OBJECTIVES:To compare the severity at diagnosis and disease activity during follow-up between juvenile (jDM) and adult-onset (aDM) dermatomyositis. METHODS:Patients with DM fulfilling the 2017 ACR/EULAR criteria and tested for myositis-specific antibodies were included. Overall severity at diagnosis was defined by at least one of the following: severe muscle impairment, symptomatic interstitial lung disease (ILD), gastrointestinal (GI) vasculitis, myocarditis, severe skin ulceration or admission to an intensive care unit. Clinically inactive disease and remission were defined according to PRINTO group criteria and IMACS guidelines. RESULTS:Two hundred and one patients were included: 123 with aDM (≥18 years) and 78 with jDM (<18 years). Female predominance was less pronounced and GI involvement was more frequent in jDM. Anti-nuclear matrix protein 2 (NXP2) antibodies (Abs) were more frequent in jDM. Severe disease at diagnosis was present in 44% of cases, with symptomatic ILD more common in adults and GI vasculitis more common in children. No difference was observed in severe muscle disease. In jDM, anti-NXP2 Abs (odds ratio [OR] = 6.29 [2.00, 23.07], P = 0.003) and joint involvement (OR = 3.44 [1.33, 11.47], P = 0.03) were associated with severe disease at diagnosis, while in aDM, anti-Mi2 Abs were associated with a lower likelihood of severe disease (OR = 0.12 [0.02, 0.42], P = 0.003). No significant difference was observed in clinically inactive disease or remission at the last follow-up. Severe infections occurred in 25% of patients. CONCLUSION:Severity profiles differ by age of DM onset. Autoantibodies are key indicators of severity at diagnosis in both juvenile DM and adult DM.

OBJECTIVES:Gastrointestinal (GI) involvement in myositis is a severe extra muscular manifestation with potentially life-threatening outcomes. However, it remains poorly characterized. We aimed to evaluate the prevalence of GI involvement in DM and to describe its characteristics in anti-nuclear matrix protein-2 (NXP2) DM. METHODS:The prevalence of GI involvement across DM subgroups was assessed in a retrospective monocentric DM cohort (n = 119). It was further investigated in a retrospective multicentric cohort of anti-NXP2 DM (n = 48). GI involvement (defined as any symptomatic GI lesion, excluding isolated dysphagia) was considered severe when requiring surgery and/or intensive care unit admission. RESULTS:In the monocentric DM cohort, severe GI involvement was observed in 18% of anti-NXP2 patients and 6% of anti-melanoma differentiation-associated protein 5 (MDA5) patients. Severe GI involvement was significantly more frequent in anti-NXP2 patients compared with other DM subgroups [hazard ratio 8.85 (95% CI 1.62-48.35)]. In the multicentric anti-NXP2 cohort, severe GI involvement (including four digestive perforations and three digestive haemorrhages) occurred in 12.5% of patients. Anti-NXP2 patients with severe GI involvement were significantly younger (median age 24.5 vs 42.5 years; P < 0.01) and more frequently presented with facial oedema at diagnosis (83% vs 33%; P = 0.03). At the time of GI involvement, 78% of anti-NXP2 patients had concomitant skin and/or muscle disease activity. No deaths were reported. CONCLUSION:Severe GI involvement represents a life-threatening complication in DM and is mainly associated with anti-NXP2 antibody. In anti-NXP2 DM, young age and facial oedema are associated with severe GI involvement.

Objectives Myositis-specific and myositis-associated autoantibodies (MSA/MAA) are important biomarkers used in the diagnosis and assessment of patients with idiopathic inflammatory myopathies. To date, limited guidance exists on how testing should be undertaken or which MSA/MAA to include in a clinically justifiable ‘myositis panel’. We aimed to investigate interlaboratory variability in 'myositis autoantibody testing' in terms of panel components, comparability of test results and approaches to reporting with a view to informing future guidelines. Methods Twenty-four quality-control sera containing MSA/MAA were shared with 15 participating laboratories located in Europe, North America, Australia and Japan. Laboratories evaluated the samples for MSA/MAA using their usual protocols. Raw data, alongside reported test results, were collated. Results Participating laboratories made use of a variety of commercial and in-house assays. Most used at least one commercial multiplex assay and each centre tested for between 14 and 33 autoantibody specificities. Near 100% concordance in the reported result was seen for almost half the samples analysed. As expected, negative results were reported where the previously identified autoantibody was not tested for, but also frequently with putative anti-OJ, anti-EJ and anti-TIF1γ samples. Of concern, the results obtained for anti-TIF1γ sera varied between laboratories using the same commercial assay. Discussion We have shown there is considerable variation in how myositis antibody testing is undertaken and the results obtained for key autoantibody specificities, which may impact on clinical decision-making. Dialogue between manufacturers, diagnostic laboratories and clinicians remains crucial and steps towards harmonisation between laboratories is urgently needed.

