OBJECTIVE:Herpes zoster (HZ) is a common adverse event associated with Janus kinase inhibitors (JAKi); however, direct comparisons using real-world data are lacking, which we aimed to clarify. METHODS:We retrospectively analyzed data from the multicenter ANSWER cohort, including 1,096 treatment courses from 765 patients with RA (84.1% female; mean age, 63.9 years; mean follow-up, 18.2 months) who initiated treatment with tofacitinib, baricitinib, peficitinib, upadacitinib, or filgotinib. Incidence rates (IRs) of HZ were calculated per 100 patient-years using exact Poisson method. Time-to-event and treatment retention analysis were performed using Kaplan-Meier methods, and hazard ratios (HRs) were estimated using Cox proportional hazards models adjusted for patient characteristics. RESULTS:During follow-up, HZ occurred in 88 treatment courses. The IRs per 100 person-years were 5.84 for tofacitinib, 6.21 for baricitinib, 3.79 for peficitinib, 7.38 for upadacitinib, and 1.73 for filgotinib. In the adjusted Cox model, filgotinib (reference) was associated with a significantly lower hazard of HZ compared with tofacitinib (HR, 7.68; 95% CI, 1.71-34.6; P=0.008), baricitinib (HR, 6.35; 95% CI, 1.48-27.1; P=0.013), and upadacitinib (HR, 4.75; 95% CI, 1.11-20.3; P=0.036), whereas no significant differences were observed in treatment retention. Patient-related variables, including age, sex, prior HZ, and vaccination history, were not significantly associated with HZ risk. CONCLUSION:Filgotinib showed a lower observed risk of HZ compared with tofacitinib, baricitinib, and upadacitinib. Given the limited number of events and observational design, further large-scale studies with longer follow-up are warranted to confirm these findings.

Selecting the optimal biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) for individual patients with rheumatoid arthritis (RA) remains an unresolved clinical challenge. We developed and externally validated a causal inference framework that integrates a double machine learning-based causal forest model with guideline-derived safety constraints for b/tsDMARD category selection. Using multi-centre registry data (4,885 treatment courses from eight Japanese rheumatology facilities), the model was trained on six facilities (n = 2,425) and externally validated on two independent facilities (n = 2,460). The framework first estimates individualised treatment effects via the causal forest with double machine learning, then applies a guideline-based safety rule that exclude JAK inhibitors for patients with multiple cardiovascular risk factors before finalising recommendations. Patients receiving treatments concordant with AI recommendations achieved significantly higher clinical disease activity index response rates than those with discordant treatments: crude analysis 33.6% vs 27.2% (absolute risk difference [ARD] = 6.4%, P = 0.002; number needed to treat = 16), propensity score-matched analysis 33.6% vs 28.2% (ARD = 5.5%, P = 0.037), and inverse probability of treatment weighting 31.6% vs 27.3% (ARD = 4.3%, P = 0.044). The system identified significant heterogeneity in conditional average treatment effects (group average treatment effects Q4–Q1: Z = 4.64, P < 0.001) and 12 clinically interpretable effect modifiers confirmed by two independent analytical methods. Treatment line-stratified analysis revealed that second-line patients derived the greatest benefit (ARD = 16.0%, number needed to treat = 6.3, P = 0.0002). These findings demonstrate that an AI framework combining data-driven causal inference with guideline-derived safety guardrails can identify patients who benefit from personalised b/tsDMARD selection in RA.

