Background: Anti-melanoma differentiation-associated gene 5 (anti-MDA5) positive dermatomyositis is a distinct subset of idiopathic inflammatory myopathies (IIMs), often associated with unique cutaneous features and interstitial lung disease (ILD). While East Asian cohorts frequently report high mortality due to rapidly progressive ILD (RP-ILD), data regarding Central and Eastern European populations remain scarce. Methods: We conducted a retrospective multicenter study of anti-MDA5 positive Caucasian patients managed at four Hungarian rheumatology centers between 2020 and 2025. Demographic, clinical, serological, and radiological data were analyzed. Antibody profiling was performed using a standardized 16-antigen immunoblot assay. Results: Anti-MDA5 positivity was confirmed in 24 out of 742 patients (3.23%) treated in the four centers. The median age at diagnosis was 49.5 years (range: 24-81). Classic dermatomyositis was the predominant clinical phenotype (75%), followed by clinically amyopathic dermatomyositis (CADM) (12.5%) and polymyositis (12.5%). ILD was identified in 58.3% of patients, presenting with organizing pneumonia (OP), non-specific interstitial pneumonia (NSIP), and usual interstitial pneumonia (UIP) patterns. At diagnosis, median creatine kinase (CK) (193.5 U/L) and C-reactive protein (CRP) (4.24 mg/L) levels remained low even in the ILD group, whereas lactate dehydrogenase (LDH) was elevated in 91.7% of the cohort. Anti-Ro52 positivity (45.8% overall) emerged as a notable predictor of ILD (odds ratio [OR]: 22.5, 95% confidence interval [CI]: 2.10-240.48; p = 0.0045), being present in 71.4% of affected patients. RP-ILD occurred in two patients (8.3%). Therapeutic management followed an early, aggressive strategy, frequently utilizing cyclophosphamide (45.8%) and methotrexate (37.5%), with Janus kinase (JAK) inhibitors or rituximab employed in refractory cases. Overall disease-specific survival was 100% during the study period (median follow-up: 72.0 months); no mortality was directly attributable to IIM-related complications. Conclusions: Our study demonstrates that anti-MDA5 positive dermatomyositis in a Hungarian cohort is characterized by heterogeneous manifestations and a significant association between anti-Ro52 and ILD. The observed dissociation between low CK/CRP and elevated LDH underscores the necessity for a high index of suspicion, with LDH serving as a superior marker for disease activity. While ILD presents a significant risk, early and intensive multi-modal intervention may yield superior survival outcomes in European patients compared to the historical mortality rates reported in Asian cohorts.

BACKGROUND:Brepocitinib is a first-in-class, oral, selective TYK2-JAK1 inhibitor that blocks cytokine signaling, which has been implicated in dermatomyositis. METHODS:In this phase 3, double-blind, randomized, placebo-controlled trial, adults with dermatomyositis were assigned in a 1:1:1 ratio to receive once-daily oral brepocitinib at a dose of 30 mg, brepocitinib at a dose of 15 mg, or placebo for 52 weeks. Standard therapies were continued, and glucocorticoids were tapered. The primary end point was the Total Improvement Score, a validated composite myositis index (with scores ranging from 0 to 100 and higher scores indicating greater improvement) at week 52. Key secondary end points, including skin disease activity, glucocorticoid tapering, and physical function, were tested in a multiplicity-controlled sequence. RESULTS:A total of 241 patients underwent randomization: 81 to receive brepocitinib 30 mg, 81 to receive brepocitinib 15 mg, and 79 to receive placebo. At week 52, the mean Total Improvement Score was 46.5, 37.5, and 31.2, respectively (difference with brepocitinib 30 mg vs. placebo, 15.3; 95% confidence interval [CI], 6.7 to 24.0; P<0.001; difference with brepocitinib 15 mg vs. placebo, 6.3; 95% CI, -2.4 to 14.9). Brepocitinib 30 mg was superior to placebo across all nine key secondary end points, including skin disease activity, systemic glucocorticoid tapering, and functional disability, with improvements observed as early as week 4. Serious infections were more frequent in the brepocitinib 30-mg group than in the placebo group (10% vs. 1%). No deaths occurred during the trial. CONCLUSIONS:In adults with dermatomyositis that was resistant to previous therapy, the use of brepocitinib at a dose of 30 mg (but not at a dose of 15 mg) resulted in significant benefits with respect to a composite myositis index, skin disease severity, glucocorticoid tapering, and functional disability. (Funded by Priovant Therapeutics; ClinicalTrials.gov number, NCT05437263.).

Anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibodies are critical biomarkers in myositis, associated with distinct clinical features and prognosis. This study aimed to evaluate the proportion of anti-MDA5 positivity and compare the diagnostic performance of local immunoblotting (IB) with gold-standard immunoprecipitation (IP). We performed a retrospective analysis of 3272 physician-requested anti-MDA5 IB determinations over a five-year period (2019-2023). A subsequent exploratory pilot study of ten Hungarian patients with myositis was conducted to compare IB results with radiolabeled protein IP. Confirmatory in-house enzyme-linked immunosorbent assay (ELISA) was used to distinguish between 140 kDa bands (anti-MDA5 vs. anti-NXP2). Indirect immunofluorescence (IIF) on HEp-2 cells was also evaluated. In the retrospective cohort, 3.7% (n = 121) of samples were non-negative. Among 64 borderline patients, only one (1.6%) had a definitive diagnosis of dermatomyositis (DM). Conversely, the proportion of confirmed myositis cases was notably higher among patients with strong positive IB results. In our exploratory cross-sectional pilot study, complete concordance between the two assays was observed for negative and strong positive results. Discrepancies were noted in borderline and weak positivity ranges, where anti-MDA5 was not detected by IP; instead, alternative autoantibodies were identified. The three IP-confirmed MDA5 positive samples were all validated by ELISA. The characteristic IIF cytoplasmic staining was identifiable in 2 out of 10 cases (20%). In our cohort, borderline IB cases were frequently potential false positives, highlighting the need for careful clinical evaluation. Borderline and weak results require clinical correlation or confirmatory testing to avoid misdiagnosis.

OBJECTIVE:To evaluate the analytical performance of commercial myositis-specific autoantibody (MSA) assays against immunoprecipitation (IP) assays. METHODS:A systematic literature search was conducted in PubMed, Web of Science, and Scopus through July 2024. Data were extracted on study design, participant characteristics, index tests, and 2 × 2 contingency tables for diagnostic performance. Study quality was assessed using the QUADAS-2 tool. Sensitivity and specificity were calculated for each dataset and presented as paired forest plots and summary receiver operating characteristic (SROC) curves. A hierarchical SROC model was used to estimate pooled sensitivity and specificity for meta-analysis. RESULTS:Of 3156 articles, 23 met inclusion criteria and were judged to have low risk of bias across all QUADAS-2 domains. The most frequently evaluated commercial assay was the line blot assay (LBA; 16 studies), followed by enzyme immunoassay (EIA; 9 studies). In the meta-analyses, the highest pooled sensitivity was observed for anti-MDA5 with EIA (95.7 %), followed by anti-SAE with LBA (88.3 %), anti-PL-12 with LBA (87.2 %), and anti-Jo-1 and anti-MDA5 with LBA (82.8 %). Lower sensitivities were observed for anti-Mi-2 (67.4 %), anti-NXP2 (69.7 %), and anti-TIF1-γ (63.8 %) with LBA. Pooled specificity ranged from 94.7 % to 99.3 % across MSA assays, but a false-positive result was a common concern for LBA, except for anti-EJ. CONCLUSION:False-positive and false-negative results remain a significant challenge in the use of commercial MSA assays.

Background: Idiopathic inflammatory myopathies (IIMs), also known as myositis, are systemic autoimmune diseases characterized by chronic inflammation affecting the skin, muscles, and internal organs. Besides traditional risk factors and immune-mediated myocarditis, continuous activity of the immune system increases cardiovascular disease (CVD) risk, meaning that cardiovascular events are the leading causes of mortality in IIM patients. Statins are the most widely used lipid-lowering therapies, which reduce cardiovascular risk, but the fear of adverse muscular events inhibits the frequency of use. Methods: Our aim was to assess the CVD risk in a myositis cohort using the SCORE2 prediction system, carotid artery Doppler ultrasound measurement, and biomarkers; recommend individual lipid-lowering treatment; and follow the efficacy and adverse events of therapy in a 6-month treatment period. Results: The study population (80 IIM patients) was a middle-aged, female-dominant myositis cohort with an average disease duration of 9 years and low median global disease activity. Based on the SCORE2 evaluation, 78.8% of patients had medium/high CVD risk, while 73.13% had asymptomatic carotid plaque. After 6 months of adequate lipid-lowering therapy, 37.5% of patients reached a lower CVD risk category, the biomarker levels of atherosclerosis significantly decreased, and no progression in carotid plaques was detected. None of the patients reported an adverse muscular event or IIM relapse. Conclusions: Our findings proved that the CVD risk of patients with myositis is high, but carefully applied lipid-lowering treatment is the key to effective risk reduction. Risk stratification and the recommendation of preventive treatment are the responsibility of the treating physician.

