BACKGROUND: Low levels of vitamin D have been associated with several autoimmune diseases. A growing body of evidence supports the association of vitamin D with skeletal muscle damage, regeneration, and energy and lipid metabolism. The aim was to analyse vitamin D and its receptor (VDR) in the muscle tissue of patients with idiopathic inflammatory myopathies (IIM) and to relate them to clinical parameters and muscle lipid and energy metabolism. METHODS: Forty-six patients with IIM and 67 healthy controls (HC) were included in the study. 27 IIM patients participated in a 24-week exercise intervention. Muscle biopsies were obtained from 7 IIM patients before/after training, 13 non-exercising IIM controls, and 21 HC. Circulating concentrations of 25(OH)D and 1,25(OH)D were measured. Gene expression of VDR and CYP27B1, the enzyme converting 25(OH)D to hormonally active 1,25(OH)D, was determined by qPCR in muscle tissue and primary muscle cells. Lipid oxidative metabolism was assessed in muscle tissue (mRNA, qPCR) and primary muscle cells (radioactive assays). RESULTS: Lower levels of active 1,25(OH)D were observed in IIM patients compared with HC (mean ± SD: 125.0 ± 45.4 vs. 164.7 ± 49.2 pmol/L; p < 0.0001). 25(OH)D was associated with CRP (r = -0.316, p = 0.037), MITAX (r = -0.311, p = 0.040) and HAQ (r = -0.390, p = 0.009) in IIM. After 24 weeks of training, active 1,25(OH)D was associated with MMT8 (r = 0.866, p < 0.0001), FI-2 (r = 0.608, p = 0.013) and HAQ (r = -0.537, p = 0.032). Gene expression of both VDR and CYP27B1 in primary muscle cells decreased after training (p = 0.031 and p = 0.078, respectively). Associations of VDR mRNA in muscle tissue with MMT-8 (IIM: r = -0.559, p = 0.013), serum CK (HC: r = 0.484, p = 0.031), myoglobin (IIM: r = 0.510, p = 0.026) and myostatin (IIM: r = -0.519, p = 0.023) were observed. The expression of VDR in differentiated muscle cells correlated negatively with the complete oxidation of palmitic acid (r = -0.532, p = 0.028). Muscle mRNA of carnitine palmitoyl transferase 1 (CPT1) (downregulated in IIM, p = 0.001) correlated positively with serum 1,25(OH) vitamin D (r = 0.410, p = 0.042). CONCLUSION: Reduced biologically active vitamin D in circulation suggests its impaired metabolism in IIM. Serum vitamin D levels and gene expression of its receptor and activating enzyme in muscle tissue were modified by regular exercise and associated with disease manifestations, physical fitness, and muscle lipid metabolism of IIM patients.

• Klíčová slova
• Lipid metabolism, Mitochondria, Muscle, Myositis, Physical activity, Vitamin D,
• MeSH
• 1-alfa-hydroxylasa 25-hydroxyvitaminu D3 metabolismus   MeSH
• dospělí MeSH
• kosterní svaly * metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metabolismus lipidů * fyziologie   MeSH
• myozitida * metabolismus   MeSH
• receptory kalcitriolu * metabolismus   MeSH
• senioři MeSH
• tělesná výkonnost * fyziologie   MeSH
• vitamin D * krev   metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 1-alfa-hydroxylasa 25-hydroxyvitaminu D3 MeSH
• receptory kalcitriolu * MeSH
• VDR protein, human MeSH Prohlížeč
• vitamin D * MeSH

