Language：English  

DOI： 10.1080/03009742.2024.2327159

Web of Science

PubMed

Language：English   Publisher：Oxford University Press  

Language：English   Publisher：Rheumatology International  

This study aimed to clarify the efficacy and safety of treatment escalation by initiating therapeutic agents in serologically active clinically quiescent (SACQ) patients with systemic lupus erythematosus (SLE). We retrospectively evaluated SACQ patients with SLE for ≥ 180 days, with the introduction of a therapeutic agent for SLE defined as exposure. The efficacy endpoints included the time to flare and time to remission, whereas the safety endpoint was the incidence of adverse events. The efficacy endpoints were assessed via Cox proportional hazards model with time-dependent covariates, which included exposure, serological activity, and prednisolone dose. Among 109 SACQ patients, 24 were initiated on the following therapeutic agents for SLE: hydroxychloroquine (10 patients), belimumab (6 patients), and immunosuppressive agents (8 patients). A total of 37 patients experienced a flare (8 and 29 patients during exposure and nonexposure periods, respectively). The time to flare was comparable between the exposure and control groups. Among 68 patients who were not in remission at the start of observation, 27 patients achieved remission (5 and 22 patients during exposure and nonexposure periods, respectively). Although both groups had a similar time to remission, the exposure group treated with belimumab had a significantly higher rate of remission than the control group. The adverse events were more frequent during the exposure period than during the nonexposure period. Thus, this study did not reveal a clear influence of treatment escalation on flare prevention and remission achievement.

DOI： 10.1007/s00296-024-05593-6

Web of Science

Scopus

PubMed

Language：English   Publisher：Rheumatology International  

This study aimed to clarify the efficacy and safety of treatment escalation by initiating therapeutic agents in serologically active clinically quiescent (SACQ) patients with systemic lupus erythematosus (SLE). We retrospectively evaluated SACQ patients with SLE for ≥ 180 days, with the introduction of a therapeutic agent for SLE defined as exposure. The efficacy endpoints included the time to flare and time to remission, whereas the safety endpoint was the incidence of adverse events. The efficacy endpoints were assessed via Cox proportional hazards model with time-dependent covariates, which included exposure, serological activity, and prednisolone dose. Among 109 SACQ patients, 24 were initiated on the following therapeutic agents for SLE: hydroxychloroquine (10 patients), belimumab (6 patients), and immunosuppressive agents (8 patients). A total of 37 patients experienced a flare (8 and 29 patients during exposure and nonexposure periods, respectively). The time to flare was comparable between the exposure and control groups. Among 68 patients who were not in remission at the start of observation, 27 patients achieved remission (5 and 22 patients during exposure and nonexposure periods, respectively). Although both groups had a similar time to remission, the exposure group treated with belimumab had a significantly higher rate of remission than the control group. The adverse events were more frequent during the exposure period than during the nonexposure period. Thus, this study did not reveal a clear influence of treatment escalation on flare prevention and remission achievement.

DOI： 10.1007/s00296-024-05593-6

Web of Science

Scopus

PubMed

Language：English   Publisher：Modern Rheumatology Case Reports  

We experienced a case of rheumatoid arthritis and JAK2V617F mutation–positive essential thrombocythemia treated with baricitinib. The patient was a 72-year-old male. He was diagnosed with rheumatoid arthritis at a local clinic in April 2018. Methotrexate (MTX) was started and the dose was increased to 16 mg/week. In October of the same year, anaemia was observed and MTX was reduced, but anaemia progressed. Blood tests showed pancytopenia, and he was referred to Rheumatology on suspicion of drug-induced pancytopenia. Pancytopenia improved with discontinuation of MTX and administration of folic acid. His platelet count was markedly increased to 1,400,000/μl at one point, decreased to 400,000/μl, and then gradually increased to 700,000–1,000,000/μl. Despite taking an antiplatelet drug, he developed cerebral infarction in June 2019. The JAK2V617F mutation was noted, and he was diagnosed with essential thrombocythemia. Hydroxycarbamide was started, but the effect was insufficient. Baricitinib, a JAK1/2 inhibitor indicated for rheumatoid arthritis, was started in August with the expectation that it would also be effective for essential thrombocythemia. The platelet count decreased to ∼400,000–600,000 cells/μl, and a decrease in the C-reactive protein level and the improvement of arthritis were noted. We report this case because it is considered to be a valuable case, suggesting that baricitinib may be effective for essential thrombocythemia.

DOI： 10.1093/mrcr/rxad012

Scopus

PubMed

Language：English   Publisher：Modern Rheumatology Case Reports  

We experienced a case of rheumatoid arthritis and JAK2V617F mutation–positive essential thrombocythemia treated with baricitinib. The patient was a 72-year-old male. He was diagnosed with rheumatoid arthritis at a local clinic in April 2018. Methotrexate (MTX) was started and the dose was increased to 16 mg/week. In October of the same year, anaemia was observed and MTX was reduced, but anaemia progressed. Blood tests showed pancytopenia, and he was referred to Rheumatology on suspicion of drug-induced pancytopenia. Pancytopenia improved with discontinuation of MTX and administration of folic acid. His platelet count was markedly increased to 1,400,000/μl at one point, decreased to 400,000/μl, and then gradually increased to 700,000–1,000,000/μl. Despite taking an antiplatelet drug, he developed cerebral infarction in June 2019. The JAK2V617F mutation was noted, and he was diagnosed with essential thrombocythemia. Hydroxycarbamide was started, but the effect was insufficient. Baricitinib, a JAK1/2 inhibitor indicated for rheumatoid arthritis, was started in August with the expectation that it would also be effective for essential thrombocythemia. The platelet count decreased to ∼400,000–600,000 cells/μl, and a decrease in the C-reactive protein level and the improvement of arthritis were noted. We report this case because it is considered to be a valuable case, suggesting that baricitinib may be effective for essential thrombocythemia.

DOI： 10.1093/mrcr/rxad012

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1136/rmdopen-2023-003693.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/1756-185X.15009.

Language：English   Publisher：RMD Open  

Objectives Understanding interpatient variation in CD4+T-cell responses is the bases for understanding the pathogenesis and management of rheumatoid arthritis (RA). We examined immune responses to SARS-CoV-2 vaccine in a cohort of patients with RA and determined factors associated with the responses. Methods Four hundred and thirty-one patients with RA having received two doses of BNT162b2, a messenger RNA-based vaccine for SARS-CoV-2, were included. Vaccine antigen-specific IgG was detected by ELISA, and antigen-specific CD4+T cells were detected by CD154 expression in response to antigenic stimulation. Expression of cytokines was concomitantly detected by intracellular staining. Associations among background variables, antigen-specific antibody production and the CD4+T-cell responses were analysed. Unsupervised hierarchical clustering was performed based on the profiles of antigen-specific cytokine production by CD4+T cells to stratify patients with RA. Results Multivariate analysis indicated that ageing negatively affects CD4+T-cell response as well as antibody production. No association was detected between the presence or the levels of rheumatoid factor/anti-cyclic citrullinated peptide antibody and anti-vaccine immune responses. Methotrexate and prednisolone reduced B cell but not T-cell responses. Conventional immunophenotyping by the expression of chemokine receptors was not associated with the actual CD4+T-cell response, except for T helper cells (Th1). Functional immunophenotyping based on the profiles of antigen-specific cytokine production of CD4+T cells stratified patients with RA into three clusters, among which Th1-dominant type less frequently underwent joint surgery. Conclusions Clinical and immunological variables that are associated with antigen-specific CD4 T-cell responses in patients with RA were determined by analysing immune responses against SARS-CoV-2 vaccine.

DOI： 10.1136/rmdopen-2023-003693

Web of Science

Scopus

PubMed

Language：English   Publisher：International Journal of Rheumatic Diseases  

Objective: To evaluate trends in results of care and management for antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). Methods: We employed multicenter cohort data collected during 2011–2021, recruiting 43 patients with granulomatosis with polyangiitis (GPA) and 91 with microscopic polyangiitis (MPA). According to the median registration date of September 2015, patients have split into two groups: an early group and a late group (both of them, n = 67). To prevent bias, a propensity score according to numerous baseline characteristics variables was calculated; 50 matching members of each group were statistically extracted. Their treatments and clinical outcomes were examined at 6, 12, and 24 months after initial remission therapy. Results: Statistics demonstrated that the baseline characteristics were similar. The late group used rituximab (RTX) more often for both remission induction and maintenance therapy, compared with the early group. The mean daily PSL doses of the late group were significantly lower than those of early group at each time point. The late group discontinued PSL 14.0% at 12 months and 23.3% at 24 months. Despite their intensive glucocorticoids (GC) tapering, the remission rates and the relapse rates were significantly fairer in the late group. The Vasculitis Damage Index (VDI) and VDI due to GC at each time point were lower in the late group, and those differences had become wider over time. Conclusion: Recent developments in AAV treatment have allowed efficient remission and prevention of relapses, which in turn enabled extensive GC tapering causing fewer sequelae.