Muscle and skin involvement are well defined in dermatomyositis but other symptoms contribute significantly to the disease burden and their treatment is not well characterized. This post hoc analysis of ProDERM assessed the effect of intravenous immunoglobulin (IVIg) treatment on other manifestations of dermatomyositis beyond muscular and cutaneous involvement. ProDERM was a randomized, placebo-controlled study. For weeks 0–16, patients with dermatomyositis received 2.0 g/kg IVIg (Octagam, 10

OBJECTIVES:The phase 3 ProDERM study demonstrated intravenous immunoglobulin (IVIg) was safe and effective in patients with dermatomyositis (DM). This analysis assessed clinical and serological predictors of IVIg response in DM patients from ProDERM. METHODS:ProDERM was a prospective, randomized, placebo-controlled study of DM patients. For weeks 0-16, patients received 2.0 g/kg IVIg (Octagam, 10%) or placebo every 4 weeks. Eligible patients entered the open-label extension phase, where all received IVIg to week 40. Univariate and multivariate analyses examined associations between baseline variables and total improvement score (TIS), including myositis disease activity assessment tool (MDAAT; assessing different organ involvement), and myositis-specific and myositis-associated autoantibodies. RESULTS:Ninety-five patients were enrolled. Univariate analyses found no significant association between TIS at week 16 or 40 and age; sex; ethnicity; disease duration/activity; cutaneous, skeletal, gastrointestinal or muscle disease activity; or previous failed or concomitant medications. Multivariate analysis found patients with higher MDAAT cutaneous scores had a better chance of at least minimal TIS improvement. Higher MDAAT pulmonary scores were associated with a lower, but still considerable, chance of improvement. Patients with TIF1-γ antibodies had a better TIS response; however, after controlling for cutaneous disease activity, there was no significant association between antibody classification (including anti-TIF1-γ) and efficacy outcome. CONCLUSION:IVIg was effective in treating DM patients regardless of demographic features and autoantibody status (for most autoantibodies). Patients with higher cutaneous disease activity and/or anti-TIF1-γ responded best to IVIg, while pulmonary disease activity predicted a lower, but still effective, IVIg response, warranting further investigation. TRIAL REGISTRATION:ClinicalTrials.gov, http://clinicaltrials.gov, NCT02728752.

Interferon signature is one of the key pathogenic pathways in idiopathic inflammatory myopathies (IIMs), particularly in dermatomyositis (DM). The aim of this study was to analyze Siglec-1, an interferon-inducible receptor, on different monocyte subsets in IIM subtypes and investigate its association with disease activity measures. Siglec-1 expression was measured by 8-color flow cytometry in 62 IIM patients and 10 healthy controls (HC). Disease activity was assessed using the International Myositis Assessment and Clinical Studies (IMACS) core set measures. Active DM patients exhibited significantly higher Siglec-1 mean fluorescence intensity (MFI) compared to inactive subgroups and HCs in every monocyte subset. Intermediate monocytes displayed the highest Siglec-1 expression across all groups and the strongest associations between disease activity markers. Siglec-1 expression on monocyte subsets was strongly associated with global, extramuscular global, constitutional, cutaneous, muscular, and gastrointestinal activity measures, but not with pulmonary, skeletal, and cardiac activities in the DM population. The best indicator of DM global disease activity among the examined biomarkers was Siglec-1 MFI on intermediate monocytes. Siglec-1 on intermediate monocytes correlates strongly with organ-specific clinical and biochemical markers of disease activity; therefore, it is a candidate biomarker for monitoring IIM disease activity. Siglec-1 could be useful in patient selection for interferon-targeted treatments.