Idiopathic inflammatory myopathies (IIM), or myositis, are a heterogeneous group of systemic autoimmune disorders that are associated with significant morbidity and mortality. Conducting high-quality clinical trials in IIM is challenging due to the rare and variable presentations of disease. To address this challenge, the Myositis Clinical Trials Consortium (MCTC) was formed. MCTC is a collaborative international alliance dedicated to facilitating, promoting, coordinating and conducting clinical trials and related research in IIM. This partnership works to advance the discovery of effective evidence-based treatments for IIM by integrating a diverse group of clinical investigators, research professionals, medical centres, patient groups, and industry partners. The Steering Committee, Core Group, and Paediatric Subcommittee of MCTC are comprised of myositis experts and junior investigators from around the world, representing a diversity of genders, geographies, and subspecialties. MCTC works alongside other current myositis organisations to complement existing work by concentrating on the operationalisation of clinical trials. Our pilot Myositis Investigators' Information Survey gathered responses from 173 myositis investigators globally and found considerable variability in proficiency with outcome measures, geographic disparities in patient recruitment, and a significant disconnect between investigators' routine myositis patient load and clinical trial enrolment. MCTC will meet the need to support and diversify myositis clinical trials by facilitating trial planning, feasibility assessments, site selection, and the training and mentoring of junior investigators/centres to establish their readiness for clinical trial participation. Through experienced leadership, strategic collaborations, and interdisciplinary discussions, MCTC will establish standards for IIM clinical trial design, protocols, and outcome measures in myositis.

• MeSH
• dítě MeSH
• dospělí MeSH
• klinické zkoušky jako téma * MeSH
• kooperační chování MeSH
• lidé MeSH
• mezinárodní spolupráce * MeSH
• mladiství MeSH
• myozitida * terapie   diagnóza   MeSH
• výzkumný projekt MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Dermatomyositis (DM) is a rare and debilitating, systemic, autoimmune disease. While heterogenous in presentation and severity, DM is primarily characterised by a spectrum of skin and muscle disease, which may include proximal muscle weakness and recalcitrant cutaneous eruptions. DM may also be associated with joint pain and stiffness, inflammatory arthritis, dysphagia, fatigue, and calcinosis. The current standard of care for DM includes glucocorticoids, immunosuppressants, and intravenous immunoglobulin (IVIg). Unfortunately, these medications are not uniformly effective and can lead to adverse events, particularly with chronic use, necessitating discontinuation of therapy. Therefore, a substantial unmet need exists for more tailored and efficacious therapies that target DM pathogenesis. Brepocitinib is an oral, once-daily, novel, and specific TYK2/JAK1 inhibitor. Brepocitinib's potent inhibition of TYK2 and JAK1 reduces the signalling of pro-inflammatory cytokines, including IFN-α/β, IL-12, IL-23, and IFNγ, that have been implicated in the pathogenesis of DM. Other JAK inhibitors have been used off-label in both case series and open-label clinical trials in patients with DM; and brepocitinib has demonstrated efficacy in phase 2 clinical trials of several other autoimmune diseases, including plaque psoriasis, psoriatic arthritis, Crohn's disease, hidradenitis suppurativa, and ulcerative colitis. Therefore, there is a strong scientific and clinical rationale for the utility and potential effectiveness of brepocitinib in the treatment of DM patients. Currently, the safety, tolerability, and efficacy of brepocitinib is being evaluated in the largest (n=225) double-blind placebo-controlled phase 3 trial in DM patients to date (VALOR - NCT0543726).

• MeSH
• dermatomyozitida * farmakoterapie   enzymologie   imunologie   diagnóza   MeSH
• heterocyklické sloučeniny tricyklické * terapeutické užití   škodlivé účinky   farmakologie   MeSH
• inhibitory Janus kinas * terapeutické užití   škodlivé účinky   MeSH
• inhibitory proteinkinas * terapeutické užití   škodlivé účinky   MeSH
• Janus kinasa 1 * antagonisté a inhibitory   metabolismus   MeSH
• kinasa TYK2 * antagonisté a inhibitory   metabolismus   MeSH
• lidé MeSH
• přemostěné cyklické sloučeniny MeSH
• pyrimidiny MeSH
• pyrroly * terapeutické užití   škodlivé účinky   MeSH
• signální transdukce účinky léků   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• 11-(2-pyrrolidin-1-ylethoxy)-14,19-dioxa-5,7,26-triazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene MeSH Prohlížeč
• heterocyklické sloučeniny tricyklické * MeSH
• inhibitory Janus kinas * MeSH
• inhibitory proteinkinas * MeSH
• JAK1 protein, human MeSH Prohlížeč
• Janus kinasa 1 * MeSH
• kinasa TYK2 * MeSH
• přemostěné cyklické sloučeniny MeSH
• pyrimidiny MeSH
• pyrroly * MeSH
• TYK2 protein, human MeSH Prohlížeč

