Yoshiya Tanaka

Objective: Tissue‐resident memory T (T _RM ) cells have been implicated in organ‐specific immune pathology; however, the pathological relevance of T _RM ‐like CD8 ⁺ T cells in systemic lupus erythematosus (SLE) remains unclear. We investigated their differentiation mechanisms and pathological significance in SLE, including associations with disease activity and organ involvement. Methods: Peripheral blood samples from 30 treatment‐naïve patients with SLE, 40 patients with rheumatoid arthritis (RA), and 30 healthy donors (HDs) were analyzed by flow cytometry. Renal biopsy specimens from 20 patients with SLE were examined by immunofluorescence. Naïve CD8 ⁺ T cells from HDs were stimulated with cytokines to induce T _RM ‐like differentiation, followed by phenotypic, functional, transcriptional, and metabolic analyses. The effects of Janus kinase (JAK) inhibitors were assessed. Results: Circulating CD8 ⁺ CD69 ⁺ CD103 ⁺ T _RM ‐like cells were more frequent in SLE than in RA and HDs ( P=0.022 and P , respectively) and correlated with anti‐dsDNA antibodies (rs=0.468, P=0.016 ) and CH50 (rs=−0.397, P=0.045 ). Patients with active kidney involvement (renal BILAG A/B; n=17) had higher T _RM ‐like cell proportions than those without active kidney involvement (n=13; P ). CD3 ⁺ CD103 ⁺ cells in renal lesions expressed granzyme B or interferon‐γ. Patients with baseline T _RM ‐like cell proportions ≥0.40% had higher urine protein‐to‐creatinine ratios and SELENA‐SLEDAI scores at week 24 (both P ). IL‐15 plus TGF‐β1 induced T _RM ‐like differentiation with effector, transcriptional, survival, and metabolic features, whereas JAK inhibition suppressed differentiation and granzyme B expression. Conclusion: Circulating T _RM ‐like CD8 ⁺ T cells were associated with SLE activity and kidney involvement. IL‐15/TGF‐β1‐dependent differentiation partly involved JAK/STAT signaling, supporting further evaluation as a biomarker and therapeutic target. image

Introduction Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by synovial inflammation and osteoclast-driven bone erosion, leading to joint destruction. T cells play a central role in driving inflammation and contribute to the pathogenesis of RA. This study aims to identify T cell subsets in RA using single-cell RNA sequencing (scRNA-seq) technology.Methods An in silico analysis of publicly available scRNA-seq datasets was conducted to identify a T cell population enriched in RA synovial tissue. To generate this population in vitro, peripheral blood T cells were stimulated with various cytokines. Gene expression was measured by quantitative PCR, and bulk RNA sequencing was used to define the transcriptomic profile of this population. Proteomic analysis was also performed to characterise its protein expression profile and functional pathways.Results A population of T cells expressing immunoglobulin genes was identified in RA synovial tissue in silico. Among the various cytokines tested, interleukin-4 specifically upregulated immunoglobulin gene expression in peripheral blood lymphocytes, particularly in naive CD8 + T cells. Transcriptomic analysis showed increased osteoclast differentiation but reduced pathways related to osteoclast differentiation regulation, RA and inflammatory responses. In contrast, proteomic analysis showed consistent downregulation of the osteoclast differentiation and inflammatory response pathways.Conclusions These findings suggest a T cell population in RA exhibiting immunoglobulin gene expression at the transcript level and reduced inflammatory and osteoclast-related pathways at the protein level.

