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This study aims to identify factors influencing the alleviation of knee joint symptoms in patients with rheumatoid arthritis treated with biologic or target synthetic disease-modifying antirheumatic drugs (b/tsDMARDs). Among 2321 patients who started b/tsDMARDs between 2010 and 2023, we focused on 295 patients who had knee swelling or tenderness at the initiation of b/tsDMARDs and continued b/tsDMARDs at least 3 months, with recorded knee symptoms 6 months later. Symptom relief after 6 months was 78.2% for interleukin 6 (IL-6) inhibitors, 68.6% for Janus kinase (JAK) inhibitors, 65.8% for tumor necrosis factor (TNF) inhibitors, and 57.6% for cytotoxic T lymphocyte-associated antigen-4-Ig (CTLA4-Ig). The initial use of b/tsDMARDs and the use of IL-6 inhibitors in comparison to CTLA4-Ig emerged as a significant factor associated with the improvement of knee joint symptoms. Among 141 patients who underwent knee radiography at baseline and two years later, the deterioration in knee joint radiographs was 7.7% for IL-6 inhibitors, 6.3% for JAK inhibitors, 21.9% for TNF inhibitors, and 25.9% for CTLA4-Ig. The use of IL-6 inhibitors was a significant factor associated with the improvement of knee joint symptoms and the inhibition of joint destruction compared to CTLA4-Ig., (© 2024. The Author(s).)

Data on the safety of Janus kinase inhibitors (JAKis) in patients with renal impairment are lacking. This study aimed to investigate the safety of JAKis compared to biological (b) DMARDs in patients with rheumatoid arthritis (RA) and renal impairment. We used a multi-centre observational registry of patients with RA in Japan (the ANSWER cohort). We assessed the drug retention rates of b/targeted synthetic DMARDs with different modes of action (tumour necrosis factor inhibitors (TNFis), immunoglobulins fused with cytotoxic T-lymphocyte antigen (CTLA-4-Ig), interleukin-6 receptor inhibitors (IL-6Ris), and JAKis) in patients with RA stratified by pre-treatment estimated glomerular filtration rate (eGFR) levels. The time to discontinuation of bDMARDs or JAKis was analysed using a multivariate Cox proportional hazards model This study included 3775 patients, who were classified into three groups (the normal group (eGFR ≥ 60 mL/min/1.73 m 2 ): 2893 patients; CKDa group (eGFR 45-60 mL/min/1.73 m 2 ): 551; and CKDb group (eGFR < 45 mL/min/1.73 m 2 ): 331). In the CKDb group, the 12-month drug retention rate due to adverse events (AE) was the lowest in patients treated with JAKi (TNFi: 93.1%; IL-6Ri: 94.1%; CTLA-4-Ig: 92.3%; JAKi: 75.1%). In the normal and CKDa groups, drug retention rates due to AE were similar among patients treated with bDMARDs and JAKi. In contrast, drug retention rates due to inefficacy were similar between bDMARDs and JAKis in all groups. In the Cox-proportional model, in the CKDb group, TNFi, IL-6Ri, and CTLA-4-Ig showed lower incidence of drug discontinuation due to AE than JAKis (TNFi: hazard ratio = 0.23 (95% confidence interval 0.09-0.61), IL-6Ri: 0.34 (0.14-0.81), CTLA-4-Ig: 0.36 (0.15-0.89)). JAKis showed the lowest drug retention due to AE in patients with moderate-to-severe and severe renal impairment (eGFR < 45 mL/min/1.73 m 2 ). Physicians should pay more attention to renal function when using JAKis than when using bDMARDs., (© 2024. The Author(s).)

Rheumatoid arthritis causes joint inflammation due to immune abnormalities, resulting in joint pain and swelling. In recent years, there have been considerable advancements in the treatment of this disease. However, only approximately 60% of patients achieve remission. Patients with multifactorial diseases shift between states from day to day. Patients may remain in a good or poor state with few or no transitions, or they may switch between states frequently. The visualization of time-dependent state transitions, based on the evaluation axis of stable/unstable states, may provide useful information for achieving rheumatoid arthritis treatment goals. Energy landscape analysis can be used to quantitatively determine the stability/instability of each state in terms of energy. Time-series clustering is another method used to classify transitions into different groups to identify potential patterns within a time-series dataset. The objective of this study was to utilize energy landscape analysis and time-series clustering to evaluate multidimensional time-series data in terms of multistability. We profiled each patient's state transitions during treatment using energy landscape analysis and time-series clustering. Energy landscape analysis divided state transitions into two patterns: "good stability leading to remission" and "poor stability leading to treatment dead-end." The number of patients whose disease status improved increased markedly until approximately 6 months after treatment initiation and then plateaued after 1 year. Time-series clustering grouped patients into three clusters: "toward good stability," "toward poor stability," and "unstable." Patients in the "unstable" cluster are considered to have clinical courses that are difficult to predict; therefore, these patients should be treated with more care. Early disease detection and treatment initiation are important. The evaluation of state multistability enables us to understand a patient's current state in the context of overall state transitions related to rheumatoid arthritis drug treatment and to predict future state transitions., Competing Interests: he Department of Advanced Medicine for Rheumatic Diseases, Kyoto University Graduate School of Medicine, is supported by Nagahama City, Shiga, Japan; Toyooka City, Hyogo, Japan; Asahi Kasei Pharma Corp.; and AYUMI Pharmaceutical Co. MH received research grants and/or speaker fees from Abbvie, Asahi Kasei, Astellas, Ayumi, Brystol Meyers, Chugai, EA Pharma, Eisai, Daiichi Sankyo, Eli Lilly, Novartis Pharma, and Tanabe Mitsubishi. M.T. received research grants and/or speaker fees from AbbVie GK, Asahi Kasei Pharma Corp., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Janssen Pharmaceutical K.K., Kyowa Kirin Co., Ltd., Pfizer Inc., Taisho Pharmaceutical Co., Ltd., Tanabe Mitsubishi Pharma Corp., Teijin Pharma, Ltd., and UCB Japan Co., Ltd. K.M. received speaking and/or consulting fees from AbbVie GK, Eisai Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corp., Bristol-Myers Squibb, Daiichi Sankyo Co., Ltd., Janssen Pharmaceutical K.K., and Asahi Kasei Pharma Corp. H.O. has received speaker fees from AbbVie, Asahi Kasei, Astellas Pharma Inc., Eisai Co. Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, and Daiichi Sankyo Co. Ltd. The other authors declare that they have no conflicts of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Yamamoto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Hounsfield units (HU) measured using computed tomography (CT) have gained considerable attention for the detection of osteoporosis. This study aimed to investigate whether opportunistic CT could predict vertebral fractures in patients with rheumatoid arthritis (RA)., Methods: A total of 233 patients with RA who underwent chest CT were included in this study. The HU values of the anterior 1/3 of the vertebral bodies based on the sagittal plane at T11-L2 after reconstruction were measured. The incidence of vertebral fractures was investigated with respect to the HU value., Results: Vertebral fractures were identified in 32 patients during a mean follow-up period of 3.8 years. In patients who experienced vertebral fractures within 2 years of CT imaging, the HU values of the vertebral bodies (T11-L2) were lower than those in patients who did not experience fractures. Receiver operating characteristic curve analysis identified that a T11 HU value of <125 was a risk factor for vertebral fracture within 2 years. Multivariate analysis showed that a T11 HU value of <125 and the existence of prevalent vertebral fractures were significant risk factors for fracture., Conclusion: HU measurements of the anterior 1/3 of the vertebral body are a potential predictor for vertebral fractures in patients with RA., (© 2024 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Objective: Atlantoaxial subluxation is a well-known serious complication encountered in patients with rheumatoid arthritis (RA). However, it is unknown whether RA affects global spinal alignment. The aim of this study was to investigate whether high disease activity in patients with RA exacerbates spinal sagittal malalignment., Methods: The authors included 197 patients with RA who were followed up for > 2 years; standing spinal radiographs were obtained in all patients. Patients were divided into persistent moderate disease activity/high disease activity (pMDA/HDA; n = 64) and non-pMDA/HDA (n = 133) groups based on the disease activity at follow-up visits. Radiographic parameters assessed included pelvic incidence, pelvic tilt (PT), lumbar lordosis (LL), thoracic kyphosis (TK), and C7 sagittal vertical axis (SVA)., Results: Over an average 5-year follow-up, increases in SVA, PT, and TK and a decrease in LL were observed. The pMDA/HDA group had a larger increase in PT and a higher incidence of vertebral fractures than the non-pMDA/HDA group. After adjusting variables using propensity score matching, the authors still found a higher rate of increase in PT (0.79°/year vs 0.01°/year, p = 0.001) in the pMDA/HDA group than in the non-pMDA/HDA group. This trend remained consistent even when patients who developed vertebral fractures were excluded., Conclusions: Spinal sagittal alignment deteriorates over time in patients with RA. High disease activity in RA exacerbates spinal deformity.

