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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.)

Objective: The aim of this study is to investigate the effects of sarilumab on unacceptable pain [UP; visual analogue scale (VAS) >40 mm] and inflammation in patients with moderately-to-severely active rheumatoid arthritis., Methods: In this post hoc analysis of the KAKEHASI study, 243 patients received methotrexate with sarilumab 150 or 200 mg or placebo every other week, over 52 weeks. The proportion of patients with UP and correlations of changes in pain VAS from baseline with uncontrolled inflammation (C-reactive protein ≥1 mg/dl) and disease activity indices were assessed., Results: Almost 80% of patients (192/243) had UP at baseline, including ∼60% of patients with uncontrolled inflammation. Among patients receiving sarilumab, inflammation decreased rapidly, with 90% of patients achieving controlled inflammation by Week 2, while 63.1% continued to have UP. The proportion of patients with UP further decreased by Week 16 (28.5%, sarilumab vs. 64.0%, placebo). By Week 52, only ∼10% of patients had UP. Changes in pain VAS correlated with most disease activity indices and patient-reported outcomes. However, marked correlations between changes in pain VAS and C-reactive protein were observed only at Week 16., Conclusion: Sarilumab treatment reduced UP and inflammation in Japanese patients with rheumatoid arthritis., (© Japan College of Rheumatology 2023. Published by Oxford University Press.)

Objectives: An interim analysis of post-marketing surveillance data to assess the safety and effectiveness of sarilumab in Japanese patients with rheumatoid arthritis refractory to previous treatment., Methods: The interim analysis included patients who initiated sarilumab therapy between June 2018 and January 2021. The primary objective of this surveillance was safety., Results: In total, 1036 patients were enrolled and registered by 12 January 2021 (interim cut-off date). Of these, 678 were included in the safety analysis [75.4% female; mean age (± standard deviation) 65.8 ± 13.0 years]. Adverse drug reactions, defined as adverse events classified as possibly or probably related to sarilumab, were reported in 170 patients (incidence: 25.1%), with white blood cell count decreased (4.4%) and neutrophil count decreased (1.6%) most frequently reported. Serious haematologic disorders (3.4%) and serious infections (including tuberculosis) (2.5%) were the most frequently reported priority surveillance items. No malignant tumour was reported. An absolute neutrophil count (ANC) below the minimum standard value did not increase the incidence of serious infections., Conclusions: Sarilumab was well tolerated, and no new safety signals were noted in this analysis. There was no difference in the frequency of serious infections between patients with an ANC below or above normal., (© Japan College of Rheumatology 2023. Published by Oxford University Press.)

Methotrexate (MTX), the anchor drug in the current treatment strategy for rheumatoid arthritis (RA), was first approved for the treatment of RA in Japan in 1999 at a recommended dose of 6-8 mg/week. The approved maximum dose of MTX has been 16 mg/week since February 2011 when MTX was approved as a first-line drug in the treatment of RA. Recent evidence of MTX-polyglutamate concentration in the red blood cells of Japanese patients with RA justifies the current daily use of MTX in Japan. Additionally, after a nationwide clinical trial, a subcutaneous MTX injection formula (7.5-15 mg/week) was approved for RA treatment in September 2022. Therefore, in March 2023, a subcommittee of the Japan College of Rheumatology updated the guidance (formerly 'guidelines') for the use of MTX in Japanese patients with RA. This article, an abridged English translation summarizing the 2023 update of the Japan College of Rheumatology guidance for the use of MTX and management of patients with RA, will be helpful to both Japanese and global rheumatology communities., (© Japan College of Rheumatology 2023. Published by Oxford University Press.)

Objectives: Anaemia is a frequent extra-articular manifestation in rheumatoid arthritis (RA); haemoglobin level changes are associated with changes in disease activity. This post-hoc analysis assessed potential relationships between haemoglobin and disease activity in Japanese patients with RA, enrolled in the KAKEHASI study (NCT02293902)., Methods: In this study, adult patients with moderate-to-severe active RA, who had an inadequate response to methotrexate, were randomised to subcutaneous sarilumab 150 mg every 2 weeks (q2w) or 200 mg q2w or placebo for 24 weeks. Post-hoc analyses were conducted on changes in haemoglobin and proportion of anaemic patients, using a mixed-effects model for repeated measures assuming an unstructured covariance. Relationships between haemoglobin and efficacy measures were explored., Results: At baseline, nearly half of patients had anaemia, defined by World Health Organization criteria (haemoglobin <12 g/dL, female; or <13 g/dL, male). At Week 24, the least squares mean change in haemoglobin levels was greater in sarilumab groups than for placebo (150 mg: 1.23 g/dL, 200 mg: 1.19 g/dL, placebo: 0.17 g/dL; p=0.0002 for both doses vs. placebo). By Week 24, the proportion of patients with anaemia was 17.8%, 22.9%, and 30.1% for sarilumab 150 mg, 200 mg, and placebo, respectively., Conclusions: In Japanese patients with RA, both doses of sarilumab were associated with greater improvement in haemoglobin levels and reduction in proportion of patients with anaemia, compared with placebo. Sarilumab may be a suitable treatment for patients with RA and anaemia.

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.)

