Search

Background Thoracoabdominal aneurysm repair is a highly complicated procedure, especially among patients with severe lung disease, resulting in respiratory problems during and after the surgery. Herein, we designed a novel intraoperative respiratory support to address this. Case presentation An open thoracoabdominal aortic aneurysm repair was performed on a 65-year-old man who had severe chronic obstructive pulmonary disease with a giant right lung bulla. One-and-a-half lung ventilation by left lower lobe blockade was maintained during the operation to avoid right barotrauma. Cardiopulmonary bypass (CPB) was established with venous cannulas in the right internal jugular vein and left femoral vein for elective venovenous extracorporeal membrane oxygenation (VV-ECMO). After aortic repair and withdrawal from CPB, the VV-ECMO was consecutively initiated using the same circuit by connecting the arterial cannula to the right internal jugular venous cannula. The patient maintained adequate oxygenation during hemostasis under the support of VV-ECMO after protamine was administered. He was weaned from VV-ECMO in the operating room and discharged without any complications. Conclusion Partial bronchial blockage and intraoperative VV-ECMO using the same circuit of CPB were useful methods for severe lung disease during a thoracoabdominal aortic repair.

Rheumatoid factor (RF) binds to the fragment crystallizable (Fc) portion of immunoglobulin. It could bind to the Fc portion of anti-TNF inhibitors (TNFi) and attenuate the clinical efficacy. We tried to determine whether the therapeutic efficacy of TNFi with Fc might be lower than that of TNFi without Fc in rheumatoid arthritis (RA) patients with high titres of RF. The Kansai Consortium for Well-being of Rheumatic Disease Patients (ANSWER) cohort is an observational multi-center registry of patients with RA in the Kansai district of Japan. RA patients treated with TNFi were included and divided into two groups based on the structural characteristics between TNFi with Fc (infliximab, adalimumab, golimumab, and etanercept) and TNFi without Fc (certolizumab pegol). Patients were classified into 4 groups according to RF titre quartiles. The sequential disease activity score in 28 joints using erythrocyte sedimentation rate (DAS28-ESR) was compared by Mann-Whitney U test between TNFi with and without Fc in each RF titre group. Multiple linear regression analysis was used to analyze the effect of TNFi without Fc for the change of DAS28-ESR adjusted after potential confounders. A total of 705 RA patients were classified into four groups (RF

The aim of this multi-centre retrospective study was to clarify the prognostic factors for respiratory-related death in patients with interstitial lung disease (ILD) complicated rheumatoid arthritis (RA). Patient background data, treatment regimen, and disease activity indicators of RA and ILD at baseline, 6 months after the diagnosis of ILD, and at the last follow-up visit were extracted. A total of 312 patients with RA-ILD (17 patients who died from respiratory-related causes and 295 survivors) were included. Patients who died from respiratory-related causes had an older median age, a higher proportion of being male, and a higher anti-cyclic citrullinated peptide antibody positivity rate than survivors (p = .0001, .038, and .016, respectively); they also had significantly higher baseline serum levels of Krebs von den Lungen-6 (KL-6) than survivors (p = .013). Patients who died from respiratory-related causes showed significantly greater changes in serum KL-6 levels between the 6-month time point and the last visit [ΔKL-6 (6 months − last)] than survivors (p = .011). Multivariate analysis showed that the ΔKL-6 (6 months − last) corrected by disease duration was a predictor of respiratory-disease-related death in patients with RA-ILD (p

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

ObjectivesThis multicenter, retrospective study evaluated the effectiveness of add-on methotrexate (MTX) or iguratimod (IGU) in patients with rheumatoid arthritis exhibiting an inadequate response to Janus kinase inhibitors (JAKis).MethodsForty-five patients were treated with new additional MTX (n = 22) or IGU (n = 23) and followed for 6 months. Patients’ background is as follows: age, 59.2 years; disease activity score of 28 joints with C-reactive protein (DAS28-CRP), 3.4; clinical disease activity index, 15.7; biological disease-modifying antirheumatic drug (DMARD)-switched cases, 77.8%; first JAKi cases, 95.6%; and JAKi treatment: tofacitinib (n = 25), baricitinib (n = 17), upadacitinib (n = 2), and peficitinib (n = 1) for 9.6 months.ResultsThirty-five patients continued the combination therapy for 6 months without a significant change in concomitant glucocorticoid or other conventional synthetic DMARDs. DAS28-CRP (MTX, 3.6 to 2.6, p ConclusionsAdding MTX or IGU to inadequate responders of JAKi can be considered as a complementary treatment.

The objective of the study was to compare the efficacy and safety of biological disease-modifying antirheumatic drugs (bDMARDs) between elderly-onset rheumatoid arthritis (EORA) and young-onset rheumatoid arthritis (YORA) patients. Patients with rheumatoid arthritis (RA) aged ≧18 years enrolled in a Japanese multicenter observational registry between 2009 and 2018 who had moderate or high disease activity when initiating bDMARDs were included. EORA was defined as RA with onset at 60 or over. After propensity score weighting for differences in confounding factors, generalized estimating equations were used to assess the relationship between the age of RA onset and bDMARD clinical effectiveness at 48 weeks after starting a bDMARD. Among a total of 7183 patients in the registry, 2815 (39.2%) were identified as EORA. The proportion of patients on bDMARDs was lower in the EORA as compared to the YORA (18.3% vs 28.0%, p

