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Resolvins, are specialized pro-resolving mediators (SPMs) derived from n-3 polyunsaturated fatty acids. They contribute actively to the resolution of inflammation, but little is known concerning their role in chronic inflammation, such as in rheumatoid arthritis (RA). Here, we performed lipid mediator (LM) profiling in tissues from the paws of SKG arthritic mice using lipid chromatography (LC)/mass spectrometry (MS)/MS-based LM metabololipidomics. We found elevated levels of SPMs including resolvin D5 (RvD5) in these tissues. Moreover, RvD5 levels were significantly correlated with arthritis disease activity. From experiments to assess the role of RvD5 in the pathology of RA, we concluded that RvD5 suppressed Th17 cell differentiation and facilitated regulatory T cell differentiation, as well as inhibiting CD4 + T cell proliferation. Furthermore, RvD5 attenuated osteoclast differentiation and interfered with osteoclastogenesis. Targeting the resolution of inflammation could be promising as a novel treatment for RA.

Background Undifferentiated arthritis (UA) often develops into rheumatoid arthritis (RA), but predicting disease progression from seronegative UA remains challenging because seronegative RA often does not meet the classification criteria. This study aims to build a machine learning (ML) model to predict the progression from seronegative UA to RA using clinical and laboratory parameters. Methods KURAMA cohort (training dataset) and ANSWER cohort (validation dataset) were utilized. Patients with seronegative UA were selected based on specific inclusion and exclusion criteria. Clinical and laboratory parameters, including demographic data, acute phase reactants, autoantibodies, and physical examination findings, were collected. Various ML models, including a Feedforward Neural Network (FNN), were developed and compared. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC), sensitivity, and other metrics. SHapley Additive exPlanations (SHAP) values were computed to interpret the importance of variables. Results KURAMA cohort included 210 patients with seronegative UA, of whom 57 (27.1%) progressed to RA. The FNN model demonstrated the highest predictive performance with an AUC of 0.924 and a sensitivity of 80.7% in the training dataset. Validation with ANSWER cohort (140 patients; 32.1% progressed to RA) showed an AUC of 0.777, sensitivity of 77.8%. MMP-3 had the highest impact on the model. Conclusions The FNN model exhibited robust performance in predicting the progression of RA from seronegative UA and maintained substantial sensitivity in an independent validation cohort. This model using only clinical and laboratory parameters has potential for predicting RA progression in patients with seronegative UA.

Background β2-glycoprotein I (β2GPI) complexed with human leukocyte antigen DR (β2GPI/HLA-DR) was found to be a major autoantibody target in antiphospholipid syndrome (APS). This study aimed to reveal the association between anti-β2GPI/HLA-DR antibodies and vascular thromboses in women with systemic rheumatic diseases. Methods We conducted a retrospective longitudinal study. We measured anti-β2GPI/HLA-DR antibodies and compared them with anti-phospholipid antibody (aPL) profiles and the adjusted global antiphospholipid syndrome score (aGAPSS). Using receiver operating characteristic (ROC) analysis, we determined the best cut-off value for arterial thrombosis. We also evaluated the validity of anti-β2GPI/HLA-DR antibodies by adding to conventional cardiovascular risk factors in multivariate logistic analysis. Results We evaluated 704 patients, including 66 (obstetric or thrombotic) APS, 13 primary APS, and 78 asymptomatic aPL carriers. Seventy-seven patients had a history of arterial thrombosis, and 14 patients had both arterial and venous thrombosis. These 14 patients, as well as patients with aGAPSS > 10 or triple-positive aPL profiles, displayed high anti-β2GPI/HLA-DR antibody titers. The ROC curve showed a sensitivity, specificity, and area under the curve (AUC) for arterial thrombosis of 33.8%, 91.4%, and 0.6009, respectively, with a cut-off value of 172.359 U/mL. The anti-β2GPI/HLA-DR antibody positivity using this cut-off value yielded an odds ratio of 5.13 (95%CI: 2.85–9.24), significantly improving the AUC from 0.677 to 0.730. Conclusion Anti-β2GPI/HLA-DR antibodies are associated with arterial thrombosis in female patients with systemic rheumatic diseases.

