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Context: Wnt/β-catenin signaling pathway is one of the pathogenic mechanisms of glucocorticoid-induced osteoporosis (GIOP). We previously reported the potential of inhibiting sclerostin as a treatment for GIOP., Objective: To compare the efficacy of romosozumab (ROMO), a monoclonal antibody against sclerostin, with existing therapy for GIOP., Methods: Patients with rheumatic diseases who had not previously received treatment for osteoporosis and were newly treated with prednisolone 15 mg/day or more were randomly assigned to receive ROMO, denosumab (DMAb), or bisphosphonates (BP). After the initiation of GC therapy, we measured the bone mineral density (BMD) of the lumbar spine, femoral neck, and total hip every 6 months and bone turnover markers every 3 months for 12 months., Results: Eleven patients were assigned to the ROMO group, 14 to the DMAb group, and 14 to the BP group. The median [25th to 75th percentile] percent change in lumbar spine BMD from baseline at 12 months was the greatest in the ROMO group (ROMO; 8.6 [3.1-12.4] %, DMAb; 3.3 [1.5-6.2] %, BP; -0.4 [-3.4-1.1] %). Among bone formation markers, serum levels of bone alkaline phosphatase were slightly elevated in the ROMO group, while those of N-terminal propeptide of type I procollagen and osteocalcin decreased in all three groups; however, these changes were smaller in the ROMO group. Serum levels of bone resorption markers and a urine bone quality marker decreased in all groups., Conclusion: Treatment with ROMO significantly increased lumbar spine BMD in GC-treated patients, suggesting that ROMO is effective for GIOP., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Objectives: To report up to 3-year safety and effectiveness of certolizumab pegol (CZP) in Japanese patients with rheumatoid arthritis from a postmarketing surveillance study., Methods: Patients enrolled previously completed 24 weeks of CZP in the 24-week postmarketing surveillance study. Adverse drug reactions (ADRs) were recorded for patients who received ≥1 CZP dose. Effectiveness outcomes were 28-joint Disease Activity Score with erythrocyte sedimentation rate and European Alliance of Associations for Rheumatology response. Week 24-156 safety and Week 0-52 effectiveness data are reported here., Results: A total of 781 patients were enrolled, with 735 and 376 patients evaluated for safety and effectiveness, respectively. Within the safety set, 17.8% (131/735) of patients reported ADRs; 9.4% (69/735) reported serious ADRs. Among patients with history of respiratory, thoracic, and mediastinal disorders, 38.4% (28/73) reported ADRs. The most frequent ADRs were infections and infestations (11.8%; 87/735); skin and subcutaneous tissue disorders (1.9%; 14/735); respiratory, thoracic, and mediastinal disorders (1.6%; 12/735). Mean 28-joint Disease Activity Score with erythrocyte sedimentation rate reduced from 4.6 (Week 0) to 2.8 (Week 52). At Week 52, 51.8% (161/311) of patients achieved European Alliance of Associations for Rheumatology Good response., Conclusions: The long-term safety and effectiveness of CZP in the real-world setting in Japan were consistent with previously reported data; no new safety signals were identified., (© Japan College of Rheumatology 2024. Published by Oxford University Press.)

Background: Coronavirus disease 2019 (COVID-19) is characterized by high interleukin-6 levels. Clinical data supporting tocilizumab, a monoclonal antibody that targets interleukin-6 receptor-alpha, for treating Japanese patients with severe COVID-19 pneumonia are needed., Methods: This single-arm phase 3 study investigated tocilizumab (8 mg/kg) plus standard of care (SOC) in Japanese patients hospitalized with severe COVID-19 pneumonia. Clinical status was assessed using a 7-category ordinal scale on day 28 (primary endpoint) and day 14 (secondary endpoint). Other secondary endpoints were time to improvement (≥2 category improvement) and time to hospital discharge. Safety was assessed as the incidence of adverse events (AEs)., Results: Among 48 patients enrolled, 44 (91.7 %) scored ≥3 on the 7-category ordinal scale at baseline. At day 28, 35 patients (72.9 %) scored 1 and 5 (10.4 %) scored 7 on the 7-category ordinal scale; 36 (75.0 %, 95 % confidence interval [CI]: 60.40 %-86.36 %) and 39 (81.3 %, 95 % CI: 67.37 %-91.05 %) patients achieved ≥2- and ≥1-category improvement, respectively; 6 patients (12.5 %, 95 % CI: 4.73 %-25.25 %) demonstrated ≥1-category worsening. At day 14, 25 (52.1 %, 95 % CI: 37.19 %-66.71 %) and 33 patients (68.8 %, 95 % CI: 53.75 %-81.34 %) achieved ≥2- and ≥1-category improvement, respectively; 5 patients (10.4 %, 95 % CI: 3.47 %-22.66 %) demonstrated ≥1-category worsening. Median times (95 % CI) to improvement and hospital discharge were 11 (9-15) and 15 (11-18) days, respectively. Forty patients (83.3 %) experienced AEs; the incidence of ≥grade 3 AEs was 25 %., Conclusion: Tocilizumab plus SOC may provide improved clinical status in Japanese patients with severe COVID-19 pneumonia; no new safety signals were identified., Competing Interests: Declaration of competing interest AH discloses consulting fees from Chugai Pharmaceutical Co. Ltd and Kowa Company Ltd. MY, NO, YK, and NM disclose research grants from Chugai Pharmaceutical Co. Ltd. MY and YK provided honoraria lectures for Chugai Pharmaceutical Co. Ltd. NM provided honoraria lectures for MSD, Shionogi Inc., Asahi Kasei Pharma, and Zeria Pharmaceutical Co., Ltd. NK, RS, and RO are employees of Chugai Pharmaceutical Co. Ltd. TN discloses consulting fees from Chugai Pharmaceutical Co. Ltd and research grants from Chugai Pharmaceutical Co. Ltd, Eli Lilly Japan K.K., and Shionogi & Co., Ltd, and provided honoraria lectures for Chugai Pharmaceutical Co. Ltd, Eli Lilly Japan K.K., AstraZeneca K.K., GlaxoSmithKline Plc, and Pfizer Japan Inc., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Lipid mediators have been suggested to play important roles in the pathogenesis of rheumatoid arthritis (RA). Lipidomics has recently allowed for the comprehensive analysis of lipids and has revealed the potential of lipids as biomarkers for the early diagnosis of RA and prediction of therapeutic responses. However, the relationship between disease activity and the lipid profile in RA remains unclear. In the present study, we performed a plasma lipidomic analysis of 278 patients with RA during treatment and examined relationships with disease activity using the Disease Activity Score in 28 joints (DAS28)-erythrocyte sedimentation rate (ESR). In all patients, five lipids positively correlated and seven lipids negatively correlated with DAS28-ESR. Stearic acid [FA(18:0)] (r = -0.45) and palmitic acid [FA(16:0)] (r = -0.38) showed strong negative correlations. After adjustments for age, body mass index (BMI), and medications, stearic acid, palmitic acid, bilirubin, and lysophosphatidylcholines negatively correlated with disease activity. Stearic acid inhibited osteoclast differentiation from peripheral blood monocytes in in vitro experiments, suggesting its contribution to RA disease activity by affecting bone metabolism. These results indicate that the lipid profile correlates with the disease activity of RA and also that some lipids may be involved in the pathogenesis of RA., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Noonan syndrome (NS) is a dominantly inherited genetic disorder with mutations in genes encoding components or regulators of the Rat sarcoma virus/mitogen-activated protein kinase pathway. Its diagnosis is based on characteristic features, including typical facial features, a short stature, congenital heart disease, mild developmental delay, and cryptorchidism. Patients with NS sometimes develop autoimmune diseases, such as Hashimoto's thyroiditis and, rarely, systemic lupus erythematosus (SLE). We herein present a 29-year-old Japanese female with NS complicated by SLE and repeated severe hypoglycaemia. The patient was diagnosed with SLE based on thrombocytopenia, nephritis, a positive antinuclear antibody titre (1:640), and a positive anti-dsDNA antibody. The patient was treated with a glucocorticoid, mycophenolate mofetil, and tacrolimus, which attenuated both SLE and hypoglycaemia. Since insulin receptor antibody levels were higher to the upper normal range and decreased after treatment, hypoglycaemia probably appeared to be attributed to type B insulin resistance syndrome. We herein present the first case of SLE in NS complicated by type B insulin resistance syndrome. Although NS is a rare disease, we need to consider the complication of autoimmune diseases, including SLE., (© Japan College of Rheumatology 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: We aimed to reveal the effect of abatacept (ABT) on atherosclerosis in rheumatoid arthritis (RA) patients, 3-year efficacy for arthritis, and safety in a population of older vs. younger patients., Methods: In this open-label, prospective, observational study, patients were stratified into four groups: younger (20-64 years old) and older (≥ 65 years) patients taking ABT (AY and AO) and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) (CY and CO). Primary endpoints were change from baseline in mean intima-media thickness (IMT) of the common carotid artery, IMT max (bulbus, bifurcation, and internal and common carotid artery), and plaque score at Week 156. Disease activity, retention rate, and adverse effects were also evaluated., Results: The ABT group (AY + AO) tended to have smaller increases in mean IMT, max IMT, and plaque score than the csDMARD group (CY + CO) at Week 156, although the differences between groups were not statistically significant. Multivariate analysis showed significantly lower increases in plaque score with ABT than with csDMARDs, only when considering disease activity at 156 weeks (p = 0.0303). Proportions of patients with good or good/moderate European League Against Rheumatism response were higher in the ABT group, without significant difference between older and younger patients. No significant differences were observed in ABT retention rates between older and younger patients. Serious adverse effects, especially infection, tended to be more frequent with ABT than with csDMARDs, although no significant differences were found., Conclusions: ABT may decelerate atherosclerosis progression and may be useful for patients with high risk of cardiovascular disease, such as older patients., Trial Registration Number: UMIN000014913., (© 2024. The Author(s).)