Herbicides, used worldwide to improve agricultural yields, are associated with pollution and significant health problems. Cardiac damage is a major concern, and the respective contributions of glyphosate (GP) and its commercial formulation, Roundup® (RU), warrant investigation. We studied the specific effects of GP and RU on isolated rat cardiac mitochondria and on H9c2 cardiomyocytes cultured for 6 and 24 h to determine whether the potential cardiotoxicity of GP and/or RU are linked to impaired mitochondrial respiration and increased hydrogen peroxide (H2O2) production. To this end, we used various mitochondrial complex substrates and a high-resolution oxygraphy. Unlike the GP alone which demonstrated no significant effect, the RU decreased cardiac mitochondrial respiration (21.90 ± 2.99 vs. 41.23 ± 7.09 pmol/s/mL, -46.9%, p = 0.007) for OXPHOS CI in respectively the RU and the control groups. RU also impaired OXPHOS CI+II (-51.5%, p = 0.003), maximal mitochondrial respiration (ETS CI+II, -46.7%, p = 0.001) and coupling (-35.4%, p = 0.0003). Similarly, 24 h exposure to RU decreased H9c2 cell number (-48.59%, p = 0.0023) but increased their mitochondrial respiration (+38.2%, p = 0.03, +37.6%, p = 0.03, +43.2%, p = 0.03 for OXPHOS CI, OXPHOS CI+II and ETS CI+II respectively). We observed a similar trend (NS) after 24 h exposure to GP. In conclusion, these results support an enhanced cardiac toxicity of the Roundup® as compared to the glyphosate. Both decreased mitochondrial respiration and increased hydrogen peroxide production were involved in isolated mitochondria impairment. After 24 h exposure to Roundup®, a compensatory mechanism potentially counterbalanced the decreased H9c2 cell number. These data support future studies aiming to reduce Roundup®-associated cardiac alterations not only by reducing its use but also by investigating the effectiveness of antioxidant and mitochondria-focused therapy.

OBJECTIVES:Several studies reported an association between Sjögren's disease (SjD) and inclusion body myositis (IBM). However, the potential specificities of IBM when associated with SjD have been poorly investigated. Here, we compared the muscular inflammatory infiltrates between IBM patients with or without associated SjD. METHODS:Formalin-fixed and paraffin-embedded muscle biopsies of patients with IBM, associated with SjD (IBM-SjD) and sporadic (sIBM) forms, from six French expert centres, were collected. Imaging mass cytometry (IMC) multiplex immunostaining (34 markers) was used to quantify and analyse inflammatory infiltrate composition. Supervised and unsupervised descriptive and comparative analyses were performed. RESULTS:Fourteen IBM-SjD and seven sIBM muscle samples were analysed. No statistically significant difference was encountered but some trends were pointed. IBM-SjD samples had a broader inflammatory infiltrate surface (median 4.8%, IQR: 1.4-8.6) than sIBM samples (median 1.6% IQR: 1.2-2.4). In both groups, the main inflammatory cells in muscle infiltrate were primarily macrophages and T cells. However, the proportion of plasma cells (14.7% IQR: 5.4-24.6 vs 8.5% IQR: 4.6-9.8) and B cells (3.1% IQR: 0.4-5.6 vs 0.5% IQR: 0.0-3.2) were higher in IBM-SjD patients. CONCLUSION:Using IMC on muscle biopsies, IBM-SjD and sIBM patients share common histological features, but there are notable distinctions (more extensive infiltrate, high numbers of B cells and plasma cells in IBM-SjD). These observations were exploratory and based on a small number of patients but may suggest IBM-SjD has distinct SjD-related pathophysiology compared with sIBM, and open to further research with potential diagnostic and therapeutic implications.

