirmed the HLA region as the most strongly associated region in IIM, with different associations between clinically-defined subgroups. Associated genes are involved in both the innate and adaptive immune response, while identification of variants reported in other autoimmune disorders suggests shared biological pathways. Targeted imputation analysis has identified key associated amino acid residues within HLA molecules that may influence antigen recognition. These amino acids increase risk for specific clinical phenotypes and autoantibody subgroups, and suggest that serology-defined subgroups may be more homogeneous. Recent data support the contribution of rare genetic variation to disease susceptibility in IIM, including mitochondrial DNA variation in sporadic inclusion body myositis and somatic mutations and loss of heterozygosity in cancer-associated myositis. Gene expression studies in skeletal muscle, blood and skin from individuals with IIM has confirmed the role of interferon signalling and other dysregulated pathways, and identified cell-type specific signatures. These dysregulated genes differentiate IIM subgroups and identify potential biomarkers. Here, we review recent genetic studies in IIM, and how these inform our understanding of disease pathogenesis and provide mechanistic insights into biological pathways.

POS0053 ABUNDANT AUTOANTIBODY ISOTYPES IN IDIOPATHIC INFLAMMATORY MYOPATHIES

BackgroundAnti-synthetase syndrome (ASSD), a sub-group of idiopathic inflammatory myopathies (IIM) is characterized by the presence of autoantibodies targeting aminoacyl tRNA synthetases (aaRS) and specific clinical manifestations such as myositis and interstitial lung disease (ILD) [1]. Some of the most common anti-aaRS autoantibodies in ASSD are anti-Jo1, -PL7, -PL12 and-EJ. In addition, many anti-aaRS positive patients are also positive for anti-Ro52. Having the combination of anti-Jo1 and anti-Ro52 increases the risk of developing ILD [2]. The presence of autoantibodies is an important part of the classification of ASSD, however only autoantibodies of IgG isotype are usually analyzed in the clinical setting. In rheumatoid arthritis there is evidence that anti-citrullinated protein/peptide antibodies (ACPA) can be found as IgG, IgA and IgM, and importantly, specific isotypes might correlate with disease activity [3, 4].ObjectivesTo verify if other autoantibody isotypes, besides IgG, might be present in sera of patients with IIM/ASSD and to compare with the corresponding frequencies in population controls (PC).MethodsStored sera collected from consecutive 366 IIM patients and 156 age/gender matched PC at Karolinska University Hospital were retrospectively selected. The serum samples were screened for the presence of autoantibodies of isotypes IgG, IgA and IgM, against a panel of 20 antigens representing Jo1 (HisRS), PL7 (ThrRS), PL12 (AlaRS), EJ (GlyRS), and Ro52 (TRIM21) using a multiplex bead array assay.ResultsWe identified IIM patients with autoantibodies of different isotypes, and a low frequency in PC (Figure 1). For anti-Jo1 autoantibodies we could detect IIM patients with only IgG (n=13), only IgM (n=8) and only IgA (n=4), but the majority had a combination of two (n=32) or three isotypes (n=16). For the other anti-aaRS autoantibodies the distribution was more equal to each of the three isotypes with anti-PL12 and anti-PL7 being represented by a slightly higher frequency of IgG and only a few patients had antibodies of more than one isotype targeting PL12, PL7 or EJ. The majority of anti-Ro52 positive IIM patients (n=52) only harbored IgG isotype. The combination of anti-Ro52 and anti-aaRS autoantibodies was identified in 28 patients (anti-Jo1 (n=19), -PL12 (n=2), -PL7 (n=3), and -EJ (n=4)). Most patients with such combination had anti-Ro52 IgG together with anti-aaRS IgG or IgG in combination with IgA and/or IgM. The exception was observed for three anti-Jo1 positive patients who had the combination anti-Ro52 IgG with only anti-Jo1 IgM and one anti-PL7 positive patient who had anti-Ro52 IgA together with anti-PL7 IgA and IgG.Figure 1.Venn diagrams showing reactivity in idiopathic inflammatory myopathies (IIM) (top) and population controls (PC) (bottom) for the three autoantibody isotypes IgG, IgA and IgM against five myositis antigens: Jo1 (HisRS), PL12 (AlaRS), ThrRS (PL7), EJ (GlyRS) and Ro52 (TRIM21).ConclusionThe frequency of the different autoantibody isotypes seems to be autoantigen dependent. Our results suggest that for anti-aaRS autoantibodies it could be important to investigate additional autoantibody isotypes, as some patients only harbor autoantibodies of IgM or IgA isotypes but not IgG. The clinical relevance of the different antibody isotypes still needs to be determined.

