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Objectives To evaluate the efficacy and safety of tofacitinib in treatment-refractory inflammatory myositis in a real-world clinical setting. Methods All patients with refractory inflammatory myositis treated with tofacitinib from a single urban centre in Vancouver, British Columbia, Canada, were included from June 2016 to December 2022. The medical records of these patients were retrospectively reviewed. Results A total of 41 patients were included, 23 with classic DM, 12 with amyopathic DM (ADM) and six with PM phenotype. The patients failed an average of four to five non-steroidal immunosuppressants before initiation of tofacitinib. In the classic DM and ADM group, tofacitinib offered clinically and statistically significant cutaneous improvement. In all myositis patients including the PM phenotype, no meaningful muscle strength response to tofacitinib was observed. 53.7% of the patients discontinued tofacitinib due to lack of benefit or death. Of the 19 patients who remained on tofacitinib at the conclusion of this study, tofacitinib demonstrated clinically and statistically significant improvement in cutaneous disease activity. Conclusion Tofacitinib appears to be highly effective in targeting cutaneous manifestations in classic DM and ADM; however, minimal benefit in muscle strength in the DM or PM phenotype were observed. [ABSTRACT FROM AUTHOR]

Objectives Clinical observations in patients with dermatomyositis (DM) and autoantibodies against the melanoma differentiation–associated protein 5 (MDA5) suggest that the autoantibodies contribute to the pathogenesis of MDA5(+) DM. To gain insight into the role of the anti-MDA5 autoantibodies, we aimed to identify their binding sites on the different domains of the MDA5 protein. Methods We developed an in-house ELISA to assess the reactivity against the MDA5 domains (conformational epitopes) in plasma (n  = 8) and serum (n  = 24) samples from MDA5(+) patients with varying clinical manifestations and disease outcomes. The reactivities were also assessed using western blot (linearized epitopes). An ELISA-based depletion assay was developed to assess cross-reactivity among the different MDA5 domains. Results All eight plasma samples consistently showed reactivity towards conformational and linearized epitopes on the helicase domains of the MDA5 protein. The ELISA-based depletion assay suggests that anti-MDA5 autoantibodies specifically target each of the three helicase domains. Twenty-two of the 24 serum samples showed reactivity in the in-house ELISA and all 22 displayed reactivity towards the helicase domains of the MDA5 protein. Conclusions Our data revealed that the main immunogenic targets of anti-MDA5 autoantibodies from MDA5(+) patients are the helicase domains. Considering that the helicase domains are responsible for the enzymatic activity and subsequent triggering of an inflammatory response, our findings suggest that binding of anti-MDA5 autoantibodies could alter the canonical activity of the MDA5 protein and potentially affect the downstream induction of a pro-inflammatory cascade. [ABSTRACT FROM AUTHOR]

Objective Autoantibodies against MDA5 (melanoma differentiation-associated protein 5) serve as a biomarker for DM (dermatomyositis) and indicate a risk factor for interstitial lung disease (ILD). MDA5 is a protein responsible for sensing RNA virus infection and activating signalling pathways against it. However, little is known about the antigen epitopes on MDA5 autoantibodies. We aimed to determine the interaction of the MDA5 autoantibody–antigen epitope. Methods Cell-based assays (CBAs), immunoprecipitation-immunoblot assays, and various immunoblotting techniques were used in the study. Results We demonstrated that DM patient autoantibodies recognize MDA5 epitopes in a native conformation–dependent manner. Furthermore, we identified the central helicase domain （3Hel） formed by Hel1, Hel2i, Hel2, and pincer as the major epitopes. As proof of principle, the purified 3Hel efficiently absorbed MDA5 autoantibodies from patient sera through immunoprecipitation-immunoblot assay. Conclusion Our study uncovered the nature of the antigen epitopes on MDA5 and can provide guidance for diagnosis and a targeted therapeutic approach development. [ABSTRACT FROM AUTHOR]

Objectives To utilize whole-body CT imaging and calcium scoring techniques as tools for calcinosis assessment in a prospective cohort of patients with adult and juvenile dermatomyositis (DM and JDM, respectively). Methods Thirty-one patients (14 DM and 17 JDM) who fulfilled Bohan and Peter Classification criteria as probable or definite DM, the EULAR-ACR criteria for definite DM, and with calcinosis identified by physical examination or prior imaging studies were included. Non-contrast whole-body CT scans were obtained using low-dose radiation procedures. Scans were read qualitatively and quantitated. We calculated the sensitivity and specificity of calcinosis detection of physician physical exam against CT. We quantified calcinosis burden using the Agatston scoring technique. Results We identified five distinct calcinosis patterns: Clustered, Disjoint, Interfascial, Confluent and Fluid-filled. Novel locations of calcinosis were observed, including the cardiac tissue, pelvic and shoulder bursa, and the spermatic cord. Quantitative measures using Agatston scoring for calcinosis were used in regional distributions across the body. Physician physical exams had a sensitivity of 59% and a specificity of 90% compared with CT detection. A higher calcium score correlated with higher Physician Global Damage, Calcinosis Severity scores, and disease duration. Conclusion Whole-body CT scans and the Agatston scoring metric define distinct calcinosis patterns and provide novel insights relating to calcinosis in DM and JDM patients. Physicians' physical examinations underrepresented the presence of calcium. Calcium scoring of CT scans correlated with clinical measures, which suggests that this method may be used to assess calcinosis and follow its progression. [ABSTRACT FROM AUTHOR]

Objectives Galectin-9, as immune checkpoint protein, plays a role in regulating autoimmunity and tumour immunity. Therefore, we explored the pathophysiological link between galectin-9 and malignancy in cancer-related DM (CRDM). Methods Serum galectin-9 were quantified via enzyme-linked immunosorbent assay, and its association with serological indices was evaluated using Spearman analysis. Receiver operating characteristic (ROC) analysis was utilized to determine the cut‐off value of galectin-9. Results Serum levels of galectin-9 were significantly higher in DM patients [23.38 (13.85–32.57) ng/ml] than those in healthy controls (HCs) [6.81 (5.42–7.89) ng/ml, P  < 0.0001], and were positively correlated with the cutaneous dermatomyositis disease area severity index activity (CDASI-A) scores (r s=0.3065, P  = 0.0172). DM patients with new-onset and untreated cancer (new-CRDM) [31.58 (23.85–38.84) ng/ml] had higher levels of galectin-9 than those with stable and treated cancer (stable-CRDM) [17.49 (10.23–27.91) ng/ml, P  = 0.0288], non-cancer-related DM (non-CRDM) [21.05 (11.97–28.02) ng/ml, P  = 0.0258], and tumour patients without DM [7.46 (4.90–8.51) ng/ml, P  < 0.0001]. Serum galectin-9 levels significantly decreased [27.79 (17.04–41.43) ng/ml vs 13.88 (5.15–20.37) ng/ml, P  = 0.002] after anti-cancer treatment in CRDM patients. The combination of serum galectin-9 and anti-transcriptional intermediary factor 1-γ (anti-TIF1-γ) antibody (AUC = 0.889, 95% CI 0.803–0.977) showed the highest predictive value for the presence of cancer in DM. Conclusion Increased galectin-9 levels were related to tumor progression in CRDM, and galectin-9 was downregulated upon cancer treatment. Monitoring serum galectin-9 levels and anti-TIF1-γ antibodies might be an attractive strategy to achieve tumour diagnosis and predict CRDM outcome. [ABSTRACT FROM AUTHOR]

Objective To investigate pathogenic mechanisms underlying JDM, we defined the effect of type I IFN, IFN-α and IFN-β, on pediatric skeletal muscle function and expression of myositis-related proteins using an in vitro engineered human skeletal muscle model (myobundle). Methods Primary myoblasts were isolated from three healthy pediatric donors and used to create myobundles that mimic functioning skeletal muscle in structural architecture and physiologic function. Myobundles were exposed to 0, 5, 10 or 20 ng/ml IFN-α or IFN-β for 7 days and then functionally tested under electrical stimulation and analyzed immunohistochemically for structural and myositis-related proteins. Additionally, IFN-β-exposed myobundles were treated with Janus kinase inhibitors (JAKis) tofacitinib and baricitinib. These myobundles were also analyzed for contractile force and immunohistochemistry. Results IFN-β, but not IFN-α, was associated with decreased contractile tetanus force and slowed twitch kinetics. These effects were reversed by tofacitinib and baricitinib. Type I IFN paradoxically reduced myobundle fatigue, which did not reverse after JAKi. Additionally, type I IFN correlated with MHC I upregulation, which normalized after JAKi treatment, but expression of myositis-specific autoantigens Mi-2, melanocyte differentiation-associated protein 5 and the endoplasmic reticulum stress marker GRP78 were variable and donor specific after type I IFN exposure. Conclusion IFN-α and IFN-β have distinct effects on pediatric skeletal muscle and these effects can partially be reversed by JAKi treatment. This is the first study illustrating effective use of a three-dimensional human skeletal muscle model to investigate JDM pathogenesis and test novel therapeutics. [ABSTRACT FROM AUTHOR]