BackgroundSeveral systemic autoimmune rheumatic diseases may affect both fetal and maternal outcomes during pregnancy. However, little information is available regarding pregnancy outcomes in women with idiopathic inflammatory myopathy. Previously published articles stated that the activity of maternal disease may worsen pregnancy outcomes. A former multicenter study suggested that anti-Jo1 antibody positivity and joint involvement could distinguish a more vulnerable group regarding pregnancy complications. Our aim was to identify prognostic factors among clinical symptoms at disease onset and auto-antibody profiles for identifying a high-risk group for poor pregnancy outcome.MethodsThe clinical data of the myositis cohort of the Division of Clinical Immunology, University of Debrecen, Hungary, were reviewed retrospectively. IIM diagnoses were made by Bohan and Peter's criteria or European Alliance of Associations for Rheumatology/American College of Rheumatology (EULAR/ACR) criteria. Disease activity was evaluated based on physician opinion. Gynecological definitions were used to evaluate fetal outcomes.ResultsReviewing clinical data of overall 763 patients (542 women and 221 men) revealed that 5.2% of female patients had pregnancies in the same time or after myositis onset. Among these, 71.4% of the mothers suffered from polymyositis (PM) and 28.6% suffered from dermatomyositis (DM). Their mean age at the time of myositis diagnosis was 25.28 years, and the average interval between myositis diagnosis and first pregnancy was 55.4 months. Maternal complications included preeclampsia in one case and pregnancy-induced myositis in 25% of cases. All cases of pregnancy-induced myositis improved after immunosuppressive treatment. Twenty-eight patients reported 60 pregnancies overall, with multiple pregnancies occurring in 57% of cases. Early or late fetal loss was detected in 41.7% of the pregnancies, and stillbirth occurred in 18.3% of deliveries. Although late fetal loss was observed mainly due to placental insufficiency in patients with anti-Jo1 positivity and complications seemed more frequent in PM cases, logistic regression analysis only confirmed that multiple pregnancies could be an independent risk factor for fetal (p = 0.0112) and interstitial lung disease of maternal complications (p = 0.02).ConclusionInternal organ involvement and the number of pregnancies could influence pregnancy outcomes in myositis patients. Patients’ family planning should be well organized and counseled by myositis experts. Prospective, multicenter collaborations are needed to precisely identify high-risk groups and state managing guidelines.

Objectives Disease flares in the post-coronavirus disease 2019 (COVID-19) vaccination period represent a prominent concern, though risk factors are poorly understood. We studied these flares among patients with idiopathic inflammatory myopathies (IIMs) and other autoimmune rheumatic diseases (AIRDs). Methods The COVAD-1 and -2 global surveys were circulated in early 2021 and 2022, respectively, and we captured demographics, comorbidities, AIRDs details, COVID-19 infection history and vaccination details. Flares of IIMs were defined as (a) patient self-reported, (b) immunosuppression (IS) denoted, (c) clinical sign directed and (d) with >7.9-point minimal clinically significant improvement difference worsening of Patient-Reported Outcomes Measurement Information System (PROMIS) PROMISPF10a score. Risk factors of flares were analysed using regression models. Results Of 15 165 total respondents, 1278 IIMs (age 63 years, 70.3% female, 80.8% Caucasians) and 3453 AIRDs were included. Flares of IIM were seen in 9.6%, 12.7%, 8.7% and 19.6% patients by definitions (a) to (d), respectively, with a median time to flare of 71.5 (10.7-235) days, similar to AIRDs. Patients with active IIMs pre-vaccination (OR 1.2; 95% CI 1.03, 1.6, P = 0.025) were prone to flares, while those receiving rituximab (OR 0.3; 95% CI 0.1, 0.7, P = 0.010) and AZA (OR 0.3, 95% CI 0.1, 0.8, P = 0.016) were at lower risk. Female gender and comorbidities predisposed to flares requiring changes in IS. Asthma (OR 1.62; 95% CI 1.05, 2.50, P = 0.028) and higher pain visual analogue score (OR 1.19; 95% CI 1.11, 1.27, P < 0.001) were associated with disparity between self-reported and IS-denoted flares. Conclusion A diagnosis of IIMs confers an equal risk of flares in the post-COVID-19 vaccination period to AIRDs, with active disease, female gender and comorbidities conferring a higher risk. Disparity between patient- and physician-reported outcomes represents a future avenue for exploration.