The aim of this multicenter, retrospective study was to clarify the retention of secondary biological disease-modifying antirheumatic drugs (bDMARDs) or Janus kinase inhibitors (JAKi) in patients with rheumatoid arthritis (RA) who were primarily treated by tocilizumab (TCZ) or abatacept (ABT) as first bDMARDs.Patients who were treated by either TCZ (n = 145) or ABT (n = 76) and then switched to either tumor necrosis factor inhibitors (TNFi), TCZ, ABT, or JAKi (including only cases switched from TCZ) from 2001 to 2019 (female 81.0%, age 59.5 years, disease duration 8.8 years; rheumatoid factor positivity 75.4%; Disease Activity Score in 28 joints using C-reactive protein 3.7; concomitant prednisolone (PSL) dose 6.0 mg/day (51.8%) and methotrexate (MTX) dose 8.0 mg/week (56.1%); 81.9% discontinued first bDMARDs due to lack of effectiveness) were included. Drug retention and discontinuation reasons were estimated at 24 months using the Kaplan-Meier method and adjusted for potential confounders by Cox proportional hazards modeling.Drug retentions for each of the reasons for discontinuation were as follows: lack of effectiveness in TCZ-switched group (TNFi (59.5%), ABT (82.2%), and JAKi (84.3%); TNFi vs. ABT; P = 0.009) and ABT-switched group (TNFi (79.6%) and TCZ (92.6%); P = 0.053). Overall retention excluding non-toxic reasons and remission for discontinuation were TNFi (49.9%), ABT (72.7%), and JAKi (72.6%) (TNFi vs. ABT; P = 0.017) in the TCZ-switched group and TNFi (69.6%) and TCZ (72.4%) (P = 0.44) in the ABT-switched group.Switching to ABT in TCZ-treated patients led to higher retention as compared with TNFi. Switching to TCZ in ABT-treated patients tended to lead to higher retention due to effectiveness, although total retention was similar as compared with TNFi. Key Point • This is the first retrospective, multi-center study aimed to clarify the retention rates of secondary bDMARDs or JAKi in patients with RA who were primarily being treated by TCZ or ABT as the first bDMARDs.

Currently, biological disease-modifying anti-rheumatic drugs (bDMARDs) with different modes of action [tumour necrosis factor inhibitor (TNFi), interleukin-6 receptor inhibitor (IL-6Ri), or cytotoxic T-lymphocyte antigen 4–immunoglobulin (CTLA4-Ig)] are used in clinical practice to treat rheumatoid arthritis (RA). However, it is unclear which type of bDMARD is the most efficacious for a specific clinical situation. C-reactive protein (CRP) is an acute-phase reactant driven by IL-6 signalling. Here, we aimed to establish whether therapeutic efficacy differs between IL-6Ri and other bDMARDs with alternative modes of action in RA patients according to their CRP level. RA patients treated with bDMARDs were enrolled from an observational multicentre registry in Japan. Patients were classified into three groups according to baseline CRP tertiles. The overall 3 year retention rates of each bDMARD category were assessed. The Clinical Disease Activity Index (CDAI) was also assessed before and 3, 6, and 12 months after bDMARD initiation. A total of 1438 RA patients were included and classified into three groups according to tertiles of baseline CRP levels (CRP1, 0–0.3; CRP2, 0.3–1.8; CRP3, 1.8–18.4 mg/dL). In CRP3, the overall 3 year drug retention rates were significantly higher for IL-6Ri than for TNFi and CTLA4-Ig (77.5 vs 48.2 vs 67.3, respectively). No significant difference was evident in terms of CDAI 12 months after bDMARD initiation in CRP1–CRP3. IL-6Ri may be a favourable therapeutic option over TNFi and CTLA4-Ig in RA patients with high CRP levels.

Background: This multi-center, retrospective study aimed to clarify the factors affecting drug retention of the Janus kinase inhibitors (JAKi) baricitinib (BAR) and tofacitinib (TOF) in patients with RA.Methods: Patients were included as follows: females, 80.6%; age, 60.5 years; DAS28-ESR, 4.3; treated with either BAR (n = 166) or TOF (n = 185) and concomitant glucocorticoid (prednisolone [PSL] equivalent) 5.3 mg/day (46.7%) or methotrexate (MTX) 8.9 mg/week (60.7%); bDMARDs- or JAKi-switched cases (76.6%). The reasons for drug discontinuation were classified into four major categories: lack of effectiveness, toxic adverse events, non-toxic reasons and remission. The drug retention rate was estimated at 24 months using the Kaplan–Meier method and adjusted for potential confounders using multivariate Cox proportional hazards modelling.Results: Adjusted discontinuation rates for the corresponding reasons were as follows: lack of effectiveness (22.3%), toxic adverse events (13.3%), non-toxic reasons (7.2%) and remission (0.0%). Prior use of anti-interleukin-6 receptor antibody (aIL-6R) was significantly associated with discontinuation due to lack of effectiveness (P = 0.021). Ageing (P = 0.015), usage of PSL ≥5 mg/day (P = 0.017) and female sex (P = 0.041) were significantly associated with discontinuation due to toxic adverse events. Factors not associated with treatment discontinuation were: number of prior bDMARDs or JAKi, concomitant MTX usage, different JAKi and prior use of TNF inhibitor, CTLA4-Ig or other JAKi.Conclusions: Prior use of aIL-6R was associated with discontinuation due to lack of effectiveness, while ageing (≥75 years), PSL usage ≥5 mg/day, and female sex were associated with discontinuation due to toxic adverse events.

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

Triangular [Mo3S4] clusters are known to serve as platforms to accommodate a metal atom M, furnishing cubic [Mo3S4M] clusters. In this study, three [Mo3S4] clusters supported by η5-cyclopentadienyl...

N2 fixation by Nature, which is a crucial process to supply bio-available forms of nitrogen, is performed by nitrogenase. This enzyme employs a unique transition metal-sulfur-carbon cluster as its active-site cofactor ([(R-homocitrate)MoFe7S9C], FeMoco), and the sulfur-surrounded Fe atoms have been postulated to capture and reduce N2. Whereas synthetic counterparts of FeMoco, metal-sulfur clusters, have displayed binding of N2 in a few examples, the reduction of N2 by any synthetic metal-sulfur clusters or even by the extracted form of FeMoco have remained elusive despite a near-50-year history of research. Here we show that the Fe atoms in our synthetic [Mo3S4Fe] cubes capture an N2 molecule and catalyze N2 silylation to form N(SiMe3)3 under treatment with excess Na and Me3SiCl. These results exemplify the first catalytic N2 reduction by a synthetic metal-sulfur cluster with an Fe center supported only by S ligands. This work demonstrates the N2-reducing capability of Fe atoms in a S-rich environment, which Nature has selected to accomplish a similar purpose. This work also suggests some critical features for successful by metal-sulfur compounds, which serve as clues to understand the origin of N2 fixation on Earth.

Nitrogen (N

Background This multi-center, retrospective study aimed to clarify retention rates and reasons for discontinuation of either tumor necrosis factor inhibitors (TNFi) or interleukin-6 inhibitors (IL-6i) in patients with elderly-onset rheumatoid arthritis (EORA). Methods Patients with rheumatoid arthritis (RA) enrolled in a Japanese multicenter observational registry between 2011 and 2020 were included. EORA was defined as RA with onset at 60 or over. To adjust confounding by indication for treatment with TNFi or IL-6i, a propensity score based on multiple baseline characteristics variables was used to compare the drug retention and causes for discontinuation between TNFi and IL-6i. Adjusted cumulative incidence of drug discontinuation for each reason was compared between the two groups using the Fine-Gray model. Results Among a total of 9,550 patients in the registry, 674 TNFi and 297 IL-6i initiators with EORA were identified. Age, the proportion of females, disease duration, and baseline disease activity at the time of TNFi or IL-6i initiation were similar between the two groups. After adjusting for differences in baseline characteristics between the two groups, overall drug discontinuation was significantly lower in the IL-6i as compared to the TNFi (HR = 0.71, 95%CI = 0.59–0.86, p p p = 0.28) or achievement of clinical remission (HR = 1.09, 95%CI = 0.62–1.91, p = 0.76) were similar between the two groups. Conclusions In EORA patients initiating a TNFi or IL-6i, significantly higher drug retention was observed with IL-6i. Discontinuation due to lack of effectiveness was significantly less frequent in IL-6i while discontinuations due to adverse event or achievement of clinical remission were similar between the two groups.

We aimed to investigate the efficacy of anti-IL-6 receptor antibody (aIL-6) and other biologic disease-modifying antirheumatic drugs (bDMARDs), such as TNF inhibitor and CTLA4-Ig in the treatment of rheumatoid arthritis (RA) in patients with knee joint involvement. We retrospectively analyzed 1059 treatment courses of patients with RA who visited our hospitals and were treated with bDMARDs. We categorized them into two groups, with or without knee joint involvement. We investigated the clinical disease activity index (CDAI) at baseline and 12 weeks after the initiation of bDMARDs. We compared the improvement of the markers between aIL-6 and other bDMARDs. Treatment with aIL-6 significantly increased ΔCDAI (n = 91, 15.4 ± 1.1; mean ± SEM) in patients with knee joint involvement, compared to other bDMARDs (n = 232, 11.0 ± 0.7) at 12 weeks (P = 0.006). Following the multivariate analysis adjusted by the CDAI levels at baseline, age, gender, concomitant use of methotrexate, and the first use of bDMARDs, ΔCDAI levels were significantly higher in aIL-6, compared to other bDMARDs (P = 0.02). However, there was no significant difference in ΔCDAI improvement between aIL-6 (n = 162, 5.9 ± 0.6) and other bDMARDs (n = 573, 6.2 ± 0.4) in patients without swollen knee joints. ΔCDAI levels were equally increased in patients with shoulder and elbow joint involvement. aIL-6 was more effective in the patients with RA and knee joint involvement, compared to other bDMARDs.

Background: This multi-center, retrospective study aimed to clarify retention rates and reasons for discontinuation of either Tumor Necrosis Factor inhibitors (TNFi) or Interleukin-6 Inhibitors (IL-6i) in patients with elderly-onset rheumatoid arthritis (EORA).Methods: Patients with rheumatoid arthritis (RA) enrolled in a Japanese multicenter observational registry between 2011 and 2020 were included. EORA was defined as RA with onset at 60 or over. To adjust confounding by indication for treatment with TNFi or IL-6i, a propensity score based on multiple baseline characteristics variables was used to compare the drug retention and causes for discontinuation between TNFi and IL-6i. Adjusted cumulative incidence of drug discontinuation for each reason was compared between the two groups using the Fine-Gray model. Results: Among a total of 9550 patients in the registry, 674 TNFi and 297 IL-6i initiators with EORA were identified. Age, the proportion of females, disease duration, and baseline disease activity at the time of TNFi or IL-6i initiation were similar between the two groups. After adjusting for differences in baseline characteristics between the two groups, overall drug discontinuation was significantly lower in the IL-6i as compared to the TNFi (HR=0.71, 95%CI=0.59-0.86, p

The aim of this multicenter, retrospective study was to clarify the retention rates of sarilumab (SAR), baricitinib (BAR), and tofacitinib (TOF) in patients with rheumatoid arthritis (RA).Patients treated with either SAR (n = 62), BAR (n = 166), or TOF (n = 185) (females, 80.9%; age, 61.0 years; disease duration, 11.1 years; rheumatoid factor positivity, 84.4%; Disease Activity Score in 28 joints using erythrocyte sedimentation rate, 4.3; concomitant prednisolone dose, 5.3 mg/day [47.0%] and methotrexate dose, 8.8 mg/week [58.4%]; biologics- or Janus kinase inhibitors-switched cases 78.4%) were included. The reasons for drug discontinuation were classified into 4 major categories (lack of effectiveness, toxic adverse events, non-toxic reasons, and remission) by each attending physician. The drug retention rate was estimated at 18 months using the Kaplan-Meier method and adjusted for potential confounders by Cox proportional hazards modeling.The discontinuation rates of SAR, BAR, and TOF for the corresponding reasons were as follows, respectively: lack of effectiveness (15.7%, 15.6%, and 21.5%; P = 0.84), toxic adverse events (15.8%, 12.1%, and 12.3%; P = 0.35), non-toxic reasons (10.9%, 7.7%, and 6.8%; P = 0.35), and remission (0.0%, 2.8%, and 0.0%; P = 1.0). The overall retention rates excluding non-toxic reasons and remission were as follows: 68.8% for SAR, 72.5% for BAR, and 66.7% for TOF (P = 0.54).After adjustment by potent confounders, SAR, BAR, and TOF showed similar discontinuation rates due to lack of effectiveness and toxic adverse events. Key Points • This is the first retrospective multicenter study that aimed to clarify the retention rates and reasons for discontinuation of SAR, BAR, and TOF in patients with RA.