DOI： 10.1111/1756-185X.15009

Web of Science

Scopus

PubMed

Language：English   Publisher：Oxford University Press  

症例は72歳男性で、高血圧、心筋梗塞、閉塞性動脈硬化症、大動脈解離の既往があり、5年前に関節症状をきたして近医を受診した。血液検査でリウマチ因子と抗環状シトルリン化ペプチド(CCP)抗体陽性を示し、関節リウマチ(RA)との診断でメトトレキサート(MTX)投与が開始された。その後、貧血の増悪と血便を認め、当院紹介となった。内視鏡検査で内痔核と診断し、血液検査の結果からMTX誘発性汎血球減少症が疑われた。このため、MTXを中止して葉酸投与を開始し、関節症状の再燃に対してプレドニゾロン(PSL)とサラゾスルファピリジン(SASP)を投与した。その後、脳梗塞を発症し、ヘパリンとエダラボンを開始、3日後にアスピリンとクロピドグレル併用、さらに7日後にクロピドグレル単剤に変更した。遺伝子解析でJAK2V617F変異が検出されたため本態性血小板血症と診断した。ヒドロキシカルバミドを投与するも治療効果が得られず、RAのコントロールも不良であったためバリシチニブを投与した。その後、血小板数とCRP値の低下、関節症状の改善が得られた。DAS28-CRPは低値を維持しており、PSLを漸減ののちに中止した。

Language：English   Publisher：International Journal of Rheumatic Diseases  

Objective: To evaluate trends in results of care and management for antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). Methods: We employed multicenter cohort data collected during 2011–2021, recruiting 43 patients with granulomatosis with polyangiitis (GPA) and 91 with microscopic polyangiitis (MPA). According to the median registration date of September 2015, patients have split into two groups: an early group and a late group (both of them, n = 67). To prevent bias, a propensity score according to numerous baseline characteristics variables was calculated; 50 matching members of each group were statistically extracted. Their treatments and clinical outcomes were examined at 6, 12, and 24 months after initial remission therapy. Results: Statistics demonstrated that the baseline characteristics were similar. The late group used rituximab (RTX) more often for both remission induction and maintenance therapy, compared with the early group. The mean daily PSL doses of the late group were significantly lower than those of early group at each time point. The late group discontinued PSL 14.0% at 12 months and 23.3% at 24 months. Despite their intensive glucocorticoids (GC) tapering, the remission rates and the relapse rates were significantly fairer in the late group. The Vasculitis Damage Index (VDI) and VDI due to GC at each time point were lower in the late group, and those differences had become wider over time. Conclusion: Recent developments in AAV treatment have allowed efficient remission and prevention of relapses, which in turn enabled extensive GC tapering causing fewer sequelae.

DOI： 10.1111/1756-185X.15009

Web of Science

Scopus

PubMed

Language：English   Publisher：RMD Open  

Objectives Understanding interpatient variation in CD4+T-cell responses is the bases for understanding the pathogenesis and management of rheumatoid arthritis (RA). We examined immune responses to SARS-CoV-2 vaccine in a cohort of patients with RA and determined factors associated with the responses. Methods Four hundred and thirty-one patients with RA having received two doses of BNT162b2, a messenger RNA-based vaccine for SARS-CoV-2, were included. Vaccine antigen-specific IgG was detected by ELISA, and antigen-specific CD4+T cells were detected by CD154 expression in response to antigenic stimulation. Expression of cytokines was concomitantly detected by intracellular staining. Associations among background variables, antigen-specific antibody production and the CD4+T-cell responses were analysed. Unsupervised hierarchical clustering was performed based on the profiles of antigen-specific cytokine production by CD4+T cells to stratify patients with RA. Results Multivariate analysis indicated that ageing negatively affects CD4+T-cell response as well as antibody production. No association was detected between the presence or the levels of rheumatoid factor/anti-cyclic citrullinated peptide antibody and anti-vaccine immune responses. Methotrexate and prednisolone reduced B cell but not T-cell responses. Conventional immunophenotyping by the expression of chemokine receptors was not associated with the actual CD4+T-cell response, except for T helper cells (Th1). Functional immunophenotyping based on the profiles of antigen-specific cytokine production of CD4+T cells stratified patients with RA into three clusters, among which Th1-dominant type less frequently underwent joint surgery. Conclusions Clinical and immunological variables that are associated with antigen-specific CD4 T-cell responses in patients with RA were determined by analysing immune responses against SARS-CoV-2 vaccine.

DOI： 10.1136/rmdopen-2023-003693

Web of Science

Scopus

PubMed

Language：English   Publisher：Oxford University Press  

症例は72歳男性で、高血圧、心筋梗塞、閉塞性動脈硬化症、大動脈解離の既往があり、5年前に関節症状をきたして近医を受診した。血液検査でリウマチ因子と抗環状シトルリン化ペプチド(CCP)抗体陽性を示し、関節リウマチ(RA)との診断でメトトレキサート(MTX)投与が開始された。その後、貧血の増悪と血便を認め、当院紹介となった。内視鏡検査で内痔核と診断し、血液検査の結果からMTX誘発性汎血球減少症が疑われた。このため、MTXを中止して葉酸投与を開始し、関節症状の再燃に対してプレドニゾロン(PSL)とサラゾスルファピリジン(SASP)を投与した。その後、脳梗塞を発症し、ヘパリンとエダラボンを開始、3日後にアスピリンとクロピドグレル併用、さらに7日後にクロピドグレル単剤に変更した。遺伝子解析でJAK2V617F変異が検出されたため本態性血小板血症と診断した。ヒドロキシカルバミドを投与するも治療効果が得られず、RAのコントロールも不良であったためバリシチニブを投与した。その後、血小板数とCRP値の低下、関節症状の改善が得られた。DAS28-CRPは低値を維持しており、PSLを漸減ののちに中止した。

Publisher：医歯薬出版  

DOI： 10.32118/ayu28710768

CiNii Research

Publisher：医歯薬出版  

DOI： 10.32118/ayu28710768

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/mrcr/rxad012.

Language：English   Publisher：Oxford University Press  

全身性エリテマトーデス(SLE)患者に対する免疫抑制剤切り替えの有効性と安全性について検討し、薬剤切り替え後の治療不応の予測因子を評価した。SLE患者39例(男性4例、女性35例、平均41.5±12.6歳)を対象に後ろ向きコホート研究を行った。有効性評価項目はSLE疾患重症度指数(SLEDAI)2000スコアの変化、プレドニゾロンの用量、12ヵ月以上にわたるSLEの状況、治療継続率、安全性評価項目は有害事象の発現頻度とした。患者の約70%は作用機序が同じ薬剤間のスイッチングであり、タクロリムスの処方が最も多く、ミコフェノール酸モフェチルがこれに続いていた。薬剤切り替えの理由は効果不十分が20例、有害事象が14例、その他が5例となっていた。SLEDAIスコアは薬剤切り替えの9ヵ月後に有意に減少し、プレドニゾロンの用量は中央値13mgから12ヵ月後に8.25mgに減少しており、3例を除いてSLE症状の安定が得られていた。治療継続率は1年後が71.4%、2年後が62.3%、3年後が53.4%、治療不応率は1年後が29.0%、2年後が46.7%、3年後が46.7%であった。投与中止に至る有害事象の発現は10例に認められたが、感染症や重篤な有害事象の発現はみられなかった。多重Coxハザード回帰分析では、治療不応の予測因子として効果不十分を理由とする薬剤切り替えが示された。SLE患者に対する免疫抑制剤の切り替えは有効かつ安全であることが明らかになった。

Language：English   Publisher：Oxford University Press  

全身性エリテマトーデス(SLE)患者に対する免疫抑制剤切り替えの有効性と安全性について検討し、薬剤切り替え後の治療不応の予測因子を評価した。SLE患者39例(男性4例、女性35例、平均41.5±12.6歳)を対象に後ろ向きコホート研究を行った。有効性評価項目はSLE疾患重症度指数(SLEDAI)2000スコアの変化、プレドニゾロンの用量、12ヵ月以上にわたるSLEの状況、治療継続率、安全性評価項目は有害事象の発現頻度とした。患者の約70%は作用機序が同じ薬剤間のスイッチングであり、タクロリムスの処方が最も多く、ミコフェノール酸モフェチルがこれに続いていた。薬剤切り替えの理由は効果不十分が20例、有害事象が14例、その他が5例となっていた。SLEDAIスコアは薬剤切り替えの9ヵ月後に有意に減少し、プレドニゾロンの用量は中央値13mgから12ヵ月後に8.25mgに減少しており、3例を除いてSLE症状の安定が得られていた。治療継続率は1年後が71.4%、2年後が62.3%、3年後が53.4%、治療不応率は1年後が29.0%、2年後が46.7%、3年後が46.7%であった。投与中止に至る有害事象の発現は10例に認められたが、感染症や重篤な有害事象の発現はみられなかった。多重Coxハザード回帰分析では、治療不応の予測因子として効果不十分を理由とする薬剤切り替えが示された。SLE患者に対する免疫抑制剤の切り替えは有効かつ安全であることが明らかになった。

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/mr/roac100.