Genome-wide association studies (GWASs) have been successful at finding associations between genetic variants and human traits, including the immune-mediated diseases (IMDs). However, the requirement of large sample sizes for discovery poses a challenge for learning about less common diseases, where increasing volunteer numbers might not be feasible. An example of this is myositis (or idiopathic inflammatory myopathies [IIM]s), a group of rare, heterogeneous autoimmune diseases affecting skeletal muscle and other organs, severely impairing life quality. Here, we applied a feature engineering method to borrow information from larger IMD GWASs to find new genetic associations with IIM and its subgroups. Combining this approach with two clustering methods, we found 17 IMDs genetically close to IIM, including some common comorbid conditions, such as systemic sclerosis and Sjögren's syndrome, as well as hypo- and hyperthyroidism. All IIM subtypes were genetically similar within this framework. Next, we colocalized IIM signals that overlapped IMD signals, and found seven potentially novel myositis associations mapped to immune-related genes, including BLK, IRF5/TNPO3, and ITK/HAVCR2, implicating a role for both B and T cells in IIM. This work proposes a new paradigm of genetic discovery in rarer diseases by leveraging information from more common IMD, and can be expanded to other conditions and traits beyond IMD.

• MeSH
• autoimunitní nemoci genetika   imunologie   MeSH
• celogenomová asociační studie * MeSH
• genetická predispozice k nemoci * MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• myozitida * genetika   imunologie   MeSH
• nemoci imunitního systému genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

OBJECTIVE: To study the trajectories of changes in damage over time and explore associations with autoantibody defined subgroups using a large international cohort of patients with idiopathic inflammatory myopathies (IIM). METHODS: Data from the MYONET registry, including patients who were tested for autoantibodies and had at least one assessment of damage using the Myositis Damage Index (MDI), were analyzed. Patients were sub-grouped according to their autoantibody profiles (myositis-specific, myositis-associated, or seronegative). The index date was defined as the time point for the first registered MDI assessment. The longitudinal trajectories of damage with autoantibody status as the main predictor were analyzed using linear mixed models. RESULTS: A total of 757 adult patients were included in this study. Each year of disease duration since diagnosis had an estimated MDI score increase of 0.16 units for the seronegative group (reference). Compared with the seronegative group as reference, patients with dermatomyositis-specific autoantibodies developed less damage per year of follow-up since diagnosis (average 0.08 less score, P = 0.04), whereas patients with anti-PM/Scl autoantibodies developed more damage per year of follow-up since diagnosis (average 0.28 higher score, P = 0.03) independent of sex and age at diagnosis. The seronegative subgroup and the immune-mediated necrotizing myopathy autoantibody subgroup had the strongest correlation between severity of muscle damage and HAQ-DI scores at five years of follow-up, rho=0.84, P < 0.001 and rho=0.72, P < 0.001, respectively. CONCLUSION: Our study is the first to describe patterns and trajectories of change in damage over time in relation to autoantibody defined subgroups in a large international multicenter cohort of patients with IIM. Patients with anti-PM/Scl scored a greater extent of damage, whereas patients with dermatomyositis-specific antibodies had less damage than seronegative patients. Severity in muscle damage had moderate to strong correlation with functional disability among the IMNM and seronegative subgroups with lower correlations for the other subgroups. These findings suggest that autoantibodies may be useful predictors of long-term damage.