Patterns of body composition and alteration after treatment in patients with newly diagnosed idiopathic inflammatory myopathies.

To define the pattern of body composition and alteration after treatment of patients with newly diagnosed idiopathic inflammatory myopathies (IIMs) using DXA. DXA was used to obtain regional and whole-body measurements of fat mass and lean tissue mass (LTM) in 50 patients with newly diagnosed IIM and matched controls. The DXA indices of fat mass and LTM were calculated. The analyses included correlations between DXA indices and clinical parameters [manual muscle test (MMT), Myositis Damage Index (MDI), Myositis Intention-to-Treat Activities Index (MITAX), handgrip, percentage forced vital capacity (%FVC) and creatine kinase level], comparison between patients with IIM and controls, comparison between IIM subgroups, receiver operating characteristic (ROC) analysis, and comparison of body composition before and after treatment. DXA LTM measurements were significantly correlated with MMT, MDI-muscle, handgrip strength, and %FVC. Patients with IIM had decreased LTM of the upper limbs and appendicular region. Male patients with IIM had significantly decreased LTM in the upper and lower limbs, whereas female patients with IIM had significantly decreased LTM in the upper limbs. Patients with IIM with anti-SRP seropositivity had lower LTM than patients with anti-SRP seronegativity. In ROC analysis, the DXA LTM indices presented good diagnostic values for distinguishing patients with newly diagnosed IIM from healthy controls. After treatment, the LTM of the upper limbs and appendicular region significantly increased. DXA is an attractive method for the evaluation of patients with newly diagnosed IIM as well as a new way of monitoring disease conditions.

Evaluation of Interstitial Lung Disease in Idiopathic Inflammatory Myopathies Through Semiquantitative and Quantitative Analysis of Lung Computed Tomography.

To perform a semiquantitative and quantitative analysis of interstitial lung disease (ILD), through computed tomography (CT), in different serological subgroups of idiopathic inflammatory myopathies (IIM) patients, to find radiologic and clinical differences of disease related to serology. This was a prospective study, which included 98 IIM patients, divided into serological subgroups: anti-aminoacyl-transfer-RNA-synthetases (anti-ARS) positive and myositis-specific autoantibodies (MSA) negative.For each baseline CT the total semiquantitative score of Warrick (WS) and the automated software (Computer-Aided Lung Informatics for Pathology Evaluation and Rating) quantitative scores interstitial lung disease % (ILD%) and vascular-related structure % (VRS%) were calculated. Pulmonary function tests included total lung capacity % (TLC%), forced vital capacity % (FVC%), and diffusing capacity of the lung for carbon monoxide % (DLCO%). Inverse correlations ( P <0.001) between the radiologic scores and the functional scores DLCO% and TLC% were found, the most relevant being between ILD% and DLCO% (ρ=-0.590), VRS% and DLCO% (ρ=-0.549), and WS and DLCO% (ρ=-0.471).Positive correlations between ILD% and VRS% (ρ=0.916; P <0.001), WS and ILD% (ρ=0.663; ρ<0.001), and WS and VRS% (ρ=0.637; P <0.001) were obtained.Statistically significant higher values of WS, ILD%, and VRS% were found in the anti-ARS group (WS=15; ILD%=11; VRS%=3.5) compared with the MSA negative one (WS=2.5; ILD%=0.84; VRS%=2.2).The nonspecific interstitial pneumonia pattern was dominant. No statistically significant differences emerged at pulmonary function tests. In this study, ILD in anti-ARS-positive and MSA-negative groups was defined through semiquantitative and quantitative analysis of lung CT. The inverse correlations between the radiologic scores and TLC% and DLCO% ( P <0.001) confirm the role of lung CT in the evaluation of ILD in IIM.