We aimed to evaluate microbiome and microbiota-derived C18 dietary polyunsaturated fatty acids (PUFAs), such as conjugated linoleic acid (CLA), and to investigate their differences that correlate with arthritis severity in collagen-induced arthritis (CIA) mice. On day 84 after induction, during the chronic phase of arthritis, cecal samples were analyzed using 16S rRNA sequencing, and plasma and cecal digesta were evaluated using liquid chromatography-tandem mass spectrometry. Differences in microbial composition between 10 control (Ctrl) and 29 CIA mice or between the mild and severe subgroups based on arthritis scores were identified. The cecal metabolite profile and its correlation with the microbiome were evaluated with respect to arthritis severity. The hydroxy and oxo metabolite levels were higher in CIA mice than in Ctrl mice, some of which, including 10-hydroxy-cis-6-18:1, were positively correlated with arthritis scores. The 9-trans,11-trans CLA levels in CIA mice had a negative linear correlation with arthritis scores. Microbial diversity was lower in severe CIA mice than in mild CIA or Ctrl mice. The abundance of relatively increased in the severe subgroup of CIA mice compared with that in the mild subgroup and was positively correlated with arthritis severity. Alterations in gut microbiota and microbiota-derived C18 PUFA metabolites are associated in CIA mice and correlated with arthritis scores, indicating that plasma or fecal C18 PUFA metabolites can be potential biomarkers for arthritis severity and dysbiosis.

Anti-SS-A (Ro) antibody-positive rheumatoid arthritis (RA) constitutes a clinically important subgroup, but its impact on retention of biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) across different modes of action (MOA) and reasons for discontinuation remains unclear. We conducted a multicenter retrospective analysis of the Japanese ANSWER cohort, including RA patients who started or switched b/tsDMARDs between 2011 and 2024 and had baseline anti-SS-A antibody testing. Among 1,452 patients (2,703 treatment courses), 255 patients (17.6%) were anti–SS-A antibody positive (507 courses, 18.8%). Propensity score matching balanced baseline characteristics, and drug retention was evaluated using Kaplan–Meier and competing risk analyses. Overall discontinuation was analyzed using Cox proportional hazards models, and Fine–Gray subdistribution hazards models were used for discontinuation by reason and for adverse event–related discontinuation stratified by MOA. After matching, 507 treatment courses from 255 anti-SS-A antibody-positive patients and 1,014 courses from 628 antibody-negative patients were analyzed. Anti-SS-A antibody positivity was not associated with overall b/tsDMARD retention (hazard ratio [HR] 1.07, 95% confidence interval [CI] 0.91–1.26, p = 0.382). In MOA-stratified analyses, positivity showed a trend toward increased discontinuation with interleukin-6 (IL-6) receptor inhibitors and cytotoxic T lymphocyte-associated antigen 4-immunoglobulin (CTLA4-Ig). In competing-risk analyses, discontinuation due to adverse events was significantly more frequent in antibody-positive patients (subdistribution hazard ratio [sHR] 1.80, 95% CI 1.28–2.52; p = 0.000685). Among adverse event-related discontinuations, anti-SS-A antibody positivity was associated with higher risks with IL-6 receptor inhibitors (sHR 2.41, 95% CI 1.24–4.71; p = 0.0098) and tumor necrosis factor (TNF) inhibitors (sHR 2.04, 95% CI 1.22–3.40; p = 0.0066), but not with CTLA4-Ig or Janus kinase (JAK) inhibitors. These findings suggest that treatment tolerability, rather than overall efficacy, may be a key determinant of b/tsDMARD survival in anti-SS-A antibody-positive RA and that MOA- and cause-specific profiles should be considered when selecting therapies in this subgroup.