Background: The perioperative pain and function of total knee arthroplasty (TKA) in patients with rheumatoid arthritis (RA) approach those in patients with osteoarthritis (OA). This study aimed to evaluate whether the clinical outcomes, especially functions, of patients with RA reached those of OA, utilizing a background-matched cohort., Methods: Patients who underwent TKA between 2013 and 2021 were enrolled. Preoperative and minimum 2-year postoperative scores, specifically the Original Knee Society Score (OKSS) and New Knee Society Score (2011KSS), between RA and OA were compared. Clinical assessments were performed on unadjusted and propensity-score matched cohorts, ensuring age, sex, body mass index, and valgus deformity rate parity., Results: In an unadjusted cohort involving 98 patients with RA and 560 patients with OA, patients with RA demonstrated inferior preoperative OKSS-Function Score (FS) but similar postoperative functional scores to OA patients. In the matched cohort of 83, patients with RA displayed lower preoperative OKSS- FS (median difference: 20, P < 0.001) and 2011KSS functional activities (difference: 9, P = 0.01) beyond minimum clinically important differences than patients with OA. Patients with RA improved more in OKSS-FS, yielding no postoperative difference compared with patients with OA. However, postoperative 2011KSS functional activities remained lower in patients with RA (difference: 9.5, P = 0.03), especially in advanced functions, than in those with OA., Conclusion: Postoperative function showed no difference between patients with RA and OA in the unadjusted cohort; within the background-matched cohort, postoperative function, especially advanced function, was inferior in patients with RA to those with OA., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘K.N. received research grants and/or honorarium for lectures from Kyocera, Asahi-Kasei Pharma, and Daiichi-Sankyo. H.I. and K.M. belong or belonged to the department that is financially supported by Nagahama City, Shiga, Japan, Toyooka City, Hyogo, Japan and five pharmaceutical companies (Tanabe-Mitsubishi, Chugai, UCB Japan, Ayumi and Asahi-Kasei Pharma). H.I. received a research grant from Bristol-Myers. S.N. received a research grant Kyocera. S.K. declares no conflicts of interest. S.M. received a research grant and honorarium for lectures from Kyocera. KURAMA cohort is supported by Daiichi-Sankyo. The sponsors had no role in the design or conduct of the study.’., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objectives: Anaemia, a common comorbidity of RA, is related to high disease activity and poor prognosis. It is unknown which biologic/targeted synthetic (b/ts)-DMARDs are optimal for patients with anaemia and RA in regulating anaemia and controlling disease activity., Methods: We investigated the change in haemoglobin (Hb) levels, drug retention rates and disease activities after the administration of b/ts-DMARDs with different modes of action [TNF inhibitors (TNFis), immunoglobulin fused with cytotoxic T-lymphocyte antigen (CTLA-4-Ig), IL-6 receptor inhibitors (IL-6Ris) and Janus kinase inhibitors (JAKis)] in patients with RA stratified by baseline Hb levels using the multicentre observational registry for patients with RA in Japan (ANSWER cohort)., Results: A total of 2093 patients with RA were classified into three groups based on tertiles of the baseline Hb levels (Hblow, anaemic; Hbint, intermediate; Hbhigh, non-anaemic). IL-6Ri increased Hb levels in all groups (the mean change at 12 months in Hblow was +1.5 g/dl, Hbint +0.7 g/dl and Hbhigh +0.1 g/dl). JAKis increased the Hb level in patients with anaemia and RA and retained or decreased the Hb level in non-anaemic patients (the mean change at 12 months in Hblow was +0.6 g/dl, Hbint 0 g/dl and Hbhigh -0.3 g/dl). In patients with anaemia and RA, overall adjusted 3-year drug retention rates were higher in JAKi followed by IL-6Ri, CTLA4-Ig and TNFi (78.6%, 67.9%, 61.8% and 50.8%, respectively). Change of disease activity at 12 months was not different among different b/ts-DMARDs treatments., Conclusion: IL-6Ri and JAKi can effectively treat patients with anaemia and RA in a real-world setting., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Advances in rheumatoid arthritis (RA) treatment, highlighted by biological disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs), have altered the paradigm of RA treatment in the last decade. Therefore, real-world clinical evidence is needed to understand how treatment strategies and outcomes have changed., Methods: Using an observational cohort of RA from 2012 to 2021, we collected cross-sectional data of RA patients annually to analyze a trend in RA management. For patients who initiated b/tsDMRDs, we evaluated treatment outcomes between b/tsDMARDs. Mixed-effect models were applied to examine the statistical implications of changes over time in treatment outcomes with a background adjustment., Results: We analyzed annual cross-sectional data from 5070 patients and longitudinal data from 1816 patients in whom b/tsDMARDs were initiated between 2012 and 2021. b/tsDMARD use increased, whereas glucocorticoid use decreased from 2012 to 2021. Disease activity and functional disability measures improved over time. The percentage of tsDMARD prescriptions considerably increased. All b/tsDMARDs showed clinical improvements in disease activity and functional disability. Statistically, TNFi showed better short-term improvements in b/tsDMARD-naïve patients, while IL6Ri demonstrated significant long-term benefits. IL6Ri had better retention rates in switched patients. After adjustment for patient characteristics, the annual change of RA disease activity and functional disability fared significantly better from 2012 to 2021., Conclusions: With the development of new RA therapeutics, overall treatment outcomes advanced in the past decade., (© 2024. The Author(s).)

Background: The biological mechanisms underlying the differential response to abatacept in patients with rheumatoid arthritis (RA) are unknown. Here, we aimed to identify cellular, transcriptomic, and proteomic features that predict resistance to abatacept in patients with RA., Methods: Blood samples were collected from 22 RA patients treated with abatacept at baseline and after 3 months of treatment. Response to treatment was defined by the European League Against Rheumatism (EULAR) response criteria at 3 months, and seven patients were classified as responders and the others as non-responders. We quantified gene expression levels by RNA sequencing, 67 plasma protein levels, and the expression of surface molecules (CD3, 19, and 56) by flow cytometry. In addition, three gene expression data sets, comprising a total of 27 responders and 50 non-responders, were used to replicate the results., Results: Among the clinical characteristics, the number of monocytes was significantly higher in the non-responders before treatment. Cell type enrichment analysis showed that differentially expressed genes (DEGs) between responders and non-responders were enriched in monocytes. Gene set enrichment analysis, together with single-cell analysis and deconvolution analysis, identified that Toll-like receptor 5 (TLR5) and interleukin-17 receptor A (IL17RA) pathway in monocytes was upregulated in non-responders. Hepatocyte growth factor (HGF) correlated with this signature showed higher concentrations in non-responders before treatment. The DEGs in the replication set were also enriched for the genes expressed in monocytes, not for the TLR5 and IL17RA pathway but for the oxidative phosphorylation (OXPHOS) pathway., Conclusions: Monocyte-derived transcriptomic features before treatment underlie the differences in abatacept efficacy in patients with RA. The pathway activated in monocytes was the TLR5 and IL17RA-HGF signature in the current study, while it was the OXPHOS pathway in the replication set. Elevated levels of HGF before treatment may serve as a potential biomarker for predicting poor responses to abatacept. These findings provide insights into the biological mechanisms of abatacept resistance, contributing valuable evidence for stratifying patients with RA., (© 2023. The Author(s).)

Objectives: Rheumatoid arthritis (RA) and Sjögren's syndrome (SS) frequently co-exist but the consequence for RA disease activity of having concomitant SS (RA/SS) is not well established. We conducted a systematic review and meta-analysis to investigate the impact of SS on disease outcomes in individuals with RA., Methods: We searched Web of Science (Core Collection, FSTA, Medline), PubMed and Cochrane databases, without language restriction. Studies reporting RA disease activity scores, joint counts, visual analogue scales (VAS), disability and joint damage, and comparing RA and RA/SS were selected. Outcomes reported in at least 3 studies in which the diagnosis of SS fulfilled classification criteria underwent meta-analysis, using a random effects model where heterogeneity was detected., Results: The literature search identified 2991 articles and abstracts; 23 underwent full-text review and 16 were included. The studies included a total of 29722 patients (8614 with RA/SS and 21108 with RA). Using studies eligible for meta-analysis (744 patients with RA/SS and 4450 with RA), we found higher DAS-28 ESR scores (mean difference 0.50, 95% CI -0.008-1.006; p=0.05), higher swollen joint count scores (mean difference 1.05, 95% CI 0.42-1.67; p=0.001), and greater functional disability as measured by HAQ (mean difference 0.19, 95% CI 0.05-0.34; p=0.009) in RA/SS compared to RA alone. Other outcome measures (tender joint count, fatigue VAS) showed a numerical trend towards higher scores in RA/SS but were not statistically significant., Conclusions: RA/SS patients appear to have higher disease activity and more functional disability than patients with RA alone. The aetiology and clinical implications of this are unclear and warrant further investigation.