• Klíčová slova
• Autoantibodies, Dermatomyositis, Inflammatory myopathies, Myositis, Organ damage,
• MeSH
• autoprotilátky * krev   imunologie   MeSH
• dermatomyozitida imunologie   krev   MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• longitudinální studie MeSH
• myozitida * imunologie   krev   MeSH
• progrese nemoci MeSH
• registrace * MeSH
• senioři MeSH
• stupeň závažnosti nemoci MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• Názvy látek
• autoprotilátky * MeSH

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/-TIF1γ/-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.

• Klíčová slova
• Anti-synthetase syndrome, Cutaneous, Dermatomyositis, Epidemiology, Extramuscular, MYONET, Malignancy, Rashes, Skin,
• MeSH
• aminoacyl-tRNA-synthetasy imunologie   MeSH
• autoprotilátky * krev   imunologie   MeSH
• dermatomyozitida * imunologie   komplikace   MeSH
• dospělí MeSH
• exantém etiologie   MeSH
• intersticiální plicní nemoci imunologie   etiologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• myozitida * imunologie   komplikace   MeSH
• nádory komplikace   MeSH
• registrace * MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• aminoacyl-tRNA-synthetasy MeSH
• autoprotilátky * MeSH

OBJECTIVE: The interplay between dysphagia, cancer, and mortality in idiopathic inflammatory myopathies (IIM) has not been carefully studied. The aim of this study was to investigate possible effect modification of cancer on the association between dysphagia and mortality in early IIM. METHODS: A multi-center cohort of 230 adult IIM patients with dysphagia assessment within 6 months of disease onset was assembled. Crude mortality rates in IIM patients exposed or not to dysphagia were estimated for the 5-year period following cohort entry. To explore possible effect modification of cancer on the association between dysphagia and mortality, adjusted Cox models stratified on cancer status were performed as well as an interaction model. RESULTS: Mortality rates per 100 person-years for IIM patients exposed to dysphagia were 2.3 (95 %CI 1.0 to 4.5) in those without cancer compared to 33.3 (95 %CI 16.6 to 59.5) in those with cancer. In stratified Cox models, the main effect of dysphagia was HR 0.5 (95 %CI 0.2 to 1.5) in non-cancer and 3.1 (95 %CI 1.0 to 10.2) in cancer patients. In the interaction model, the combination of dysphagia and cancer yielded a HR of 6.4 (1.2 to 35.1). CONCLUSION: In this IIM cohort, dysphagia in non-cancer patients was not associated with increased mortality, while it was in presence of cancer, supporting effect modification of cancer on the association between dysphagia and mortality. This suggests that IIM patients with and without cancer differ and separate analyses for the two groups should be conducted when the outcome of interest is mortality.

• Klíčová slova
• Cancer, Dysphagia, Idiopathic inflammatory myopathy, Mortality,
• MeSH
• dospělí MeSH
• lidé MeSH
• myozitida * komplikace   MeSH
• nádory * komplikace   MeSH
• poruchy polykání * komplikace   MeSH
• retrospektivní studie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

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.

• Klíčová slova
• Idiopathic inflammatory myopathies, Inflammation, Myositis, Patient reported outcome measures,
• MeSH
• hodnocení výsledků zdravotní péče MeSH
• krevní sedimentace MeSH
• lidé MeSH
• longitudinální studie MeSH
• myozitida * komplikace   MeSH
• zánět MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

