INTRODUCTION:IgG4-related disease (RD) is characterized by multiple organ inflammation and enlargement, nodular or hypertrophic lesions, significant infiltration of B cells and IgG4-positive plasma cells, and characteristic fibrosis on histology. It causes diverse organ damage, decreased quality of life, and increased mortality. AREAS COVERED:Treatment typically involves systemic glucocorticoids, which show good initial response rates. However, treatment resistance and flares upon dose reduction or discontinuation are commonly observed. Although the toxicity of glucocorticoids gathers attention, no glucocorticoid-sparing agent has been approved. The involvement of the immune system, including B cells and plasmacytes, in pathological processes has been demonstrated, and the Phase III MITIGATE trial using an anti-CD19 antibody inebilizumab met its primary endpoint, with inebilizumab recently receiving the first regulatory approval for treatment of IgG4-RD in the United States, the European Union, Japan, and others. EXPERT OPINION:This article provides an overview of advances in treatment strategies for IgG4-RD, shedding light upon the characteristics of inebilizumab and results of the clinical trials. Various targeted therapies under the development are expected to overcome limitations in safety and efficacy of glucocorticoids and to reduce risk of organ damage and fibrosis.

OBJECTIVES:This study aimed to develop and validate a prediction model for the future progression of difficult-to-treat rheumatoid arthritis (D2T RA) and support the precise use of biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs). METHODS:Data were analysed from 1221 patients with rheumatoid arthritis in the FIRST registry, a multicentre collaborative database, who initiated their first b/tsDMARD. 25 prediction models for D2T RA were generated using 43 baseline characteristics prior to initiating the first b/tsDMARD. Model performances were tested. A scoring system based on the selected model was designed and internally validated for use in routine clinical practice. RESULTS:Among the 1221 patients, 193 (15.8%) progressed to D2T RA after a median of 54.0 months. These patients had higher tender joint count, global assessment, pain scale, Health Assessment Questionnaire score and Clinical Disease Activity Index score and more frequent coexisting lung disease. Among the machine learning models tested, Lasso logistic regression performed best (area under the curve 0.71), identifying pain scale, erythrocyte sedimentation rate and coexisting lung disease as key predictors. The scoring system based on these predictors demonstrated comparable performance. Among patients identified as high risk for D2T RA by the scoring system, interleukin-6 receptor inhibitors (IL-6Ri) significantly reduced D2T RA progression (relative risk (RR): 0.48). CONCLUSION:This study developed and validated a scoring system to predict D2T RA progression and identify patients at high risk and suggested the advantages of IL-6Ri. This system may advance precision medicine in RA and may contribute to controlling unmet needs.

To evaluate the intermediate treatment targets for Still's disease proposed by EULAR/PReS recently, we conducted this post-hoc analysis of the Phase III trial of tocilizumab and its long-term extension to assess the achievement probability of these targets with tocilizumab. Additionally, we assessed the associations of the intermediate treatment targets with long-term outcomes, including glucocorticoid-free clinically inactive disease (CID) and recurrence. Given the predefined glucocorticoid tapering schedule, we also evaluated the achievement of CID irrespective of glucocorticoid dosage when assessing treatment targets at Months 3 and 6. Twenty-one patients were followed for a median of 39.8 months. The week 4 target was achieved in 57.1%, while 47.6% and 38.1% achieved CID at months 3 and 6, respectively. At the final visit, 57.1% and 28.6% achieved CID and glucocorticoid-free CID, respectively. Achievement of the week 4 target and CID at month 6 was associated with subsequent glucocorticoid-free CID (50% vs. 0%, p = 0.01; 62.5% vs. 7.7%, p = 0.01). Month 6 CID achievers had higher baseline swollen joint counts and lower interferon-γ levels. In conclusion, achievement of intermediate treatment targets was associated with long-term CID, suggesting that these targets may also be useful in treatment with tocilizumab. CLINICAL TRIAL REGISTRATION:UMIN000012987, UMIN000018414.