P223 Predictors of mortality in idiopathic inflammatory myopathy-associated interstitial lung disease - a systematic review and meta-analysis

Abstract Background/Aims Interstitial Lung Disease (ILD) affects approximately 30% of patients with idiopathic inflammatory myopathies (IIM). It is a leading cause of morbidity and mortality in IIM patients. Natural history of ILD varies widely from rapidly-progressive to indolent with minimal symptoms. IIM describes a collection of related autoimmune, inflammatory disorders predominantly affecting combinations of muscles, skin and lungs. Improving understanding of ILD clinical course will aid prognostication and guide sub-categorisation to improve future research in the field. We performed a systematic review and meta-analysis of prognostic factors in IIM-ILD. Methods MEDLINE and EMBASE databases were interrogated on 18/03/2021 using a pre-defined search protocol (PROSPERO ID:CRD42021240206). Studies providing summary data relating to numbers of survivors vs non-survivors according to any baseline criteria were selected. Baseline characteristics reported in ≥ 5 papers were included for meta-analysis. Risk of bias was assessed by Newcastle-Ottawa score. Stata-16 software was used for meta-analyses using a random effects model to report difference as odds ratio for binary variables, and hedge’s g standardised mean difference for continuous variables. A continuity correction was applied for zero effect studies. Heterogeneity was measured by I2, and publication bias assessed with Egger’s test. Results The search returned 4211 articles. 722 were relevant for abstract review, with 454 requiring full text assessment. 78 studies were eligible for inclusion. Overall mortality was 26.1% (+/-0.14 SD). 62 studies were from Asia, two from Mexico and four from Europe, with mortality rates of 26.5%, 13.6% and 25.3% respectively. The strongest risk factor is anti-MDA-5 antibody (OR 6.03). Conversely anti-tRNA-synthetase antibodies (ARS) are protective. When ARS+ was compared to MDA-5-/ARS- patients only, this difference between the groups disappeared. Anti-MDA-5 titre showed a non-significant effect direction towards higher mortality. ANA, anti-SS-A/Ro52 did not significantly impact mortality. Clinical predictors of increased mortality were male gender, acute/sub-acute onset, clinically amyopathic disease (CADM), dyspnoea, ulceration, fever and increasing age. Additional investigations shown to positively predict mortality were CRP, ferritin, LDH, AaO2 gradient, ground glass opacity and fibrosis HRCT scores. Whereas higher SP-D, lymphocytes, %FVC and %DLCO were protective. Conclusion Whilst many factors were associated with increased mortality in IIM-ILD, heterogeneity between studies is high with all having moderate to high risk of bias. A majority of the data come from studies in Japanese and Chinese populations where anti-MDA5 disease appears to be particularly prevalent and associated with deleterious outcomes. Extrapolating to local populations may not be appropriate. The domination of studies by anti-MDA5 disease may be masking risk factors relevant to other IIM subgroups. Due to the rarity of IIMs, these subgroups are often researched together, however this meta-analysis highlights the need to better categorise IIM patients in clinical research. Disclosure J.R. Hannah: None. T. Gordon: None. M. Rooney: None. J. Galloway: None. P. Gordon: None.

Pathophysiological Mechanisms and Treatment of Dermatomyositis and Immune Mediated Necrotizing Myopathies: A Focused Review.

Idiopathic inflammatory myopathies (IIM), collectively known as myositis, are a composite group of rare autoimmune diseases affecting mostly skeletal muscle, although other organs or tissues may also be involved. The main clinical feature of myositis is subacute, progressive, symmetrical muscle weakness in the proximal arms and legs, whereas subtypes of myositis may also present with extramuscular features, such as skin involvement, arthritis or interstitial lung disease (ILD). Established subgroups of IIM include dermatomyositis (DM), immune-mediated necrotizing myopathy (IMNM), anti-synthetase syndrome (ASyS), overlap myositis (OM) and inclusion body myositis (IBM). Although these subgroups have overlapping clinical features, the widespread variation in the clinical manifestations of IIM suggests different pathophysiological mechanisms. Various components of the immune system are known to be important immunopathogenic pathways in IIM, although the exact pathophysiological mechanisms causing the muscle damage remain unknown. Current treatment, which consists of glucocorticoids and other immunosuppressive or immunomodulating agents, often fails to achieve a sustained beneficial response and is associated with various adverse effects. New therapeutic targets have been identified that may improve outcomes in patients with IIM. A better understanding of the overlapping and diverging pathophysiological mechanisms of the major subgroups of myositis is needed to optimize treatment. The aim of this review is to report on recent advancements regarding DM and IMNM.