Objective Among specific autoantibodies in DM, the anti–small ubiquitin-like modifier activating enzyme (SAE) antibody is rare. We aim to describe the clinical characteristics, cancer prevalence, and muscle pathology of anti-SAE–positive DM. Methods Patients with a diagnosis of DM and sera positive for the anti-SAE antibody were recruited from 19 centres in this retrospective observational study. The available muscular biopsies were reviewed. We conducted a comparison with anti-SAE–negative DM and a review of the literature. Results Of the patients in the study (n  = 49), 84% were women. Skin involvement was typical in 96% of patients, with 10% having calcinosis, 18% ulceration and 12% necrosis; 35% presented with a widespread skin rash. Muscular disease affected 84% of patients, with mild weakness [Medical Research Council (MRC) scale 4 (3, 5)], although 39% of patients had dysphagia. Muscular biopsies showed typical DM lesions. Interstitial lung disease was found in 21% of patients, mainly with organizing pneumonia pattern, and 26% of patients showed dyspnoea. Cancer-associated myositis was diagnosed in 16% of patients and was responsible for the majority of deaths, its prevalence being five times that of the general population. IVIG therapy was administered to 51% of the patients during the course of the disease. Comparison with anti-SAE–negative DM (n  = 85) showed less and milder muscle weakness (P  = 0.02 and P  = 0.006, respectively), lower creatinine kinase levels (P  < 0.0001) and less dyspnoea (P  = 0.003). Conclusion Anti-SAE positive DM is a rare subgroup associated with typical skin features but a potentially diffuse rash, a mild myopathy. Interstitial lung disease defines an organizing pneumonia pattern. Cancer associated DM prevalence is five times that of the general population. Trial registration ClinicalTrials.gov, http://clinicaltrials.gov , NCT04637672. [ABSTRACT FROM AUTHOR]

Objective The ACR-EULAR Myositis Response Criteria (MRC) were developed as a composite measure using absolute percentage change in six core set measures (CSMs). We aimed to further validate the MRC by assessing the contribution of each CSM, frequency of strength vs extramuscular activity improvement, representation of patient-reported outcome measures (PROM), and frequency of CSM worsening. Methods Data from adult dermatomyositis/polymyositis patients in the rituximab (n  = 147), etanercept (n  = 14), and abatacept (n  = 19) trials, and consensus patient profiles (n  = 232) were evaluated. The Total Improvement Score (TIS), number of improving vs worsening CSMs, frequency of improvement with and without muscle-related CSMs, and contribution of PROM were evaluated by MRC category. Regression analysis was performed to assess contribution of each CSM to the MRC. Results Of 412 adults with dermatomyositis/polymyositis, there were 37%, 24%, 25%, and 14% with no, minimal, moderate, and major MRC improvement, respectively. The number of improving CSMs and absolute percentage change in all CSMs increased by improvement category. In minimal-moderate improvement, only physician-reported disease activity contributed significantly more than expected by MRC. Of patients with at least minimal improvement, 95% had improvement in muscle-related measures and a majority (84%) had improvement in PROM. Patients with minimal improvement had worsening in a median of 1 CSM, and most patients with moderate-major improvement had no worsening CSMs. Physician assessment of change generally agreed with MRC improvement categories. Conclusion The ACR-EULAR MRC performs consistently across multiple studies, further supporting its use as an efficacy end point in future myositis therapeutic trials. [ABSTRACT FROM AUTHOR]

Objectives To identify potential risk factors and prognostic factors of Pneumocystis jirovecii pneumonia (PJP) infection in anti-melanoma differentiation-associated gene 5 antibody-positive DM (anti-MDA5+ DM) patients, and to evaluate the diagnostic performance of metagenomic next-generation sequencing (mNGS). Methods Anti-MDA5+ DM patients who underwent mNGS or real-time PCR for PJP detection were recruited. The potential risk factors for PJP occurrence and death were analysed via Logistic regression and Cox proportional hazards regression, respectively. The diagnostic efficacy of mNGS was compared with the conventional methods. Results 91 patients were enrolled and 44 were assigned to PJP+ group. The PJP detection rate was 48.4%. PJP often occurred in the first 3 months (68.2%) of the disease; this period also showed the highest mortality rate (20.5%). Fever and increased lactate dehydrogenase (LDH) were independent risk factors for PJP occurrence, while trimethoprim-sulfamethoxazole (TMP/SMZ) prophylaxis was an independent protective factor (all P  < 0.05). Older age and increased LDH were predictors for mortality in patients with anti-MDA5+ DM and PJP (all P  < 0.05). In addition, we found that mNGS had a sensitivity of 100.0% and specificity of 90.0% in diagnosing PJP, with the highest area under the curve of 0.95 (P  < 0.001). Conclusion PJP has high prevalence and mortality in anti-MDA5+ DM. It is crucial for clinicians to identify high-risk patients and promptly institute TMP/SMZ to prevent PJP. mNGS is the preferred approach for pathogen detection in anti-MDA5+ DM when PJP is suspected. [ABSTRACT FROM AUTHOR]

Objectives The B-cell depleting biologic, rituximab, is used to treat refractory autoimmune myositis. However, the beneficial effects of rituximab appear to outweigh the known contribution of B cells in myositis. We aimed to elucidate how myositis patients respond differently to rituximab and possible alternative mechanisms of action. Methods Here we have: (i) comprehensively investigated concurrent mRNA and microRNA expression in muscle biopsies taken at baseline and 16 weeks post treatment in 10 patients who were part of the rituximab in myositis (RIM) trial; and (ii) investigated the beneficial effect of rituximab on myositis muscle cells. Results Our analyses identified an increased number of changes in gene expression in biopsies from patients who had a clinical response to rituximab (n  =   5) compared with non-responders (n  =   5). The two groups had completely different changes in microRNA and mRNA expression following rituximab therapy, with the exception of one mRNA, BHMT2. Networks of mRNA and microRNA with opposite direction of expression changes highlighted ESR1 as upregulated in responders. We confirmed ESR1 upregulation upon rituximab treatment of immortalized myotubes and primary human dermatomyositis muscle cells in vitro , demonstrating a direct effect of rituximab on muscle cells. Notably, despite showing a response to rituximab, human dermatomyositis primary muscle cells did not express the rituximab target, CD20. However, these cells expressed a possible alternative target of rituximab, sphingomyelinase-like phosphodiesterase 3 b (SMPDL3B). Conclusion In addition to B-cell depletion, rituximab may be beneficial in myositis due to increased ESR1 signalling mediated by rituximab binding to SMPDL3B on skeletal muscle cells. [ABSTRACT FROM AUTHOR]

Objectives Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive DM is characterized by rapidly progressive interstitial lung disease and has a poor prognosis. We aimed to investigate whether anti-MDA5 antibody titres and cytokine levels predict clinical course, and evaluate changes in both parameters before and after diagnosis. Methods This was a retrospective, single-centre study in 38 patients with anti-MDA5 antibody-positive DM. We compared clinical characteristics and laboratory data at diagnosis between patients in the treatment response (n  = 23) and non-response (n  = 15) groups, and between those in the relapse (n  = 5) and non-relapse (n  = 24) groups. We also measured serum anti-MDA5 antibody titres and cytokine levels before and after diagnosis. Results The non-response group was older, had a higher ground-glass opacity score, lower PaO2/FiO2, higher CRP level, and higher anti-MDA5 antibody titre than the response group. No cytokines significantly differed between groups at diagnosis. The relapse group had a significantly higher anti-MDA5 antibody titre than the non-relapse group. In the survivor group, the anti-MDA5 antibody titre and levels of IFN-α, IFN-γ, monocyte chemotactic protein-1 (MCP-1), IL-6, IL-33, CRP, and ferritin were significantly lower 6 months post-treatment than at diagnosis. Macrophage-associated cytokines such as IL-6, IL-8, IL-18 and MCP-1 increased after anti-MDA5 antibody positivity in three patients who were anti-MDA5 antibody-positive before diagnosis. Conclusion The anti-MDA5 antibody titre at diagnosis may predict the clinical course. Levels of macrophage-associated cytokines significantly declined at 6 months post-treatment, and they may have increased after anti-MDA5 antibody titre positivity. [ABSTRACT FROM AUTHOR]