Objectives: To evaluate the renal response to mycophenolate mofetil (MMF) as maintenance therapy for lupus nephritis (LN) in Japanese patients, we compared the efficacy of MMF and the sequential use of monthly intravenous cyclophosphamide (IVCY) followed by tacrolimus (TAC)., Methods: We examined 14 patients with LN who were treated with continuous MMF as induction and maintenance therapies (MMF group) and 10 patients with LN who received monthly IVCY as induction therapy followed by maintenance therapy with TAC (IVCY-TAC group). We assessed the therapeutic effects of each treatment regimen on renal manifestations and serological findings over a 36-month period after treatment initiation., Results: Mean urine protein-to-creatinine ratios in the MMF and IVCY-TAC groups significantly decreased from 2.75 to 0.11 g/gCr and from 3.26 to 0.22 g/gCr, respectively. Significant improvements in serum immunological variables (serum complement C3 or C4 levels and the anti-double-stranded DNA antibody titer) and reductions in the SLE disease activity index and daily prednisolone dosages were observed in both groups during induction therapy and were maintained during maintenance therapy. Efficacy was similar between the MMF and IVCY-TAC groups., Conclusion: MMF has potential as an effective treatment for renal manifestations in Japanese patients throughout induction and maintenance therapies for LN, as an alternative to conventional IVCY-TAC therapy, and as a glucocorticoid-sparing agent., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MK received speaker fees from Ayumi Pharmaceutical Corporation, Asahi Kasei Pharma Corp, AstraZeneca K.K., Gilead Sciences Inc., and GlaxoSmithKline K.K. TN received speaker fees from Eisai Co., Ltd, Astellas Pharma Inc., Janssen Pharmaceutical K.K., Ayumi Pharmaceutical Corporation, Pfizer Japan Inc., Asahikasei Pharma Corp., Eli Lilly Japan K.K., Takeda Pharmaceutical Co., Ltd, Nippon Boehringer Ingelheim Co., Ltd, Isho Pharmaceutical Co., Ltd, UCB Japan Co., Ltd, Ono Pharmaceutical Co., Ltd, AstraZeneca K.K., Mochida Pharmaceutical Co., Ltd, GlaxoSmithKline plc., Taisho Pharmaceutical Co., Ltd, Mitsubishi-Tanabe Pharma Co., Kyowa Kirin Co., Ltd, Taiho Pharmaceutical Co., Ltd, Mylan N.V., UCB Japan Co. Ltd, and AbbVie GK., consultant fees from UCB Japan Co., Ltd, Eisai Co., Ltd, and Chugai Pharmaceutical Co., and grants from Chugai Pharmaceutical Co., Eisai Co., Ltd, Teijin Pharma Ltd, Eli Lilly Japan K.K., Bristol-Myers K.K., Ono Pharmaceutical Co., Ltd, Asahikasei Pharma Corp., Mitsubishi-Tanabe Pharma Co., Ayumi Pharmaceutical Co., Shionogi & Co., Ltd, Nippon Kayaku Co., Ltd, AbbVie GK, Nippon Boehringer Ingelheim Co., Ltd, Mochida Pharmaceutical Co., Ltd, Sanofi K.K., Abbott Japan LLC, and Taisho Pharmaceutical Co., Ltd. TN participated on a Data Safety Monitoring Board or Advisory Board of Chugai Pharmaceutical Co.

Objective: This study aimed to evaluate the Ministry of Health, Labour and Welfare (MHLW) diagnostic criteria for antineutrophil cytoplasmic antibody-associated vasculitis compared to the new American College of Rheumatology/European Alliance of Associations for Rheumatology 2022 criteria., Methods: Two nationwide cohort studies were used, and participants were categorised as having eosinophilic granulomatosis with polyangiitis, granulomatosis with polyangiitis (GPA), or microscopic polyangiitis (MPA) according to the American College of Rheumatology/European Alliance of Associations for Rheumatology 2022 and MHLW criteria., Results: Of the entire patient population, only 10 (2.1%) were unclassifiable according to the MHLW probable criteria, while a significant number of patients (71.3%) met at least two criteria. The MHLW probable criteria for MPA had some challenges in differentiating between MPA and eosinophilic granulomatosis with polyangiitis, and the same was true for MHLW probable criteria for GPA in differentiating MPA from GPA. Nevertheless, improved classification results were obtained when the MHLW probable criteria were applied in the order of eosinophilic granulomatosis with polyangiitis, MPA, and GPA., Conclusions: The application of MHLW criteria could categorise a substantial number of patients with antineutrophil cytoplasmic antibody-associated vasculitis into one of the three antineutrophil cytoplasmic antibody-associated vasculitis diseases. The classification was in accordance with the American College of Rheumatology/European Alliance of Associations for Rheumatology 2022 criteria when considering the order of application., (© Japan College of Rheumatology 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: The objective of this study was to compare the American College of Rheumatology/European Alliance of Associations for Rheumatology 2022 criteria with the previous classification algorithm for anti-neutrophil cytoplasmic antibody-associated vasculitis., Methods: We used data from two nationwide, prospective, inception cohort studies. The enrolled patients were classified as having eosinophilic granulomatosis with polyangiitis (EGPA), granulomatosis with polyangiitis (GPA), or microscopic polyangiitis (MPA) according to the new criteria; these criteria were compared with Watts' algorithm., Results: Among 477 patients, 10.7%, 9.9%, and 75.6% were classified as having EGPA, GPA, and MPA, respectively; 6.1% were unclassifiable. Three patients met both the EGPA and MPA criteria, and eight patients met both the GPA and MPA criteria. Of 78 patients with GPA classified using Watts' algorithm, 27 (34.6%) patients were reclassified as having MPA. Ear, nose, and throat involvement was significantly less frequent in patients reclassified as having MPA than in those reclassified as having GPA. Of 73 patients unclassifiable using Watts' algorithm, 62 were reclassified as having MPA. All patients reclassified as having MPA were myeloperoxidase-anti-neutrophil cytoplasmic antibody positive, and 46 had interstitial lung disease., Conclusion: Although the American College of Rheumatology/European Alliance of Associations for Rheumatology 2022 criteria cause overlapping multiple criteria fulfilments in some patients, those items contribute to classifying unclassifiable patients using Watts' algorithm into MPA., (© Japan College of Rheumatology 2023. Published by Oxford University Press.)

Objectives: To evaluate the long-term safety and efficacy of E6011, a humanized anti-fractalkine monoclonal antibody, in patients with rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX)., Methods: Active RA patients with an inadequate response to MTX were randomly assigned to the E6011 or placebo group and received the study drug subcutaneously every 2 weeks during a 24-week double-blind study period. Subjects who completed evaluations at Week 24 were rolled over into the extension phase and received open-label E6011 (200 or 400 mg) every 2 weeks until Week 102. The safety analysis was conducted up to Week 104, and the efficacy analysis was conducted up to Week 84., Results: A total of 169 subjects completed the double-blind treatment phase and were rolled over into the extension phase. In total, 167 (98.8%) subjects experienced any adverse events, and the incidence of treatment-related adverse events was 56.2%. The American College of Rheumatology 20 response rates were observed between 40 and 70% during the extension phase., Conclusions: E6011 was safe and well tolerated with no notable safety concerns up to 102 weeks in RA patients with an inadequate response to MTX., (© Japan College of Rheumatology 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: The objective of the study is to evaluate the long-term safety and efficacy of E6011, a humanized anti-fractalkine monoclonal antibody, in patients with rheumatoid arthritis with an inadequate response to biological disease-modifying antirheumatic drugs., Methods: In the double-blind treatment phase (24 weeks), placebo or E6011 400 mg was administered until Week 10. Thereafter, E6011 200 mg or 400 mg was administered to Week 22. Subjects who completed the evaluation at Week 24 of the treatment phase were rolled over into the extension phase. The extension phase lasted until Week 104, and all subjects received E6011 400 mg or 200 mg every 2 weeks in an open-label manner until Week 102., Results: A total of 47 subjects completed the double-blind treatment phase and were rolled over into the extension phase. In total, 46 (97.9%) subjects experienced any adverse events, and the incidence of treatment-related adverse events was 57.4%. No clear efficacy trend in the American College of Rheumatology 20% response rates was observed., Conclusions: E6011 was well tolerated in active rheumatoid arthritis patients who had shown an inadequate response to biologic disease-modifying antirheumatic drugs, but no clear benefit in the American College of Rheumatology 20% response rates was observed. Further studies are needed to clarify the clinical benefit of E6011., (© Japan College of Rheumatology 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: This dose-escalation part of an ongoing Phase I study assessed the tolerability, safety and pharmacokinetics of mosunetuzumab in Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL)., Methods: Mosunetuzumab was administered intravenously, with step-up dosing in a 3 + 3 design, on Days 1, 8 and 15 of Cycle 1, and Day 1 of each subsequent 21-day cycle for up to 17 cycles to patients across five cohorts with different target doses (2.8, 6.0, 13.5, 27.0 or 60.0 mg)., Results: As of 5 July 2022, 23 patients had received mosunetuzumab. The median patient age was 63.0 years, 56.5% of patients were male, and 69.6% of patients had diffuse large B-cell lymphoma, 17.4% had transformed follicular lymphoma (FL) and 13.0% had FL. The median number of prior lines of therapy was 4. Mosunetuzumab was well tolerated and there were no deaths. The most common adverse events (any grade) were neutropenia/neutrophil count decreased (47.8%) and cytokine release syndrome (34.8%). Most cytokine release syndrome events were Grade 1/2 (one Grade 3), and most occurred within 24 hours of the first dose of mosunetuzumab. The apparent half-life of mosunetuzumab was 4.1-5.0 days. Two patients achieved a complete response, and 11 patients achieved a partial response., Conclusions: This study demonstrated that mosunetuzumab has an acceptable safety profile and antitumor activity in Japanese patients with relapsed/refractory B-cell NHL. The recommended Phase II dose of 1.0/2.0/60.0/60.0/30.0 mg was tolerable and there were no new or different safety signals compared with the global Phase I study., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Objectives: To report 24-week safety and effectiveness of certolizumab pegol (CZP) in Japanese patients with rheumatoid arthritis from a post-marketing surveillance study., Methods: Enrolled patients were newly receiving CZP. All adverse events (AEs) and adverse drug reactions (ADRs) were recorded for patients who received ≥1 CZP dose. Effectiveness outcomes included: 28-joint Disease Activity Score with erythrocyte sedimentation rate (DAS28-ESR) and European Alliance of Associations for Rheumatology (EULAR) response. Missing data were imputed using the last observation carried forward., Results: 3727 patients were enrolled; safety and effectiveness were evaluated in 3586 and 1794 patients, respectively. 24.9% of patients reported AEs (893/3586), 14.7% reported ADRs (528/3586), 8.3% (298/3586) reported serious AEs and 5.3% (190/3586) reported serious ADRs. Selected serious ADRs of interest: infections (110; 3.1%), tuberculosis (6; 0.2%), interstitial pneumonia (15; 0.4%), malignancy (8; 0.2%), and hepatic function disorder (7; 0.2%). No allergic reactions, autoimmune disease, cardiac failure, demyelinating diseases, or pancytopenia were reported. Mean DAS28-ESR reduced from 4.8 (baseline) to 3.4 (final evaluation). At final evaluation, 34.7% of patients achieved EULAR good response., Conclusions: These real-world safety and effectiveness results were consistent with previously reported data, with no new safety signals identified. Long-term, real-world CZP safety and effectiveness data are needed., (© Japan College of Rheumatology 2022. Published by Oxford University Press.)

This randomized, open-label, multicenter, parallel study imitating real-world clinical practice assessed the effect of switching to weekly teriparatide in patients with glucocorticoid-induced osteoporosis (GIO) with a lumbar spine/proximal femur bone mineral density (BMD) T-score ≤ -2.0 or ≤-1.0 and a fragility fracture. Forty-four patients were randomized. The mean durations of the corticosteroid and bisphosphonate administrations were 90.0 and 51.3 months. The baseline BMD at L1-L4 was 0.828 and 0.826 g/cm 2 in Groups B (bisphosphonate) and T (teriparatide); at the femur (total), these values were 0.689 and 0.661 g/cm 2 . The mean change in BMD was numerically higher with teriparatide vs. bisphosphonate but not statistically significant. The mean percentage changes from baseline in BMD at L1-L4 after a 72-week treatment were 0.5% and 4.1% in Groups B and T. The incidence of new fractures was higher in the patients taking bisphosphonates vs. those receiving once-weekly teriparatide at 72 weeks (18.2% vs. 11.8%) and 144 weeks (22.7% vs. 17.6%). The mean percentage change in femur (trochanter) BMD (0.035 [0.007-0.063]; p = 0.02) was significantly greater with teriparatide vs. bisphosphonates. Adverse events (AEs) were more frequent with teriparatide vs. bisphosphonates. Switching to once-weekly teriparatide tended to increase lumbar spine BMD and reduce the occurrence of new fractures vs. bisphosphonates.

Introduction: To describe clinical characteristics of patients in Japan with coronavirus disease 19 (COVID-19) and pre-existing rheumatic disease and examine the possible risk factors associated with severe COVID-19., Methods: Adults with rheumatic disease and a COVID-19 diagnosis who were registered in the COVID-19 Global Rheumatology Alliance (C19-GRA) physician-reported registry from Japan between 15 May 2020 and 12 May 2021 were included. Multivariable logistic regression models were used to assess factors associated with severe COVID-19 progression, defined as death or requiring oxygen inhalation., Results: In total, 222 patients were included in the study. Rheumatoid arthritis (48.2%), gout (14.4%), and systemic lupus erythematosus (8.1%) were the most common types of rheumatic disease, 55.1% of patients were in remission and 66.2% had comorbid disease. Most patients were hospitalised (86.9%) for COVID-19, 43.3% received oxygen, and 9.0% died. Older age (≥ 65 years), corticosteroid use, comorbid diabetes, and lung diseases are associated with higher risk for severe COVID-19 progression (odds ratio (OR) 3.52 [95% confidence interval (CI) 1.69-7.33], OR 2.68 [95% CI 1.23-5.83], OR 3.56 [95% CI 1.42-8.88], and OR 2.59 [95% CI 1.10-6.09], respectively)., Conclusions: This study described clinical characteristics of COVID-19 patients with rheumatic diseases in Japan. Several possible risk factors for severe COVID-19 progression were suggested. Key points • Clinical characteristics of 222 adult patients in Japan with coronavirus disease 19 (COVID-19) and pre-existing rheumatic diseases were described. • Most patients were hospitalised (86.9%) for COVID-19 in Japan, 43.3% received oxygen, and 9.0% died. • The COVID-19 characteristics of patients with rheumatic diseases did not show any obvious different pattern from those of the general population in Japan. • In this study, older age (≥ 65 years), corticosteroid use, comorbid diabetes, and lung diseases are associated with higher risk for severe COVID-19 progression., (© 2022. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Objective: We compared the 52-week effectiveness and safety of tofacitinib (TOF) and abatacept (ABT) in patients with RA in a real-world setting and investigated a role of human leucocyte antigens (HLA)-DRB1 shared epitope (SE) in the effectiveness., Methods: RA patients starting TOF ( n  = 187) and ABT ( n  = 183) were enrolled. Effectiveness was compared after reducing the selection bias to a minimum using the inverse probability of treatment weighting (IPTW) based on propensity scores. The influence of SE alleles on effectiveness was compared within each treatment group. A treatment group comparison was also performed within SE-positive and SE-negative groups., Results: Herpes zoster and some laboratory abnormalities were more frequent in the TOF group than in the ABT group. Patient characteristics did not differ significantly between treatment groups after adjustments with IPTW. The TOF group had a significantly higher proportion of DAS in 28 joints using ESR (DAS28-ESR) remission at week 52 than the ABT group. The DAS28-ESR at week 12 and thereafter was not affected by the copy number of SE alleles in the TOF group, but decreased significantly as the copy number increased in the ABT group. In SE-positive patients, remission and drug retention rates did not differ significantly between the two treatment groups. In SE-negative patients, the TOF group showed significantly higher remission and drug retention rates than the ABT group., Conclusion: The present results suggest that TOF is more effective with regard to remission at week 52 based on treatment responses in SE-negative RA patients., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

