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Populations of Japanese macaques were significantly reduced in most areas from the 1900s to the 1960s and then recovered mainly in the northeastern part of Honshu. A drastic reduction in population size reduces genetic variability through a bottleneck effect. Demographic expansion after the reduction that accumulates new mutations can reduce the bottleneck effects or drive the recovery of genetic variability. We examined the genetic status of a small island population (Kinkazan Island) and a larger mainland population (southern Tohoku) of Japanese macaques that experienced recent demographic bottlenecks and recovery using eight microsatellite loci. The two populations were significantly genetically different from each other. The Kinkazan population exhibited lower genetic variability, remarkable evidence of bottleneck (i.e., significant heterozygosity excess and lower frequency of rare alleles), and a considerably smaller effective population size based on genetic data than based on the current census size. These results indicate that the genetic status has not completely recovered from the demographic bottleneck despite a full recovery in census size on Kinkazan Island. New mutations might rarely have accumulated because of the small carrying capacity of the island. Therefore, the genetic variability of the population would have been restrained by the severe bottleneck size, small carrying capacity, and long-term isolation. On the other hand, the bottleneck effect seems to be limited in the southern Tohoku population considering higher genetic variability, non-significant heterozygosity excess in many mutation conditions, and the highest frequency of rare alleles.

Background:The American College of Rheumatology (ACR)/EULAR Remission Criteria for Rheumatoid Arthritis was revised in 2022[1]. The threshold for the patient global assessment (PtGA) of Boolean criteria was changed from 1 cm to 2 cm (Boolean 2.0). Verification using randomized control trial (RCT) data showed that Boolean 2.0 increased agreement with index-based remission criteria (clinical disease activity index [CDAI] and simplified disease activity index [SDAI]) without diminishing the predictive ability of radiographic progression and good functional outcomes. However, these associations should also be assessed using real-world data because participants in an RCT may not necessarily be representative of the patient population in a clinical setting.Objectives:We aimed to assess an association of achieving Boolean 2.0 with the good functional outcome using data from the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort.Methods:Among patients with rheumatoid arthritis (RA) enrolled in the IORRA cohort between 2022 and 2023, we included those with available data for tender joint count (TJC), swollen joint count (SJC), patient global assessment (PtGA), the Japanese version of Health Assessment Questionnaire (J-HAQ), and C-reactive protein (CRP) levels (mg/dL) at baseline (2022 spring), and J-HAQ six months and 12 months later. PtGA was measured using a 0–10 cm scale. The cutoff for remission was set at SDAI ≤ 3.3[2,3] and CDAI ≤ 2.83. Boolean 1.0 and Boolean 2.0 requires PtGA≤1.0 and PtGA≤2.0, respectively, in addition to TJC≤1, SJC≤1, and CRP levels≤1. The good functional outcome was defined as J-HAQ≤0.5 and ΔJ-HAQ (changes in J-HAQ from baseline) ≤0. The association between achieving each remission criteria and the good functional outcome was analyzed using a multivariable logistic regression model. We adjusted for potential confounders, including sex, age, disease duration, body mass index (BMI), seropositivity (defined as positivity of either rheumatoid factor or anti-cyclic citrullinated peptide antibody), use of non-steroidal anti-inflammatory drugs, glucocorticoids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), biologic DMARDs and targeted synthetic DMARDs at baseline.Results:A total of 1,738 patients were enrolled, with a mean (±SD) age of 63.0±12.7 years, and predominantly female (87.6%). The mean disease duration was 18.3±10.2 years, and 86.4% of patients were seropositive. At baseline, the mean CDAI, SDAI, and J-HAQ were 4.0, 4.3, and 0.5, respectively. Fulfillment of each remission criteria was as follows: Boolean 1.0, 659 (37.9%); Boolean 2.0, 882 (50.7%); SDAI, 951 (54.7%); CDAI, 917 (52.8%). The good functional outcome was achieved by 52.9% of patients after six months and 51.6% after one year. The likelihood ratio of the good functional outcome after six months and one year in patients fulfilling each criteria of clinical remission, is presented in Table 1. The adjusted odds ratio (95% CI) for achieving good functional outcomes one year later was as follows: Boolean 1.0, 3.5 (2.7–4.4); Boolean 2.0, 2.4 (1.9–3.0); SDAI, 2.5 (2.0–3.1); CDAI, 2.7 (2.1–3.3).Conclusion:A higher proportion patients fulfilled Boolean 2.0 compared to Boolean 1.0. The association between Boolean 2.0 and the achievement of the good functional outcome appeared to be weaker than that of Boolean 1.0, but was comparable with the other index-based criteria.REFERENCES:[1] Studenic P et al. Arthritis Rheumatol. 