Background: Rheumatoid factor (RF) binds to the Fc portion of immunoglobulin and can bind to the Fc portion of anti-TNF monoclonal antibodies (TNFi), attenuating their clinical efficacy. We tried to determine whether the therapeutic efficacy is different between TNFi with or without the immunoglobulin Fc portion in rheumatoid arthritis (RA) patients depending upon the RF titres.Methods: RA patients treated with TNFi were enrolled from an observational multi-centre registry in Japan. TNFi treatments were divided into two groups based on the structural characteristics between TNFi with Fc (infliximab, adalimumab, golimumab, etanercept) and TNFi without Fc (certolizumab-pegol). Patients were classified into 4 groups according to RF titre quartiles. The sequential disease activity score in 28 joints using erythrocyte sedimentation rate (DAS28-ESR) were compared by the Mann-Whitney U test between TNFi with and without the immunoglobulin Fc portion in each RF titre group.Results: A total of 705 RA patients were included and classified into four groups according to quartiles of baseline RF titres (RF1; RF 0-15.0 IU/mL, RF2; 15.0-55.0, RF3; 55.0-166, RF4; 166-7555). In RF4, RA patients treated with TNFi without Fc had a significantly lower DAS28-ESR than those treated with TNFi with Fc (3.2 (2.3-4.2) vs. 2.7 (2.0-3.0)) (median, IQR) after 12 months of follow-up, while there were no significant differences in RF1, RF2, and RF3.Conclusion: TNFi without Fc (certolizumab-pegol) may be more efficacious than TNFi with Fc in RA patients with high RF titres.

Background Japan has now become a super-aged society. Notably, as the Japanese society ages, the prevalence of falls, which represent an aging-related problem, has increased. Locomotive syndrome (LS) is a condition of decreased mobility due to locomotive organ disorder. The loco-check is simple tool to detect early-stage LS. The loco-check comprises seven items relating to daily activities. Higher numbers of affirmative answers in the loco-check are negatively associated with physical functions. The purpose of this study was to examine the potential correlation between the number of affirmative answers given on the “loco-check” survey and the likelihood of experiencing at least one fall during the following one-year period. Methods This prospective study included 154 cases (35 men, 119 women), all aged 65 years or older, answered the loco-check at baseline. As part of their normal treatment process, the participants made monthly visits to the out-patient department; thus, at each of these visits for the following 12 months a medical doctor interviewed each patient to determine whether they had experienced a fall during the previous month. Results The mean age of the sample was 77.3 years, and the median number of affirmative answers given was 2.0. The number of affirmative answers significantly correlated with the cases which had a fall event within the follow-up period. Specifically, an increase in one “yes” answer on the loco-check increased the relative risk of fall (odds ratio: 1.32; 95% Confidence interval (CI): 1.03–1.70). In addition, the risk of fall was high in cases which showed the number of affirmative answers given on the loco-check ≥4 (odds ratio: 9.26; 95% CI: 1.05–81.7). Conclusion The number of affirmative answers given on the loco-check is positively correlated with a fall event within the following year.

A synthetic protocol was developed for a series of cubane-type [Mo3 S4 M] clusters that incorporate halides of first-row transition metals (M) from Groups 4-10. This protocol is based on the anionic cluster platform [Cp*3 Mo3 S4 ]- ([1]- ; Cp*=η5 -C5 Me5 ), which crystallizes when K(18-crown-6) is used as the counter cation. Treatment of in situ-generated [1]- with such transition-metal halides led to the formation of [Mo3 S4 M] clusters, in which the M/halide ratio gradually changes from 1:2 to 1:1.5 and to 1:1, when moving from early to late transition metals. This trend suggests a tendency for early transition metals to tolerate higher oxidation states and adopt larger ionic radii relative to late transition metals. The properties of the [Mo3 S4 Fe] cluster 6 a were investigated in detail by using 57 Fe Mossbauer spectroscopy and computational methods.

Background Tapering of biological disease-modifying anti-rheumatic drugs (DMARDs) is recommended by European League Against Rheumatism (EULAR) in patients with stable rheumatoid arthritis (RA) disease activity. Discontinuation of biological DMARDs can be successful in some patients. However, the predictive factors enabling established patients with RA to remain free of biological DMARDs is unclear. Recently, ultrasonography (US) has become an important imaging tool to identify subclinical synovitis, even in patients with remission. There have been few reports on whether residual synovitis as shown by US can predict relapse of disease activity after discontinuation of biological DMARDs. Objectives We aimed to investigate the usefulness of US for predicting relapse in patients in remission for RA after discontinuation of adalimumab (ADA). Methods Patients who were using ADA and in remission (Disease Activity Score 28-joint count C reactive protein (DAS28-CRP) Results Fifty-three patients were included. Ten (18.9%) patients relapsed up to week 24 and 20 (37.7%) patients relapsed up to 52 weeks. The relapsed patients tended to have a long disease duration, but baseline US findings could not predict relapse. Increases in the PD score were observed during follow-up in some relapsed patients. Disease activity control was good after ADA was restarted in the relapsed group, and there was no difference in progression of the mTSS in the relapsed and non-relapsed groups. Conclusion Predicting relapse by baseline US findings after discontinuation of ADA in remission is difficult. However, an increased PD score in a following US examination might be useful for early detection of relapse. Radiographic progression is not significantly different in patients with relapse and those without relapse. References [1] Iwamoto T, Ikeda K, Hosokawa J, et al. Prediction of relapse after discontinuation of biologic agents by ultrasonographic assessment in patients with rheumatoid arthritis in clinical remission: high predictive values of total gray-scale and power Doppler scores that represent residual synovial inflammation before discontinuation. Arthritis Care Res (Hoboken). 2014;66:1576-81. Disclosure of Interests Tadashi Okano Speakers bureau: AbbVie, Ryota Hara: None declared, Makoto Wada: None declared, Tatsuya Koike Speakers bureau: AbbVie, Astellas Pharma Inc., Bristol-Myers Squibb, Chugai Pharmaceutical, Eisai, Janssen, Lilly, Mitsubishi Tanabe Pharma Corporation, MSD, Ono Pharmaceutical, Pfizer, Roche, Takeda Pharmaceutical, Teijin Pharma, and UCB, Kenji Mamoto: None declared, Yuko Sugioka: None declared, Masahiro Tada Speakers bureau: Abbvie, Astellas Pharma, Bristol-Myers Squibb, Chugai Pharmaceutical, Eisai, Janssen Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical, Pfizer Japan, Takeda Pharmaceutical , Takanori Fujimura: None declared, Sho Sendo: None declared, Takaichi Okano: None declared, Yoshihide Ichise: None declared, Ikuko Naka: None declared, Heiseki Yu: None declared, Akihiko Nakabayashi: None declared, Yoshinobu Matsuura: None declared, Takahiro Yoshikawa: None declared, Masao Tamura: None declared, Masayasu Kitano: None declared, Yasuhide Kanayama: None declared