Background: Efficacy of combination therapy with methotrexate and biological disease-modifying antirheumatic drugs is well established in the management of patients with rheumatoid arthritis; however, the optimal dose of methotrexate to administer with a tumour necrosis factor inhibitor remains unclear. We aimed to clarify the efficacy and safety of adalimumab combined with reduced methotrexate dose compared with the maximum tolerated methotrexate dose in patients with rheumatoid arthritis and an inadequate response to methotrexate monotherapy., Methods: In this open-label, randomised controlled trial, we recruited methotrexate-naive patients with rheumatoid arthritis and a disease duration of less than 2 years across 24 secondary or tertiary care hospitals across Japan, South Korea, and Taiwan. At initiation, methotrexate was given orally and increased to the maximum tolerated dose by week 12. Patients who did not achieve remission on the basis of the Simplified Disease Activity Index (SDAI) at week 24 were randomly assigned (1:1) to receive adalimumab (40 mg biweekly) combined with a continued maximum tolerated dose of methotrexate or adalimumab combined with a reduced dose of methotrexate. The primary endpoint was non-inferiority of adalimumab plus reduced-dose methotrexate to adalimumab plus maximal-dose methotrexate based on SDAI remission at week 48, assessed in the modified full-analysis set with a pre-specified non-inferiority margin of -15%, based on a two-sided 90% CI. Adverse events were assessed in the safety analysis set. This trial is registered with ClinicalTrials.gov, NCT03505008 and has been completed., Findings: From April 18, 2018, to June 2, 2020, from 323 patients screened, 300 were enrolled, and 291 patients were included in the full analysis set. The mean age was 57·7 years (SD 15·2), 217 (75%) were female, 74 (25%) were male, and all patients were of Asian ethnicity. The mean SDAI at study enrolment was 26·5 (SD 12·4). 52 patients discontinued the study before week 24 or at week 24 before randomisation. At week 24, 105 (36%) of 291 patients achieved remission and continued methotrexate monotherapy through week 48. 134 (46%) did not achieve remission at week 24 and were randomly assigned to receive adalimumab plus the maximum tolerated dose of methotrexate (n=68) or adalimumab plus reduced-dose methotrexate (n=66). Remission at week 48 was achieved in 25 (38%) of 66 and 27 (44%) of 61 patients, respectively, with an adjusted risk difference of 6·4% (90% CI -7·0 to 19·8), which met the non-inferiority margin of -15%. Adverse events after week 24 tended to be more frequent in the maximum tolerated dose group than in the reduced-dose group (24 [35%] vs 13 [20%], p=0·054). Between week 24 and 48, there were 14 serious adverse events (6 in the methotrexate monotherapy group, 5 in the adalimumab plus maximal-dose methotrexate, and 3 in the adalimumab plus reduced-dose methotrexate group), and no deaths., Interpretation: The MIRACLE study showed that the efficacy of adalimumab combined with reduced methotrexate dose was not inferior to that with the maximum tolerated methotrexate dose, with a tendency to a better safety profile., Funding: Eisai., Competing Interests: Declaration of interests HTam has received speaker honoraria from AbbVie and Eisai. KI has received grants from Mitsubishi-Tanabe Pharma, speaker honoraria from AbbVie, Eisai, Mitsubishi-Tanabe Pharma, Astellas Pharma, UCB, Daiichi-Sankyo, Eli Lilly, Gilead Sciences, Asahi Kasei Pharma, Chugai Pharma, and Bristol-Myers Squibb. TM received grants, research support, or speaker fees from AbbVie, Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Chugai Pharma, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead Sciences, Kirin, Pfizer, and UCB. KS has received grants, research support from Novartis, Astellas Pharma, AbbVie, Bristol-Myers Squibb, and Yuhan Corporation, and consulting fees from KD Bio. SH has received grants from AbbVie, Asahi Kasei Pharma, Eisai, Otsuka, Sanofi, Shionogi, Chugai, Pfizer, Mitsubishi-Tanabe Pharma, Eli Lilly, and UCB; speaker honoraria from AbbVie, Asahi Kasei Pharma, Astellas Pharma, Ayumi Pharma, Bristol-Myers Squibb, Celgene Corporation, Chugai Pharma, Eisai, Gilead Sciences, GlaxoSmithKline, Eli Lilly, Janssen, Kyorin Pharmaceutical, Novartis, Pfizer, Sanofi, Mitsubishi-Tanabe Pharma, and UCB; paid instructor fees from AbbVie and Mitsubishi-Tanabe Pharma; and consulting fees from AbbVie, Astellas Pharma, Bristol-Myers Squibb, Eisai, Gilead Sciences, and Eli Lilly. SS has received grants from Asahi Kasei Pharma, AbbVie, Chugai Pharma, Eli Lilly, Eisai, Teijin, Pfizer, Ayumi Pharma, and Daiichi Sankyo. HY has received research grants from Asahi Kasei Pharma, Mitsubishi-Tanabe Pharma, Chugai Pharma, Eisai, and Taisho Pharma; speaker fees from AbbVie, Janssen, Gilead Sciences, Nippon Boehringer Ingelheim, and Nippon Shinyaku. MK has received grants from Nippon Boehringer Ingelheim, Ono Pharma, and MBL; royalties from MBL; consulting fees from Nippon Boehringer Ingelheim, Mochida Pharmaceutical, and Kissei Pharmaceutical; speaker honoraria from AbbVie, Asahi Kasei Pharma, Astellas Pharma, Chugai Pharma, Nippon Shinyaku, Mitsubishi-Tanabe Pharma, and Nippon Boehringer Ingelheim. TI has received payment or honoraria from AbbVie, Asahi Kasei Pharma, Astellas Pharma, Bristol-Myers Squibb, Chugai Pharma, Eisai, Eli Lilly, Gilead Sciences, Janssen, Pfizer, Boehringer Ingelheim, Novartis, and GlaxoSmithKline. HK has received a research grant from AbbVie, Asahi Kasei Pharma, Boehringer, Chugai Pharma, Eisai, Mitsubishi-Tanabe Pharma, and Taisho; speaker honoraria fees from AbbVie, Asahi Kasei Pharma, Astellas Pharma, Boehringer, Bristol-Myers Squibb, Chugai Pharma, Eisai, Eli Lilly, Gilead Sciences, Janssen, Mitsubishi-Tanabe Pharma, Novartis, Pfizer, and UCB. TK has received grants or research support and speaker fees from AbbVie, Astellas Pharma, Bristol-Myers Squibb, Chugai Pharma, Daiichi-Sankyo, Eli Lilly, Pfizer, Eisai, UCB, and Taisho. TTan, MM, and HM are shareholders and employees of Eisai. YS has received speaker honoraria from Eisai and Kowa Pharmaceuticals; and consulting fees from Mochida Pharmaceutical. TTak received grants from AbbVie, Asahi Kasei Pharma, Ayumi Pharma, Chugai Pharma, Eisai, Eli Lilly, Mitsubishi-Tanabe Pharma, and Ono Pharma; consulting fees from AbbVie, Chugai Pharma, Eli Lilly, and Gilead Sciences, and Mitsubishi-Tanabe Pharma; and payment or honoraria from AbbVie, Asahi Kasei Pharma, Astellas Pharma, Bristol-Myers Squibb, Chugai Pharma, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead Sciences, Janssen, Mitsubishi-Tanabe Pharma, and Pfizer. YK has received grants from AbbVie, Asahi Kasei Pharma, Ayumi Pharma, Chugai Pharma, Eisai, Mitsubishi-Tanabe Pharma, Boehringer Ingelheim, and Asahi Kasei Pharma; payment or honoraria from AbbVie, Asahi Kasei Pharma, Astellas Pharma, Bristol-Myers Squibb, Chugai Pharma, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead Sciences, Janssen, Mitsubishi-Tanabe Pharma, Pfizer, Boehringer Ingelheim, Asahi Kasei Pharma, and Novartis. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: To investigate sustained remission following the discontinuation of tofacitinib in patients with rheumatoid arthritis., Methods: Patients who had an inadequate response to methotrexate (MTX) with or without biological disease-modifying antirheumatic drugs were randomly divided into two groups at baseline, and tofacitinib treatment in combination with MTX was administered to both groups. Either MTX or tofacitinib was then withdrawn if patients achieved Clinical Disease Activity Index remission at week 52. The primary outcome was the proportion of patients who sustained clinical remission at week 104., Results: A total of 113 patients participated in this study. Among them, a total of 48 patients achieved remission at week 52. After discontinuation of tofacitinib, only 29.2% (7/24) of patients remained remission, while 50.0% (10/20) of patients, which was numerically higher but not statistically significant, sustained remission after MTX discontinuation. A greater proportion of bio-naïve patients achieved remission at week 52 and sustained low disease activity with tofacitinib discontinuation at week 104. Additionally, the patients who were able to discontinue tofacitinib without flares had lower rheumatoid factor (p=0.04) and lower anti-cyclic citrullinated peptide antibody (p=0.051) before discontinuation of tofacitinib. No severe adverse events were recorded after discontinuation of tofacitinib or MTX. In patients who relapsed after tofacitinib discontinuation, 71.4% achieved remission with resumption of tofacitinib., Conclusions: This study implies that a blanket cessation of tofacitinib may not be suitable for all patients, given that 58% of the participants experienced relapse. However, the withdrawal of tofacitinib is unlikely to result in the acquisition of treatment-resistance., Competing Interests: Competing interests: SK has received consulting fees, speaking fees and/or honoraria from Eli Lilly, Bristol-Myers, GlaxoSmithKline and research grants from Daiichi-Sankyo, Abbvie, Boehringer Ingelheim and Astellas. YM has received consulting fees, speaking fees and/or honoraria from Eli Lilly and has received research grants from GlaxoSmithKline. KA has received research grants from Asahi-Kasei Pharma and speaking fees from Abbvie GK, Chugai Pharmaceutical Co, Eisai, Eli Lilly and Pfizer Japan. KM has received research grants from Asahi-Kasei Pharma and Chugai. HK has received speaking fees and/or honoraria from AbbVie, Asahi-Kasei, Bristol-Myers, Chugai, Eisai, Eli Lilly, Janssen, Mitsubishi-Tanabe, Pfizer and UCB, and received research grants from Asahi-Kasei, Abbvie, Chugai, Eisai, Mitsubishi-Tanabe and Taisho. SN has received consulting fees, speaking fees and/or honoraria from Bristol-Myers, AstraZeneca, Pfizer, GlaxoSmithKline, Astellas, Asahi-Kasei, Sanofi, Abbvie, Eisai, Chugai, Gilead, Boehringer Ingelheim and has received research grants from Mitsubishi-Tanabe. YK has received consulting fees, speaking fees and/or honoraria from Abbvie, Asahi Kasei, Daiichi-Sankyo, Chugai, Takeda, Mitsubishi-Tanabe, Bristol-Myers, Astellas, Eisai, Janssen, Novartis, Pfizer, Boehringer Ingelheim, Asahi-Kasei, Eli Lilly, GlaxoSmithKline, UCB, and has received research grants from Mitsubishi-Tanabe, Chugai and Abbvie. KY has received consulting fees, speaking fees and/or honoraria from Pfizer, Chugai Pharma, Takeda Industrial Pharma, Astellas Pharma, Abbvie, Bristol-Myers Squibb, Mitsubishi-Tanabe Pharma, GlaxoSmithKline, Eli Lilly, Janssen Pharma, Eisai Pharma, Actelion Pharmaceuticals Japan, Asahi Kasei Pharma Corp, Ono Pharma, Otsuka Pharma, Nippon Shinyaku, Gilead G.K, Daiichi Sankyo, Boehringer Ingelheim Japan, Japan Tobacco, Hisamitsu Pharma, MSD, Sanofi, AYUMI Pharma, Nippon Kayaku. YTanaka has received speaking fees and/or honoraria from Behringer-Ingelheim, Eli Lilly, Abbvie, Gilead, AstraZeneca, Bristol-Myers, Chugai, Daiichi-Sankyo, Eisai, Pfizer, Mitsubishi-Tanabe, GlaxoSmithKline, received research grants from Asahi-Kasei, Abbvie, Chugai, Eisai, Takeda, Daiichi-Sankyo, Behringer-Ingelheim., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Objectives: To describe the immunogenicity profile of sarilumab in Japanese patients with rheumatoid arthritis (RA)., Methods: Patients enrolled in the KAKEHASI and HARUKA studies were included in our analysis. In these studies, patients received sarilumab 150 mg or 200 mg every 2 weeks for 52 or 28 weeks in combination with methotrexate (MTX) (KAKEHASI), or for 52 weeks as monotherapy or in combination with non-MTX conventional synthetic disease-modifying anti-rheumatic drugs (HARUKA). Anti-drug antibodies (ADAs) and neutralising antibodies (NAbs) were assessed in the pooled population., Results: Positive ADA assay responses occurred in 10/149 (7.1%) patients treated with sarilumab 150 mg and 13/185 (7.0%) patients treated with sarilumab 200 mg, with persistent responses in 2 (1.4%) and 4 (2.2%) patients, respectively. Peak ADA titre was 30. No patients treated with the 150 mg dose and one patient (0.5%) treated with the 200 mg dose exhibited NAbs. There was no evidence of an association between ADA formation and hypersensitivity reactions or reduced efficacy., Conclusions: ADAs, which occurred at a low frequency and titre, did not affect the safety or efficacy of sarilumab 150 or 200 mg administered as monotherapy or combination therapy in Japanese patients with RA in the KAKEHASI or HARUKA studies., (© Japan College of Rheumatology 2021. Published by Oxford University Press.)