2003;75:15–22.[2] Felson DT, et al. Ann Rheum Dis. 2011;70:404–13.[3] Aletaha,D et al. Clin Exp Rheumatol. 2005;23:S100–8.Table 1. The proportion of achievement and likelihood ratio (LR) of the good functional outcome for each criteria. Positive and negative LRs were calculated to evaluate the predictive ability for achieving a good functional outcome based on each remission criteria.Acknowledgements:NIL.Disclosure of Interests:Tomoaki Higuchi Asahi Kasei Corp., Boehringer Ingelheim Japan Inc., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Janssen Pharmaceutical K.K., Pfizer Japan Inc., Taisho Pharmaceutical Co., Ltd., Taisho Pharmaceutical holdings Co., ltd., Ribomic Inc., Eiichi Tanaka AbbVie Japan GK, Asahi Kasei Corp., Astellas Pharma Inc., Ayumi Pharmaceutical Co., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., GlaxoSmithKline K.K., Kyowa Pharma Chemical Co., Ltd., Janssen Pharmaceutical K.K., Mochida Pharmaceutical Co., Ltd., Pfizer Japan Inc., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., Eisuke Inoue Bristol Myers Squibb Co., Ltd., Pfizer Japan Inc., Nippontect systems Co., Ltd., RCR Co., Ltd., Naohiro Sugitani: None declared, Mai Abe: None declared, Kumiko Saka: None declared, Eri Sugano: None declared, Moeko Ochiai: None declared, Rei Yamaguchi: None declared, Katsunori Ikari Asahi Kasei Corp., Astellas Pharma Inc., AbbVie Japan GK, Ayumi Pharmaceutical Co., Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Janssen Pharmaceutical K.K., Kaken Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Takeda Pharmaceutical Co. Ltd., Teijin Pharma Ltd., UCB Japan Co. Ltd, Masayoshi Harigai AbbVie Japan GK, AstraZeneca K.K., Ayumi Pharmaceutical Co., Boehringer Ingelheim Japan Inc., Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eisai Co. Ltd., Eli Lilly Japan K.K., GlaxoSmithKline K.K., Gilead Sciences Inc., Janssen Pharmaceutical K.K., Kissei Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Nippon Shinyaku Co., Ltd., Novartis Japan, Pfizer Japan Inc., CIMIC Holdings Co., Ltd., Mitsubishi Tanabe Pharma Co., Teijin Pharma Ltd., UCB Japan Co. Ltd., AbbVie, Boehringer-Ingelheim, Bristol Myers Squibb Co., Kissei Pharmaceutical Co., Ltd., Teijin Pharma Ltd.

The ORIGAMI study is a multicenter, observational study to evaluate the effectiveness, safety, and patient-reported outcomes of abatacept (ABA) in Japanese patients with csDMARD-resistant, Simplified Disease Activity Index (SDAI)-moderate, biologic-naïve rheumatoid arthritis (RA). ABA has shown better effectiveness/efficacy in RA patients with anti-cyclic citrullinated peptide antibody (ACPA) positive (1) and high ACPA titer (2) compared to ACPA negative and low ACPA titer, respectively. However, more accurate predictors of effectiveness in clinical practice are needed than ACPA status. This post-hoc analysis is aimed to determine the association between ACPA and ABA effectiveness (disease activity and physical function) or retention rate and to investigate other factors associated with the effectiveness of ABA in patients enrolled in the ORIGAMI study. Of the 279 patients in the effectiveness analysis set of the ORIGAMI study, 270 patients with baseline ACPA measurement were analyzed. The patients were divided into the ACPA-positive group (ACPA +ve, ≥4.5 U/mL at baseline) and the ACPA-negative group (ACPA –ve, <4.5 U/mL). Patients' characteristics, changes in disease activity and physical function (Japanese Health Assessment Questionnaire; J-HAQ) through 52 weeks, and retention rates of ABA at week 52 were evaluated. Baseline characteristics and use of concomitant drugs were analyzed as independent variables by multiple regression analysis using a standard linear model adjusted by SDAI at week 0 to identify factors associated with SDAI change at week 52. In addition, the interaction effects among ACPA status, RF status, and the factor that was significantly associated with SDAI change in multiple regression analysis on changes in SDAI were explored. The numbers of ACPA +ve