Objective.To investigate whether abatacept (ABA) causes more adverse events (AE) than conventional synthetic disease-modifying antirheumatic drugs (csDMARD) after orthopedic surgery in patients with rheumatoid arthritis (RA).Methods.A retrospective multicenter nested case–control study was performed in 18 institutions. Patients receiving ABA (ABA group) were matched individually with patients receiving csDMARD and/or steroids (control group). Postoperative AE included surgical site infection, delayed wound healing, deep vein thrombosis or pulmonary embolism, flare, and death. The incidence rates of the AE in both groups were compared with the Mantel-Haenszel test. Risk factors for AE were analyzed by logistic regression model.Results.A total of 3358 cases were collected. After inclusion and exclusion, 2651 patients were selected for matching, and 194 patients in 97 pairs were chosen for subsequent comparative analyses between the ABA and control groups. No between-group differences were detected in the incidence rates of each AE or in the incidence rates of total AE (control vs ABA: 15.5% vs 20.7% in total, 5.2% vs 3.1% in death).Conclusion.Compared with csDMARD and/or steroids without ABA, adding ABA to the treatment does not appear to increase the incidence rates of postoperative AE in patients with RA undergoing orthopedic surgery. Large cohort studies should be performed to add evidence for the perioperative safety profile of ABA.

Background The aim of this study is to evaluate the retention rates and reasons for discontinuation for seven biological disease-modifying antirheumatic drugs (bDMARDs) in a real-world setting of patients with rheumatoid arthritis (RA). Methods This multi-center, retrospective study assessed 4466 treatment courses of 2494 patients with bDMARDs from 2009 to 2017 (females, 82.4%; baseline age, 57.4 years; disease duration 8.5 years; rheumatoid factor positivity 78.6%; Disease Activity Score in 28 joints using erythrocyte sedimentation rate, 4.3; concomitant prednisolone (PSL) 2.7 mg/day (43.1%) and methotrexate (MTX) 5.0 mg/week (61.8%); and 63.6% patients were bio-naïve). Treatment courses included tocilizumab (TCZ; n = 895), etanercept (ETN; n = 891), infliximab (IFX; n = 748), abatacept (ABT; n = 681), adalimumab (ADA; n = 558), golimumab (GLM; n = 464), and certolizumab pegol (CZP; n = 229). Drug retention rates and discontinuation reasons were estimated at 36 months using the Kaplan-Meier method and adjusted for potential confounders (age, sex, disease duration, concomitant PSL and MTX, and switched number of bDMARDs) using Cox proportional hazards modeling. Results A total of 56.9% of treatment courses were stopped, with 25.8% stopping due to lack of effectiveness, 12.7% due to non-toxic reasons, 11.9% due to toxic adverse events, and 6.4% due to disease remission. Drug retention rates for each discontinuation reason were as follows: lack of effectiveness [from 65.5% (IFX) to 81.7% (TCZ); with significant differences between groups (Cox P

Triangular [Mo

Systemic amyloid A (AA) amyloidosis secondary to rheumatoid arthritis (RA) is a serious complication, often leading to end-stage renal disease (ESRD) or death. Intervention with biologic agent, which has brought a paradigm shift in the treatment of RA, may improve the prognosis of AA amyloidosis. Among RA patients in ANSWER Cohort in Japan, 11 patients with biopsy-proven AA amyloidosis were identified and retrospectively investigated. Median age at the diagnosis of AA amyloidosis was 64 years and median disease duration of RA was 16 years. ESRD occurred in 5 patients, and 3 of them died. Seven patients received the treatment with biologic agents. Poor prognosis such as ESRD or death was associated with advanced renal dysfunction, insufficient anti-inflammatory treatment and longer disease duration of RA, whereas good prognosis was associated with no renal involvement or mild renal dysfunction, and the use of biologic agents. This observation, along with presentations of all identified cases, suggests the importance of disease control during mild kidney damage using potent anti-inflammatory drug such as biologic agent to improve prognosis..

A 66-year-old man underwent nephrectomy for right renal cell carcinoma (cT3bNOMl (PUL)). Thereafter, he was treated with sunitinib for lung metastasis as the first-line therapy for 5 months and then axitinib as the second-line therapy for 2 months. Because lung metastasis progressed despite molecular targeted therapies, nivolumab was used as the third-line treatment. Three months later, he complained of painful stiffness in hands and wrist joints symmetrically. He was diagnosed as having rheumatoid arthritis. Treatment with nivolumab was discontinued and prednisolone and methotrexate were started. Although the painful stiffness in joints was improved l month later, synovitis remained partially 6 months after starting treatment of disease with anti-rheumatic drugs. Therefore, treatment for rheumatoid arthritis was continued. On the other hand, because the lung lesion had progressed 2 months after discontining nivolumab, everolimus was used as the fourth-line therapy.