Objectives Randomised controlled trials (RCTs) use restrictive eligibility criteria, raising concerns about external validity for heterogeneous routine-care populations. We aimed to characterise real-world patients with rheumatoid arthritis who would be ineligible for phase III RCTs, to evaluate their outcomes on biological/targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) in routine care and to assess how eligibility status influences comparative effectiveness estimates.Methods We analysed 5462 patients who initiated b/tsDMARDs between 2003 and 2023. RCT ineligibility was defined using common phase III trial exclusions (eg, renal/hepatic impairment). Outcomes were treatment persistence and Clinical Disease Activity Index remission at 26 weeks. Comparative effectiveness across drug classes was estimated using propensity score weighting, stratified by RCT eligibility.Results Overall, 39.7% (2167/5462) met at least one RCT exclusion criterion and ineligible patients had higher baseline disease activity and worse functional status. However, after propensity score adjustment for clinical characteristics, remission rates did not differ between groups (24.0% vs 23.2%; OR 0.90; 95% CI 0.78 to 1.04). The proportion ineligible differed by b/tsDMARDs, highest with interleukin 6 inhibitors (47.4%) and CTLA4-Ig (45.1%) and lowest with Janus kinase (JAK) inhibitors (31.0%). In the RCT-eligible cohort, remission with JAK inhibitors exceeded that with tumour necrosis factor inhibitors (OR 1.39; 95% CI 1.09 to 1.76), consistent with head-to-head RCTs. In the RCT-ineligible cohort, this advantage was attenuated and no longer statistically significant (OR 1.24; 95% CI 0.81 to 1.91).Conclusions Approximately 40% of routine-care patients would be RCT ineligible. Although these patients achieved comparable adjusted outcomes, between-drug differences were smaller than in trial-eligible populations. Real-world comparative analysis should therefore consider composition and calendar time when interpreting treatment effects.

Objectives We established a multicentre prospective registry of patients with systemic sclerosis (SSc) in Japan to evaluate the outcomes in the modern treatment era. This report presents the baseline characteristics of patients enrolled in the registry. Methods Adult SSc patients were prospectively enrolled from 20 medical centres across Japan. Baseline data, including demographics, organ involvement, autoantibody profiles, and patient-reported outcomes, were collected using a dedicated electronic data capture system. Results A total of 835 patients were eligible for analysis. The cohort was predominantly female (85.1%), with a median age of 64 years at enrolment, and 35.0% had diffuse cutaneous SSc. Autoantibodies included anticentromere (38.9%), anti-topoisomerase I (topo I; 33.5%), anti-RNA polymerase III (RNAP III; 12.4%), and anti-U1 RNP (12.9%). Interstitial lung disease (ILD) was the most common organ manifestation (56.0%), followed by upper gastrointestinal (GI) involvement (42.5%), heart involvement (5.3%), pulmonary hypertension (3.4%), scleroderma renal crisis (1.9%), and lower GI involvement (1.2%). Patients with anti-topo I had the worst patient global assessment, whereas those with anti-RNAP III patients had the worst physician global assessment. Conclusions This prospective registry captures real-world data on SSc patients, providing a valuable resource for understanding the clinical spectrum and outcomes in contemporary practice in Japan.