OBJECTIVES: We aimed to evaluate cardiovascular (CV) risk in patients with idiopathic inflammatory myopathies (IIM) compared with healthy controls (HC) and to assess its association with disease-specific features. METHODS: Ninety IIM patients and 180 age-/sex-matched HC were included. Subjects with a history of CV disease (angina pectoris, myocardial infarction and cerebrovascular/peripheral arterial vascular events) were excluded. All participants were prospectively recruited and underwent examinations of carotid intima-media thickness (CIMT), pulse wave velocity (PWV), ankle-brachial index (ABI), and body composition. The risk of fatal CV events was evaluated by the Systematic COronary Risk Evaluation (SCORE) and its modifications. RESULTS: Compared with HC, IIM patients had a significantly higher prevalence of traditional CV risk factors, carotid artery disease (CARD), abnormal ABI and PWV. After propensity score matching (using traditional CV risk factors), the prevalence of CARD and pathological PWV remained significantly higher in IIM than HC. No significant difference in SCORE was observed. The most unfavourable CV risk profile was observed in patients with necrotizing myopathy, especially in statin-induced anti-HMGCR+ patients. The calculated CV risk scores by SCORE, SCORE2 and SCORE multiplied by the coefficient 1.5 (mSCORE) were reclassified according to CIMT and the presence of carotid plaques. SCORE was demonstrated to be most inaccurate in predicting CV risk in IIM. Age, disease activity, lipid profile, body composition parameters and blood pressure were the most significant predictors of CV risk in IIM patients. CONCLUSION: Significantly higher prevalence of traditional risk factors and subclinical atherosclerosis was observed in IIM patients compared with HC.

• Klíčová slova
• atherosclerosis, cardiovascular risk, inflammation, myositis,
• MeSH
• analýza pulzové vlny MeSH
• intimomediální šíře tepenné stěny MeSH
• kardiovaskulární nemoci * epidemiologie   etiologie   MeSH
• lidé MeSH
• myozitida * epidemiologie   MeSH
• nemoci arterie carotis * MeSH
• rizikové faktory kardiovaskulárních chorob MeSH
• rizikové faktory MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

OBJECTIVES: To develop and validate the cut-offs in the Juvenile DermatoMyositis Activity Index (JDMAI) to distinguish the states of inactive disease (ID), low disease activity (LDA), moderate disease activity (MDA) and high disease activity (HDA) in children with juvenile dermatomyositis (JDM). METHODS: For cut-off definition, data from 139 patients included in a randomised clinical trial were used. Among the six versions of the JDMAI, JDMA1 (score range 0-40) and JDMAI2 (score range 0-39) were selected. Optimal cut-offs were determined against external criteria by calculating different percentiles of score distribution and through receiver operating characteristic curve analysis. External criteria included the modified Pediatric Rheumatology International Trials Organization (PRINTO) criteria for clinically ID in JDM (for ID) and PRINTO levels of improvement in the clinical trial (for LDA and HDA). MDA cut-offs were set at the score interval between LDA and HDA cut-offs. Cut-off validation was conducted by assessing construct and discriminative ability in two cohorts including a total of 488 JDM patients. RESULTS: The calculated JDMAI1 cut-offs were ≤2.4 for ID, ≤6.6 for LDA, 6.7-11 for MDA and >11 for HDA. The calculated JDMAI2 cut-offs were ≤5.2 for ID, ≤8.5 for LDA, 8.6-11.3 for MDA and >11.3 for HDA. The cut-offs discriminated strongly among disease activity states defined subjectively by caring physicians and parents, parents' satisfaction or non-satisfaction with illness outcome, levels of pain, fatigue, physical functional impairment and physical well-being. CONCLUSIONS: Both JDMAI1 and JDMAI2 cut-offs revealed good metrologic properties in validation analyses and are, therefore, suited for application in clinical practice and research.

• Klíčová slova
• Autoimmune Diseases, Dermatomyositis, Outcome Assessment, Health Care,
• MeSH
• dermatomyozitida * diagnóza   MeSH
• dítě MeSH
• lékaři * MeSH
• lidé MeSH
• randomizované kontrolované studie jako téma MeSH
• revmatologie * MeSH
• ROC křivka MeSH
• stupeň závažnosti nemoci MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH