Search

Objective: The objective of the study was to develop a nursing practice scale for rheumatoid arthritis treatment with biological disease-modifying anti-rheumatic drugs., Methods: An anonymous self-administered questionnaire survey was administered to 1826 nurses, 960 of whom were Certified Nurses by Japan Rheumatism Foundation (CNJRFs) and 866 were registered nurses (RNs). Using exploratory factor analysis, criterion validity, and known-groups technique, we assessed the reliability and validity of the self-created 19-item nursing practice scale to evaluate the care provided to patients with rheumatoid arthritis receiving biological disease-modifying anti-rheumatic drugs based on the nurse's role as clarified from a literature review of relevant studies., Results: A total of 698 (38.4%) responses were collected from 407 CNJRFs and 291 RNs. Exploratory factor analysis was conducted on 18 items to examine three factors: 'nursing to enhance patients' capacity for self-care', 'nursing in which patients participate in decision-making', and 'nursing in which team medical care is promoted'. Cronbach's α was .95. The Spearman's coefficient was ρ = .738 for criterion validity. Using the known-groups technique, CNJRFs had higher total scale scores than RNs (P < .05)., Conclusions: The results confirmed the reliability, criterion validity, and construct validity of the scale., (© Japan College of Rheumatology 2023. Published by Oxford University Press.)

Objectives: The variable region of most ACPA IgG molecules in the serum of RA patients carries N-glycan (N-glycanV). To analyse the pathogenicity of N-glycanV of ACPAs, we analysed the pathogenicity of a monoclonal ACPA, CCP-Ab1, with or without N-glycanV, which had been isolated from a patient with RA., Methods: CCP-Ab1 with no N-glycosylation site in the variable region (CCP-Ab1 N-rev) was generated, and antigen binding, the effect on in vitro differentiation of osteoclasts from bone marrow mononuclear cells of autoimmune arthritis-prone SKG mice (the cell size of TRAP+ cells and bone resorption capacity) and the in vivo effect on the onset or exacerbation of autoimmune arthritis in SKG mice were evaluated in comparison with glycosylated CCP-Ab1., Results: Amino acid residues in citrullinated peptide (cfc1), which are essential for binding to CCP-Ab1 N-rev and original CCP-Ab1, were almost identical. The size of TRAP+ cells was significantly larger and osteoclast bone resorption capacity was enhanced in the presence of CCP-Ab1, but not with CCP-Ab1 N-rev. This enhancing activity required the sialic acid of the N-glycan and Fc region of CCP-Ab1. CCP-Ab1, but not CCP-Ab1 N-rev, induced the exacerbation of experimental arthritis in the SKG mouse model., Conclusions: These data showed that N-glycanV was required for promoting osteoclast differentiation and bone resorption activity in both in vitro and in vivo assays. The present study demonstrated the important role of N-glycanV in the exacerbation of experimental arthritis by ACPAs., (© 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.)

Objectives: To evaluate the long-term safety and efficacy of filgotinib (FIL) for Japanese patients with rheumatoid arthritis (RA) and limited/no prior methotrexate (MTX) exposure. We present a Japanese population subanalysis of a global randomised-controlled trial at Week 52 and interim long-term extension (LTE) to Week 48 through June 2020., Methods: Patients were randomised to FIL 200 mg plus MTX, FIL 100 mg plus MTX, FIL 200 mg, or MTX for 52 weeks. At completion, eligible patients could enrol in the LTE. Those receiving FIL continued; those receiving MTX were rerandomised (blinded) to FIL 200 or 100 mg upon discontinuation of MTX. After a 4-week washout period, MTX could be re-added., Results: Adverse event rates at Week 52 and in the LTE to Week 48 were comparable across treatment groups. Week 52 American College of Rheumatology 20% improvement (ACR20) rates were 83% (19/23), 82% (9/11), 75% (9/12), and 76% (19/25) for FIL 200 mg plus MTX, FIL 100 mg plus MTX, FIL 200 mg, and MTX, respectively. Through LTE Week 48, ACR20 rates were maintained., Conclusions: In the 56 Japanese patients treated with FIL, efficacy was maintained through Week 52 and beyond, with no increases in the incidence of adverse events., (© Japan College of Rheumatology 2022. Published by Oxford University Press.)

Objectives: To present safety and efficacy of the JAK1 preferential inhibitor filgotinib in Japanese patients with prior inadequate response (IR) to methotrexate (MTX) from a 52-week randomised controlled parent study (PS) and long-term extension (LTE) through June 2020., Methods: The PS (NCT02889796) randomised MTX-IR patients to filgotinib 200 (FIL200) or 100 mg (FIL100), adalimumab (ADA) 40 mg, or placebo; all took stable background MTX. At week (W) 24, placebo patients were rerandomised to FIL200 or FIL100. The primary endpoint was W12 American College of Rheumatology 20% improvement; safety was assessed by adverse event (AE) reporting. For the LTE (NCT03025308), eligible filgotinib patients continued FIL200/FIL100; ADA patients were rerandomised (blinded) to FIL200 or FIL100; all continued MTX., Results: In all, 114/147 Japanese patients completed the PS, 115 enrolled in LTE, and 103 remained on study in June 2020. In the PS, AEs were consistent with the overall population, and W24 efficacy was maintained or improved through W52, comparable with the overall population. LTE AE incidences were similar between doses; filgotinib efficacy was consistent from baseline to W48 and similar between PS ADA and filgotinib patients., Conclusions: Among MTX-IR Japanese patients, filgotinib maintained efficacy over 1 year; LTE safety was consistent with the PS., (© Japan College of Rheumatology 2022. Published by Oxford University Press.)

Objective: Characterize safety of the Janus kinase-1 preferential inhibitor filgotinib (FIL) in Japanese patients with moderately to severely active rheumatoid arthritis (RA)., Methods: Data from three Phase 3 trials (NCT02889796, NCT02873936, and NCT02886728) and a long-term extension (NCT03025308) through September 2019 were integrated; patients received ≥1 dose of FIL 200 (FIL200) or 100 mg (FIL100) daily, or placebo (PBO). We calculated exposure-adjusted incidence rates (EAIRs) per 100 patient-years FIL exposure (100PYE) for treatment-emergent adverse events (TEAEs) and adverse events of special interest., Results: Among 3691 total patients and 6080.7 PYE, 229 Japanese patients received FIL for 311.4 PYE (median 1.5, maximum 2.5 years). During the 12-week PBO-controlled period, serious TEAEs and TEAEs leading to study drug disruption were comparable between FIL and PBO. Serious infection rates were 1.9%, 0%, and 2% for FIL200, FIL100, and PBO during the PBO-controlled period; long-term FIL200 and FIL100 EAIRs were 3.8 and 2.1/100PYE. No herpes zoster (HZ) or major adverse cardiovascular events (MACEs) occurred during the PBO-controlled period; long-term FIL200 and FIL100 EAIRs were 3.0 and 2.1/100PYE (HZ) and 0.6 and 0/100PYE (MACE)., Conclusion: Long-term FIL treatment (median 1.5, maximum 2.5 years exposure) was well tolerated at 100- and 200-mg doses in Japanese patients with RA., (© Japan College of Rheumatology 2022. Published by Oxford University Press.)

Objectives: To evaluate the effectiveness and safety of abatacept over 52 weeks in biologic-naïve rheumatoid arthritis (RA) patients with moderate disease activity in the prospective, 5-year, observational study (ORIGAMI study) in Japan., Methods: Abatacept (125 mg) was administered subcutaneously once a week. Clinical outcomes included Simplified Disease Activity Index (SDAI) remission at Week 52 (primary endpoint), Japanese Health Assessment Questionnaire (J-HAQ), EuroQol 5-Dimension Questionnaire (EQ-5D), treatment retention, and safety. The results were compared with those of conventional synthetic disease-modifying antirheumatic drug (csDMARD) controls from the ongoing Institute of Rheumatology, Rheumatoid Arthritis (IORRA) registry., Results: Overall, 325 patients were enrolled, with a mean age of 66.9 ± 12.7 years. The proportion of patients achieving SDAI remission (≤3.3) at Week 52 was 18.9% (95% CI: 14.3-23.6) and low disease activity (≤11) was 53.3% (95% CI: 47.4-59.1). A significant improvement was observed in J-HAQ and EQ-5D over 52 weeks in both the abatacept and csDMARD groups. The probability of abatacept treatment retention at Week 52 was 69.9% (95% CI: 64.7-75.5). Adverse events and serious adverse events were reported in 50.0% and 12.1% of patients, respectively., Conclusions: Abatacept significantly improved disease activity, physical disability, and quality of life for up to 52 weeks in RA patients in a real-world setting., (© Japan College of Rheumatology 2021. Published by Oxford University Press.)

Objectives: Evaluate the efficacy and safety of the Janus kinase-1 inhibitor filgotinib in Japanese patients with rheumatoid arthritis (RA) and inadequate response to methotrexate (MTX)., Methods: Data from 147 Japanese patients in FINCH 1, a 52-week global Phase 3 study, were analysed up to 24 weeks. Patients received once-daily filgotinib 200 or 100 mg, biweekly adalimumab, or placebo, all with stable background MTX., Results: In the Japanese population, American College of Rheumatology 20% response rates at Week 12 (primary endpoint) were 77.5%, 65.9%, 53.6%, and 36.8% for filgotinib 200 mg, filgotinib 100 mg, adalimumab, and placebo. Proportions of patients achieving Disease Activity Score with 28 joints <2.6 at Week 24: filgotinib 200 mg, 65.0%; filgotinib 100 mg, 51.2%; adalimumab, 42.9%; and placebo, 5.3%. Incidence rates of serious infections: filgotinib 200 mg, 2.5%; filgotinib 100 mg, 0%; adalimumab, 10.7%; and placebo, 5.3%. Treatment-emergent laboratory abnormalities Grade ≥3 occurred in five (12.5%) filgotinib 200 mg, three (7.3%) filgotinib 100 mg, one (3.6%) adalimumab, and no placebo patients. No deaths were reported among Japanese patients., Conclusions: Filgotinib once daily combined with MTX was effective and generally safe and well tolerated up to Week 24 in Japanese patients with RA and inadequate response to MTX., (© Japan College of Rheumatology 2022. Published by Oxford University Press.)

Objectives: To evaluate the efficacy and safety of filgotinib for Japanese patients with rheumatoid arthritis (RA) and limited or no prior methotrexate (MTX) exposure., Methods: Data up to 24 weeks were analysed for 71 Japanese patients from a 52-week global Phase 3 study. Patients with RA and limited or no prior MTX exposure were randomised in a 2:1:1:2 ratio to filgotinib 200 mg plus MTX, filgotinib 100 mg plus MTX, filgotinib 200 mg, or MTX. Maximum MTX dose was 15 mg/week. Primary endpoint was proportion achieving 20% improvement in American College of Rheumatology criteria (ACR20) at Week 24., Results: Week 24 ACR20 rates in Japanese patients were 82.6%, 90.9%, 83.3%, and 80.0% for filgotinib 200 mg plus MTX, filgotinib 100 mg plus MTX, filgotinib 200 mg, and MTX, respectively. Greater ACR20 rates with filgotinib vs MTX occurred at Week 2. Greater proportions receiving filgotinib vs MTX achieved DAS28-CRP <2.6 at Weeks 12 and 24. Adverse event rates were comparable across treatments and between the Japanese and overall populations., Conclusions: While Week 24 ACR20 rates were similar, filgotinib provided faster responses and higher remission rates vs MTX. In Japanese patients with RA and limited or no prior MTX exposure, filgotinib was generally well tolerated., (© Japan College of Rheumatology 2022. Published by Oxford University Press.)

Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammatory bone destruction in which tumor necrosis factor alpha (TNF-α) plays a key role. Bovine lactoferrin (bLF) is a multifunctional protein with anti-inflammatory and immunomodulatory properties. This study aimed to clarify the inhibitory effects of bLF on the pathological progression of RA. The mannan-induced arthritis model in SKG mice (genetic RA model) was used. Orally applied liposomal bLF (LbLF) markedly reduced ankle joint swelling and bone destruction. Histologically, pannus formation and osteoclastic bone destruction were prevented in the LbLF-treated animals. Moreover, orally administered LbLF improved the balance between Th17 cells and regulatory T cells isolated from the spleen of mannan-treated SKG mice. In an in vitro study, the anti-inflammatory effects of bLF on TNF-α-induced TNF-α production and downstream signaling pathways were analyzed in human synovial fibroblasts from RA patients (RASFs). bLF suppressed TNF-α production from RASFs by inhibiting the nuclear factor kappa B and mitogen-activated protein kinase pathways. The intracellular accumulation of bLF in RASFs increased in an applied bLF dose-dependent manner. Knockdown of the lipoprotein receptor-related protein-1 (LRP1) siRNA gene reduced bLF expression in RASFs, indicating that exogenously applied bLF was mainly internalized through LRP-1. Immunoprecipitated proteins with anti-TNF receptor-associated factor 2 (TRAF2; an adapter protein/ubiquitin ligase) included bLF, indicating that bLF binds directly to the TRAF2-TRADD-RIP complex. This indicates that LbLF may effectively prevent the pathological progression of RA by suppressing TNF-α production by binding to the TRAF2-TRADD-RIP complex from the RASFs in the pannus. Therefore, supplemental administration of LbLF may have a beneficial effect on preventive/therapeutic reagents for RA., Competing Interests: AI and HI are employees of Sunstar Inc. Besides that, the authors declare no conflicts of interest associated with this manuscript. The funder provided support in the form of salaries for authors [AI and HI] but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The all authors including AI and HI declare no conflicts of interest associated with this manuscript.

Objectives: To evaluate efficacy and safety of filgotinib in Japanese RA patients who have failed or were intolerant to one or more biologic disease-modifying antirheumatic drugs (bDMARD) from the global FINCH 2 study (NCT02873936)., Methods: This subgroup analysis was performed using the predefined statistical analyses. The FINCH 2 study is a randomized, double-blind, placebo-controlled, Phase 3 study in adult RA patients with inadequate response to bDMARDs. The randomized patients were treated with once-daily filgotinib 200 mg, filgotinib 100 mg or placebo on a background of csDMARDs for 24 weeks., Results: Of 449 patients enrolled in the overall population, 40 patients were enrolled from Japan. In the Japanese population, the American College of Rheumatology 20% response rates at week 12 (primary endpoint) were 83.3% and 53.3% for filgotinib, 200 mg and 100 mg, respectively, vs 30.8% for placebo. Filgotinib was well tolerated, similar to the overall population., Conclusions: Both doses of once-daily filgotinib 200 mg and filgotinib 100 mg were effective, and generally well-tolerated in Japanese patients with active refractory RA., (© 2021 Japan College of Rheumatology.)

Introduction: Lipopolysaccharide (LPS) contamination of commercially available proteins has seriously impeded research on citrullinated fibrinogen (cit-Fb) in rheumatoid synovial cells (RSCs)., Methods: RSCs obtained from 4 rheumatoid arthritis patients who underwent full knee arthroplasty were cultured, stimulated with cit-Fb, and cytokine expression levels were measured. We then evaluated polymyxin-B (PMB), heat inactivation, and rough (R)-type LPS mutants for rapid detection of LPS contamination., Results: cit-Fb induced expression of CXCL10 and IFNB in RSCs via the toll-like receptor. PMB inhibited cit-Fb-mediated CXCL10 gene expression but not protein expression induced by 20 μg/mL cit-Fb. Heat inactivation did not affect LPS-mediated CXCL10 or IL-6 induction; however, cit-Fb-mediated CXCL10expression was inhibited. Wild-type LPS from Escherichia coli (WT-LPS) strongly induces CXCL10 expression, but induction by Ra-LPS was weak, and induction by Rc- and Re-LPS was minimal. Re-LPS suppression of WT-LPS-mediated CXCL10 induction in RSCs and peripheral blood monocytes (PBMs) was dose dependent. Furthermore, Re-LPS completely suppressed cit-Fb-mediated CXCL10 induction in RSCs and PBMs., Conclusion: To easily identify LPS contamination during routine experiments, our results suggest that Re-LPS is a better tool for rapid detection of LPS contamination compared to PMB and heat treatment., (© 2021 S. Karger AG, Basel.)