Objectives: This study aimed to evaluate treatment persistence and safety following subcutaneous methotrexate (MTX) initiation in Japanese patients with rheumatoid arthritis and clinical outcomes after direct switching from oral to subcutaneous MTX. Methods: We retrospectively studied 101 patients with rheumatoid arthritis initiating subcutaneous MTX. Efficacy and safety were analysed in patients switching because of adverse events. The primary endpoint was the 26-week retention rate. Results: Gastrointestinal intolerance was the commonest reason for switching from oral to subcutaneous MTX. Overall retention rate was 87.1% (88/101). Among switchers, the 26-week retention rate was 92.0% (81/88), and the MTX dose increased in 46.6% (41/88). In patients not receiving biologic or targeted synthetic disease-modifying anti-rheumatic drugs at switching (n = 50), the retention rate was 96.0% (48/50), and the mean MTX dose increased (10.3 ± 2.8 to 12.0 ± 2.8 mg/week; P < .0001). The Clinical Disease Activity Index improved by week 26 (13.2 ± 10.1 to 8.2 ± 7.8; P < .0001), with 30.0% (15/50) achieving remission. Conclusions: Switching from oral to subcutaneous MTX in patients with rheumatoid arthritis who are intolerant to oral MTX may enable continued treatment and dose optimization and be associated with improved disease activity.

Objective: Real‐world initial treatment strategies in SSc‐PAH remain incompletely described. We aimed to characterise these strategies across haemodynamic thresholds and risk strata and evaluate outcome associations. Methods: We analysed treatment‐naïve SSc‐PAH patients in EUSTAR (2000–2021) fulfilling the 2022 haemodynamic definition. Initial therapy comprised treatment initiated within 4 months of RHC. As‐treated (AT) analyses were primary and intention‐to‐treat (ITT) analyses supportive. Outcomes were all‐cause mortality and 36‐month PAH progression. Results: Among 301 patients, 198 (66%) initiated therapy and 170 maintained therapy for ≥3 months. Therapy was initiated in 31% with milder haemodynamic impairment (mPAP 21–24 mmHg and/or PVR 2–3 WU) versus 79% fulfilling the previous haemodynamic definition; combination therapy increased from 14% to 67% across low‐ to high‐risk strata. Over a median 3.9 years, 125 (42%) died and 85/227 (37%) progressed. Adjusted ITT analyses showed no association with either outcome, whereas adjusted AT analyses showed lower mortality risk with sustained monotherapy and combination therapy (HR 0.50, 95% CI 0.27–0.92 and HR 0.40, 95% CI 0.18–0.88, respectively) and lower PAH progression risk with sustained initial therapy (HR 0.37, 95% CI 0.18–0.76). In the milder haemodynamic subgroup, the mortality estimate was directionally consistent but imprecise. Conclusion: Initial treatment strategies reflected haemodynamic severity and baseline risk, while variation suggested potential implementation gaps. Sustained initial therapy was associated with lower risks of mortality and PAH progression. Contrasting ITT and AT estimates highlight challenges in observational treatment–outcome comparisons. Findings in the milder haemodynamic subgroup support dedicated prospective studies. image

Objectives: To characterize clinical manifestations, major organ involvement, real-world treatment patterns and factors associated with severity classification in Japanese patients with mixed connective tissue disease (MCTD), aiming to clarify its heterogeneous clinical spectrum. Methods: This nationwide retrospective multicentre study analyzed clinical data from 249 patients who strictly fulfilled the 2019 Japanese Ministry of Health, Labour and Welfare diagnostic criteria for MCTD, derived from an initial real-world registry of 311 clinically diagnosed patients. Clinical features, autoantibodies and therapeutic regimens were summarized and compared between patients with severe vs nonsevere disease. Results: The cohort was 93.1% female (median onset age 40.6 years). Common findings, specifically Raynaud’s phenomenon and/or swelling of the fingers or dorsum of the hands, were present in 100%. Phenotypically, an overlap of systemic lupus erythematosus (SLE)-like and systemic sclerosis (SSc)-like features was most frequent (56.0%), while 32.0% had manifestations across all three phenotypic domains (SLE-, SSc- and IIM-like). Major organ involvement occurred in 32.9% of patients, including pulmonary arterial hypertension in 12.8%. Approximately 28.7% of evaluable patients were classified as severe. Off-scale-high anti-U1-RNP antibody status was not associated with severity classification (P = 0.492) or with broad phenotypic categories. Glucocorticoids and immunosuppressive agents were used in 66.7% and 56.5% of the patients, respectively. Conclusions: Mixed connective tissue disease exhibits marked clinical heterogeneity. Severity classification was not associated with off-scale-high anti-U1-RNP antibody status or broad phenotypic categories. These findings support rigorous cardiopulmonary screening and management tailored to the dominant clinical phenotype.