Background: Established assessment tools for patients with rheumatoid arthritis (RA), including disease activity scores (DASs), disease activity indexes (DAIs), visual analog scales (VASs), and health assessment questionnaires (HAQs), are widely used. However, comparative associations between joint involvement and disease status assessment tools have rarely been investigated., Methods: We included a dataset of 4016 patients from a large RA cohort from 2012 to 2019. The tenderness and swelling of each joint were counted as a symptom, with 70 and 68 affected joints throughout the body, respectively. The relative contribution of various joints to the disease status assessment tools, VAS scores, and functional disability indexes was analyzed using multiple regression analysis., Results: The wrist showed the most significant contribution overall, especially in DASs and VASs, while the metacarpophalangeal and proximal interphalangeal joints made significant contributions to DASs and DAIs, but not to VASs and HAQs. The shoulder and the elbow significantly contributed to HAQs, but only the shoulder did to the VASs. The knee universally contributed to all of the tools, but the ankle played a minor but important role in most assessment tools, especially in HAQs. Similar but different contribution ratios were found between the sets of DASs, DAIs, VASs, or HAQs., Conclusions: Each joint makes a unique contribution to these assessment tools. The improvement or aggravation of symptoms in each joint affects the assessment tools in different manners., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: AO, HO, TF, KMurat, and MT belong to the department financially supported by two local governments in Japan (Nagahama City, Shiga and Toyooka City, Hyogo) and five pharmaceutical companies (Mitsubishi Tanabe Pharma Co., Chugai Pharmaceutical Co., Ltd., AYUMI Pharmaceutical Co., Asahi Kasei Pharma Co. and UCB Japan Co., Ltd.). KURAMA cohort study is supported by grant from Daiichi Sankyo Co. Ltd. HI has received a research grant and/or speaker fee from Bristol-Myers Squibb. MT has received research grants and/or speaker fees from Abbvie Inc., Asahi Kasei Pharma Co., Astellas Pharma Inc., Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co., Ltd., Eisai Co. Ltd., Eli Lilly Japan K.K., Janssen Pharmaceutical K.K., Kyowa Kirin Co. Ltd., Pfizer Inc., Taisho Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Co., Teijin Pharma Ltd.,and UCB Japan Co. Ltd. AO reports grants from Pfizer Inc., Bristol-Myers Squibb., Ayumi, The Health Care Science Institute, and Advantest, and personal fees from Asahi Kasei Pharma Co., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K, Ono Pharmaceutical Co., Mitsubishi Tanabe Pharma, Eisai Co. Ltd., Abbvie Inc., Takeda Pharmaceutical Company Limited, and Daiichi Sankyo Co. Ltd.. MH receives grants and /or speaker fees from Abbvie Inc., Asahi Kasei Pharma Co., Astellas Pharma Inc., AYUMI Pharmaceutical Co., Bristol-Meyers, Chugai Pharmaceutical Co. Ltd, Daiichi Sankyo Co. Ltd, EA Pharma, Eisai Co. Ltd., Eli Lilly Japan K.K., Nihon Shinyaku, Novartis Pharma, and Mitsubishi Tanabe Pharma Co.. AU, MA, SI, AMu, KN, KMurak, HY, AMo and SM declared no conflicts of interest. This study is conducted as an investigator initiate study. The sponsors were not involved in the study design; in the collection, analysis, interpretation of data; in the writing of this manuscript; or in the decision to submit the article for publication. The authors, their immediate families, and any research foundations with which they are affiliated have not received any financial payments or other benefits from any commercial entity related to the subject of this article., (Copyright: © 2023 Umemoto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Patients with rheumatoid arthritis (RA) are prone to muscle atrophy due to inflammatory cytokines and corticosteroid use and immobility due to joint pain and deformity. Although resistance training is effective and safe in reversing muscle atrophy in RA, some patients are unable to perform a conventional high-load exercise program due to disease-related limitations. This study aims to examine the efficacy of individualized exercise therapy on physical function in elderly patients with RA who are at a high risk for sarcopenia., Methods: This study is a single-center, parallel-group, two-arm, healthcare provider- and outcome assessor-blinded, superiority randomized controlled trial with a 1:1 allocation ratio. A total of 160 participants with RA between 60 and 85 years of age with a positive screening test for sarcopenia will be included. The intervention group will receive nutritional guidance and a four-month individualized exercise program in addition to the usual treatment. The control group will receive nutritional guidance in addition to the usual care. The primary endpoint will be physical function assessed using the Short Physical Performance Battery (SPPB) at 4 months. The data on outcome measures will be collected at baseline and at the two- and four-month follow-ups. Linear mixed-effects models for repeated measures will be conducted using the modified intention-to-treat analysis population., Discussion: This study will provide evidence on whether a personalized exercise program can improve physical function and quality of life in elderly patients with RA. Some limitations include limited generalizability due to the single-center study and lack of blinding of the patients to the intervention assignment because of the nature of the exercise. Physical therapists may use this knowledge in their daily practice to improve RA treatment. Tailored exercise may enhance the health outcomes of the RA population and contribute to a reduction in healthcare costs., Trial Registration: The study protocol was retrospectively registered at the University hospital Medical Information Network-Clinical Trial Repository (UMIN-CTR) (registration number: UMIN000044930, https://www.umin.ac.jp/ctr/index-j.htm ) on January 4, 2022., (© 2023. The Author(s).)

Background: Anti-citrullinated protein/peptide antibodies (ACPAs) are present in patients at onset and have important pathogenic roles during the course of rheumatoid arthritis (RA). The characteristics of several molecules recognized by ACPA have been studied in RA, but the positivity rate of autoantibodies against each antigen is not high, and the pathogenic mechanism of each antibody is not fully understood. We investigated the role of anti-citrullinated osteopontin (anti-cit-OPN) antibodies in RA pathogenesis., Methods: Enzyme-linked immunosorbent assays on RA patients' sera were used to detect autoantibodies against OPN. Fibroblast-like synoviocytes (FLS) isolated from RA patients were used to test the binding activity and inflammatory response of OPN mediated by anti-cit-OPN antibodies, and their effect was tested using an inflammatory arthritis mouse model immunized with cit-OPN. Anti-cit-OPN antibody positivity and clinical characteristics were investigated in the patients as well., Results: Using sera from 224 RA patients, anti-cit-OPN antibodies were positive in approximately 44% of RA patients, while approximately 78% of patients were positive for the cyclic citrullinated peptide (CCP2) assay. IgG from patients with anti-cit-OPN antibody increased the binding activity of OPN to FLSs, which further increased matrix metalloproteinase and interleukin-6 production in TNF-stimulated FLSs. Mice immunized with cit-OPN antibodies experienced severe arthritis. Anti-cit-OPN antibodies in RA patients decreased the drug survival rate of tumor necrosis factor (TNF) inhibitors, while it did not decrease that of CTLA4-Ig., Conclusions: Anti-cit-OPN antibodies were detected in patients with RA. IgG from patients with anti-cit-OPN antibodies aggravated RA, and anti-cit-OPN antibody was a marker of reduced the survival rate of TNF inhibitors in RA patients., (© 2023. The Author(s).)

Secondary non-response to infliximab (IFX) occurs in some patients with rheumatoid arthritis (RA). Although therapeutic drug monitoring (TDM) is a useful tool to optimize IFX therapy, it is unclear whether it can help to identify the risk of secondary non-response. This study aimed to explore the utility of serum levels of IFX or other biomarkers to predict IFX discontinuation owing to secondary non-response. A single-center, retrospective study was conducted using the Kyoto University Rheumatoid Arthritis Management Alliance cohort database between 2011 and 2020. Serum IFX levels were measured using liquid chromatography-tandem mass spectrometry. An electrochemiluminescence assay was used to quantify serum levels of tumor necrosis factor-α and interleukin-6 and detect anti-drug antibodies. Eighty-four out of 310 patients were eligible for this study. The cutoff levels of biomarkers were determined by receiver operating characteristic analysis. IFX persistence was similar between groups stratified using IFX levels, tumor necrosis factor-α levels, interleukin-6 levels, and anti-drug antibodies positivity. The group with lower IFX and higher interleukin-6 levels had the worst therapy persistence (p = 0.017) and the most frequent disease worsening (90.0%, p < 0.001). Evaluating both interleukin-6 and IFX levels, not just IFX alone, enabled us to identify patients at risk of discontinuing IFX treatment. These findings support the utility of measuring IFX and interleukin-6 levels for successful maintenance therapy for RA.

Objective: Currently, biological disease-modifying anti-rheumatic drugs (bDMARDs) with different modes of action [tumour necrosis factor inhibitor (TNFi), interleukin-6 receptor inhibitor (IL-6Ri), or cytotoxic T-lymphocyte antigen 4-immunoglobulin (CTLA4-Ig)] are used in clinical practice to treat rheumatoid arthritis (RA). However, it is unclear which type of bDMARD is the most efficacious for a specific clinical situation. C-reactive protein (CRP) is an acute-phase reactant driven by IL-6 signalling. Here, we aimed to establish whether therapeutic efficacy differs between IL-6Ri and other bDMARDs with alternative modes of action in RA patients according to their CRP level., Method: RA patients treated with bDMARDs were enrolled from an observational multicentre registry in Japan. Patients were classified into three groups according to baseline CRP tertiles. The overall 3 year retention rates of each bDMARD category were assessed. The Clinical Disease Activity Index (CDAI) was also assessed before and 3, 6, and 12 months after bDMARD initiation., Results: A total of 1438 RA patients were included and classified into three groups according to tertiles of baseline CRP levels (CRP 1 , 0-0.3; CRP 2 , 0.3-1.8; CRP 3 , 1.8-18.4 mg/dL). In CRP 3 , the overall 3 year drug retention rates were significantly higher for IL-6Ri than for TNFi and CTLA4-Ig (77.5 vs 48.2 vs 67.3, respectively). No significant difference was evident in terms of CDAI 12 months after bDMARD initiation in CRP 1 -CRP 3 ., Conclusion: IL-6Ri may be a favourable therapeutic option over TNFi and CTLA4-Ig in RA patients with high CRP levels.