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: In Japan, clinical records of patients with intractable diseases, including microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA), are compiled into a database. This study aimed to understand the current treatment status and changes in treatment regimens from our previous survey., Methods: Using data from 2012 and 2013, patients with new-onset MPA and GPA were extracted and analysed., Results: We analysed 1278 MPA and 215 GPA patients. The average age was 71.7 and 62.7 years, respectively. Methylprednisolone pulse therapy was used in 51.2% of MPA patients and 40.5% of GPA patients; the initial prednisolone-equivalent glucocorticoid dose was 39.5 mg/day in MPA and 46.6 mg/day in GPA. Concomitant intravenous or oral cyclophosphamide (CY) was administered to 22.6% of MPA and 56.3% of GPA. Young age, bloody sputum, low serum creatinine, and high C-reactive protein levels were independently associated with CY use in MPA. Compliance with treatment protocol for Japanese patients with myeloperoxidase (MPO)-anti-neutrophilic cytoplasmic antibody-associated vasculitis study criteria or the 2011 clinical practice guidelines for rapidly progressive glomerulonephritis was 42.7% and 49.7%, respectively., Conclusions: MPA was more prevalent than GPA in the registry. Compared to patients with GPA, MPA patients were older and used CY less frequently. No apparent changes in treatment trends were observed from the previous survey., (© Japan College of Rheumatology 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Fibrosing interstitial lung disease (ILD) develops due to the impaired reparative processes following lung tissue damage. Cellular senescence has been reported to contribute to the progression of fibrosis. However, the mechanisms by which these senescent cells initiate and/or drive the progression of lung tissue fibrosis are not yet fully understood. We demonstrated that p21 WAF1/CIP1 - and p16 INK4A -pathway-dependent senescence in type 2 alveolar epithelial cells (AEC2) were both involved in the initiation and progression of lung fibrosis in murine bleomycin (BLM)-induced ILD. p21 WAF1/CIP1 -senescent AEC2 emerged rapidly, as early as 1 day after the intratracheal instillation of BLM. Their number subsequently increased and persisted until the later fibrosis phase. Very few p16 INK4A -senescent AEC2 emerged upon the instillation of BLM, and their increase was slower and milder than that of p21 WAF1/CIP1+ AEC2. AEC2 enriched with senescent cells sorted from BLM-ILD lungs expressed senescence-associated secretory phenotype (SASP)-related genes, including Il6 , Serpin1 , Tnfa , Ccl2 , Tgfb , and Pdgfa , at the initiation and chronic phases of fibrosis, exhibiting distinct expression patterns of magnitude that were dependent on the disease phase. Ly6C + inflammatory monocytes increased in the lungs immediately after the instillation of BLM and interstitial macrophages increased from day 3. The expression of Acta2 and Col1a1 was upregulated as early as day 1, indicating the activation of fibroblasts. We speculated that IL-6, plasminogen activator inhibitor-1 (PAI-1), and TGF-β contributed to the accumulation of senescent cells during the progression of fibrosis in an autocrine and paracrine manner. In addition, CCL2, produced in large amounts by senescent AEC2, may have induced the infiltration of Ly6C + inflammatory monocytes in the early phase, and TGF-β and PDGFa from senescent AEC2 may contribute to the activation of fibroblasts in the very early phases. Our study indicated that senescent AEC2 plays a role in the pathogenesis of fibrosing ILD throughout the course of the disease and provides insights into its pathogenesis, which may lead to the development of new therapeutic methods targeting senescent cells or SASP molecules., Competing Interests: The 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., (Copyright © 2022 Yamada, Nishio, Motomura, Mizutani, Yamada, Mikami and Nanki.)

Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder of unknown aetiology that is categorised as a non-hereditary disease. Neonatal haemophagocytic lymphohistiocytosis (HLH) is also a rare, but potentially fatal condition. Neonatal HLH is one of the causes of neonatal acute liver failure that often requires urgent liver transplantation. The relationship between AOSD during pregnancy and neonatal HLH currently remains unclear. We encountered a case of AOSD that developed during pregnancy, and an offspring was born with neonatal HLH resulting in severe liver failure. The mother with AOSD only presented with liver dysfunction during pregnancy; however, disease activity was exacerbated after delivery. The maternal clinical course was quite severe and refractory that she required biological therapy in addition to high-dose corticosteroids and immunosuppressants. Additionally, the severe condition of the neonate with HLH and acute liver failure required intensive care with the administration of steroids and intravenous immunoglobulin treatments and ultimately liver transplantation. This is the first case that severe maternal AOSD associated with a neonatal HLH resulted in severe clinical courses. Physicians need to be aware of the risk of a mother with AOSD delivering an offspring with neonatal HLH with potentially acute liver failure., (© Japan College of Rheumatology 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: This study aimed to clarify the epidemiological and clinical features and treatment of patients with polyarteritis nodosa (PAN) in Japan., Methods: We used the database of the Ministry of Health, Labour and Welfare (MHLW) of Japan in 2013 and 2014. We analysed 121 patients who were antineutrophil cytoplasmic antibodies negative among the patients certified as PAN according to the MHLW diagnostic criteria., Results: The analysis included 60 males and 61 females, with a mean age of 52.9 ± 21.0 years. As a general manifestation, fever was observed in 53.7%. Regarding organ involvement, skin manifestations (82.6%), joint and muscle manifestations (75.2%), and neuropsychiatric manifestations (50.4%) were common. Male patients had a higher proportion of mononeuritis multiplex involving motor neuropathy than female patients. Elderly patients had a higher proportion of general and respiratory manifestations. Glucocorticoids were used for treatment in all patients, and 19.0% underwent methylprednisolone pulse. Concomitant immunosuppressants were used in 25.6%, one-third of whom received cyclophosphamide. Methylprednisolone pulse and cyclophosphamide were mostly used in patients with life-threatening organ involvement., Conclusions: PAN developed in middle-aged people and led to numerous clinical manifestations. The common manifestations varied with age, and treatment was determined based on the type of organ involvement and disease severity., (© Japan College of Rheumatology 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: To investigate the risk factors and clinical characteristics of lymphoproliferative disorder (LPD) in Japanese patients with rheumatoid arthritis (RA)., Methods: We enrolled patients with RA aged ≥20 years who visited the participating hospitals between April 2011 and July 2011. We investigated the risk factors for LPD using a Cox proportional hazard model and described pathological features and vital prognosis of LPD in patients with RA., Results: We enrolled 9815 patients with the following characteristics at baseline: female 79.4%, median age 63 years; median disease duration 7 years; median DAS28-CRP (3) 3.1; prevalence of MTX use 60.0%. Sixty-eight patients (0.69%) developed LPD in 3-year observation period. Multivariable analysis showed that age by decade (hazard ratio [95% confidence interval], 1.47 [1.18-1.85]) and MTX use at baseline (2.35 [1.25-4.42] for ≤8 mg/week, 4.39 [2.07-9.32] for >8 mg/week versus non-use) were significant risk factors of LPD. Of 55 patients with pathological diagnosis, diffuse large B cell lymphoma was the most frequent (54%). The 5-year mortality of LPD was 24%. The major cause of death was lymphoma (81%)., Conclusion: This nationwide study revealed risk factors, clinical characteristics, and prognosis of LPD in the largest number of Japanese patients with RA., (© 2021 Japan College of Rheumatology.)