Language：English   Publisher：Modern Rheumatology  

Objectives: The incidence and prognosis of Coronavirus Disease 2019 (COVID-19) and rheumatic disease vary among ethnicities and regions. COVID-19 outcomes in rheumatic disease patients remain unclear, especially in the Asia-Pacific region. This study aimed to clarify the demographic and clinical factors that may influence COVID-19 prognosis in rheumatic disease patients. Methods: This was a case series of patients registered with the COVID-19 national registry of Japan College of Rheumatology between 3 June 2020 and 30 June 2021. Multivariable logistic regression was used to estimate the risk of hospitalization or death. Age, sex, smoking status, rheumatic disease diagnosis, comorbidities, and rheumatic disease medications are taken immediately before infection was analysed. Results: A total of 220 patients from 55 institutions in Japan were included in the study, among whom 186 (84.5%) were hospitalized and 11 (5.0%) died. COVID-19 treatments were provided to 126 patients (57.3%) and mainly comprised glucocorticoids, favipiravir, remdesivir, and tocilizumab. In the multiple logistic regression model, older age and a history of hypertension were associated with hospitalization, while older age was associated with mortality. No specific treatment was correlated with mortality or hospitalization by the multivariate analysis. Conclusions: Older age and hypertension were associated with a poor prognosis in Japanese COVID-19 patients with connective tissue disease. Factors not directly related to connective tissue disease were closely associated with the prognosis.

DOI： 10.1093/mr/roac104

Scopus

PubMed

Language：English   Publisher：Modern Rheumatology  

Objectives: The incidence and prognosis of Coronavirus Disease 2019 (COVID-19) and rheumatic disease vary among ethnicities and regions. COVID-19 outcomes in rheumatic disease patients remain unclear, especially in the Asia-Pacific region. This study aimed to clarify the demographic and clinical factors that may influence COVID-19 prognosis in rheumatic disease patients. Methods: This was a case series of patients registered with the COVID-19 national registry of Japan College of Rheumatology between 3 June 2020 and 30 June 2021. Multivariable logistic regression was used to estimate the risk of hospitalization or death. Age, sex, smoking status, rheumatic disease diagnosis, comorbidities, and rheumatic disease medications are taken immediately before infection was analysed. Results: A total of 220 patients from 55 institutions in Japan were included in the study, among whom 186 (84.5%) were hospitalized and 11 (5.0%) died. COVID-19 treatments were provided to 126 patients (57.3%) and mainly comprised glucocorticoids, favipiravir, remdesivir, and tocilizumab. In the multiple logistic regression model, older age and a history of hypertension were associated with hospitalization, while older age was associated with mortality. No specific treatment was correlated with mortality or hospitalization by the multivariate analysis. Conclusions: Older age and hypertension were associated with a poor prognosis in Japanese COVID-19 patients with connective tissue disease. Factors not directly related to connective tissue disease were closely associated with the prognosis.

DOI： 10.1093/mr/roac104

Scopus

PubMed

Language：English   Publisher：Oxford University Press  

リウマチ性疾患日本人患者におけるCOVID-19の予後因子について検討した。日本リウマチ学会の全国COVID-19レジストリに2020年6月3日～2021年6月30日に登録された患者を対象とした。多変量ロジスティック回帰で入院または死亡のリスクを推定した。年齢、性別、喫煙状況、リウマチ性疾患の診断、併存疾患、感染前に服用したリウマチ性疾患治療薬を解析した。全国55施設の患者220例(女性65.0%、中央値61.5歳)を解析対象とした。186例(84.5%)が入院、11例(5.0%)が死亡した。126例(57.3%)がCOVID-19治療を受けた。多変量ロジスティック回帰モデルで、入院と関連した因子は年齢の高さおよび高血圧の既往、死亡と関連した因子は年齢の高さであった。多変量解析で、特定の治療法と死亡や入院に相関は認められなかった。以上より、リウマチ性疾患の日本人患者においてCOVID-19の予後不良と関連を認めたのは年齢の高さと高血圧で、リウマチ性疾患と直接関与しない因子であった。

Language：English   Publisher：Oxford University Press  

リウマチ性疾患日本人患者におけるCOVID-19の予後因子について検討した。日本リウマチ学会の全国COVID-19レジストリに2020年6月3日～2021年6月30日に登録された患者を対象とした。多変量ロジスティック回帰で入院または死亡のリスクを推定した。年齢、性別、喫煙状況、リウマチ性疾患の診断、併存疾患、感染前に服用したリウマチ性疾患治療薬を解析した。全国55施設の患者220例(女性65.0%、中央値61.5歳)を解析対象とした。186例(84.5%)が入院、11例(5.0%)が死亡した。126例(57.3%)がCOVID-19治療を受けた。多変量ロジスティック回帰モデルで、入院と関連した因子は年齢の高さおよび高血圧の既往、死亡と関連した因子は年齢の高さであった。多変量解析で、特定の治療法と死亡や入院に相関は認められなかった。以上より、リウマチ性疾患の日本人患者においてCOVID-19の予後不良と関連を認めたのは年齢の高さと高血圧で、リウマチ性疾患と直接関与しない因子であった。

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3389/fimmu.2022.1016914.

researchmap

Language：English   Publisher：Modern rheumatology  

OBJECTIVES: To evaluate the impact of medication on antibody response to severe acute respiratory syndrome coronavirus-2 mRNA vaccines in Japanese patients with rheumatic diseases. METHODS: This prospective multicentre cohort study evaluated the humoral response in 12 different medication groups. Antibody levels before the first vaccination and 3-6 weeks after the second vaccination were measured using the Elecsys Anti-SARS-CoV-2 S assay. Statistical analysis included comparing antibody titres among the different medication groups using the Kruskal-Wallis test followed by the Bonferroni-Dunn test and multiple linear regression analysis. RESULTS: 295 patients were analysed. The seroconversion rate was 92.2% and the median antibody titre was 255 U/ml (interquartile range, 34.1-685) after the second mRNA vaccination. Antibody levels were significantly lower in the groups treated with Tumour necrosis factor inhibitor with methotrexate, abatacept, mycophenolate mofetil (MMF), MMF or mizoribine combined with calcineurin inhibitor, and rituximab or cyclophosphamide compared with those treated with sulfasalazine and/or bucillamine or calcineurin inhibitor (p < 0.01). The correlation between antibody titre and treatment was significant after adjusting for age, gender, and glucocorticoid dose (p < 0.01). CONCLUSIONS: Additional early vaccination is required in patients treated with Tumour necrosis factor inhibitor and methotrexate, abatacept, MMF, MMF or mizoribine combined with calcineurin inhibitor and rituximab or cyclophosphamide.

