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:Relapsing polychondritis is characterized by recurrent flares, and comparative evidence for relapse prevention using biologics remains limited. We evaluated the association between biologic exposure and relapse incidence. METHODS:This single-centre retrospective cohort study (Kyoto University Hospital, 2000-23) investigated adults with relapsing polychondritis. Follow-up was divided into periods without biologics (No-Bio), with TNF-α inhibitors (TNFi) or with IL-6 receptor inhibitor (IL-6Ri). Primary outcomes were relapsing polychondritis relapse and hospitalized infection. Period-level incidence rate ratios (IRRs) were estimated using negative binomial regression with a log(person-time) offset and adjusted for prespecified covariates, and adjusted absolute event rates and rate differences were estimated by regression standardization. RESULTS:Over 503.5 person-years, 55 patients were included (never-Bio, n = 28; ever-Bio, n = 27). Within the ever-Bio cohort, crude relapse rates were 46.9, 22.4 and 12.5 per 100 person-years during the No-Bio, TNFi and IL-6Ri periods, respectively. In adjusted models, both TNFi and IL-6Ri were associated with lower relapse rates than the No-Bio period (TNFi: IRR 0.4, 95% CI 0.2-0.8; adjusted rate difference, -54.0 events per 100 person-years, 95% CI -141.5 to -5.5; IL-6Ri: IRR 0.2, 95% CI 0.1-0.4; adjusted rate difference, -68.3 events per 100 person-years, 95% CI -149.8 to -21.4). Hospitalized infection estimates were imprecise (TNFi: IRR 0.3, 95% CI 0.1-1.4; IL-6Ri: IRR 0.7, 95% CI 0.2-2.6). CONCLUSION:Biologic exposure was associated with lower relapse rates than during No-Bio periods in relapsing polychondritis, whereas estimates for hospitalized infection were imprecise.

Immune checkpoint inhibitors (ICIs) can cause de novo inflammatory arthritis and flares of pre-existing rheumatoid arthritis (RA). This study aimed to describe and explore the clinical characteristics and treatment outcomes of these arthritis groups in a single-center, exploratory cohort. We retrospectively analyzed patients who developed inflammatory arthritis after ICI therapy, including pre-existing RA flares and the de novo cases. The de novo cases were operationally classified based on the 2010 ACR/EULAR classification criteria into those who fulfilled the criteria (ICI-RA) and those who did not (ICI-IA). Of 41 de novo cases, 10 and 31 patients were classified into ICI-RA and ICI-IA, respectively. Six patients with RA experienced flares. At baseline, serum IgA was numerically higher in the RA flare group than in the non-flare group (median 482.5 vs. 266 mg/dL). At onset, the ICI-IA group exhibited higher eosinophil counts than the RA flare group (median 140 vs. 7/µL), although prior glucocorticoid exposure may have influenced these values. At 365 days, cumulative treatment discontinuation rates were 34.1% for ICI-IA, 20.0% for ICI-RA, and 0% for RA flares. These operationally defined subgroups exhibited heterogeneous clinical courses. These hypothesis-generating findings support future prospective cohorts with detailed immunophenotyping.

To clarify the impact of lower limb and hindfoot alignment and its changes on foot and ankle-related quality of life (QOL) over a 4-year period in patients with rheumatoid arthritis (RA). A total of 258 RA patients (516 feet) who underwent plain X-ray examination with hip-to-calcaneal (HC) view at baseline and a 4-year follow-up, along with Self-Administered Foot Evaluation Questionnaire (SAFE-Q) data at the follow-up were analyzed after excluding patients with prior lower limb surgery or severe ankle destruction (Larsen classification ≥ III or Takakura-Tanaka classification ≥ IIIa). Radiographic parameters representing lower limb and hindfoot alignment were measured using HC view, including hip-knee-ankle angle (HKA), tibio-calcaneal angle (TCA), talar tilt angle (TTA), and the changes of these angles. Clinical and laboratory factors collected included age, sex, BMI, autoantibody titer and positivity, methotrexate (MTX) use, biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) use, cumulative glucocorticoid dose, and Clinical Disease Activity Index. The primary outcome was the association between clinical and radiographic factors and ankle-related QOL. A generalized linear mixed model was used for statistical analysis. The mean age was 62.4 years, 87.2% were female, and 89.9% were seropositive. Over 4 years, hindfoot valgus (TCA) progressed from 4.3° to 6.0°. GLMM showed that age and cumulative glucocorticoid dose negatively affected QOL, while male sex, methotrexate dose, and b/tsDMARDs use were positively associated. Among radiographic parameters, valgus progression of TCA was significantly associated with poorer SAFE-Q outcomes in the "Shoe-related" and "General Health Perception" domains. Baseline HKA predicted valgus progression of TCA, whereas higher BMI, male sex, and larger baseline TCA predicted varus progression. Progressive hindfoot valgus deformity over 4 years, rather than static alignment, negatively impacts foot- and ankle-related QOL in RA patients, particularly in shoe-related function and general health perception. Baseline knee varus deformity predicts longitudinal hindfoot valgus progression.