Background Systemic sclerosis (SSc) is a chronic autoimmune-mediated connective tissue disorder. Although the etiology of the disease remains undetermined, SSc is characterized by fibrosis and proliferative vascular lesions of the skin and internal organs. SSc involves the gastrointestinal tract in more than 90 % of patients. Soluble guanylate cyclase (sGC) stimulator is used to treat pulmonary artery hypertension (PAH) and has been shown to inhibit experimental skin fibrosis. Methods Female C57BL/6J mice were treated with BLM or normal saline by subcutaneous implantation of osmotic minipump. These mice were sacrificed on day 28 or day 42. Gastrointestinal pathologies were examined by Masson Trichrome staining. The expression of fibrosis-related genes in gastrointestinal tract was analyzed by real-time PCR, and the levels of collagen in the tissue were measured by Sircol collagen assay. To evaluate peristaltic movement, the small intestinal transport (ITR%) was calculated as [dyeing distance × (duodenum − appendix)] − 1 × 100 (%). We treated BLM-treated mice with sGC stimulator or DMSO orally and analyzed them on day 42. Results Histological examination revealed that fibrosis from lamina propria to muscularis mucosa in the esophagus was significantly increased in BLM-treated mice, suggesting that BLM induces esophageal hyperproliferative and prefibrotic response in C57BL/6J mice. In addition, the gene expression levels of Col3a1, CCN2, MMP-2, MMP-9, TIMP-1, and TIMP-2 in the esophagus were significantly increased in BLM-treated mice. More severe hyperproliferative and prefibrotic response was observed in the mice sacrificed on day 42 than the mice sacrificed on day 28. The ITR% was found to be significantly lower in BLM-treated mice, suggesting that gastrointestinal peristaltic movement was reduced in BLM-treated mice. Furthermore, we demonstrated that sGC stimulator treatment significantly reduced hyperproliferative and prefibrotic response of esophagus and intestine in BLM-treated mice, by histological examination and Sircol collagen assay. Conclusions These findings suggest that BLM induces gastrointestinal hyperproliferative and prefibrotic response in C57BL/6J mice, and treatment with sGC stimulator improves the BLM-induced gastrointestinal lesion.

Glutamine metabolism and the mechanistic target of rapamycin (mTOR) pathway are activated cooperatively in the differentiation and activation of inflammatory immune cells. But the combined inhibition of both pathways was rarely investigated. This study investigated how inhibiting both glutamine metabolism with 6-diazo-5-oxo-L-norleucine (DON) and mTOR with rapamycin affects immune cells and the arthritis in a mouse model. We revealed that rapamycin and DON additively suppressed CD4 + T cell proliferation, and both of them inhibited Th17 cell differentiation. While DON inhibited the differentiation of dendritic cells and macrophages and facilitated that of Ly6G + granulocytic (G)-MDSCs more strongly than did rapamycin, G-MDSCs treated with rapamycin but not DON suppressed CD4 + T cell proliferation in vitro . The combination of rapamycin and DON significantly suppressed the arthritis in SKG mice more strongly than did each monotherapy in vivo . The numbers of CD4 + T and Th17 cells in the spleen were lowest in mice treated with the combination therapy. Thus, combined treatment with rapamycin and DON additively ameliorated the arthritis in SKG mice, possibly by suppressing CD4 + T cell proliferation and Th17 differentiation. These results suggest the combination of rapamycin and DON may be a potential novel therapy for arthritis.

Valganciclovir (VGCV) is the first-line drug for preemptive therapy of cytomegalovirus (CMV) infections. However, even when administered at the dose specified in the package insert, there is significant interindividual variability in the plasma concentrations of ganciclovir (GCV). In addition, correlations have been reported between the area under the concentration-time curve and therapeutic efficacy or adverse events. Therefore, therapeutic drug monitoring (TDM) can be used to improve the efficacy and safety of preemptive VGCV therapy. This study aims to evaluate whether the dosage adjustment of VGCV based on TDM in patients undergoing preemptive therapy for CMV infections is associated with the successful completion rate of treatment without severe hematological adverse effects. This phase II, single-center, single-arm trial aims to enroll 40 patients admitted at the Department of Rheumatology and Clinical Immunology, Kobe University Hospital, who will receive oral VGCV as preemptive therapy for CMV infections. Participants will begin treatment with VGCV at the dose recommended in the package insert, with subsequent dose adjustments based on weekly TDM results. The primary end point will be the proportion of patients who achieve CMV antigenemia negativity within 3 weeks without severe hematological adverse events. The secondary end points will include weekly changes in CMV antigen levels, total VGCV dose, and duration of preemptive therapy. For safety evaluation, the occurrence, type, and severity of VGCV-related adverse events will be analyzed. Additionally, this study will explore the correlations between the efficacy and safety of preemptive therapy and the pharmacokinetic parameters of GCV, CMV-polymerase chain reaction values, and nudix hydrolase 15 (NUDT15) genetic polymorphisms. The correlation between GCV plasma concentrations obtained from regular venous blood and blood concentrations will be examined using dried blood spots. This study began with patient recruitment in September 2024, with 5 participants enrolled as of June 16, 2025. The target enrollment is 40 participants, and the anticipated study completion is set for July 2027. This is the first study to investigate the impact of TDM intervention in patients receiving VGCV as preemptive therapy. The findings are postulated to provide valuable evidence regarding the utility of TDM in patients receiving VGCV as preemptive therapy. Japan Registry of Clinical Trials jRCTs051240080; https://jrct.mhlw.go.jp/latest-detail/jRCTs051240080. DERR1-10.2196/72549.

