Systematic review and meta-analysis for the 2024 update of the Japan College of Rheumatology clinical practice guidelines for the management of rheumatoid arthritis.

OBJECTIVES: To update evidence on the efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) and provide information to the taskforce for the 2024 update of the Japan College of Rheumatology (JCR) clinical practice guidelines (CPG) for the management of rheumatoid arthritis (RA). METHODS: We searched various databases for randomised controlled trials on RA published until June 2022, with no language restriction. For each of the 15 clinical questions, 2 independent reviewers screened the articles, evaluated the core outcomes, and performed meta-analyses. RESULTS: Subcutaneous injection of methotrexate (MTX) showed similar efficacy to oral MTX in MTX-naïve RA patients. Ozoralizumab combined with MTX improved drug efficacy compared to the placebo in RA patients with inadequate response (IR) to csDMARD. Rituximab with and without concomitant csDMARDs showed similar efficacy to other bDMARDs in bDMARD-IR RA patients. Combined Janus kinase inhibitors and MTX achieved similar clinical responses and equal safety during a 4-year period compared to tumour necrosis factor inhibitors in MTX-IR RA patients. Biosimilars showed efficacy equivalent to that of the original bDMARDs in csDMARD-IR and bDMARD-IR RA patients. CONCLUSION: This systematic review provides latest evidence for the 2024 update of the JCR CPG for RA management.

Evaluation of anti-severe acute respiratory syndrome coronavirus 2 antibody levels in coronavirus disease breakthrough infection during immunosuppressive therapy in a patient with connective tissue disease-related interstitial lung disease.

Herein, we report the case of a 67-year-old man with severe coronavirus disease (COVID-19) pneumonia and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine breakthrough infection during immunosuppressive therapy for connective tissue disease-related interstitial lung disease (CTD-ILD). The patient received glucocorticoids combined with tacrolimus as maintenance therapy. His serum anti-SARS-CoV-2-immunoglobulin G (IgG) antibody levels were extremely low at the onset of COVID-19 pneumonia, even after the second dose of SARS-CoV-2 mRNA vaccine (BNT162b2). After treatment for COVID-19 pneumonia, the levels of anti-SARS-CoV-2-IgG antibodies increased. These results indicated a lack of the ability to produce neutralising antibodies from immune cells despite the booster vaccination. Therefore, we suggest that advanced-age patients with CTD-ILD receiving immunosuppressive therapy with polypharmacy require consistent personal protection, vaccination of close caregivers, increased awareness, and booster vaccination. Moreover, we recommend that tacrolimus should be withdrawn for a while after vaccination under controlled conditions.

Transition from epoprostenol to selexipag in a patient with systemic sclerosis and pulmonary hypertension during the postoperative period of colon cancer surgery: A case report.

Introduction: Most pulmonary vasodilators are administered orally; however, in patients with pulmonary hypertension undergoing gastrointestinal surgery, a switch to parenteral drugs is needed. Parenteral pulmonary vasodilators carry a risk of infection and reduced quality of life owing to long-term central venous catheterization; therefore, it is preferable to switch them to oral vasodilators after surgery. Here, we present the case of a patient with systemic sclerosis complicated by pulmonary hypertension and colon cancer, for which treatment was successfully switched from epoprostenol to selexipag postoperatively. Case Description: A 59-year-old woman, who was diagnosed with mixed group I and III pulmonary hypertension and systemic sclerosis, was on oral triple pulmonary vasodilators for pulmonary hypertension and Raynaud's phenomenon. She was diagnosed as having colon cancer 3 months before admission. Despite the severe pulmonary condition and treatment with oral triple pulmonary vasodilators, colon cancer resection surgery was performed with the management for pulmonary hypertension through multidisciplinary treatments in collaboration with cardiology specialists. Medications for patients with pulmonary hypertension undergoing gastrointestinal surgery need to be switched from oral vasodilators to epoprostenol perioperatively. On postoperative day 19, 0.4 mg/day of selexipag was administered with epoprostenol. Subsequently, the epoprostenol dosage was gradually decreased, and selexipag was increased. On postoperative day 30, the dose of selexipag was increased to 1.2 mg/day and epoprostenol was discontinued. The patient was discharged on postoperative day 40. Conclusion: In our case, transition from epoprostenol to selexipag contributed to a more useful management strategy for systemic sclerosis and pulmonary hypertension in the postoperative period.