Objective: To evaluate treatment satisfaction, disease outcomes, and perspectives of patients with poorly controlled rheumatoid arthritis (RA) treated with conventional synthetic, targeted synthetic, or biologic disease-modifying antirheumatic drugs (DMARDs), we conducted a subgroup (post hoc) analysis of Japanese patients participating in the SENSE study., Methods: Data for Japanese patients (n/N = 118/1629) from the global, multicenter, cross-sectional, observational SENSE study were analyzed. The primary endpoint was the global satisfaction subscore assessed using the Treatment Satisfaction Questionnaire for Medication (TSQM) version 1.4. Other patient-reported outcomes included self-reported RA medication adherence and Work Productivity and Activity Impairment-RA. Patient perspectives included patients' expectations and preference of pharmacologic treatment., Results: Median (range) age and RA disease duration were 67.0 (18.0-87.0) years and 8 (0.0-54) years, respectively; 81.4% of patients were female. Mean (SD) TSQM global satisfaction subscore was 56.8 (17.5), and only 5.9% of patients reported good satisfaction with treatment (TSQM global ≥80). Mean (SD) self-reported treatment adherence using VAS was high (93.5% [13.8%]). Mean (SD) total work productivity impairment was 45.6% (32.0%); presenteeism contributed toward more total work productivity impairment (43.9% [30.4%]) than absenteeism (8.3% [24.4%]). Patients expected improvement in all parameters from their treatment, especially improvement in joint symptoms. Most patients (80.7%) preferred oral medication and 18.7% preferred monotherapy. Patient acceptability of potentially manageable side effects was high (7.5%-34.0%). Although most patients (81.3%) found combination therapy acceptable, 43.2% were receiving DMARD monotherapy., Conclusion: Although most Japanese patients with RA with moderate-to-high disease activity were dissatisfied with their current DMARD treatment, high treatment adherence, high acceptability of combination therapy, high acceptability of manageable potential side effects, and preference for oral medication were reported. Data support the development of a more individualized and patient-centric approach for RA treatment., Competing Interests: YK has received research grants from AbbVie Japan GK, Asahi Kasei Pharm, Astellas Pharma Inc., Ayumi Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Daiichi-Sankyo, Inc., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., and Teijin Pharma Ltd. for the submitted work. YK has also received speaker’s fee from AbbVie Japan GK, Ayumi Pharmaceutical Co. Ltd., Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Pfizer Japan Inc., and Teijin Pharma Ltd. outside of the submitted work. ES has received research support or speakers fee from AbbVie Japan GK, Asahi Kasei Pharma, Ayumi Pharmaceutical Co., Ltd, Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Janssen, Pfizer Japan Inc., Mitsubishi Tanabe Pharma Co., and UCB for the submitted work. NM is an employee of AbbVie and owns stock or stock options. ON was an employee of AbbVie at the time of the study and during publication development, and may have received stock and/or stock options from AbbVie. 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. YT do not have any conflicts of interest to disclose.