Objective Denosumab, an anti-RANKL monoclonal antibody, was reported to improve bone mineral density (BMD) and reduce fracture risk, offering favorable efficacy against postmenopausal osteoporosis. However, some patients have experienced a reduced BMD despite denosumab therapy. Methods We performed an observational study to clarify the clinical efficacy of denosumab for osteoporosis in rheumatic disease patients. Serum levels of bone turnover markers and lumber BMD in 100 rheumatic disease patients were examined at baseline and 6 and 12 months after denosumab therapy. The independent influence of changes in the BMD was examined by multiple regression analyses adjusted for patient characteristics and bone turnover markers. Results As bone resorption markers, serum levels of N-telopeptide crosslinked of type I collagen (NTx) and tartrate-resistant acid phosphatase isoform 5b were statistically decreased after 12 months. As bone formation markers, serum levels of osteocalcin, procollagen type I N-terminal peptide, and bone alkaline phosphatase were significantly decreased after 12 months. The mean BMD was significantly increased after 12 months. However, in 10 patients, the BMD decreased. A multivariate analysis of factors related to BMD changes highlighted a young age, low prednisolone dosage, and reduction in NTx. Conclusions Denosumab increases the BMD to combat osteoporosis in rheumatic disease patients, and potential predictors of a better response to denosumab include a young age, reduction in bone turnover markers, and low-dose glucocorticoid use.

Coronavirus disease 2019 (COVID-19) remains a global threat to humanity. Its pathogenesis and different phases of disease progression are being elucidated under the pandemic. Active viral replication activates various immune cells and produces large amounts of inflammatory cytokines, which leads to the cytokine storm, a major cause of patient death. Therefore, viral inhibition is expected to be the most effective early in the course of the disease, while immunosuppressive treatment may be useful in the later stages to prevent disease progression. Based on the pathophysiology of rheumatic diseases, various immunomodulatory and immunosuppressive drugs are used for the diseases. Due to their mechanism of action, the antirheumatic drugs, including hydroxychloroquine, chloroquine, colchicine, calcineurin inhibitors (e.g., cyclosporine A and tacrolimus), glucocorticoids, cytokines inhibitors, such as anti-tumor necrosis factor-α (e.g., infliximab), anti-interleukin (IL)-6 (e.g., tocilizumab, sarilumab, and siltuximab), anti-IL-1 (e.g., anakinra and canakinumab) and Janus kinase inhibitors (e.g., baricitinib and tofacitinib), cytotoxic T lymphocyte-associated antigen 4 blockade agents (e.g., abatacept), and phosphodiesterase 4 inhibitors (e.g., apremilast), have been tried as a treatment for COVID-19. In this review, we discuss the mechanisms of action and clinical impact of these agents in the management of COVID-19.

Competing Interests: Conflicts of interest and sources of funding: T.N. received grant support from Chugai Pharmaceutical Co, Ltd. H.S., S.Y., S.M., M.K., and T.N. received speaker fee or consulting fee from Chugai Pharmaceutical Co, Ltd.

Introduction: Abatacept efficacy in older patients with rheumatoid arthritis (RA) has been primarily demonstrated via retrospective comparisons with younger patients. The objective of this study was to compare efficacy of abatacept in older vs. younger patients with RA, and efficacy of abatacept with that of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) in both age groups., Methods: This prospective, multicenter, observational study (UMIN000014913) enrolled csDMARD-refractory patients without previous biological DMARD treatment. Abatacept (A) or csDMARDs (C) were administered at the treating physician's discretion to older (O, ≥ 65 years) and younger (Y, 20-64 years) patients, producing AO, AY, CO, and CY groups. Clinical efficacy after 24 weeks was evaluated using European League Against Rheumatism (EULAR) erythrocyte sedimentation rate response criteria., Results: Overall, 202 patients were evaluated. Compared with the CO group, more patients in the AO group achieved a EULAR good or moderate response (p < 0.0001). Compared with the CY group, more patients in the AY group achieved a EULAR good or moderate response (p < 0.01). Similar proportions of patients in the AO and AY groups achieved a EULAR good response or a good or moderate response. Few adverse events were reported., Conclusions: This prospective study demonstrated that abatacept is efficacious and safe in older patients with RA and a history of being refractory to csDMARDs. Abatacept was shown to be more efficacious than adding or switching to a new csDMARD in both younger and older csDMARD-refractory patients with RA., Trial Registration: UMIN000014913., (© 2021. The Author(s).)

To explore the biological and immunological basis of human rheumatoid arthritis and human atherosclerosis, we planned and reported a detailed design and rationale for Orencia Atherosclerosis and Rheumatoid Arthritis Study (ORACLE Arthritis Study) using highly sensitive, high-throughput, human autoantibody measurement methods with cell-free protein synthesis technologies. Our previous study revealed that subjects with atherosclerosis had various autoantibodies in their sera, and the titers of anti-Th2 cytokine antibodies were correlated with the severity of atherosclerosis. Because rheumatoid arthritis is a representative autoimmune disease, we hypothesized that both rheumatoid arthritis and atherosclerosis are commonly developed by autoantibody-mediated autoimmune processes, leading to incessant inflammatory changes in both articular joint tissues and vessel walls. We planned a detailed examination involving carotid artery ultrasonography, measurements of adhesion molecules, such as ICAM-1 (intercellular adhesion molecule 1) and VCAM-1 (vascular cell adhesion molecule 1) for the evaluation of atherosclerosis progression, and high-throughput, high-sensitivity, autoantibody analyses using cell-free technologies, with detailed examinations of the disease activity of rheumatoid arthritis. Analyses of correlations and associations between biological markers and degrees of carotid atherosclerosis over time under consistent conditions may enable us to understand the biological and humoral immunity background of human atherosclerosis and autoimmune diseases.