DOI： 10.1093/mr/roac030

Web of Science

Scopus

PubMed

Language：English   Publisher：Modern rheumatology  

OBJECTIVES: To evaluate the impact of medication on antibody response to severe acute respiratory syndrome coronavirus-2 mRNA vaccines in Japanese patients with rheumatic diseases. METHODS: This prospective multicentre cohort study evaluated the humoral response in 12 different medication groups. Antibody levels before the first vaccination and 3-6 weeks after the second vaccination were measured using the Elecsys Anti-SARS-CoV-2 S assay. Statistical analysis included comparing antibody titres among the different medication groups using the Kruskal-Wallis test followed by the Bonferroni-Dunn test and multiple linear regression analysis. RESULTS: 295 patients were analysed. The seroconversion rate was 92.2% and the median antibody titre was 255 U/ml (interquartile range, 34.1-685) after the second mRNA vaccination. Antibody levels were significantly lower in the groups treated with Tumour necrosis factor inhibitor with methotrexate, abatacept, mycophenolate mofetil (MMF), MMF or mizoribine combined with calcineurin inhibitor, and rituximab or cyclophosphamide compared with those treated with sulfasalazine and/or bucillamine or calcineurin inhibitor (p < 0.01). The correlation between antibody titre and treatment was significant after adjusting for age, gender, and glucocorticoid dose (p < 0.01). CONCLUSIONS: Additional early vaccination is required in patients treated with Tumour necrosis factor inhibitor and methotrexate, abatacept, MMF, MMF or mizoribine combined with calcineurin inhibitor and rituximab or cyclophosphamide.

DOI： 10.1093/mr/roac030

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Language：English   Publisher：Oxford University Press  

日本人リウマチ患者を対象に12種類の投薬群において、SARS-CoV-2 mRNAワクチン接種前と2回目の接種3～6週後および6ヵ月後に抗体価を測定する前向き多施設コホート研究を実施した。本研究では、2回目接種後3～6週目までの中間解析をまとめた。1回目のワクチン接種前と2回目のワクチン接種の3～6週間後に、Elecsys抗SARS-CoV-2 Sアッセイを用いて抗体レベルを測定した。統計解析として、Kruskal-Wallis検定とBonferroni-Dunn検定、および重回帰分析を用いて、異なる投薬群間で抗体価を比較した。患者295例(年齢中央値57歳)を分析した。その結果、セロコンバージョン率は92.2%で、2回目のmRNAワクチン接種後の抗体価中央値は255U/mL(四分位範囲34.1～685)であった。メトトレキサート(MTX)を併用したTNF阻害剤、MTXを併用しないアバタセプト、ミコフェノール酸モフェチル(MMF)、MMF/ミゾリビンとカルシニューリン阻害剤(CNI)の併用、およびリツキシマブ/シクロホスファミド群の患者は、スルファサラジン/ブシラミン群およびCNI群の患者よりも有意に抗体価が低かった(p<0.01)。さらに、抗体価と治療との相関は、年齢、性別、グルココルチコイド投与量で調整した後でも有意であった(p<0.01)。

Language：English   Publisher：Oxford University Press  

日本人リウマチ患者を対象に12種類の投薬群において、SARS-CoV-2 mRNAワクチン接種前と2回目の接種3～6週後および6ヵ月後に抗体価を測定する前向き多施設コホート研究を実施した。本研究では、2回目接種後3～6週目までの中間解析をまとめた。1回目のワクチン接種前と2回目のワクチン接種の3～6週間後に、Elecsys抗SARS-CoV-2 Sアッセイを用いて抗体レベルを測定した。統計解析として、Kruskal-Wallis検定とBonferroni-Dunn検定、および重回帰分析を用いて、異なる投薬群間で抗体価を比較した。患者295例(年齢中央値57歳)を分析した。その結果、セロコンバージョン率は92.2%で、2回目のmRNAワクチン接種後の抗体価中央値は255U/mL(四分位範囲34.1～685)であった。メトトレキサート(MTX)を併用したTNF阻害剤、MTXを併用しないアバタセプト、ミコフェノール酸モフェチル(MMF)、MMF/ミゾリビンとカルシニューリン阻害剤(CNI)の併用、およびリツキシマブ/シクロホスファミド群の患者は、スルファサラジン/ブシラミン群およびCNI群の患者よりも有意に抗体価が低かった(p<0.01)。さらに、抗体価と治療との相関は、年齢、性別、グルココルチコイド投与量で調整した後でも有意であった(p<0.01)。

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DOI： 10.1093/rheumatology/kead082

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Language：English   Publisher：Frontiers in Immunology  

Background: Systemic sclerosis (SSc) is a multiple-organ disease characterized by vascular damage, autoimmunity, and tissue fibrosis. Organ injuries such as interstitial lung diseases (ILD), resulting from inflammatory and fibrosis processes, lead to poor prognosis. Although autoantibodies are detected in the serum of patients with SSc, the mechanisms by which immune cells are involved in tissue inflammation and fibrosis is not fully understood. Recent studies have revealed carcinoembryonic antigen related cell adhesion molecule (CEACAM)-positive monocytes are involved in murine bleomycin-induced lung fibrosis. We investigated CEACAM-positive monocytes in patients with SSc to clarify the role of monocytes in the pathogenesis of SSc. Methods: The proportion of of CEACAM-positive classical monocytes in healthy controls (HCs) and patients with rheumatoid arthritis (RA) and SSc was evaluated using flow cytometry. The correlation between the proportion of CEACAM-positive monocytes and clinical parameters was analyzed in patients with SSc. Gene expression microarrays were performed in CEACAM-positive and negative monocytes in patients with SSc. Infiltration of CEACAM-positive monocytes into scleroderma skin was evaluated by immunohistochemical staining. Results: The proportion of CEACAM-positive classical monocytes was increased in patients with early SSc within 2 years after diagnosis, which positively correlated with ESR, serum IgG, and serum KL-6 and negatively correlated with %forced vital capacity. The percentage of CEACAM-positive monocytes decreased after immunosuppressive therapy. CEACAM6-positive cells among classical monocytes were significantly increased in patients with SSc compared with HCs and patients with rheumatoid arthritis. SSc serum induced CEACAM6 expression on monocytes from HCs. Functionally, CEACAM-positive monocytes produced higher levels of TNF-α and IL-1β compared to CEACAM-negative cells and showed activation of the NF-κB pathway. Furthermore, CEACAM6-positive monocytes infiltrated the dermis of SSc. Conclusions: CEACAM-positive monocytes showed inflammatory phenotypes and may be involved in the tissue inflammation and fibrosis in early SSc. CEACAM-positive monocytes may be one of biomarkers to detect patients with progressive ILD, requiring therapeutic intervention.

DOI： 10.3389/fimmu.2022.1016914

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Language：English   Publisher：Frontiers in Immunology  

Background: Systemic sclerosis (SSc) is a multiple-organ disease characterized by vascular damage, autoimmunity, and tissue fibrosis. Organ injuries such as interstitial lung diseases (ILD), resulting from inflammatory and fibrosis processes, lead to poor prognosis. Although autoantibodies are detected in the serum of patients with SSc, the mechanisms by which immune cells are involved in tissue inflammation and fibrosis is not fully understood. Recent studies have revealed carcinoembryonic antigen related cell adhesion molecule (CEACAM)-positive monocytes are involved in murine bleomycin-induced lung fibrosis. We investigated CEACAM-positive monocytes in patients with SSc to clarify the role of monocytes in the pathogenesis of SSc. Methods: The proportion of of CEACAM-positive classical monocytes in healthy controls (HCs) and patients with rheumatoid arthritis (RA) and SSc was evaluated using flow cytometry. The correlation between the proportion of CEACAM-positive monocytes and clinical parameters was analyzed in patients with SSc. Gene expression microarrays were performed in CEACAM-positive and negative monocytes in patients with SSc. Infiltration of CEACAM-positive monocytes into scleroderma skin was evaluated by immunohistochemical staining. Results: The proportion of CEACAM-positive classical monocytes was increased in patients with early SSc within 2 years after diagnosis, which positively correlated with ESR, serum IgG, and serum KL-6 and negatively correlated with %forced vital capacity. The percentage of CEACAM-positive monocytes decreased after immunosuppressive therapy. CEACAM6-positive cells among classical monocytes were significantly increased in patients with SSc compared with HCs and patients with rheumatoid arthritis. SSc serum induced CEACAM6 expression on monocytes from HCs. Functionally, CEACAM-positive monocytes produced higher levels of TNF-α and IL-1β compared to CEACAM-negative cells and showed activation of the NF-κB pathway. Furthermore, CEACAM6-positive monocytes infiltrated the dermis of SSc. Conclusions: CEACAM-positive monocytes showed inflammatory phenotypes and may be involved in the tissue inflammation and fibrosis in early SSc. CEACAM-positive monocytes may be one of biomarkers to detect patients with progressive ILD, requiring therapeutic intervention.