Background:A number of previous reports suggested that obesity is one of the baseline factors indicates refractory to biologic disease-modifying antirheumatic drugs (bDMARDs). However, difference of the significant responses appears on obesity patients depending on each kind of drug is yet unclear. However, it is yet unclear how the significant responses on obesity patients vary on each kind of drug.Objectives:To assess whether obesity affects clinical outcome in rheumatoid arthritis (RA) treated with each molecular-targeted agent including bDMARDs and tofacitinib.Methods:In Kansai consortium for well-being of rheumatic disease patients (ANSWER) cohort, which was the real-world retrospective cohort of clinical database for rheumatic diseases, RA patients who initiated biological / targeted disease modifying anti-rheumatic drugs were included and consecutively followed. Obesity was defined as BMI over than 25, and patients were divided between obese (“Ob”) and non-obese (“non-Ob”) patients. SDAI (simplified disease activity index) was compared between non-Ob and Ob at month 0, 3, 6, 9, 12 after the indicated drugs were administered. Using logistic regression analysis, odds ratio (OR) and their corresponding 95% confidence intervals (95% CIs) were further calculated to estimate achievement rate of SDAI remission defined as lower than 3.3 by obesity and other relevant clinical parameters. Once after the drugs were discontinued by any unfavorable reason, disease activities were no more scored and the Last Observation Carried Forward (LOCF) imputation method was used for SDAI at month 3 and thereafter.Results:A total of 1936 patients met in the inclusion criteria were under the analysis. In each drug, SDAI remission rate (non-Ob, Ob, p-value by Chi-square test) at month 12 was as follows; Infliximab (IFX, n=135): 43%, 38%, NS (not significant); Etanercept (ETN, n=188): 44%, 19%, p=0.0122; Adalimumab (ADA, n=169): 50%, 56%, NS; Golimumab (GLM, n=315): 36%, 30%, NS; Certolizumab pegol (CZP, n=131): 33%, 56%, p=0.0287; Tocilizumab (TCZ, n=423): 41%, 29%, p=0.0456; Abatacept (ABT, n=144): 26%, 23%, NS; Tofacitinib (TOF, n=69): 27%, 23%, NS. In multivariate analysis to predict SDAI remission at month 12, obesity was an independent protective factor in CZP (OR: 0.29, 95% CIs: 0.10 – 0.83), but was an independent risk factor in TCZ (OR: 1.9, 95% CIs: 1.01 – 3.61) irrespective of age, sex, disease duration, SDAI at month 0 or number of previous bDMARDs. Any other drug including ETN did not show significant result between non -Ob and Ob in the multivariate analysis.Conclusion:Obese patients were more resistant to TCZ but more effective in CZP than non-obese patients.References:[1]Ann Rheum Dis. 2018;77(10):1405-1412. Joint Bone Spine. 2019;86(2):173-183.Disclosure of Interests:Kosaku Murakami Speakers bureau: AbbVie, Eisai, and Mitsubishi Tanabe Pharma., Motomu Hashimoto Grant/research support from: Bristol-Myers Squibb, Eisai, and Eli Lilly and Company., Speakers bureau: Bristol-Myers Squibb and Mitsubishi Tanabe Pharma., Koichi Murata Grant/research support from: KMurata belong to a department that has been financially supported by four pharmaceutical companies (Mitsubishi-Tanabe, Chugai, AYUMI and UCB Japan)., Employee of: KMurata belong to a department that has been financially supported by four pharmaceutical companies (Mitsubishi-Tanabe, Chugai, AYUMI and UCB Japan)., Speakers bureau: KMurak has received speaking fees, and/or consulting fees from Eisai Co. Ltd, Chugai Pharmaceutical Co. Ltd., Pfizer Japan Inc, Bristol-Myers Squibb, Mitsubishi-Tanabe Pharma Corporation, UCB, Daiichi Sankyo Co. Ltd. and Astellas Pharma Inc., Wataru Yamamoto: None declared, Ryota Hara Speakers bureau: RH received a speaker fee from AbbVie, Masaki Katayama: None declared, Akira Onishi Speakers bureau: AO received a speaker fee from Chugai, Ono Pharmaceutical, Eli Lilly, Mitsubishi-Tanabe, Asahi-Kasei, and Takeda, Kengo Akashi: None declared, Koji Nagai: None declared, Yonsu Son: None declared, Hideki Amuro: None declared, Toru Hirano Grant/research support from: TH received a research grant and/or speaker fee from Astellas, Chugai, Nippon Shinyaku, Abbvie, Eisai, and Ono Pharmaceutical, Speakers bureau: TH received a research grant and/or speaker fee from Astellas, Chugai, Nippon Shinyaku, Abbvie, Eisai, and Ono Pharmaceutical, Kosuke Ebina Grant/research support from: KE has received research grants from Abbie, Asahi-Kasei, Astellas, Chugai, Eisai, Ono Pharmaceutical, and UCB Japan., Employee of: KE is affiliated with the Department of Musculoskeletal Regenerative Medicine, Osaka University, Graduate School of Medicine, which is supported by Taisho., Speakers bureau: KE has received payments for lectures from Abbie, Asahi-Kasei, Astellas, Ayumi, Bristol-Myers Squibb, Chugai, Eisai, Eli Lilly, Janssen, Mitsubishi-Tanabe, Ono Pharmaceutical, Sanofi, and UCB Japan., Kohei Nishitani Grant/research support from: KN belong to a department that has been financially supported by four pharmaceutical companies (Mitsubishi-Tanabe, Chugai, AYUMI and UCB Japan)., Masao Tanaka Grant/research support from: AbbVie, Asahi Kasei Pharma, Astellas Pharma, Ayumi Pharmaceutical, Chugai Pharmaceutical, Eisai, Mitsubishi Tanabe Pharma, Taisho Pharmaceutical, and UCB Japan., Speakers bureau: AbbVie, Asahi Kasei Pharma, Astellas Pharma, Bristol-Myers Squibb, Chugai Pharmaceutical, Eisai, Eli Lilly and Company, Janssen Pharmaceutical, Mitsubishi Tanabe Pharma, Novartis Pharma, Pfizer, Taisho Pharmaceutical, Takeda Pharmaceutical, and UCB Japan., Hiromu Ito: None declared, Koichiro Ohmura Grant/research support from: Astellas Pharma, AYUMI Pharmaceutical, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Japan Blood Products Organization, Mitsubishi Tanabe Pharma, Nippon Kayaku, Nippon Shinyaku, Sanofi, and Takeda Pharmaceutical., Speakers bureau: AbbVie, Actelion Pharmaceuticals Japan, Asahi Kasei Pharma, AYUMI Pharmaceutical, Bristol-Myers Squibb, Chugai Pharmaceutical, Eisai, Eli Lilly and Company, GlaxoSmithKline, Janssen Pharmaceutical, Mitsubishi Tanabe Pharma, Novartis Pharma, and Sanofi.