Objective: Sarilumab, as monotherapy or in combination with conventional synthetic DMARDs, such as MTX, has demonstrated improvement in clinical outcomes in patients with RA. The primary objective of this post hoc analysis was to compare the efficacy of sarilumab (200 mg every 2 weeks) monotherapy (MONARCH study) with that of sarilumab and MTX combination therapy (MOBILITY study) at week 24., Methods: The endpoints assessed were mean change from baseline in the Clinical Disease Activity Index (CDAI), 28-joint Disease Activity using CRP (DAS28-CRP), CRP, haemoglobin (Hb), pain visual analogue scale (VAS) and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue. Least square (LS) mean change from baseline (95% CI) at week 24 for all endpoints was compared between the treatment arms for adjusted comparisons., Results: This analysis included 184 patients on sarilumab monotherapy and 399 patients on sarilumab plus MTX. Differences (P < 0.05) were observed in ethnicity, region, body mass index group, rheumatoid factor, anti-cyclic citrullinated peptide antibodies, swollen joint count, CRP, CDAI and oral glucocorticoid use between these treatment groups. After adjusting for these differences in a mixed-effect model repeated measure, LS mean change from baseline for all assessments was similar between the treatment groups with overlapping CIs: CDAI, -28.79 vs -26.21; DAS28-CRP, -2.95 vs -2.81; CRP, -18.31 vs -16.46; Hb, 6.59 vs 8.09; Pain VAS, -33.62 vs -31.66; FACIT-Fatigue, 9.90 vs 10.24., Conclusion: This analysis demonstrated that the efficacy of sarilumab monotherapy was similar to that of sarilumab and MTX combination therapy., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective We evaluated the performance of the revised classification criteria for assessing different systemic autoimmune rheumatic diseases and their overlap syndromes. Methods A total of 652 patients with or highly suspected of having systemic lupus erythematosus (SLE), systemic sclerosis (SSc), polymyositis (PM)/dermatomyositis (DM) or rheumatoid arthritis (RA) were included in this study. The 1997 revised American College of Rheumatology (ACR) and the 2019 European League Against Rheumatism (EULAR)/ACR criteria for SLE, the 1980 ACR and the 2013 ACR/EULAR criteria for SSc, the criteria by Bohan and Peter and the 2017 EULAR/ACR criteria for PM/DM, and the 1987 revised ACR and 2011 ACR/EULAR criteria for RA were used for disease classification. Results The old and new criteria and a clinical diagnosis were used to respectively classify 103, 106 and 105 SLE patients; 35, 47 and 58 SSc patients; 18, 23 and 33 PM/DM patients; and 297, 389 and 468 RA patients. Sensitivity increased from 82.9% to 92.4% in SLE, from 56.9% to 79.3% in SSc, from 54.5% to 66.7% in PM/DM, and from 62.6% to 80.8% in RA. SLE-SSc was the predominant type of clinical overlap syndrome, while SLE-RA was the most classifiable. Conclusion The revised classification criteria for all the diseases showed an improved sensitivity, and SLE-overlap syndrome was predominant, regardless of the criteria sets.

Objectives: Methotrexate (MTX) is used as an anchor drug in the treatment of rheumatoid arthritis (RA), although more than a half of the patients with RA require additional treatments. We designed a prospective study involving two medical centers in Japan to examine the association between the expression of MTX-related genes including a drug transporter ATP-binding cassette sub-family G member 2 (ABCG2) gene and the clinical response to MTX in MTX-naive patients with RA., Methods: The primary endpoint of this study was good response based on the European League Against Rheumatism (EULAR) response criteria by Disease Activity Score using 28-joint count (DAS28). We evaluated the association between the baseline expression of six genes involved in the intracellular pharmacokinetics of MTX, including ABCG2, as well as their temporal changes, and the clinical response at week 12 from the initiation of MTX., Results: Based on the clinical response at 12 weeks after the initiation of MTX, 24 patients were classified into good responders ( n  = 9) and non-good responders ( n  = 15; 10 moderate responders and 5 non-responders) groups. A univariate logistic regression analysis of the baseline gene expression levels to predict the EULAR good response at week 12 showed a significant association with ABCG2 expression alone. Furthermore, the rate of baseline expression of ABCG2 mRNA above the cut-off value determined using a receiver operating characteristic curve was higher in good responders than in non-good responders ( p  = .012). Moreover, ABCG2 expression decreased in almost all good responders, but not in non-good responders, after MTX treatment for 12 weeks (median -76% vs. +41% from baseline, respectively; p  = .011). The ABCG2 expression level did not correlate with DAS28 at baseline or week 12., Conclusions: Our study revealed that good response to MTX is associated with a decrease in the expression of ABCG2 in patients with RA.

Introduction: Upadacitinib is a Janus kinase inhibitor with demonstrated efficacy in patients with rheumatoid arthritis (RA)., Objective: The aim of this study was to assess the long-term safety of upadacitinib in patients with active RA from Japan compared with global clinical trial populations., Methods: Pooled data in patients enrolled from Japan (the 'Japanese population'; SELECT-SUNRISE, SELECT-EARLY, and SELECT-MONOTHERAPY) were compared with that from global (Japan and ex-Japan) upadacitinib clinical trial populations and summarized descriptively., Results: The Japanese population (mean age 57.0 years; mean RA duration 6.1 years) received upadacitinib 7.5 mg (n = 121), 15 mg (n = 126), and 30 mg (n = 124) once daily, while the global population (mean age 54.8 years; mean RA duration 9.1 years) received upadacitinib 6 mg twice daily/15 mg once daily (n = 2883) and 12 mg twice daily/30 mg once daily (n = 1375). Most patients were female (79.3%). The exposure-adjusted incidence rates (EAIRs) of serious adverse events in the Japanese population were 11.5, 12.2, and 21.2 per 100 patient-years (PY) with upadacitinib 7.5, 15, and 30 mg, respectively. Herpes zoster rates were higher in the Japanese population (7.8, 12.4, and 16.7 per 100 PY with 7.5, 15, and 30 mg, respectively) versus global populations (3.7 and 7.0 per 100 PY with 15 and 30 mg, respectively). Prior herpes zoster was a significant risk factor for herpes zoster., Conclusions: The safety profile of upadacitinib was generally similar between Japanese and global RA populations, except for higher EAIRs for serious adverse events and infections, including herpes zoster, in the Japanese population., Trial Registration Numbers: SELECT-EARLY: NCT02706873; SELECT-NEXT: NCT02675426; SELECT-COMPARE: NCT02629159; SELECT-MONOTHERAPY: NCT02706951; SELECT-BEYOND: NCT02706847; SELECT-SUNRISE: NCT02720523; BALANCE I: NCT01960855; BALANCE II: NCT02066389.

To elucidate the disease-flare process in rheumatoid arthritis (RA) after discontinuing biological disease-modifying antirheumatic drugs (bDMARDs), we first focused on RA-flare prediction after achieving stringent remission criteria. Patients with RA who maintained a simplified disease activity index ≤ 3.3 for ≥ 3 months during November 2014-January 2018 in our medical centre in Tokyo, Japan, were eligible. The primary endpoint was flare (disease activity score 28-erythrocyte sedimentation rate ≥ 3.2 with increase from baseline > 0.6) within 2 years after bDMARD discontinuation. Comprehensive clinical assessments, ultrasonographic evaluation of 40 joints, and blood sampling for 12 biomarkers were performed every 2-3 months for 2 years unless patients experienced flare. Flare-positive and flare-negative patients were compared using univariate and Kaplan-Meier analyses. Thirty-six patients (80.6% female, median disease duration, 5.2 years; median treatment period with discontinued bDMARD, 2 years; median remission duration, 18 months) were enrolled. Twenty patients (55.6%) experienced RA flare 43-651 (median, 115) days after the first skipped date of bDMARDs. Two patients who withdrew without disease flare were excluded from the comparison. Clinical and ultrasonographic evaluations did not show significant between-group differences; Kaplan-Meier analysis showed that higher baseline soluble tumour necrosis factor receptor 1 (sTNFR1) concentration impacted subsequent disease flare (p = 0.0041); higher baseline interleukin (IL)-2 concentration was exclusively beneficial to patients with lower sTNFR1 (p = 0.0058), resulting in remission maintenance in 83.3% of patients with lower sTNFR1 and higher IL-2. We demonstrated the usefulness of combined biomarker evaluation for predicting sustained remission after bDMARD discontinuation in RA.