Selecting the optimal biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) for patients with rheumatoid arthritis remains challenging. We developed and externally validated a causal inference framework combining double machine learning-based causal forests with guideline-derived safety constraints. Using multi-centre registry data from eight Japanese rheumatology facilities (4885 treatment courses), the model was trained on six facilities (n = 2425) and externally validated on two facilities (n = 2460). The framework estimates individualised treatment effects and applies a guideline-based safety rule that excludes Janus kinase inhibitors for patients with multiple cardiovascular risk factors. Patients receiving AI-concordant treatments had higher response rates than those receiving discordant treatments: 33.6% vs 27.2% in crude analysis (absolute risk difference [ARD] = 6.4%, P = 0.002; number needed to treat [NNT] = 16), with consistent effects after propensity score matching (ARD = 5.5%, P = 0.037) and inverse probability of treatment weighting (ARD = 4.3%, P = 0.044). The model identified treatment-effect heterogeneity (group average treatment effects Q4–Q1: Z = 4.64, P < 0.001) and 12 clinically interpretable effect modifiers confirmed by two analytical methods. Benefit was greatest in second-line patients (ARD = 16.0%, NNT = 6.3, P = 0.0002), supporting personalised b/tsDMARD selection.

Prioritizing causal variants in a regulatory region of the genome remains challenging. Here we introduce the Expression Modifier Score (EMS) v2, allowing prioritization of regulatory variants with high precision. EMSv2 achieves higher prediction performance compared to alternative methods, especially in tissues with low sample size such as brains. We show that the power gain is attributed to implementation of (1) features accounting for long-range DNA sequence interaction, (2) customization of loss-function in training, and (3) multi-task learning framework. We then apply EMSv2 to an independent eQTL data from a Japanese population to demonstrate that EMSv2 outperforms alternative methods in regulatory variant prioritization and can be utilized for functionally-informed fine-mapping in a distinct population. We also show that EMSv2 can be utilized in combination with the gene-level polygenic prioritization score (PoPS) to prioritize complex trait-causal regulatory variants. Our work accelerates regulatory variant prioritization in the human genome. Expression Modifier Score v2 integrates Enformer-derived features and multi-task learning to prioritize regulatory variants and support interpretation of noncoding genetic associations.

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.

The gut microbiota is a critical regulator of systemic immune homeostasis; accumulating evidence implicates specific commensal bacteria, termed “pathobionts,” in autoimmune disease pathogenesis. However, the definition of pathobionts remains context-dependent, as their effects are influenced by host genetics and host–microbe interactions. In this review, we summarize representative pathobionts supported by functional evidence in selected extraintestinal autoimmune diseases and discuss how these mechanisms may inform phage-based microbiome-targeted interventions. Mechanistically, pathobionts contribute to autoimmune disease through multiple pathways, including molecular mimicry, induction of intestinal T helper 17 and T follicular helper cell responses, disruption of regulatory T cell homeostasis, intestinal barrier dysfunction, and bacterial translocation from the gut to extraintestinal sites. These processes highlight the central role of gut-associated lymphoid tissue in initiating systemic autoimmunity, and targeting disease-associated microbes represents a promising therapeutic strategy. Whole-phage therapy, which enables highly specific bacterial elimination, has shown efficacy in preclinical immune-mediated disease models, but may be affected by variable in vivo replication, bacterial receptor-mediated resistance, anti-phage immune responses, and ecological effects on the resident microbiome. Phage-derived enzymes that lyse bacterial cell walls, such as endolysins, represent a complementary therapeutic modality that specifically targets bacterial peptidoglycan through cell wall-binding and catalytic domains. Collectively, these findings support the concept that pathobiont-targeted interventions, particularly phage-based strategies, may provide microbiome-directed, immunosuppression-sparing therapeutic approaches for selected patient subsets.