Neutropenia is a common adverse event of tocilizumab (TCZ) in rheumatoid arthritis (RA) patients; however, the association between the decrease in neutrophil counts and the TCZ clinical efficacy remains inconclusive. This study aimed to examine whether TCZ-induced neutrophil decrease at 1 month predicts clinical remission within 1 year. We reviewed medical records of RA patients initiating TCZ between May 2011 and September 2019 in our hospital. The Clinical Disease Activity Index (CDAI) was evaluated at baseline (before initiating TCZ) and 1, 3, 6, and 12 months after administration. Clinical remission was defined when CDAI decreased ≤ 2.8. The ratio of neutrophil counts 1 month after initiating TCZ to those at baseline (neutrophil ratio) was also calculated. Among 255 TCZ-treated patients, 169 with valid CDAI and neutrophil counts were enrolled (with median age of 60 years and 79% females). Rheumatoid factor and anti-cyclic citrullinated peptide antibody were positive in 75% and 83%, respectively, and 56% of the patients had concomitant methotrexate (median dose: 8 mg/week). Multivariate logistic regression analysis suggested baseline CDAI (odds ratio (OR) 0.96, p = 0.045), concomitant PSL (OR 0.42, p = 0.030), and the neutrophil ratio (OR 0.19, p = 0.011) as predictors of CDAI remission. Neutrophil ratio ≤ 0.8 was associated with achieving remission (Fisher's exact test, p = 0.02) with no apparent increase of severe infection. More than 20% reduction of neutrophil count 1 month after initiating TCZ predicts clinical remission within 1 year at an early treatment phase., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Biologics are structurally heterogeneous and can undergo biotransformation in the body. Etanercept (ETN) is a fusion protein composed of a soluble tumor necrosis factor (TNF) receptor and the Fc portion of human immunoglobulin G1. The N-terminus of ETN has a putative sequence cleaved by dipeptidyl peptidase-4 (DPP-4). The purpose of this study was to investigate the biotransformation of ETN in humans and mice and evaluate its effects on functional properties., Methods: An analytical method using liquid chromatography-mass spectrometry (LC-MS/MS) was established. The N-terminal heterogeneity of ETN was assessed in the serum of patients with rheumatoid arthritis or mice receiving ETN. The in vitro N-terminal truncation was explored using recombinant DPP-4. The binding affinity to TNF-α or TNF-β was investigated using an in-house enzyme-linked immunosorbent assay., Results: In the formulations, about 90% of ETN had an intact N-terminus, while the N-terminal truncated form was most abundant in the serum of the patients with rheumatoid arthritis and mice. Recombinant human DPP-4 cleaved two amino acids from the N-terminus of ETN in vitro. Sitagliptin, a DPP-4 inhibitor, inhibited N-terminal truncation both in vivo and in vitro. However, N-terminal truncation did not affect the binding ability to TNF-α or TNF-β and the pharmacokinetics of ETN. ETN biosimilars exhibited similar characteristics to the reference product in vivo and in vitro., Conclusions: ETN undergoes N-terminal truncation in the body, and DPP-4 cleaves exogenous ETN via N-terminal proteolysis. The application of an MS-based assay will detect novel biotransformation of therapeutic proteins., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by localized and generalized bone loss. The risk of fractures is doubled in patients with RA. Denosumab, an anti-RANKL monoclonal antibody, is used for those with osteoporosis at high risk fracture and it has inhibitory effect of progressive bone erosion in patients with RA. While the increase in bone mineral density by denosumab has been reported in patients with RA, preventive effect of fracture by denosumab remains unknown. This study aimed to evaluate the efficacy of denosumab in treating clinical fracture risk in patients with RA., Methods: Patients with RA who received denosumab treatment between 2013 and 2019 were retrospectively evaluated using the ANSWER (Kansai Consortium for the Well-Being of Rheumatic Disease Patients) cohort data. Fracture rates were evaluated between 0 and 6 months (reference period) versus > 6 months (post-reference period) of denosumab use., Results: A total of 873 patients with RA received denosumab, and their characteristics were as follows: 88% females, mean age 68 years, and average disease duration 14.5 years. The hazard rates of all clinical fractures were 0.69 (per 100 person-years) in the reference period and 0.35 in the post-reference period, indicating a 49.2% decrease (p = 0.03)., Conclusions: Denosumab suppresses the risk of clinical fractures in patients with RA., (© Japan College of Rheumatology 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Rheumatoid factor (RF) binds to the fragment crystallizable (Fc) portion of immunoglobulin. It could bind to the Fc portion of anti-TNF inhibitors (TNFi) and attenuate the clinical efficacy. We tried to determine whether the therapeutic efficacy of TNFi with Fc might be lower than that of TNFi without Fc in rheumatoid arthritis (RA) patients with high titres of RF. The Kansai Consortium for Well-being of Rheumatic Disease Patients (ANSWER) cohort is an observational multi-center registry of patients with RA in the Kansai district of Japan. RA patients treated with TNFi were included and divided into two groups based on the structural characteristics between TNFi with Fc (infliximab, adalimumab, golimumab, and etanercept) and TNFi without Fc (certolizumab pegol). Patients were classified into 4 groups according to RF titre quartiles. The sequential disease activity score in 28 joints using erythrocyte sedimentation rate (DAS28-ESR) was compared by Mann-Whitney U test between TNFi with and without Fc in each RF titre group. Multiple linear regression analysis was used to analyze the effect of TNFi without Fc for the change of DAS28-ESR adjusted after potential confounders. A total of 705 RA patients were classified into four groups (RF 1 ; RF 0-15.0 IU/mL, RF 2 ; 15.0-55.0, RF 3 ; 55.0-166, RF 4 ; 166-7555). In RF 4 , RA patients treated with TNFi without Fc had a significantly lower DAS28-ESR than those treated with TNFi with Fc [3.2 (2.3-4.2) vs. 2.7 (2.0-3.0)] after 12 months. This effect of TNFi without Fc for the change of DAS28-ESR after 12 months treatment retained in multivariate analysis in RF 4 . TNFi without Fc may be more efficacious than TNFi with Fc in RA patients with high RF titres., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The factors influencing long-term responses to a tumor necrosis factor inhibitor (TNFi) in rheumatoid arthritis (RA) patients currently remain unknown. Therefore, we herein conducted a multi-omics analysis of TNFi responses in a Japanese RA cohort. Blood samples were collected from 27 biological disease-modifying antirheumatic drug (DMARD)-naive RA patients at the initiation of and after three months of treatment with TNFi. Treatment responses were evaluated at one year. Differences in gene expression levels in peripheral blood mononuclear cells (PBMCs), plasma protein levels, drug concentrations, and the presence/absence of anti-drug antibodies were investigated, and a cell phenotypic analysis of PBMCs was performed using flow cytometry. After one year of treatment, thirteen patients achieved clinical remission (responders), while the others did not or switched to other biologics (non-responders). Differentially expressed genes related to treatment responses were enriched for the interferon (IFN) pathway. The expression of type I IFN signaling-related genes was higher in non-responders than in responders before and after treatment ( P = 0.03, 0.005, respectively). The expression of type II IFN signaling-related genes did not significantly differ before treatment; however, it increased in non-responders and decreased in responders, with a significant difference being observed after three months of treatment ( P = 1.2×10 -3 ). The total number of lymphocytes and C-X-C Motif Chemokine Ligand 10 (CXCL10) protein levels were associated with the type I IFN signature ( P = 6.7×10 -7 , 6.4×10 -3 , respectively). Hepatocyte growth factor (HGF) protein levels before treatment predicted fold increases in type II IFN ( P = 0.03). These IFN signature-related indices (the number of lymphocytes, CXCL10, and HGF) significantly differed between responders and non-responders ( P = 0.01, 0.01, and 0.04, respectively). A single-cell analysis revealed that the type I IFN signature was more highly enriched in monocytes than in other cell types. A deconvolution analysis of bulk-RNA sequence data identified CD4+ and CD8+ T cells as the main sources of the type II IFN signature in non-responders. Collectively, the present results demonstrated that the dynamics of the type I and II IFN pathways affected long-term responses to TNFi, providing information on its biological background and potential for clinical applications., Competing Interests: RW received speaker fees from Mitsubishi Tanabe Pharma, Pfizer, Sanofi, AbbVie, Asahi Kasei, Eisai, Eli Lilly, Bristol-Myers Squibb, and Janssen. KOk, TO, YH are employees of Astellas Pharma Inc. KOh received research grants and/or speaker’s fees from Abbvie, Actelion, Asahikasei Pharma, Astellas, AYUMI, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, GSK, Janssen, JB, Mitsubishi Tanabe, Nippon Kayaku, Nippon Shinyaku, Novartis, Sanofi, and Takeda. KMurat received a speaking fee from Eisai Co., Ltd., Chugai Pharmaceutical Co., Ltd.; Asahi Kasei Pharma Corp.; and Mitsubishi Tanabe Pharma Corporation. MT has received research grants and/or speaker fees from AbbVie GK, Asahi Kasei Pharma Corp., Astellas Pharma Inc., Ayumi Pharmaceutical Corp., Bristol-Myers Squibb, Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Pfizer Inc., UCB Japan Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corp., Novartis Pharma K.K., Taisho Pharma Co., Ltd. AM has received research grants from AbbVie, Asahi Kasei Pharma, Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical and speaker fees from Eli Lilly, AbbVie, Ono Pharmaceutical, Pfizer, Astellas Pharmaceutical, and Chugai Pharmaceutical Co., Ltd. MH received a research grant and/or speaker’s fees from Bristol-Myers, Eisai, Eli Lilly, and Mitsubishi Tanabe Pharma. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Astellas Pharma Inc. The funder had the following involvement with the study: approval of the submission for publication., (Copyright © 2022 Iwasaki, Watanabe, Ito, Fujii, Okuma, Oku, Hirayama, Ohmura, Murata, Murakami, Yoshitomi, Tanaka, Matsuda, Matsuda, Morinobu and Hashimoto.)

Objective: Hypoxia occurs in tumors, infections, and sites of inflammation, such as in the affected joints of patients with rheumatoid arthritis (RA). It alleviates inflammatory responses and increases bone resorption in inflammatory arthritis by enhancing osteoclastogenesis. The mechanism by which the hypoxia response is linked to osteoclastogenesis and inflammatory bone resorption is unclear. This study was undertaken to evaluate whether the protein lysine-specific demethylase 1 (LSD1) metabolically integrates inflammatory osteoclastogenesis and bone resorption in a state of inflammatory arthritis., Methods: LSD1-specific inhibitors and gene silencing with small interfering RNAs were used to inhibit the expression of LSD1 in human osteoclast precursor cells derived from CD14-positive monocytes, with subsequent assessment by RNA-sequencing analysis. In experimental mouse models of arthritis, inflammatory osteolysis, or osteoporosis, features of accelerated bone loss and inflammatory osteolysis were analyzed. Furthermore, in blood samples from patients with RA, cis-acting expression quantitative trait loci (cis-eQTL) were analyzed for association with the expression of hypoxia-inducible factor 1α (HIF-1α), and associations between HIF-1α allelic variants and extent of bone erosion were evaluated., Results: In human osteoclast precursor cells, RANKL induced the expression of LSD1 in a mechanistic target of rapamycin-dependent manner. Expression of LSD1 was higher in synovium from RA patients than in synovium from osteoarthritis patients. Inhibition of LSD1 in human osteoclast precursors suppressed osteoclast differentiation. Results of transcriptome analysis identified several LSD1-mediated hypoxia and cell-cycle pathways as key genetic pathways involved in human osteoclastogenesis. Furthermore, HIF-1α protein, which is rapidly degraded by the proteasome in a normoxic environment, was found to be expressed in RANKL-stimulated osteoclast precursor cells. Induction of LSD1 by RANKL stabilized the expression of HIF-1α protein, thereby promoting glycolysis, in conjunction with up-regulation of the transcription factor E2F1. Analyses of cis-eQTL revealed that higher HIF-1α expression was associated with increased bone erosion in patients with RA. Inhibition of LSD1 decreased pathologic bone resorption in mice, both in models of accelerated osteoporosis and models of arthritis and inflammatory osteolysis., Conclusion: LSD1 metabolically regulates osteoclastogenesis in an energy-demanding inflammatory environment. These findings provide potential new therapeutic strategies targeting osteoclasts in the management of inflammatory arthritis, including in patients with RA., (© 2022 American College of Rheumatology.)