Objective: Joint destruction in rheumatoid arthritis (RA) includes both bone and cartilage lesions. Since joint space narrowing (JSN) is not a direct evaluation of cartilage using radiography, we aimed to examine the validity of ultrasound (US) cartilage evaluation using a semiquantitative method in patients with RA., Methods: We enrolled 103 patients with RA who were in remission or showing low disease activity and 42 healthy subjects. The cartilage thickness of the bilateral metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of the second to fifth fingers was measured by US, and the recorded images were scored semiquantitatively using a scale of 0-2. In addition, the JSN of the corresponding joints was scored using a hand radiograph. The relationships between total cartilage thickness, its semiquantitative score, and JSN score were assessed using Spearman's rank correlation coefficients., Results: Total cartilage thickness was significantly thinner in patients with RA compared to healthy subjects for both the MCP and PIP joints (both P < 0.001). The semiquantitative sum of 16 joints ranged from 2 to 26 (median 8) in patients with RA, which was significantly greater than the 0-11 (median 4) in healthy subjects (P < 0.001). In patients with RA, the semiquantitative score showed a significant negative correlation with cartilage thickness (ρ = -0.64, P < 0.001) and a significant positive correlation with JSN score (ρ = 0.66, P < 0.001). Furthermore, these scores showed a significant correlation with RA disease duration., Conclusion: A simplified and direct evaluation of finger joint cartilage damage by semiquantitative US score is valid and useful for patients with RA., (© 2019 The Authors. Arthritis Care & Research published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Background: The objective of the study was to evaluate the efficacy and safety of upadacitinib over 84 weeks in Japanese patients with active rheumatoid arthritis (RA) and an inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs., Methods: All patients completing a 12-week, randomized, double-blind treatment period entered a blinded extension and continued upadacitinib 7.5, 15, or 30 mg once daily (QD), or were switched from placebo to upadacitinib 7.5, 15, or 30 mg QD. Efficacy and safety were assessed over 84 weeks., Results: Of 197 randomized patients, 187 (94.9%) completed the 12-week period and entered the blinded extension; 152 (77.2%) patients were ongoing at week 84. At week 84, the proportions of patients achieving a 20% improvement in American College of Rheumatology criteria (ACR20) were 85.7%, 77.6%, and 58.0% with continued upadacitinib 7.5, 15, and 30 mg, respectively (nonresponder imputation), and were similar in patients who had switched from placebo. Favorable response rates were also observed for more stringent measures of response (ACR50/70) and remission (defined by the Disease Activity Score of 28 joints with C-reactive protein, Clinical Disease Activity Index, or Simplified Disease Activity Index). The 15 mg and 30 mg doses of upadacitinib were associated with more rapid and numerically higher initial responses for some measures of disease activity and remission compared with the 7.5 mg dose. Rates of adverse events, infection, opportunistic infection, serious infection, and herpes zoster were lower with upadacitinib 7.5 and 15 mg versus 30 mg., Conclusions: Upadacitinib demonstrated sustained efficacy and was well tolerated over 84 weeks in Japanese patients with RA, with upadacitinib 15 mg offering the most favorable benefit-risk profile., Trial Registration: ClinicalTrials.gov NCT02720523 . Registered on March 22, 2016.

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

Objective: To evaluate upadacitinib efficacy and safety dose response in Japanese patients with active RA and an inadequate response to conventional synthetic DMARDs (csDMARDs)., Methods: This was a multicentre, phase IIb/III, dose-ranging study conducted in Japan, in which patients on previously stable csDMARDs were randomized to receive upadacitinib 7.5, 15 or 30 mg once daily or matching placebo for a 12-week double-blind period. The primary endpoint was a 20% improvement in ACR criteria (ACR20) response at week 12 using non-responder imputation. Key secondary endpoints included ACR50, ACR70 and 28-joint DAS with CRP (DAS28-CRP) remission and low disease activity. Adverse events were also assessed., Results: Of 197 patients treated, 187 completed the double-blind period. At week 12, more patients receiving upadacitinib 7.5, 15 or 30 mg vs placebo met the ACR20 response (75.5%, 83.7%, 80.0% vs 42.9%; P < 0.001), with significant differences observed as early as week 1. Stringent responses, including ACR50, ACR70 and DAS28-CRP <2.6, were achieved by significantly higher proportions of patients on upadacitinib than placebo and by numerically higher proportions on upadacitinib 15 or 30 mg vs upadacitinib 7.5 mg. Adverse events and infections (serious infections, opportunistic infections and herpes zoster) were more common with upadacitinib vs placebo and numerically highest with upadacitinib 30 mg. There were no venous thromboembolic events reported., Conclusion: Efficacy of upadacitinib was demonstrated in this population of Japanese patients with RA and an inadequate response to csDMARDs. Safety and tolerability were consistent with other upadacitinib RA studies. The 15 mg dose of upadacitinib showed the most favourable benefit-risk profile., Trial Registration: ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT02720523., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Patient-reported outcome (PRO) is included in the remission criteria of rheumatoid arthritis (RA). We aimed to determine the effect of age on PRO and the subsequent achievement of clinical and functional RA remission criteria. Three hundred and one patients with non-rheumatic diseases were evaluated using the 0-10 cm visual analog scale (VAS) assessment for musculoskeletal symptoms and a functional health assessment questionnaire-disability index (HAQ-DI). These assessments were compared with those obtained from 149 patients with RA with negative tender/swollen joint counts and normal serum C-reactive levels (objective clinical remission). Of the 301 patients, 32.2%, 26.6%, and 41.2% were classified as non-elderly (< 65 years), early elderly (65-74 years), and late-elderly (≥ 75 years) patients, respectively. VAS > 1 cm and HAQ-DI ≥ 0.5 were observed in 7.3% and 14.5%, respectively, in late-elderly patients, whereas ≤ 1.0% of non-elderly and early elderly patients for the both. Among 149 RA patients in objective remission, however, > 20% and > 10% of early elderly patients (and even non-elderly patients) had VAS > 1 cm and HAQ-DI ≥ 0.5, respectively, and 34.0% and 35.8% of late-elderly patients with RA had VAS > 1 cm and HAQ-DI ≥ 0.5, respectively. Multivariate logistic analysis revealed that age and RA were associated with the non-achievement of VAS ≤ 1 cm and HAQ-DI < 0.5. Therefore, the effect of age, which was independent of the presence of RA even without any objective disease activity, on PRO and the non-achievement of clinical and functional remission criteria was demonstrated.

Aim: PF-06438179/GP1111 (PF-SZ-IFX) is a biosimilar of reference infliximab (Remicade ® ). This analysis compared the efficacy of PF-SZ-IFX and reference infliximab sourced from the European Union (IFX-EU) in patient subgroups from a randomized, comparative study of PF-SZ-IFX versus IFX-EU., Methods: Patients with rheumatoid arthritis were randomized 1:1 to PF-SZ-IFX (n = 324) or IFX-EU (n = 326); study drug (3 mg/kg) was administered intravenously at weeks 0, 2, and 6, then every 8 weeks thereafter. Subgroup analyses of efficacy endpoints such as American College of Rheumatology criteria for ≥20% clinical improvement (ACR20), change in high-sensitivity C-reactive protein (hs-CRP), and change in Disease Activity Score in 28 joints, four components based on hs-CRP (DAS28-CRP) at weeks 14 and 30 were performed by age, gender, race, region, immunogenicity status, and treatment history., Results: Overall, ACR20 response rates as well as changes in DAS28-CRP and hs-CRP at week 14 were similar between PF-SZ-IFX and IFX-EU within the subgroups of age, gender, race, region, treatment history, and immunogenicity status. Results to week 30 support overall similarity in efficacy between the two treatment arms in all subgroups., Conclusion: Overall, PF-SZ-IFX and IFX-EU were similar in efficacy within the analyzed subgroups of age, gender, race, region, treatment history, and immunogenicity status. The efficacy results from these subgroup analyses were aligned with the previously described results for the overall population up to week 30., (© 2020 The Authors. International Journal of Rheumatic Diseases published by Asia Pacific League of Associations for Rheumatology.)