An altered gut microbiota, particularly the expansion of Prevotellaceae members, is implicated in the pathogenesis of rheumatoid arthritis (RA), yet the mechanisms behind this phenomenon remain unclear. Here, we demonstrate that Palleniella intestinalis, a member of the Prevotellaceae family, induces 100% of arthritis incidence in genetically resistant C57BL/6 mice. Inoculation with P. intestinalis modifies gut microbiota ecology, increases intestinal permeability, and selectively activates colonic CD11b+CD11c+ myeloid cells, facilitating T helper 17 (Th17) differentiation and driving joint inflammation. In vitro, outer membrane vesicles (OMVs) from P. intestinalis and Segatella copri (formerly known as Prevotella copri) prime bone marrow-derived dendritic cells (BMDCs) to drive Th17 differentiation in an interleukin-6 (IL-6)-dependent manner. Similar innate immune activation with elevated IL-6 levels was observed in gut biopsies from new-onset patients with RA. Transfer of Prevotellaceae-derived OMVs or Prevotellaeae-primed BMDCs replicates the heightened arthritis incidence in resistant mice, highlighting the critical role of intestinal immune activation in RA.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease characterized by optic neuritis and transverse myelitis, with an unclear genetic background. A genome-wide meta-analysis of NMOSD in Japanese individuals (240 patients and 50,578 controls) identified significant associations with the major histocompatibility complex region and a common variant close to CCR6 (rs12193698; p = 1.8 × 10-8, odds ratio [OR] = 1.73). In single-cell RNA sequencing (scRNA-seq) analysis (25 patients and 101 controls), the CCR6 risk variant showed disease-specific expression quantitative trait loci effects in CD4+ T (CD4T) cell subsets. Furthermore, we detected somatic mosaic chromosomal alterations (mCAs) in various autoimmune diseases and found that mCAs increase the risk of NMOSD (OR = 3.37 for copy number alteration). In scRNA-seq data, CD4T cells with 21q loss, a recurrently observed somatic event in NMOSD, showed dysregulation of type I interferon-related genes. Our integrated study identified novel germline and somatic mutations associated with NMOSD pathogenesis.

OBJECTIVES:The impact of individual biological/targeted synthetic DMARD (b/tsDMARD) on kidney function in patients with RA remains unclear. This study aimed to determine the comparative effects of b/tsDMARDs on chronic kidney disease (CKD) incidence in patients with RA. METHODS:This multicentre cohort study included patients with RA who had baseline estimated glomerular filtration rate (eGFR) of ≥60 ml/min/1.73 m2 and started a TNF inhibitor (TNFi), cytotoxic T-lymphocyte-associated antigen-4-Ig (CTLA4-Ig), interleukin-6 receptor inhibitor, or Janus kinase inhibitor (JAKi) in Japan. Multiple propensity score-based inverse probability weighting (IPW) was used to adjust confounders. The incidence of CKD was compared among b/tsDMARDs using IPW mixed-effect Cox proportional hazards models and linear mixed-effect models with IPW-examined trajectories of eGFR. RESULTS:Among 2187 patients with 3068 treatment courses and up to 11 years of follow-up, CKD occurred in 275 cases. Compared with the CTLA4-Ig group, the TNFi group had a significantly lower CKD incidence [hazard ratio (HR) 0.67, 95% CI 0.46-0.97, P = 0.04], whereas the JAKi group had a significantly higher incidence (HR 2.16, 95% CI 1.23-3.79, P = 0.01). The trajectory of eGFR was significantly greater in the JAKi group than in the CTLA4-Ig group (CTLA4-Ig: -1.28 ml/min/1.73 m2/year, JAKi: -2.29 ml/min/1.73 m2/year, P < 0.001). CONCLUSIONS:TNFi use was associated with reduced CKD incidence, whereas JAKi showed a less protective association for kidney function in patients with RA.