Immune checkpoint inhibitors (ICIs) have been game changer in cancer therapy but can trigger diverse immune-related adverse events (irAEs) that impact multiple organs. This review offers a unified perspective on irAE risk assessment, underlying mechanisms, and therapeutic strategies aimed at maintaining anticancer efficacy while safeguarding patient well-being. We explore predictive tools—including baseline profiles of several cytokines, HLA genotype, and markers such as interleukin-6—for identifying high-risk individuals. Key drivers of irAEs were dysregulated T- and B-cell responses, antigenic cross-reactivity, and gut microbiome imbalances. Management follows a graduated approach: initial glucocorticoid intervention, followed by biologics (anti-TNF agents, IL-6 receptor blockers) or small-molecule inhibitors (JAK inhibitors) in refractory cases. Real-world data support cautious ICI use in pre-existing autoimmune disorders under stringent monitoring. We also discuss the emerging notion of “inverse irAEs,” where immunosuppression may predispose to secondary malignancies, underscoring the importance of long-term surveillance. Finally, we highlight the urgent need for expansive, multicenter studies to refine irAE management to enhance therapeutic outcomes.

OBJECTIVE:To investigate the long-term safety and efficacy of tocilizumab, an IL-6 receptor inhibitor, in patients with adult-onset Still's disease. METHODS:Patients who completed the precedent phase III trial of tocilizumab for adult-onset Still's disease were enrolled in a long-term extension (LTE) study. Patients received i.v. tocilizumab (8 mg/kg every 2 weeks) until its approval in Japan. The primary end point was safety and tolerability, and secondary endpoints included the ACR coreset response, glucocorticoid doses, tocilizumab dosing interval, remission defined as achieving ACR50 without fever and other laboratory parameters. Efficacy was assessed every 12 weeks. RESULTS:All 22 patients who had completed the precedent phase III trial participated in the LTE study. Sixteen (72.7%) completed the LTE study, with the mean observation period of 168.9 ± 10.8 weeks. Whereas three (13.6%) patients experienced serious adverse events, resulting in two patients withdrawn from the trial, no new safety signal was detected. Treatment efficacy was maintained through the LTE study, with the ACR70 response rate of 68.2% and 95.2% reduction in glucocorticoid doses from the start of the phase III trial and glucocorticoid-free remission of 40.9% at the last visit. Laboratory markers such as CRP and ferritin remained well controlled. The dosing interval was successfully extended in 63.6% of patients, with the overall mean tocilizumab interval at the final visit of 3.4 weeks. CONCLUSIONS:During the observation period, no new safety findings were observed with the long-term use of tocilizumab. Response to tocilizumab was sustained even with an extended dosing interval, with substantial glucocorticoid dose reduction or discontinuation. CLINICAL TRIAL REGISTRATION:UMIN000018414.