Objectives Anti-melanoma differentiation-associated gene 5 antibody positive dermatomyositis (MDA5+DM), is susceptible to development of rapidly progressive interstitial lung disease (RPILD), which has been predominantly reported in East Asia. A Japanese genome-wide study has identified a WDFY4 variant rs7919656 linkage. We sought to evaluate this genetic marker and exploit its possible clinical relevance in Chinese MDA5+DM. Methods We genotyped and compared the minor allele A frequency of WDFY4 rs7919656 in patients with MDA5+DM (n  = 254) including 190 clinically amyopathic dermatomyositis (CADM), MDA5-DM (n  = 53), anti-synthetases syndrome (ASyS, n  = 72) and healthy controls (n  = 192). Association of the WDFY4 variant with clinical phenotype was evaluated using logistic regression. Results Although the minor allele A frequencies of WDFY4 rs7919656 in MDA5+DM and CADM were comparable to that in healthy controls, we observed a significant correlation between the WDFY4 variant (GA+AA genotype) and the incidence of RPILD in MDA5+DM (OR: 2.11; 95% CI: 1.21, 3.69; P  = 0.007). Moreover, this variant was an independent risk factor for RPILD in multivariate analysis (OR: 4.98; 95% CI: 1.59, 17.19; P  = 0.008), along with other well-recognized risk factors, i.e. forced vital capacity % predicted, diffusing capacity for carbon monoxide % predicted, serum ferritin and prednisolone exposure. In addition, this variant was associated with higher expression of WDFY4 in PBMCs of MDA5+DM, especially those with RPILD. WDFY4 overexpression was also observed in lung biopsy of MDA5+DM-RPILD bearing the variant genotype. Conclusion We found that the WDFY4 variant was associated with an increased risk of RPILD, not with disease susceptibility in Chinese MDA5+DM. [ABSTRACT FROM AUTHOR]

Objectives Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive rapidly progressive interstitial lung disease (RP-ILD) is a life-threatening disease, the aetiology of which remains unclear. To detect potential diagnostic markers, a transcriptome analysis of the lung sample from a patient with anti-MDA5 antibody-positive RP-ILD was performed. Methods RNA sequencing analyses of an autopsy lung sample from a 74-year-old woman with anti-MDA5 antibody-positive RP-ILD was performed and compared with an age- and sex-matched normal lung sample. Genes with changes of gene expression ≥5-fold were considered differentially expressed genes and analysed by Metascape. The levels of leukaemia inhibitory factor (LIF) were measured in the serum samples from 12 cases of anti-MDA5 antibody-positive ILD, 12 cases of anti-aminoacyl tRNA synthetase (ARS) antibody-positive ILD, 10 cases of anti-transcription intermediary factor 1γ/anti-Mi-2 antibody DM and 12 healthy volunteers. Results Gene ontology enrichment analysis on the RNA sequencing data showed a strong association with antigen binding. Upregulated expressions of IL-1β, IL-6 and LIF were also detected. Serum LIF levels were significantly elevated in anti-MDA5 antibody-positive ILD patients {median 32.4 pg/ml [interquartile range (IQR) 13.2–125.7]} when compared with anti-ARS antibody-positive ILD patients [4.9 pg/ml (IQR 3.1–19.7), P  < 0.05] and DM patients [5.3 pg/ml (IQR 3.9–9.7), P  < 0.05]. Conclusion Our present study suggested that upregulation of LIF might be a new potential disease marker specific for anti-MDA5 antibody-positive ILD. [ABSTRACT FROM AUTHOR]

Objectives EF is a rare disease characterized by fibrosis and inflammation of the fascia, scleroderma-like skin indurations and optional blood eosinophilia. We aimed to expand the knowledge about its aetiology and pathogenesis. Methods Biopsy specimens from 16 EF patients were assessed by histology, immunohistochemistry and quantitative reverse transcription PCR in comparison with anti-Mi-2+ DM patients and non-disease controls. Results Histologically, EF shows mild to severe inflammation at the muscle–fascia interface, with frequent involvement of the underlying muscle tissue, though varying in degree. CD206+ macrophages predominate and eosinophils are detected within the fascia in the majority of cases, however in quite small numbers, and seen infrequently within the muscle. Activators of the so-called Th2–M2 pathway like STAT6 and IL-4 are upregulated leading to high expression levels of CD206. Activators of the so-called Th1–M1 pathway like STAT1 and IFN-γ (IFNG) are also upregulated, though not translating into a significant upregulation of the effector molecule COX2. Interestingly, activators or chemoattractants of eosinophils show no significant upregulation in EF compared with DM. EF shows features of perifascicular pathology comparable to DM, with upregulation of MHC class I and II; however, this is not accompanied by perifascicular atrophy or any signs of a type I IFN response or hypoxia-mediated processes. Conclusions Our findings highlight a specific immune phenotype of leucocyte infiltrates in EF along features of perifascicular pathology similar to DM, while there is no evidence of hypoxia-mediated or type I IFN–associated processes with perifascicular fibre atrophy, indicating different pathomechanisms of muscle involvement. [ABSTRACT FROM AUTHOR]

Objectives To describe the 8-year longitudinal study and long-term prognosis of a large inception cohort of anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive (MDA5+) DM-interstitial lung disease (ILD) patients. Methods In total, 216 patients diagnosed with MDA5+ DM-ILD were enrolled and followed up to analyse long-term survival rate. Demographic and clinical variables were collected at baseline and each temporal end point. Seventy patients who survived the first year were analysed for the long-term serological and respiratory outcomes. Results A total of 85 patients (39.3%) died during the follow-up period up to 96 months, with 89% of the deaths occurring in the first year after diagnosis. Long-term outcome was reported in 70 patients. Serological markers including anti-MDA5 antibody showed significant improvement with time. Radiographic findings and pulmonary function also improved notably in the follow-up period, especially in rapidly progressive ILD group, as measured by high-resolution computed tomography imaging scores, the estimated forced vital capacity, estimated diffusing capacity of lung carbon monoxide and dyspnoea scores. Early application of anti-fibrosis therapy helped to improve long-term pulmonary function. Conclusions MDA5+ DM-ILD patients had a high mortality rate despite aggressive treatment. Patients who survived the first year usually showed a significant improvement in serological markers and pulmonary function during the long-term follow-up. [ABSTRACT FROM AUTHOR]

Objective To assess the role of the anti-TIF1γ auto-antibody (aAb) IgG2 isotype as a biomarker of cancer in anti-TIF1γ aAb-positive adult DM. Methods International multicentre retrospective study with the following inclusion criteria: (i) diagnosis of DM according to ENMC criteria; (ii) presence of anti-TIF1γ IgG aAb determined using an in-house addressable laser bead immunoassay (ALBIA) from cryopreserved serums sampled at time of DM diagnosis and (iii) available baseline characteristics and follow-up data until the occurrence of cancer and/or a minimum follow-up of 1 year for patients without known cancer at diagnosis. Detection and quantification of anti-TIF1γ IgG2 aAb was done using the in-house ALBIA. In addition, a recent ELISA commercial kit was used for anti-TIF1γ IgG aAb quantification. Results A total of 132 patients (mean age 55±15 years) of whom 72 (54.5%) had an associated cancer were analysed. The association between the presence of cancer and the presence of anti-TIF1γ IgG2 aAb was statistically significant (P  = 0.026), with an OR of 2.26 (95% CI: 1.10, 4.76). Patients with cancer displayed significantly higher anti-TIF1γ IgG2 aAb ALBIA values with a median value of 1.15 AU/ml (IQR: 0.14–9.76) compared with 0.50 AU/ml (IQR: 0.14–1.46) for patients without cancer (P  = 0.042). In addition, patients with cancer displayed significantly higher anti-TIF1γ IgG aAb ELISA values with a median value of 127.5 AU/ml (IQR: 81.5–139.6) compared with 93.0 AU/ml (IQR: 54.0–132.9) for patients without cancer (P  = 0.004). Conclusion These results suggest considering anti-TIF1γ IgG2 ALBIA and IgG ELISA values as biomarkers of cancer in anti-TIF1 γ aAb-positive adult DM. [ABSTRACT FROM AUTHOR]

Objectives Anti-melanoma differentiation-associated gene 5 positive (anti-MDA5+) DM has a close relationship with rapidly progressive interstitial lung disease (RPILD) and is associated with high mortality. However, data regarding the time-dependent risk of RPILD and deaths during disease progression are limited. We conducted this study to investigate whether the risk of RPILD and death were time-dependent or not in anti-MDA5+ DM. Methods We assessed a cohort of 272 patients with anti-MDA5+ DM. The clinical characteristics of patients with anti-MDA5+ were collected, and COX regression was used to analyse independent risk factors for RPILD and death. We also described changes in risk of RPILD and death over time and their potential clinical implications. Results There were 272 anti-MDA5+ DM patients enrolled in this study. According to the multivariate cox regression analysis, short disease course, high CRP level, anti-Ro52 positive and anti-MDA5 titre (++∼+++) were independent risk factors of RPILD. High creatine kinase level, high CRP level and RPILD were independent risk factors for death, and >90% RPILD and 84% mortality occurred in the first 6 months after disease onset. Notably, the first 3 months is a particularly high-risk period, with 50% of RPILD and 46% of deaths occurring. Hazards regarding RPILD and mortality diminished over time during a median follow-up of 12 months. Conclusion These results suggest significant, time-dependent changes in RPILD and mortality risk in anti-MDA5+ DM patients, providing a cut-off time window to estimate disease progression and poor prognosis. [ABSTRACT FROM AUTHOR]