DOI： 10.3389/fimmu.2022.1016914

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DOI： 10.1093/mr/roac100

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DOI： 10.1093/mr/roac100

Language：English   Publisher：Modern Rheumatology Case Reports  

A 25-year-old woman was admitted to our hospital with severe pulmonary arterial hypertension associated with systemic lupus erythematosus (SLE-PAH). Her mean pulmonary arterial pressure was 56 mmHg, and her SLE Disease Activity Index-2 K score was 14 on admission. In addition to a strong immunosuppressive regimen, which included steroid pulse therapy followed by high-dose oral prednisolone (1 mg/kg) and intravenous cyclophosphamide, an upfront combination of vasodilator therapy, including oral tadalafil, macitentan, and intravenous epoprostenol, was administered in the early phase. Two months later, her mean pulmonary arterial pressure was 29 mmHg, and her other haemodynamic markers showed significant improvement. She refused to start life-long intravenous epoprostenol therapy and so was switched to oral selexipag and inhaled iloprost. The transition was successful, and she has experienced no exacerbations of SLE-PAH during the 10 months since the onset of pulmonary arterial hypertension. To the best of our knowledge, this is the first report of intravenous epoprostenol being switched to alternative oral and inhaled therapy in a patient with SLE-PAH. In combination with adequate immunosuppressive therapy, it is probably easier to make this transition in patients with SLE-PAH than in those with pulmonary arterial hypertension of a different aetiology. Continuous infusion of epoprostenol can have potentially life-threatening complications and a detrimental effect on the quality of life. Our alternative treatment strategy was successful, and we hope that it will prove beneficial in other cases.

DOI： 10.1093/mrcr/rxac009

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Language：English   Publisher：Modern Rheumatology Case Reports  

A 25-year-old woman was admitted to our hospital with severe pulmonary arterial hypertension associated with systemic lupus erythematosus (SLE-PAH). Her mean pulmonary arterial pressure was 56 mmHg, and her SLE Disease Activity Index-2 K score was 14 on admission. In addition to a strong immunosuppressive regimen, which included steroid pulse therapy followed by high-dose oral prednisolone (1 mg/kg) and intravenous cyclophosphamide, an upfront combination of vasodilator therapy, including oral tadalafil, macitentan, and intravenous epoprostenol, was administered in the early phase. Two months later, her mean pulmonary arterial pressure was 29 mmHg, and her other haemodynamic markers showed significant improvement. She refused to start life-long intravenous epoprostenol therapy and so was switched to oral selexipag and inhaled iloprost. The transition was successful, and she has experienced no exacerbations of SLE-PAH during the 10 months since the onset of pulmonary arterial hypertension. To the best of our knowledge, this is the first report of intravenous epoprostenol being switched to alternative oral and inhaled therapy in a patient with SLE-PAH. In combination with adequate immunosuppressive therapy, it is probably easier to make this transition in patients with SLE-PAH than in those with pulmonary arterial hypertension of a different aetiology. Continuous infusion of epoprostenol can have potentially life-threatening complications and a detrimental effect on the quality of life. Our alternative treatment strategy was successful, and we hope that it will prove beneficial in other cases.

DOI： 10.1093/mrcr/rxac009

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Language：English   Publisher：Frontiers in Immunology  

ANCA (anti-neutrophil cytoplasmic antibody)-associated vasculitis (AAV) is the condition in which ANCA, as an autoantibody, is associated with the pathogenesis of vasculitis in small blood vessels, mainly in the ear, nose, throat, kidney, lung, and nerves. These diseases are important because they can be fatal due to renal failure and pulmonary hemorrhage if not promptly and appropriately treated. Recently accumulated evidence has shown that C5a produced by the complement alternative pathway primes neutrophils, which in turn activate the complement alternative pathway, leading to the pathogenesis of AAV. Avacopan (CCX168), a C5aR antagonist was shown to be effective against AAV, and it has been a novel therapeutic option, becoming a novel anti-complement drug to modulate inflammatory diseases.

DOI： 10.3389/fimmu.2022.926044

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Language：English   Publisher：Frontiers in Immunology  

ANCA (anti-neutrophil cytoplasmic antibody)-associated vasculitis (AAV) is the condition in which ANCA, as an autoantibody, is associated with the pathogenesis of vasculitis in small blood vessels, mainly in the ear, nose, throat, kidney, lung, and nerves. These diseases are important because they can be fatal due to renal failure and pulmonary hemorrhage if not promptly and appropriately treated. Recently accumulated evidence has shown that C5a produced by the complement alternative pathway primes neutrophils, which in turn activate the complement alternative pathway, leading to the pathogenesis of AAV. Avacopan (CCX168), a C5aR antagonist was shown to be effective against AAV, and it has been a novel therapeutic option, becoming a novel anti-complement drug to modulate inflammatory diseases.

DOI： 10.3389/fimmu.2022.926044

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/mrcr/rxac009.

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DOI： 10.1186/s13075-022-02820-y

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DOI： 10.3389/fimmu.2022.926044.

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Language：English   Publisher：Oxford University Press  

症例は25歳女性で、咳嗽および労作時呼吸困難を主訴に来院した。7年前に全身性エリテマトーデス(SLE)と診断され、プレドニゾロン(PSL)5mgを服用していた。SLEの再燃を疑い、入院となった。抗核抗体は2560倍、抗dsDNA抗体は11.3IU/mL、抗Sm抗体96.2U/mLであった。右心カテーテル検査で平均肺動脈圧は56mmHg、心係数は1.25L/min/m2、肺血管抵抗は27.1 Wood単位であった。SLEに伴う肺動脈高血圧症と診断した。心不全の重症度はNYHA心機能分類でIV度、SLEの重症度はSLEDAIスコアで14点であった。ステロイドパルス療法を施行し、経口PSLおよびシクロホスファミド静注療法を開始した。肺高血圧症に対してマシテンタンとタダラフィルを投与したが、効果は限定的であった。エポプロステノール静注を開始したところ、2ヵ月後にSLEDAIスコアは2点に改善した。エポプロステノール在宅持続静注療法を勧めたが患者が拒否したため、経口セレキシパグおよびイロプロスト吸引投与に切り替えた。10ヵ月後の再診で症状の再燃はなかった。

Language：English   Publisher：Oxford University Press  

症例は25歳女性で、咳嗽および労作時呼吸困難を主訴に来院した。7年前に全身性エリテマトーデス(SLE)と診断され、プレドニゾロン(PSL)5mgを服用していた。SLEの再燃を疑い、入院となった。抗核抗体は2560倍、抗dsDNA抗体は11.3IU/mL、抗Sm抗体96.2U/mLであった。右心カテーテル検査で平均肺動脈圧は56mmHg、心係数は1.25L/min/m2、肺血管抵抗は27.1 Wood単位であった。SLEに伴う肺動脈高血圧症と診断した。心不全の重症度はNYHA心機能分類でIV度、SLEの重症度はSLEDAIスコアで14点であった。ステロイドパルス療法を施行し、経口PSLおよびシクロホスファミド静注療法を開始した。肺高血圧症に対してマシテンタンとタダラフィルを投与したが、効果は限定的であった。エポプロステノール静注を開始したところ、2ヵ月後にSLEDAIスコアは2点に改善した。エポプロステノール在宅持続静注療法を勧めたが患者が拒否したため、経口セレキシパグおよびイロプロスト吸引投与に切り替えた。10ヵ月後の再診で症状の再燃はなかった。

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/mrcr/rxac009.

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Mizoribine (MZR) is an immunosuppressive agent that selectively inhibits inosine monophosphate dehydrogenase; its actions are considerably similar to those of mycophenolate mofetil (MMF). This study aimed to clarify whether MZR can be a good treatment option for systemic lupus erythematosus (SLE) and to compare the efficacy and safety of MZR and MMF in patients with active SLE. METHODS: We retrospectively compared the efficacy, continuation rate, and safety of MZR (52 patients) and MMF (31 patients) after adjusting for stabilized inverse probability of treatment weighting based on propensity scores. The efficacy endpoints were as follows: cumulative incidence of lupus low disease activity state (LLDAS) or remission attainment and flares and change in prednisolone dose over 2 years. Drug continuation rates were defined as the time from drug initiation to discontinuation for any cause, owing to the lack of efficacy, or owing to adverse events. The safety endpoint was the frequency of adverse events. RESULTS: Overall, 25 (48.1%) and 13 (25.0%) patients in the MZR group and 18 (58.1%) and 15 (48.3%) in the MMF group achieved LLDAS and remission during the follow-up period, respectively; thus, the cumulative incidence of LLDAS and remission attainment of the two groups was similar after adjustment. Prednisolone dose was steadily reduced in both the groups, and the change in prednisolone dose was nearly identical between the two groups. Drug discontinuation rate due to adverse events and the frequency of all adverse events and infections were higher in the MMF group than in the MZR group, albeit without significance after adjustment. CONCLUSION: MZR is as effective as MMF in controlling SLE activity. The adverse events of MZR, whose profile differs from MMF, are comparable to or less than those of MMF. MZR may be a valuable option as an immunosuppressive agent for SLE, as well as MMF.