Mortality and its risk factors in critically ill patients with connective tissue diseases: A meta-analysis

BackgroundSystemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS), systemic sclerosis (SSc), idiopathic inflammatory myopathies (IIM) and rheumatoid arthritis (RA) are connective tissue diseases (CTD) whose complications can lead to management in the intensive care unit (ICU). ObjectivesTo estimate by meta-analysis ICU mortality rates for CTD. MethodsA systematic literature review was performed to identify articles studying critically ill CTD patients. A random-effects model was chosen for analysis. Pooled proportion mortality was calculated using aggregated-data meta-analysis with a random-effects model and assessment of heterogeneity with the I2 statistic. Risk of bias was assessed using the quality assessment tool. ResultsOf the 5694 individual publications, a sample of 31 independent cohorts was used for the meta-analysis totalling 5007 patients. The main cause for admission was sepsis (43%) followed by “flare-ups” (40%). The overall pooled proportion of mortality of CTD patients across all 31 studies was 33% (95%CI: 28–38%). In the IIM subgroup and that of SSc, mortality was 70% (95%CI: 46–86%) and 40% (95%CI: 25–47%), respectively. In the SLE subgroup, mortality was similar to the overall pooled mortality of 35% (95%CI: 29–42%). Subgroup mortality for RA and pSS patients was respectively 20% (95%CI: 11–33%) and 17% (95%CI: 6–41%); lower than the overall pooled mortality. Heterogeneity in each subgroup remained high. ConclusionThe overall pooled proportion of mortality of ICU patients with CTD was 33% (95%CI: 28–38%), with a high heterogeneity (I2= 89%). In the subgroup analysis, mortality was higher for patients with IIM and SSc.

Bilateral leg pain and unilateral calf atrophy caused by polymyositis accompanying lumbar spinal stenosis and disc herniation: a case report

Polymyositis is a subgroup of idiopathic inflammatory myopathies characterized by symmetric proximal limb weakness and chronic skeletal muscle inflammation. We herein report the first case of bilateral leg pain and unilateral calf atrophy caused by polymyositis accompanying lumbar spinal stenosis and disc herniation. A 52-year-old man presented with intermittent claudication and calf pain that had become gradually aggravated during the last 3 months. Magnetic resonance imaging showed spinal stenosis at the L3/4 and L4/5 levels and lumbar disc herniation at the L4/5 level. Preoperative laboratory investigations revealed elevated muscle enzyme concentrations. Magnetic resonance imaging also showed atrophy, fatty degeneration, and edema in both calf muscles. Histological examination showed inflammatory myositis and fibrosis in the perifascicular connective tissues. The patient was diagnosed with polymyositis. We performed decompressive laminectomy at the L3/4 and L4/5 levels and discectomy at the L4/5 level. After administration of prednisolone for 6 months and methotrexate for 3 months, the patient’s bilateral calf pain and abnormal laboratory findings improved. The combination of surgical decompression and adequate medical treatment resulted in a successful recovery. Polymyositis should be suspected in patients with lumbar spinal stenosis or lumbar disc herniation who exhibit increased muscle enzyme concentrations or lower extremity muscle atrophy.

Contribution of Rare Genetic Variation to Disease Susceptibility in a Large Scandinavian Myositis Cohort.

Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of complex autoimmune conditions characterized by inflammation in skeletal muscle and extramuscular compartments, and interferon (IFN) system activation. We undertook this study to examine the contribution of genetic variation to disease susceptibility and to identify novel avenues for research in IIMs. Targeted DNA sequencing was used to mine coding and potentially regulatory single nucleotide variants from ~1,900 immune-related genes in a Scandinavian case-control cohort of 454 IIM patients and 1,024 healthy controls. Gene-based aggregate testing, together with rare variant- and gene-level enrichment analyses, was implemented to explore genotype-phenotype relations. Gene-based aggregate tests of all variants, including rare variants, identified IFI35 as a potential genetic risk locus for IIMs, suggesting a genetic signature of type I IFN pathway activation. Functional annotation of the IFI35 locus highlighted a regulatory network linked to the skeletal muscle-specific gene PTGES3L, as a potential candidate for IIM pathogenesis. Aggregate genetic associations with AGER and PSMB8 in the major histocompatibility complex locus were detected in the antisynthetase syndrome subgroup, which also showed a less marked genetic signature of the type I IFN pathway. Enrichment analyses indicated a burden of synonymous and noncoding rare variants in IIM patients, suggesting increased disease predisposition associated with these classes of rare variants. Our study suggests the contribution of rare genetic variation to disease susceptibility in IIM and specific patient subgroups, and pinpoints genetic associations consistent with previous findings by gene expression profiling. These features highlight genetic profiles that are potentially relevant to disease pathogenesis.