Osteoclast differentiation is promoted under inflammatory conditions and osteoclasts play a major role in bone destruction in rheumatoid arthritis (RA). Chemokine (C-X3-C motif) ligand 1 (CX3CL1), also known as fractalkine, functions as a chemoattractant and adhesion molecule, and is involved in the pathogenesis of RA. The blockade of CX3CL1 inhibits the migration of macrophages and osteoclast precursor cells into the inflamed synovium. In the present study, we investigated the direct stimulatory effects of CX3CL1 on osteoclast differentiation from human peripheral blood monocytes and monocyte-derived dendritic cells. A stimulation with CX3CL1 significantly promoted osteoclast differentiation from CD16 - monocytes and also monocyte-derived dendritic cells induced by macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL). On the other hand, CD16 + monocytes treated with M-CSF and RANKL did not differentiate into osteoclasts, even with CX3CL1. Calcium resorption was significantly increased by monocyte-derived osteoclasts, but not by dendritic cell-derived osteoclasts, following the addition of CX3CL1. The present results suggest that CX3CL1 directly regulates osteoclast differentiation. CX3CL1 may play important roles in the pathogenesis of RA, not only through the accumulation of inflammatory cells, but also through osteoclastogenesis., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: The aim of this study was to compare the clinical effectiveness of tofacitinib and abatacept and clarify the impact of the HLA-DRB1 shared epitope (SE) on responses to these treatments in patients with rheumatoid arthritis (RA)., Methods: After adjustments by propensity score matching, 70 out of 161 patients receiving tofacitinib and 70 out of 131 receiving abatacept were extracted. The clinical effectiveness of both drugs over 24 weeks and the impact of the copy numbers of SE on effectiveness outcomes were investigated., Results: The percentage of patients in remission in the 28-joint count disease activity score using the erythrocyte sedimentation rate (DAS28-ESR) did not significantly differ between patients receiving tofacitinib and abatacept at week 24 (32% vs 37%, p = 0.359). The mean change at week 4 in DAS28-ESR from baseline was significantly greater in patients receiving tofacitinib than in those receiving abatacept (- 1.516 vs - 0.827, p = 0.0003). The percentage of patients in remission at week 4 was 30% with tofacitinib and 15% with abatacept (p = 0.016). When patients were stratified by the copy numbers of SE alleles, differences in these numbers did not affect DAS28-ESR scores of patients receiving tofacitinib. However, among patients receiving abatacept, DAS28-ESR scores were significantly lower in patients carrying 2 copies of SE alleles than in those carrying 0 copies at each time point throughout the 24-week period. Furthermore, the percentage of patients in remission with DAS28-ESR at week 24 was not affected by the copy numbers of SE alleles in patients receiving tofacitinib (p = 0.947), whereas it significantly increased as the copy numbers became higher in patients receiving abatacept (p = 0.00309). Multivariable logistic regression analyses showed a correlation between the presence of SE and DAS28-ESR remission in patients receiving abatacept (OR = 25.881, 95% CI = 3.140-213.351, p = 0.0025), but not in those receiving tofacitinib (OR = 1.473, 95% CI = 0.291-7.446, p = 0.639)., Conclusions: Although the clinical effectiveness of tofacitinib and abatacept was similar at week 24, tofacitinib was superior to abatacept for changes from baseline in DAS28-ESR and the achievement of remission at week 4. SE positivity was associated with the achievement of DAS28-ESR remission by week 24 in patients receiving abatacept, but not in those receiving tofacitinib., (© 2021. The Author(s).)

Objectives: To evaluate the safety and efficacy of E6011, a novel humanized anti-fractalkine monoclonal antibody, in patients with active rheumatoid arthritis (RA) with an inadequate response to biological disease-modifying antirheumatic drugs (DMARDs)., Methods: Active RA patients inadequately responding to biological DMARDs were randomly assigned to placebo or E6011 400-mg group at a 1:1 ratio, and administered E6011 at weeks 0, 1, 2, and subsequently every 2 weeks. Primary endpoint was American College of Rheumatology (ACR)20 response at week 12., Results: Of 64, 33 received placebo, 31 received E6011 400-mg. The ACR20 response rate at week 12 (non-responder imputation) was 27.3% and 22.6% in the placebo and E6011 groups, respectively. ACR50, ACR70 response rates at week 12 were 3.0%, 0% in the placebo and 9.7%, 3.2% in the E6011 group. Exploratory PK exposure analysis revealed that the effect of E6011 tended to be clearer in patients with higher serum trough E6011 concentration. E6011 was well tolerated with no notable safety concerns., Conclusions: E6011 400-mg was well tolerated but had no clear efficacy at week 12 in RA patients with inadequate response to biologics. Further investigations are warranted to determine the optimal clinical dose and evaluation period for E6011.

Background: Several recent studies suggest that serum anti-p53 antibodies (s-p53-Abs) may be combined with other markers to detect esophageal and colorectal cancer. In this study, we assessed the sensitivity and specificity of s-p53-Abs detection of a new electrochemiluminescence immunoassay (ECLIA; Elecsys anti-p53)., Methods: Elecsys anti-p53 assay was used to analyze the level of s-p53-Abs in blood sera from patients with esophageal or colorectal cancer taken before treatment. Control blood sera from healthy volunteers, patients with benign diseases, and patients with autoimmune diseases served as a reference. In addition, squamous cell carcinoma antigen (SCC-Ag) and cytokeratin 19 fragments (CYFRA21-1) were assessed in patients with esophageal cancer, and carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 were assessed in patients with colorectal cancer., Results: Samples from 281 patients with esophageal cancer, 232 patients with colorectal cancer, and 532 controls were included in the study. The median value of s-p53-Abs in control samples was < 0.02 μg/mL (range < 0.02-29.2 μg/mL). Assuming 98% specificity, the cut-off value was determined as 0.05 μg/mL. s-p53-Abs were detected in 20% (57/281) of patients with esophageal cancer and 18% (42/232) of patients with colorectal cancer. In combination with SCC-Ag and CEA, respectively, s-p53-Abs detected 51% (144/281) of patients with esophageal and 53% (124/232) of patients with colorectal cancer., Conclusions: The new s-p53-Abs assay Elecsys anti-p53 was useful in detecting esophageal and colorectal cancers with high specificity. Adding s-p53-Abs to conventional markers significantly improved the overall detection rates.

Objective: Our previous study suggested that suppression of Wnt/β-catenin signaling by increasing serum Wnt co-receptor inhibitors, sclerostin and Dickkopf-1, impairs bone formation in the first week after starting glucocorticoid therapy. The objective of this study was to investigate the involvement of the Wnt/β-catenin signaling pathway and its clinical significance in the subsequent suppression of bone formation., Methods: A total of 53 patients with systemic autoimmune diseases who received initial glucocorticoid therapy with prednisolone (30-60 mg daily) were prospectively enrolled. We measured serum levels of Wnt3a and Wnt inhibitors, secreted Frizzled-related protein 1 (sFRP-1) and Wnt inhibitory factor 1 (Wif-1), before starting glucocorticoid therapy and every week for 4 weeks after its initiation., Results: Serum levels of sFRP-1 and Wif-1 slightly decreased compared with before glucocorticoid therapy from the second week. The serum Wnt3a level decreased from the first week. The ratios of Wnt3a to sFRP-1 and that of Wnt3a to Wif-1 both decreased from the first week onward., Conclusion: The reduction of the ratio of Wnt3a to Wnt inhibitors, sFRP-1 and Wif-1, suppresses Wnt signaling, which may result in impaired bone formation. Taken together with our previous studies, glucocorticoids may suppress Wnt signaling by inhibiting co-receptors of the Wnt/β-catenin signaling pathway in the early phase of glucocorticoid therapy and inhibiting its ligand in the subsequent weeks, which together impair bone formation. Key Points • The decrease in Wnt pathway-related molecules by glucocorticoids impairs bone formation. • Glucocorticoids inhibit co-receptors of Wnt signaling in the early phase of therapy. • Glucocorticoids inhibit ligands of Wnt signaling in the subsequent phase of therapy.

