Language：English   Publisher：Oxford University Press  

日本リウマチ学会は、日本における自己免疫性リウマチ性疾患(AIRD)患者のリアルワールドでのCOVID-19の実態を調べるため、COVID-19のレジストリ研究を行った。今回、本レジストリのデータを解析して、オミクロンBA.5株流行期を含む時期のリウマチ性疾患患者の予後と治療の経時的変化を評価した。主要評価項目は低酸素血症の発生率および死亡率とした。2020年6月～2022年12月のCOVID-19感染患者797例のうち、760例を評価した。COVID-19発症時期は、2021年6月(時期A)までが301例、2021年6月～12月(時期B)が88例、2022年1月～6月(時期C)が171例、2022年7月～12月(時期D)が200例であった。低酸素血症の発生率は、時期A～Dの順にそれぞれ34.9%、27.2%、13.8%、6.1%、死亡率はそれぞれ5.6%、3.5%、1.8%、0%であった。ワクチン接種歴および2022年7月～12月のオミクロンBA.5流行期の発症は、年齢、性別、肥満、ステロイド投与量、合併症で調整した多変量モデルにおいて、低酸素血症と負の相関を示した。

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

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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

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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

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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

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Publisher：医歯薬出版  

DOI： 10.32118/ayu28710768

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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。

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DOI： 10.1093/mr/roac100.

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。

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DOI： 10.3389/fimmu.2022.1016914.

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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   Publishing type：Research paper (scientific journal)   Publisher：Rheumatology (United Kingdom)  

Objectives: Recently, the involvement of basophils and IgE-type autoantibodies in the pathogenesis of SLE has been elucidated using mouse models; however, few studies have been conducted in humans. In this study, the role of basophils and anti-double-stranded DNA (dsDNA) IgE in SLE was examined using human samples. Methods: The correlation between disease activity and serum levels of anti-dsDNA IgE in SLE was evaluated using enzyme-linked immunosorbent assay. Cytokines produced by IgE-stimulated basophils from healthy subjects were assessed using RNA sequences. The interaction of basophils and B cells to promote B cell differentiation was investigated using a co-culture system. The ability of basophils from patients with SLE with anti-dsDNA IgE to create cytokines that may be involved in B cell differentiation in response to dsDNA was examined using real-time PCR. Results: Anti-dsDNA IgE levels in the serum of patients with SLE correlated with disease activity. Healthy donor basophils produced IL-3, IL-4 and TGF-β1 after anti-IgE stimulation. Co-culture of B cells with anti-IgE-stimulated basophils increased plasmablasts which were cancelled by neutralizing IL-4. After encountering the antigen, basophils released IL-4 more quickly than follicular helper T cells. Basophils isolated from patients with anti-dsDNA IgE promoted IL-4 expression by adding dsDNA. Conclusions: These results suggest that basophils contribute to the pathogenesis of SLE by promoting B cell differentiation via dsDNA-specific IgE in patients similar to the process described in mouse models.

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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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：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)   Publisher：Arthritis Research and Therapy  

Background: To analyse the subsequent clinical course of patients with rheumatoid arthritis (RA) who either continued or discontinued biologic agents after hospitalization for infections. Methods: We retrospectively reviewed the clinical records of 230 RA patients with 307 hospitalizations for infections under biologic therapy between September 2008 and May 2014 in 15 institutions for up to 18 months after discharge. The risks of RA flares and subsequent hospitalizations for infections from 61 days to 18 months after discharge were evaluated. Results: Survival analyses indicated that patients who continued biologic therapy had a significantly lower risk of RA flares (31.4% vs. 60.6%, P < 0.01) and a slightly lower risk of subsequent infections (28.7% vs. 34.5%, P = 0.37). Multivariate analysis showed that discontinuation of biologic therapy, diabetes, and a history of hospitalization for infection under biologic therapy were associated with RA flares. Oral steroid therapy equivalent to prednisolone 5 mg/day or more and chronic renal dysfunction were independent risk factors for subsequent hospitalizations for infections. Conclusions: Discontinuation of biologic therapy after hospitalization for infections may result in RA flares. Continuation of biologic therapy is preferable, particularly in patients without immunodeficiency.

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DOI： 10.1093/mrcr/rxac009.

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)   Publisher：Therapeutic Advances in Musculoskeletal Disease  

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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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   Publishing type：Research paper (scientific journal)  

DOI： 10.1155/2022/6852189.

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

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

DOI： 10.4049/jimmunol.2100323.