Objective To assess the longitudinal changes in nailfold videocapillaroscopy (NVC) in patients expressing myositis-specific autoantibodies [anti-aminoacyl-tRNA synthetase (ARS), anti-transcriptional intermediary factor 1 (TIF1), and anti-melanoma differentiation-associated gene 5 (MDA5)]. Methods This study was performed retrospectively, at a single site, on an observational cohort. Seventy-one idiopathic inflammatory myopathy patients were included (25 patients expressed anti-MDA5 Abs, 24 patients expressed anti-TIF1 Abs, and 22 patients expressed anti-ARS Abs). NVC findings included giant, enlarged, and reduced capillaries, haemorrhages, capillary ramification, disorganization of the vascular array, and capillary loss. NVC findings were compared from baseline to after disease activity stabilization. Results The frequency of enlarged capillaries at baseline was different among the three groups, and was significantly higher in patients with anti-TIF1 Abs compared with those with anti-ARS Abs (88% vs 55%, P  < 0.05). Reduced capillaries were significantly increased in patients with anti-TIF1 Abs compared with those with anti-MDA5 (96% vs 44%, P  < 0.0001) or anti-ARS Abs (96% vs 50%, P  < 0.0005). Both enlarged and reduced capillaries improved after stabilization in patients with anti-MDA5 Abs (P  < 0.0001 and P  < 0.05, respectively). These improvements were not observed in patients expressing anti-TIF1 and anti-ARS Abs. However, a significant reduction in haemorrhages was observed in all three groups (P  < 0.0001 for each group). Conclusions The results of this study demonstrate that longitudinal changes in NVC findings may vary depending on myositis-specific Ab expression. Therefore, it is crucial to assess individual NVC findings separately, as each finding may impact disease activity in a different manner. [ABSTRACT FROM AUTHOR]

Objectives Pain is commonly reported in people living with myositis. This study assesses the presence of pain in the subtypes of myositis as well as the frequency of opioid and non-opioid pain medication use. Methods A survey was developed and distributed by Myositis Support and Understanding, a patient-led advocacy organization, to members of its group. Multivariate logistic regression analysis and chi-squared tests were performed. Results A total of 468 participants completed the survey. A total of 423 participants (DM n  = 183, PM n  = 109 and IBM n  = 131) were included, based on reported diagnosis, for final analysis. Some 91.5% of myositis participants reported current or past pain, with 99% attributing their pain to myositis. There was a lower likelihood of pain in participants aged >60 years [odds ratio (OR) 0.2, 95% confidence interval (CI) 0.1, 0.6, P  = 0.003]. The percentage of participants reporting pain was statistically different based on myositis type (DM 97.2%, IBM 80.9% and PM 94.5%, P  < 0.001), with a higher likelihood of pain in DM compared with IBM (OR 3.7, 95% CI 1.3, 10.2, P  = 0.011). There was a lower likelihood of pain in participants aged >60 years (OR 0.2, 95% CI 0.1, 0.6, P  = 0.003). Of the 387 participants reporting pain, 335 reported using pain medications (69% prescribed opioids). Male sex, age >60 years and myositis subtype were not associated with likelihood of non-opioid use. Conclusion Pain is a commonly reported symptom in myositis with variable treatment strategies, including opioid medications. This study highlights the importance of addressing pain as part of myositis treatment as well as the need for future studies understanding treatment effectiveness. [ABSTRACT FROM AUTHOR]

Objective To investigate the association between the anti-melanoma differentiation associated gene 5 (MDA5) IgG subclasses and prognosis of patients with dermatomyositis (DM)-associated interstitial lung disease (ILD). Methods This retrospective study included 122 anti-MDA5 positive DM-ILD patients admitted from October 2017 to October 2020 as training cohort, and additional 68 patients from August 2014 to September 2017 as validation cohort. The levels of anti-MDA5 total IgG and IgG subclasses were measured using in-house enzyme-linked immunosorbent assays, and analysed in association with the patient prognosis. Results In the training cohort, the concentrations of anti-MDA5 IgG1 and IgG3 in non-survivors were significantly higher than in survivors (P  < 0.05), whereas there were no significant differences in the IgG2 and IgG4 levels. Kaplan–Meier survival analysis revealed that the levels of anti-MDA5 total IgG, IgG1 and IgG3 were associated with mortality (P  < 0.05). Multivariate analysis revealed anti-MDA5 IgG1 >13 U/ml and anti-MDA5 IgG3 >11 U/ml were independent risk factors for death of DM-ILD patients (P  < 0.05). Anti-MDA5 IgG1 was confirmed as an independent risk factor in the validation cohort, while anti-MDA5 IgG3 was not. Anti-MDA5 IgG1 showed greater discriminable power for patient prognosis (Youden index 0.494) than anti-MDA5 total IgG, IgG3, or the combination of IgG1 and IgG3 (Youden index 0.356, 0.32 and 0.447, respectively). Conclusion Anti-MDA5 IgG1 and IgG3 are significantly associated with poor prognosis in DM-ILD patients, and anti-MDA5 IgG1 is more efficient as a prognostic biomarker in DM-ILD patients. [ABSTRACT FROM AUTHOR]

Objectives This study aimed to investigate the high-resolution CT (HRCT) characteristics of anti-melanoma differentiation-associated gene 5 (MDA5) antibody positive dermatomyositis-associated interstitial lung disease (anti-MDA5 DM-ILD), and to clarify the underlying mechanisms of the clinical phenomenon. Methods Clinical data and HRCT patterns were compared between anti-MDA5 DM-ILD (n  = 32) and antisynthetase syndrome-associated ILD (ASS-ILD) (n  = 29). RNA sequencing of whole-blood samples from the two groups, and in vitro experiments using human embryonic lung fibroblasts (HELFs) were conducted to explore the potential mechanisms of the clinical findings. Results The anti-MDA5 DM-ILD subset had a significantly higher incidence of rapidly progressive ILD (RPILD) than ASS-ILD (65.6% vs 37.9%; P  = 0.031). The relative percentage of the lung fibrosis HRCT pattern was significantly lower in the anti-MDA5 DM-ILD group, especially the RPILD subgroup (P  = 0.013 and 0.003, respectively). RNA sequencing detected the upregulated genes including interferon-induced helicase C domain 1 (encoding MDA5), and a trend towards downregulated expression of TGF-β signalling components in anti-MDA5 DM-ILD. In vitro culture of HELFs revealed that upregulated expression of MDA5 in HELFs was correlated with the downregulated expression of alpha smooth muscle actin, connective tissue growth factor, collagen I and collagen III by suppressing the TGF-β signalling pathway. Conclusions Anti-MDA5 DM-ILD patients have significantly less lung fibrosis and elevated MDA5 expression. The upregulated expression of MDA5 has relations with the suppression of the pro-fibrotic function of fibroblasts via the TGF-β signalling pathway, which may partially explain the mechanism of the clinical phenomenon. [ABSTRACT FROM AUTHOR]

Objectives Statin-associated immune-mediated necrotizing myopathy (IMNM) and idiopathic inflammatory myositis (IIM) are myopathies with overlapping features. This study compared the manifestations of IMNM to IIM in Native Americans. Method Twenty-one Native American patients with inflammatory myopathy (IM) were characterized as to diabetes mellitus, hyperlipidaemia, statin exposure, myopathy diagnosis, muscle histology, autoimmune and myositis-specific autoantibodies, therapy and outcome. Results IM consisted of 52.4% IMNM, 42.9% IIM and 4.8% metabolic myopathy. IMNM vs IIM patients were older [61.6 years (s. d. 9.8) vs 39.8 (14.3)], diabetes mellitus (100% vs 55.6%), hyperlipidaemia (100% vs 33.3%), statin-exposure (100% vs 22.2%), creatine kinase [CK; 11 780 IU (s. d. 7064) vs 1707 (1658)], anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) antibodies (85.7% vs 11.1%) and necrotizing IM (81.8% vs 11.1%), but shorter disease duration [26.2 months (s. d. 395) vs 78.4 (47.9)], RP (9.1% vs 55.6%), cutaneous manifestations (0% vs 55.6%), ANA (18.2% vs 66.7%) or any autoantibody (18.2% vs 88.9%) (all P  < 0.05). MRI abnormalities, histologic IM, myositis-specific autoantibodies, pulmonary hypertension, oesophageal dysfunction, interstitial lung disease, disability and persistently elevated CK were similar. IMNM vs IIM was treated more with IVIG (72.7% vs 11.1%; P  = 0.009) and less with antimetabolites (45.5% vs 88.9%; P  = 0.05) and rituximab (18.2% vs 55.6%; P  = 0.09). Conclusions IMNM may occur in Native Americans and is associated with diabetes mellitus, hyperlipidaemia, statin use and older age and is characterized by marked CK elevation, necrotizing myopathy and anti-HMGCR antibodies with few cutaneous or vascular manifestations. [ABSTRACT FROM AUTHOR]

