Matsubara Mayflower Hospital

Aberrant immune responses to viral pathogens contribute to pathogenesis, but our understanding of pathological immune responses caused by viruses within the human virome, especially at a population scale, remains limited. We analyzed whole-genome sequencing datasets of 6,321 Japanese individuals, including patients with autoimmune diseases (psoriasis vulgaris, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), pulmonary alveolar proteinosis (PAP) or multiple sclerosis) and coronavirus disease 2019 (COVID-19), or healthy controls. We systematically quantified two constituents of the blood DNA virome, endogenous HHV-6 (eHHV-6) and anellovirus. Participants with eHHV-6B had higher risks of SLE and PAP; the former was validated in All of Us. eHHV-6B-positivity and high SLE disease activity index scores had strong correlations. Genome-wide association study and long-read sequencing mapped the integration of the HHV-6B genome to a locus on chromosome 22q. Epitope mapping and single-cell RNA sequencing revealed distinctive immune induction by eHHV-6B in patients with SLE. In addition, high anellovirus load correlated strongly with SLE, RA and COVID-19 status. Our analyses unveil relationships between the human virome and autoimmune and infectious diseases.

JAK/STAT signaling inhibition exerts therapeutic effects on angiogenesis in rheumatoid arthritis (RA). However, whether the inhibitory effect differs among JAK inhibitors because of differing selectivity is unknown. Therefore, we compared the inhibitory effects of tofacitinib, baricitinib, peficitinib, upadacitinib, and filgotinib on angiogenesis. RA-derived fibroblast-like synoviocytes (RA-FLS) were seeded on type I collagen gel, and human umbilical vein endothelial cells (HUVECs) were directly added. The control and aforementioned JAK inhibitors were added to the medium, followed by stimulation with interleukin (IL)-6 and soluble IL-6 receptor (sIL-6R). Each JAK inhibitor's concentration was determined based on estimated blood concentrations. The vascular endothelial growth factor (VEGF) concentration was evaluated with an enzyme-linked immunosorbent assay using the medium from the first exchange. A migration assay was performed, and HUVEC migration was evaluated using CD31 fluorescence immunostaining. Hematoxylin-eosin staining showed that compared with the non-JAKi treatment group, the JAKi treatment group markedly degenerated in the sub-lining and deep lining, with decreased lymphocyte infiltration and neovascularization [Rooney's score subscale, non-JAKi vs JAKi (median, 6.5 vs 2.5, p = 0.005)]. In vitro, IL-6 and sIL-6R administration increased VEGF production from RA-FLS and promoted neovascularization in HUVECs, and JAK-inhibitor administration, which decreased VEGF production from RA-FLS and suppressed HUVEC migration, inhibited neovascularization in RA-FLS and HUVEC co-cultures. The JAK inhibitors suppressed IL-6-induced angiogenesis via decreased VEGF production and HUVEC migration in RA-FLS and HUVEC co-cultures. No significant differences were observed among the JAK inhibitors, whose anti-angiogenic effect may be an important mechanism for RA treatment. Key Points • JAK inhibitors inhibit angiogenesis in RA by reducing VEGF production from RA-derived fibroblast-like synoviocytes. • Our study provides new insights into RA treatment by elucidating the anti-angiogenic effect of JAK inhibitors.