Objective: Our objective was to evaluate the long-term efficacy, safety, and immunogenicity of the infliximab biosimilar, PF-06438179/GP1111 (PF-SZ-IFX), in patients with rheumatoid arthritis (RA) who continued biosimilar treatment throughout 78 weeks or who switched from reference infliximab (Remicade ® ) sourced from the EU (IFX-EU) at week 30 or week 54 in the REFLECTIONS B537-02 study., Methods: In this phase III, double-blind, active-controlled study, patients with moderate-to-severe active RA were initially randomized to PF-SZ-IFX or IFX-EU, each with methotrexate (treatment period [TP] 1; N = 650). At week 30, patients receiving PF-SZ-IFX continued PF-SZ-IFX; patients receiving IFX-EU were re-randomized to continue IFX-EU or switch to PF-SZ-IFX (TP2; n = 566). From weeks 54 to 78, all patients received open-label treatment with PF-SZ-IFX (TP3; n = 505). Efficacy, safety, and immunogenicity data were analyzed during TP3., Results: Efficacy was sustained and comparable across groups at week 78, with American College of Rheumatology criteria for ≥ 20% clinical improvement response rates of 75.9% (biosimilar group), 77.8% (week 30 switch group), and 68.3% (week 54 switch group). The incidence of treatment-emergent adverse events was 28.9%, 29.4%, and 30.2%, respectively. The proportion of patients who were antidrug antibody (ADA) positive and neutralizing antibody positive (as a percentage of ADA-positive patients) was stable and comparable between groups., Conclusions: Results to week 78 continue to support the efficacy, safety, and immunogenicity of PF-SZ-IFX in patients with moderate-to-severe active RA. There were no clinically meaningful differences between groups, independent of a single treatment transition from IFX-EU to PF-SZ-IFX at week 30 or week 54., Trial Registration Number: NCT02222493.

Objectives: To determine long-term safety and efficacy of sarilumab as monotherapy or with non-methotrexate (MTX) conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in Japanese patients with active rheumatoid arthritis (RA). Methods: In this double-blind, randomized study (NCT02373202), patients received subcutaneous sarilumab 150 mg q2w (S150) or 200 mg q2w (S200) as monotherapy or with non-MTX csDMARDs for 52 weeks. The primary endpoint was safety. Results: Sixty-one patients received monotherapy (S150, n  = 30; S200, n  = 31) and 30 received combination therapy (S150 + csDMARDs, n  = 15; S200 + csDMARDs, n  = 15). Rates of treatment-emergent adverse events (TEAEs) were 83.3%/90.3%/93.3%/86.7% for S150/S200/S150 + csDMARDs/S200 + csDMARDs, respectively. Nasopharyngitis and neutropenia were the most frequently reported TEAEs. One serious infection was reported in each monotherapy group and in the S200 + csDMARDs group. There were no cases of grade 4 neutropenia; no patients with grade 3 neutropenia experienced associated serious infection. Improvements in ACR20/50/70 response rates were generally similar between the two monotherapy groups and between the two combination groups; improvements in physical function (Health Assessment Questionnaire-Disability Index, HAQ-DI) and DAS28-CRP were observed at weeks 24 and 52 (all groups). Conclusion: The safety profile of sarilumab was consistent with known class effects of interleukin-6 signaling blockade therapeutics. Sarilumab as mono- or combination therapy improved clinical signs/symptoms and physical function in Japanese RA patients.

Objective: To investigate the efficacy, safety and immunogenicity of PF-06438179/GP1111 (PF-SZ-IFX) compared with European reference infliximab (Remicade ® ; ref-IFX) in patients with moderate-to-severe, active rheumatoid arthritis after continued long-term use of PF-SZ-IFX, and in patients who were switched from ref-IFX to PF-SZ-IFX., Methods: REFLECTIONS B537-02 was a double-blind, active-controlled, multinational study in which patients (N=650) were initially randomised to PF-SZ-IFX or ref-IFX for 30 weeks (treatment period [TP] 1). During weeks 30-54 (TP2), the PF-SZ-IFX group (n=280) continued treatment with PF-SZ-IFX (PF-SZ-IFX/PF-SZ-IFX) and patients in the ref-IFX group (n=286) were rerandomised (1:1) to continue ref-IFX (ref-IFX/ref-IFX) (n=143) or switch to PF-SZ-IFX (ref-IFX/PF-SZ-IFX) (n=143) for a further 24 weeks. Efficacy, safety, immunogenicity and pharmacokinetics were evaluated., Results: During TP2, patients in all three treatment groups continued to maintain comparable treatment response. At week 54, the American College of Rheumatology (ACR20) response rates were 71.1% (PF-SZ-IFX/PF-SZ-IFX), 64.3% (ref-IFX/ref-IFX) and 70.6% (ref-IFX/PF-SZ-IFX). Observations for other endpoints, including ACR50/70, Disease Activity Score in 28 Joints Based on High-Sensitivity C Reactive Protein(DAS28-CRP) remission, and mean change in DAS28-CRP and Health Assessment Questionnaire-Disability Index, were also comparable. Treatment-emergent adverse events were reported in 36.8% (PF-SZ-IFX/PF-SZ-IFX), 33.6% (ref-IFX/ref-IFX) and 37.8% (ref-IFX/PF-SZ-IFX) of patients; there were no clinically meaningful differences in the safety profiles between groups. The percentage of patients who were antidrug antibody-positive was generally stable through the treatment period and comparable overall between the PF-SZ-IFX/PF-SZ-IFX (52.1%; neutralising: 80.8%), ref-IFX/ref-IFX (60.1%; neutralising: 84.9%) and ref-IFX/PF-SZ-IFX (58.0%; neutralising 78.3%) groups., Conclusions: The similar efficacy, safety and immunogenicity of PF-SZ-IFX compared with ref-IFX were maintained for up to 54 weeks and were not affected by blinded treatment switch from ref-IFX to PF-SZ-IFX at week 30., Trial Registration Number: NCT02222493., Competing Interests: Competing interests: RA has received honoraria and research grants from Bristol-Myers Squibb, Celltrion, Chugai Pharmaceutical, Eli Lilly, Janssen, Novartis, Roche and Pfizer. BB has received consulting fees, speaking fees and honoraria from Pfizer and Sandoz. TH has declared no conflicts of interest. HK has received consulting fees, speaking fees and/or honoraria from Asahi Kasei Pharma, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan KK, Janssen Pharmaceutical KK, Mitsubishi Tanabe Pharma, Novartis Pharma KK and Pfizer Japan, and research grants from AbbVie GK, Asahi Kasei Pharma, Astellas Pharma, Chugai Pharmaceutical, Eisai, Mitsubishi Tanabe Pharma, Novartis Pharma KK, Sanofi Pharma and UCB Japan. SCR has received research grants and consulting fees, speaking fees and/or honoraria from Pfizer. VT has no conflicts of interest. GB was an employee of Hexal (a Sandoz company) at the time of writing this manuscript. OvR is an employee of Hexal (a Sandoz company). CC, SH, MR and MZ are employees of Pfizer. SC has received consulting fees from Amgen, Boehringer-Ingelheim, Coherus, Merck, Pfizer and Sandoz and has received research grants from Amgen, Boehringer-Ingelheim, Coherus, Merck and Pfizer.

Background: Sarilumab is a human immunoglobulin G1 anti-interleukin-6 (IL-6) receptor monoclonal antibody that blocks IL-6 from binding to membrane-bound and soluble IL-6 receptor α. This bridging study assessed the efficacy and safety of sarilumab + methotrexate (MTX) in Japanese patients with active rheumatoid arthritis (RA) and inadequate response to MTX (MTX-IR)., Methods: In this phase III study, 243 patients were randomized 2:2:1:1 to receive subcutaneous sarilumab 150 mg every 2 weeks (q2w), sarilumab 200 mg q2w, placebo switching to sarilumab 150 mg q2w + MTX at 24 weeks, or placebo switching to sarilumab 200 mg q2w at 24 weeks, all in combination with MTX, for a total of 52 weeks (double-blind, placebo-controlled 24-week period followed by a single-blind 28-week extension). The primary endpoint was the proportion of patients achieving American College of Rheumatology 20% improvement criteria (ACR20) responses at week 24., Results: ACR20 response rates at week 24 were 67.9%, 57.5%, and 14.8% for sarilumab 150 mg, sarilumab 200 mg, and placebo, respectively. Serious treatment-emergent adverse events were reported by 9.9%, 6.3%, 0%, and 13.3% of patients in the sarilumab 150 mg, sarilumab 200 mg, placebo to sarilumab 150 mg, and placebo to sarilumab 200 mg groups, respectively. No deaths occurred. The incidence of infections ranged from 52.5 to 67.9%, with five serious infections for the sarilumab 150 mg group and one for the group switched from placebo to 200 mg sarilumab. Absolute neutrophil count < 1.0 Giga/l occurred in 13.6% and 7.5% of patients in the sarilumab 150 and 200 mg groups, respectively, and was not associated with infection., Conclusions: In Japanese MTX-IR RA patients treated with sarilumab (150 and 200 mg q2w) in combination with MTX, sustained clinical efficacy was shown by significant improvement in signs, symptoms, and physical function; bridging between this and a previous global study was achieved. At week 52, the safety profiles of both doses of sarilumab were generally similar, as previously observed and as expected based on IL-6 class., Trial Registration: ClinicalTrials.gov, NCT02293902 . Registered on 19 November 2014.