Objective: To retrospectively evaluate whether oral glucocorticoid (GC) administration can be tapered or discontinued over a 2-year observation period in patients with rheumatoid arthritis (RA) undergoing a stable oral GC treatment, without deterioration in the disease status., Methods: Methotrexate (MTX) and prednisolone (PSL) dosages were increased and decreased, respectively, to the maximum extent possible. Concomitant biological or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) were used as required. Changes in PSL and MTX use and disease status were evaluated at baseline (BL), year-1, and year-2., Results: Thirty-six patients were enrolled (median age, 65.4 years; disease duration, 7.1 years). The proportion of patients using PSL decreased over 2 years (100-13.9%, p  < .0001). While no change was observed in the proportion of patients using MTX, the average administered dose increased at year-1 ( p  = .06). Moreover, b/tsDMARDs were administered in nine patients (two in year-1, seven in year-2). The Clinical Disease Activity Index remission rate increased from 25.0% to 38.9%. Serious adverse events were identified in two patients., Conclusions: Oral GC administration was discontinued without deterioration in the rheumatoid arthritis disease control.

A 77-year-old Japanese woman with a 21-year history of seropositive, erosive rheumatoid arthritis (RA) and a 10-year history of methotrexate (MTX) therapy was admitted with malaise and mild consciousness disturbance. Laboratory data showed hypercalcemia, acute kidney injury, normocytic anaemia, and thrombocytopenia. As we first assumed drug-induced toxicity by MTX and eldecalcitol, both were discontinued and leucovorin rescue therapy and calcitonin were administered. However, her condition continued to worsen. Serum protein electrophoresis showed only a small M-peak, immunoelectrophoresis of both the serum and urine demonstrated Bence-Jones kappa (κ) type monoclonal protein without immunoglobulin heavy chain, and bone marrow examination revealed proliferation of plasma cells. We diagnosed her with Bence-Jones κ type multiple myeloma (MM) and transferred her to the department of haematology of a higher order medical institution. Conclusively, the diagnosis of immunoglobulin (Ig) D-κ type MM, a rare variant of this disorder, was determined in accordance with serum immunofixation. Several previous studies have suggested that pre-existing RA is a risk factor for MM. Although IgD MM is characterised by its clinical severity and poor prognosis compared to other subtypes, it is often misdiagnosed or mistaken as light chain type MM, as in the present case, because of the low level of IgD M-protein, resulting in delayed diagnosis. Physicians must take MM into consideration as a differential diagnosis when inactive RA patients present with inexplicable elevated calcium, renal failure, anaemia, and bone lesion symptoms and should be aware of IgD MM to establish the correct diagnosis promptly.

Objective: In plasma from a patient with rheumatoid arthritis (RA), we previously isolated a human monoclonal anti-citrullinated protein antibody (ACPA), CCP-Ab1, that recognizes various citrullinated antigens. In this study, we aimed to explore the physiologic target of CCP-Ab1 and the role of molecular evolution, through affinity maturation, of this ACPA in the onset and the exacerbation of RA., Methods: The target protein of CCP-Ab1 was identified in the plasma of a patient with RA and purified under native conditions. Germline-reverted (GL-rev) CCP-Ab1 was generated, and its reactivity was compared to that of mature CCP-Ab1. The functions of CCP-Ab1 and GL-rev CCP-Ab1 in the onset or exacerbation of autoimmune arthritis were analyzed using autoimmune arthritis-prone SKG mice., Results: CCP-Ab1 bound citrullinated fibrinogen under native conditions. In cultures with GL-rev CCP-Ab1, the binding affinity to citrullinated fibrinogen was drastically reduced (P < 0.05). The elements implicated in GL-rev CCP-Ab1 binding to a citrullinated peptide, cfc1-cyc, were almost identical to those implicated in CCP-Ab1 binding. In arthritis-prone SKG mice, CCP-Ab1, but not GL-rev CCP-Ab1, induced significant exacerbation of experimental arthritis (P < 0.05). Increased production of interleukin-6, both in the joint tissue and in the serum, was observed in SKG mice treated with CCP-Ab1 compared to those treated with GL-rev CCP-Ab1 (P < 0.05). Furthermore, the immune complex formed by CCP-Ab1 and fibrinogen was detected at higher concentrations in the synovial tissue of SKG mice administered CCP-Ab1 (P < 0.05 versus control treatment groups)., Conclusion: These data show that germline-encoded CCP-Ab1, which binds weakly to citrullinated fibrinogen, undergoes hypermutation through the activation of naive B cells by citrullinated peptides/proteins, thereby stimulating high reactivity to citrullinated fibrinogen. These findings deepen our understanding of the role of molecular evolution of ACPAs in the onset and exacerbation of RA., (© 2020, American College of Rheumatology.)