Background Dermatomyositis is an idiopathic inflammatory myopathy characterised by rashes and progressive muscle weakness. The recent ProDERM (Progress in DERMatomyositis) study is the first large randomised, placebo-controlled trial to establish the efficacy and safety of intravenous immunoglobulin (IVIg) in adult patients with dermatomyositis. Objectives of this analysis were to closely examine the safety and tolerability of IVIg in patients from the ProDERM study. Methods ProDERM was a double-blind, randomised, placebo-controlled, multicentre, phase 3 study. In the first period (weeks 0–16), adults with active dermatomyositis received 2.0 g/kg IVIg (Octagam 10%; Octapharma AG) or placebo every 4 weeks. In the open-label extension period (weeks 16–40), all patients received IVIg for 6 additional cycles; dose reduction (1.0 g/kg) was permitted if patients were stable. Treatment-emergent adverse events (TEAEs) were documented. Results The 95 patients enrolled were randomised to receive IVIg ( N = 47) or placebo ( N = 48) in the first period, with 5 switching from placebo to IVIg. Overall, 664 IVIg infusion cycles were administered. During the first period, 113 TEAEs were possibly/probably related to treatment in 30/52 patients (57.7%) receiving IVIg and 38 in 11 patients (22.9%) on placebo. Eight patients discontinued therapy due to IVIg-related TEAEs. Eight thromboembolic events (TEEs) occurred in six patients on IVIg; six in five patients were deemed possibly/probably related to IVIg. Patients with TEEs exhibited more baseline TEE risk factors than those without TEEs (2.4–15.2-fold higher). Lowering infusion rate reduced the rate of TEEs, and none occurred at the lower IVIg dose. No haemolytic transfusion reactions or deaths occurred. Conclusions Results from this study demonstrate that IVIg has a favourable safety profile for treatment of adult dermatomyositis patients and provides evidence that will help to inform treatment choice for these patients. Dermatomyositis patients receiving high-dose IVIg should be monitored for TEEs, and a low rate of infusion should be used to minimise TEE risk, particularly in those with pre-existing risk factors. Trial registration ProDERM study (NCT02728752).

Aim: To explore if patient global assessment (PGA) is associated with inflammation over time and if associations are explained by other measures of disease activity and function in patients with idiopathic inflammatory myopathies (IIM). Methods: PGA and systemic inflammatory markers prospectively collected over five years were retrieved from the International MyoNet registry for 1200 patients with IIM. Associations between PGA, erythrocyte sedimentation rate (ESR), C -reactive protein (CRP) and creatine kinase (CK) were analyzed using mixed models. Mediation analysis was used to test if the association between PGA and inflammatory markers during the first year of observation could be explained by measures of disease activity and function. Results: PGA improved, and inflammatory markers decreased during the first year of observation. In the mixed models, high levels of inflammatory markers were associated with worse PGA in both men and women across time points during five years of observation. In men, but not in women, the association between elevated ESR, CRP and poorer PGA was explained by measures of function and disease activity. With a few exceptions, the association between improved PGA and reduced inflammatory markers was partially mediated by improvements in all measures of function and disease activity. Conclusion: Increased levels of systemic inflammation are associated with poorer PGA in patients with IIM. In addition to known benefits of lowered inflammation, these findings emphasize the need to reduce systemic inflammation to improve subjective health in patients with IIM. Furthermore, the results demonstrate the importance of incorporating PGA as an outcome measure in clinical practice and clinical trials.

Vaccination against coronavirus disease 2019 (COVID‐19) is relatively safe in patients with idiopathic inflammatory myopathies (IIM); however, myositis flares following vaccination have been poorly studied. We aimed to evaluate the frequency, features, and outcomes of disease relapses in patients with IIM following COVID‐19 vaccination.

OBJECTIVE COVID-19 vaccines have a favorable safety profile in patients with autoimmune rheumatic diseases (AIRDs) such as idiopathic inflammatory myopathies (IIMs), however hesitancy continues to persist among these patients.Therefore, we studied the prevalence, predictors, and reasons for hesitancy in patients with IIMs, other AIRDs, non-rheumatic autoimmune diseases (nrAIDs) and healthy controls (HCs), using data from the two international COVID-19 Vaccination in Autoimmune Diseases (COVAD) e-surveys. METHODS The 1st and 2nd COVAD patient self-reported e-surveys were circulated from March to December 2021, and February to June 2022 (ongoing). We collected data on demographics, comorbidities, COVID-19 infection and vaccination history, reasons for hesitancy, and patient reported outcomes. Predictors of hesitancy were analyzed using regression models in different groups. RESULTS We analyzed data from 18,882 (COVAD-1) and 7666 (COVAD-2) respondents. Reassuringly, hesitancy decreased from 2021 (16.5%) to 2022 (5.1%) [OR 0.26; 95%CI: 0.24-0.30, p < 0.001]. However, concerns/fear over long-term safety had increased [OR 3.6;95% CI:2.9-4.6, p < 0.01].We noted with concern greater skepticism over vaccine science among patients with IIMs than AIRDs [OR:1.8; 95%CI: 1.08-3.2, p = 0.023] and HCs [OR: 4; 95%CI: 1.9-8.1, p < 0.001], as well as more long-term safety concerns/fear [IIMs vs AIRDs; OR: 1.9; 95%CI: 1.2-2.9, p = 0.001; IIMs vs HCs; OR: 5.4 95%CI: 3-9.6), p < 0.001].Caucasians [OR 4.2 (1.7-10.3)] were likely to be more hesitant, while those with better PROMIS physical health score were less hesitant [OR 0.9 (0.8-0.97)]. CONCLUSION Vaccine hesitancy has decreased from 2021 to 2022, long-term safety concerns remain among patients with IIMs, particularly in Caucasians and those with poor physical function.