Objectives: The role of anticoagulation in systemic sclerosis (SSc) with precapillary pulmonary hypertension (PH) remains controversial, with conflicting evidence regarding its impact on survival, including potential harmful effects. Aiming to address this research gap, we evaluated both mortality and PH worsening in a large SSc-precapillary PH cohort, additionally accounting for SSc-specific risk factors in our analyses, to better inform individualized treatment decisions. Methods: This retrospective cohort study included SSc patients from the European Scleroderma Trials and Research database with precapillary PH confirmed by right heart catheterization (RHC). The association of oral anticoagulants (OAC) use with survival and PH worsening was assessed using Kaplan–Meier estimates and multivariable Cox regression models. To minimize confounding, propensity score matching was additionally performed. Results: Among 614 patients included, 143 (23%) received OAC at the time of RHC. At baseline, patients on OAC had worse hemodynamic parameters. No significant association was found between OAC use and survival (HR 0.983 95%CI 0.724–1.334) or PH worsening (HR 1.070 95%CI 0.811–1.412). These findings remained consistent after propensity score matching and in the subgroup of 230 SSc patients with precapillary PH without interstitial lung disease. Conclusion: In this large SSc cohort with precapillary PH, we did not observe any clinical benefit associated with OAC, neither in terms of survival nor of PH worsening. Further prospective studies are needed to determine whether specific patient subgroups may benefit from anticoagulation therapy.

Objective: We compared demographic and clinical characteristics between patients with late-onset (LO) and early-onset (EO) systemic lupus erythematosus (SLE) and examined their longitudinal associations with treatment targets and long-term outcomes, irreversible organ damage accrual, and health-related quality of life (HRQOL). Methods: We analyzed prospectively collected data from patients enrolled in the Asia Pacific Lupus Collaboration cohort. Patients diagnosed with SLE at age > 50 years were classified as having LO-SLE, whereas those diagnosed at age ≤ 50 years were classified as having EO-SLE. Longitudinal associations with treatment targets (Low Lupus Disease Activity State [LLDAS] and Definition of Remission in SLE [DORIS] remission), organ damage accrual (Systemic Lupus International Collaborating Clinics/American College of Rheumatology [SLICC/ACR] Damage Index), and HRQOL (36-item Short Form Health Survey v2 physical and mental component summary [PCS and MCS] scores) were examined using multivariable multilevel logistic, recurrent event survival, and linear mixed-effects models, respectively. Disease activity, flares, medication exposure, and other clinical characteristics were also compared between groups. Results: Among 3917 patients studied, 346 (8.8%) had LO-SLE and 3571 (91.2%) had EO-SLE. Compared to patients with EO-SLE, those with LO-SLE had lower disease activity, lower glucocorticoid and immunosuppressant exposure, and higher attainment of treatment targets. LO-SLE was associated with higher odds of attaining LLDAS (odds ratio [OR] 2.33, 95% CI 1.66-3.28) and DORIS remission (OR 2.22, 95% CI 1.45-3.38). However, patients in this group were at a greater risk of damage accrual (hazard ratio 1.82, 95% CI 1.50-2.21) and lower PCS scores, meaning poorer physical health (regression coefficient [RC] −3.63, 95% CI −4.58 to −2.68), but not MCS scores (RC 0.68, 95% CI −0.50 to 1.86). Conclusion: Despite higher attainment of treatment targets, patients with LO-SLE experienced greater damage accrual and poorer physical health, suggesting that disease activity targets alone may not fully identify outcome risk in LO-SLE.

