Solo Addition of Mepolizumab Turned Antineutrophil Cytoplasmic Antibody Negative and Achieved Glucocorticoid Discontinuation in a Patient with Eosinophilic Granulomatosis with Polyangiitis: A Case Report.

The IL-5 inhibitor mepolizumab is beneficial in eosinophilic granulomatosis with polyangiitis (EGPA), and the inhibition of antineutrophil cytoplasmic antibody (ANCA) production has been suggested as a possible mechanism. We herein report a 78-year-old Japanese man with EGPA who received solo mepolizumab 300 mg twice for elevated ANCA levels, which led to subsequent GC discontinuation after achieving remission. The patient was able to be freed from the adverse events associated with long-term GC treatment, and the sole addition of mepolizumab also proved that mildly elevated ANCA could be converted to a negative result, thus leading to GC discontinuation.

Initiation of belimumab with higher daily prednisolone is effective for rapid glucocorticoid reduction: A 96-week retrospective study.

Objectives: For appropriate glucocorticoid (GC) reduction, we investigated the optimal strategy including baseline factors that could reduce GC more than 50% with 96 weeks of belimumab.

Methods: This is a retrospective cohort study of Kakogawa Central City hospital from 2019 to 2023. We identified SLE patients who were receiving 200 mg of belimumab weekly by subcutaneous injection for 96 weeks.

The clock gene Bmal1 controls inflammatory mediators in rheumatoid arthritis fibroblast-like synoviocytes.

Object: To clarify the involvement of clock genes in the production of inflammatory mediators from RA-FLS, we examined the role of Bmal1, one of the master clock genes.

Methods: RA-FLSs were stimulated with IL-1β (0, 20 ng/mL), IL-6 (0, 20 ng/mL), IL-17 (0, 20 ng/mL), TNF-α (0, 20 ng/mL) or IFN-γ (0, 20 ng/mL) to examine the expression of Bmal1, MMP-3, CCL2, IL-6, IL-7 and IL-15 by qPCR and immunofluorescence staining. After silencing Bmal1, RA-FLSs were stimulated with IL-1β (0, 20 ng/mL), TNF-α (0, 20 ng/mL) or IFN-γ (0, 20 ng/mL) to examine the expressions of inflammatory mediators; MMP-3, CCL2, IL-6 and IL-15 by qPCR, ELISA and immunofluorescence staining.

Mepolizumab exerts crucial effects on glucocorticoid discontinuation in patients with eosinophilic granulomatosis with polyangiitis: a retrospective study of 27 cases at a single center in Japan.

Objectives: To investigate the efficacy of mepolizumab in patients with eosinophilic granulomatosis with polyangiitis (EGPA) and factors contributing to glucocorticoid (GC) discontinuation.

Methods: We retrospectively studied EGPA patients treated with mepolizumab who were on GC at the time of induction of mepolizumab, at Japanese single center as of January 2023. Patients were classified into those who were able to discontinue GC at the time of the investigation (GC-free group) and those who continued (GC-continue group).

Tocilizumab suppresses NF-kappa B activation via toll-like receptor 9 signaling by reducing cell-free DNA in rheumatoid arthritis.

Endogenous DNA is released into the bloodstream as cell-free DNA (cfDNA) following cell death and is associated with various pathological conditions. However, their association with therapeutic drugs against rheumatoid arthritis (RA) remains unknown. Therefore, we investigated the significance of cfDNA in RA treated with tocilizumab and tumour necrosis factor inhibitor (TNF-I).

A case of chronic eosinophilic pneumonia associated with rheumatoid arthritis in glucocorticoid-free remission with JAK inhibitor: A case report.