and –ve patients were 226 and 44, respectively. ACPA values (mean ± SD, U/mL) were 280.3 ± 376.8 and 0.9 ± 0.7, and rheumatoid factor (RF) values were 174.8 ± 302.6 and 20.9 ± 61.7 in the ACPA +ve and –ve groups, respectively. Mean (95% confidence interval) changes in SDAI at week 52 were −11.3 (−12.4 to −10.3) and −8.0 (−10.5 to −5.5), and those in J-HAQ were −0.27 (−0.34 to −0.20) and −0.16 (−0.34 to 0.01) in the ACPA +ve and –ve groups, respectively. In the Kaplan–Meier analysis, the retention rates of ABA at week 52 in the ACPA +ve and –ve groups were 72.1% and 58.7%, (discontinuation for any reason), and 91.6% and 75.7% (discontinuation because of lack of effectiveness), respectively. In a multiple regression analysis, the duration of disease (< 1 year) was associated with the change in SDAI at week 52. With respect to SDAI changes, the estimated difference of ACPA +ve and disease duration (< 1 year), ACPA +ve and disease duration (≥1 year), and ACPA –ve and disease duration (< 1 year), versus ACPA −ve and disease duration (≥ 1 year), were −4.26 (p = 0.022), −0.82 (p = 0.618), and −0.93 (p = 0.716), respectively (Fig. 1). The estimated difference of ACPA +ve and RF +ve, ACPA +ve and RF –ve, and ACPA –ve and RF +ve, versus ACPA –ve and RF –ve, were −2.48 (p = 0.060), −2.77 (p = 0.107), and −5.48 (p = 0.087), respectively. A higher retention rate as well as better effectiveness of ABA on disease activity and physical function in ACPA +ve group versus ACPA –ve group were shown in the simple subgroup analysis. ABA effectiveness on the SDAI change was significantly better in patients with disease duration <1 year and ACPA +ve compared to those with ACPA −ve and disease duration ≥ 1 year. [1]Harrold LR et al. J Rheumatol 2018;45(1):32–39. [2]Sokolove J et al. Ann Rheum Dis 2016;75(4):709–714. [Display omitted] Kenta Misaki Speakers bureau: Eisai Co., Ltd., AbbVie GK, Eli Lilly Japan K.K., Ono Pharmaceutical Co., Ltd., Grant/research support from: Ono Pharmaceutical Co., Ltd., Eiichi Tanaka Speakers bureau: AbbVie GK, Asahi Kasei Pharma Corporation, Astellas Pharma Inc, Ayumi Pharmaceutical Corporation, Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., GlaxoSmithKline K.K., Kyowa Pharma Chemical Co., Ltd., Janssen Pharmaceutical K.K., Mochida Pharmaceutical Co., Ltd., Pfizer, Takeda Pharmaceutical Co., Ltd, and Teijin Pharma Ltd., Eisuke Inoue Speakers bureau: Pfizer Japan, Bristol-Myers Squibb K.K., Katsuki Tsuritani Employee of: Bristol-Myers Squibb K.K., Shigeru Matsumoto Employee of: Ono Pharmaceutical Co., Ltd., Hisashi Yamanaka Consultant of: Bristol-Myers Squibb K.K., masayoshi harigai Speakers bureau: AbbVie GK, Ayumi Pharmaceutical Corporation, Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Pfizer Japan Inc., and Takeda Pharmaceutical Co., Ltd., Consultant of: AbbVie GK, Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., and Gilead Sciences Inc., Grant/research support from: AbbVie GK, and Asahi Kasei Corp., Astellas Pharma Inc., Ayumi Pharmaceutical Corporation, Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd. Daiichi-Sankyo, Inc., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation., Nippon Kayaku Co., Ltd., Taisho Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd.

The 2019 update of the European League Against Rheumatism (EULAR) treatment recommendations strongly recommends co-administration of corticosteroids (CSs) with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in patients with RA as bridging therapy to improve the success rate of the first-line treatment and to avoid disease flare-ups1; however, current treatment guidelines for RA in Japan do not clearly mention about their use. Poor disease management after the initial diagnosis can affect the overall use of health services and the economic burden on patients. To describe medical costs and resource use in patients with early RA treated with and without oral or injectable corticosteroids (CSs) as part of their initial treatment with disease-modifying antirheumatic drugs (DMARDs) in Japan. We used a large Japanese administrative claims database constructed by the Japan Medical Data Center (JMDC)2. Patients with the International Classification of Diseases 10th revision (ICD-10) codes for RA were enrolled at the first DMARDs prescription after no DMARDs prescription period for 6-months (index date) in the period from 1/1/2012 to 12/31/2017. Patients who were observable for 12 months after the index date as a follow-up period were included. Patients treated with CSs within the follow-up period were compared with those without them (CS and