ObjectivesThis multicentre retrospective study in Japan aimed to assess the retention of biological disease-modifying antirheumatic drugs and Janus kinase inhibitors (JAKi), and to clarify the factors affecting their retention in a real-world cohort of patients with rheumatoid arthritis.MethodsThe study included 6666 treatment courses (bDMARD-naïve or JAKi-naïve cases, 55.4%; tumour necrosis factor inhibitors (TNFi) = 3577; anti-interleukin-6 receptor antibodies (aIL-6R) = 1497; cytotoxic T lymphocyte-associated antigen-4-Ig (CTLA4-Ig) = 1139; JAKi=453 cases). The reasons for discontinuation were divided into four categories (ineffectiveness, toxic adverse events, non-toxic reasons and remission); multivariate Cox proportional hazards modelling by potential confounders was used to analyse the HRs of treatment discontinuation.ResultsTNFi (HR=1.93, 95% CI: 1.69 to 2.19), CTLA4-Ig (HR=1.42, 95% CI: 1.20 to 1.67) and JAKi (HR=1.29, 95% CI: 1.03 to 1.63) showed a higher discontinuation rate due to ineffectiveness than aIL-6R. TNFi (HR=1.28, 95% CI: 1.05 to 1.56) and aIL-6R (HR=1.27, 95% CI: 1.03 to 1.57) showed a higher discontinuation rate due to toxic adverse events than CTLA4-Ig. Concomitant use of oral glucocorticoids (GCs) at baseline was associated with higher discontinuation rate due to ineffectiveness in TNFi (HR=1.24, 95% CI: 1.09 to 1.41), as well as toxic adverse events in JAKi (HR=2.30, 95% CI: 1.23 to 4.28) and TNFi (HR=1.29, 95%CI: 1.07 to 1.55).ConclusionsTNFi (HR=1.52, 95% CI: 1.37 to 1.68) and CTLA4-Ig (HR=1.14, 95% CI: 1.00 to 1.30) showed a higher overall drug discontinuation rate, excluding non-toxicity and remission, than aIL-6R.

To achieve a better patient experience with self-injection, an assessment of potential demographic, physical, and psychological barriers is necessary. The aim of this study was to examine the demographic, physical, and psychological characteristics associated with the experiences of self-injection in patients with rheumatoid arthritis (RA). In this study, overall patient experience with subcutaneous self-injection was assessed using the Self-Injection Assessment Questionnaire. Upper limb function was assessed using the three domains of the Health Assessment Questionnaire associated with upper extremity disability (dressing and grooming, eating, and grip). Structural equation modeling was used to estimate the association between the demographic and clinical characteristics of patients with RA and their experiences with self-injection in the theoretical model. Data from 83 patients with RA were analyzed. Compared with younger patients, elderly patients were more likely to experience lower self-confidence, self-image, and ease of use. Female patients had lower ease of use than male patients. In terms of upper limb function, patients with more difficulty in performing activities of daily living were more likely to have a lower self-image. Self-injection perceptions before learning the method of injection, such as fear of needles and anxiety about self-injection, were associated with post-injection feelings, injection site reactions, self-confidence, and ease of use. To optimize patients' experiences with self-injection, healthcare workers should assess each patient's age, sex, upper limb function, and pre-self-injection perceptions as demographic, physical, and psychological barriers.