OBJECTIVES:Cardiovascular disease (CVD) accounts for ∼40% of deaths among patients with RA, yet the burden of heart failure (HF) within this population remains poorly characterized. Using the Kyoto University Rheumatoid Arthritis Management Alliance (KURAMA) cohort, we aimed to quantify the prevalence of HF among RA outpatients and develop a practical HF screening tool that uses variables readily available to rheumatologists in routine clinical practice. METHODS:A cross-sectional study of 542 outpatients with RA was conducted. Their HF status was determined using a prespecified multistep algorithm that integrated clinical history, loop diuretic use, N-terminal pro-B-type natriuretic peptide (NT-proBNP), echocardiography and careful differentiation from interstitial lung disease (ILD). Adaptive LASSO regression was applied to identify independent factors associated with HF and construct a detection score using non-cardiac variables. RESULTS:HF was detected in 26.5% of patients with RA. Older age, lower haemoglobin (Hb) levels, higher serum creatinine (CRE) levels and higher Simplified Disease Activity Index (SDAI) were identified as independent non-cardiac factors associated with HF. A four-factor HF detection score was constructed based on adjusted odds ratios. The area under the receiver operating characteristic curve (AUC) for the discrete score based on variables routinely available in rheumatology clinics was 0.793, comparable to that of NT-proBNP ≥ 125 pg/ml alone (AUC = 0.814). CONCLUSION:HF affects over one in four RA outpatients. A simple four-factor score may serve as a practical first-line triage tool to identify patients who warrant further cardiac evaluation and cardiology referral.

To evaluate the long-term impact of mRNA-based COVID-19 vaccination on autoantibody titers, rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA), and disease control in rheumatoid arthritis (RA). RA patients with at least five visits before COVID-19 vaccination started were included and categorized by their vaccination status. Changes in RF and ACPA titers were analyzed using generalized linear mixed models to assess intra-patient trends over up to seven vaccine doses. Comparisons of autoantibody titers, seroconversion rates, and disease flares between vaccinated and non-vaccinated patients were performed using weighted generalized linear models with propensity score overlap weighting to adjust for confounding. Among 427 patients (359 vaccinated, 68 non-vaccinated), RF showed a slight but statistically significant decrease after repeated mRNA vaccinations (p < 0.001), while ACPA remained stable (p = 0.325). No significant differences in RF or ACPA were observed between the vaccinated and non-vaccinated patients after covariate adjustment. RF seroconversion occurred in 19.1% of RF-negative vaccinated patients and 11.8% of non-vaccinated patients and ACPA seroconversion occurred in 8.2% of ACPA-negative vaccinated patients and 13.3% of non-vaccinated patients, showing no statistically significant difference. No significant differences were found in the number of disease flares (3.82 ± 4.05 in vaccinated, 4.73 ± 5.38 in non-vaccinated). mRNA-based COVID-19 vaccination did not lead to increased autoantibody titers, seroconversion rates, or disease flare. Instead, successive vaccine doses led to a significant RF decrease, suggesting that the mRNA vaccine has a potentially beneficial immunomodulatory effect and support the safety of repeated boosters in RA.

OBJECTIVES:We evaluated real-world disease activity, treatment patterns and pregnancy outcomes in women with rheumatoid arthritis (RA) utilizing a multicentre Japanese cohort. Feasibility and impact of a treat-to-target (T2T) approach during pregnancy were also examined. METHODS:A retrospective observational study analysed 118 pregnancies in patients with RA from the multicentre ANSWER cohort (2013-2023) across eight Japanese academic institutions. Clinical characteristics, treatment regimens and RA Disease Activity Scores of 28 joints based on C-reactive protein (DAS28-CRP) were assessed at preconception, during each trimester and postpartum. Pregnancy and neonatal outcomes were analysed. RESULTS:Of 118 pregnancies, 92.8% achieved full-term deliveries (median birthweight: 2949 g). Remission or low disease activity was maintained in ∼85% of patients throughout pregnancy, with increased postpartum disease activity. Patients who continued biologic disease-modifying antirheumatic drugs (bDMARDs) during pregnancy (n = 35) exhibited significantly lower DAS28-CRP scores during the second and third trimesters compared with those who discontinued (n = 24) (P = 0.007 and P = 0.0002, respectively). Etanercept or certolizumab pegol use was associated with favourable disease control. Tocilizumab (n = 6) or abatacept (n = 2) was not associated with adverse maternal or neonatal outcomes. Glucocorticoid use was associated with increased disease activity. Salazosulfapyridine use correlated with increased birth weight (P = 0.003) and gestational age (P = 0.051). CONCLUSION:T2T management, including selective continuation of bDMARDs, was associated with favourable maternal disease control and reassuring pregnancy outcomes. Although the absence of long-term follow-up is a limitation, these findings provide real-world evidence supporting this approach. Larger prospective studies are required to confirm maternal and neonatal safety beyond the early postpartum.

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.