Objectives: This study aimed to identify therapeutic predictors of abatacept (ABT) treatment in rheumatoid arthritis (RA) in vitro and in patients., Methods: T cell cytokine, monokine, and chemokine levels in culture supernatants or serum were determined using flow cytometry bead-based immunoassays. CXCL10 mRNA and protein expressions were also assessed using qPCR and ELISA analyses, respectively. In the patient study, 25 ABT-treated patients were analysed retrospectively. The patients were divided into low disease activity (LDA) or non-low disease activity (non-LDA) groups at 24 weeks of ABT treatment. Seven T cell cytokines and CXCL10 levels were compared in these two groups., Results: Peripheral blood mononuclear cells (PBMC) from healthy donors were stimulated by immobilised anti-CD3 with or without ABT for three days, and the levels of 13 T cell cytokines in culture supernatants were determined. ABT significantly inhibited anti-CD3-induced production of IFN-γ. To examine the effect of these T cell cytokines in rheumatoid synovial cells (RSC), RSCs were stimulated with 10% of culture supernatants from anti-CD3-stimulated PBMCs with or without ABT, and the levels of 23 cytokines were determined. Only CXCL10 was significantly reduced by ABT-treated supernatants. In the patient study, CXCL10 levels at baseline were not different between the LDA and non-LDA groups, whereas CXCL10 levels at 24 weeks were significantly decreased in the LDA group only., Conclusions: ABT treatment significantly affected IFN-γ and CXCL10 cytokine levels in vitro. In addition, serum CXCL10 levels were associated with better responses in ABT treatment.

Objective: To investigate the reactivity of monoclonal anti-citrullinated protein antibody (ACPA) obtained from peripheral blood B cells of rheumatoid arthritis (RA) patients with human autoantigens as well as environmental proteins by determining the essential epitope for the ACPA., Methods: A human monoclonal ACPA (cyclic citrullinated peptide antibody 1 [CCP-Ab1]) was obtained by screening peripheral blood lymphocytes from 31 patients with RA using a novel monoclonal antibody-secreting cell (ASC) screening system, the immunospot-array assay on a chip. The essential epitope for CCP-Ab1 was determined using epitope mapping. Then, human, microbial, and plant proteins that share the essential epitope identified were searched using BLAST. Finally, representative proteins identified by the search were produced in vitro, and their reactivity with CCP-Ab1 was examined., Results: CCP-Ab1 bound CCP in a citrulline-indispensable manner. In CCP, the 6 amino acid residues required for CCP-Ab1 binding were identified. In the BLAST search, 38 human, 56 viral, 1,383 fungal, 547 bacterial, and 1,072 plant proteins were found to share the essential epitope, and CCP-Ab1 reacted with all of the recombinant citrullinated proteins tested, which included the various environmental factors, such as various plant proteins that are part of the daily diet., Conclusion: Our findings demonstrate, for the first time, that a monoclonal ACPA (CCP-Ab1) derived from RA patients cross-reacts not only with various autoantigens but also with numerous plant and microbial proteins. We propose that countless environmental factors, including microbes and diet, may trigger the generation of ACPAs that then cross-react with various citrullinated human autoantigens through molecular mimicry to induce RA., (© 2015, American College of Rheumatology.)