Rationale: Chronic eosinophilic pneumonia (CEP) presents eosinophil infiltrations in the lung due to allergic reactions. Most CEP patients continue to take glucocorticoids, and their prolonged use induces various side effects. In this case report, based on the efficacy of baricitinib in patients with rheumatoid arthritis (RA) and CEP, we aimed to show that the administration of Janus kinase (JAK) inhibitors, when RA is complicated by an allergic disease, can stabilize the disease state and help avoid the adverse effects of long-term systemic glucocorticoid administration.

Increased Circulating Cell-Free DNA in Eosinophilic Granulomatosis With Polyangiitis: Implications for Eosinophil Extracellular Traps and Immunothrombosis.

Background: Endogenous DNA derived from nuclei or mitochondria is released into the blood circulation as cell-free DNA (cfDNA) following cell damage or death. cfDNA is associated with various pathological conditions; however, its clinical significance in antineutrophil cytoplasmic antibody-associated vasculitis (AAV) remains unclear. This study aimed to evaluate the clinical significance of cfDNA in AAV.

Cell-Free DNA in Rheumatoid Arthritis.

Endogenous DNA derived from the nuclei or mitochondria is released into the bloodstream following cell damage or death. Extracellular DNA, called cell-free DNA (cfDNA), is associated with various pathological conditions. Recently, multiple aspects of cfDNA have been assessed, including cfDNA levels, integrity, methylation, and mutations.

Chronotherapy targeting cytokine secretion attenuates collagen-induced arthritis in mice.

Objective: Diurnal variation of symptoms are observed in rheumatoid arthritis, especially in productions of cytokines that show peak concentrations during mid night. In contrast, cytokines of collagen-induced arthritis (CIA) mice increase in daytimes under Mid-light condition. By using chronotherapy, differences in drug efficacies according to administration time of Baricitinib, a wide ranged cytokine blocker, were examined in CIA mice.

Conditional Upregulation of IFN-α Alone Is Sufficient to Induce Systemic Lupus Erythematosus.

The cause of systemic lupus erythematosus (SLE) is unknown. IFN-α has been suggested as a causative agent of SLE; however, it was not proven, and to what extent and how IFN-α contributes to the disease is unknown. We studied the contribution of IFN-α to SLE by generating inducible IFN-α transgenic mice and directly show that conditional upregulation of IFN-α alone induces a typical manifestation of SLE in the mice not prone to autoimmunity, such as serum immune complex, autoantibody against dsDNA (anti-dsDNA Ab), and the organ manifestations classical to SLE, such as immune complex-deposited glomerulonephritis, classical splenic onion-skin lesion, alopecia, epidermal liquefaction, and positive lupus band test of the skin.

Expressions of circadian clock genes represent disease activities of RA patients treated with biological DMARDs.

Rheumatoid Arthritis (RA) is the autoimmune disease representing the circadian variations of symptoms such as morning stiffness of joints or increased production of cytokines around midnight. Clock genes have been reported to affect on the pathogenesis of RA, however, the detailed relation between clock genes and disease activities of RA has remained unclear. In this study, 15 RA patients treated with biological disease modifying anti-rheumatic drugs (bDMARDs) were enrolled (TNF inhibitor, 5; IL-6 inhibitor, 5; CTLA4-IgG, 5).

Methotrexate upregulates circadian transcriptional factors PAR bZIP to induce apoptosis on rheumatoid arthritis synovial fibroblasts.

Background: Effects of methotrexate (MTX) on the proliferation of rheumatoid arthritis (RA) synovial fibroblasts are incompletely understood. We explored actions of MTX in view of circadian transcriptions of synovial fibroblasts.

Methods: Under treatment with MTX, expression of core circadian clock genes, circadian transcriptional factor proline and acidic amino acid-rich basic leucine zipper (PAR bZIP), and proapoptotic molecule Bcl-2 interacting killer (Bik) was examined by real-time polymerase chain reaction.

TNF-α induces expression of the circadian clock gene Bmal1 via dual calcium-dependent pathways in rheumatoid synovial cells.