Objective Anti-melanoma differentiation-associated protein 5 (MDA5)-positive DM is associated with rapidly progressive interstitial lung disease (RP-ILD) and high mortality. This multicentre retrospective study aimed to identify predictors of mortality and RP-ILD. Methods Anti-MDA5-positive DM patients were identified from the Hong Kong Myositis Registry and the Clinical Data Analysis and Reporting System. Clinical characteristics were reviewed. Risk factors for mortality and RP-ILD were identified. Results Among the 116 recruited patients, 100 (86.2%) had ILD, 47 (40.5%) had RP-ILD and 44 (37.9%) patients died. Cox regression analysis revealed RP-ILD [hazard ratio (HR) 9.735 (95% CI 3.905, 24.272)], age >52 years [HR 4.750 (95% CI 1.692, 13.333)], ferritin level >2800 pmol/l [HR 3.042 (95% CI 1.323, 6.997)] and lactate dehydrogenase (LDH) >400 IU/l [HR 2.290 (95% CI 1.009, 5.198)] were independent predictors of mortality. With regard to RP-ILD, analyses showed that potential predictors at baseline included age >50 years [HR 2.640 (95% CI 1.277, 5.455)], LDH >300 IU/l [HR 3.189 (95% CI 1.469, 6.918)], fever [HR 1.903 (95% CI 0.956, 3.790)] and neutrophil:lymphocyte ratio >7.0 [HR 1.967 (95% CI 0.942, 4.107)]. We proposed a prediction model based on fever, LDH, age and white cell count (FLAW) to stratify the risk of development of RP-ILD. The probability of RP-ILD in a patient with a score of 4 was 100%. A small internal validation cohort showed the odds of RP-ILD with FLAW scores of 0, 1, 2 and 3 were 0%, 0%, 42.9% and 75%, respectively. Conclusions Anti-MDA5-associated RP-ILD is significantly associated with poor survival rates. The FLAW model maybe useful to predict the development of RP-ILD. [ABSTRACT FROM AUTHOR]

Objectives To assess the efficacy and safety of branched chain amino acids (BCAAs) in the treatment of PM/DM prior to official approval of their use in Japan. Methods Treatment naïve adults with PM/DM were enrolled in a randomized, double-blind trial to receive either TK-98 (drug name of BCAAs) or placebo in addition to conventional treatment. After 12 weeks, patients with an average manual muscle test (MMT) score <9.5 were enrolled in an open label extension study for a further 12 weeks. The primary endpoint was the change of the MMT score at 12 weeks. The secondary endpoints were the clinical response and the change of functional index (FI). Results Forty-seven patients were randomized either to the TK-98 (n  = 24) or placebo (n  = 23) group. The changes of MMT scores at 12 weeks were 0.70 (0.19) [mean (s. e. m.)] and 0.69 (0.18), respectively (P  = 0.98). Thirteen patients from the TK-98 group and 12 from the placebo group were enrolled in the extension study. The MMT scores in both groups improved similarly. The increase of the FI scores of the shoulder flexion at 12 weeks was significantly greater in the TK-98 group [27.9 (5.67) vs 12.8 (5.67) for the right shoulder flexion, and 27.0 (5.44) vs 13.4 (5.95) for the left shoulder; P  < 0.05]. Frequencies of adverse events up to 12 weeks were similar. Conclusion BCAAs showed no effect on the improvement of the muscle strength evaluated by MMT and the clinical response. However, they were partly effective for improving dynamic repetitive muscle functions. Trial registration UMIN-CTR Clinical Trial, https://center6.umin.ac.jp/ , UMIN000016233 [ABSTRACT FROM AUTHOR]

Objectives In the present study, we aimed to assess the prevalence and clinical significance of anti-Ro52 antibodies in a cohort of patients with idiopathic inflammatory myopathy-associated interstitial lung disease (IIM-ILD) with different myositis-specific autoantibodies (MSAs). Methods A cohort of 267 IIM-ILD patients, including 62 patients with PM, 126 patients with DM and 79 patients with clinically amyopathic DM (CADM) were retrospectively analysed in this study. Clinical and laboratory findings, pulmonary function tests (PFTs), HRCT patterns and treatment information were compared between patients with and without anti-Ro52 antibodies. The association between prognosis and anti-Ro52 antibodies was also evaluated based on different MSA subgroups. Results Anti-Ro52 antibodies were more frequent in patients with anti-MDA5 (62.1%, P  < 0.01) and anti-Jo1 (64.9%, P  < 0.01) antibodies than in those with other MSAs. The proportion of patients with anti-Jo1 antibodies was higher in the anti-Ro52 antibody-positive group than in the anti-Ro52 antibody-negative group. Patients with anti-Ro52 antibodies were more likely to exhibit the Gottron sign than the anti-Ro52 antibody-negative group (P  < 0.001). Furthermore, it was a predictive factor for rapid progression interstitial lung disease (RP-ILD) (P  = 0.001) and was also associated with a higher mortality rate (log-rank test, P  = 0.001). Furthermore, RP-ILD was more frequently exhibited in anti-MDA5- and anti-Ro52-positive patients. Moreover, anti-Ro52 antibody positivity was closely associated with a higher mortality rate in anti-MDA5-ILD patients (log-rank test, P  < 0.05). Conclusions Anti-Ro52 antibodies were highly prevalent in patients with anti-MDA5 and anti-Jo1 antibodies. Within all patients with IIM-ILD, those with anti-Ro52 autoantibodies had a higher frequency of RP-ILD and a poorer prognosis, especially in the anti-MDA5 antibody subgroup. [ABSTRACT FROM AUTHOR]

Objectives To determine the prevalence and associations of autoantibodies targeting a muscle-specific autoantigen, four-and-a-half-LIM-domain 1 (FHL1), in South Australian patients with histologically-confirmed idiopathic inflammatory myopathies (IIM) and in patients with SSc. Material and methods Sera from patients with IIM (n  = 267) from the South Australian Myositis Database (SAMD), SSc (n  = 174) from the Australian Scleroderma Cohort Study (ASCS) and healthy controls (HC, n  = 100) were analysed for anti-FHL1 autoantibodies by Enzyme-Linked ImmunoSorbent Assay (ELISA). Results Autoantibodies to FHL1 were more frequent in patients with IIM (37/267, 13.8%) compared with SSc (12/174, 7%) (P  < 0.02) and HC (2/100, 2%) (P  < 0.001). The most common IIM subtypes among FHL1+ IIM patients were (32%) and IBM (2/37, 32%). No statistically significant differences in muscular or extra-muscular manifestations of IIM were found when comparing patients who were anti-FHL1+ with their anti-FHL1– counterparts. In 29/37 (78%) anti-FHL1+ patients, no myositis-specific autoantibodies (MSA) were present. In FHL1+ muscle biopsies, there was less frequent infiltration by CD45+ cells (P  = 0.04). There was a trend for HLA alleles DRB1*07 and DRB1*15 to be more frequent in anti-FHL1+ compared with anti-FHL1– patients (9/25 vs 19/113, P  = 0.09 and 8/25 vs 15/114, P  = 0.09, respectively). Conclusions We report a substantial prevalence (13.8%) of anti-FHL1 autoantibodies in a large cohort of patients with histologically confirmed IIM; 75% of these cases did not have a detectable myositis-specific autoantibody. Anti-FHL1 autoantibodies were also detected in a subgroup of patients with SSc (7%), indicating that anti-FHL1 autoantibodies may not be myositis-specific. The trend towards an HLA-DR association might indicate a specific immune response to the FHL1 protein. [ABSTRACT FROM AUTHOR]