OBJECTIVE:This study aimed to compare drug retention rates according to the baseline neutrophil-to-lymphocyte ratio (NLR) in patients with RA initiating biologic/targeted synthetic DMARDs (b/tsDMARDs). METHODS:Data were obtained from 774 treatment courses with moderate to high disease activity at the initiation of b/tsDMARD therapy from the Kansai Multicentre ANSWER cohort. Patients were categorized into NLRlow group and NLRhigh group based on the median NLR value of 3.30. A multivariate Cox proportional hazards model, adjusted for potential confounders, was used to estimate hazard ratios (HRs) for drug retention over 2 years. RESULTS:Patients in the NLRhigh group exhibited significantly higher baseline Clinical Disease Activity Index (CDAI) scores (P = 0.004) and more frequent glucocorticoid use (P < 0.001) than those in the NLRlow group. In the NLRlow group, drug retention rates did not significantly differ among tumour necrosis factor inhibitors (TNFi), anti-IL-6 receptor antibodies (aIL-6R), cytotoxic T lymphocyte antigen 4 immunoglobulin (CTLA4-Ig) and Janus kinase inhibitors (JAKi). In contrast, within the NLRhigh group, treatment with aIL-6R and JAKi was associated with significantly higher retention rates compared with TNFi (HR = 0.53, 95% CI: 0.32-0.88; HR = 0.36, 95% CI: 0.20-0.64, respectively). At 12 months, CDAI scores did not significantly differ among the four treatment groups in either NLR group. CONCLUSION:In patients with elevated baseline NLR values, aIL-6R and JAKi may offer superior drug retention compared with TNFi when initiating b/tsDMARD therapy.

High-riding vertebral artery (HRVA) at C2 is more prevalent in patients with rheumatoid arthritis (RA) than in the general population, but its clinical significance remains unclear. Recent evidence in non-RA individuals suggests that unilateral HRVA may contribute to atlantoaxial joint degeneration (AAJD) through asymmetric mechanical stress. This study investigated whether unilateral HRVA is similarly associated with the progression of AAJD in RA. We retrospectively analyzed 336 RA patients from the single institutional cohort who underwent CT scans, including C1-C2, between 2011 and 2024. HRVA was defined as a C2 internal height < 2 mm and/or isthmus height < 5 mm. Morphological parameters (C1 lateral mass height, C1/2 coronal inclination, and C1/2 relative rotation angle) and AAJD grades were evaluated. Logistic regression was used to identify factors associated with moderate-to-severe AAJD (grade ≥ 2). HRVA was observed in 147 patients (116 unilateral). Compared with patients without HRVA, those with unilateral HRVA had longer RA duration (17.5 vs. 12.9 years, p < 0.01) and higher ACPA positivity (78.8% vs. 66.9%, p < 0.05), but no differences in disease activity or medication use. Moderate-to-severe AAJD was significantly more frequent in the unilateral HRVA group (62.9% vs. 42.3%, p < 0.001). Multivariate analysis identified older age, longer RA duration, and unilateral HRVA as independent risk factors for AAJD. These findings indicate that unilateral HRVA is independently associated with atlantoaxial facet joint degeneration in patients with RA in addition to aging and disease duration, suggesting a role of asymmetric mechanical loading in cervical joint pathology.

Patients with rheumatoid arthritis (RA) are at a higher risk for sarcopenia than the general population. Exercise therapy can improve muscle strength in older adults; however, its efficacy in older patients with RA has not been fully established. This study aimed to evaluate the efficacy of a personalized exercise program on physical function in older patients with RA at high risk for sarcopenia. A single-centre, parallel-group, two-arm, superiority randomized controlled trial was conducted in patients with RA aged 60–85 years who were at risk of sarcopenia. The intervention group (n = 69) underwent a 16-week personalized exercise program in addition to nutritional guidance and standard care, whereas the control group (n = 65) received only nutritional guidance and standard care. The primary outcome was the change in the total Short Physical Performance Battery (SPPB) scores from baseline to week 16. A total of 140 patients were randomized. Of these, 134 initiated the assigned intervention. There was a 0.2-point difference in SPPB total score from baseline to week 16 between the intervention group (+ 0.4 points) and the control group (+ 0.2 points); 95