Methotrexate (MTX), the anchor drug in the current treatment strategy for rheumatoid arthritis (RA), was first approved for treatment of RA in Japan in 1999 at the recommended dose of 6-8 mg/week; it was approved as first-line drug with the maximum dose of 16 mg/week in February 2011. However, more than half of Japanese patients with RA are unable to tolerate a dose of 16 mg/week of MTX. Moreover, some serious adverse events during the treatment with MTX, such as pneumocystis pneumonia (PCP) and lymphoproliferative disorders (LPD) have been observed much more frequently in Japan than in other countries. Therefore, this article, an abridged English translation summarizing the 2016 update of the Japan College of Rheumatology (JCR) guideline for the use of MTX in Japanese patients with RA, is not intended to be valid for global use; however, it is helpful for the Japanese community of rheumatology and its understanding might be useful to the global community of rheumatology.

Objectives: The objective of this study is to evaluate the safety and effectiveness of subcutaneous tocilizumab (TCZ-SC) in a real-world clinical setting in Japan., Methods: This single arm, 26-week prospective observational study enrolled patients with RA who were either TCZ naïve or switched from TCZ-IV to TCZ-SC (TCZ-IV-SC group) (UMIN Clinical Trials Registry UMIN000011102). All patients received TCZ-SC 162 mg every 2 weeks and data were collected until week 26 or discontinuation., Results: Overall 784 (78.1%) were TCZ naïve and 219 (21.8%) were in the TCZ-IV-SC group. 70.9% received disease-modifying antirheumatic drugs at baseline. Adverse events (AEs) and serious AEs occurred in 28.2% and 4.9% of patients, respectively (TCZ-naïve: 29.5% and 5.2%; TCZ-IV-SC: 23.2% and 4.1%). Infections and infestations were the most common AEs (7.4%) and serious AEs (1.7%). Two TCZ-naïve patients died. TCZ-naïve patients had an improvement in median Clinical Disease Activity Index (CDAI) score and mean Disease Activity Score in 28 joints as measured by erythrocyte sedimentation rate (DAS28-ESR) from baseline to week 26. The TCZ-IV-SC group had similar median CDAI scores and mean DAS28-ESR over 26 weeks., Conclusions: There were no unexpected safety signals with TCZ-SC. TCZ-SC was effective in reducing disease activity in TCZ-naïve patients and maintaining remission in TCZ-IV-SC patients.

Background: This double-blind, active-controlled, randomized, multinational study evaluated the efficacy, safety, pharmacokinetics (PK), and immunogenicity of PF-06438179/GP1111 (IxifiTM/Zessly®), an infliximab biosimilar, vs infliximab (Remicade®) reference product sourced from the European Union (infliximab-EU) in biologic-naïve patients with moderate to severe active rheumatoid arthritis (RA) despite methotrexate therapy. This paper reports results from the initial 30-week treatment period., Methods: Patients (N = 650) were stratified by geographic region and randomized 1:1 to PF-06438179/GP1111 or infliximab-EU (3 mg/kg intravenous at weeks 0, 2, and 6, then every 8 weeks). Dose escalation to 5 mg/kg was allowed starting at week 14 for patients with inadequate RA response. The primary endpoint was American College of Rheumatology criteria for ≥ 20% clinical improvement (ACR20) response at week 14. Therapeutic equivalence was declared if the two-sided 95% CI for the treatment difference was within the symmetric equivalence margin of ± 13.5%. Statistical analysis was also performed with a two-sided 90% CI using an asymmetric equivalence margin (- 12.0%, 15.0%)., Results: Patients (80.3% female; 79.4% seropositive) had a mean RA duration of 6.9 years, and mean baseline Disease Activity Score in 28 joints, four components based on C-reactive protein was 6.0 in both arms. Week 14 ACR20 in the intention-to-treat population was 62.7% for PF-06438179/GP1111 and 64.1% for infliximab-EU. Week 14 ACR20 using nonresponder imputation was 61.1% for PF-06438179/GP1111 and 63.5% for infliximab-EU, and the 95% (- 9.92%, 5.11%) and 90% (- 8.75%, 4.02%) CIs for the treatment difference (- 2.39%) were entirely contained within the prespecified symmetric and asymmetric equivalence margins, respectively. No differences were observed between arms for secondary efficacy endpoints. Overall postdose antidrug antibody (ADA) rates through week 30 were 48.6% and 51.2% for PF-06438179/GP1111 and infliximab-EU, respectively. Efficacy and immunogenicity were similar between treatments for patients with dose escalation (at or after week 14), as well as between treatments for patients without dose escalation. Safety profiles of PF-06438179/GP1111 and infliximab-EU were similar, with no clinically meaningful differences observed between arms, including after ADA development. Serum drug concentrations were similar between arms at each time point during the initial 30-week treatment period., Conclusion: PF-06438179/GP1111 and infliximab-EU demonstrated similar efficacy, safety, immunogenicity, and PK with or without dose escalation in patients with moderate to severe active RA on background methotrexate., Trial Registration: ClinicalTrials.gov, NCT02222493 . Registered on 21 August 2014. EudraCT, 2013-004148-49 . Registered on 14 July 2014.

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

As of February 2018, 5 originator TNF inhibitors(infliximab, etanercept, adalimumab, golimumab and certolizumab pegol)and biosimilar agents of infliximab and etanercept are available for rheumatoid arthritis(RA)in Japan. The effectiveness of TNF inhibitors considerably improves with concomitant methotrexate regardless of their immunogenicity. The Japan College of Rheumatology guideline for TNF inhibitor use in RA has been updated in March 2017 according to recent evidences. During the remission induction phase, maintenance of drug trough level above effective blood concentration is paramount, while the tapering and withdrawal of TNF inhibitors may be considered after achieving sustained remission.

Objective: The aim of the study is to assess the factors associated with clinical remission of patients with rheumatoid arthritis (RA) in daily clinical practice., Methods: This analysis was based on the data of 304 RA patients in our center between May 2014 and March 2015. The following information was included: tender, swollen, and symptomatic joint counts, patient's and physician's global assessments, functional disability, laboratory and radiographic data, and RA treatments received., Results: The patients were predominantly female (77.6%), with a median age of 71 years and a median disease duration of 5.8 years. Clinical remission rate, determined using the simplified disease activity index (SDAI), was 49.7%. Patient's and physician's global assessments (/10cm) showed a higher score among patients who did not achieve SDAI remission than among those who did (median: 3.2 versus 0.3, p < 0.0001; and median: 1.8 versus 0.3, p < 0.0001, respectively). The contribution of serum C-reactive protein values (mg/dL) to SDAI was limited (median: 0.19 versus 0.06; p < 0.0001), as well as tender or swollen joint counts (median = 0 or 1). On multivariate analysis of factors not directly related to the disease activity, age was an independent risk factor for non-remission, and global assessment scores by patients and physicians showed an age-dependent increase, while counts of tender, swollen and symptomatic joints were comparable among elderly and non-elderly patients., Conclusion: Global assessment of disease activity was age-dependent and independent of joint counts, and it provides a critical determinant of clinical non-remission., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To examine the association between Fcγ receptor (FcγR) polymorphisms and the development of hypersensitivity reactions to adalimumab in patients with rheumatoid arthritis., Methods: Sixty-five patients receiving adalimumab were enrolled in the study. Genetic polymorphisms for FcγR3B were genotyped in FCGR3B NA1/2 alleles by real allelic discrimination assay. Clinical information and the occurrence of a hypersensitivity reaction to adalimumab were collected from the patients' charts., Results: A hypersensitivity reaction was observed in 12% of the patients. Clinical information obtained from patients with a reaction and those without were the same. The FCGR3B NA1/NA1, NA1/NA2, and NA2/NA2 alleles were found in 75%, 13%, and 13% of the patients with hypersensitivity reaction, respectively, and in 28%, 42%, and 30% of those without a hypersensitivity reaction, respectively (p = 0.04). Multivariate logistic regression analysis identified only the NA1/NA1 as an independent relevant factor for a hypersensitivity reaction to adalimumab (OR 7.7, p = 0.01)., Conclusions: The FCGR3B NA1/NA1 genotype is associated with hypersensitivity reactions to adalimumab.