OBJECTIVES:Autoantibody internalisation has been implicated in autoimmune disease pathogenesis, yet its mechanisms and generalisability across diseases, cell types, and tissues remain poorly defined. We sought to address these gaps. METHODS:Bulk RNA sequencing was performed on 814 muscle biopsies from patients with autoimmune diseases and healthy controls, including an external validation cohort of 41 additional samples. Purified patient immunoglobulin (Ig) G was electroporated into primary human cells to assess functional effects in vitro. Immunofluorescence evaluated localisation of immunoglobulins across diseases and tissues. Spatial transcriptomics assessed disease-specific gene expression, cellular injury, and inflammatory responses. RESULTS:Using anti-Mi2 dermatomyositis and anti-PM/Scl scleromyositis as model diseases, we validated reproducible, autoantibody-specific transcriptomic signatures consistent with autoantigen dysfunction across cohorts and confirmed that electroporation of purified patient IgG into healthy primary cells recapitulates these disease-associated transcriptional programmes. Spatial transcriptomics linked these signatures to cellular injury and distinct inflammatory responses, including activation of type I interferon and TGFβ signalling in anti-Mi2 dermatomyositis and type II interferon signalling in anti-PM/Scl scleromyositis. These programmes were observed predominantly not only in muscle fibres but also in macrophages, endothelial cells, and fibroblasts/fibroadipogenic progenitors. Spatial transcriptomics further revealed transfer of immunoglobulin RNA from antibody-secreting cells to adjacent target cells expressing disease-specific transcriptional programmes. Antibody internalisation, previously described in myositis muscle, was also observed in skin from patients with anti-Mi2 and anti-PM/Scl and in tissues from anti-U1RNP mixed connective tissue disease, anti-Ku overlap syndrome, and anti-Scl70 systemic sclerosis. CONCLUSIONS:Together, these findings establish autoantibody internalisation as a mechanism of tissue injury in autoimmunity, suggesting its broader relevance across autoantibody-mediated diseases.

Background: Sarcopenia and malnutrition may contribute to persistent functional vulnerability after lung transplantation, yet their prevalence using actual criteria, relationship and clinical correlates remain incompletely defined. Methods: Ninety-nine adult lung transplant recipients (Ltx) were included in the study during their routine follow-up. Sarcopenia was defined using EWGSOP2 criteria, integrating muscle strength, dual-energy X-ray absorptiometry-derived appendicular lean mass, and physical performance. Malnutrition was assessed using GLIM criteria before transplantation and at follow-up. Clinical, nutritional, biological, body-composition, and pulmonary-function variables were compared according to sarcopenia status. Results: Sarcopenia was identified in 17 recipients (17.2%), including 12 (12.1%) with severe sarcopenia. Malnutrition was frequent before transplantation and persisted at follow-up, affecting 52 of 98 recipients (53.1%) before transplantation and 23 of 99 recipients (23.2%) after transplantation. Sarcopenia was related to underlying diseases leading to transplantation (mainly COPD and ILD) and sarcopenic Ltx were older (66.1 ± 6.7 vs. 57.7 ± 12.6 years; p = 0.05), had greater smoking exposure (38.2 ± 25.6 vs. 22.2 ± 20.2 pack-years; p = 0.02) and prednisone dose (13.5 ± 8.1 vs. 8.9 ± 2.7 mg/day; p = 0.001). Despite a trend towards lower albuminemia (40.5 ± 4.7 vs. 42.1 ± 4.3 g/L; p = 0.07), malnutrition was not associated with sarcopenia status. Lung function improved substantially after transplantation, with mean FEV1 increasing from 25.7 ± 16.6% to 82.0 ± 25.4% predicted at assessment (p < 0.001); however, FEV1 at assessment did not differ considering sarcopenia status. Conclusions: In lung transplant recipients, EWGSOP2-defined sarcopenia was common and largely uncaptured by BMI, malnutrition status, routine biomarkers, adiposity indices, or spirometry recovery. Malnutrition was reduced by personalized nutritional support but persisted in many patients, supporting more systematic muscle-health and nutritional assessment to allow reduced post-transplant morbidity.