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)   Publisher：Clinical and Experimental Rheumatology  

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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Modern Rheumatology  

Objectives: We aimed to reveal the effectiveness of hydroxychloroquine (HCQ) compared with tacrolimus (TAC), an immunosuppressive agent, in patients with systemic lupus erythematosus (SLE) with persistent activity on standard treatment. Methods: We retrospectively compared the efficacy and safety of the treatment between 18 patients receiving HCQ and 27 patients receiving TAC. None of the patients were in the lupus low disease activity state (LLDAS) at the beginning of this study. The efficacy end points were the cumulative incidence of LLDAS attainment without additional immunosuppressive agents, drug continuation rate, and treatment failure-free survival. The safety end point was the frequency of adverse events. Results: Eight (44.4%) patients in the HCQ group and 10 (37.0%) patients in the TAC group achieved LLDAS during the follow-up period; thus, the cumulative incidences of LLDAS attainment of the two treatments were nearly identical. The drug continuation and treatment failure-free survival rates were also not different between the two groups. The frequency of adverse events showed no clear differences between the two groups. Conclusions: The efficacy and safety of an add-on treatment with HCQ are similar to those with TAC. Patients with persistently active SLE can benefit from HCQ in efforts to achieve at least low disease activity.

DOI： 10.1093/mr/roab010

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Language：English  

DOI： 10.1155/2022/6852189

PubMed

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

DOI： 10.1186/s13075-021-02618-4

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

DOI： 10.1177/09612033211031989

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

DOI： 10.1038/s41598-021-95711-2

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

DOI： 10.1016/j.jneuroim.2021.577631.

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

DOI： 10.3389/fimmu.2021.713225

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

DOI： 10.1080/24725625.2021.1905220.

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

DOI： 10.1097/MD.0000000000025406

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

DOI： 10.3389/fimmu.2021.654623

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

DOI： 10.1080/24725625.2021.1896096.

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

DOI： 10.1016/j.cellimm.2020.104263

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

DOI： 10.3389/fimmu.2020.02042

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

DOI： 10.1111/cei.13477

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

Objectives We examined the efficacy and safety of rituximab (RTX) maintenance therapy for patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in Japan.

Methods We conducted a retrospective study using a multi-center cohort database of vasculitis patients. All maintenance treatment courses were divided into three groups: a RTX group, a group treated with other immunosuppressant drugs (IS) and a group receiving glucocorticoid monotherapy (GC). The primary endpoint was the comparison of relapse-free survival after 1 year. We also analyzed the occurrence of severe adverse events (SAEs) to assess safety.

Results We included 123 courses of 107 patients (RTX n = 14, IS n = 64, GC n = 45). Twelve of 14 in the RTX group patients were diagnosed with granulomatosis with polyangiitis (GPA). The relapse-free survival of RTX maintenance therapy was comparable to that in the other groups (p = 0.122). After 1 year of treatment, the RTX group was administered lower steroid doses and one-third of them could withdraw corticosteroid. The overall incidence of SAE was 0.54/patient-year in the RTX group, 0.39/patient-year in the IS group and 0.34/patient-year in the GC group.

Conclusions RTX maintenance therapy could be effective and safe in Japanese GPA patients.

DOI： 10.1080/14397595.2020.1790778

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

DNase 1-like 3 (DNase1L3), which belongs to DNase1 family, was originally identified as one of apoptosis- and necrosis-related endonucleases that fragmentate intranucleosomal DNA. A loss-of-function mutation has been reported in murine models of systemic lupus erythematosus (SLE) and in familial SLE patients. These reports suggest DNase1L3 plays an important role in the prevention of developing SLE; however, expression and function of DNase1L3 in human immune systems have been largely unclarified. As previous reports showed DNase1L3 is expressed in hematopoietic organs, we first analyzed expression levels of DNase1L3 in each subset of human peripheral blood cells by quantitative real-time PCR. Plasmacytoid dendritic cells showed the highest expression levels of DNase1L3 mRNA among peripheral blood cells. IL-4 enhanced DNase1L3 expression in monocytes, monocyte-derived dendritic cells, and monocyte-derived macrophages (MDMs), but not in T cells, B cells, or plasmacytoid dendritic cells. Together with IL-4, all-trans retinoic acid and apoptotic cells efficiently upregulated expression of DNalse1L3 in MDMs. As a result of intracellular signaling analysis, Jak1-IRS2-ERK/PI3K pathway was essential for IL-4-induced DNase1L3 expression. IL-4-treated monocyte-derived dendritic cells and MDMs secreted active DNase1L3 protein that could degrade liposome-DNA complexes, which were resistant to DNase1. Our results indicate DNase1L3 is secreted by innate immune cells and may play a critical role in the tissue homeostasis and on prevention of developing autoimmunity by degrading self-DNA.

