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 diagnóza imunologie MeSH
- inhibitory proteinkinas * terapeutické užití škodlivé účinky MeSH
- Janus kinasa 1 * antagonisté a inhibitory MeSH
- kinasa TYK2 * antagonisté a inhibitory MeSH
- lidé MeSH
- signální transdukce účinky léků MeSH
- výsledek terapie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
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.
- MeSH
- autoprotilátky krev imunologie MeSH
- dermatomyozitida * farmakoterapie imunologie MeSH
- dospělí MeSH
- dvojitá slepá metoda MeSH
- imunologické faktory * terapeutické užití MeSH
- intravenózní imunoglobuliny * terapeutické užití MeSH
- lidé středního věku MeSH
- lidé MeSH
- prospektivní studie MeSH
- senioři MeSH
- stupeň závažnosti nemoci MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
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.
- 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
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
OBJECTIVE: Idiopathic inflammatory myopathies (IIMs, myositis) are rare systemic autoimmune disorders that lead to muscle inflammation, weakness, and extramuscular manifestations, with a strong genetic component influencing disease development and progression. Previous genome-wide association studies identified loci associated with IIMs. In this study, we imputed data from two prior genome-wide myositis studies and analyzed the largest myositis data set to date to identify novel risk loci and susceptibility genes associated with IIMs and its clinical subtypes. METHODS: We performed association analyses on 14,903 individuals (3,206 patients and 11,697 controls) with genotypes and imputed data from the Trans-Omics for Precision Medicine reference panel. Fine-mapping and expression quantitative trait locus colocalization analyses in myositis-relevant tissues indicated potential causal variants. Functional annotation and network analyses using the random walk with restart (RWR) algorithm explored underlying genetic networks and drug repurposing opportunities. RESULTS: Our analyses identified novel risk loci and susceptibility genes, such as FCRLA, NFKB1, IRF4, DCAKD, and ATXN2 in overall IIMs; NEMP2 in polymyositis; ACBC11 in dermatomyositis; and PSD3 in myositis with anti-histidyl-transfer RNA synthetase autoantibodies (anti-Jo-1). We also characterized effects of HLA region variants and the role of C4. Colocalization analyses suggested putative causal variants in DCAKD in skin and muscle, HCP5 in lung, and IRF4 in Epstein-Barr virus (EBV)-transformed lymphocytes, lung, and whole blood. RWR further prioritized additional candidate genes, including APP, CD74, CIITA, NR1H4, and TXNIP, for future investigation. CONCLUSION: Our study uncovers novel genetic regions contributing to IIMs, advancing our understanding of myositis pathogenesis and offering new insights for future research.
Kreatínkináza (CK) predstavuje intracelulárny enzým zapojený do energetického metabolizmu buniek, ktorý je lokalizovaný v tkanivách s vysokými energetickými nárokmi ako sú kostrové svaly alebo myokard. Sérová hladina CK odráža integritu svalovej membrány, v dôsledku čoho možno hyperCKémiu označiť ako nešpecifický marker svalového poškodenia. Diferenciálna diagnostika hyperCKémie v detskom veku zahŕňa nielen neuromuskulárne ochorenia, ale tiež spektrum ochorení, ktorých iniciálna diagnostika patrí aj do rúk skúseného pediatra. Korešpondujúci autorka: MUDr. Patrícia Balážová Klinika detskej neurológie LF UK a NÚDCH v Bratislave patricia.balazova@nudch.eu
Creatine kinase (CK) is an enzyme located in tissues with high energy demands, such as skeletal muscles or myocardium. It plays an essential role in cells’ energy metabolism. The level of CK in the blood reflects the muscle membrane’s integrity, and elevated CK levels can indicate muscle damage. However, diagnosing the cause of elevated CK levels in children requires the expertise of an experienced pediatrician. This may be due to not only neuromuscular diseases but also a range of other diseases.