Peripheral arterial disease is a leading cause of amputation and/or death worldwide. Phosphodiesterase 4 (PDE 4) inhibitors demonstrated beneficial effects in ischemia–reperfusion (IR) settings, but whether PDE 4 inhibition protects skeletal muscle against IR deleterious effects is unknown. We therefore performed limb IR (two hours each) in twenty-one male Swiss mice (12–16-week-old) treated or not with Rolipram (1 mg/kg i.p. 30 min before ischemia and 5 min before reperfusion). The muscles were analyzed 4 h after the onset of ischemia. IR significantly increased leucocyte infiltration (93.13 ± 6.886 vs. 150.1 ± 18.38 cells/mg of muscle, p < 0.05) and apoptosis (Bax/Bcl2 ratio, +239%, p < 0.05), together with enhanced mitochondrial fission transcripts (+224% for Drp1, p < 0.01 and +368%, p < 0.0001 for Fis1), and decreased mitochondrial respiration and antioxidant defense. PDE 4 inhibition reduced leucocyte infiltration (150.1 ± 18.38 vs. 55.58 ± 13.83; p < 0.01) and apoptosis (+67%, NS) in association with reduced fission markers (+91% for Drp 1 and +111%, p < 0.05, for Fis 1). Muscle mitochondrial respiration did not improve. In conclusion, PDE 4 inhibition using Rolipram partly protected skeletal muscles against IR-induced deleterious effects. These data support further studies investigating the usefulness of leucocytes modulation in lower-limb IR and a potential beneficial effect of PDE 4 inhibition in peripheral arterial disease.

OBJECTIVES:Interstitial lung disease (ILD) is the principal determinant of morbidity and mortality in antisynthetase syndrome (ASyS). Data regarding ASyS-ILD trajectory phenotypes and factors influencing ILD clinical course remain scarce. We aimed to identify longitudinal ILD trajectories in patients with ASyS-ILD. METHODS:A total of 92 patients with ASyS and ILD diagnosed by high-resolution computed tomography (HRCT), with forced vital capacity (FVC) measurement at ILD diagnosis and at least one additional measurement during follow-up, were included. Latent class mixed models (LCMMs) and linear mixed-effects models were performed to determine groups of patients with similar FVC trajectories and to identify risk factors associated with longitudinal FVC change. RESULTS:The 3-class model demonstrated the best fit. Class 1 (n=17) had intermediate baseline FVC but declined over time, with higher rates of ILD relapse, pulmonary hypertension, and chronic respiratory failure. Class 2 (n=44) included younger patients with higher baseline FVC that remained stable during follow-up. Class 3 (n=31) had lower baseline FVC and more rapidly progressive ILD at diagnosis but improved over time. In mixed-effects models, nonspecific interstitial pneumonia and organizing pneumonia patterns were associated with a more favorable longitudinal FVC trajectory (β=6.5; 95%CI, 1.8-11; P=.008 and β=7.7; 95%CI, 2.0-13; P=.009, respectively). CONCLUSIONS:We identified three phenotypes of ILD trajectories in patients with ASyS, including one group with declining FVC and poor respiratory prognosis. HRCT ILD pattern was the factor most predictive of longitudinal FVC change.

COVID-19 is a public health issue with a significant mortality rate and potential long-lasting disabling symptoms responsible for the long-COVID syndrome. Mitochondrial dysfunction is a key mechanism but whether peripheral blood mononuclear cell (PBMC) mitochondrial respiration changes might be associated with mortality and/or occurrence and severity of long-COVID syndrome remains to be investigated. We determined mitochondrial respiratory chain oxygen consumption in twenty COVID-19 patients hospitalized in the intensive care unit and analyzed their remaining symptoms at the third year after hospital release. PBMC mitochondrial respiration was decreased in COVID-19 patients compared to the control group (14.13 ± 2.35 vs. 6.21 ± 0.88 pmol/s/106 cell, p = 0.0006 for the OXPHOS state by CII). Considering COVID severity, such a decrease was greater in long-COVID patients and in patients who deceased (4.91 ± 0.75, p = 0.008 and 4.94 ± 1.11 pmol/s/106 cell, p = 0.04, respectively). PBMC markers of inflammation also increased with the severity of COVID (1.0 ± 0.08 vs. 14.45 ± 2.07, p = 0.02 for ISG15 in patients who died) and ISG15 negatively correlated with PBMC mitochondrial respiration (r = −0.67, p = 0.02 for CII). In conclusion, this study shows that the greater the impairment in PBMC mitochondrial respiration in patients hospitalized in the intensive care unit for COVID-19, the greater the mortality rate and the more severe the long-COVID symptoms—three years after hospital discharge. Further, PBMC markers of inflammation also increased with the severity of COVID and ISG15 negatively correlated with PBMC mitochondrial respiration. These results support that PBMC mitochondrial respiration might be a biomarker of COVID severity and further studies investigating whether modulation of PBMC mitochondrial respiration might improve COVID-19 patients’ prognosis.