The proinflammatory protein HMGB1 is a substrate of transglutaminase-2 and forms high-molecular weight complexes with autoantigens.

High-mobility group box 1 (HMGB1) is a chromatin-associated protein that, in response to stress or injury, translocates from the nucleus to the extracellular milieu, where it functions as an alarmin. HMGB1's function is in part determined by the complexes (HMGB1c) it forms with other molecules. However, structural modifications in the HMGB1 polypeptide that may regulate HMGB1c formation have not been previously described. In this report, we observed high-molecular weight, denaturing-resistant HMGB1c in the plasma and peripheral blood mononuclear cells of individuals with systemic lupus erythematosus (SLE) and, to a much lesser extent, in healthy subjects. Differential HMGB1c levels were also detected in mouse tissues and cultured cells, in which these complexes were induced by endotoxin or the immunological adjuvant alum. Of note, we found that HMGB1c formation is catalyzed by the protein-cross-linking enzyme transglutaminase-2 (TG2). Cross-link site mapping and MS analysis revealed that HMGB1 can be cross-linked to TG2 as well as a number of additional proteins, including human autoantigens. These findings have significant functional implications for studies of cellular stress responses and innate immunity in SLE and other autoimmune disease.

A case of systemic lupus erythematosus with multiple nodules in the bilateral lungs and vertebrae.

We encountered a case of a middle-aged woman with systemic lupus erythematosus. As the patient had progressive peripheral neuropathy including foot drop, we intended to treat her with intensive immunosuppressive therapy as soon as possible. Pretreatment assessment, however, revealed multiple nodular lesions in the lungs and bones, suggesting disseminated tumor metastasis or miliary tuberculosis. To our surprise, gallium and bone scintigraphy as well as cytodiagnosis revealed no sign of malignancy or infection, leading us to suspect the presence of another multisystem disorder. The presence of subependymal nodules and a periungual fibroma strongly suggested tuberous sclerosis (TS). A genetic test revealed a mutation in the TSC1 gene and confirmed the diagnosis. Thus, the multiple nodular lesions were most likely a hyperplasia due to TS. Although the odds of a comorbidity of more than one multisystem disorder are considered to be quite low, it should be kept in mind that when such a situation does exist, the comorbidity may make the presenting symptoms extremely diverse.

Aberrant histone acetylation contributes to elevated interleukin-6 production in rheumatoid arthritis synovial fibroblasts.

Accumulating evidence indicates that epigenetic aberrations have a role in the pathogenesis of rheumatoid arthritis (RA). However, reports on histone modifications are as yet quite limited in RA. Interleukin (IL)-6 is an inflammatory cytokine which is known to be involved in the pathogenesis of RA. Here we report the role of histone modifications in elevated IL-6 production in RA synovial fibroblasts (SFs). The level of histone H3 acetylation (H3ac) in the IL-6 promoter was significantly higher in RASFs than osteoarthritis (OA) SFs. This suggests that chromatin structure is in an open or loose state in the IL-6 promoter in RASFs. Furthermore, curcumin, a histone acetyltransferase (HAT) inhibitor, significantly reduced the level of H3ac in the IL-6 promoter, as well as IL-6 mRNA expression and IL-6 protein secretion by RASFs. Taken together, it is suggested that hyperacetylation of histone H3 in the IL-6 promoter induces the increase in IL-6 production by RASFs and thereby participates in the pathogenesis of RA.