- Klíčová slova
- hyperCKemie,
- MeSH
- dítě MeSH
- hypotyreóza diagnóza klasifikace metabolismus MeSH
- kreatinkinasa * analýza klasifikace krev MeSH
- lidé MeSH
- myozitida diagnóza klasifikace metabolismus MeSH
- neuromuskulární nemoci * diagnóza klasifikace metabolismus MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- přehledy MeSH
- MeSH
- artritida diagnóza etiologie imunologie klasifikace mikrobiologie MeSH
- myozitida diagnóza etiologie klasifikace MeSH
- osteoartróza diagnóza farmakoterapie klasifikace MeSH
- revmatoidní artritida diagnostické zobrazování diagnóza farmakoterapie MeSH
- revmatologie * klasifikace MeSH
- spondylartritida diagnóza etiologie klasifikace MeSH
- systémový lupus erythematodes diagnóza klasifikace komplikace MeSH
- vaskulitida diagnóza etiologie klasifikace MeSH
- Publikační typ
- přehledy MeSH
Autoimunní revmatická onemocnění jsou rozmanitou skupinou stavů, které se mohou projevovat tvorbou autoprotilátek, funkčními poruchami imunity a systémovými projevy. Diagnostika může být obtížná kvůli mnoha nespecifickým projevům. Klíčovým testem, který v praxi využíváme, je stanovení orgánově nespecifických autoprotilátek. Autoprotilátky vyskytující se u osob se systémovými revmatickými chorobami mohou sloužit nejen jako markery pro klasifikaci, diagnózu a prognózu onemocnění, ale také při hodnocení aktivity onemocnění a při rozhodování o léčebném postupu. Autoprotilátky také často hrají přímou úlohu v patogenezi jednotlivých onemocnění.
Autoimmune rheumatic diseases represent a diverse group of conditions that may manifest with the production of autoantibodies, immune dysfunction, and systemic symptoms. Diagnosis can be challenging due to many nonspecific manifestations. A key test used in practice is the detection of organ-nonspecific autoantibodies. Autoantibodies present in individuals with systemic rheumatic diseases can serve not only as markers for classification, diagnosis, and prognosis but also in assessing disease activity and guiding treatment decisions. Autoantibodies often also play a direct role in the pathogenesis of individual diseases.
- MeSH
- antigeny jaderné imunologie MeSH
- antinukleární protilátky imunologie MeSH
- autoimunitní nemoci diagnóza imunologie MeSH
- autoprotilátky * imunologie klasifikace MeSH
- imunologické techniky metody MeSH
- lidé MeSH
- myozitida imunologie MeSH
- protilátky proti cytoplazmě neutrofilů imunologie MeSH
- protilátky imunologie klasifikace MeSH
- revmatické nemoci * diagnóza imunologie MeSH
- revmatoidní faktor imunologie MeSH
- systémová sklerodermie imunologie MeSH
- systémový lupus erythematodes diagnóza imunologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
- MeSH
- chronická kritická ischemie končetin diagnóza farmakoterapie MeSH
- hydroxymethylglutaryl-CoA-reduktasy imunologie škodlivé účinky MeSH
- imunosupresiva aplikace a dávkování terapeutické užití MeSH
- inhibitory agregace trombocytů aplikace a dávkování terapeutické užití MeSH
- komorbidita MeSH
- lidé MeSH
- myozitida chemicky indukované terapie MeSH
- nemoci svalů * chemicky indukované terapie MeSH
- senioři MeSH
- statiny * škodlivé účinky terapeutické užití MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- kazuistiky MeSH
- MeSH
- dyslipidemie farmakoterapie MeSH
- glukokortikoidy aplikace a dávkování terapeutické užití MeSH
- imunosupresiva terapeutické užití MeSH
- infarkt myokardu bez ST elevací terapie MeSH
- lidé MeSH
- myozitida chemicky indukované diagnóza farmakoterapie MeSH
- nemoci svalů * chemicky indukované diagnóza farmakoterapie MeSH
- senioři MeSH
- statiny * aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- Check Tag
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