Tumor necrosis factor (TNF)-α is responsible for expressions of several clock genes and affects joint symptoms of rheumatoid arthritis (RA) with diurnal fluctuation. We tried to determine the mechanism involved in over-expression of Bmal1, induced by TNF-α, in primary cultured rheumatoid synovial cells. Cells were incubated with intra-cellular Ca chelator BAPTA-AM, calcineurin inhibitor FK506 and p300/CBP (CREB binding protein) inhibitor C646, respectively, or transfected with p300 and CBP small interfering RNA (siRNA) before stimulation with TNF-α.

A variant of death-receptor 3 associated with rheumatoid arthritis interferes with apoptosis-induction of T cell.

Rheumatoid arthritis (RA) is a chronic polyarthritis of unknown etiology. To unravel the molecular mechanisms in RA, we performed targeted DNA sequencing analysis of patients with RA. This analysis identified a variant of the () gene, a member of the family of apoptosis-inducing genes, which contains four single-nucleotide polymorphisms (SNPs) and a 14-nucleotide deletion within exon 5 and intron 5.

Circulating cell free DNA: a marker to predict the therapeutic response for biological DMARDs in rheumatoid arthritis.

Aim: To evaluate the correlation between circulating cell-free DNA (ccfDNA) in plasma and clinical disease activities in patients with rheumatoid arthritis (RA).

Method: The study group included 30 patients with RA who started biological disease-modifying anti-rheumatic drugs (DMARDs) therapy. The concentration of ccfDNA in plasma was measured by quantitative real-time polymerase chain reaction at baseline to 24 weeks in every 4-week period from 30 patients and 21 healthy individuals.

Involvement of the circadian rhythm and inflammatory cytokines in the pathogenesis of rheumatoid arthritis.

Among the symptoms of patients with rheumatoid arthritis (RA), joint stiffness is influenced by diurnal rhythm and reaches peak in the morning, which is a common complaint and reflects the circadian nature of disease manifestation. In addition, inflammatory cytokines, which reach peak secretion early in the morning are major players causing the morning stiffness. In this review, we explore the link between the circadian clock and inflammation, focusing on the interactions of various clock genes with the immune-pathways underlying the pathology of rheumatoid arthritis.

IFN-γ-producing effector CD8 T lymphocytes cause immune glomerular injury by recognizing antigen presented as immune complex on target tissue.

We investigated the role of effector CD8 T cells in the pathogenesis of immune glomerular injury. BALB/c mice are not prone to autoimmune disease, but after 12 immunizations with OVA they developed a variety of autoantibodies and glomerulonephritis accompanied by immune complex (IC) deposition. In these mice, IFN-γ-producing effector CD8 T cells were significantly increased concomitantly with glomerulonephritis.

Shorter disease duration is important for tocilizumab to achieve Boolean remission.

Objective: To determine the optimal conditions for inducing rheumatoid arthritis (RA) into disease remission by tocilizumab (TCZ), we analyzed the TCZ therapy carried out in our facility.

Method: The study group comprised 116 patients with RA who started TCZ therapy at Kobe University Hospital and Konan-Kakogawa Hospital. The clinical response to TCZ was evaluated by the 2011 Boolean definition and the disease activity score of 28 joints erythrocyte sedimentation rate 4 (DAS28-ESR4).

A study on the selection of DMARDs for the combination therapy with adalimumab.

We evaluated whether or not the effect of adalimumab (ADA) in combination with the disease-modifying antirheumatic drugs (DMARDs) other than methotrexate (MTX) is comparable to the ADA+MTX therapy for the treatment of rheumatoid arthritis (RA). A total of 216 patients with active RA at Kohnan Kakogawa Hospital and Kobe University Hospital were enrolled. Clinical and functional outcomes were compared among 4 groups, ADA alone (A group), ADA + MTX (B group), ADA + MTX + other DMARDs (C group), and ADA + other DMARDs (D group), and the retention rates of ADA were evaluated with or without MTX.