OBJECTIVES:We aimed to assess the incidence of cancer-associated myositis among patients with anti-synthetase syndrome, identify factors associated with cancer-associated myositis, and assess its impact on prognosis. METHODS:We conducted a retrospective multicenter study, including adult patients with anti-synthetase syndrome. Factors associated with cancer were assessed using a multivariable logistic regression model. Unsupervised analysis was used to identify a cluster of patients associated with cancer. Cox proportional hazard ratio model was used to assess impact of cancer-associated myositis on mortality. RESULTS:Among the 122 patients included, 14 (11.4%) met cancer-associated myositis criteria. Standardized incidence ratio was 5.4 (5.14 to 5.65, P < .0001). Patients with cancer-associated myositis were older, more often had a history of cancer, and had lower creatine kinase level and less muscular weakness. They had a significantly worse overall survival compared with those without (log-rank test χ2 = 16.2, P < .0001). Age and history of cancer were independently associated with cancer-associated myositis. Patients with cancer-associated myositis segregated within a cluster characterized by an older age, a milder muscular involvement, and less Jo-1 antibodies. Finally, cancer-associated myositis was an independent predictor of death. CONCLUSION:Cancer-associated myositis is not rare in anti-synthetase syndrome, with higher incidence compared with the general population. Due to its higher mortality, cancer should be carefully screened, especially in older patients with history of cancer.

OBJECTIVES:Anti-MDA5 dermatomyositis (anti-MDA5 DM) is the most severe subtype of dermatomyositis, due to its pulmonary involvement. Current treatment involves corticosteroids and immunosuppressants, but variability in responses exists. This study aims to evaluate the efficacy and safety of Janus kinase (JAK)- and calcineurin-inhibitor combination (JAK-CNI) in anti-MDA5 DM patients. METHODS:A nested case-control study was conducted within a retrospective cohort of 234 anti-MDA5 DM patients. Patients receiving JAK-CNI were matched 1:2 with comparators. All-cause mortality or transplant within a year was compared using Cox proportional hazards models. Infectious and noninfectious side effects were also assessed. RESULTS:Twenty-seven patients receiving JAK-CNI were compared to 52 matched controls. Almost all these patients had pulmonary involvement. Thirty-nine (49%) died or were transplanted during follow-up. No significant improvement in survival or transplant-free survival was observed with JAK-CNI compared with comparators (hazard ratios 1.02, 95% confidence intervals [0.48-2.16]). Results were consistent regardless of intensive care unit (ICU) admission status and when analyses were restricted to patients with rapidly progressive interstitial lung disease. A trend toward a beneficial effect of the JAK-CNI combination was observed in non-ICU patients. Infectious complications were frequent (n = 49, 62%), with no excess risk in patients receiving JAK-CNI. CONCLUSION:JAK-CNI showed a similar outcome to other immunosuppressive combinations. However, as the study included the most severe cases, the potential benefit of early JAK-CNI introduction in less severe forms cannot be dismissed, as suggested by the nonsignificant trend in non-ICU patients. Future studies are needed to clarify the optimal timing and patient selection for JAK-CNI therapy in anti-MDA5 DM.