OBJECTIVES:We aimed to identify the impact of rheumatoid factor (RF) or anticyclic citrullinated peptide antibody (ACPA) titres on the retention of biological disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase inhibitors (JAKis) in patients with rheumatoid arthritis. METHODS:We retrospectively analysed 5312 courses of bDMARDs or JAKis from the ANSWER cohort. To calculate hazard ratios (HRs) for treatment discontinuation, we used multivariate Cox proportional hazards modelling, adjusted for potential confounders. RESULTS:HRs for discontinuation due to ineffectiveness were calculated based on RF classification, revealing that anti-interleukin-6 receptor (aIL-6R) antibodies exhibited the highest retention rates regardless of RF titre. In the RF-positive group, tumour necrosis factor inhibitors (TNFis) showed lower retention rates, whereas cytotoxic T lymphocyte-associated antigen-4-Ig (CTLA4-Ig) and JAKis followed aIL-6R in the retention rates. When classified based on ACPA, aIL-6R also exhibited the highest retention rates across all ACPA groups. TNFis showed lower retention rates compared with other agents in the ACPA-positive group, whereas CTLA4-Ig showed lower retention rates in the ACPA-negative group compared with other agents. CONCLUSIONS:Considering effectiveness, aIL-6R showed the highest retention rates regardless of seropositivity. Although CTLA4-Ig and JAKis followed aIL-6R in RF or ACPA-positive cases, CTLA4-Ig showed the lowest retention rates in ACPA-negative cases.

Aberrant immune responses to viral pathogens contribute to pathogenesis, but our understanding of pathological immune responses caused by viruses within the human virome, especially at a population scale, remains limited. We analyzed whole-genome sequencing datasets of 6,321 Japanese individuals, including patients with autoimmune diseases (psoriasis vulgaris, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), pulmonary alveolar proteinosis (PAP) or multiple sclerosis) and coronavirus disease 2019 (COVID-19), or healthy controls. We systematically quantified two constituents of the blood DNA virome, endogenous HHV-6 (eHHV-6) and anellovirus. Participants with eHHV-6B had higher risks of SLE and PAP; the former was validated in All of Us. eHHV-6B-positivity and high SLE disease activity index scores had strong correlations. Genome-wide association study and long-read sequencing mapped the integration of the HHV-6B genome to a locus on chromosome 22q. Epitope mapping and single-cell RNA sequencing revealed distinctive immune induction by eHHV-6B in patients with SLE. In addition, high anellovirus load correlated strongly with SLE, RA and COVID-19 status. Our analyses unveil relationships between the human virome and autoimmune and infectious diseases. Analysis of the blood DNA virome in patients with COVID-19 and autoimmune disease associates endogenous HHV-6 (eHHV-6) and high anellovirus load with increased disease risk, most notably for systemic lupus erythematosus. eHHV-6 carriers show a distinct immune response.

AIM:This multicenter retrospective study evaluated the differential impact of concomitant methotrexate (MTX) and glucocorticoids (GCs) administration by dosage on the effectiveness and safety of biological disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase inhibitors (JAKi) in a real-world cohort of patients with rheumatoid arthritis, adjusting for clinical backgrounds variables. METHODS:The study included 3751 treatment courses (bDMARD- or JAKi-naïve cases, 48.9%; tumor necrosis factor inhibitors: 1668; tocilizumab [TCZ]: 865; abatacept [ABT]: 825; JAKi: 393). Hazard ratios for treatment retention were calculated using multivariate Cox proportional hazards models, adjusted for potential confounders. Improvement in the clinical disease activity index (ΔCDAI) with each formulation was analyzed using mixed-effects models for repeated measures, stratified by concomitant MTX and GCs dosages. RESULTS:Compared to MTX(-), a lower dose of MTX (< 10 mg/week) was associated with significant improvement in ΔCDAI with golimumab (GLM), TCZ, and JAKi and reduced discontinuation due to ineffectiveness of etanercept (ETN). A higher MTX dose (≥ 10 mg/week) demonstrated a similar trend. Compared to GCs(-), a lower dose of GCs (≤ 5 mg/day; prednisolone equivalent) was associated with a diminished ΔCDAI with GLM and an increased discontinuation due to ineffectiveness of ADA and GLM. A higher dose of GCs (> 5 mg/day) was associated with increased discontinuation due to safety with ETN, CZP, and JAKi. CONCLUSIONS:The effects of concomitant MTX and GCs dosages on the effectiveness and safety of biologics and JAKi vary among agents. MTX did not mitigate safety issues, and GCs did not enhance effectiveness of any agents, regardless of dosage.