BackgroundThe approved COVID-19 vaccines showed clear safety and efficacy in reduction of severe SARS-CoV-2 disease. Patients with idiopathic inflammatory myopathies (IIM) were not well represented in these vaccine trials and there are limited data in the literature about development of confirmed disease flare after COVID-19 vaccination.ObjectivesTo evaluate frequency, features and outcome of disease relapses in patients with IIM following SARS–CoV-2 vaccination.MethodsA cohort of 176 IIM patients (mean age:57.6 years, 117 females, 59 males, 106 PM, 70 DM) were interviewed after the 3rd wave of COVID-19 pandemic and prospectively followed. Relapses were determined using the IMACS disease state criteria, outcome of the flares with myositis response criteria, calculating the total improvement score (TIS).ResultsA total of 146 (82.9%) patients received vaccination and 17/146 (11.6%) patients had relapse within 3 months and 13/146 (8.9%) patients within one month. The relapse rate of unvaccinated patients (1/30; 3.3%) was not significantly different (p>0.1). No fatal flare has been observed. Three months after the post-vaccination relapses, 70.6% of the patients (12/17) achieved improvement of disease activity (average TIS score:30±15.81; 7 minor, 5 moderate and 0 major improvement). Six months after flares improvement was detected in 14/16 (87.5%) of relapsed patients (average TIS score: 43±20.17; 3 minimal, 7 moderate and 4 major). Forward stepwise logistic regression analysis revealed that the active state of myositis at time of injection (p<0.0001; OR: 31.2 CI: 9.0 – 108) and the application of BNT162b2 vaccination (p=0.026; OR: 4.06 CI: 1.1 – 14.7) were significantly associated with the occurrence of relapse.ConclusionMinority of the vaccinated IIM patients had confirmed disease flare after COVID-19 vaccination and majority of the relapses improved after individualized treatment. Active disease state at the time of vaccination probably contributes to the increased risk of post vaccination myositis flare.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Background: Dermatomyositis (DM) is a rare chronic systemic autoimmune disease with characteristic skin rash and progressive proximal muscle weakness. Current therapies encompass corticosteroids and other immunosuppressants and intravenous immunoglobulins (IVIg), however, none of these therapies are proven by randomized controlled phase 3 studies. There have been no large randomized clinical trials supporting the efficacy and safety of IVIg in DM. Objectives: The ProDERM study aimed to evaluate the efficacy and safety/tolerability of IVIg in DM patients in a double-blind, randomized, placebo-controlled, international multi-center, phase III clinical trial. Methods: The trial consisted of a double-blind, placebo-controlled First Period (16 weeks), in which adult patients with definite or probable DM (according to Bohan and Peter criteria) were randomized 1:1 to either high dose IVIg (2g/kg every 4 weeks) or placebo. Patients on placebo and patients without clinical worsening while on IVIg treatment entered the open label Extension Period (24 weeks) and received 2g/kg IVIg infusions every 4 weeks. To be included, subjects must have active disease with a manual muscle testing-8 (MMT-8) score < 142/150. Patients who showed clinical worsening (defined according to Oddis et al, 2013 - with slight adaptation) at 2 consecutive visits between week 8 and week 16 were switched to the alternate treatment arm. Primary endpoint was the proportion of responders in the IVIg vs. placebo arm at week 16, where response was defined per 2016 ACR/EULAR Myositis response criteria of at least minimal improvement [Total Improvement Score (TIS) ≥ 20 points)] and without clinical worsening at 2 consecutive visits up to week 16. Results: A total of 95 adult DM patients (mean age: 53 years; 75% females; 92% Caucasian) were enrolled, with 47 and 48 randomized to IVIg and placebo, respectively. Baseline clinical characteristics (including medical history and prior DM medication) were balanced between the 2 arms. The study met the primary endpoint at week 16, with the proportion of responders being significantly higher in the IVIg group (37/47; 78.7%) as compared to the placebo group (21/48; 43.8%; p-value 0.0008; Table 1). Table 1. Total Improvement Score – Analysis of Proportion of Responders at Week 16 (Full Analysis Set, N=95) TIS Response octagam 10% N=47 Placebo N=48 Difference octagam 10% – placebo Number (%) of responders 37 (78.72%) 21 (43.75%) Difference in response rates 34.97 [95% CI] p-value a [16.70, 53.24] 0.0008 a Cochran-Mantel-Haenszel TestCI=confidence interval; N=number of patients; TIS=total improvement score In the analysis of responders per improvement category at Week 16, a 45.2% higher response rate for at least moderate improvement (TIS ≥n40 points; p < 0.0001) and a 23.6% higher response rate for at least major improvement (TIS ≥060 points; p < 0.0062) was observed in the IVIG group as compared to the placebo group. The mean (SD) TIS was significantly higher in IVIg group [48.4 (24.4)] than in placebo arm [21.6 (20.2)] at week 16 (Fig 1). Figure 1. After switching to IVIG in the Extension Period the placebo group attained a similar response rate at Week 40 as did the IVIg treated patients at Week 16, i.e approx. 70% for minimal improvement. In line with the overall primary endpoint, secondary end points including all of the sub-components of TIS except muscle enzyme (MMT-8, MD global, Extramuscular global, patient global, HAQ,) as well as CDASI (Cutaneous Dermatomyositis Disease Area and Severity Index), also showed statistically significant improvement under IVIg treatment compared to placebo treatment. The safety and tolerability profile of IVIg was consistent with previously reported safety outcomes for IVIg administration. Conclusion: This is the first large international phase III randomized, placebo-controlled trial demonstrating the efficacy and safety of IVIg as a treatment for patients with DM. References: [1]Oddis, C. V. et al. Arthritis Rheum (2013), 65, 314–324 Acknowledgements: Acknowledgments to all participating investigators, centers and patients and their families Disclosure of Interests: Rohit Aggarwal Consultant of: Q32, Alexion, Argenx, AstraZeneca, BMS, Boehringer Ingelheim, Corbus, Csl Behring, EMD Serono, Janssen, Kezar, Mallinckrodt, Kyverna, Octapharma, Orphazyme, Pfizer., Grant/research support from: BMS, Mallinckrodt, Pfizer, EMD Serono, Christina Charles-Schoeman Consultant of: Pfizer, Abbvie, Octapharma, Gilead, Regeneron-Sanofi, Grant/research support from: Bristol Myers Squibb, Pfizer, Abbvie, Octapharma, Joachim Schessl Speakers bureau: Octapharma, Grifols, CSL Behring, Consultant of: Octapharma, Zsuzsanna Bata-Csorgo Speakers bureau: Novartis, Sanofi-Genzyme, Ewopharma, Consultant of: Sanofi-Genzyme, Novartis, Ewopharma, Mazen Dimachkie Consultant of: ArgenX, Catalyst, Cello, CSL-Behring, EcoR1, Kezar, Momenta, NuFactor, Octapharma, RaPharma/UCB, RMS Medical, Sanofi Genzyme, Shire Takeda, Spark Therapeutics and UCB Biopharma., Grant/research support from: Alexion, Alnylam Pharmaceuticals, Amicus, Biomarin, Bristol-Myers Squibb, Catalyst, Corbus, CSL-Behring, GlaxoSmithKline, Genentech, Grifols, Kezar, Mitsubishi Tanabe Pharma, Novartis, Octapharma, Orphazyme, Ra Pharma/UCB, Sanofi Genzyme, Sarepta Therapeutics, Shire Takeda, Spark Therapeutics, UCB Biopharma, Viromed/Healixmith., Zoltán Griger Speakers bureau: Abbvie, CSL-Behring, Eli-Lilly, Roche, Boehringer Ingelheim, Consultant of: Octapharma, Sergey Moiseev: None declared, Chester V Oddis Consultant of: EMD Serono; Alexion Pharmaceuticals, Inc, Grant/research support from: Genentech (Clinical trial support); Bristol Myers Squibb (Clinical trial support), Elena Schiopu Consultant of: Octapharma, Grant/research support from: Octapharma, Janssen (Johnson & Johnson), BMS, Pfizer, Abbvie, Jirˇí Vencovský Speakers bureau: Abbvie, Biogen, MSD, Pfizer, Roche, Sanofi, UCB, Consultant of: Abbvie, Boehringer, Eli Lilly, Octapharma, Gilead, Irene Beckmann Employee of: Octapharma, Todd Levine Shareholder of: Corinthian Reference Labs, CND Life Sciences, Consultant of: Grifols, Octapharma, Alexion, Elisabeth Clodi Employee of: Octapharma PPG, Vienna Austria, and the ProDERM Investigators: None declared

IntroductionPruritus is a common excruciating symptom in systemic autoimmune diseases such as dermatomyositis (DM) but the pathogenesis is not fully understood. We intended to investigate the targeted expression analysis of candidate molecules involved in the development of pruritus in lesional vs. non-lesional skin samples of patients affected with active DM. We looked for correlations between the investigated pruriceptive signaling molecules, disease activity, and itching sensation of DM patients.MethodsInterleukins (IL-33 and IL-6), tumor necrosis factor α (TNF-α), peroxisome proliferator-activated receptor γ (PPAR-γ), and ion channels belonging to the transient receptor potential (TRP) family were analyzed. The expression of TNF-α, PPAR-γ, IL-33, IL-6, and TRP channels in lesional DM skin was evaluated by RT-qPCR and immunohistochemistry and was compared with non-lesional DM skin samples. Pruritus, disease activity, and damage of DM were evaluated by the 5-D itch scale and Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), respectively. Statistical analysis was performed with IBM SPSS 28 software.ResultsA total of 17 active DM patients participated in the study. We could show that the itching score was positively correlated with the CDASI activity score (Kendall's tau-b = 0.571; p = 0.003). TNF-α gene expression was significantly higher in lesional DM skin than in non-lesional DM skin (p = 0.009) and differed in the subgroups of patients with different itch intensities (p = 0.038). The mRNA expression of lesional IL-6 correlated positively with 5-D itch and CDASI activity score (Kendall's tau-b = 0.585; p = 0.008 and 0.45; p = 0.013, respectively). TRPV4 expressions were positively correlated with CDASI damage score (Kendall's tau-b = 0.626; p < 0.001), but the mRNA expressions of the TRP family, PPAR-γ, IL-6, and IL-33 were not different in lesional and non-lesional samples. Immunohistochemistry analysis did not find significant alterations in the expressions of TNF-α, PPAR-γ, IL-6, and IL-33 in lesional and non-lesional regions.DiscussionOur results argue that cutaneous disease activity, TNF-α, and IL-6 might play a central role in DM-associated itch, while TRPV4 plays a central role in tissue regeneration.