BACKGROUND:IgG4-related disease is a chronic fibroinflammatory condition that can affect virtually any organ system. Glucocorticoid agents are a cornerstone of therapy but are limited by toxic effects, and relapse is common after discontinuation. Obexelimab is a bifunctional monoclonal antibody that inhibits B-cell activity through coengagement of CD19 and FcγRIIb without inducing B-cell depletion. METHODS:In this phase 3, double-blind, randomized, placebo-controlled trial, patients with active IgG4-related disease received subcutaneous obexelimab at a dose of 250 mg or placebo once weekly for 52 weeks. For patients in both groups, glucocorticoids were tapered in a standardized schedule to discontinuation at week 8. The primary end point was the time to the first flare of IgG4-related disease for which rescue therapy was required, as determined by both the investigator and the independent adjudication committee. Key secondary end points included complete remission at week 52 and the cumulative dose of glucocorticoid rescue therapy through week 52. RESULTS:From January 2023 through November 2024, a total of 194 patients underwent randomization (with 97 assigned to each group). The time to the first disease flare that required rescue therapy was significantly longer with obexelimab than with placebo (hazard ratio, 0.44; 95% confidence interval, 0.28 to 0.71; P<0.001); flares were reported in 26 patients (26.8%) in the obexelimab group and in 53 patients (54.6%) in the placebo group. Obexelimab showed a significant benefit over placebo with respect to all the key secondary end points, including complete remission (37.1% vs. 19.6%, P = 0.005) and the cumulative dose of glucocorticoid rescue therapy (329.5 mg vs. 929.8 mg, P = 0.004). Adverse events included arthralgias (in 19.6% of the patients in the obexelimab group vs. 11.3% of those in the placebo group), hypersensitivity (in 16.5% vs. 11.3%), and diarrhea (in 11.3% vs. 6.2%). Serious adverse events occurred in 10.3% of the patients in the obexelimab group and in 18.6% of those in the placebo group. CONCLUSIONS:Among patients with active IgG4-related disease, weekly obexelimab treatment led to a significantly lower risk of disease flare and significantly less glucocorticoid exposure than placebo. (Funded by Zenas BioPharma; INDIGO ClinicalTrials.gov number, NCT05662241.).

OBJECTIVES:This study aimed to assess the noninferiority of spacing a tumour necrosis factor (TNF) inhibitor or reducing the methotrexate dose with continued treatment in patients with rheumatoid arthritis. METHODS:The SORAIRO trial was a multicentre, open-label, randomised, noninferiority study. Patients who had been in remission or low disease activity based on the Clinical Disease Activity Index (CDAI) in the preceding phase III trial of ozoralizumab, a next-generation TNF inhibitor, were enrolled. The precalculated sample size was 141. Patients were randomised into continued treatment, ozoralizumab spacing, or methotrexate dose reduction groups. The primary endpoint was a noninferiority of low disease activity maintenance at week 48 with a prespecified noninferiority margin of -18%. RESULTS:A total of 144 patients were analysed. The mean age was 58.2 years, 75.0% were female, and the mean CDAI was 2.70 with 61.8% in remission. The low disease activity at week 48 was 97.9% in the continued treatment group, 79.2% in the ozoralizumab spacing group (difference, -21.6; 95% CI, -39.9 to -5.7), and 72.7% in the methotrexate dose reduction group (difference, -30.4; 95% CI, -54.0 to -10.5). In the baseline remission subgroup, remission maintenance rates were comparable in the 3 groups (77.4%, 76.7%, 79.2%, respectively). No significant differences were demonstrated in changes in the Health Assessment Questionnaire Disability Index and modified total Sharp score. Adverse events occurred in 68.0%, 59.2%, and 58.0%, respectively. CONCLUSIONS:Treatment tapering may not be feasible in patients with low disease activity, whereas both extending the TNF inhibitor interval and reducing the methotrexate dose may be reasonable options for patients in remission.