DOI： 10.1177/1759720X221096367

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DOI： 10.1021/acsomega.2c00719

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DOI： 10.1021/acsomega.2c00719

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Language：English   Publisher：Journal of Immunology  

T follicular regulatory (Tfr) cells are a subset of CD4+ T cells that express CXCR5 and migrate into germinal centers (GCs). They regulate GC reactions by communicating with T follicular helper (Tfh) and B cells. TNF inhibitors are used in inflammatory diseases; however, the generation of autoantibodies or anti-drug Abs sometimes causes problems. Because TNFR2 signaling is important for suppressive functions of regulatory T cells, we investigated the role of TNFR2 on human Tfr cells. Tfr cells stimulated with MR2-1 (an anti-TNFR2 agonistic Ab) were analyzed for cell proliferation, Foxp3 expression, and surface molecules. Tfh/B cell proliferation, IgM production, and differentiation in cocultures with MR2-1-stimulated Tfr cells were examined. Tfr cells express a high level of TNFR2. MR2-1 stimulation altered the gene expression profile of Tfr cells. Cell proliferation and Foxp3 expression of Tfr cells were enhanced by MR2-1. MR2-1-stimulated Tfr cells expressed ICOS and Programmed cell death protein 1 and significantly suppressed Tfh/B cell proliferation, IgM production, and B cell differentiation. TNFR2-stimulated Tfr cells retained the migration function according to the CXCL13 gradient. In conclusion, we showed that TNFR2-stiumulated Tfr cells can regulate Tfh and B cells. Aberrant antibody production during TNF inhibitor treatment might be, at least in part, associated with TNFR2 signaling inhibition in Tfr cells. In addition, expansion and maturation of Tfr cells via TNFR2 stimulation in vitro may be useful for a cell-based therapy in inflammatory and autoimmune diseases to control GC reactions.

DOI： 10.4049/jimmunol.2100323

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Language：English   Publisher：Journal of Immunology  

T follicular regulatory (Tfr) cells are a subset of CD4+ T cells that express CXCR5 and migrate into germinal centers (GCs). They regulate GC reactions by communicating with T follicular helper (Tfh) and B cells. TNF inhibitors are used in inflammatory diseases; however, the generation of autoantibodies or anti-drug Abs sometimes causes problems. Because TNFR2 signaling is important for suppressive functions of regulatory T cells, we investigated the role of TNFR2 on human Tfr cells. Tfr cells stimulated with MR2-1 (an anti-TNFR2 agonistic Ab) were analyzed for cell proliferation, Foxp3 expression, and surface molecules. Tfh/B cell proliferation, IgM production, and differentiation in cocultures with MR2-1-stimulated Tfr cells were examined. Tfr cells express a high level of TNFR2. MR2-1 stimulation altered the gene expression profile of Tfr cells. Cell proliferation and Foxp3 expression of Tfr cells were enhanced by MR2-1. MR2-1-stimulated Tfr cells expressed ICOS and Programmed cell death protein 1 and significantly suppressed Tfh/B cell proliferation, IgM production, and B cell differentiation. TNFR2-stimulated Tfr cells retained the migration function according to the CXCL13 gradient. In conclusion, we showed that TNFR2-stiumulated Tfr cells can regulate Tfh and B cells. Aberrant antibody production during TNF inhibitor treatment might be, at least in part, associated with TNFR2 signaling inhibition in Tfr cells. In addition, expansion and maturation of Tfr cells via TNFR2 stimulation in vitro may be useful for a cell-based therapy in inflammatory and autoimmune diseases to control GC reactions.

DOI： 10.4049/jimmunol.2100323

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DOI： 10.1155/2022/6852189.

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DOI： 10.1155/2022/6852189.

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DOI： 10.4049/jimmunol.2100323.

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DOI： 10.4049/jimmunol.2100323.

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OBJECTIVES: Emerging evidence has shown the importance of inflammasome activation in the progression of autoimmune diseases. In this study, we aimed to identify the main cell types activating inflammasome in autoimmune diseases and to clarify the intracellular pathway of inflammasome activation in systemic lupus erythematosus (SLE). METHODS: Active caspase-1 in each subset of human peripheral blood cells from healthy controls (n=18), SLE (n=51), and other rheumatic diseases (n=36) were fluorescently probed with FLICA™-caspase-1 followed by flow cytometric analysis. The correlation of caspase-1 activation in monocytes and clinical parameters in SLE patients were evaluated. In-vitro experiments were performed to identify the pathway involved in caspase-1 activation induced by SLE serum in monocytes. RESULTS: Active caspase-1 in monocytes was upregulated in SLE patients. Cluster of differentiation 14 (CD14)-positive and CD16-positive monocytes showed considerable activation of caspase-1 compared with the other subsets of monocytes. Serum titres of anti-double stranded DNA antibodies were positively correlated with active caspase-1 in monocytes, and serum complement component 3 and platelet count were negatively correlated with active caspase-1 in monocytes. The SLE serum-induced activation of caspase-1 and IL-1β secretion were down-regulated by inhibition of NLR family pyrin domain containing 3 (NLRP3), cyclic GMP-AMP synthase (cGAS), or stimulator of interferon genes (STING). CONCLUSIONS: These findings suggest that targeting inflammasome by regulating cGAS/STING and NLRP3 are potential therapeutic strategies for SLE.

DOI： 10.55563/clinexprheumatol/eakvlv

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標準治療後にも活動性が持続するSLEに対するヒドロキシクロロキン(HCQ)とタクロリムス(TAC)の有効性を比較検討した。SLE患者45例をHCQ投与群18例(全例女性、平均41.0±9.2歳)とTAC投与群27例(男性2例、女性25例、平均42.7±11.2歳)に分類し、有効性評価項目はループス低疾患活動性(LLDAS)達成率、退薬率、治療継続生存期間とし、安全性評価項目は有害事象の発現率とした。観察期間中にLLDASを呈したのはHCQ群が8例(44.4%)、TAC群が10例(37.0%)であり、累積LLDAS達成率に群間差はみられなかった。投与中止はHCQ群が3例、TAC群が5例であり、中止理由はHCQが全例有害事象であり、TAC群は有害事象が2例、不応が2例、禁忌薬剤の使用が1例となっていた。1年投与継続率はHCQ群が88.5%、TAC群が81.0%とほぼ同等であった。また、有害事象の発現率に有意な群間差はみられず、両群とも感染症が最も多かった。持続する活動性SLEに対するヒドロキシクロロキンとタクロリムスの治療効果と安全性はほぼ同等であることが示された。

Language：English   Publisher：Oxford University Press  

標準治療後にも活動性が持続するSLEに対するヒドロキシクロロキン(HCQ)とタクロリムス(TAC)の有効性を比較検討した。SLE患者45例をHCQ投与群18例(全例女性、平均41.0±9.2歳)とTAC投与群27例(男性2例、女性25例、平均42.7±11.2歳)に分類し、有効性評価項目はループス低疾患活動性(LLDAS)達成率、退薬率、治療継続生存期間とし、安全性評価項目は有害事象の発現率とした。観察期間中にLLDASを呈したのはHCQ群が8例(44.4%)、TAC群が10例(37.0%)であり、累積LLDAS達成率に群間差はみられなかった。投与中止はHCQ群が3例、TAC群が5例であり、中止理由はHCQが全例有害事象であり、TAC群は有害事象が2例、不応が2例、禁忌薬剤の使用が1例となっていた。1年投与継続率はHCQ群が88.5%、TAC群が81.0%とほぼ同等であった。また、有害事象の発現率に有意な群間差はみられず、両群とも感染症が最も多かった。持続する活動性SLEに対するヒドロキシクロロキンとタクロリムスの治療効果と安全性はほぼ同等であることが示された。

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: Emerging evidence has shown the importance of inflammasome activation in the progression of autoimmune diseases. In this study, we aimed to identify the main cell types activating inflammasome in autoimmune diseases and to clarify the intracellular pathway of inflammasome activation in systemic lupus erythematosus (SLE). METHODS: Active caspase-1 in each subset of human peripheral blood cells from healthy controls (n=18), SLE (n=51), and other rheumatic diseases (n=36) were fluorescently probed with FLICA™-caspase-1 followed by flow cytometric analysis. The correlation of caspase-1 activation in monocytes and clinical parameters in SLE patients were evaluated. In-vitro experiments were performed to identify the pathway involved in caspase-1 activation induced by SLE serum in monocytes. RESULTS: Active caspase-1 in monocytes was upregulated in SLE patients. Cluster of differentiation 14 (CD14)-positive and CD16-positive monocytes showed considerable activation of caspase-1 compared with the other subsets of monocytes. Serum titres of anti-double stranded DNA antibodies were positively correlated with active caspase-1 in monocytes, and serum complement component 3 and platelet count were negatively correlated with active caspase-1 in monocytes. The SLE serum-induced activation of caspase-1 and IL-1β secretion were down-regulated by inhibition of NLR family pyrin domain containing 3 (NLRP3), cyclic GMP-AMP synthase (cGAS), or stimulator of interferon genes (STING). CONCLUSIONS: These findings suggest that targeting inflammasome by regulating cGAS/STING and NLRP3 are potential therapeutic strategies for SLE.