Difficult-to-treat rheumatoid arthritis (D2T RA) is a multifactorial condition in which disease activity of RA persists despite consecutive treatment with biological or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs). To evaluate the prevalence and predictive risk factors of D2T RA in our institution, a single-center, retrospective study was conducted. Medical records of RA patients, who visited our hospital from 2011 to 2020 and had a follow-up of more than 6 months, were retrospectively reviewed. D2T RA was defined as RA with a disease activity score of 28 - erythrocyte sedimentation rate (DAS28-ESR) of 3.2 or higher at the last visit, despite the use of at least two b/tsDMARDs. A logistic regression model was used to identify risk factors. A total of 672 patients were enrolled. The mean age at disease onset was 52.1 years and females were dominant (76.3%). After a mean follow-up of 46.6 months, patients with D2T RA accounted for 7.9% of overall patients. Multivariate analysis identified high rheumatoid factor (RF) levels (≥156.4 IU/mL, odds ratio [OR]: 1.95), DAS28-ESR (OR: 1.24), and coexisting pulmonary disease (OR: 2.03) as predictive risk factors of D2T RA. In conclusion, high RF levels, high DAS28-ESR, and coexisting pulmonary disease at baseline can predict the development of D2T RA.

Objectives: We aimed to clarify the clinical implication of ultrasound (US)-detected foot joint inflammation in tightly controlled patients with rheumatoid arthritis (RA)., Methods: We evaluated bilateral foot joints (second to fifth metatarsophalangeal joints of forefoot; tarsometatarsal, cuneonavicular and midtarsal joints of midfoot) of 430 RA patients for synovitis using Power Doppler (PD) imaging by US. We made a cross-sectional and a 3-year longitudinal analysis about the associations of US-detected synovitis with clinical, laboratory and radiographic data as well as foot-specific outcomes using a self-administered foot evaluation questionnaire (SAFE-Q)., Results: The US-detected foot synovitis was seen in 28% of patients. The US-detected synovitis was closely related to 28 joint-disease activity score (DAS28) more in the forefoot than in the midfoot, while related to joint destruction in both. Multiple regression analyses showed significant associations between midfoot PD positivity and SAFE-Q in the remission group. SAFE-Q was worsened after the 3-year interval, but PD positivity at baseline did not contribute to the changes. On the other hand, destruction of the joints with US-detected synovitis significantly progressed in 3 years than with not., Conclusions: US-detected synovitis on foot joints were related to systemic inflammation, clinical symptoms, and future joint destruction with region specificity., (© 2021 Japan College of Rheumatology.)

Objectives: We prospectively evaluated whether the addition of iguratimod (IGU) could sustain clinical remission in rheumatoid arthritis (RA) patients after tapering of methotrexate (MTX)., Methods: The study included 47 patients; 25 patients in the MTX maintenance group, and 22 patients in the IGU addition group who were treated with additional IGU and tapering of MTX dose. Clinical efficacy and safety were evaluated at 12, 24, and 36 weeks., Results: In the IGU addition group, the dose of MTX could be reduced from 8.6 ± 2.4 mg/week at baseline to 4.7 ± 2.2 mg/week at 36 weeks (p < .001). Clinical remission was maintained (disease activity score [DAS]28-ESR 1.48 ± 0.63 at baseline and 1.69 ± 0.76 at 36 weeks, p = .911), and disease activity remained low (clinical disease activity index [CDAI] 2.4 ± 1.5 at baseline and 3.1 ± 3.4 at 36 weeks, p = .825). The US-GLOSS score significantly decreased from 9.2 ± 5.3 at baseline to 6.4 ± 4.3 at 36 weeks (p = .034). In the IGU addition group, two patients discontinued IGU because of stomatitis and three patients relapsed during the follow-up period (flare rate: 15.0%). There was no significant difference in RA disease activity at 36 weeks between the two groups., Conclusion: Additional use of IGU can effectively reduce the MTX dose required by patients during clinical remission without inducing a flare., (© 2021 Japan College of Rheumatology.)

Objectives: To study the perceptions and behavioural changes related to the coronavirus disease 2019 (COVID-19) in patients with rheumatoid arthritis (RA) and determine their associations with patient characteristics, such as health literacy., Methods: This cross-sectional study was conducted from September to November of 2020 and included 400 outpatients with RA aged 18 and above. We measured self-reported perceptions as outcomes, such as awareness, knowledge and behaviours related to COVID-19. Health literacy and other characteristics as exposures were investigated using self-report questionnaires and electronic health records. To analyse the association between patient factors and the outcomes, multivariable linear and logistic regression models were performed., Results: In total, 365 patients completed the survey. More than half (51%) of patients reported that they were 'very worried' about possible infection with COVID-19, whereas over 80% believed the possibility of getting COVID-19 was low. In the multivariable analyses, patients with low health literacy had limited knowledge about COVID-19 and did not change daily routines and perform preventive measures., Conclusions: In this pandemic, healthcare providers may need to be aware of more vulnerable individuals and share COVID-19 related information promptly and effectively with their patients. Key Points • This cross-sectional study aimed to investigate the perceptions and behavioural changes related to COVID-19 in patients with RA. • All patients were aware of COVID-19 and most of them worried about getting infected. • Health literacy, age, sex, disease activity and rheumatic drugs were associated with perceptions and behaviours related to COVID-19., (© 2021. International League of Associations for Rheumatology (ILAR).)

Aim: This study aimed to assess the relationship between pain catastrophizing and achievement of 28-joint Disease Activity Score-defined remission of rheumatoid arthritis (RA), considering the presence or absence of systemic inflammation, and to evaluate associated factors for pain catastrophizing., Method: This cross-sectional study included 421 RA outpatients. The relationship between pain catastrophizing and remission was analyzed by adjusting several confounding factors. Univariable and multivariable analyses were performed to determine the relationship between pain catastrophizing and RA-related factors, comorbidities, and lifestyle habits., Results: The prevalence of pain catastrophizing was 26%. Pain catastrophizing was negatively associated with remission (odds ratio 0.62, 95% confidence interval 0.38-1.00, P = .048). A multinomial logistic analysis showed that the presence of pain catastrophizing was an independent factor that was negatively correlated with the achievement of remission in the absence of systemic inflammation (odds ratio 0.51, 95% confidence interval 0.28-0.93, P = .029). Factors associated with elevated ratings on the Pain Catastrophizing Scale were a history of falls within the past year, a Health Assessment Questionnaire score >0.5, and smoking habit. Further, patients' subjective symptoms, including patient global assessment minus evaluator global assessment values ≥20 and high tender joint count minus swollen joint counts, were associated with elevated pain catastrophizing., Conclusion: Pain catastrophizing is a major obstacle to achieving remission in RA patients with normal C-reactive protein levels. Advanced physical disability, smoking habit, and history of falls were associated with pain catastrophizing, in addition to patients' subjective symptoms., (© 2021 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Sarcopenia is an age-related disease with an increased risk of mortality. It is emerging that low serum 25-hydroxyvitamin D [25(OH)D] affects the sarcopenic state in general, but in rheumatoid arthritis (RA), these associations are not understood although the prevalence of vitamin D insufficiency is high in RA. We conducted a cross-sectional study of older female outpatients from our cohort (KURAMA) database. We measured skeletal muscle mass, handgrip strength, and gait-speed to diagnose severe sarcopenia. The serum 25(OH)D concentration was measured using electrochemiluminescence immunoassay. A total of 156 female patients with RA (sarcopenia:44.9%, severe sarcopenia: 29.5%, and without sarcopenia: 25.6%) were enrolled. Classification of vitamin D status at a cutoff point of median 25(OH)D concentration revealed that low 25(OH)D status was associated with a high prevalence of severe sarcopenia and with low measured values of muscle mass, handgrip, and gait speed. Furthermore, multivariable logistic regression analysis identified that low 25(OH)D status was associated with a high prevalence of severe sarcopenia (OR 6.00; 95% CI 1.99-18.08).The same association was observed when the cut-off value was set at 20 ng/ml. In components of sarcopenia, both low physical performance and muscle mass were associated with low 25(OH)D status. In conclusion, vitamin D status was inversely associated with severe sarcopenia, low physical performance, and low skeletal muscle mass. Modification of vitamin D status including vitamin D supplementation should be investigated as a therapeutic strategy for sarcopenic patients with RA., (© 2021. The Author(s).)