non-CS group). The primary endpoint was mean medical cost per patient in the 12-month follow-up period. The secondary endpoints were costs for drugs, treatments, and materials and the proportions of patients using the subcategories of each resource. Drugs were divided into medications for RA or for comorbidities including adverse events (AEs). Costs in JPY were converted into EUR (1 EUR = 125 JPY in 2020). Eligible patients of 1,670 and 1,487 were identified as the CS and non-CS group (median age: 51 years and 50 years). Total mean costs were significantly higher in the CS group (CS, 4,448 EUR, non-CS 3,208 EUR; P< 0.05). Drug, treatment, and material costs were significantly higher in the CS group than in the non-CS group (drug for RA and AEs, CS 2,367 EUR, non-CS 1,581 EUR, P < 0.05; drug for RA only, CS 2,265 EUR, non-CS 1,516 EUR, P < 0.05; treatment, CS 1,987 EUR, non-CS 1,562 EUR, P < 0.05; material, CS 94 EUR, non-CS 65 EUR; P < 0.05). The resource use in almost all drug subcategories were higher in the CS group (Table 1), as well as in all treatment and material subcategories. Patients with early RA treated with CSs in the first year after starting DMARDs tended to use more resources and have higher medical costs than patients not treated with CSs. [1]Smolen JS et al., Ann Rheum Dis. 2020;79(6):685-699. [2]JMDC claims database, Tokyo, Japan. Eiichi Tanaka Speakers bureau: AbbVie GK, Asahi Kasei Pharma Corporation, Astellas Pharma Inc, Ayumi Pharmaceutical Corporation, Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., GlaxoSmithKline K.K., Kyowa Pharma Chemical Co., Ltd., Janssen Pharmaceutical K.K., Mochida Pharmaceutical Co., Ltd., Pfizer, Takeda Pharmaceutical Co., Ltd, and Teijin Pharma Ltd., Eisuke Inoue Speakers bureau: Pfizer Japan, Bristol-Myers Squibb K.K., Ryoko Sakai Speakers bureau: Bristol Myers Squibb Co., Ltd., Grant/research support from: Tokyo Women's Medical University (TWMU), particularly the Division of Multidisciplinary Management of Rheumatic Diseases, Department of Rheumatology, has received unrestricted research grants from Ayumi Pharmaceutical Co.; Chugai Pharmaceutical Co., Ltd.; Eisai Co., Ltd., Nippon Kayaku Co., Ltd.; Taisho Toyama Pharmaceutical Co., Ltd.; Takeda Pharmaceutical Co., Ltd.; Mitsubishi Tanabe Pharma Co.; and Teijin Pharma Ltd., with which TWMU paid the salaries of RS., Iwasaki Katsuhiko: None declared, Ayako Shoji: None declared, masayoshi harigai Speakers bureau: AbbVie GK, Ayumi Pharmaceutical Corporation, Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Pfizer Japan Inc., and Takeda Pharmaceutical Co., Ltd., Consultant of: AbbVie GK, Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., and Gilead Sciences Inc., Grant/research support from: AbbVie GK, and Asahi Kasei Corp., Astellas Pharma Inc., Ayumi Pharmaceutical Corporation, Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd. Daiichi-Sankyo, Inc., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation., Nippon Kayaku Co., Ltd., Taisho Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd. Table 1Number and proportion of patients who used drugsType of drugDrug use, n (%)CS (N = 1,670)Non-CS (N = 1,487)P-valuecsDMARDsTotal1,635 (97.9)1,447 (97.3)0.328Methotrexate1,481 (88.7)1,315 (88.4)0.870Others790 (47.3)551 (37.1)< 0.001bDMARDsTotal342 (20.5)181 (12.2)< 0.001TNFi252 (15.1)129 (8.7)< 0.001IL6i93 (5.6)40 (2.7)< 0.001T-cell40 (2.4)17 (1.1)0.012AnalgesicsTotal1,512 (90.5)1,274 (85.7)< 0.001Acetaminophen379 (22.7)273 (18.4)0.003Acetaminophen / Opioids84 (5.0)37 (2.5)< 0.001NSAIDs1,459 (87.4)1,214 (81.6)< 0.001Opioids16 (1.0)10 (0.7)0.491Others198 (11.9)101 (6.8)< 0.001AntibioticsTotal1,086 (65.0)873 (58.7)< 0.001Antibacterial drugs1,022 (61.2)800 (53.8)< 0.001Antifungal drugs133 (8.0)86 (5.8)0.019Antiviral drugs172 (10.3)129 (8.7)0.136Antiparasitic drugs5 (0.3)8 (0.5)0.443Anti-osteoporotic drugs341 (20.4)95 (6.4)< 0.001bDMARDs=biological disease-modifying antirheumatic drugs; CSs=corticosteroids; csDMARDs=conventional synthetic disease-modifying antirheumatic drugs; IL6i=interleukin-6 inhibitor; NSAID=non-steroidal anti-inflammatory drug; T-cell=selective T-cell co-stimulation modulator; TNFi=tumor necrosis factor α inhibitor; P-values were calculated using Chi-square test