This post hoc analysis assessed tofacitinib and adalimumab efficacy and safety, stratified by baseline methotrexate (MTX) dose, in patients with rheumatoid arthritis (RA) in the Oral Rheumatoid Arthritis triaL (ORAL) Strategy study. ORAL Strategy (NCT02187055) was a global, 1-year, phase 3b/4 study. Patients with RA and an inadequate response to MTX were randomized to tofacitinib 5 mg twice daily (BID), tofacitinib 5 mg BID plus MTX, or adalimumab 40 mg once every 2 weeks plus MTX, with MTX dosed per the last weekly dose pre-randomization. This post hoc analysis stratified patients by MTX dose in tertiles normalized by body mass index (BMI) and weight at baseline. Efficacy was assessed using American College of Rheumatology (ACR) 50 response rates at month 6 (primary endpoint); safety was assessed throughout. Efficacy and safety were analyzed descriptively. Of 1146 patients, 97 received MTX < 15 mg/week at baseline, 712 received 15–17.5 mg/week, and 337 received > 17.5 mg/week. In the tofacitinib and adalimumab combination therapy groups, similar ACR50 response rates at month 6 were observed across the baseline BMI-normalized MTX dose tertiles. This trend was also observed in the tofacitinib monotherapy group; however, the ACR50 response rates at month 6 were numerically higher with combination versus tofacitinib monotherapy, regardless of baseline BMI-normalized MTX dose tertile. Generally similar results were observed for the baseline weight-normalized MTX data. No clear trends across baseline BMI-normalized MTX dose tertiles were observed for safety outcomes. In ORAL Strategy, tofacitinib efficacy was generally similar, and there were no clear safety trends regardless of baseline BMI-normalized MTX dose. ClinicalTrials.gov identifier, NCT02187055.

IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory condition that can cause irreversible organ dysfunction and life-threatening complications. Although glucocorticoids are the standard first-line therapy, frequent flares necessitate prolonged use, which is in turn associated with toxicity. Inebilizumab, a CD19-targeted antibody approved in Japan in November 2025, demonstrated efficacy in the phase 3 MITIGATE trial. However, the trial’s eligibility criteria and controlled environment may not reflect the heterogeneity of the routine clinical setting or the long-term profile in the Japanese population. This study (4SigHT Study) aims to evaluate the long-term effectiveness and safety of inebilizumab in Japan. This multicenter, prospective, observational study plans to enroll 100 patients with definite or probable IgG4-RD who are initiating inebilizumab at up to 40 sites in Japan. The study runs from March 1, 2026 to March 31, 2032. It includes up to 14 scheduled visits over a maximum duration of 312 weeks and reflects real-world decisions without mandated interventions. Comprehensive baseline assessments capture disease characteristics, comorbidities, vaccination history, and clinical history, including the frequency and nature of flares over the preceding 52 weeks. Longitudinal data are collected via an electronic data capture system. To ensure data robustness, the study employs a rigorous adjudication process. Suspected flares treated by investigators are adjudicated by an independent data and safety monitoring board using standardized organ-specific flare criteria. The primary outcome is the proportion of participants with an adjudicated clinical flare through week 52. Secondary outcomes include treatment-free complete remission, glucocorticoid-free complete remission, time to clinical flare, annual clinical flare rate, proportion of patients who initiate additional treatment, time to treatment initiation for new or worsening symptoms, and cumulative glucocorticoid dose. Furthermore, the study evaluates the long-term safety of inebilizumab over 6 years. The study is registered with the Japan Registry of Clinical Trials (jRCT1031250749).

Objective To evaluate the long‐term effects of anifrolumab on hematologic and serologic parameters over four years. Methods This analysis included 536 patients with moderate‐to‐severe systemic lupus erythematosus (SLE) who received intravenous anifrolumab 300 mg (n = 358) or placebo (n = 178) in the 52‐week, phase 3 TULIP‐1/2 trials (NCT02446912 and NCT02446899) and continued the same treatment in the 3‐year, long‐term extension (LTE, NCT02794285), or would have done if not discontinued early; 369 patients entered the LTE. Changes from baseline to week 208 in lymphocytes, hemoglobin, platelets, neutrophils, complement C3, C4, anti–double‐stranded DNA (dsDNA), and Igs were analyzed descriptively. British Isles Lupus Assessment Group–based Composite Lupus Assessment (BICLA) response at week 52 was analyzed by treatment and lymphocyte, hemoglobin, and platelet normalization in responders versus nonresponders, regardless of treatment. Results Numerically greater improvements from baseline in lymphocyte, hemoglobin, platelet, and neutrophil levels were observed with anifrolumab over placebo. Comparing anifrolumab versus placebo, lymphocyte and hemoglobin normalization rates were higher and platelet normalization was comparable. BICLA response was associated with lymphocyte, hemoglobin, and platelet normalization over four years, regardless of treatment. Conversely, BICLA responses were higher with anifrolumab versus placebo, irrespective of baseline lymphocyte, hemoglobin, and platelet levels. Improvements in anti‐dsDNA, C3, C4, and Igs from baseline were greater with anifrolumab versus placebo. Conclusion The normalization of hematologic parameters and sustained improvements in serologic markers support the long‐term efficacy of anifrolumab in patients with moderate‐to‐severe SLE. Clinical response to anifrolumab was associated with improvements in biomarkers, suggesting restoration of overall immune health.

BackgroundMetabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by insulin resistance and metabolic syndrome, with type 2 diabetes mellitus (T2DM) as a major risk factor. Additionally, MASLD has been linked to liver fibrosis, which is associated with increased cardiovascular risk. Although noninvasive liver fibrosis markers are widely used, the association of these markers with atherosclerosis and continuous glucose monitoring (CGM) indices in T2DM remains unclear. We aimed to investigate the associations of the fibrosis-4 (FIB-4) index with atherosclerosis and CGM indices in patients with T2DM.MethodsThis study was an exploratory subanalysis of a prospective observational cohort. Among 999 outpatients with T2DM who underwent baseline CGM, 887 patients (excluding heavy alcohol consumers) were analyzed. FIB-4, a noninvasive marker of liver fibrosis, was calculated. Associations of FIB-4 with carotid ultrasound, vascular wave velocity tests, and CGM indices were explored.ResultsAfter adjusting for disease duration, body mass index (BMI), glycated hemoglobin (HbA1c), gamma-glutamyl transferase, and complications, FIB-4 severity category showed significant associations with mean intima-media thickness (IMT), common carotid artery (CCA) maximum IMT, and brachial-ankle pulse wave velocity in ordinal logistic analyses. Consistent with the ordinal logistic analyses, FIB-4 was independently associated with mean IMT in multivariable linear regression. Among the CGM indices, FIB-4 was positively associated with both mean glucose and the standard deviation (SD) of mean glucose. Moreover, FIB-4 was negatively associated with time in range (TIR) and positively with time above range (TAR).ConclusionsIn Japanese patients with T2DM, FIB-4 is associated with carotid thickening and arterial stiffness. Moreover, FIB-4 correlates with the duration of hyperglycemia, suggesting that liver fibrosis may be linked to atherosclerosis through mechanisms involving poor glycemic control. Assessment of liver fibrosis in T2DM is imperative, necessitating monitoring of atherosclerosis and cardiovascular diseases (CVDs) in cases of suspected advanced liver fibrosis.Trial RegistrationThe study has been registered (UMIN000032325) in the University Hospital Medical Information Network Clinical Trials Registry, a nonprofit organization in Japan that meets the requirements of the International Committee of Medical Journal Editors.

Lupus nephritis (LN) is a common and severe manifestation of systemic lupus erythematosus (SLE). We sought to evaluate treatment patterns, treat-to-target state attainment, and outcomes of patients with active LN on non-biologic, conventional therapy, in a large real-world cohort from the Asia–Pacific region. Adult patients enrolled in a multinational lupus cohort were studied for evidence of active LN, defined based on the SLE Disease Activity Index-2000 (SLEDAI-2K)-proteinuria threshold (> 0.5 g/24 h or > 0.05g/mmol), ≥ 2 visits of data, and no exposure to biologics. The subset of these patients who had kidney biopsy-confirmed LN was retrospectively determined. Attainment of treatment goals, including modified versions of complete renal response (mCRR) and primary efficacy renal response (mPERR), lupus low disease activity state (LLDAS) and DORIS remission (REM), and organ damage accrual, were assessed over time following the first visit with proteinuria. One thousand one hundred eighty patients were studied for a median 2.7 [IQR 1.0, 5.0] years, 435 (37