AIM:To investigate the association of large joint involvement (LJI) with disease activity and drug retention in patients with rheumatoid arthritis (RA) who started receiving a biological disease-modifying antirheumatic drug or Janus kinase inhibitor.METHODS:Patients with RA from a Japanese multicenter observational registry were enrolled. Our definition of large joints included the shoulder, elbow, hip, knee, and ankle joints. Linear mixed-effects models were used to examine changes in the clinical disease activity index (CDAI) score at Week 24 as the primary outcome, and drug retention rates were compared between patients with and without LJI using Cox proportional hazards models. We examined the potential effect modifications of changes in the CDAI by baseline characteristics.RESULTS:Overall, 2507 treatment courses from 1721 patients were included (LJI, 1744; no LJI, 763). Although LJI was associated with significantly higher changes in CDAI from baseline at Week 24 (difference in change in CDAI: -5.84 [-6.65 to -5.03], p < .001), CDAI was significantly higher in patients with LJI over time. Retention rates were similar in both groups. The association of LJI with changes in disease activity was more prominent in patients with a short disease duration, negative anti-citrullinated peptide antibodies, and interleukin-6 receptor inhibitor (IL-6Ri) use.CONCLUSION:Although LJI was associated with a greater reduction in disease activity from baseline, higher disease activity at baseline was not offset over time in patients with LJI, demonstrating that LJI is an unfavorable predictor. An early treat-to-target strategy using an IL-6Ri may be beneficial for patients with LJI.

Objectives: This multicentre, retrospective study aimed to compare retention and reasons for discontinuation between Janus kinase inhibitors (JAKi) and biologic disease-modifying antirheumatic drugs in patients with elderly-onset rheumatoid arthritis (EORA). Methods: Patients with RA enrolled in a Japanese multicentre observational registry between 2015 and 2022 were included. EORA was defined as RA with onset at 60 or over. To adjust confounding factors by indication for initiation of tumor necrosis factor inhibitors (TNFi), interleukin-6 inhibitors (IL-6i), cytotoxic T-lymphocyte associated antigen 4 immunoglobulin (CTLA4-Ig) blockers, or JAKi, a propensity score based on baseline characteristics was used to compare drug retention. To assess the reasons for discontinuation, retention rates for ineffectiveness, adverse events, and remission were analyzed as secondary outcomes. Results: A total of 572 patients with 835 treatment courses were identified (314 TNFi, 175 IL-6i, 228 CTLA4-Ig, and 118 JAKi). After adjusting for differences in baseline characteristics, drug retention was significantly higher for IL-6i (HR = 0.38, 95%CI = 0.27-0.55, p< 0.01) as compared with TNFi. Discontinuation due to lack of effectiveness was lower with the JAKi (HR = 0.38, 95%CI = 0.22-0.66, p< 0.01) and the IL-6i (HR = 0.29, 95%CI = 0.19-0.46, p< 0.01) as compared with the TNFi although the CTLA4-Ig had a similar HR to TNFi. The adjusted incidence of discontinuation due to adverse event was higher in the JAKi (HR = 2.86, 95%CI = 1.46-5.59, p< 0.01) than the TNFi. Conclusions: In EORA patients, IL-6i and JAKi had longer retention and less discontinuation due to ineffectiveness than TNFi. The potential risks of JAKi should be approached with an individualized perspective.

