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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.)

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.)

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.)

Objective: To elucidate the systemic and local risk factors and the effect of surgical procedures for delayed wound healing after forefoot surgery in patients with rheumatoid arthritis (RA)., Methods: Fifty forefoot surgeries were performed in 39 patients using resection arthroplasty or a joint-preserving procedure (25 feet for each procedure). The associations between the occurrence of delayed wound healing and clinical variables, radiological assessment, or surgical procedures were analyzed., Results: Delayed wound healing was recorded in nine feet of eight patients. The duration of RA was significantly longer in the delayed healing group than that in the healed group. Age, sex, smoking history, concomitant diabetes, and RA medication did not differ between the groups. Radiological evaluation showed significant differences between groups in metatarsophalangeal dorsal flexion angle. The shortened length of the fourth and the fifth metatarsal bones affected the occurrence of the complication. The joint-preserving procedure had significantly less delayed wound healing compared with resection arthroplasty., Conclusions: Preoperative dorsoplantar deformity and perioperative tissue damage can cause delayed wound healing after forefoot surgery in RA patients.