BackgroundIt has been reported that patients with rheumatoid arthritis (RA) differ in disease progression and responsiveness to treatment depending on their serological status. Examining time trends in serological status may lead to the recognition of changes in the phenotype of RA. Recent reports revealed that the incidence of rheumatoid factor (RF)-positive RA had been decreasing[1,2]. This needs to be further investigated in other registries and races; however, data from a large observational study of Japanese are lacking.ObjectivesWe aimed to investigate the time trend of seropositivity in Japanese RA patients.MethodsThis is a retrospective study using data from the Institute of Rheumatology Rheumatoid Arthritis (IORRA) cohort. Among patients enrolled in the IORRA cohort between 2000 and 2021, patients with a disease duration of <3 years at enrolment were included. Seropositive status was defined as positive for rheumatoid factor (RF) (cut-off: 15 IU/mL) and/or anti-cyclic citrullinated peptide (CCP) antibody (second generation; cut-off: 4.5 U/mL). Patients with one negative and one unmeasured or both unmeasured were excluded. The time period was divided into 2000–2010 and 2011–2021. The effect of the time period on seropositivity was analyzed using multivariable analysis after adjusting for age, sex, smoking, and body mass index (BMI) at enrollment.ResultsOf 6,514 patients enrolled, 5,289 (81.2%) patients were female, and the median age was 54.9 (interquartile range: 44.0–64.5). 5,142 (88.2%) were seropositive, and the proportion of serological status differed between 2000–2010 (n=4,261) and 2011–2021 (n=2,004) (Figure 1). The proportion of seropositive patients was 90.2% in 2000–2010 and 84.0% in 2011–2021. The positivity for RF and anti-CCP antibody was decreased over time: 74.9% and 78.1% in 2000–2010 and 70.0% and 74.3% in 2011–2021, respectively. The time period (2011–2021) was associated with seronegativity (adjusted odds ratio [OR]: 1.51, 95% confidence interval [CI]: 1.24–1.83). Additionally, the time period (2011–2021) was also associated with RF negativity (adjusted OR: 1.44, 95% CI: 1.23–1.68) and anti-CCP negativity (adjusted OR: 1.30, 95% CI: 1.10–1.52).ConclusionAnalysis of the IORRA cohort data revealed a decrease in seropositivity in Japanese patients with RA. The phenotype of RA in the clinical setting may have been changing over time.References[1] Kaipiainen-Seppanen O, et al. J Rheumatol. 2006; 33(11):2132–8.[2] Myasoedova E, et al. Ann Rheum Dis. 2020; 79(4):440–4.Figure 1.Time trend of the serological status in the study population. The number of each group was shown in the graph.Acknowledgements:NIL.Disclosure of InterestsTomoaki Higuchi: None declared, Eiichi Tanaka Speakers bureau: AbbVie Japan GK; Asahi Kasei Corp.; Astellas Pharma Inc.; Ayumi Pharmaceutical Co.; Chugai Pharmaceutical Co., Ltd.; Eisai Co., Ltd.; Eli Lilly Japan K.K.; GlaxoSmithKline K.K.; Kyowa Pharma Chemical Co., Ltd.; Janssen Pharmaceutical K.K.; Mochida Pharmaceutical Co., Ltd.; Pfizer Japan Inc.; Takeda Pharmaceutical Co., Ltd.; and Teijin Pharma Ltd., Eisuke Inoue Speakers bureau: Bristol Myers Squibb Co., Ltd.; Pfizer Japan Inc.; Nippontect systems Co., Ltd.; RCR Co., Ltd., Mai Abe: None declared, Kumiko Saka: None declared, Eri Sugano: None declared, Naohiro Sugitani: None declared, Moeko Ochiai: None declared, Rei Yamaguchi: None declared, Katsunori Ikari Speakers bureau: Asahi Kasei Corp.; Astellas Pharma Inc.; AbbVie Japan GK; Ayumi Pharmaceutical Co.; Bristol Myers Squibb Co., Ltd.; Chugai Pharmaceutical Co., Ltd.; Eisai Co., Ltd.; Eli Lilly Japan K.K.; Janssen Pharmaceutical K.K.; Kaken Pharmaceutical Co. Ltd.; Mitsubishi Tanabe Pharma Co.; Pfizer Japan Inc.; Takeda Pharmaceutical Co. Ltd.; Teijin Pharma Ltd.; and UCB Japan Co. Ltd., Yamanaka Hisashi Consultant of: CorEvitas LLC, Masayoshi Harigai Speakers bureau: AbbVie Japan GK; AstraZeneca K.K.; Ayumi Pharmaceutical Co.; Boehringer Ingelheim Japan Inc.; Bristol Myers Squibb Co., Ltd.; Chugai Pharmaceutical Co., Ltd.; Eisai Co., Ltd.; Eli Lilly Japan K.K.; GlaxoSmithKline K.K.; Gilead Sciences Inc.; Janssen Pharmaceutical K.K.; Kissei Pharmaceutical Co., Ltd.; Nippon Kayaku Co., Ltd.; Nippon Shinyaku Co., Ltd.; Novartis Japan; Pfizer Japan Inc.; CIMIC Holdings Co., Ltd.; Mitsubishi Tanabe Pharma Co.; Teijin Pharma Ltd.; and UCB Japan Co. Ltd., Consultant of: AbbVie; Boehringer-Ingelheim; Bristol Myers Squibb Co.; Kissei Pharmaceutical Co., Ltd.; and Teijin Pharma Ltd., Grant/research support from: Grant/research support from: AbbVie Japan GK; Asahi Kasei Corp.; Astellas Pharma Inc.; Ayumi Pharmaceutical Co.; Boehringer Ingelheim Japan, Inc.; Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Daiichi-Sankyo, Inc., Eisai Co., Ltd.; Kaken Pharmaceutical Co., Ltd.; Kissei Pharmaceutical Co., Ltd.; Mitsubishi Tanabe Pharma Co.; Nippon Kayaku Co., Ltd.; Sekisui Medical; Taisho Pharmaceutical Co., Ltd.; and Teijin Pharma Ltd.