Background:Several recent clinical trials studied treatment adherence to methotrexate (MTX) and placebo in rheumatoid arthritis (RA) cases. However, no real-world studies on treatment adherence focus on phase-1 (P1) treatment with conventional synthetic (cs) disease-modifying anti-rheumatic drug (DMARD) monotherapy.Objectives:We investigated the 2-year continuity of P1 treatment in patients with RA who were DMARD-naïve and examined the factors influencing these retention rates.Methods:We assessed the eligibility of 934 patients with RA visiting our institution between 2013 and 2023. We excluded patients in whom treatment was started by a previous physician (n=520), to clarify the duration of the DMARD intervention, those who were administered the first DMARD in a clinical study(n=5), and those who received treatment deviating from the recommended EULAR management algorithm (n=22).We retrospectively examined continuity using Kaplan-Meier analysis for the MTX (MTX-G) and other csDMARD (DMARD-G) treatment arms performed in P1 for eligible subjects (n=386), with the following two dropout patterns:1)P1 treatment continuation rates with dropouts for P1 treatment discontinuation for any reason at 2 years.2)P1 treatment continuation rates with dropouts for transition to phase-2 (P2) treatment at 2 years.Additionally, factors influencing the P2 transition(P1→P2), such as the choice of first treatment, age at intervention, sex, response to treatment from the start of intervention to 13 weeks (early response), and risk factors in P2 (rheumatoid factor (RF), anti-CCP antibody (ACPA), high disease activity (HDA) at the first visit (DAS28ESR>5.1), and bone erosion (ERO) on radiography), were used in the COX regression analysis.Results:Treatment choice in P1 was made by the physician-in-charge, considering the comorbidities. Among the patients enrolled according to eligibility, 300 were in the MTX-G and 86 in the DMARD-G. The MTX-G included patients (n=12, 4.0%) with a history of other DMARD use within 2 weeks. The DMARD-G included the administration of salazosulfapyridine (82.6%), tacrolimus (10.9%), and other csDMARDs (8.8%). Treatment of patients transferred to P2 (n=209) included b/tsDMARD (add-on or switching) in 39.7%, add-on csDMARDs in 52.2%, and switching to csDMARD in 8.1%. Kaplan-Meier analysis showed that the continuation rates for P1 in the MTX-G and DMARD-G were 52.8% and 50.0% at Wk52, and 42.7% and 38.2% at Wk104, respectively, with no statistically significant differences in the initial drug choice. The continuation rates for P1→P2 were 54.0% and 51.5% at Wk52, and 44.4%and 42.9% at Wk104 in the MTX-G and DMARD-G, respectively, without statistically significant differences in the initial treatment choice. Reasons for P1→P2 transition included no response (0.9%), poor response (66.6%), loss of efficacy (21.5%), interstitial pneumonitis (1.4%), reduced eGFR (0.5%), liver dysfunction (1.9%), malignancy (0.5%), and others (10.5%). COX regression analysis of P1→P2 transition with candidate influencing factors as covariates showed a statistically significant difference (OR: 2.361; 95%CI 1.671–3.338, p<.001) in the early response.Conclusion:The first DMARD choice in the P1 treatment, considering complications, did not impact treatment continuity. However, MTX therapy has been shown to be more effective than other csDMARD in terms of treatment continuation rates and survival outcomes for P1→P2 patients. Therefore, the policy of recommending the use of MTX in the absence of contraindications, also supported by the EULAR recommendations, is likely to be maintained. As the treatment response up to 3 months after the treatment intervention influences P1→P2 transition, it is suggested that rheumatologists treating RA should follow the treat-to-target concept and appropriately assess disease activity monthly during the first 3 months of the initial treatment. Determining early P2 transition based on treatment response for up to three months may be useful in providing good outcomes for patients with RA.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:Takafumi Hagiwara Asahi Kasei Pharma Corporation., Astellas Pharma Inc., AbbVie GK, Eli Lilly Japan K.K., CHUGAI PHARMACEUTICAL Co., LTD. Eisai Co., Ltd, AYUMI Pharmaceutical Corporation., Taisho Pharmaceutical Holdings., UCB Japan Co., Ltd., Mitsubishi Chemical Group Corporation., Japan Blood Products Organization., GlaxoSmithKline K.K., and Sanofi K.K., Yuuya Yano Japan Blood Products Organization., Shintarou Tsumura: None declared, Noriyuki Namura: None declared, Kazuya Kamada: None declared, Satoshi Kashiwagi Astellas Pharma Inc., UCB Japan Co. LtD., Otsuka Pharmaceutical Co., Ltd., Eisai Co., Ltd., AYUMI Pharmaceutical Corporation., Eli Lilly Japan K.K., Asahi Kasei Pharma Corporation., and Mitsubishi Chemical Group Corporation., Tsukasa Matsubara Astellas Pharma Inc., Bristol-Myers Squibb., AbbVie GK, Eli Lilly Japan K.K., Pfizer Japan Inc., Gilead Sciences K.K., CHUGAI PHARMACEUTICAL CO., LTD. Eisai Co., Ltd, and AYUMI Pharmaceutical Corporation.

