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
• cvičení fyziologie   MeSH
• dospělí MeSH
• kosterní svaly * metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metabolismus lipidů * fyziologie   MeSH
• myozitida * metabolismus   MeSH
• receptory kalcitriolu * metabolismus   genetika   MeSH
• senioři MeSH
• tělesná výkonnost * fyziologie   MeSH
• vitamin D * metabolismus   krev   analogy a deriváty   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
• CYP27B1 protein, human MeSH Prohlížeč
• receptory kalcitriolu * MeSH
• VDR protein, human MeSH Prohlížeč
• vitamin D * 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

BACKGROUND: In patients with idiopathic inflammatory myopathies (IIM), autoantibodies are associated with specific clinical phenotypes suggesting a pathogenic role of adaptive immunity. We explored if autoantibody profiles are associated with specific HLA genetic variants and clinical manifestations in IIM. METHODS: We included 1348 IIM patients and determined the occurrence of 14 myositis-specific or -associated autoantibodies. We used unsupervised cluster analysis to identify autoantibody-defined subgroups and logistic regression to estimate associations with clinical manifestations, HLA-DRB1, HLA-DQA1, HLA-DQB1 alleles, and amino acids imputed from genetic information of HLA class II and I molecules. FINDINGS: We identified eight subgroups with the following dominant autoantibodies: anti-Ro52, -U1RNP, -PM/Scl, -Mi2, -Jo1, -Jo1/Ro52, -TIF1γ or negative for all analysed autoantibodies. Associations with HLA-DRB1∗11, HLA-DRB1∗15, HLA-DQA1∗03, and HLA-DQB1∗03 were present in the anti-U1RNP-dominated subgroup. HLA-DRB1∗03, HLA-DQA1∗05, and HLA-DQB1∗02 alleles were overrepresented in the anti-PM/Scl and anti-Jo1/Ro52-dominated subgroups. HLA-DRB1∗16, HLA-DRB1∗07 alleles were most frequent in anti-Mi2 and HLA-DRB1∗01 and HLA-DRB1∗07 alleles in the anti-TIF1γ subgroup. The HLA-DRB1∗13, HLA-DQA1∗01 and HLA-DQB1∗06 alleles were overrepresented in the negative subgroup. Significant signals from variations in class I molecules were detected in the subgroups dominated by anti-Mi2, anti-Jo1/Ro52, anti-TIF1γ, and the negative subgroup. INTERPRETATION: Distinct HLA class II and I associations were observed for almost all autoantibody-defined subgroups. The associations support autoantibody profiles use for classifying IIM which would likely reflect underlying pathogenic mechanisms better than classifications based on clinical symptoms and/or histopathological features. FUNDING: See a detailed list of funding bodies in the Acknowledgements section at the end of the manuscript.

• Klíčová slova
• Autoantibody, HLA, Idiopathic inflammatory myopathy, Myositis,
• MeSH
• alely MeSH
• autoprotilátky * genetika   MeSH
• fenotyp MeSH
• genetická predispozice k nemoci MeSH
• haplotypy MeSH
• HLA-DRB1 řetězec genetika   MeSH
• lidé MeSH
• myozitida * genetika   imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• autoprotilátky * MeSH
• HLA-DRB1 řetězec MeSH

Idiopathic inflammatory myopathies (IIM), also known as myositis, are a heterogeneous group of autoimmune disorders with varying clinical manifestations, treatment responses and prognoses. Muscle weakness is usually the classical clinical manifestation but other organs can be affected, including the skin, joints, lungs, heart and gastrointestinal tract, and they can even result in the predominant manifestations, supporting that IIM are systemic inflammatory disorders. Different myositis-specific auto-antibodies have been identified and, on the basis of clinical, histopathological and serological features, IIM can be classified into several subgroups - dermatomyositis (including amyopathic dermatomyositis), antisynthetase syndrome, immune-mediated necrotizing myopathy, inclusion body myositis, polymyositis and overlap myositis. The prognoses, treatment responses and organ manifestations vary among these groups, implicating different pathophysiological mechanisms in each subtype. A deeper understanding of the molecular pathways underlying the pathogenesis and identifying the auto-antigens of the immune reactions in these subgroups is crucial to improving outcomes. New, more homogeneous subgroups defined by auto-antibodies may help define disease mechanisms and will also be important in future clinical trials for the development of targeted therapies and in identifying biomarkers to guide treatment decisions for the individual patient.