Objective: Although mental disorder is one of the most common comorbidities of rheumatoid arthritis (RA) and is known as a critical influence on RA remission rates, there is little knowledge regarding a possible therapeutic strategy for depression or anxiety in a RA population. Most recently, clinical evidence of dietary improvement for depression has emerged in a general population, but the relationship between dietary habits and mental disorder has not been investigated in RA. The purpose of this study is to elucidate clinical associations between mental disorder (depression/anxiety), dietary habits and disease activity/physical function in patients with RA., Methods: A cross-sectional study was performed with 267 female outpatients from the KURAMA database. Using the Hospital Anxiety and Depression Scale (HADS), we classified the participants into three groups by depression state, and their characteristics were compared. Using the 20-items on the self-reported food frequency questionnaire, we investigated the relationship between dietary habits and depression or anxiety, adopting a trend test and a multivariate standardized linear regression analysis for the HADS score of depression or that of anxiety as a dependent variable., Results: According to the classified stage of depression, current disease activity (DAS28-CRP: 28-Joint RA Disease Activity Score-C-reactive protein) and the health assessment questionnaire disability Index (HAQ-DI) were significantly increased. Trend analyses revealed that the depression score was inversely associated with the consumption of three food (fish, vegetables and fruit) out of twenty as was the anxiety score with only fish intake. Furthermore, multiple linear regression analysis revealed that the depression score was negatively associated with frequent fish intake (≥ 3 times per week) (Estimate -0.53, p = 0.033), HAQ-DI score within normal range (Estimate -0.88, p ≤ 0.001) and MTX use (Estimate -0.60, p ≤ 0.023). For the anxiety score, multivariate analysis showed similar but not significant associations with variables except for HAQ-DI score., Conclusions: In a RA population, both depression and anxiety had a significant and negative association with HAQ-DI score, and depression rather than anxiety had negative association with frequent fish intake. Modification of dietary habits such as increased fish consumption may have a beneficial effect on the depression state in RA patients., Competing Interests: M.H., R.W., K.M. (Murata), and M.T. (Tanaka) are members of a department financially supported by Nagahama City, Shiga, Japan, Toyooka City, Hyogo, Japan and five pharmaceutical companies (Tanabe-Mitsubishi, Chugai, UCB Japan, Ayumi and Asahi-Kasei). This study (KURAMA cohort study) is supported by a grant from Daiichi Sankyo Co. Ltd. M.H. receives grants and/or speaker fees from Bristol-Meyers, Eisai, Eli Lilly, and Tanabe Mitsubishi. R.W. receives speaker’s fee from Mitsubishi Tanabe Pharma, Pfizer, Sanofi, AbbVie, Asahi Kasei, Eisai, Eli Lilly, Bristol-Myers Squibb, and Janssen. K.N. (Nishitani) receives a research grant from Asahi-Kasei Pharma. H.I. receives a research grant and/or speaker fee from Bristol-Myers, Kyocera, and Asahi-Kasei. S.M. receives grants and/or speaker fees from Daiichi Sankyo, Asahi-Kasei, Chugai, Ayumi, and Tanabe Mitsubishi. A.M. receives speaking fees and/or research grants from Eli Lilly Japan K.K., Ono Pharmaceutical Co., Pfizer Inc., UCB Japan, AbbVie G.K., Asahi Kasei Pharma and Chugai Pharmaceutical Co. Ltd. H.M., M.K., Y.F., M.T., K.I., N.I., Y.O., W.Y., R.W, K.M.(Murakami), K.M. (Murata), M.U, K.N. (Nin), H.A., and N.I. declare no conflicts of interest. The sponsors had no role in the design of the study, the collection or analysis of the data, the writing of the manuscript or the decision to submit the manuscript for publication. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The authors, their immediate families, and any research foundations with which they are affiliated have not received any financial payments or other benefits from any commercial entity related to the subject of this article.

Background: Excessive salt intake is thought to exacerbate both development of hypertension and autoimmune diseases in animal models, but the clinical impact of excessive salt in rheumatoid arthritis (RA) patients is still unknown. We performed a cross-sectional study to clarify the associations between salt load index (urinary sodium-to-potassium ratio (Na/K ratio)), current disease activity, and hypertension in an RA population., Methods: Three hundred thirty-six participants from our cohort database (KURAMA) were enrolled. We used the spot urine Na/K ratio as a simplified index of salt loading and used the 28-Joint RA Disease Activity Score (DAS28-ESR) as an indicator of current RA disease activity. Using these indicators, we evaluated statistical associations between urinary Na/K ratio, DAS28-ESR, and prevalence of hypertension., Results: Urinary Na/K ratio was positively associated with measured systolic and diastolic blood pressure and also with prevalence of hypertension even after covariate adjustment (OR 1.34, p <  0.001). In addition, increased urinary Na/K ratio was significantly and positively correlated with DAS28-ESR in multiple regression analysis (estimate 0.12, p <  0.001), as was also the case in gender-separated and prednisolone-separated sub-analyses., Conclusion: Urinary Na/K ratio was independently associated with current disease activity as well as with prevalence of hypertension in RA patients. Thus, dietary modifications such as salt restriction and potassium supplementation should be investigated as a potential candidate for attenuating both disease activity and hypertension in RA patients.

Frailty is a geriatric syndrome characterized by anabolic-catabolic imbalance and multisystem dysregulation resulting in increased adverse health outcomes, and is closely related with dietary habits in the general population. Although chronic inflammatory diseases are thought to accelerate development of frailty, correlations between rheumatoid arthritis (RA), frailty and dietary habits have not been examined. We performed a cross-sectional study using our cohort database (KURAMA cohort), and classified 306 participants into three groups (robust, prefrail and frail) according to the Study of Osteoporotic Fracture (SOF) criteria. Multivariate logistic analysis revealed that the presence of frailty/prefrailty was significantly correlated with the disease activity score (DAS28-ESR) (OR 1.70 (1.30-2.22), p < 0.0001). Additional analyses of frailty and food intake showed that 5 foods (fish, meat, milk, vegetables and fruits) of 20 groups on the questionnaire were inversely associated with the prevalence of frail/prefrail categories. In multivariate analysis with the five nutrients, fish intake (> two times a week) was an independent covariate negatively correlated with frailty/prefrailty (OR 0.35 (0.19-0.63), p = 0.00060). In conclusion, habitual fish intake may play a key role in nutritional intervention to prevent progression of frailty and RA.

Objectives: We evaluated long-term control of rheumatoid arthritis (RA) in Japanese paid workers (PWs) and house workers (HWs) treated with subcutaneous tocilizumab (TCZ-SC) and explored factors affecting response to TCZ-SC regarding work productivity., Methods: This study collected data from patients with RA in the TCZ-SC +/- conventional synthetic disease-modifying antirheumatic drugs group. Factors affecting the response to tocilizumab regarding work productivity were explored using logistic regression. Differences in quality-adjusted life years (QALYs) between with/without response were analysed by a linear regression., Results: Data were analysed for 357/360 patients. Patients with a ≥ 75% improvement in activity impairment (AI) were considered responders. EuroQol-5 Dimension (EQ-5D), six-item Kessler psychological distress scale score (K6), Health Assessment Questionnaire Disability Index (HAQ-DI), and the patient's disease global health by visual analogue scale were significant contributors to TCZ-SC response based on improvements in AI. Work Functioning Impairment Scale, presenteeism, EQ-5D, K6, and HAQ-DI significantly contributed to the improvement of overall work impairment in PWs. Shorter disease duration also was related to TCZ-SC response based on AI improvements. Responders had significantly larger mean QALYs than non-responders (difference = 0.2614; p  < .001)., Conclusions: These real-world clinical data support long-term work productivity control with TCZ-SC for biologic-naïve HWs and PWs with RA.

Background: The positivity of anti-citrullinated protein/peptide antibodies (ACPAs) is a clinically useful diagnostic and prognostic marker in rheumatoid arthritis (RA). However, the significance of ACPA titer and its fluctuation remain unclear. This study aimed to assess the role of ACPA titer and its fluctuation on disease activity and the prognosis of RA., Methods: Data obtained from the Kyoto University Rheumatoid Arthritis Management Alliance (KURAMA) cohort was analyzed. Patients whose ACPA was measured at least twice between 2011 and 2019 and whose ACPA was positive at least once were included in this study. The association between the clinical variable and ACPA titer or its change was investigated., Results: ACPA titer was measured in a total of 3286 patients, 1806 of whom were ACPA-positive at least once. Among them, the ACPA titer level was measured more than once in 1355 patients. Very weak correlation was observed between the ACPA titer level and disease activity. Additionally, there was no trend in the fluctuation of ACPA titer level in each patient; ACPA titer level fluctuated in some patients, but not in others. Patients with high variable levels of ACPA titer were more likely to relapse from remission. In the analysis of two consecutive ACPA measurements, the titer changes predicted the relapse from remission within a year of the second measurement., Conclusions: The ACPA titer level fluctuated in some patients. Very weak correlation was observed between the ACPA titer level and disease activity. Fluctuation in ACPA titer level predicted relapse from remission in patients with RA.

Objective: The aim of this longitudinal study was to examine the clinical significance of soluble lectin-like oxidized low-density lipoprotein receptor 1 (sLOX-1) in patients with rheumatoid arthritis., Methods: We gathered demographic and clinical data for a large rheumatoid arthritis cohort at 3 time points. Blood samples were collected at each time point; the number of samples was 282 cases in 2012, 431 cases in 2013, and 500 cases in 2014. Plasma sLOX-1 was measured by enzyme-linked immunosorbent assay. Correlations between sLOX-1 and clinical data were analyzed. Predictive factors associated with changes in sLOX-1 and rheumatoid factor (RF) were analyzed by multivariate linear regression., Results: Plasma sLOX-1 level was significantly correlated with RF titer and other clinical parameters. The longitudinal analyses showed that changes in sLOX-1 were significantly correlated with changes in RF titers and with those at baseline. Multivariate linear regression analysis revealed that changes in RF and baseline RF were predictive factors for changes in sLOX-1. Conversely, the changes in RF were significantly correlated with the changes in sLOX-1 in all years. A stepwise regression analysis showed that the change in sLOX-1 was a predictive factor for the change in RF., Conclusions: The change in sLOX-1 has predictive value for assessing the change in RF, indicating the usefulness of sLOX-1 in clinical practice.

Objective: Previous studies have not fully evaluated the measurement properties of the Work Functioning Impairment Scale (WFun) in clinical situations and there are no data from patients with rheumatoid arthritis (RA). This study aimed to investigate the convergent validity and responsiveness of the WFun in patients with RA. Methods: This substudy was a part of the multicenter, observational, prospective FIRST ACT-SC study. In total, 322 paid workers with RA received anti-rheumatic drugs at baseline. The WFun, Disease Activity Score based on 28 joints and erythrocyte sedimentation rate (DAS28-ESR), Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI), Work Productivity and Activity Impairment Questionnaire (WPAI), and Japanese Health Assessment Questionnaire Disability Index (HAQ-DI) were administrated at baseline and weeks 12, 24, and 52. Multilevel regression analyses were performed. Results: High average WFun scores were associated with higher score categories of the DAS28-ESR, CDAI, SDAI, WPAI and HAQ-DI. Average WFun change scores linearly decreased with decreases on each instruments. Conclusion: The findings indicate that the WFun has reasonable measurement properties: the scale demonstrated validity and responsiveness with RA patients. The WFun could be useful in assessing presenteeism in patients with RA.