Objective: Ultrasonography has been prevalently used as a valid and objective modality for joint examination in patients with rheumatoid arthritis (RA). This study aimed to examine and compare the concordance between ultrasound, clinical assessment, and patient-reported assessment of joint synovitis in RA., Methods: Fifty patients with RA (84% female, median age 69 years, median disease duration 31 months, and median Disease Activity Score in 28 joints 3.8) completed the self-evaluation of joint symptoms, including pain and considerable stiffness in the (proximal) interphalangeal, metacarpophalangeal, wrist, elbow, shoulder, knee, and ankle joints. These joints were also examined by a physician in order to assess the presence of tenderness or swelling; the presence of imaging synovitis was assessed by ultrasonography., Results: In a total of 1,492 evaluated joints, symptoms (pain and stiffness), tenderness, and swelling were noted in 288 (19.3%), 182 (12.2%), and 220 (14.7%) joints, respectively, while ultrasound indicated synovitis in 317 (21.2%) joints. Overall concordance with ultrasound findings was lowest for joint tenderness (κ = 0.30), followed by symptoms (κ = 0.39), and by swelling (κ = 0.43), irrespective of the evaluated joint, except for the elbow. Moreover, the percentages of inflamed joints detected only on the basis of symptoms, tenderness, or swelling were 18.6%, 2.2%, and 8.5%, respectively, of all joints with signs of synovitis on ultrasonography., Conclusion: Joint swelling showed the best concordance with ultrasonography, followed by patient-reported joint symptoms, and joint tenderness. Joint symptoms, rather than tenderness evaluation, may be a better clinical indicator of synovitis in RA patients., (© 2016, American College of Rheumatology.)

Objective: To evaluate the safety and effectiveness of certolizumab pegol (CZP) in a real-world setting among Japanese patients with rheumatoid arthritis., Methods: Post-marketing surveillance data from 2,579 patients treated with CZP were analyzed. Adverse events (AEs) observed during the 24-week CZP treatment period were recorded. Disease activity was evaluated using DAS28-ESR and DAS28-CRP at baseline, Week 12, Week 24, or at withdrawal., Results: The total period of exposure to CZP was 1313.8 patient-years (PY). AEs were reported in 658 (25.5%) patients, at an event rate (ER) of 73.68/100 PY. The most frequent serious AEs were pneumonia, herpes zoster, and interstitial lung disease, at ER per 100 PY of 2.06, 1.29, and 1.22, respectively. Mean disease activity scores at baseline, as measured by DAS28-ESR and DAS28-CRP, were 4.77 ± 1.34 and 4.21 ± 1.27, respectively. Mean changes from baseline at the last observation were -1.29 ± 1.46 and -1.30 ± 1.42, respectively. EULAR good or moderate responses were achieved in 65% of patients. Longer disease duration, prior biologics use, and treatment without MTX co-therapy were associated with EULAR no response., Conclusion: In this interim analysis, no new safety signals were observed. Clinical response to CZP was observed in approximately two thirds of patients.

Background: According to EULAR recommendations, biologic DMARDs (bDMARDs) such as tumor necrosis factor inhibitor, tocilizumab (TCZ), and abatacept (ABT) are in parallel when prescribing to rheumatoid arthritis (RA) patients who have shown insufficient response to conventional synthetic DMARDs. However, most prediction studies of therapeutic response to bDMARDs using gene expression profiles were focused on a single bDMARD, and consideration of the results from the perspective of RA pathophysiology was insufficient. The aim of this study was to identify the specific molecular biological features predicting the therapeutic outcomes of three bDMARDs (infliximab [IFX], TCZ, and ABT) by studying blood gene expression signatures of patients before biologic treatment in a unified test platform., Methods: RA patients who responded inadequately to methotrexate and were later commenced on any one of IFX (n = 140), TCZ (n = 38), or ABT (n = 31) as their first biologic between May 2007 and November 2011 were enrolled. Whole-blood gene expression data were obtained before biologic administration. Patients were categorized into remission (REM) and nonremission (NON-REM) groups according to CDAI at 6 months of biologic therapy. We employed Gene Set Enrichment Analysis (GSEA) to identify functional gene sets differentially expressed between these two groups for each biologic. Then, we compiled "signature scores" for these gene sets, and the prediction performances were assessed., Results: GSEA showed that inflammasome genes were significantly upregulated with IFX in the NON-REM group compared with the REM group. With TCZ in the REM group, B-cell-specifically expressed genes were upregulated. RNA elongation, apoptosis-related, and NK-cell-specifically expressed genes were upregulated with ABT in the NON-REM group. Logistic regression analyses showed that "signature scores" of inflammasomes, B-cell-specifically expressed, and NK-cell-specifically expressed genes were significant, independently predictive factors for treatment outcome with IFX, TCZ, and ABT, respectively. The AUCs of ROC curves of these signature scores were 0.637, 0.796, and 0.768 for IFX, TCZ, and ABT, respectively., Conclusions: We have identified original gene expression predictive signatures uniquely underlying the therapeutic effects of IFX, TCZ, and ABT. This is, to our knowledge, the first attempt to predict therapeutic effects of three drugs concomitantly using a unified gene expression test platform.

As of January 2016, 5 originator TNF inhibitors (infliximab, etanercept, adalimumab, golimumab and certolizumab pegol) and an infliximab biosimilar are available for rheumatoid arthritis (RA) in Japan. The efficacy and effectiveness of TNF inhibitors improve with concomitant methotrexate even for the least immunogenic agent. The Japan College of Rheumatology guideline for TNF inhibitor use in RA has been updated in March 2015, including recent evidences of effectiveness and safety partly from the postmarketing surveillance data in Japan. During the remission induction phase, maintenance of drug trough level above effective blood concentration is paramount, while the tapering and withdrawal of TNF inhibitors may be considered after achieving sustained remission.

Objectives: To explore the effectiveness and safety of tocilizumab (TCZ) with or without methotrexate (MTX) in active rheumatoid arthritis (RA) patients showing inadequate responses to DMARDs and/or TNF inhibitors in clinical practice., Methods: We observed consecutive 115 RA patients initiating TCZ treatment in Keio University Hospital, dividing them into two groups with (TCZ + MTX group) or without MTX (TCZ group), and evaluated clinical, functional and structural outcomes besides safety at week 52., Results: Overall mean age, RA duration, and DAS28-ESR were 55.4, 8.4 years, and 5.0, respectively. Proportions of the prior use of TNF inhibitors and concomitant MTX were 45.5% and 57.4%, respectively. Mean dose of concomitant MTX was 8.4 mg/week. Baseline characteristics were comparable between the groups. TCZ improved disease activity measured by DAS28-ESR to 2.1 at week 52 overall, without significant difference between the groups. Clinical (DAS28-ESR < 2.6), functional (HAQ-DI ≤ 0.5), and structural (ΔTSS ≤ 0.5) remission rates in the TCZ group and the TCZ + MTX group were 79.1%/63.8% (P = 0.10), 62.8%/54.4% (P = 0.40), and 70.0%/53.8% (P = 0.61), respectively. Retention rates were 81.0% in the TCZ + MTX group and 88.5% in the TCZ group (P = 0.47). The rate of serious adverse events was comparable between the groups., Conclusions: TCZ was clinically, functionally, and radiographically effective and safe either with or without low-dose MTX.

Objectives: We examined whether the addition of another conventional disease-modifying anti-rheumatic drugs (DMARDs) to methotrexate (MTX) upon infliximab (IFX) discontinuation in well-controlled rheumatoid arthritis (RA) patients could suppress subsequent disease flare., Methods: RA patients maintaining DAS28-CRP (Disease Activity Score of 28 joints with C-reactive protein) scores < 2.6 for ≥ 6 months with IFX were randomized either to receive addition of bucillamine (BUC) to MTX (BUC + MTX group; n = 24) or not (MTX group; n = 31) upon discontinuing IFX. The primary endpoint was the flare rate within 2 years of IFX discontinuation., Results: Six patients discontinuing MTX during the study were excluded from analyses. Seventeen patients (63.0%) experienced flares in the MTX group, which was significantly reduced in the BUC + MTX group (31.8%; p = 0.045). Further, the flare rates differed significantly between remission and non-remission by a Boolean definition upon IFX discontinuation in the MTX group (40.0% vs. 91.7%, respectively; p = 0.014), but they were comparable in the BUC + MTX group. BUC treatment was interrupted in seven patients due to rash, proteinuria and incompliance., Conclusions: DMARDs combination therapy may be a better treatment strategy than MTX monotherapy for maintaining RA control after successful discontinuation of biological agents.