BackgroundWe previously reported that rheumatoid arthritis (RA) patients with chronic kidney disease (CKD) were at increased risk of failure to achieve remission and of occurrence of hospitalized infections [1]. Although biologic disease-modifying anti-rheumatic drugs (bDMARDs) are a promising treatment option, their effectiveness and safety for this population have not been fully evaluated to date.ObjectivesTo determine the optimal bDMARD selection for treatment of RA patients with decreased kidney function, we compared the retention rates of patients receiving tumor necrosis factor inhibitor (TNFi), interleukin-6 inhibitor (IL-6i), and abatacept (ABT) in RA patients using data from the IORRA cohort, the real-world data registry of Japanese RA patients.MethodsRenal function was calculated using the Japanese versions of the equations for estimated glomerular filtration ratio (eGFRcr). Deceased renal function was defined as eGFRCr <60 mL/min/1.73m2. Among RA patients enrolled in the IORRA cohort between 2003 and 2020, data from patients with decreased kidney function who started bDMARDs were extracted. Renal function and use of bDMARDs by the extracted patients were identified in their medical records. Reasons for discontinuation were classified as ineffectiveness, adverse events caused by bDMARDs, or other reasons. Retention rates due to ineffectiveness or adverse events caused by TNFi (adalimumab or adalimumab biosimilar [ADA], certolizumab pegol [CZP], etanercept or etanercept biosimilar [ETN], golimumab [GLM], infliximab or infliximab biosimilar [IFX]), IL-6i (tocilizumab [TCZ], sarilumab [SAR]) and ABT spanning 36 months were calculated using the Kaplan-Meier method, and adjusted hazard ratio [aHR] of discontinuation of each bDMARD was calculated using the Cox proportional hazard model, with adjustments for age, sex, disease duration, clinical disease activity index (CDAI), methotrexate (MTX)/ prednisolone (PSL) use, and previous bDMARD use at baseline.ResultsA total of 238 treatment courses administered to 191 patients with decreased renal function were included. Median eGFRCr was 52.5 mL/min/1.73m2 (interquartile range: 43.3–57.4). The numbers of bDMARD users were as follows: TNFi, 143 (ADA, 15; CZP, 5; ETN, 67; GLM, 30; IFX, 26); IL-6i, 59 (all were TCZ); and ABT, 36, respectively. ABT users were older than IL-6i users, and TNFi users had higher eGFRCr and a higher proportion of MTX and previous DMARD use than the other groups. Sex, seropositivity, CDAI, health assessment questionnaire, and the proportion of PSL use were similar between groups. The retention rates at 36 months were 59.9%, 72.9%, and 61.7% for TNFi, IL-6i, and ABT, respectively. aHR of discontinuation when TNFi served as reference was 0.60 (95% confidence interval: 0.32–1.10) for IL-6i, and 0.85 (95% confidence interval: 0.44–1.64) for ABT.ConclusionBecause the retention rate of IL-6i was numerically high compared with TNFi and ABT in this study, IL-6i may offer a treatment advantage in RA patients with decreased renal function.Reference[1] Higuchi et al. Mod Rheumatol. 2022;32(5):875–884.Figure 1.The Kaplan-Meier curve of the retention rates of bDMARDs in patients with RA with decreased renal function.AcknowledgementsWe would like to thank Editage (www.editage.com) for English language editing. This work was supported by a research grant from the Ministry of Health, Labour and Welfare (20FC1044).Disclosure of InterestsTomoaki Higuchi: None declared, Eiichi Tanaka Speakers bureau: AbbVie Japan GK; Asahi Kasei Corp.; Astellas Pharma Inc.; Ayumi Pharmaceutical Co.; Chugai Pharmaceutical Co., Ltd.; Eisai Co., Ltd.; Eli Lilly Japan K.K.; GlaxoSmithKline K.K.; Kyowa Pharma Chemical Co., Ltd.; Janssen Pharmaceutical K.K.; Mochida Pharmaceutical Co., Ltd.; Pfizer Japan Inc.; Takeda Pharmaceutical Co., Ltd.; and Teijin Pharma Ltd., Eisuke Inoue Speakers bureau: Bristol Myers Squibb Co., Ltd.; Pfizer Japan Inc.; Nippontect systems Co., Ltd.; RCR Co., Ltd., Mai Abe: None declared, Kumiko Saka: None declared, Eri Sugano: None declared, Naohiro Sugitani: None declared, higuchi yoko: None declared, Moeko Ochiai: None declared, Rei Yamaguchi: None declared, Katsunori Ikari Speakers bureau: Asahi Kasei Corp.; Astellas Pharma Inc.; AbbVie Japan GK; Ayumi Pharmaceutical Co.; Bristol Myers Squibb Co., Ltd.; Chugai Pharmaceutical Co., Ltd.; Eisai Co., Ltd.; Eli Lilly Japan K.K.; Janssen Pharmaceutical K.K.; Kaken Pharmaceutical Co. Ltd.; Mitsubishi Tanabe Pharma Co.; Pfizer Japan Inc.; Takeda Pharmaceutical Co. Ltd.; Teijin Pharma Ltd.; and UCB Japan Co. Ltd., Yamanaka Hisashi Consultant of: CorEvitas LLC, Masayoshi Harigai Speakers bureau: AbbVie Japan GK; AstraZeneca K.K.; Ayumi Pharmaceutical Co.; Boehringer Ingelheim Japan Inc.; Bristol Myers Squibb Co., Ltd.; Chugai Pharmaceutical Co., Ltd.; Eisai Co., Ltd.; Eli Lilly Japan K.K.; GlaxoSmithKline K.K.; Gilead Sciences Inc.; Janssen Pharmaceutical K.K.; Kissei Pharmaceutical Co., Ltd.; Nippon Kayaku Co., Ltd.; Nippon Shinyaku Co., Ltd.; Novartis Japan; Pfizer Japan Inc.; CIMIC Holdings Co., Ltd.; Mitsubishi Tanabe Pharma Co.; Teijin Pharma Ltd.; and UCB Japan Co. Ltd., Consultant of: AbbVie; Boehringer-Ingelheim; Bristol Myers Squibb Co.; Kissei Pharmaceutical Co., Ltd.; and Teijin Pharma Ltd., Grant/research support from: AbbVie Japan GK; Asahi Kasei Corp.; Astellas Pharma Inc.; Ayumi Pharmaceutical Co.; Boehringer Ingelheim Japan, Inc.; Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Daiichi-Sankyo, Inc., Eisai Co., Ltd.; Kaken Pharmaceutical Co., Ltd.; Kissei Pharmaceutical Co., Ltd.; Mitsubishi Tanabe Pharma Co.; Nippon Kayaku Co., Ltd.; Sekisui Medical; Taisho Pharmaceutical Co., Ltd.; and Teijin Pharma Ltd.