OBJECTIVE:The study objective was to assess the role of CCL19+ lymph node stromal cells of the joint-draining popliteal lymph node (pLN) for the development of arthritis.METHODS:CCL19+ lymph node stromal cells were spatiotemporally depleted for five days in the pLN before the onset of collagen-induced arthritis (CIA) using Ccl19-Cre × iDTR mice. In addition, therapeutic treatment with recombinant CCL19-immunoglobulin G (IgG), locally injected in the footpad, was used to confirm the results. RNA sequencing of lymph node stromal cells combined with T cell coculture assays using tropomyosin receptor kinase (Trk) family inhibitors together with in vivo local pLN small interfering RNA (siRNA) treatments were used to elucidate the pathway by which CCL19+ lymph node stromal cells initiate the onset of arthritis.RESULTS:Spatiotemporal depletion of CCL19+ lymph node stromal cells prevented disease onset in CIA mice. These inhibitory effects could be mimicked by local CCL19-IgG treatment. The messenger RNA sequencing analyses showed that CCL19+ lymph node stromal cells down-regulated the expression of the tropomyosin receptor kinase A (TrkA) just before disease onset. Blocking TrkA in lymph node stromal cells led to increased T cell proliferation in in vitro coculture assays. Similar effects were observed with the pan-Trk inhibitor larotrectinib in cocultures of lymph node stromal cells of patients with rheumatoid arthritis and T cells. Finally, local pLN treatment with TrkA inhibitor and TrkA siRNA led to exacerbated arthritis scores.CONCLUSION:CCL19+ lymph node stromal cells are crucially involved in the development of inflammatory arthritis. Therefore, targeting of CCL19+ lymph node stromal cells via TRK could provide a tool to prevent arthritis.

Objectives To investigate the predictive factors for difficult-to-treat rheumatoid arthritis (D2T RA) and assess the efficacy of biologic DMARDs (bDMARDs) and Janus kinase inhibitors (JAKi).Methods Retrospective analysis was conducted on data from the ANSWER cohort comprising 3623 RA patients treated with bDMARDs or JAKi in Japan. Multivariate Cox proportional hazards modelling was used to analyse the hazard ratios (HRs) for treatment retention.Results Of the 3623 RA patients, 450 (12.4%) met the first two criteria of the EULAR D2T RA definition (defined as D2T RA in this study). Factors contributing to D2T RA included age over 75 (compared with those under 65, hazard ratio [HR] = 0.46; 95% CI: 0.31, 0.69), higher rheumatoid factor (RF) titres (HR = 1.005; 95% CI: 1.00, 1.01), higher clinical disease activity index (HR = 1.02; 95% CI: 1.01, 1.03), lower methotrexate dosage (HR = 0.97; 95% CI: 0.95, 0.99), and comorbidities like hypertension (HR = 1.53; 95% CI: 1.2, 1.95) and diabetes (HR = 1.37; 95% CI: 1.09, 1.73). Anti-IL-6 receptor antibodies (aIL-6R, HR = 0.53; 95% CI: 0.37, 0.75) and JAKi (HR = 0.64; 95% CI: 0.46, 0.90) were associated with fewer discontinuations due to ineffectiveness compared with TNF inhibitors. Oral glucocorticoid usage (HR = 1.65; 95% CI: 1.11, 2.47) was linked to increased discontinuation due to toxic adverse events.Conclusion Younger onset, higher RF titres, and comorbidities predicted D2T RA development. For managing D2T RA, aIL-6R and JAKi exhibited superior drug retention.

