piperidines and Polymyositis

Interstitial lung diseases (ILDs) have been reported to be associated with myositis (including polymyositis and dermatomyositis). These myositis-associated ILDs carry significant morbidity and mortality. This review summarizes recent findings on myositis-associated ILD with a focus on pathogenesis and emerging treatment.. Recent advances in genetics have revealed 22 myositis-associated genome-wide loci, which were significantly enriched in regulatory regions in immune cells. An analysis of such disease-associated loci elucidated potential drug targets (e.g., TYK2 targeted by tofacitinib). In another study, an intronic variant in WDFY4 in association with clinically amyopathic dermatomyositis (CADM) had an effect for higher expression of a truncated WDFY4 isoform. Truncated WDFY4 markedly enhanced the MDA5-mediated NF-κB activation and cell apoptosis, indicating the dysregulated WDFY4-MDA5 pathway as a novel pathogenesis of CADM. As a novel strategy, tofacitinib treatment showed a promising improvement in survival and clinical features of CADM-associated ILD.. The genetic differences in the myositis-susceptible loci may explain the heterogeneous phenotypes and treatment responses in myositis-associated ILD. The understanding of pathogenesis with the genetic background as well as autoantibodies will enable the practice of personalized treatment in the management of the disease.

Topics: Apoptosis; Autoantibodies; Dermatomyositis; Humans; Interferon-Induced Helicase, IFIH1; Intracellular Signaling Peptides and Proteins; Lung Diseases, Interstitial; Molecular Targeted Therapy; Myositis; NF-kappa B; Phenotype; Piperidines; Polymyositis; Pyrimidines; Signal Transduction; TYK2 Kinase

B-cell secretion of autoantibodies drives autoimmune diseases, including systemic lupus erythematosus and idiopathic inflammatory myositis. Few therapies are presently available for treatment of these patients, often resulting in unsatisfactory effects and helping only some of the patients. We developed a screening assay for evaluation of novel targets suspending B-cell maturation into antibody secreting cells, which could contribute to future drug development. The assay was employed for testing 43 high quality chemical probes and compounds inhibiting under-explored protein targets, using primary cells from patients with autoimmune disease. Probes inhibiting bromodomain family proteins and histone methyl transferases demonstrated abrogation of B-cell functions to a degree comparable to a positive control, the JAK inhibitor tofacitinib. Inhibition of each target rendered a specific functional cell and potential disease modifying effect, indicating specific epigenetic protein targets as potential new intervention points for future drug discovery and development efforts.

Topics: Adult; Aged; Autoimmune Diseases; B-Lymphocytes; Case-Control Studies; Cells, Cultured; Cytokines; Epigenesis, Genetic; Female; Humans; Immunoglobulin Isotypes; Leukocytes, Mononuclear; Lupus Erythematosus, Systemic; Male; Middle Aged; Molecular Probes; Myositis, Inclusion Body; Piperidines; Polymyositis; Pyrimidines

Topics: Antirheumatic Agents; Biopsy; Disease Progression; Drug Resistance, Multiple; Electromyography; Female; Humans; Janus Kinase Inhibitors; Medication Therapy Management; Middle Aged; Monitoring, Immunologic; Muscle Strength; Muscle Weakness; Piperidines; Polymyositis; Pyrimidines; Pyrroles; Treatment Outcome