Herein, we present the first case of chronic Campylobacter fetus infection-related glomerulonephritis (IRGN) in a 69-year-old man with a permanent cardiac pacemaker. The patient had a prior episode of fever and glomerulonephritis of undetermined etiology, and at that time, low-dose steroid therapy resulted in improved urinary findings and kidney function. This time the patient again developed deterioration of kidney function with microhematuria, proteinuria, high serum C-reactive protein levels, and positive titers of anti-double-stranded DNA antibody and proteinase 3 anti-neutrophil cytoplasmic antibody (ANCA). A kidney biopsy revealed endocapillary and mesangial hypercellularity, interstitial infiltration of neutrophils, and positive staining for C3 and IgM in the mesangium and glomerular capillary walls. Notably, histological staining for nephritis-associated plasmin receptor (NAPlr)/plasmin activity was also positive. Similar laboratory and pathological findings in the first and second kidney biopsies and repeated detection of C. fetus in blood cultures led to the diagnosis of IRGN associated with persistent pacemaker-related infection. The nephritis improved following antibiotic therapy targeting C. fetus. C. fetus can cause sustained bacteremia and prolonged infection of indwelling devices, and can be a causative organism for recurrent IRGN. Clinicians must distinguish IRGN from autoimmune diseases such as lupus nephritis and ANCA-associated vasculitis.

OBJECTIVES:While biologic or targeted synthetic DMARDs (b/tsDMARDs) improve mental status in RA patients with high disease activity, their effects after achieving low disease activity (LDA) or remission are unclear. We compared the effectiveness of b/tsDMARDs on mental status in RA patients who had reached treatment targets. METHODS:We analysed RA patients who achieved LDA or remission using b/tsDMARDs. Mental health was assessed at baseline and 1 year using the Hospital Anxiety and Depression Scale (HADS). Minimal clinically important difference (MCID) thresholds were calculated. Using weighted generalized linear models with propensity score overlap weighting, we estimated the relative risk (RR) of achieving clinically meaningful improvement, defined as an improvement exceeding the MCID threshold for HADS anxiety (HADS-A) or depression (HADS-D) (primary outcome), and analysed the change in HADS subscale scores (secondary outcome) comparing b/tsDMARDs classes. RESULTS:A total of 363 treatment courses from 328 RA patients were analysed. Compared with tumour necrosis factor inhibitor (TNFi) treatment, non-TNF-targeted therapies were associated with higher rates of clinically meaningful improvement in HADS-A (RR 1.80, 95% CI 1.25-2.59) and HADS-D (RR 1.44, 95% CI 1.02-2.06). Among these, IL-6 receptor inhibitors (IL-6Ris) and Janus kinase inhibitors (JAKis) were associated with a significant improvement in anxiety. No significant difference was observed in HADS-D improvement across b/tsDMARD classes. CONCLUSION:In RA patients who achieved treatment targets, non-TNF-targeted therapies, particularly IL-6Ri and JAKi, significantly improved anxiety and depression at 1 year compared with TNFi.

BACKGROUND:Type I interferonopathy is characterized by aberrant upregulation of type I interferon signaling. The mRNA interferon signature is a useful marker for activation of the interferon pathway and for diagnosis of type I interferonopathy; however, early diagnosis is challenging. OBJECTIVE:This study sought to identify the proteomic interferon signature in dried blood spot (DBS) samples. The aim was to evaluate the usefulness of the interferon signature for neonatal screening and to gain insight into presymptomatic state of neonates with inborn errors of immunity (IEIs). METHODS:DBS samples from healthy newborns/adults, patients with type I interferonopathy or other IEIs as well as from neonates with viral infections, including some samples obtained during the presymptomatic neonatal period, were examined by nontargeted proteome analyses. Expression of interferon-stimulated genes (ISGs) was evaluated and a DBS-interferon signature was defined. Differential expression/pathway analysis was also performed. RESULTS:The ISG products IFIT5, ISG15, and OAS2 were detected. Expression of IFIT5 and ISG15 was upregulated significantly in individuals with type I interferonopathy. We defined the sum of the z scores for these as the DBS-interferon signature, and found that patients with IEIs other than type I interferonopathy, such as chronic granulomatous disease (CGD), also showed significant elevation. Additionally, neonatal samples of type I interferonopathy and CGD patients showed high interferon signatures. Pathway analysis of neonatal CGD samples revealed upregulation of systemic lupus erythematosus-like pathways. CONCLUSION:Upregulation of the interferon pathway exists already at birth-not only in neonates with type I interferonopathy but also in other IEIs, including CGD.