DOI： 10.4049/jimmunol.1901304

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

We aimed to identify predictors of inadequate response to glucocorticoid (GC) treatment in patients with polymyalgia rheumatica (PMR). We retrospectively studied 32 patients as a derivation cohort and 24 patients as a validation cohort. The patients were divided into two groups according to the response to GC treatment: GC-responders and GC-inadequate responders (GC-IRs). We compared laboratory data and bilateral shoulder ultrasound findings between the groups. Receiver operating characteristic (ROC) analysis was performed to determine the optimal cutoff value of candidate predictors of treatment response; the predictors were examined using multivariate logistic analysis. Gray-scale ultrasound findings of long head of the biceps (LHB) tenosynovitis and subacromial/subdeltoid (SAD) bursitis were scored semiquantitatively (0–3). A total gray-scale score (TGSS) was calculated as the sum of the gray-scale scores. In the derivation cohort, serum lactate dehydrogenase (LDH) levels and TGSS were significantly higher in GC-IRs than in GC-responders. On ROC analysis, the cutoff values of serum LDH levels ≥ 175 IU/ml and TGSS ≥ 5 were found to be the candidate predictors. Multivariate logistic analysis revealed an independent association of both the predictors with inadequate response to GC treatment. In the validation cohort, patients with one or both predictors exhibited a higher incidence of inadequate response to GC treatment. These findings indicate that the severities of LHB tenosynovitis and SAD bursitis evaluated using ultrasound and serum LDH levels are independent predictors of inadequate response to GC treatment in patients with PMR. Treatment adjustment based on prediction model may allow precise treatment of patients with PMR.

DOI： 10.1007/s00296-020-04512-9

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

Objectives: We investigated the effect of daily folic acid supplementation on methotrexate (MTX) toxicity and efficacy in Japanese patients with rheumatoid arthritis (RA). Methods: We followed 19 patients treated with MTX who switched from taking weekly 5 mg folic acid supplementation (weekly regimen) to 1.25 mg daily (daily regimen). White blood cell (WBC) and platelet (PLT) counts, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) levels were collected for 24 weeks following the change. Results: We observed no significant changes in WBC or PLT counts. AST and ALT levels, which had exceeded the upper limits of their normal ranges at the beginning of the study, were improved significantly at weeks 4 and 8, no subsequent deterioration in liver function was found. Further, no significant changes in ESR and CRP levels were observed. Conclusion: Our data indicate that supplementing 1.25 mg of folic acid daily rather than 5 mg weekly reduces toxicity caused by MTX without affecting its efficacy.

DOI： 10.1080/14397595.2020.1743493

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

DOI： 10.3899/jrheum.190373

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

Background: Recent studies show that innate lymphoid cells (ILCs) contribute to the development of chronic inflammation and autoimmune disease. In this study, we assessed the ILC function in the development of rheumatoid arthritis (RA). Methods: In a mouse model of collagen-induced arthritis (CIA), we identified and purified the ILC subsets in peripheral blood (PB), local lymph nodes (LNs), and joints by fluorescence-activated cell sorting and used quantitative PCR to assess the expression levels of representative cytokines. We also correlated the frequencies of each ILC subset in synovial fluid (SF) with clinical parameters in RA patients. Results: In the CIA model, the proportion of CCR6+ ILC3s to total ILCs in joints with active inflammation significantly increased relative to non-arthritic joints (median 29.6% vs 16.7%, p = 0.035). CCR6+ ILC3s from mice with arthritis expressed significantly higher levels of IL-17A and IL-22 mRNA than did comparable cells from control mice (p < 0.0001 and p = 0.015). In RA patients, the proportion of CCR6+ ILCs in SF was positively correlated with tender joint counts (TJC) and swollen joint counts (SJC) (ρ=0.689, p = 0.0032 and ρ=0.644, p = 0.0071, respectively). Levels of CC chemokine ligand 20 (CCL20) increased in SF of patients with RA and were significantly correlated with CCR6+ ILC number (ρ=0.697, p = 0.0001). Conclusion: CCR6+ ILC3s may play some roles in the development of RA through the production of IL-17 and IL-22.

