piperidines and Myositis

Recipients of allogeneic hematopoietic stem cell transplantation (HSCT) are at increased risk for inflammatory myositis; histological subsets reported include dermatomyositis, necrotising myopathy and chronic graft-versus-host disease (cGVHD)-related myositis. Though corticosteroids and various immunosuppressive therapies have been used, there is a lack of consensus guidelines dictating therapy.. Recent evidence suggests the fascia as a preferential target in cGVHD myositis, with conditioning regimens promoting fascial microtrauma. Positron emission tomography (PET) can be a useful diagnostic tool, and case reports suggest that the Bruton's tyrosine kinase inhibitor ibrutinib may have therapeutic potential. Emerging therapies include targeted B cell depletion with rituximab, and extracorporeal photophoresis. Clinicians need to be vigilant for the development of inflammatory myositis post-allogeneic HSCT as most patients respond to treatment. Advances in immunohistochemistry to determine the dominant cell type and cytokine profile may enable targeted and individualised therapies.

Topics: Adenine; Chronic Disease; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Myositis; Piperidines; Pyrimidines; Rituximab

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

Myositis is a known complication of chronic graft-vs-host disease (cGVHD) following allogeneic haematopoietic stem cell transplantation, but can be difficult to diagnose and manage. We present the case of a 57 year old man with cGVHD in whom the full manifestations of myositis were suppressed for some time, likely due to partial treatment of his condition with immunosuppression including ibrutinib. Though initial muscle biopsy showed necrotising myopathy without significant inflammation, on cessation of ibrutinib he developed increasing weakness and creatine kinase levels, with repeat muscle biopsy showing histological changes more in keeping with dermatomyositis. The close temporal correlation of his clinical course with commencement and cessation of ibrutinib suggests a potential role for ibrutinib in treating inflammatory myopathy in cGVHD.

Topics: Adenine; Biopsy; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Myositis; Piperidines; Treatment Outcome

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Carbazoles; Female; Humans; Lung Neoplasms; Middle Aged; Myositis; Piperidines; Protein Kinase Inhibitors

Topics: Disease Progression; Humans; Lung Diseases, Interstitial; Male; Middle Aged; Myositis; Piperidines; Pyrimidines; Time Factors

Muscle wound healing process is a typical inflammation-evoked event. The monoacylglycerol lipase (MAGL) inhibitor (4-nitrophenyl)4-[bis(1,3-benzodioxol -5-yl)-hydroxymethyl]piperidine-1-carboxylate (JZL184) has been previously reported to reduce inflammation in colitis and acute lung injury in mice, which provide a new strategy for primary care of skeletal muscle injury. We investigated the effect of JZL184 on inflammation in rat muscle contusion model, and found decreased neutrophil and macrophage infiltration and pro-inflammatory cytokine expression. With extension of post-traumatic interval, myofiber regeneration was significantly hindered with increased collagen types I and ІІІ mRNAfibroblast infiltration as well as promoted fibrosis. Furthermore, 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-morpholin-4-ylpyrazole-3-carboxamide (AM281, a selective cannabinoid CB1 receptor antagonist) and [6-iodo-2-methyl-1-(2-morpholin-4-ylethyl)indol-3-yl]-(4-methoxyphenyl)methanone (AM630, a selective cannabinoid CB2 receptor antagonist) treatment alleviated the anti-inflammatory effect of JZL184. Our findings demonstrate that JZL184 is able to inhibit the inflammatory response and interfere with contused muscle healing, in which the anti-inflammatory action may be mediated through cannabinoid CB1 and CB2 receptors.

Topics: Animals; Anti-Inflammatory Agents; Benzodioxoles; Cannabinoid Receptor Antagonists; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type III; Contusions; Cytokines; Disease Models, Animal; Enzyme Inhibitors; Fibroblasts; Fibrosis; Inflammation Mediators; Macrophages; Male; Monoacylglycerol Lipases; Muscle, Skeletal; Myositis; Neutrophil Infiltration; Neutrophils; Piperidines; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; RNA, Messenger; Signal Transduction; Time Factors; Wound Healing

Pain associated with cancer and chronic musculoskeletal disorders can be difficult to control. We used murine models of cancer and inflammatory muscle pain to examine whether the cannabinoid receptor agonist WIN55,212-2 reduces hyperalgesia originating in deep tissues. C3H/He mice were anesthetized and implanted with osteolytic NCTC clone 2472 cells into the humeri or injected with 4% carrageenan into the triceps muscles of both forelimbs. At the time of peak hyperalgesia, WIN55,212-2 (1-30mg/kg) or vehicle was administered intraperitoneally and forelimb grip force was measured 0.5-24h later. WIN55,212-2 produced time- and dose-related antihyperalgesia in both models. A 10mg/kg dose of WIN55,212-2 fully reversed carrageenan-evoked muscle hyperalgesia. However, 30mg/kg of WIN55,212-2 attenuated tumor-evoked hyperalgesia only approximately 50%. After controlling for the difference in magnitude of hyperalgesia between the two models, WIN55,212-2 was still more potent at reducing hyperalgesia in the inflammatory model. In the cancer pain model, the antihyperalgesic effect of WIN55,212-2 was partially blocked by pretreatment with the selective CB1 (SR141716A) but not the CB2 (SR144528) receptor antagonist. In contrast, both antagonists blocked antihyperalgesic effects of WIN55,212-2 on carrageenan-evoked muscle hyperalgesia. Catalepsy and loss of motor coordination, known side effects of cannabinoids, did not account for the antihyperalgesia produced by WIN55,212-2. These data show that cannabinoids attenuate deep tissue hyperalgesia produced by both cancer and inflammatory conditions. Interestingly, cannabinoids differentially modulated carrageenan- and tumor-evoked hyperalgesia in terms of potency and receptor subtypes involved suggesting that differences in underlying mechanisms may exist between these two models of deep tissue pain.

Topics: Animals; Benzoxazines; Calcium Channel Blockers; Camphanes; Cannabinoids; Carrageenan; Catalepsy; Disease Models, Animal; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Interactions; Fibrosarcoma; Haloperidol; Hand Strength; Humerus; Hyperalgesia; Male; Mice; Mice, Inbred C3H; Morpholines; Myositis; Naphthalenes; Neoplasm Transplantation; Neoplasms; Pain; Piperidines; Psychomotor Performance; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant

Topics: Animals; Body Weight; Dogs; Female; Hyperglycemia; Islets of Langerhans; Liver; Male; Maleates; Morphinans; Myositis; Organ Size; Pancreatic Diseases; Pancreatitis; Parasympatholytics; Piperidines; Rats