• MeSH
• autoimunitní nemoci * diagnóza   MeSH
• autoprotilátky MeSH
• dermatomyozitida * patologie   terapie   MeSH
• lidé MeSH
• myozitida s inkluzními tělísky * patologie   MeSH
• myozitida * diagnóza   patologie   MeSH
• svalová slabost MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Intramural MeSH
• Názvy látek
• autoprotilátky MeSH

Idiopathic inflammatory myopathies (IIM), also known as myositis, are a heterogeneous group of autoimmune disorders with varying clinical manifestations, treatment responses and prognoses. Muscle weakness is usually the classical clinical manifestation but other organs can be affected, including the skin, joints, lungs, heart and gastrointestinal tract, and they can even result in the predominant manifestations, supporting that these are systemic inflammatory disorders. Different myositis-specific autoantibodies have been identified and, on the basis of clinical, histopathological and serological features, IIMs can be classified into several subgroups — dermatomyositis (including amyopathic dermatomyositis), antisynthetase syndrome, immune-mediated necrotizing myopathy, inclusion body myositis, polymyositis and overlap myositis. The prognoses, treatment responses and organ manifestations vary among these groups, implicating different pathophysiological mechanisms in each subtype. A deeper understanding of the molecular pathways underlying the pathogenesis and identifying the autoantigens of the immune reactions in these subgroups is crucial to improve outcomes. New, more homogeneous subgroups defined by autoantibodies may help define disease mechanisms, and will also be important in future clinical trials to develop targeted therapies and in identifying biomarkers to guide treatment decisions for the individual patient.

• MeSH
• lidé MeSH
• myozitida * diagnóza   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

OBJECTIVES: To describe the prevalence and clinical associations of autoantibodies to a novel autoantigen, eukaryotic initiation factor 3 (eIF3), detected in idiopathic inflammatory myositis. METHODS: Sera or plasma from 678 PM patients were analysed for autoantigen specificity by radio-labelled protein immunoprecipitation (IPP). Samples immunoprecipitating the same novel autoantigens were further analysed by indirect immunofluorescence and IPP using pre-depleted cell extracts. The autoantigen was identified through a combination of IPP and MALDI-TOF mass spectrometry, and confirmed using commercial antibodies and IPP-western blots. Additional samples from patients with DM (668), DM-overlap (80), PM-overlap (191), systemic sclerosis (150), systemic lupus erythematosus (200), Sjogren's syndrome (40), rheumatoid arthritis (50) and healthy controls (150) were serotyped by IPP as disease or healthy controls. RESULTS: IPP revealed a novel pattern in three PM patients (0.44%) that was not found in disease-specific or healthy control sera. Indirect immunofluorescence demonstrated a fine cytoplasmic speckled pattern for all positive patients. Mass spectrometry analysis of the protein complex identified the target autoantigen as eIF3, a cytoplasmic complex with a role in the initiation of translation. Findings were confirmed by IPP-Western blotting. The three anti-eIF3-positive patients had no history of malignancy or interstitial lung disease, and had a favourable response to treatment. CONCLUSION: We report a novel autoantibody in 0.44% of PM patients directed against a cytoplasmic complex of proteins identified as eIF3. Although our findings need further confirmation, anti-eIF3 appears to correlate with a good prognosis and a favourable response to treatment.

• Klíčová slova
• autoantibodies, autoantigens, myositis,
• MeSH
• autoantigeny imunologie   MeSH
• autoprotilátky krev   MeSH
• biologické markery krev   MeSH
• dospělí MeSH
• eukaryotický iniciační faktor 3 krev   imunologie   MeSH
• hmotnostní spektrometrie metody   MeSH
• imunoprecipitace metody   MeSH
• imunosupresiva aplikace a dávkování   MeSH
• lidé středního věku MeSH
• lidé MeSH
• polymyozitida farmakoterapie   imunologie   patofyziologie   MeSH
• progrese nemoci * MeSH
• referenční hodnoty MeSH
• retrospektivní studie MeSH
• revmatická horečka imunologie   patofyziologie   MeSH
• senzitivita a specificita MeSH
• Sjögrenův syndrom imunologie   patofyziologie   MeSH
• studie případů a kontrol MeSH
• stupeň závažnosti nemoci MeSH
• systémový lupus erythematodes imunologie   patofyziologie   MeSH
• western blotting metody   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• autoantigeny MeSH
• autoprotilátky MeSH
• biologické markery MeSH
• eukaryotický iniciační faktor 3 MeSH
• imunosupresiva MeSH