Background:Most of rheumatoid arthritis (RA) practice guidelines and recommendations suggest stopping of molecular target drugs such as biological and targeted synthetic disease-modifying antirheumatic drugs before orthopaedic surgeries. However, there are still concerns on increasing complications after surgeries, and no convincing data are available yet [2].Objectives:We aimed to investigate whether stopping of molecular target drugs before operations increase postoperative complications after orthopaedic surgeries in patients with RA in clinical practice by a multicenter cohort study.Methods:We collected cases of orthopaedic surgeries for patients with RA undergone from April, 2011 to March, 2017, in 19 specialized institutions in Japan. Demographic data, types of operations, drugs used for RA, stopping time periods of them, and postoperative complications within a year were recorded. We compared the incidence ratios of postoperative complications between stopping and no-stopping groups, among drug types, and among types of operations. Multivariate analyses were performed to investigate risk factors for delayed wound healing, surgical site infection (SSI), flare-up and death.Results:A total of 1953 cases were eligible for analyses. The averages of age, duration of the disease, and disease activity score 28 (DAS28)-CRP at the time of operation were 71.8 years, 18.6 years and 2.84, respectively. Methotrexate (MTX) and oral glucocorticoid were used in 59.5% and 58.0% of the patients. We set up two standards of stopping time period, and there were no statistical differences in incidence ratios of delayed wound healing, SSI and death in both standards, but the incidence ratio of flare-up was statistically higher in the stopping group. The incidence ratio of flare up was higher in IL-6 inhibitor group, and that of delayed wound healing was higher in major surgery group.Conclusion:The perioperative stopping of molecular target drugs may increase the incidence ratio of flare up in orthopaedic surgeries in patients with RA but does not influence those of other postoperative complications such as SSI.REFERENCES:[1] Ito H, et al. Non-Drug and Surgical Treatment Algorithm and Recommendations for the 2020 Update of the Japan College of Rheumatology Clinical Practice Guidelines for the Management of Rheumatoid Arthritis - Secondary Publication. Mod Rheumatol. 2023 Jan 3;33(1):36-45.[2] Ito H, et al. Does abatacept increase postoperative adverse events in rheumatoid arthritis compared with conventional synthetic disease-modifying drugs? J Rheumatol 2020;47;502-509.Acknowledgements:NIL.Disclosure of Interests:Hiromu Ito BMS, Hajime Ishikawa: None declared, Shigeyoshi Tsuji: None declared, Masanori Nakayama: None declared, Keiichiro Nishida: None declared, Takeshi Mochizuki: None declared, Kosuke Ebina: None declared, Toshihisa Kojima: None declared, Takumi Matsumoto: None declared, Ayako Kubota: None declared, Arata Nakajima: None declared, Atsushi Kaneko: None declared, Isao Matsushita: None declared, Ryota Hara: None declared, Koji Sakuraba: None declared, Yukio Akasaki: None declared, Tsukasa Matsubara: None declared, Yuichi Mochida: None declared, Katsuaki Kanbe: None declared, Natsuko Nakagawa: None declared, Koichi Murata: None declared, Masahide Hamaguchi: None declared, Shigeki Momohara: None declared.

To investigate the cell types that undergo apoptosis in TNF-α inhibitor (TNFI)- and IL-6 inhibitor (IL-6I)-treated synovia of RA patients, and to observe and compare histological changes in them. Synovial tissue was collected during total knee arthroplasty from 20 RA patients who were divided into three groups based on RA treatment received: conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs, control group), TNFI, or IL-6I. Tissue samples were subjected to haematoxylin and eosin staining, terminal deoxynucleotidyl transferase fluorescein-deoxyuridine triphosphate nick end labelling (TUNEL), immuno-histochemistry (IHC) and immunofluorescence staining for, respectively, histopathological assessment, apoptosis detection and IHC evaluation and scoring. TUNEL-positive cells were detected surrounding the discoid fibrosis unique to the TNFI group, while those in the IL-6I group were distributed widely, especially surrounding the blood vessels. IHC revealed that in TNFI-treated tissue, CD86- and CD80-positive cells were detected only in the lining and sublining layer, while CD163- and CD206-positive cells were detected more broadly; in the IL-6I-treated tissue, all four were detected widely but their levels were lower than in the control group. Immunofluorescence also revealed macrophages mainly were the apoptotic cells in the lining and sublining layers of TNFI group. TUNEL Expression levels of CD20- and CD3-positive cells were remarkably lower in the IL-6I group, compared with the control and TNFI groups. TNFIs and IL-6Is target different action sites and synovial cell types, resulting in histopathological features of synovium distinct from one another.