Objectives We aimed to review whether PM and DM patients have an increased cardiovascular (CV) risk, including ischaemic heart disease (IHD), cerebrovascular accidents (CVA) and venous thromboembolism. Methods We searched PubMed, Embase and the Cochrane database for relevant studies from inception to February 2021. Results Twenty-two studies comprising 25 433 patients were included. With PM/DM vs general populations, the risk was significantly increased for CV events [relative risk (RR) = 2.37, 95% CI: 1.86, 3.02]. The RR of CV events for males with PM/DM was higher than for females (RR = 1.43; 95% CI: 1.17, 1.74). PM/DM patients followed for one to five years had a significantly higher CV risk than those followed for five to ten years (RR = 3.51, 95% CI: 1.95, 6.32). The risk was increased for North Americans (RR = 4.28, 95% CI: 2.57, 7.11), Europeans (RR = 2.29, 95% CI: 1.58, 3.31) and Asians (RR = 2.03, 95% CI: 1.41, 2.90). Our meta-analysis found that the elevated CV event risk was related to PM (RR = 2.35, 95% CI: 1.51, 3.66) and DM (RR = 2.55, 95% CI: 1.66, 3.93). Subgroup analyses showed that the risk was significantly increased for IHD (RR = 1.76, 95% CI: 1.40, 2.21), CVA morbidity (RR = 1.31, 95% CI: 1.03, 1.67) and ischaemic stroke (IS) (RR = 1.47, 95% CI: 1.26, 1.73), with no statistically significant increased risk of haemorrhagic stroke mortality (RR = 1.43, 95% CI: 0.92, 2.21). The CV event risk was increased for venous thromboembolism (RR = 4.60, 95% CI: 3.17, 6.66), deep venous thrombosis (RR = 5.53, 95% CI: 3.25, 9.39) and pulmonary embolism (RR = 5.26, 95% CI: 2.62, 10.55). Conclusion This meta-analysis found that PM/DM patients had a ∼2.37 times increased CV risk, particularly males diagnosed in the previous five years. PM/DM may be an independent risk factor for developing IHD, IS, deep venous thrombosis and pulmonary embolism. [ABSTRACT FROM AUTHOR]

Objectives This study aimed to quantify nailfold capillary (NFC) abnormalities in anti–melanoma differentiation–associated gene 5 (MDA5) -positive DM patients and to evaluate the association with clinical parameters, including serum biomarkers. In addition, we aimed to clarify the period leading to remission of NFC abnormalities during immunosuppressive treatment in patients with DM. Methods A prospective observational study was conducted including patients (n  = 10) who first visited Hiroshima University Hospital and were diagnosed with DM or clinically amyopathic DM with anti-MDA5 antibodies. We compared the NFC abnormalities detected by nailfold-video capillaroscopy (NVC), physical findings, blood tests, respiratory function tests, and vascular-related growth factors measured using a LEGENDplexTM Multi-Analyte Flow Assay Kit. Results NFC abnormalities improved in all patients from 2 to 17 weeks after the initiation of immunosuppressive treatment. The NVC scores were inversely correlated with anti-MDA5 antibody titres at baseline. NVC scores and forced vital capacity were positively correlated. Baseline values of M-CSF and stem cell factor were correlated with anti-MDA-5 titres. Conclusion Our study suggested that NVC scores and disease activity were inversely correlated before treatment. Vascular-related growth factors, such as M-CSF and stem cell factor, may be associated with the disease mechanism in patients with anti-MDA5 antibody-positive DM. [ABSTRACT FROM AUTHOR]

Objective To compare muscle ultrasound (MUS) parameters in patients with juvenile JDM and healthy controls, and examine their association with JDM disease activity measures and MRI. Methods MUS of the right mid-rectus femoris was performed in 21 patients with JDM meeting probable or definite Bohan and Peter criteria and 28 demographically matched healthy control subjects. MUS parameters were quantitated by digital image processing and correlated with JDM disease activity measures and semi-quantitative thigh MRI short tau inversion recovery (STIR) and T1 scores. Results Rectus femoris MUS echogenicity was increased (median 47.8 vs 38.5, P  = 0.002) in patients with JDM compared with controls. Rectus femoris MUS echogenicity correlated with Physician Global Activity (PGA), Manual Muscle Testing (MMT), and Childhood Myositis Assessment Scale (CMAS) (rs 0.4–0.54). Some MUS parameters correlated with functional quantitative measures of muscle strength: resting RF area on MUS strongly correlated with knee extension quantitative muscle testing (rs 0.76), and contracted area correlated with proximal MMT, knee extension quantitative muscle testing, and CMAS (rs 0.71–0.80). MUS echogenicity correlated with both STIR and T1 MRI (rs 0.43), and T1 MRI correlated inversely with RF contracted area (rs -0.49) on MUS. There were differences in pre- and post-exercise vascular power and colour Doppler on MUS in patients with JDM vs controls, with the percentage change of post-exercise vascular power Doppler lower in JDM compared with controls (7.1% vs 100.0%). Conclusions These data suggest MUS may be a valuable imaging modality to assess JDM disease activity and damage. [ABSTRACT FROM AUTHOR]

Objectives We aimed to identify disease-specific surface proteins on extracellular vesicles (EVs) as novel serum biomarkers of PM/DM. Methods We performed liquid chromatography–tandem mass spectrometry (LC/MS) on purified EVs from sera of 10 PM/DM patients, 23 patients with other autoimmune diseases and 10 healthy controls (HCs). We identified membrane proteins preferentially present in EVs of PM/DM patients by bioinformatics and biostatistical analyses. We developed an EV sandwich ELISA for directly detecting serum EVs expressing disease-specific membrane proteins and evaluated their clinical utility using sera from 54 PM/DM, 24 RA, 20 SLE, 13 SSc and 25 Duchenne and Becker types of muscular dystrophy (DMD/BMD) patients and 36 HCs. Results LC/MS analysis identified 1220 proteins in serum EVs. Of these, plexin D1 was enriched in those from PM/DM patients relative to HCs or patients without PM/DM. Using a specific EV sandwich ELISA, we found that levels of plexin D1+ EVs in serum were significantly greater in PM/DM patients than in HCs or RA, SLE or DMD/BMD patients. Serum levels of plexin D1+ EVs were greater in those PM/DM patients with muscle pain or weakness. Serum levels of plexin D1+ EVs were significantly correlated with levels of aldolase (r s = 0.481), white blood cells (r s = 0.381), neutrophils (r s = 0.450) and platelets (r s = 0.408) in PM/DM patients. Finally, serum levels of plexin D1+ EVs decreased significantly in patients with PM/DM in clinical remission after treatment. Conclusion We identified levels of circulating plexin D1+ EVs as a novel serum biomarker for PM/DM. [ABSTRACT FROM AUTHOR]

Objectives Myositis-specific autoantibodies (MSAs) define distinct clinical subsets of idiopathic inflammatory myopathies (IIMs). The anti-nuclear matrix protein 2 (NXP2) antibody, a MSA detected in juvenile/adult IIMs, has been reported to be associated with a high risk of subcutaneous calcinosis, subcutaneous oedema and internal malignancies. The study aimed to clarify the clinical features of anti-NXP2 antibody-positive IIMs in detail. Methods This was a multicentre retrospective observational study on 76 anti-NXP2 antibody-positive patients. The antibody was detected via a serological assay using immunoprecipitation and western blotting. The patients were selected from 162 consecutive Japanese patients with IIMs. Results The cohort of anti-NXP2 antibody-positive IIMs included 29 juvenile patients and 47 adult patients. Twenty-seven (35.5%) patients presented with polymyositis phenotype without dermatomyositis-specific skin manifestations (heliotrope rash or Gottron sign/papules); this was more common in the adults than children (48.9% vs 15.8%, P  < 0.01). Nine (11.8%) patients had subcutaneous calcinosis, and 20 (26.3%) patients had subcutaneous oedema. In addition, the proportion of patients with muscle weakness extending to the distal limbs was high (36 patients [47.4%]) in this cohort. Adult patients had a higher prevalence of malignancy than the general population (age-standardized incidence ratio of malignancies: 22.4). Conclusion Anti-NXP2 antibody-positive IIMs, which include dermatomyositis sine dermatitis, are characterized by atypical skin manifestations and extensive muscular involvement. [ABSTRACT FROM AUTHOR]

Objectives The aims were to identify all incident adult cases of systemic autoimmune myopathies (SAMs) in the city of Leeds, UK, and to estimate the risk of cancer in SAMs as compared with the general population. Methods Cases of SAMs were ascertained by review of all muscle biopsy reports from the Neuropathology Laboratory. A review of medical records was undertaken for each case to review the clinical diagnosis and collect epidemiological data such as age, ethnicity, sex and comorbidities, including cancer. Leeds denominator population numbers were publicly obtainable. Results A total of 206 biopsy reports were identified and, after review, 50 incident cases were included in the study between June 2010 and January 2021. Of the 50 cases, 27 were male and 23 were female. The mean incidence rate of SAMs in Leeds throughout the study period was 7.42/1 000 000 person-years. The proportion of SAMs cases with a confirmed malignancy was 22%. Compared with the general population, the relative risk of cancer was significantly greater in the SAMs population (31.56; P  < 0.01). Conclusions The incidence rate of SAMs in Leeds was consistent with data from previous literature; however, disagreement exists between different methods of SAMs case inclusion due to varying clinical criteria and definitions. SAMs are associated with an increased risk of cancer, but the pathogenesis of this relationship still requires investigating. This study supports the practice of malignancy screening and long-term surveillance in patients with SAMs. [ABSTRACT FROM AUTHOR]