DOI： 10.55563/clinexprheumatol/eakvlv

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PubMed

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/mr/roab010

Web of Science

Scopus

PubMed

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Language：English  

DOI： 10.1155/2022/6852189

PubMed

Language：English  

DOI： 10.1155/2022/6852189

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1177/09612033211031989

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1186/s13075-021-02618-4

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.jneuroim.2021.577631.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41598-021-95711-2

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1080/24725625.2021.1905220.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3389/fimmu.2021.713225

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1097/MD.0000000000025406

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1080/24725625.2021.1905220.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1080/24725625.2021.1896096.

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3389/fimmu.2021.654623

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.cellimm.2020.104263

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1080/14397595.2020.1743493

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3389/fimmu.2020.02042

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s00296-020-04512-9

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1080/14397595.2020.1790778

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/cei.13477

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.4049/jimmunol.1901304

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1080/14397595.2020.1743493

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s00296-020-04512-9

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3899/jrheum.190373

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1186/s13075-019-1984-x

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1186/s13075-019-1823-0

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE:
To assess the long-term efficacy and safety of infliximab (IFX) treatment for refractory uveitis associated with Behçet's disease (BD) and to identify predictors of long-term IFX therapy outcomes.

METHODS:
We retrospectively studied 44 consecutive BD patients with uveitis who were started on IFX therapy and analyzed the efficacy and safety of IFX and the treatment continuation rate. To determine predictors of IFX responsiveness, we analyzed the clinical characteristics of the patients who received regular maintenance therapy and those who required treatment intensification. The serum cytokine levels prior to IFX were measured through the Bio-Plex human cytokine assays.

RESULTS:
IFX significantly reduced the frequency of ocular attacks and improved the visual acuity of patients with BD-related uveitis. However, approximately half of the patients required dose escalations, necessitating a shortening of the intervals between IFX infusions due to loss of efficacy during the 5-year treatment. The frequency of ocular attacks was significantly higher in patients with complete BD than in patients with incomplete BD. A multiplex cytokine analysis revealed that patients with BD-related uveitis exhibited increased serum IL-2, IL-6, IL-8, and MCP-1 levels. Moreover, among BD patients, the serum IL-2 and IL-6 levels were particularly high in those who maintained remission and received regular IFX treatments.

CONCLUSION:
We confirmed the long-term efficacy and tolerability of IFX in patients with BD-related uveitis. Our results indicate that complete BD may be less responsive to IFX and that the pretreatment serum cytokine profiles may be useful for predicting the long-term IFX therapy outcomes.

DOI： 10.5152/eurjrheum.2017.17068

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1371/journal.pone.0196368

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DOI： 10.2169/internalmedicine.9652-17

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DOI： 10.3109/14397595.2015.1060668

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1186/s13075-015-0547-z

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1155/2014/271548

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.2169/internalmedicine.53.2168

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s10165-012-0735-5

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s00296-009-1244-5

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/rheumatology/keq050

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/rheumatology/ken071

Language：English   Publishing type：Research paper (scientific journal)  

Objective. Three anti-tumor necrosis factor α (anti-TNFα) agents have been proved to be effective for rheumatoid arthritis (RA) and other inflammatory disorders. Infliximab and adalimumab have been generated as anti-TNFα monoclonal antibodies, while etanercept is engineered from human type II TNF receptors. In spite of all 3 agents' equal efficacy for RA, both infliximab and adalimumab are effective for other diseases such as Crohn's disease and Wegener's granulomatosis, while etanercept is not. We undertook this study to understand the different clinical effects of these anti-TNFα agents by analyzing their biologic activities on transmembrane TNFα. Methods. Jurkat T cells stably expressing an uncleavable form of transmembrane TNFα were used for the following studies: 1) flow cytometric analysis of binding activities of anti-TNF agents to cell surface transmembrane TNFα, 2) complement-dependent cytotoxicity (CDC), 3) antibody-dependent cell-mediated cytotoxicity (ADCC) by using peripheral blood mononuclear cells, and 4) outside-to-inside (reverse) signal transduction through transmembrane TNFα estimated by apoptosis and cell cycle analysis using flow cytometry. Results. All of the anti-TNFα agents bound to transmembrane TNFα. Infliximab and adalimumab exerted almost equal CDC activities, while etanercept showed considerably lower activity. ADCC activities were almost equal among these 3 agents. Adalimumab and infliximab induced apoptosis and cell cycle arrest in transmembrane TNFα-expressing Jurkat T cells, reflecting an outside-to-inside signal transduction through transmembrane TNFα. Conclusion. Three different anti-TNF agents showed different biologic effects on transmembrane TNFα. This finding suggests that CDC and outside-to-inside signals by anti-TNFα antibodies may explain the successful clinical efficacy of adalimumab and infliximab in Crohn's disease and Wegener's granulomatosis.

DOI： 10.1002/art.23447

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DOI： 10.1093/rheumatology/kem321

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DOI： 10.1136/ard.2006.065961

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DOI： 10.1136/ard.2006.058917

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DOI： 10.1016/j.bbrc.2005.02.159

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Language：Japanese   Book type：General book, introductory book for general audience

Event date： 2022.4

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：パシフィコ横浜   Country：Japan  

Event date： 2022.4

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Venue：パシフィコ横浜   Country：Japan  

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Event date： 2022.4

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Venue：パシフィコ横浜   Country：Japan  

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Event date： 2021.8

Language：English   Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2019.4 - 2019.6

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：京都   Country：Japan  

【背景】腎機能は加齢に伴い低下することが知られている。超高齢社会の本邦では腎機能低下が関節リウマチ(RA)の治療に関しても影響を与えることが推察される。【目的】当院におけるRA患者の腎機能別の生物学的抗リウマチ薬(bDMARDs)使用状況を検討する。【方法】2018年9月時点でbDMRADs投与を受けていた203例について、年齢・eGFR別にbDMARDs使用状況を検討した。【結果】治療効果面でMTX併用が必要と考えられる、抗TNF抗体製剤の多くは腎機能低下に乏しい症例に対して使用されていた。また、単独治療で有効性の期待される非TNF製剤は腎機能低下例でも多く使用されていた。

Event date： 2023.8

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：別府市   Country：Japan  

Event date： 2023.8

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Venue：別府市   Country：Japan  

Event date： 2023.4 - 2024.4

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Venue：福岡市   Country：Japan  

Event date： 2023.4

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Venue：福岡国際会議場   Country：Japan  

Event date： 2023.4

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Venue：福岡国際会議場   Country：Japan  

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Venue：福岡国際会議場   Country：Japan  

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Venue：福岡国際会議場   Country：Japan  

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Venue：福岡国際会議場   Country：Japan  

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Venue：福岡国際会議場   Country：Japan  

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Venue：福岡国際会議場   Country：Japan  

Event date： 2023.3

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：アクロス福岡   Country：Japan  

Event date： 2023.3

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Venue：アクロス福岡   Country：Japan  

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Event date： 2022.7

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：リーガロイヤルホテル小倉   Country：Japan  

Event date： 2022.7

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Venue：リーガロイヤルホテル小倉   Country：Japan  

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Event date： 2022.4

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Venue：パシフィコ横浜   Country：Japan  

Event date： 2022.4

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Venue：パシフィコ横浜   Country：Japan  

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Event date： 2022.3

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Venue：久留米シティプラザ   Country：Japan  