Objective We assess the clinical characteristics of patients with cryopyrin‐associated periodic syndrome (CAPS) in Japan and evaluate the real‐world efficacy and safety of interleukin‐1 (IL‐1) inhibitors, primarily canakinumab. Methods Clinical information was collected retrospectively, and serum concentrations of canakinumab and cytokines were analyzed. Results A total of 101 patients were included, with 86 and 15 carrying heterozygous germline and somatic mosaic mutations, respectively. We identified 39 mutation types, and the common CAPS‐associated symptoms corresponded with those in previous reports. Six patients (5.9% of all patients) died, with four of the deaths caused by CAPS‐associated symptoms. Notably, 73.7% of patients (100%, 79.6%, and 44.4% of familial cold autoinflammatory syndrome, Muckle–Wells syndrome, and chronic infantile neurological cutaneous articular syndrome/neonatal onset multisystem inflammatory disease, respectively) achieved complete remission with canakinumab, and early therapeutic intervention was associated with better auditory outcomes. In some patients, canakinumab treatment stabilized the progression of epiphysial overgrowth and improved height gain, visual acuity, and renal function. However, 23.7% of patients did not achieve inflammatory remission with crucial deterioration of organ damage, with two dying while receiving high‐dose canakinumab treatment. Serological analysis of canakinumab and cytokine concentrations revealed that the poor response was not related to canakinumab shortage. Four inflammatory nonremitters developed inflammatory bowel disease (IBD)—unclassified during canakinumab treatment. Dual biologic therapy with canakinumab and anti–tumor necrosis factor‐α agents was effective for IBD– and CAPS‐associated symptoms not resolved by canakinumab monotherapy. Conclusion This study provides one of the largest epidemiologic data sets for CAPS. Although early initiation of anti–IL‐1 treatment with canakinumab is beneficial for improving disease prognosis, some patients do not achieve remission despite a high serum concentration of canakinumab. Moreover, IBD may develop in CAPS after canakinumab treatment. image

Objectives This 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.Methods The 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.Results TNFi (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).Conclusions TNFi (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.

OBJECTIVES:This multicenter, retrospective study evaluated the effectiveness of add-on methotrexate (MTX) or iguratimod (IGU) in patients with rheumatoid arthritis exhibiting an inadequate response to Janus kinase inhibitors (JAKis). METHODS:Forty-five patients were treated with new additional MTX (n = 22) or IGU (n = 23) and followed for 6 months. Patients' background is as follows: age, 59.2 years; disease activity score of 28 joints with C-reactive protein (DAS28-CRP), 3.4; clinical disease activity index, 15.7; biological disease-modifying antirheumatic drug (DMARD)-switched cases, 77.8%; first JAKi cases, 95.6%; and JAKi treatment: tofacitinib (n = 25), baricitinib (n = 17), upadacitinib (n = 2), and peficitinib (n = 1) for 9.6 months. RESULTS:Thirty-five patients continued the combination therapy for 6 months without a significant change in concomitant glucocorticoid or other conventional synthetic DMARDs. DAS28-CRP (MTX, 3.6 to 2.6, p < 0.05; IGU, 3.3 to 2.1, p < 0.001) and clinical disease activity index (MTX, 16.7 to 8.8, p < 0.05; IGU, 14.6 to 6.5, p < 0.01) improved significantly from baseline. Using the 2019 European League Against Rheumatism criteria, 45.4% (MTX) and 39.1% (IGU) achieved moderate or good response and 40.9% (MTX) and 39.1% (IGU) achieved American College of Rheumatology 20% improvement criteria. CONCLUSIONS:Adding MTX or IGU to inadequate responders of JAKi can be considered as a complementary treatment.

Interaction between the gut microbiome and host plays a key role in human health. Here, we perform a metagenome shotgun-sequencing-based analysis of Japanese participants to reveal associations between the gut microbiome, host genetics, and plasma metabolome. A genome-wide association study (GWAS) for microbial species (n = 524) identifies associations between the PDE1C gene locus and Bacteroides intestinalis and between TGIF2 and TGIF2-RAB5IF gene loci and Bacteroides acidifiaciens. In a microbial gene ortholog GWAS, agaE and agaS, which are related to the metabolism of carbohydrates forming the blood group A antigen, are associated with blood group A in a manner depending on the secretor status determined by the East Asian-specific FUT2 variant. A microbiome-metabolome association analysis (n = 261) identifies associations between bile acids and microbial features such as bile acid metabolism gene orthologs including bai and 7β-hydroxysteroid dehydrogenase. Our publicly available data will be a useful resource for understanding gut microbiome-host interactions in an underrepresented population.