Objective: To clarify the relationship among serum adiponectin, body composition, current disease activity and therapeutics of rheumatoid arthritis (RA)., Methods: We conducted a cross-sectional study in RA patients under treatment with agents including biological disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase (JAK) inhibitors. A total of 351 subjects from the Kyoto University RA Management Alliance cohort (KURAMA) were enrolled in the analysis. We classified the participants into five body composition groups according to the cut-off points for obesity and visceral fat used in Japan: body mass index (BMI), 18.5 kg/m2 for underweight and 25.0 kg/m2 for obesity, and visceral fat area (VFA), 100 cm2 for visceral adiposity., Results: Classification of body composition revealed that serum adiponectin levels and disease activity score (DAS28-ESR) in the low BMI group were significantly higher than those in the normal and overweight groups. Because both increased serum adiponectin and low BMI were previously reported as poor prognostic factors of RA, we performed multiple regression analysis to determine which factor was correlated with RA disease activity. Serum adiponectin level, but not BMI, was positively associated with DAS28-ESR (estimate = 0.0127, p = 0.0258). Subanalysis also showed that the use of bDMARD or JAK inhibitor did not have an obvious influence on circulating adiponectin., Conclusions: Classification of body composition and multiple regression analysis revealed a positive and independent correlation between serum adiponectin and DAS28-ESR in Japanese RA patients. Thus, serum adiponectin may be an important marker reflecting high disease activity of RA regardless of current medications., Competing Interests: M.H., K.M.(Murakami), K.M.(Murata), K.N., and M.T. belong to the department which is financially supported by four pharmaceutical companies (Chugai, Tanabe-Mitsubishi, UCB Japan, Ayumi). H.I. receives grants and/or speaker fees from Bristol-Meyers, Asahi-Kasei, and Kyocera. KURAMA cohort study is supported by a grant from Daiichi Sankyo Co. Ltd. M.H. receives grants and/or speaker fees from Bristol-Meyers, Eisai, Eli Lilly, and Tanabe Mitsubishi. H.M., M.K., Y.F., T.Y., M.S., and N.I. declare no conflicts of interest. The sponsors had no role in the design of the study, the collection or analysis of the data, the writing of the manuscript or the decision to submit the manuscript for publication. and this commercial affiliation does not alter our adherence to PLOS ONE policies on sharing data and materials. The authors, their immediate families, and any research foundations with which they are affiliated have not received any financial payments or other benefits from any commercial entity related to the subject of this article.

A family history of rheumatoid arthritis (RA) is a strong risk factor for developing RA, affecting both genetically and environmentally. However, whether family history provides clinically relevant information in the modern classification and treatment remains largely unknown. This study aimed to determine whether a family history of RA is associated with a different clinical presentation of RA and treatment response. We retrospectively evaluated the demographic data and disease activity of newly diagnosed RA patients at baseline, 1 year, and 2 years after onset, using the ANSWER (Kansai consortium for the well-being of rheumatic disease patients) cohort data. Thirty-one patients (11.9%) among 260 newly diagnosed RA patients had a family history of RA up to second degree. There was no significant difference in the age at onset, time from onset to first visit, sex, positivity or value of rheumatoid factor or anti-cyclic citrullinated peptide antibody (ACPA), or disease activity between patients with and without a family history of RA. However, patients who had a family history of RA and were ACPA positive showed significantly lower erythrocyte sedimentation rate, and C-reactive protein. Disease activity in patients with a family history was not worse at baseline, after 1 year or 2 years of treatment. The Larsen score 2 years after onset was equivalent between the patients with and without a family history of RA in ACPA-positive patients. Family history of RA in ACPA-positive patients is not associated with high disease activity at baseline and is not a predictor of poor outcome 2 years after onset.

To identify the risk factors for destruction of large joints in the lower extremities in patients with rheumatoid arthritis (RA) during a 4-year follow-up period in a prospective study.We enrolled consecutive patients who participated in both 2012 and 2016. Clinical data, disease activity, and types of medication were collected in 2012. Standard anteroposterior radiographs of weight-bearing joints (hips, knees, and ankles) were taken in 2012 and 2016. Radiographic progression was defined as progression in the Larsen grade or the need for joint arthroplasty or arthrodesis. The association between baseline characteristics and the incidence of radiographic progression was statistically assessed.A total of 213 patient were enrolled, and, after exclusion, 186 patients were analyzed. Sixty 9 patients (37.1%) showed radiographic progression in 1 of the large joints in the lower extremities. Multivariate regression analysis showed that radiographic progression was associated with older age, higher disease activity, and the presence of radiographic destruction at the baseline. The lower dosage of oral prednisolone was a significant risk factor compared with higher dosage when used.Patients with the risk factors should be followed closely to limit the progression of large joint destruction in the lower extremities.

Background: Rheumatoid arthritis (RA) is known to cause secondary osteoporosis and fragility fractures. This study aimed to identify biomarkers predictive of bone mineral density (BMD) change at three anatomical sites in patients with RA., Methods: We conducted a prospective longitudinal study in patients with RA. In 2012, we recruited 379 patients from an RA cohort, 329 of whom underwent evaluation of blood and urine biomarkers together with measurement of BMD in the lumbar spine, proximal femur, and distal forearm. The BMD in these three regions was reassessed in 2014. We performed multivariate linear regression analysis to identify those factors associated with BMD change., Results: The averages of age, body mass index, and disease activity score in 28 joints (DAS28) at baseline were 63.2 (minimum to maximum, 32-85), 21.3 (12.3-30.0), and 3.2 (0.1-5.9), respectively. Univariate analysis showed that the annual BMD change was significantly associated with the use of steroid, bisphosphonate (BP) or vitamin D (VitD), and serum homocysteine in the lumber spine; DAS28, the use of BP or VitD, CRP, and anti-cyclic citrullinated peptide antibody (ACPA) in the proximal femur; and the dosage of MTX, the use of BP or VitD, and serum tartrate-resistant acid phosphatase 5b (TRACP-5b) in the distal forearm, respectively., Conclusions: Predictive biomarkers for BMD change in RA patients differ at each anatomical site. Practitioners should treat each anatomical site with different markers and prescribe osteoporosis drugs to prevent fractures for RA patients.

Aim: Age at disease onset has been implicated as an indicator of disease activity and severity in rheumatoid arthritis (RA). This study aimed to investigate how old age at disease onset affects patient treatment and prognosis in early RA., Methods: Data from the Kyoto University Rheumatoid Arthritis Management Alliance (KURAMA) cohort was analyzed. From 2011 to 2015, a total of 2182 patients with RA were enrolled in the cohort; 239 patients were newly diagnosed with RA and were followed up for 2 years. The patients were divided into the following two groups: the young-onset RA (YORA) which included patients <60 years old (n = 117) and elderly-onset RA (EORA) which comprised patients ≥60 years old (n = 122). The clinical and laboratory data were compared at baseline, at 1 year, and at 2 years after onset., Results: Disease activity was higher in EORA than in YORA at baseline. Although disease activity was equivalent between EORA and YORA at 1 or 2 years, more EORA patients had bone erosions at baseline and at 2 years. More than 25% of the anti-citrullinated protein autoantibody (ACPA)-positive EORA patients without erosions at baseline had bone erosions even if they attained clinical remission at 1 or 2 years, while ~10% of YORA patients had erosions., Conclusion: Bone erosions were more frequently found in EORA. Clinical remission at 1 or 2 years was not enough to protect bone erosions in the ACPA-positive EORA patients. Optimal treatment strategies preventing radiological damage should be considered for EORA., (© 2018 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

We report the case of a 66-year-old man with seropositive rheumatoid arthritis who developed neurologically asymptomatic rheumatoid meningitis (RM) revealed by MRI. RM worsened and chest CT showed pericardial effusion, pleural effusion, and bilateral consolidation, and his serum C3 level was decreased. We diagnosed systemic rheumatic vasculitis based on these findings. After a review of more than 20 previously reported cases of RM, this is the first case of RM without central nerve system symptoms.

In human inflammatory sites, PD-1 hi CXCR5 - CD4 + T cells are involved in the formation of ectopic lymphoid-like structures (ELSs) by the secretion of chemokine CXCL13, but how the transcription of CXCL13 is regulated in CD4 + T cells is still unclear. Here we show that Sox4 is a key transcription factor for CXCL13 production in human CD4 + T cells under inflammatory conditions. In vitro TGF-β + , IL-2-neutralizing culture conditions give rise to PD-1 hi CXCR5 - CD4 + T cells that preferentially express CXCL13, and transcriptome analysis and lentiviral overexpression indicate Sox4 association with the CXCL13 transcription. In vivo, Sox4 is significantly upregulated in synovial CD4 + T cells, when compared with blood CD4 + T cells, from patients with rheumatoid arthritis (RA), and further correlates with ELS formation in RA synovium. Overall, our studies suggest that Sox4 contributes to CXCL13 production and ELS formation at inflammatory sites in humans.