Objectives The aim of our work was to identify specific patterns in clinical features and nailfold capillary changes that may help in screening for pulmonary arterial hypertension (PAH) in patients with systemic lupus erythematosus (SLE).Methods We identified patients with SLE and type I PAH (n=20) without other connective tissue diseases and collected demographic, clinical and laboratory features. We selected as controls patients with SLE who underwent cardiopulmonary screening to exclude PAH (n=87): we collected demographic, clinical and laboratory features and performed nailfold videocapillaroscopy (NVC).Results All patients with SLE-PAH were women; age and disease duration were not different from patients with SLE without PAH. Lupus anticoagulant (LAC)+and anti-ribonucleoprotein (RNP)+were more prevalent in patients with SLE-PAH (respectively, PAH 45.0% vs no-PAH 20.5%, p=0.042; PAH 45.0% vs no-PAH 19.5%, p=0.035). No differences were observed for anti-Sm, anti-Ro, anti-La and anti-cardiolipin and anti-beta2GPI antibodies. Among clinical features, mucocutaneous and central nervous system involvement were more prevalent in patients with SLE-PAH than in SLE controls (respectively, PAH 65.0% vs no-PAH 34.5%, p=0.024; PAH 25.0% vs no-PAH 8.0%, p=0.046). Raynaud’s phenomenon (RP) was more prevalent in patients with SLE-PAH than in SLE controls (PAH 60.0% vs no-PAH 13.8%, p<0.001). RP was a predictor of PAH in patients with SLE (OR 3.8 (0.9–14.8)). We performed NVC on nine patients with PAH and on controls: we observed a significantly higher prevalence of scleroderma pattern at NVC in SLE-PAH than controls (PAH 66.7% vs no-PAH 9.2%, p<0.001). Patients with SLE-PAH showed a lower number of capillary density and a higher frequency of giant capillaries.Conclusions Our data showed that LAC+, RNP+, RP and a scleroderma pattern at NVC was indicative for patients with SLE-PAH. Our results pointed to generalised microvascular involvement and a hypercoagulation state in patients with SLE-PAH. The variables we identified could be used to implement a screening algorithm to identify patients with SLE at risk of developing PAH.

Background: Body composition assessment is important in professional football as a measure of overall adaptation of the athlete to the training demand and calorie intake. However, it is operator-dependent, relying on subject positioning and the focus angle of the X-rays. In addition, the usual appendicular lean mass index (ALMI) does not include the pelvitrochanteric muscles, which are often implicated in athlete injuries. Methods: Three independent operators compared the reproducibility of dual-energy X-ray absorptiometry (DEXA) including pelvi-trochanteric muscle mass in twenty professional football players, using the standard and a new method. Results: Mean age, weight, and height of the footballers were 25.9 ± 4.9 years, 79.4 ± 9.4 kg, and 1.83 ± 0.09 m. Using the standard method, the ALMI was 9.28 ± 0.62, 9.20 ± 0.65, and 9.13 ± 0.64 kg/m2 for the first, second and third operator, respectively. When including the pelvi-trochanteric muscles, the ALMI values were 11.90 ± 0.66, 11.84 ± 0.63, and 11.83 ± 0.65 kg/m2 for the three operators. The difference between the two methods was significant (p < 0.001). The mean inter-operator difference was similar regardless of the method used (0.099 ± 0.06 kg/m2). The intraclass correlation coefficients (ICC) (A,1) were 0.949 [0.881; 0.979] for the standard method and 0.977 [0.951; 0.990] for the new method. The ICC (C,1) was 0.960 [0.918; 0.983] for the standard method and 0.979 [0.957; 0.991] for the new method. Conclusions: Thus, both new and conventional methods showed excellent reproducibility. However, reproducibility and inter-operator variability were better with the adjustment of the new scan lines. Moreover, the inclusion of a larger gluteal and adductors muscle mass was easy to achieve, providing additional information that could potentially be useful for early diagnosis and/or prevention of future muscular injuries in elite athletes.

To explore the link between moderate to severe oropharyngeal dysphagia and cancer in autoimmune myositis (AIM) other than inclusion body myositis (IBM). The medical records of patients with AIM seen in rheumatology in two university hospitals from January 2000 to December 2022 were retrospectively reviewed. Using an updated AIM subclassification, patients were classified by expert opinion as pure dermatomyositis (DM), immune-mediated necrotizing myopathy (IMNM), scleromyositis, lupomyositis, anti-MDA-5 syndrome, antisynthetase syndrome (ASyS) or polymyositis syndrome. Objective oropharyngeal dysphagia at myositis diagnosis was defined by an abnormal videofluoroscopic swallowing study and/or the need for percutaneous gastrojejunostomy. The presence of cancer within 3 years of myositis diagnosis was recorded. Pure DM accounted for 50