Objective To determine the prevalence, profile and predictors of infections in an Indian cohort with idiopathic inflammatory myopathies (IIM). Methods We reviewed the records of a retrospective cohort with IIM enrolled from consecutive patients being followed up in the clinic, and these constituted the observation cohort. A newly diagnosed inception cohort with IIM were followed prospectively as the validation cohort for confirmation of observations and comparison with the observation cohort. Results Among the 68 patients in the observation cohort (average age 33.4 years, female:male 4.2:1), 37 (54.4%) experienced 54 infections between them; of these 54 infections, 21 (38.8%) were major and recurrent infections and they occurred in 11 patients (16.17%) over 3.08 years. Tuberculosis was the most common infection (12, 22.2%), with a predominance of extrapulmonary forms. Serum protein [odds ratio (OR) 0.44], platelets (0.44) at disease onset and daily steroid dose (1.04) predicted major infections on multivariate analysis. A higher daily dose of steroids at first infection correlated with number of recurrent infections. The infection-free 1-year survival was 73.8%. Of the 70 patients in the validation cohort (average age 35.7 years, female:male 3.7:1), 3 had myositis attributed to an infection. A similar proportion of the cohort experienced infections (22, 33.3%) with similar number of major (10, 45.4%) and recurrent (4, 18%) infections being recorded. The most common infection was community-acquired pneumonia, followed by tuberculosis, with serum albumin (OR 0.25) at disease onset being the only predictor. The one-year infection-free survival rate was 64.7%. Those who had a major infection had increased mortality at 1 year, with a survival rate of 60%, compared with 89.09% in those without. In both cohorts, a daily prednisone dose >6.25 mg predisposed to major infections. Conclusion Major and recurrent infections are common in Indian IIM patients and confer higher risk for future infections and lower survival. Respiratory and atypical bacterial infections such as tuberculosis occur throughout the disease course. [ABSTRACT FROM AUTHOR]

Objective The aim of our study was to investigate clinical and histopathological findings in adult DM patients positive for anti-Mi2 (anti-Mi2+) antibodies compared with DM patients negative for anti-Mi2 (anti-Mi2–). Methods Clinical data of adult DM patients, who fulfilled EULAR/ACR 2017 classification criteria, were gathered from electronic medical records of three tertiary Rheumatology Units. Histopathological study was carried out on 12 anti-Mi2+ and 14 anti-Mi2– muscle biopsies performed for diagnostic purpose. Nine biopsies from immune mediated necrotizing myopathy (IMNM) patients were used as control group. Results Twenty-two anti-Mi2+ DM [90.9% female, mean age 56.5 (15.7) years] were compared with 69 anti-Mi2– DM patients [71% female, mean age 52.4 (17) years]. Anti-Mi2+ patients presented higher levels of serum muscle enzymes than anti-Mi2– patients [median (IQR) creatine-kinase fold increment: 16 (7–37) vs 3.5 (1–9.9), P  <0.001] before treatment initiation. Moreover, a trend towards less pulmonary involvement was detected in anti-Mi2+ DM (9.1% vs 30.4%, P  =0.05), without any case of rapidly progressive interstitial lung disease. At muscle histology, anti-Mi2+ patients showed more necrotic/degenerative fibres than anti-Mi2– patients [mean 5.3% (5) vs 0.8% (1), P  <0.01], but similar to IMNM [5.9% (6), P  >0.05]. In addition, the endomysial macrophage score was similar between anti-Mi2+ and IMNM patients [mean 1.2 (0.9) vs 1.3 (0.5), P  >0.05], whereas lower macrophage infiltration was found in anti-Mi2– DM [mean 0.4 (0.5), <0.01]. Conclusions Anti-Mi2+ patients represent a specific DM subset with high muscle damage. Histological hallmarks were a higher prevalence of myofiber necrosis, endomysial involvement and macrophage infiltrates at muscle biopsy. [ABSTRACT FROM AUTHOR]

Objectives Muscle cell necrosis is the most common pathological manifestation of idiopathic inflammatory myopathies. Evidence suggests that glycolysis might participate in it. However, the mechanism is unclear. This study aimed to determine the role of glycolysis in the muscle damage that occurs in DM/PM. Methods Mass spectrometry was performed on muscle lesions from DM/PM and control subjects. The expression levels of pyruvate kinase isozyme M2 (PKM2), the nucleotide-binding and oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and pyroptosis-related genes in muscle tissues or plasma were determined by real-time PCR, western blot analysis, IF and ELISA. In addition, IFNγ was used to stimulate myotubes, and the relationships among PMK2 expression, NLRP3 inflammasome activation and pyroptosis were investigated. Results Mass spectrometry and bioinformatics analysis suggested that multiple glycolysis processes, the NLRP3 inflammasome and programmed cell death pathway-related proteins were dysregulated in the muscle tissues of DM/PM. PKM2 and the NLRP3 inflammasome were upregulated and positively correlated in the muscle fibres of DM/PM. Moreover, the pyroptosis-related proteins were increased in muscle tissues of DM/PM and were further increased in PM. The levels of PKM2 in muscle tissues and IL-1β in plasma were high in patients with anti‐signal recognition particle autoantibody expression. The pharmacological inhibition of PKM2 in IFNγ-stimulated myotubes attenuated NLRP3 inflammasome activation and subsequently inhibited pyroptosis. Conclusion Our study revealed upregulated glycolysis in the lesioned muscle tissues of DM/PM, which activated the NLRP3 inflammasome and leaded to pyroptosis in muscle cells. The levels of PKM2 and IL-1β were high in patients with anti‐signal recognition particle autoantibody expression. These proteins might be used as new biomarkers for muscle damage. [ABSTRACT FROM AUTHOR]

Objectives The objective of this study was to compare the results obtained from different assays for the detection of anti-Mi-2 antibodies, which are important markers in the diagnosis of DM. Methods The study included 82 patients (68 females/14 males), most of whom had DM (n = 57), followed by PM (n = 16) and juvenile DM (n = 9). All samples were tested using a novel particle-based multi-analyte technology (PMAT) (Inova Diagnostics, research use only) in parallel with a line immunoassay (LIA: Euroimmun). To assess clinical specificity for the PMAT assay, a total of 775 disease and healthy controls were tested. Results 29 samples were positive by at least one test for anti-Mi-2 antibodies. Of those, 24 were Mi-2β LIA+, five were Mi-2α LIA+ and 23 Mi-2 PMAT+. The comparison shows varying agreement between the different methods (kappa 0.27–0.77). When LIA results were used as reference for receiver operating characteristics analysis, high area under the curve values were found for both PMAT vs LIA Mi-2α and LIA Mi-2β. When analysing the results in the context of the myositis phenotype, PMAT associated closest with the DM phenotype. In the control group, 3/775 controls (all low levels) were anti-Mi-2+ resulting in a sensitivity and specificity of 28.1% and 99.6%, respectively. Conclusion Overall, good agreement was found between LIA and PMAT for anti-Mi-2 antibodies, which is important for the standardization of autoantibodies. Anti-Mi-2β antibodies measured by PMAT tend be more highly associated with the clinical phenotype of DM. [ABSTRACT FROM AUTHOR]

The article discusses research which investigated safety and effectiveness of rituximab in anti-synthetase antibody positive and negative patients with idiopathic inflammatory myopathy (IIM). Topics explored include the clinical characteristics and prevalence of IIM, the selection and evaluation of patients from the Swedish Rheumatology Quality Register, and brief details about the rituximab dosage administered and patient outcomes observed.