CX3C Motif Chemokine Ligand 1 (CX3CL1; fractalkine) has been implicated in the pathogenesis of rheumatoid arthritis (RA) and its inhibition was found to attenuate arthritis in mice as well as in a clinical trial. Therefore, we investigated the effects of an anti-CX3CL1 monoclonal antibody (mAb) on immune-mediated interstitial lung disease (ILD) in SKG mice, which exhibit similar pathological and clinical features to human RA-ILD. CX3CL1 and CX3C chemokine receptor 1 (CX3CR1), the receptor for CX3CL1, were both expressed in the fibroblastic foci of lung tissue and the number of bronchoalveolar fluid (BALF) cells was elevated in ILD in SKG mice. No significant changes were observed in lung fibrosis or the number of BALF cells by the treatment with anti-CX3CL1 mAb. However, significantly greater reductions were observed in the number of M1 macrophages than in M2 macrophages in the BALF of treated mice. Furthermore, CX3CR1 expression levels were significantly higher in M1 macrophages than in M2 macrophages. These results suggest the stronger inhibitory effects of the anti-CX3CL1 mAb treatment against the alveolar infiltration of M1 macrophages than M2 macrophages in ILD in SKG mice. Thus, the CX3CL1-CX3CR1 axis may be involved in the infiltration of inflammatory M1 macrophages in RA-ILD.

Objective: To evaluate the efficacy and safety of E6011, a humanized IgG2 monoclonal antibody against human fractalkine (FKN), in a phase II, double-blind, placebo-controlled study in rheumatoid arthritis (RA) patients., Methods: Patients with moderate-to-severe RA who had an inadequate response to methotrexate were randomly assigned to a placebo group or to E6011 100-mg, 200-mg, or 400/200-mg groups at a 2:1:2:2 ratio. During the 24-week period, patients received the study drug subcutaneously at weeks 0, 1, and 2 and then once every 2 weeks. The primary end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12., Results: Study drugs were administered to 190 patients (placebo, n = 54; E6011 100 mg, n = 28; E6011 200 mg, n = 54; E6011 400/200 mg, n = 54), and 169 patients completed treatment. A significant difference from placebo was not found in ACR20 response rates at week 12 (37.0% [placebo], 39.3% [100 mg], 48.1% [200 mg], and 46.3% [400/200 mg], using nonresponder imputation). As a secondary end point, ACR20 response rate in the 200-mg and 400/200-mg groups attained statistical significance at week 24 (35.2% [placebo], 39.3% [100 mg], 53.7% [200 mg], and 57.4% [400/200 mg]). Subsequent exploratory subgroup analysis revealed greater efficacy of E6011, particularly in patients with a higher baseline proportion of CD16+ monocytes; ACR20 response rates in this patient subgroup at week 24 were 30.0% (placebo), 46.7% (100 mg), 57.7% (200 mg), and 69.6% (400/200 mg). E6011 administered for 24 weeks was well tolerated., Conclusion: This is the first evidence that E6011, a novel cell trafficking inhibitor targeting the FKN-CX 3 CR1 interaction, is modestly effective with 24 weeks of treatment in RA patients, although the primary end point was not met., (© 2020 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objectives: Iguratimod (IGU) is a conventional synthetic disease-modifying drug that has been approved based on its additive effects with methotrexate (MTX) for the treatment of rheumatoid arthritis (RA). The objective of the study is to establish the effectiveness of IGU with versus IGU without MTX irrespective of whether MTX is well tolerated or not by the patients., Methods: Disease activity scores in 177 RA patients treated using IGU were retrospectively evaluated at baseline and after 4, 12, and 24 weeks, and adverse events (AEs) were noted., Results: IGU reduced the disease activity parameters, disease activity score (DAS)-ESR, DAS-CRP, the simplified disease activity index (SDAI), and clinical disease activity index (CDAI) in the concomitant MTX and non-MTX, female and male, and young and elderly patient groups after 24 weeks. Multivariate analysis demonstrated that IGU was more effective with concomitant MTX and in elderly and male patients. Severe AEs were observed only in the elderly group: two cases of pneumonia, 1 of pneumocystis pneumonia, 1 of heart failure, and 1 of salivary gland adenoma., Conclusions: IGU is effective for RA, especially with concomitant MTX, and in elderly and male patients. Key Points • Iguratimod is effective for RA, especially with concomitant MTX, and in elderly and male patients. • Since all serious adverse events were in the elderly group in this study, sufficient monitoring for adverse events, especially for elderly RA patients, is needed during iguratimod therapy.

Introduction : Rheumatic diseases are inflammatory diseases that damage target organs via multiple subsets of immune cells. Fractalkine (FKN) acts as chemoattractant as well as adhesion molecule. It contributes to the pathogenesis of rheumatoid arthritis (RA) and other rheumatic diseases through multiple mechanisms: the migration of monocytes and cytotoxic effector T cells, the proliferation and activation of fibroblast-like synoviocytes, angiogenesis, and osteoclastogenesis. FKN has potential as a new therapeutic target, and clinical trials on anti-FKN monoclonal antibodies for RA are ongoing. FKN-targeted therapy has been developed and a humanized anti-FKN monoclonal antibody is currently being tested in phase 2 clinical trials. Areas covered : This review summarizes accumulated evidence on the involvement of FKN in RA and other rheumatic diseases, including systemic lupus erythematosus (SLE), systemic sclerosis, inflammatory myositis, Sjögren's syndrome (SS), osteoarthritis, and systemic vasculitis. Expert opinion : A phase 1/2a clinical trial on anti-FKN demonstrated its safety, tolerability, and clinical efficacy. Anti-FKN therapy has potential in the treatment of atherosclerosis and interstitial lung diseases associated with RA. Based on recent findings, other rheumatic diseases, including SLE, polymyositis/dermatomyositis, and SS, may also be treated using anti-FKN therapy.