Objectives: To examine the effectiveness of tocilizumab (TCZ) in preventing joint destruction in patients with inadequate response to tumor necrosis factor inhibitors (TNF-IR) by assessing X-rays., Methods: RA patients were extracted from the Retrospective actemra investigation for optimal needs of RA patients (REACTION) study. Parameters and components of disease activity were evaluated during anti-TNF treatment and during TCZ treatment. X-ray images of hands and feet at the beginning of this study during anti-TNF treatment (Pre), at the start point of TCZ treatment (Baseline) and after TCZ treatment (Post) were collected for assessing joint destruction., Results: Forty-five patients from the REACTION study fulfilled the criteria of clinical TNF-IR. During anti-TNF treatment, mean DAS28-ESR rose from 5.35 to 5.87 (mean observation duration, 16 months) but improved significantly to 2.94 (P < 0.0001) at 52 weeks after switching to TCZ. Mean change in van der Heijde-modified Sharp score (TSS) during anti-TNF treatment was 3.17 in this TNF-IR population. After switching to TCZ, mean change in TSS was 1.20 (P < 0.05). Rate of radiographic non-progression improved to 66.7% during TCZ treatment from 40.0% during anti-TNF treatment. The predictive factor for no radiographic progression after switching to TCZ was a HAQ disability index (HAQ-DI) score of ≤ 1.88 at switching to TCZ., Conclusion: TCZ was a good treatment option for improving signs and symptoms and inhibiting progression of joint damage in patients with clinical and structural TNF-IR.

Objective: To determine the effect of methotrexate (MTX) on plasma levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-α and to investigate their associations with clinical and radiographic responses in patients with early rheumatoid arthritis (RA)., Methods: Sixty-two untreated RA patients with the disease duration of ≤36 months in whom MTX was initiated were consecutively identified in our prospective RA cohort and included in this study. Concomitant use of prednisolone and synthetic disease-modifying anti-rheumatic drugs with MTX was allowed, but patients who used biological agents were excluded. Plasma IL-6 and TNF-α levels were measured at the time of diagnosis (baseline) and 1 year later. The relationships of the clinical and radiographic data with plasma levels of IL-6 and TNF-α were analyzed., Results: The median age of the patients was 57 years, 49 patients were female, and the median disease duration was 3 months. Forty-six (74.2 %) patients were anti-cyclic citrullinated protein antibody-positive. Serum C-reactive protein (CRP), plasma IL-6, and DAS28 decreased significantly (p <0.001) after MTX treatment, but plasma TNF-α did not. Radiographic progression was significantly correlated with disease activity score and plasma IL-6 levels but not with CRP or TNF-α after MTX treatment. Patients with plasma IL-6 level above 4.03 pg/ml showed clinically relevant radiographic progression with a sensitivity of 91.7 % and a specificity of 88.0 %., Conclusion: In this early RA cohort, we demonstrated a significant (p <0.001) reduction of plasma IL-6, but not TNF-α, during MTX treatment. The post-treatment IL-6 level was a strong indicator of radiographic progression.

Pharmacological management of rheumatoid arthritis (RA) has been rapidly progressed in recent years, which is appeared in the "treat to target" movement and the recommendations developed by some established international/domestic rheumatology associations. The baseline evaluation of poor prognostic factors as well as disease activity with composite measures is necessary for a personalized management. Methotrexate is currently the anchor drug, and other conventional or biological antirheumatic drugs should be added to it for refractory patients. The development of various novel agents including signal transduction inhibitors should promote further advances in the management of RA and other systemic autoimmune and/or inflammatory diseases.

Etanercept (ETN) is a fusion protein of the receptor (CD120b) for tumor necrosis factor (TNF) and the Fc portion of IgG1. A phase III trail and the JESMR study, both performed in Japan, implicated the importance of concomitant methotrexate (MTX) use in the treatment of rheumatoid arthritis (RA). Further evidences, including the TEAR study and the PRESERVE study, supported the recent treatment strategy for RA, being divided into at least two phases: remission induction phase(step-up or initial combination) and its maintenance phase (step-down). Thus, optimization of RA treatment chiefly based on MTX and anti-TNF biological agents is in progress.

Objective: The associations between elevated levels of serum Krebs von den Lungen-6 (KL-6) and treatment of rheumatoid arthritis (RA) with tumor necrosis factor (TNF) inhibitors were investigated in five Japanese clinical trials., Methods: Percentages and incidence rates were calculated for elevated serum KL-6 levels. Adverse events associated with elevated levels of serum KL-6 were investigated., Results: In RISING, a clinical trial for infliximab, 15.6 % of the enrolled patients met criterion B (KL-6 ≥500 U/ml and >1.5-fold increase over the baseline value) by week 54. In HIKARI, 7.8 % of the certolizumab pegol (CZP) group and 0 % of the placebo group met criterion B during the double-blind (DB) period (p = 0.003). In J-RAPID, 8.4 % of the methotrexate (MTX) + CZP and 3.9 % of the MTX + placebo groups met criterion B during the DB period. In GO-MONO, 1.8 % of the golimumab (GLM) and 1.3 % of the placebo groups met criterion B during the DB period. In GO-FORTH, 7.1 % of the MTX + GLM and 0 % of the MTX + placebo groups met criteron B during the DB period (p = 0.017). No adverse events accompanied the elevation of serum KL-6 levels in 95.7 % of these patients., Conclusion: Serum KL-6 levels may increase during anti-TNF therapy without significant clinical events. In these patients, continuing treatment with TNF inhibitors under careful observation is a reasonable option.

Objective: We investigated associations between treatment with methotrexate (MTX) or biological disease-modifying antirheumatic drugs (DMARDs) and elevation of serum Krebs von den Lungen-6 (KL-6) levels in Japanese patients with rheumatoid arthritis (RA)., Methods: Using a standardized form, data were collected retrospectively from medical records and analyzed descriptively., Results: Of a total of 198 RA patients with KL-6 serum levels measured at initiation of treatment (month 0) and two or more times by month 12, 27 (17.9 %) of 151 RA patients treated with biological DMARDs, including infliximab, etanercept, adalimumab, and tocilizumab (the biological DMARDs group), and 5 (10.6 %) of 47 patients treated without biological DMARDs but with MTX (MTX group), met criterion B (max. KL-6 ≥500 U/ml and >1.5-fold from baseline) by 12 months. The majority of patients (n = 28) meeting criterion B had no apparent interstitial lung disease or malignancy. Of these 28 patients, 21 had serum KL-6 levels available after reaching their maximum level, and 13 (61.9 %) of the 21 then met criterion R [decrease to less than 500 U/ml or to less than (baseline + 0.5 × (maximum - baseline))] by month 12., Conclusion: Serum KL-6 levels may increase during treatment with MTX or these biological DMARDs without significant clinical events.

We retrospectively investigated the ability of adalimumab (ADA) to reduce disease activity, improve physical function, and retard the progression of structural damage in 167 patients with rheumatoid arthritis. Clinical and functional outcomes were compared between patients with or without prior biologic treatment and those with or without concomitant methotrexate (MTX) treatment. At week 52, 38.3% achieved clinical remission: 42.4 and 28.6% of patients achieved remission in those without and with previous biologics, respectively, while 42.7 and 12.5% of patients achieved remission in those with and without concomitant MTX, respectively. ADA treatment significantly reduced the rate of radiographic progression from 27.1 ± 46.0 (median 13.6; 25th-75th percentiles 8.3 to 28.9) at baseline to 0.8 ± 5.0 (median 0.0; 25th-75th percentiles -0.9 to 2.0) at week 52 (P < 0.0001). Radiographic progression was absent in 59.8% of patients. Sixty adverse events (34.21/100 patient-years) were reported, 16 of which were serious (9.12/100 patient-years). ADA therapy is highly effective for reducing disease activity, improving physical function, and limiting radiographic progression. It is generally safe and well tolerated by Japanese RA patients in routine clinical practice.

Despite numerous attempts to uncover the mechanism of other iatrogenic immunodeficiency-associated lymphoproliferative diseases (OIIA-LPDs), this mechanism remains poorly understood, especially in rheumatoid arthritis (RA) patients. We analyzed the data on 23 patients with LPDs and RA. Patients were categorized into three groups according to whether they had methotrexate (MTX); MTX-regressive LPDs, MTX-persistent LPDs or other drugs-mediated LPDs. The LPDs seen in OIIA-LPDs-RA might have a unique behavior to think about several rare phenotypes. The overall survival of all patients was 74% at 5 years, and those of the three groups were 100%, 64% and 60%, respectively. Among the 6 patients who died, 4 had LPDs that were detected late, and thus adequate treatment was not given. In addition, several patients with diffuse large B cell lymphoma with a complex karyotype achieved complete remission (CR). Only one among the 17 patients who achieved CR relapsed. OIIA-LPDs-RA appeared to have a better prognosis than other more common types of lymphomas. Regarding RA treatment, various anti-RA drugs were given to the patients after developing LPDs, including MTX, but no recurrent patients were documented.