Search

Objective: Targeting synovial fibroblasts (SF) using a cyclin-dependent kinase (CDK) 4/6 inhibitor (CDKI) could be a potent therapy for RA via inhibition of proliferation and MMP-3 production. This study was designed to elucidate the mechanism of chondroprotective effects on SFs by CDK 4/6 inhibition., Methods: CDK4/6 activity was inhibited using CDKI treatment or enhanced by adenoviral gene transduction. Chondroprotective effects were evaluated using a collagen-induced arthritis model (CIA). Gene and protein expression were evaluated with quantitative PCR, ELISA and Western blotting. The binding of nuclear extracts to DNA was assessed with an electrophoresis mobility shift assay. RNA-Seq was performed to identify gene sets affected by CDKI treatment., Results: CDKI attenuated cartilage destruction and MMP-3 production in CIA. In RASFs, CDKI impaired the binding of AP-1 components to DNA and inhibited the production of MMP-1 and MMP-3, which contain the AP-1 binding sequence in their promoter. CDK4/6 protected JUN from proteasome-dependent degradation by inhibiting ubiquitination. The RNA-Seq analysis identified CDKI-sensitive inflammatory genes, which were associated with the pathway of RA-associated genes, cytokine-cytokine receptor interaction and IL-17 signalling. Notably, the AP-1 motif was enriched in these genes., Conclusion: The mechanism of chondroprotective effects by CDK4/6 inhibition was achieved by the attenuation of AP-1 transcriptional activity via the impaired stability of JUN. Because the pharmacologic inhibition of CDK4/6 has been established as tolerable in cancer treatment, it could also be beneficial in patients with RA due to its chondroprotective and anti-inflammatory effects., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: The hallmark histopathology of PM is the presence of CD8+ T cells in the non-necrotic muscle cells. The aim of this study was to clarify the pathological significance of CD8+ T cells in muscle cells., Methods: C2C12 cells were transduced retrovirally with the genes encoding MHC class I (H2Kb) and SIINFEKL peptide derived from ovalbumin (OVA), and then differentiated to myotubes (H2KbOVA-myotubes). H2KbOVA-myotubes were co-cultured with OT-I CD8+ T cells derived from OVA-specific class I restricted T cell receptor transgenic mice as an in vitro model of PM to examine whether the CD8+ T cells invade into the myotubes and if the myotubes with the invasion are more prone to die than those without. Muscle biopsy samples from patients with PM were examined for the presence of CD8+ T cells in muscle cells. The clinical profiles were compared between the patients with and without CD8+ T cells in muscle cells., Results: Analysis of the in vitro model of PM with confocal microscopy demonstrated the invasion of OT-I CD8+ T cells into H2KbOVA-myotubes. Transmission electron microscopic analysis revealed an electron-lucent area between the invaded CD8+ T cell and the cytoplasm of H2KbOVA-myotubes. The myotubes invaded with OT-I CD8+ T cells died earlier than the uninvaded myotubes. The level of serum creatinine kinase was higher in patients with CD8+ T cells in muscle cells than those without these cells., Conclusion: CD8+ T cells invade into muscle cells and contribute to muscle injury in PM. Our in vitro model of PM is useful to examine the mechanisms underlying muscle injury induced by CD8+ T cells., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

We describe a case of severe dermatomyositis (DM) complicated by rhabdomyolysis, acute tubular necrosis, and hemophagocytosis. The case failed to respond to corticosteroids, but showed rapid and significant improvement after the addition of intravenous immunoglobulin (IVIG). While the prognosis of DM is poor when it is complicated by rhabdomyolysis, the early administration of IVIG has the potential to be the cornerstone of its management.

A 51-year-old woman presented with one-month history of fever, productive cough, dyspnea, hoarseness and polyarthritis. Computed tomography (CT) depicted diffuse bronchotracheal stenosis, which deteriorated in exhalation. Three-dimensional CT revealed airway stenosis from the trachea to the lobar bronchi. We made a diagnosis of relapsing polychondritis (RP). Administration of high-dose glucocorticoid and oral cyclophosphamide resolved the symptoms and the bronchial stenosis. It was noteworthy that all features presented were bronchial chondritis and polyarthritis. RP should be considered when patients have polyarthritis with respiratory symptoms. The dynamic expiratory CT and three-dimensional image reconstructions are useful for detecting and following up bronchotracheal involvement.

We present two patients with rheumatoid arthritis (RA) who developed necrotizing crescentic glomerulonephritis (NCGN) during etanercept therapy. Both patients developed proteinuria and hematuria, and one progressed to renal failure. Renal biopsy revealed NCGN. In both patients, nephritis improved following discontinuation of etanercept and administration of prednisolone. Physicians should be aware of etanercept-induced GN in patients with RA on anti-tumor necrosis factor therapy.

A 31-year-old woman had recurrent mild flare-ups of polymyositis for years. Fourteen days after low-dose methotrexate was added in an attempt to taper the corticosteroid, she began to feel abdominal and lower back pain, followed by generalized pustulosis, severe liver dysfunction, and disseminated intravascular coagulation. On the diagnosis of varicella-zoster virus (VZV) hepatitis, acyclovir, immune globulin and plasmapheresis were given with a favorable outcome. Physicians should be aware that VZV infection could complicate severe hepatitis in immuno-suppressed patients.

We describe two cases of leflunomide-related interstitial pneumonia (IP). A 75-year-old woman with rheumatoid arthritis (RA) developed rapidly progressing IP 45 days after institution of leflunomide. She died of respiratory failure, and an autopsy revealed a mixed pattern of acute and organizing diffuse alveolar damage. A 69-year-old woman with RA also developed acute IP 3 months after institution of leflunomide. Methylprednisolone pulse therapy and cholestyramine ameliorated her IP. The implication of leflunomide in the pathogenesis of IP was suggested.