Event date： 2022.3

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Venue：久留米シティプラザ   Country：Japan  

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Event date： 2021.9

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：熊本城ホール   Country：Japan  

Event date： 2021.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：web開催   Country：Japan  

Event date： 2021.4

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2021.4

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Country：Japan  

Event date： 2021.4

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Event date： 2021.4

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Event date： 2020.4

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Event date： 2020.4

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Event date： 2020.4

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Country：Japan  

Event date： 2019.11

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Country：Japan  

Event date： 2019.10

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Country：Japan  

Event date： 2019.9

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Venue：Hotel & Resorts BEPPUWAN   Country：Japan  

Event date： 2019.9 - 2020.6

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Venue：佐伯市医師会   Country：Japan  

Event date： 2019.9

Language：Japanese  

Venue：長崎ブリックホール   Country：Japan  

Event date： 2019.5

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Venue：別府市医師会館   Country：Japan  

Event date： 2018.11

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Venue：大分県別府市   Country：Japan  

Event date： 2018.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：大分県玖珠郡   Country：Japan  

Event date： 2018.4

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Venue：東京   Country：Japan  

Event date： 2017.12

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：大分市   Country：Japan  

Event date： 2017.9

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：北九州市   Country：Japan  

Event date： 2017.6

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Venue：別府市   Country：Japan  

Event date： 2017.2

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：別府市   Country：Japan  

Event date： 2016.11

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Venue：大分市   Country：Japan  

Event date： 2016.4

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：横浜市   Country：Japan  

Event date： 2016.4

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Venue：横浜市   Country：Japan  

Event date： 2016.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：大分市   Country：Japan  

Event date： 2015.12

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：大分市   Country：Japan  

Event date： 2015.9

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Venue：大分市   Country：Japan  

Event date： 2015.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：鹿児島   Country：Japan  

Event date： 2015.3

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：アクロス福岡   Country：Japan  

症例は85歳男性。2014年9月、関節痛にて当院紹介、RF陽性、ACPA陽性でRAと診断。初診時に右肺尖に陳旧性の陰影あり。喀痰抗酸菌陰性、IGRA陰性であった。RAに対してサラゾスルファピリジン(SASP)内服を開始した。SASP開始後6週後の定期受診時に微熱あり、GRNX内服するも発熱はさらに高熱となり、2日後に入院。CTにて両肺にスリガラス影出現を認めた。皮疹や好酸球増多は認めなかった。抗菌薬点滴にても発熱・炎症所見は持続し、スリガラス影の拡大、胸水出現を認めた。酸素化障害も認め、ステロイドパルス療法により改善を認めた。本例は呼吸状態不良のため組織学的検索が行えなかったが、経過から薬剤性肺炎が考えられた。SASPは肺障害の少ない薬剤とされるが、注意が必要と考えられここに報告する。

Event date： 2014.11

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：福岡国際会議場   Country：Japan  

症例は83歳男性。　76歳時、口腔乾燥感主訴に近医膠原病外来受診し精査受けるも、自己抗体陰性で明らかな異常所見認めなかった。発熱や関節痛、筋痛などの自覚症状を認めないものの、徐々にCRPが上昇し、悪性腫瘍も含めて全身精査行われたが明らかな異常所見なく、78歳時よりリウマチ性多発筋痛症疑いにて、PSL5mg内服で改善認めるも漸減にて再燃を繰り返していた。
　83歳時CRP上昇、肝機能障害、両下腿浮腫、心嚢液貯留を認め入院となった。心嚢ドレナージを施行するも培養・細胞診で明らかな異常所見なし。PET-CTで両側大腿骨頚部などに多発性のFDG集積を認めた。長管骨病変、CRP上昇、心血管病変からErdheim-Chester Disease(ECD)が疑われた。
非ランゲルハンス細胞性組織球症の一つであるECDはIFNαや抗TNFα製剤の有効性が報告されている。稀な疾患ではあるが、漿膜炎・骨病変・CRP上昇などでリウマチ科を受診する可能性があり、認知しておくべき疾患と考えられここに報告する。

Event date： 2014.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：石橋文化センター   Country：Japan  

Event date： 2014.4

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：グランドプリンス新高輪（東京都）   Country：Japan  

症例は72歳男性。66歳時に関節リウマチ（RA）と診断、70歳時よりメトトレキセート（MTX）内服開始され、関節症状は改善傾向だった。また、69歳頃より湿性咳嗽と喀痰を認めるようになり、抗生物質内服行うも無効だった。その後、関節症状の増悪を認め、当科を紹介受診となり治療方針決定目的に入院した。RAは高疾患活動性であり、骨びらんも認めた。胸部CTで左肺下葉に小葉中心性粒状影とすりガラス影を認め、肺機能検査で末梢気道の閉塞性パターンを呈していた。抗HTLV-1抗体陽性であり、気管支擦過細胞診では成人T細胞白血病疑い、経気管支鏡的肺生検ではMTX関連リンパ腫疑いの診断だった。そのため胸腔鏡下肺生検（VATS）を施行した。胚中心を伴うリンパ濾胞を認めたが、フローサイトメトリーでは異常な細胞集団を認めなかった。また、T細胞受容体・免疫グロブリンの遺伝子再構成も認めなかったため濾胞性細気管支炎（FB）と診断しMTX併用での生物学的製剤導入を行った。FBはRAに合併する比較的稀な気管支病変であり、画像上は様々な鑑別疾患を有する。合併する肺病変に応じたRAの治療法の見直しが必要となるため、VATSによる肺病変の診断が重要であった。

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

免疫性炎症疾患(immune-mediated chronic inflammatory diseases: IMIDs)の治療においては、近年病態に関わるサイトカインや細胞表面分子の理解が進み、関節リウマチを中心に生物学的製剤が導入され高い効果を上げている。一方で膠原病の代表疾患ともいえる全身性エリテマトーデス(Systemic lupus erythematosus: SLE)は種々の免疫異常を伴い、従来から病態に関する基礎的研究が精力的に行われているが、生物学的製剤に関してはリツキシマブなどの有効性を示すcase seriesはあるものの有効性は限定的であり、50年ぶりにSLEの治療薬として米国で臨床導入されたベリムマブも難治性・高疾患活動性のSLEに対する十分な効果があるとは言いがたい。そうした新規治療の確立が望まれる中で、期待される治療の一つである臍帯由来間葉型幹細胞移植(Umbilical cord mesenchymal stem cell transplantation: UC-MSCT)について最近の知見について概説する。

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

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Type：Peer review 

Number of peer-reviewed articles in foreign language journals：11

Number of peer-reviewed articles in Japanese journals：0

Proceedings of International Conference Number of peer-reviewed papers：0

Proceedings of domestic conference Number of peer-reviewed papers：20

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

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Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

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Type：Peer review 

Number of peer-reviewed articles in foreign language journals：14

Number of peer-reviewed articles in Japanese journals：0

Proceedings of International Conference Number of peer-reviewed papers：0

Proceedings of domestic conference Number of peer-reviewed papers：29

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Type：Peer review 

Number of peer-reviewed articles in foreign language journals：4

Number of peer-reviewed articles in Japanese journals：0

Proceedings of International Conference Number of peer-reviewed papers：0

Proceedings of domestic conference Number of peer-reviewed papers：0

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Type：Peer review 

Number of peer-reviewed articles in foreign language journals：2

Number of peer-reviewed articles in Japanese journals：0

Proceedings of International Conference Number of peer-reviewed papers：0

Proceedings of domestic conference Number of peer-reviewed papers：0

Type：Competition, symposium, etc. 

Number of participants：18

Type：Competition, symposium, etc. 

Number of participants：20

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

Number of participants：1,134

Type：Competition, symposium, etc. 

Number of participants：15

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

Audience： General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Seminar, workshop

Type：Seminar, workshop

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Audience： General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Seminar, workshop

Audience： General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Lecture

Type：Lecture

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Type：Seminar, workshop

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Audience： General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Lecture

Type：Visiting lecture

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Audience： General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Lecture

Type：Visiting lecture

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Audience： General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Lecture

Type：Lecture

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別府市医師会と共同で、ゆけむりネットリウマチ班を立ち上げ、別府地域における関節リウマチ早期診断に関する取り組みを開始している。

Type：Other

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Audience： General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Lecture

Type：Lecture

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Audience： General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Seminar, workshop

Audience： General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Lecture

Type：Lecture

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Type：Seminar, workshop

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Audience： General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Lecture

Type：Lecture

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Audience： General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Lecture

Type：Lecture

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