Objective To identify biomarkers for assessing myositis-associated interstitial lung disease (ILD). Methods We reviewed consecutive patients from our institution who had been newly diagnosed with PM, DM, or clinically amyopathic DM during the years 2002–2017. The patients were divided into two groups according to the presence of ILD, and the ILD group was further subdivided into three groups according to the clinical courses of induction failure, relapse and non-relapse. Baseline and time-course changes in the parameters were compared between groups. Results Among 110 patients enrolled, 75 (68%) had ILD. Baseline serum Krebs von den Lungen-6 (KL-6) was significantly higher in the ILD group than in the non-ILD group (1120 vs 236 U/ml; P < 0.001). In the ILD group consisting of the induction failure cases (n = 3), the relapse group (n = 24) and the non-relapse group (n = 48), baseline serum KL-6 was significantly different between the three groups [1971 vs 1870 vs 935 U/ml, respectively; P = 0.003 (relapse group vs non-relapse group)]. The time-course changes in serum KL-6 revealed that KL-6 significantly increased along with relapse, with the increase of 625 U/ml relevant to relapse. Conclusion Serum KL-6 is a useful biomarker for assessing the disease activity of myositis-associated ILD. [ABSTRACT FROM AUTHOR]

Objective Based on the antibody profiles of inflammatory myositis patients, we investigated the type 1 IFN (T1-IFN) signature in serum and DM skin to determine the relationship between T1-IFN and vasculopathy in anti-melanoma differentiation-associated 5 gene (MDA5) antibody-positive DM patients. Methods We examined 47 patients with new-onset inflammatory myositis. We divided them into three groups: the anti-MDA5 antibody-positive patients (MDA5 group, n = 16), the anti-aminoacyl-tRNA synthetase antibody-positive patients (aminoacyl-tRNA synthetase group, n = 12), and the double-negative patients (n = 19). Serum T1-IFN signatures were revealed by a functional reporter assay, and we evaluated the T1-IFN signatures of skin based on Mx1 expression by immunohistochemistry. Results The numbers of patients with classical DM, clinically amyopathic DM and interstitial lung disease were 1, 15 and 13 in the MDA5 group, 2, 3 and 11 in the aminoacyl-tRNA synthetase group, and 10, 1 and 4 in the double-negative group, respectively. The signs of vasculopathies (i.e. palmer papules, skin ulcers and mononeuritis multiplex) were identified only in the MDA5 patients. Most of the MDA5 group showed the highest serum T1-IFN signatures among the three groups. In the histological analysis of DM skin, perivascular inflammations were significant in the MDA5 group. The MDA5 group's Mx1 expression was significantly strong, distributed in blood vessels and interstitial fibroblasts, and had spread to deep dermis. Conclusion Anti-MDA5 antibody-positive DM patients showed high T1-IFN signatures in serum and affected skin. The high T1-IFN signatures of the MDA5 antibody-positive DM patients in serum and deep vasculatures suggested that T1-IFN may have important roles in the vasculopathy of these patients. [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to investigate the clinical and immunological significance of nailfold videocapillaroscopy (NVC) abnormalities in patients with idiopathic inflammatory myopathies (IIMs). Methods Seventy consecutive Japanese patients with untreated IIMs, enrolled between April 2014 and August 2017, were prospectively studied. Clinical features, NVC findings, autoantibody profile by immunoprecipitation and ELISA, and histopathological findings of skin biopsies of DM rash were assessed at baseline and after 1-year of immunosuppressive therapy. Results NVC abnormalities were found in 55.7% (39/70) of IIM patients, with significantly higher prevalence in DM (65.4%) compared with PM (27.8%) (P = 0.01). In subsets of patients classified by autoantibody specificities, the prevalence of NVC abnormalities was significantly higher in patients with anti-MDA5 (87.5%) and anti-transcriptional intermediary factor 1γ (88.9%) vs anti-aminoacyl-tRNA synthetase (26.9%, P < 0.001). Perivascular lymphocytic infiltration in the upper dermis of skin rash biopsy of DM was more severe in patients with NVC abnormalities (P < 0.05). Unexpectedly, NVC abnormalities disappeared in 75% of IIM patients after 1-year of immunosuppressive therapy in contrast to stable NVC changes seen in scleroderma patients. Conclusion Nailfold microvascular abnormalities were common in DM patients, associated with anti-MDA5 and transcriptional intermediary factor 1γ antibodies, and perivascular inflammation in skin histology. NVC abnormalities in IIMs may become clinically useful markers for defining subsets of DM and understanding the pathogenesis of the clinical features seen in these patients. [ABSTRACT FROM AUTHOR]

Objectives To investigate the expression of IL-18 in symptomatic and asymptomatic muscle tissues of patients with PM and DM and the effects of conventional immunosuppressive treatment on such expression. Methods Two cohorts of patients were included in this study. The first cohort consisted of 10 new-onset myositis patients. IL-18 expression was compared between symptomatic and asymptomatic muscle biopsies that were taken prior to treatment. The second cohort consisted of another 10 patients with repeated muscle biopsies before and after 8 months with conventional immunosuppressive treatment. Using immunohistochemistry, IL-18 expression in muscle tissues was compared before and after treatment. Biopsies from seven healthy individuals were included as controls. Results IL-18 expression was predominantly localized to inflammatory cells and capillaries in patients and mostly to capillaries in healthy controls. Total IL-18 expression in muscle tissues from the new-onset patients, at both symptomatic and asymptomatic sites, was significantly higher compared with healthy controls (P = 0.007 and P = 0.002) with no statistical difference in appearances between symptomatic and asymptomatic sites. The number of IL-18 positive capillaries was not different among symptomatic, asymptomatic and healthy muscles. Total IL-18 expression appeared lower in biopsies from patients receiving and improving with immunosuppressive treatment, particularly the number of IL-18 positive inflammatory cells but not the number of IL-18 positive capillaries, which was consistent with significantly decreased expression of CD68+macrophages (P = 0.04). Conclusion IL-18 is highly expressed in muscle tissue in the context of inflammatory myopathies and based on its plausible effector functions could provide a novel therapeutic target in future. [ABSTRACT FROM AUTHOR]

The porcine terminal small intestinal starch digestive activity and capacity undergo further developmental changes during the acute and adaptive weaning transition. Objective of this study was to address the hypothesis that weanling porcine growth promotion associated with therapeutic antimicrobials was mediated via improving intestinal starch digestion. A total of 170 crossbred barrows (n = 34 pens; 5 barrows/pen), weaned on d 19-21 with an average initial BW of 6.9±0.1 kg, were randomly assigned to two dried whey, corn and SBM-based diets, i.e., control vs. antimicrobials, for 21 d according to a randomized complete block design. The therapeutic multiantimicrobial diet was supplemented with aureomycin 220, tiamulin 31.2 and ZnO 2,358 at mg/kg diet. The apparent ileal, cecal and total tract digestibility values of total starch and DM were determined by using the titanium dioxide as the digestibility marker (0.30% in the diets). There were no differences (P > 0.05) in the starch digestibility at the ileal (control, 98.3±0.9% vs. antimicrobials, 98.3±0.5%), cecal (control, 96.3±0.6% vs. antimicrobials, 97.1±0.6%) and total tract (control, 98.5±0.3% vs. antimicrobials, 98.7±0.3%) levels between the two diets. Furthermore, there were no differences (P > 0.05) in the DM digestibility at the ileal (control, 75.7±2.2% vs. antimicrobials, 72.7±2.0%), cecal (control, 80.6±1.2% vs. antimicrobials, 81.3±1.2%) and total tract (control, 85.8±0.8% vs. antimicrobials, 84.7±0.9%) levels between the two diets. The Spearman's correlation analyses revealed no significant associations (P > 0.05) between the growth performance endpoints of ADG, ADFI and F: G and the digestibility values of total starch and DM at the levels of ileal, cecal and total tract. Our results suggest that starch is near complete digestion at the distal small intestine, thus not limiting growth and feed conversion efficiency of weanling pigs fed corn and SBM-based diets. Hence, therapeutic multi-antimicrobial effects are unlikely channeled through modulating digestive utilization efficiency of starch and DM in weanling pigs. [ABSTRACT FROM AUTHOR]

Students' beliefs and goals can powerfully influence their learning success. Those who believe intelligence is a fixed entity (entity theorists) tend to emphasize 'performance goals,' leaving them vulnerable to negative feedback and likely to disengage from challenging learning opportunities. In contrast, students who believe intelligence is malleable (incremental theorists) tend to emphasize 'learning goals' and rebound better from occasional failures. Guided by cognitive neuroscience models of top--down, goal-directed behavior, we use event-related potentials (ERPs) to understand how these beliefs influence attention to information associated with successful error correction. Focusing on waveforms associated with conflict detection and error correction in a test of general knowledge, we found evidence indicating that entity theorists oriented differently toward negative performance feedback, as indicated by an enhanced anterior frontal P3 that was also positively correlated with concerns about proving ability relative to others. Yet, following negative feedback, entity theorists demonstrated less sustained memory-related activity (left temporal negativity) to corrective information, suggesting reduced effortful conceptual encoding of this material--a strategic approach that may have contributed to their reduced error correction on a subsequent surprise retest. These results suggest that beliefs can influence learning success through top--down biasing of attention and conceptual processing toward goal-congruent information. [ABSTRACT FROM AUTHOR]