Background:Rheumatoid arthritis (RA) is a chronic inflammatory disorder leading to disability and reduced quality of life. Effective treatment with biologic disease-modifying antirheumatic drugs (bDMARD) poses a significant economic burden. The abatacept (ABT) versus adalimumab comparison in biologic-naive RA subjects with background methotrexate (AMPLE) trial1 was a head-to-head randomized study.Objectives:To assess the cost-effectiveness (CE) of early initiation of ABT on Japanese RA patients with data from the IORRA database (ID).2Methods:A model based on the AMPLE study was used to estimate the CE of ABT 1st versus ABT 2nd lines in a cohort of 1000 patients based on responses on ACR20/50/70, HAQ-DI, CDAI and SDAI estimated from the real-clinical data of the ID. Unit costs for direct medical costs of adverse events (AEs), proportions of patients with concomitant medications or outpatient/inpatient visits; doses and duration of concomitant medications were taken from the JMDC claims database.3 Uncertainty was assessed in sensitivity analyses (SA) where cost parameters were tested on their ±30% levels. Results were compared between subgroups using cut-offs of 65-years of age and 1.5 of HAQ, or 5-years of treatment duration. The study used a Japanese healthcare payers’ perspective over a 2-year time horizon.Results:Incremental costs were all in favor of ABT 2nd line with 137 MJPY (1.1 M€, 120 JPY=1 €), 6 MJPY (0.05 M€), 41 MJPY (0.3 M€), 8 MJPY (0.07 M€) and 2.2 MJPY (0.02 M€) for bDMARDs, concomitant medication, AEs, serious AE, and hospitalizations due to infections, respectively. In total, the incremental costs were expected to be 195 MJPY (1.6 M€) higher for ABT as 1st line treatment, but the cost per responding patient and per patient in remission favored ABT 1st line across most response outcomes (Table 1).Table 1.Total costs per responder and patient in remission per 2-yearDifference in cost per health gain(ABT first line - ABT second line)Cost per responding patient (kJPY)ACR20-2,927 (-24 k€)ACR50-6,406 (-53 k€)ACR70-10,822 (-90 k€)HAQ-DI-5,120 (-43 k€)Cost per patient in remission (kJPY)DAS28828 (7 k€)CDAI-7,019 (-58 k€)SDAI-5,584 (-47 k€)ABT=abatacept; ACR20/50/70= 20/50/70% improvement of the American college of rheumatology criteria; HAQ-DI=health assessment questionnaire disability index; DAS28=disease activity score; CDAI=clinical disease activity index; SDAI=simplified disease activity indexSA showed that the cost for bDMARDs drives the difference in healthcare costs between the cohorts (-685 MJPY to 1,074 MJPY). For sub-groups of patients ≥65 years, <65 years, HAQ≥1.5, HAQ <1.5, treatment duration ≥5 years, <5 years the total 2-yearly costs per responder (SDAI remission) were 106 kJPY (0.9 k€), 321 kJPY (2.7 k€), 1,353 kJPY (11.3 k€), 106 kJPY (0.9 k€), 231 kJPY (1.9 k€) and 178 kJPY (1.5 k€) lower for ABT 1st line, respectively.Conclusion:Savings per responding patient are expected if ABT are prescribed as 1st line versus 2nd or 3rd line treatment, irrespective of age, disease duration and functional impairment level.References:[1]Sokolove J MS et al., Anna rheum dis. 2015;74(Suppl 2)[2]IORRA cohort database, Tokyo Women’s Medical University, Tokyo, Japan[3]JMDC claims database, Tokyo, JapanDisclosure of Interests:Eiichi Tanaka Consultant of: ET has received lecture fees or consulting fees from Abbvie, Asahi Kasei pharma co., Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo Co., Eisai Pharmaceutical, Janssen Pharmaceutical K.K., Nippon Kayaku, Pfizer, Takeda Pharmaceutical, Taisho Toyama Pharmaceutical Co., and UCB Pharma., Speakers bureau: ET has received lecture fees or consulting fees from Abbvie, Asahi Kasei pharma co., Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo Co., Eisai Pharmaceutical, Janssen Pharmaceutical K.K., Nippon Kayaku, Pfizer, Takeda Pharmaceutical, Taisho Toyama Pharmaceutical Co., and UCB Pharma., Eisuke Inoue Speakers bureau: EI has received speaker fee from Bristol-Meyers, Pfizer, Merck serono., Ayako Shoji Consultant of: To conduct this work, Jonas Nilsson Consultant of: To conduct this study, Christos Papagiannopoulos Consultant of: To conduct this study, Dhanda Devender Shareholder of: BMS, Employee of: BMS, Yoshio Anazawa Shareholder of: BMS, Employee of: BMS, Yuri Yoshizawa Shareholder of: BMS, Employee of: BMS, masayoshi harigai Grant/research support from: AbbVie Japan GK, Ayumi Pharmaceutical Co., Bristol Myers Squibb Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Co., Nippon Kayaku Co., Ltd., and Teijin Pharma Ltd. MH has received speaker’s fee from AbbVie Japan GK, Ayumi Pharmaceutical Co., Boehringer Ingelheim Japan, Inc., Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., GlaxoSmithKline K.K., Kissei Pharmaceutical Co., Ltd., Oxford Immuotec, Pfizer Japan Inc., and Teijin Pharma Ltd. MH is a consultant for AbbVie, Boehringer-ingelheim, Kissei Pharmaceutical Co., Ltd. and Teijin Pharma.