Objectives: To compare clinical characteristics, including the frequency of cutaneous, extramuscular manifestations and malignancy, between adults with anti-synthetase syndrome (ASyS) and DM. Methods: Using data regarding adults from the MYONET registry, a cohort of DM patients with anti-Mi2/-TIF1 gamma/-NXP2/-SAE/-MDA5 autoantibodies, and a cohort of ASyS patients with anti-tRNA synthetase autoantibodies (anti-Jo1/-PL7/-PL12/-OJ/-EJ/-Zo/-KS) were identified. Patients with DM sine dermatitis or with discordant dual autoantibody specificities were excluded. Sub-cohorts of patients with ASyS with or without skin involvement were defined based on presence of DM-type rashes (heliotrope rash, Gottron's papules/sign, violaceous rash, shawl sign, V-sign, erythroderma, and/or periorbital rash). Results: In total 1054 patients were included (DM, n = 405; ASyS, n = 649). In the ASyS cohort, 31% (n = 203) had DM-type skin involvement (ASyS-DMskin). A higher frequency of extramuscular manifestations, including Mechanic's hands, Raynaud's phenomenon, arthritis, interstitial lung disease and cardiac involvement differentiated ASyS-DMskin from DM (all P < 0.001), whereas higher frequency of any of four DM-type rashes-heliotrope rash (n = 248, 61% vs n = 90, 44%), violaceous rash (n = 166, 41% vs n = 57, 9%), V-sign (n = 124, 31% vs n = 28, 4%), and shawl sign (n = 133, 33% vs n = 18, 3%)-differentiated DM from ASyS-DMskin (all P < 0.005). Cancer-associated myositis (CAM) was more frequent in DM (n = 67, 17%) compared with ASyS (n = 21, 3%) and ASyS-DMskin (n = 7, 3%) cohorts (both P < 0.001). Conclusion: DM-type rashes are frequent in patients with ASyS; however, distinct clinical manifestations differentiate these patients from classical DM. Skin involvement in ASyS does not necessitate increased malignancy surveillance. These findings will inform future ASyS classification criteria and patient management.