Patients with RA often require alterations of their therapeutic regimen throughout the course of their illness, guided by specific outcomes in line with the treat-to-target principle. Importantly, a significant portion of the RA population fails to achieve sufficient disease control in the long term. Several years ago, the umbrella notion of difficult-to-treat (D2T) RA was introduced to facilitate more structured care and research efforts for patients who remain symptomatic despite having received multiple courses of targeted medications. D2T RA represents a heterogeneous condition sustained by a complex interplay of underlying factors. Biological therapies and Janus kinase inhibitors have demonstrated efficacy in alleviating disease activity in patients refractory to conventional treatments. The use of tailored non-pharmacological therapies (physiotherapy, psychological interventions, etc.) to complement pharmacotherapy chiefly addresses symptoms unrelated to ongoing inflammation. In this narrative review, we examine the current use and relevance of pharmacological and non-pharmacological approaches for D2T RA.

OBJECTIVES:To evaluate the induction of antidrug antibodies (ADAs) and the expression of neutralising antibodies (NAbs) during ozoralizumab treatment, a trivalent anti-TNFα NANOBODY® compound for rheumatoid arthritis, and their impact on safety and efficacy. METHODS:Data from a phase II/III trial of ozoralizumab co-administered with methotrexate (OHZORA) and a phase III trial without methotrexate (NATSUZORA) were analysed. Participants were stratified by ADA and NAb status. Safety and efficacy outcomes were compared across subgroups. RESULTS:ADA induction was observed in 29.2 (OHZORA) and 44.3% (NATSUZORA) of participants; NAb expression was observed in 7.5 and 19.3%, respectively. ADA induction was not associated with treatment continuation or safety. In NATSUZORA, reduced efficacy was observed in the NAb-positive participants, although approximately half of those participants maintained low disease activity through week 52. In OHZORA, NAb expression showed no significant impact on efficacy. Several NAb-positive participants in either trial showed sustained disease control in the long-term extension (HOSHIZORA). CONCLUSIONS:ADA induction had no apparent impact on safety. The effect of NAb expression on efficacy was limited particularly in OHZORA, suggesting that methotrexate co-administration may reduce NAb development and contribute to the optimal preservation of efficacy and safety in clinical practice.

OBJECTIVES:To evaluate the long-term safety of filgotinib as a treatment for moderately to severely active rheumatoid arthritis for up to 5 years in Japanese patients. METHODS:Safety was assessed in Japanese patients receiving filgotinib 200 mg (FIL200) or filgotinib 100 mg (FIL100) in three Phase 3 multinational trials (NCT02889796, NCT02873936, and NCT02886728) and a long-term extension trial (NCT03025308) through May 2022. RESULTS:The pooled Japanese population included 124 patients receiving FIL200 and 107 receiving FIL100, with 413.6 and 352.9 patient-years of exposure [median (maximum) of 3.9 (5.0) and 3.7 (5.1) years], respectively. Overall, 97% of patients experienced treatment-emergent adverse events [EAIR 29.1 (95% confidence interval: 25.5-33.2)], and 73% experienced treatment-related adverse events [21.8 (18.7-25.4)]; rates were similar between FIL200 and FIL100. In the FIL200 and FIL100 groups, EAIRs (95% confidence intervals) were 2.7 (1.5-4.8) and 2.0 (0.9-4.2) for serious infections and 3.1 (1.8-5.4) and 2.6 (1.3-4.9) for herpes zoster. No venous or arterial systemic thromboembolism occurred. There were 0 and 2 incidents of all-cause mortality in the FIL200 and FIL100 groups, respectively. CONCLUSIONS:Long-term filgotinib treatment was well tolerated at 200 and 100 mg in Japanese patients with rheumatoid arthritis over a period of up to 5 years, confirming previous global analyses.