Drug retention rates and relevant risk factors for drug discontinuation due to adverse events in rheumatoid arthritis patients receiving anticytokine therapy with different target molecules.

Objective: To compare reasons for discontinuation and drug retention rates per reason among anticytokine therapies, infliximab, etanercept and tocilizumab, and the risk of discontinuation of biological agents due to adverse events (AE) in patients with rheumatoid arthritis (RA).

Method: This prospective cohort study included Japanese RA patients who started infliximab (n=412, 636.0 patient-years (PY)), etanercept (n=442, 765.

Time-dependent increased risk for serious infection from continuous use of tumor necrosis factor antagonists over three years in patients with rheumatoid arthritis.

Objective: To investigate associations between continuous treatments with tumor necrosis factor (TNF) antagonists and risk for developing serious infections (SIs) over 3 years in Japanese patients with rheumatoid arthritis (RA) enrolled in the Registry of Japanese RA Patients for Long-Term Safety (REAL) database.

Methods: We analyzed 727 RA patients who had started either infliximab or etanercept (the anti-TNF group; 1,480.1 patient-years [PY]) and 571 RA patients who had started conventional nonbiologic disease-modifying antirheumatic drugs (the unexposed group; 1,104.

Role of the MICA polymorphism in systemic lupus erythematosus.

Objective: To study the genetic contribution of major histocompatibility complex class I polypeptide-related sequence A (MICA), important in natural killer (NK) cell function, in patients with systemic lupus erythematosus (SLE).

Methods: Japanese patients with SLE (n=716), those with rheumatoid arthritis (RA) (n=327), and healthy control subjects (n=351) were genotyped for the Val129 Met polymorphism (rs1051792) and transmembrane (TM) alanine-encoding GCT repeats, termed A4, A5, A5.1, A6, and A9, in the MICA gene.

Incidence and risk factors for serious infection in patients with rheumatoid arthritis treated with tumor necrosis factor inhibitors: a report from the Registry of Japanese Rheumatoid Arthritis Patients for Longterm Safety.

Objective: To compare tumor necrosis factor-α (TNF-α) inhibitors to nonbiological disease-modifying antirheumatic drugs (DMARD) for the risk of serious infection in Japanese patients with rheumatoid arthritis (RA).

Methods: Serious infections occurring within the first year of the observation period were examined using the records for patients recruited to the Registry of Japanese Rheumatoid Arthritis Patients for Longterm Safety (REAL), a hospital-based prospective cohort of patients with RA. The analysis included 1144 patients, 646 of whom were treated with either infliximab or etanercept [exposed group: 592.

Pathogenesis of joint destruction in rheumatoid arthritis.

Synovial mesenchymal cells, matrix metalloproteinases (MMPs), and osteoclasts are the three major players directly responsible for the pathogenesis of rheumatoid joint destruction. First, synovial mesenchymal cells, internally driven by a transcription factor c-Fos/AP-1, not only directly invade cartilage and bone as a granulation tissue called "pannus" but also release inflammatory cytokine interleukin (IL)-1β. IL-1β induces MMPs and activates osteoclasts.

Heat shock protein 90 maintains the tumour-like character of rheumatoid synovial cells by stabilizing integrin-linked kinase, extracellular signal-regulated kinase and protein kinase B.

Objective: To clarify the contribution of heat shock protein 90 (HSP90) to the pathogenesis of RA, we studied the effects of geldanamycin (GA), an inhibitor of HSP90, on excessive cellular extension and resistance to apoptosis induction of rheumatoid synovial cells.

Methods: Expression of integrin-α5β1 and integrin-linked kinase (ILK) in synovial cells was determined by western blot. The peripheral localization of ILK, reorganization of F-actin, complex formation of ILK with particularly interesting new cysteine-histidine protein (PINCH) and α-parvin, and activation of Rac/cdc42 in synovial cells were examined by using immunohistochemistry and immunoprecipitation.