Factor XIII is one of the twelve coagulation factors and also known as a fibrin-stabilizing factor. In 2012, we encountered a male RA patient with hemorrhagic factor XIII deficiency who had been treated with tocilizumab for two years. There are few reports regarding the relationship between tocilizumab (a humanized monoclonal antibody against the interleukin-6 receptor (IL-6R)) and factor XIII. We measured the factor XIII activity levels in the plasma of 40 RA patients (10 patients treated without biologics, 30 patients treated with biologics (15 patients treated with necrosis factor inhibitors and 15 patients treated with tocilizumab)) and 19 healthy controls. Consequently, the tocilizumab group exhibited lower levels than the other three groups according to the Steel-Dwass test (P<0.01). Furthermore, we compared the plasma factor XIII activity levels and the plasma factor XIII concentrations in the RA patients treated with biologics. Pearson's correlation test was used to assess the relationship between the factor XIII activity levels and the plasma factor XIII concentrations (r=0.449, P=0.019). According to the multiple regression analysis, the treatment with tocilizumab is an independent risk factor for plasma factor XIII reduction in RA patients. In conclusion, RA patients treated with tocilizumab, an IL-6R blocker, are at risk of developing acquired factor XIII deficiency. The mechanisms underlying the reduced factor XIII activity observed in RA patients treated with tocilizumab may result from the quantitative reduction in the plasma. These data imply that IL-6 plays an important role in maintaining the factor XIII activity level.

Tumor necrosis factor (TNF)-α inhibitors are increasingly being used to treat rheumatoid arthritis. Infliximab (INF) is a TNF-α inhibitor that is usually used in combination with methotrexate (MTX). Interstitial lung disease (ILD) during combination therapy has been attributed to MTX rather than INF. However, INF-associated ILD without combination with MTX has recently been reported. We describe herein a case of severe ILD secondary to INF without MTX therapy.

The aim of the present study was to assess the influence of tumor necrosis factor (TNF)-blocking therapies on weight-bearing joints in patients with rheumatoid arthritis. Changes in clinical variables and radiological findings in 213 weight-bearing joints (69 hip joints, 63 knee joints, and 81 ankle joints) of 42 consecutive patients were investigated at baseline and at 1 year of TNF-blocking therapies. Structural damage to the weight-bearing joints was assessed using the Larsen scoring method. Detailed comparisons of the sizes and locations of erosions were performed for each set of radiographs of the respective joints. Assessment of radiographs of the 213 weight-bearing joints indicated progression of the Larsen grade in eight joints. Another five joints without Larsen grade progression showed apparent radiographic progression of joint damage based on increases in bony erosions. Overall, 13 joints (6%) of eight patients (19%) showed progression of joint damage after 1 year of TNF-blocking therapies. Analysis of each baseline grade indicated that radiographic progression of joint damage was inhibited in most grade 0-II joints. On the other hand, all hip and knee joints with pre-existing damage of grade III/IV showed apparent progression even in patients with good response. The results further suggested that radiographic progression may occur in less damaged joints when the patients were non-responders to the therapy. Among the weight-bearing joints, ankle joints showed different radiographic behavior and four ankle joints displayed improvement of radiographic damage. Early initiation of anti-TNF therapy should be necessary especially when the patients are starting to show early structural damage in weight-bearing joints.

Matrix metalloproteinase-3 (MMP-3) , which is induced by inflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) in rheumatoid synovium, degrades a number of extracellular matrix components of cartilage, and plays central roles in rheumatoid joint destruction. In addition, serum MMP-3 level is a clinically useful maker for predicting joint destruction and for disease activity in rheumatoid arthritis (RA) . In this review, I summarized the role of MMP-3 in rheumatoid joint destruction, and clinical usefulness of serum MMP-3 level as a laboratory marker in RA.

Geode, a subchondral cyst, is sometimes seen in the femur, knee, or wrist in a patient with rheumatoid arthritis (RA). But the onset of a giant geode at the olecranon is extremely rare in a patient with RA. We describe herein a rare case of a giant geode at the olecranon in a patient with RA.

We report a 62-year-old man with rheumatoid arthritis (RA) who developed nodulosis after methotrexate (MTX) treatment. The epithelioid cells of nodules were positive for matrix metalloproteinases (MMP)-2, MMP-3, MMP-9, and Ki67. The synovial tissues obtained from the same patient were negative for MMP-3, MMP-9, and Ki67. This study demonstrated that MTX-induced nodules are different from synovial tissues in terms of MMP expression, suggesting the presence of different pathologic mechanisms and differential MTX susceptibility.