Aim: To compare risks of malignancy, opportunistic infections, and venous thromboembolism between the targeted synthetic disease‐modifying antirheumatic drugs (tsDMARDs) and biologic DMARDs (bDMARDs) at the 2nd and 3rd lines of therapy (LOT). Methods: We conducted a cohort study using the National Database of Health Insurance Claims (2013–2021). Patients with rheumatoid arthritis (RA) initiating tsDMARDs or bDMARDs after conventional synthetic DMARDs (csDMARDs) were identified at the 2nd LOT or 3rd LOT. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox models weighted by inverse probability of treatment weighting. Results: Among 498 813 csDMARD initiators, 66 638 and 4177 initiated bDMARDs and tsDMARDs at 2nd LOT; 14 085 and 1757 initiated bDMARDs and tsDMARDs at 3rd LOT. For malignancy, HRs (95% CIs) for tsDMARDs versus bDMARDs were 0.92 (0.60–1.43) at 2nd LOT and 0.94 (0.53–1.65) at 3rd LOT. HRs (95% CIs) for pneumocystis pneumonia (PCP) and deep vein thrombosis (DVT) were as follows: PCP, 0.98 (0.75–1.29) at 2nd LOT and 1.12 (0.81–1.54) at 3rd LOT; DVT, 1.13 (0.64–1.99) at 2nd LOT and 0.96 (0.52–1.78) at 3rd LOT. In contrast, herpes zoster (HZ) risk was consistently higher with tsDMARDs (2nd LOT: HR, 2.61 [95% CI, 2.24–3.05]; 3rd LOT: HR, 2.90 [95% CI, 2.38–3.53]). Conclusions: In the nationwide Japanese cohort, tsDMARDs did not show increased malignancy risk compared to bDMARDs, and PCP risk had no clear difference at 2nd and 3rd LOTs, whereas the risk of HZ was higher with tsDMARDs.

Objectives: To evaluate the effectiveness and safety of biological disease-modifying antirheumatic drugs (bDMARDs) in rheumatoid arthritis (RA)-associated progressive pulmonary fibrosis (PPF). Methods: Real-world data were retrospectively collected in RA-associated PPF during the first year after bDMARD initiation. The primary outcome was change in pulmonary function and computed tomography (CT) visual scores at week 52. The secondary outcomes included comparisons of pulmonary function, CT scores, Clinical Disease Activity Index (CDAI), drug retention rates and adverse event rates over 52 weeks among the tumour necrosis factor inhibitor (TNFi), cytotoxic T-lymphocyte-associated antigen 4 immunoglobulin (CTLA4-Ig) and interleukin-6 receptor inhibitor (IL-6Ri), using propensity score-based inverse probability of treatment weighting (PS-IPTW). Results: Among 2484 patients with RA initiating bDMARDs, 443 had RA-associated interstitial lung disease (ILD) and 135 had RA-associated PPF (TNFi, n = 35; CTLA4-Ig, n = 45; IL-6Ri, n = 55). Treatment with bDMARDs markedly improved CDAI at week 52, and pulmonary function and CT scores remained stable. PS-IPTW-adjusted comparisons showed no significant differences in CDAI, CT scores or drug retention rates among the bDMARD groups. However, forced vital capacity (FVC) improved in IL-6Ri compared with TNFi (−3.2% vs + 3.3%, P = 0.011; Cohen’s d = 0.630). Adverse events were less frequent in CTLA4-Ig. Multivariate logistic regression analysis identified IL-6Ri treatment, non-usual interstitial pneumonia (UIP) pattern and lower CDAI at week 52 as independent predictors of FVC improvement. Conclusion: Tight control of RA disease activity with bDMARDs appears crucial in RA-associated PPF. In this real-world comparative study, IL-6Ri may have contributed to improved FVC, whereas CTLA4-Ig may have a favourable safety profile.