The objective of this study is to evaluate efficacy and safety of abatacept in biologic-naïve, anti-citrullinated protein antibody (ACPA)-positive Japanese patients with active rheumatoid arthritis (RA) by background methotrexate (MTX) dose. In this post hoc analysis of a randomized, double-blind, placebo-controlled phase 4 study (NCT01758198), patients received intravenous abatacept (∼10 mg/kg) or placebo both with MTX (≥6 mg/week). Efficacy (Disease Activity Score 28 using C-reactive protein [DAS28 (CRP)] and Health Assessment Questionnaire-Disability Index [HAQ-DI]) was assessed by baseline MTX dosage (≤8 and >8 mg/week) to week 16; safety was assessed by MTX dosage ≤8 and >8 mg/week. Change from baseline in DAS28 (CRP) and HAQ-DI was assessed using longitudinal repeated measures analysis. Overall, 101 and 102 patients received abatacept + MTX ≤8 and >8 mg/week, while 96 and 106 patients received placebo + MTX ≤8 and >8 mg/week, respectively. Regardless of baseline MTX dose received, mean changes from baseline in DAS28 (CRP) and HAQ-DI in abatacept groups were similar; repeated measures analysis showed similar trends in changes from baseline in DAS28 (CRP) and HAQ-DI. Abatacept safety profile was consistent with previous observations. Post hoc analysis demonstrated similar efficacy and safety of abatacept in biologic-naïve ACPA-positive Japanese patients with RA regardless of baseline MTX dose.

ObjectivesTo evaluate efficacy and safety of abatacept+methotrexate (MTX) in biologic-naive, anticitrullinated protein antibody (ACPA)-positive Japanese patients with active rheumatoid arthritis (RA) and early erosion versus placebo+MTX.MethodsIn this phase IV, multicentre, double-blind study (NCT01758198), patients were randomised (1:1) to receive intravenous abatacept (~10 mg/kg) or placebo, plus MTX (≥6 mg/week). Primary efficacy objectives were to compare American College of Rheumatology 20 (ACR20) response rates at week 16 and mean change from baseline in van der Heijde-modified total Sharp score (vdH-mTSS) at week 24 between abatacept+MTX and placebo+MTX groups.ResultsOverall, 203 and 202 patients received abatacept+MTX and placebo+MTX, respectively. At week 16, ACR20 response rates were higher in the abatacept (75.4%) versus placebo group (27.7%; p<0.001). Mean change from baseline in vdH-mTSS at week 24 was 0.84 in the abatacept and 1.26 in the placebo group (p=0.017). Radiographic non-progression rates (change in vdH-mTSS≤smallest detectable change (2.4)) were 88.1% and 75.4% in abatacept and placebo groups, respectively. Adjusted mean change from baseline in Disease Activity Score 28 (C-reactive protein) (DAS28 (CRP)) at week 16 demonstrated a numerically greater reduction in the abatacept versus placebo group. Proportions of patients with DAS28 (CRP), Simplified Disease Activity Index and Clinical Disease Activity Index remission up to week 52 were higher in the abatacept versus placebo group. The abatacept safety profile was consistent with previous observations.ConclusionsCompared with MTX alone, abatacept+MTX improved clinical symptoms and inhibited structural damage progression in ACPA-positive, Japanese patients with RA, early erosion and inadequate response to MTX.

The isomaltulose based liquid formula (MHN-01), suppresses postprandial plasma glucose and insulin levels in healthy persons and patients with impaired glucose tolerance (IGT) or type 2 diabetes. MHN-01 intake as a part of breakfast also suppresses glucose and insulin levels after lunch, suggesting second meal effect. The objective of this study was to investigate the effects of nutritional counseling and long-term (24 weeks) MHN-01 ingestion on biomarkers of metabolic syndrome. Forty-one subjects with criteria of metabolic syndrome participated in this study composed with the control period (0–12 week) followed by nutritional counseling and the experimental period (12–36 week) followed by 200 kcal (837 kJ) of MHN-01 or dextrin-based standard balanced liquid formula (SBF) loading as a part of breakfast. In 16 of 41 subjects became to out of criteria for liquid formula loading study during control period (unqualified group). In the unqualified group, several biomarkers were improved. In experimental period, serum HbA1c levels significantly increased in SBF group (n = 12) but did not change in MHN-01 group (n = 10). Thus, intake of 837 kJ MHN-01 as a part of breakfast may be effective for suppression of deteriorating glucose metabolism in metabolic syndrome.