The study aimed to evaluate the effect of heat stress on the developments of cacao somatic embryos under in vitro condition. Somatic embryos were induced from petal explants of ICCRI 4 cacao clone using DKW medium with the addition of 2.4-D and kinetin. Mature stage of cotyledonary somatic embryos were cultured on a germination medium and incubated at temperatures of 25 (control), 35, 40, 45 and 35 followed by 45 °C with sub-cultured on the same medium monthly. The results showed cacao somatic embryos were turned brown and suffered death after 16, 5 and 3 days of incubation at temperatures of 40, 35-45 and 45°C, respectively, while somatic embryos cultured at temperatures of 25 and 35°C could develop to form normal plantlets. The temperature of 40-45°C might be the lethal temperature for cacao somatic embryos. The results of this study gave illustration how heat stress affected cacao embryo development and could be used as a base information for developing an in vitro selection method for heat stress tolerance in cacao.

Summary Despite improvements in rheumatoid arthritis disease activity of in the past 10 years, the incidence of self-reported non-vertebral fractures did not decrease in our cohort of 9,987 patients. This study may indicate that osteoporosis treatment and non-vertebral fracture prevention remain important regardless of the rheumatoid arthritis disease activity. Introduction Although rheumatoid arthritis (RA) is a risk factor for osteoporosis and fractures, few studies have described the association between disease activity and the fracture incidence in patients with RA. This study aimed to investigate changes in the non-vertebral fracture incidence between 2001 and 2010 in our Institute of Rheumatology Rheumatoid Arthritis (IORRA) cohort. Methods The IORRA is a prospective observational cohort study of Japanese RA patients. A total of 9,987 patients with RA were enrolled in this cohort from 2000 to 2010. The clinical parameter and non-vertebral fracture occurrence data were collected biannually through self-reported questionnaires. Incidences of self-reported non-vertebral fractures were also analyzed via standardization according to gender, age, and disease activity during each 2-year period. Results From 2001 to 2010, the percentage of patients with 28-joint disease activity score remission increased from 7.8 to 39.7 %, prednisolone intake decreased from 51.4 to 41.3 %, and bisphosphonate intake increased from 5.0 to 23.4 %. The non-vertebral fracture incidence rates were 24.6/1,000 person-years in 2001 and 35.5/1,000 person-years in 2010, with no apparent change even after standardization. The overall non-vertebral fracture incidence was significantly higher in the autumn/winter than in the spring/summer ( p  = 0.02). Conclusion Despite improvements in disease activity and functional disability, the non-vertebral fracture incidence exhibited no apparent change between 2001 and 2010 in our patients with RA. Osteoporosis treatment and non-vertebral fracture prevention remain important regardless of the disease control in patients with RA.

Kecapi ( Sandoricum koetjape Merr.) is a local fruit belonging to the Meliaceae family. The market price of this fruit is unstable due to inconsistent production and fruit quality. Kecapi’s cultivation system can be improved by modifying the environment in which LED (Light Emitting Diode) is used as artificial light. This study aims to determine changes in morphological, physiological, and anatomical responses to LED light’s different spectrum and intensity levels. The research used a two-factor, completely randomized design (CRD) consisting of an LED spectrum (purple and white) and two light intensities. The results showed the changes in morphological and physiological responses in high-intensity treatment with the white spectrum of LED (WH). The low intensity with the white spectrum of LED (WL) increased leaf chlorophyll content and photosynthesis rate. The anatomical response has in the low-intensity purple LED (PL) treatment. Increased leaf width occurred in high intensity with the purple LED spectrum (PH). Glucose content in the leaf decreased in all treatments, and increased fructose content in the leaf only occurred in the low-intensity purple spectrum of LED treatment.