Background:It has been reported that rheumatoid arthritis (RA) patients who have large joint involvement associated with higher serological inflammatory markers and more functional disability1. Moreover, a previous report showed that these patients were more difficult to achieve clinical remission. However, it remains unclear which biologics are effective in the patients with RA who have large joint involvement.Objectives:The aim of this study is to investigate the efficacy of anti-IL-6 receptor antibody (aIL-6) or TNF-inhibitor (TNFi) in the treatment of RA patients who have knee joint involvement.Methods:We enrolled the 784 patients who visited our hospitals in 2003 to 2019 and were treated with aIL-6 or TNFi more than 12 weeks. We divided the patients into 2 groups with or without knee joint involvement for further analysis. Knee joint involvement was defined as the patients had at least one swelling joint of knee at baseline. We investigated the CDAI levels at baseline and 12 weeks after the initiation of biologics.Results:Interestingly, the patients who had knee joint involvement with aIL-6 significantly ameliorated ΔCDAI (n=95, 15.0±10.8; mean±SD) compared to those with TNFi (n=148, 11.4±10.3) at 12 weeks (P=0.003). aIL-6 group consists of 95 tocilizumab treated patients. TNFi group includes 25 adalimumab, 25 certolizumab pegol, 14 etanercept, 54 golimumab and 30 infliximab treated patients. Baseline clinical characteristics of the 243 RA patients who had knee joint involvement were shown in Table 1. Mean ages, sex and disease durations were not significantly different between the two groups. Baseline CDAI levels of aIL-6 group (24.8±11.8) were slightly elevated compared to those of TNFi group (21.7 ±10.9). Multivariate analysis adjusted for age, gender and baseline CDAI levels revealed that aIL-6 significantly improved ΔCDAI levels compared to TNFi (P=0.04). By contrast, in the RA patients who had no swelling of knee joints, there was no significant difference of ΔCDAI improvement between aIL-6 group (n=156, 5.5±7.4) and TNFi group (n=385, 6.7±8.9).Table 1.Baseline clinical characteristics of 243 RA patients who had knee joint involvementaIL-6 group(n=95)TNFi group(n=148)p ValueAge (mean±SD)60.7±15.261.9±14.40.58Gender (female, %)80.079.10.97Duration (year)9.3 ±10.38.4±10.50.56DAS28ESR (mean±SD)5.3±1.25.2 ±4.80.03CDAI (mean ±SD)24.8±11.821.7 ±10.90.04MTX use, (%)45.462.20.02MTX dose (mg/day)8.7 ±3.39.0 ±3.50.61PSL use, (%)44.345.60.74PSL dose (mg/day)5.5 ±3.55.1 ±2.90.55Conclusion:Thus, these findings suggest that anti-IL-6 receptor antibody was more effective in the RA patients with knee joint involvement compared to TNF- inhibitor.References:[1]Burgers LE, et al.Ann Rheum Dis. 2018;77:e33.Disclosure of Interests:Yuichi Maeda Grant/research support from: YM received a research grant and/or speaker fee from Eli Lilly, Chugai, Pfizer, Bristol-Myers Squibb, and Mitsubishi-Tanabe, Speakers bureau: YM received a research grant and/or speaker fee from Eli Lilly, Chugai, Pfizer, Bristol-Myers Squibb, and Mitsubishi-Tanabe, Toru Hirano Grant/research support from: TH received a research grant and/or speaker fee from Astellas, Chugai, Nippon Shinyaku, Abbvie, Eisai, and Ono Pharmaceutical, Speakers bureau: TH received a research grant and/or speaker fee from Astellas, Chugai, Nippon Shinyaku, Abbvie, Eisai, and Ono Pharmaceutical, Ryota Hara Speakers bureau: RH received a speaker fee from AbbVie, Kosuke Ebina Grant/research support from: KE has received research grants from Abbie, Asahi-Kasei, Astellas, Chugai, Eisai, Ono Pharmaceutical, and UCB Japan., Employee of: KE is affiliated with the Department of Musculoskeletal Regenerative Medicine, Osaka University, Graduate School of Medicine, which is supported by Taisho., Speakers bureau: KE has received payments for lectures from Abbie, Asahi-Kasei, Astellas, Ayumi, Bristol-Myers Squibb, Chugai, Eisai, Eli Lilly, Janssen, Mitsubishi-Tanabe, Ono Pharmaceutical, Sanofi, and UCB Japan., Motomu Hashimoto Grant/research support from: Bristol-Myers Squibb, Eisai, and Eli Lilly and Company., Speakers bureau: Bristol-Myers Squibb and Mitsubishi Tanabe Pharma., Wataru Yamamoto: None declared, Kosaku Murakami Speakers bureau: AbbVie, Eisai, and Mitsubishi Tanabe Pharma., Takuya Kotani: None declared, Kenichiro Hata: None declared, Yonsu Son: None declared, Hideki Amuro: None declared, Akira Onishi Speakers bureau: AO received a speaker fee from Chugai, Ono Pharmaceutical, Eli Lilly, Mitsubishi-Tanabe, Asahi-Kasei, and Takeda, Jinno Sadao: None declared, Masaki Katayama: None declared, Atsushi Kumanogoh Grant/research support from: AK received a research grant and/or speaker fee from Mitsubishi-Tanabe, Chugai, Eisai, Asahi-Kasei, Astellas, Abbvie, Bristol-Myers Squibb, Ono Pharmaceutical, and Pfizer, Speakers bureau: AK received a research grant and/or speaker fee from Mitsubishi-Tanabe, Chugai, Eisai, Asahi-Kasei, Astellas, Abbvie, Bristol-Myers Squibb, Ono Pharmaceutical, and Pfizer