Background: Following the onset of rheumatoid arthritis (RA), patients experience a functional decline caused by various joint symptoms which affects their activities of daily living and can lead to reduced work productivity. We evaluated the effect of a 52-week treatment with tocilizumab by subcutaneous injection (TCZ-SC) among biologic-naive Japanese house workers (HWs) and paid workers (PWs) with RA in a real-world clinical practice., Methods: This multicenter, observational, prospective study enrolled 377 and 347 RA patients into TCZ-SC and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs)-alone groups, respectively. The primary endpoint was the change in percentage of overall work impairment (OWI) among PWs at week 52 assessed using the Work Productivity and Activity Impairment Questionnaire (WPAI). Inverse probability of treatment weighting analyses were used to compare treatments. The Work Functioning Impairment Scale, disease activity, quality of life (QOL) measures, and safety were also assessed., Results: The weighted change in OWI from baseline for PWs was -18.9% (TCZ-SC group) and -19.0% (csDMARDs group) at week 52, without a significant between-group difference (adjusted treatment difference 0.1, 95% confidence interval (CI) -6.3 to 6.5; P = 0.978). Changes in WPAI activity impairment in the overall group (between-group difference -6.4, 95% CI -10.7 to -2.2; P = 0.003) and HWs (-9.5, 95% CI - 16.0 to -2.9; P = 0.005) were significantly better with TCZ-SC than with csDMARDs at week 52. TCZ-SC-treated HWs showed significant improvement in all QOL assessments (Frenchay Activities Index, EuroQol 5 Dimension (EQ-5D), Japanese Health Assessment Questionnaire Disability Index (HAQ-DI), and 6-item Kessler scale (K6)) at week 52; PWs did not show any between-group differences for these QOL measures. Disease activity (Disease Activity Score 28-erythrocyte sedimentation rate, Clinical Disease Activity Index, and Simplified Disease Activity Index) and QOL measures (EQ-5D, HAQ-DI, and K6) improved over time in the overall group. No new safety concerns were raised with TCZ-SC., Conclusions: Despite the lack of differences in OWI between groups at week 52, the overall group (particularly HWs) receiving TCZ-SC in addition to csDMARDs showed significant improvements in activity impairment, disease activity, and QOL versus those receiving csDMARDs alone. This study may promote the evaluation of work productivity improvements in HWs and PWs by RA treatment.

Objective: To search for signs and symptoms before serious infection (SI) occurs in tocilizumab (TCZ)-treated rheumatoid arthritis (RA) patients., Methods: Individual case safety reports, including structured (age, sex, adverse event [AE]) and unstructured (clinical narratives) data, were analyzed by automated text mining from a Japanese post-marketing AE-reporting database (16 April 2008-10 April 2015) assuming the following: treated in Japan; TCZ RA treatment; ≥1 SI; unable to exclude causality between TCZ and SIs., Results: The database included 7653 RA patients; 1221 reports met four criteria, encompassing 1591 SIs. Frequent SIs were pneumonia (15.9%), cellulitis (9.9%), and sepsis (5.0%). Reports for 782 patients included SI onset date; 60.7% of patients had signs/symptoms ≤28 days before SI diagnosis, 32.7% had signs/symptoms with date unidentified, 1.7% were asymptomatic, and 4.9% had unknown signs/symptoms. The most frequent signs/symptoms were for skin (swelling and pain) and respiratory (cough and pyrexia) infections. Among 68 patients who had normal laboratory results for C-reactive protein, body temperature, and white blood cell count, 94.1% had signs or symptoms of infection., Conclusion: This study identified prodromal signs and symptoms of SIs in RA patients receiving TCZ. Data mining clinical narratives from post-marketing AE databases may be beneficial in characterizing SIs.

Objective: To determine the factors associated with gait parameters in female patients with rheumatoid arthritis (RA)., Methods: The gait analysis was performed in a large cohort of RA patients, and three basic gait parameters (step length, cadence and gait speed) were calculated. Clinical and laboratory data were also collected. Factors associated with gait parameters were analyzed using multivariable linear regression in the three models with forced entry. Then, we divided those patients with Health Assessment Questionnaire disability index (HAQ) scores ≤ 0.5 into two groups according to their gait speed that were compared to identify the characteristics of patients with a good HAQ score but poor walking ability., Results: A total of 318 female patients were analyzed. Knee extension strength had the strongest positive association with all three gait parameters (P < 0.0001), while methotrexate use was also positively associated with all three gait parameters (step length: P < 0.05, cadence: P < 0.05 in model 1 and 2; P < 0.01 in model 3, gait speed: P < 0.01). The disease activity score was negatively associated with step length and gait speed (step length, gait speed: P < 0.01 in model 1 and 2; P < 0.05 in model 3). 26% of patients with good HAQ scores showed slow gait speed. Patients with good HAQ scores and slow gait speed had higher disease activity scores (P < 0.05) and lower knee extension strength (P < 0.0001) than those with good HAQ scores and normal gait speed., Conclusions: High knee extension strength, low disease activity and administration of methotrexate were strongly associated with good walking ability in female patients with RA. And, even if patients showed good HAQ scores, about quarter of those patients had poor walking ability, and they showed higher disease activity, lower knee extension strength, compared to the patients with normal gait speed.

Purpose: To identify the factors influencing spinal sagittal alignment, bone mineral density (BMD), and Oswestry Disability Index (ODI) outcome measures in patients with rheumatoid arthritis (RA)., Methods: We enrolled 272 RA patients to identify the factors influencing sagittal vertical axis (SVA). Out of this, 220 had evaluation of bone mineral density (BMD) and vertebral deformity (VD) on the sagittal plane; 183 completed the ODI questionnaire. We collected data regarding RA-associated clinical parameters and standing lateral X-ray images via an ODI questionnaire from April to December 2012 at a single center. Patients with a history of spinal surgery or any missing clinical data were excluded. Clinical parameters included age, sex, body mass index, RA disease duration, disease activity score 28 erythrocyte sedimentation rate (DAS28-ESR), serum anti-cyclic citrullinated peptide antibody, serum rheumatoid factor, serum matrix metalloproteinase-3, BMD and treatment type at survey, such as methotrexate (MTX), biological disease-modifying anti-rheumatic drugs, and glucocorticoids. We measured radiological parameters including pelvic incidence (PI), lumbar lordosis (LL), and SVA. We statistically identified the factors influencing SVA, BMD, VD, and ODI using multivariate regression analysis., Results: Multivariate regression analysis showed that larger SVA correlated with older age, higher DAS28-ESR, MTX nonuse, and glucocorticoid use. Lower BMD was associated with female, older age, higher DAS28-ESR, and MTX nonuse. VD was associated with older age, longer disease duration, lower BMD, and glucocorticoid use. Worse ODI correlated with older age, larger PI-LL mismatch or larger SVA, higher DAS28-ESR, and glucocorticoid use., Conclusions: In managing low back pain and spinal sagittal alignment in RA patients, RA-related clinical factors and the treatment type should be taken into consideration.

Rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) display unique aggressive behavior, invading the articular cartilage and promoting inflammation. Using an integrative analysis of RA risk alleles, the transcriptome and methylome in RA FLS, we recently identified the limb bud and heart development ( LBH ) gene as a key dysregulated gene in RA and other autoimmune diseases. Although some evidence suggests that LBH could modulate the cell cycle, the precise mechanism is unknown and its impact on inflammation in vivo has not been defined. Our cell cycle analysis studies show that LBH deficiency in FLS leads to S-phase arrest and failure to progress through the cell cycle. LBH-deficient FLS had increased DNA damage and reduced expression of the catalytic subunit of DNA polymerase α. Decreased DNA polymerase α was followed by checkpoint arrest due to phosphorylation of checkpoint kinase 1. Because DNA fragments can increase arthritis severity in preclinical models, we then explored the effect of LBH deficiency in the K/BxN serum transfer model. Lbh knockout exacerbated disease severity, which is associated with elevated levels of IL-1β and checkpoint kinase 1 phosphorylation. These studies indicate that LBH deficiency induces S-phase arrest that, in turn, exacerbates inflammation. Because LBH gene variants are associated with type I diabetes mellitus, systemic lupus erythematosus, RA, and celiac disease, these results suggest a general mechanism that could contribute to immune-mediated diseases., (Copyright © 2017 by The American Association of Immunologists, Inc.)

Hypoxia augments inflammatory responses and osteoclastogenesis by incompletely understood mechanisms. We identified COMMD1 as a cell-intrinsic negative regulator of osteoclastogenesis that is suppressed by hypoxia. In human macrophages, COMMD1 restrained induction of NF-κB signaling and a transcription factor E2F1-dependent metabolic pathway by the cytokine RANKL. Downregulation of COMMD1 protein expression by hypoxia augmented RANKL-induced expression of inflammatory and E2F1 target genes and downstream osteoclastogenesis. E2F1 targets included glycolysis and metabolic genes including CKB that enabled cells to meet metabolic demands in challenging environments, as well as inflammatory cytokine-driven target genes. Expression quantitative trait locus analysis linked increased COMMD1 expression with decreased bone erosion in rheumatoid arthritis. Myeloid deletion of Commd1 resulted in increased osteoclastogenesis in arthritis and inflammatory osteolysis models. These results identify COMMD1 and an E2F-metabolic pathway as key regulators of osteoclastogenic responses under pathological inflammatory conditions and provide a mechanism by which hypoxia augments inflammation and bone destruction., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: Modern three-component total ankle arthroplasty (TAA) has favorable clinical results and survival rates. However, radiographic deterioration and worsening of clinical symptoms may occur in patients with rheumatoid arthritis (RA) or non-inflammatory arthritis (NA). The associations between outcomes and clinical and radiological factors are not clear. We compared midterm clinical and radiographic outcomes after TAA between patients with RA and those with NA., Methods: Twenty-six TAAs were performed using a three-component prosthesis, the FINE Total Ankle System during the study period. Fourteen TAAs with 11 RA patients undergoing primary TAA were compared with twelve TAAs with 12 NA patients. Clinical and radiographic outcomes were evaluated before and after operation, and at the final follow-up., Results: The Japanese Society for Surgery of the Foot (JSSF) scale improved significantly following TAA in both groups (p = 0.0039 and 0.0156, respectively). Tibial subsidence, talar subsidence and age were significantly associated with postoperative JSSF score only in the NA group (p = 0.0027, 0.0017 and p < 0.0001, respectively). Stepwise regression analysis showed that talar subsidence was an independent predictor of a worse JSSF score in the NA group (F = 10.3)., Conclusions: The final clinical outcome was negatively influenced by talar subsidence in patients with NA, but not in those with RA.