Background:EULAR recommendation announced that biological disease-modifying antirheumatic drugs (bDMARDs) and janus kinase inhibitors (JAKi) are considered as equivalent in the treatment of rheumatoid arthritis (RA). However, we still lack reliable evidence of direct comparison between these agents’ retention, which may reflect both effectiveness and safety.Objectives:The aim of this multi-center (7 university-related hospitals), retrospective study is to clarify retention rates and reasons for discontinuation of 7 bDMARDs and tofacitinib (TOF), one of the JAKi, in both bDMARDs-naïve and bDMARDs-switched cases.Methods:This study assessed 3,897 patients and 4,415 treatment courses of with bDMARDs and TOF from 2001 to 2019 (2,737 bDMARDs-naïve patients and 1,678 bDMARDs-switched patients [59.5% switched to their second agent], female 82.3%, baseline age 57.4 years, disease duration 8.5 years; rheumatoid factor positivity 78.4%; DAS28-ESR 4.3; concomitant prednisolone [PSL] 6.1 mg/day [42.4%] and methotrexate [MTX] 8.5 mg/week [60.9%]). Treatment courses included abatacept (ABT; n=663), adalimumab (ADA; n=536), certolizumab pegol (CZP; n=226), etanercept (ETN; n=856), golimumab (GLM; n=458), infliximab (IFX; n=724), tocilizumab (TCZ; n=851), and TOF (n=101/only bDMARDs-switched cases). Reasons for discontinuation were classified into four categories by each attending physician: 1) lack of effectiveness, 2) toxic adverse events, 3) non-toxic reasons, and 4) remission. Retention rates of each discontinuation reason were estimated at 36 months using the Kaplan-Meier method and adjusted for potential clinical confounders (age, sex, disease duration, concomitant PSL and MTX, starting date and number of switched bDMARDs) using Cox proportional hazards modeling.Results:Adjusted drug retention rates for each discontinuation reason were as follows: lack of effectiveness in the bDMARDs-naïve group (from 70.8% [CZP] to 85.1% [ABT]; P=0.001 between agents) and the bDMARDs-switched group (from 52.8% [CZP] to 78.7% [TCZ]; PConclusion:Remarkable differences were observed in drug retention of 7 bDMARDs and TOF between bDMARDs-naïve and bDMARDs-switched cases.Disclosure of Interests:Kosuke Ebina Grant/research support from: KE has received research grants from Abbie, Asahi-Kasei, Astellas, Chugai, Eisai, Ono Pharmaceutical, and UCB Japan., Employee of: KE is affiliated with the Department of Musculoskeletal Regenerative Medicine, Osaka University, Graduate School of Medicine, which is supported by Taisho., Speakers bureau: KE has received payments for lectures from Abbie, Asahi-Kasei, Astellas, Ayumi, Bristol-Myers Squibb, Chugai, Eisai, Eli Lilly, Janssen, Mitsubishi-Tanabe, Ono Pharmaceutical, Sanofi, and UCB Japan., Toru Hirano Grant/research support from: TH received a research grant and/or speaker fee from Astellas, Chugai, Nippon Shinyaku, Abbvie, Eisai, and Ono Pharmaceutical, Speakers bureau: TH received a research grant and/or speaker fee from Astellas, Chugai, Nippon Shinyaku, Abbvie, Eisai, and Ono Pharmaceutical, Yuichi Maeda Grant/research support from: YM received a research grant and/or speaker fee from Eli Lilly, Chugai, Pfizer, Bristol-Myers Squibb, and Mitsubishi-Tanabe, Speakers bureau: YM received a research grant and/or speaker fee from Eli Lilly, Chugai, Pfizer, Bristol-Myers Squibb, and Mitsubishi-Tanabe, Wataru Yamamoto: None declared, Motomu Hashimoto Grant/research support from: Bristol-Myers Squibb, Eisai, and Eli Lilly and Company., Speakers bureau: Bristol-Myers Squibb and Mitsubishi Tanabe Pharma., Koichi Murata Grant/research support from: KMurata belong to a department that has been financially supported by four pharmaceutical companies (Mitsubishi-Tanabe, Chugai, AYUMI and UCB Japan)., Employee of: KMurata belong to a department that has been financially supported by four pharmaceutical companies (Mitsubishi-Tanabe, Chugai, AYUMI and UCB Japan)., Speakers bureau: KMurak has received speaking fees, and/or consulting fees from Eisai Co. Ltd, Chugai Pharmaceutical Co. Ltd., Pfizer Japan Inc, Bristol-Myers Squibb, Mitsubishi-Tanabe Pharma Corporation, UCB, Daiichi Sankyo Co. Ltd. and Astellas Pharma Inc., Tohru Takeuchi Grant/research support from: TT received a research grant from Chugai, CoverLetter and a speaker fee from Astellas, Chugai, Eisai, Mitsubishi-Tanabe, Abbvie, Bristol-Myers Squibb, Ayumi, Daiichi Sankyo, Eisai, Takeda, and Asahi-Kasei, Employee of: TT is affiliated with a department that is financially supported by six pharmaceutical companies (Mitsubishi-Tanabe, Chugai, Ayumi, Astellas, Eisai, and Takeda), Hideyuki Shiba: None declared, Yonsu Son: None declared, Hideki Amuro: None declared, Akira Onishi Speakers bureau: AO received a speaker fee from Chugai, Ono Pharmaceutical, Eli Lilly, Mitsubishi-Tanabe, Asahi-Kasei, and Takeda, Kengo Akashi: None declared, Ryota Hara Speakers bureau: RH received a speaker fee from AbbVie, Masaki Katayama: None declared, Keiichi Yamamoto: None declared, Atsushi Kumanogoh Grant/research support from: AK received a research grant and/or speaker fee from Mitsubishi-Tanabe, Chugai, Eisai, Asahi-Kasei, Astellas, Abbvie, Bristol-Myers Squibb, Ono Pharmaceutical, and Pfizer, Speakers bureau: AK received a research grant and/or speaker fee from Mitsubishi-Tanabe, Chugai, Eisai, Asahi-Kasei, Astellas, Abbvie, Bristol-Myers Squibb, Ono Pharmaceutical, and Pfizer, Makoto Hirao Speakers bureau: MHirao received a speaker fee from Astellas, Ono Pharmaceutical, Eli Lilly, Mitsubishi-Tanabe, Pfizer, Ayumi, and Takeda