DOI： 10.1186/s13075-019-1984-x

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

Background: The effectiveness of autologous haematopoietic stem cell transplantation (auto-HSCT) in treating severe systemic sclerosis (SSc) is established; however, the necessity of purified CD34+ cell grafts and the appropriate conditioning regimen remain unclear. This study aimed to compare the efficacy and safety of CD34-selected auto-HSCT with unmanipulated auto-HSCT to treat severe SSc. Methods: This study was a post hoc analysis of a phase I/II clinical trial conducted in Japan. Nineteen patients with severe SSc were enrolled. Peripheral blood stem cells (PBSCs) were mobilised with cyclophosphamide (4 g/m
²
) and filgrastim (10 μg/kg/day). Following PBSC collection by apheresis, CD34+ cells were immunologically selected in 11 patients. All patients were treated with high-dose cyclophosphamide (200 mg/kg) monotherapy as a conditioning regimen and received CD34-selected (n = 11) or unmanipulated auto-HSCT (n = 8). Changes in skin sclerosis and pulmonary function were assessed over an 8-year follow-up period. Differences in the changes, toxicity, progression-free survival (PFS) and overall survival were compared between patients who had received CD34-selected auto-HSCT and those who had received unmanipulated auto-HSCT. Results: Skin sclerosis progressively improved after transplantation over an 8-year follow-up period in both groups, and the improvement was significantly greater in the CD34-selected group than in the unmanipulated group. Forced vital capacity in the CD34-selected group continuously increased over 8 years, whereas in the unmanipulated group it returned to baseline 3 years after transplantation. Toxicity and viral infections, such as cytomegalovirus infection and herpes zoster, were more frequently found in the CD34-selected group than in the unmanipulated group. The frequency of severe adverse events, such as bacterial infections or organ toxicity, was similar between the two groups. No treatment-related deaths occurred in either treatment group. PFS of the CD34-selected group was greater than that of the unmanipulated group, and the 5-year PFS rates of the CD34-selected and unmanipulated group were 81.8% and 50% respectively. Conclusions: CD34-selected auto-HSCT may produce favourable effects on improvement of skin sclerosis and pulmonary function compared with unmanipulated auto-HSCT. Use of CD34-selected auto-HSCT with high-dose cyclophosphamide monotherapy as a conditioning regimen may offer an excellent benefit-to-risk balance.

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

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

We herein report a case of concurrent cardiac sarcoidosis and large-vessel aortitis detected by¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET) and followed up during immunosuppressive therapy. After high-dose prednisolone administration (1 mg/kg), serial FDG-PET showed that almost all of the abnormal FDG uptake in the heart and extracardiac region, including the abdominal to bilateral iliac arteries, had been disappeared. During the tapering of prednisolone, additive methotrexate therapy was needed to treat the recurrence of cardiac sarcoidosis. FDG-PET is a useful tool for detecting cardiac sarcoidosis concomitant with large-vessel aortitis and monitoring the effectiveness of immunosuppressive therapy.

DOI： 10.2169/internalmedicine.9652-17

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

Objective. Aspects of health-related quality of life (HRQoL) are important for assessing perceived health status and treatment burden. We evaluated HRQoL using Short Form 36 Health Survey (SF-36) and factors associated with HRQoL. Methods. We collected basic and lifestyle-related, clinical, and treatment characteristics among 119 female Japanese patients with systemic lupus erythematosus (SLE). Odds ratios (ORs) and their 95% confidence intervals were assessed for associations between HRQoL and selected factors. Results. Irregularity of sleep was significantly associated with risk of lower role physical (RP) (OR = 8.27), vitality (VT) (OR = 8.45), and role emotional (OR = 10.7) domains. Compared with clerical work, non-clerical work was significantly associated with risk of lower RP (OR = 7.39), and unemployment was significantly associated with risk of lower VT (OR = 41.0). Daily soybean intake was associated with improved General Health or GH (OR = 0.17). Compared with Systemic Lupus Collaborative Clinics Damage Index (SDI) = 0, SDI > 2 was associated with risk of lower PF (OR = 7.88), RP (OR = 4.29), and bodily pain (OR = 3.06) domains. Conclusion. Reduced HRQoL was observed in our SLE patients. Interventions addressing sleep and work disturbances, as well as daily soybean consumption, could alter the HRQoL of SLE patients.

DOI： 10.3109/14397595.2015.1060668

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

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

DOI： 10.1186/s13075-015-0547-z

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

Viral infection is known to induce transient autoimmunity in humans. Acute cytomegalovirus (CMV) infection is implicated in occasional thrombosis formation. We here, for the first time, report a 19-year-old female who had an acute CMV infection, leading to a deep venous thrombosis and a pulmonary embolism along with transient appearance of lupus anticoagulant. The pathological role of antiphospholipid antibodies in CMV-mediated thrombosis is discussed.

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)  

Objective: We examined the prevalence and risk factors of vertebral fracture in female Japanese patients with systemic lupus erythematosus (SLE). Methods: We performed lateral radiographs of the thoracic and lumbar spine and bone mineral density (BMD) measurements and collected demographic, lifestyle, clinical, and treatment characteristics of 52 SLE patients. Vertebral fractures were defined as a >20 % reduction of vertebral body height. Odds ratios (ORs) and their 95 % confidence intervals (CIs) were computed to assess the strength of associations between vertebral fractures and selected factors among SLE patients. Results: At least one vertebral fracture was detected in 50 % of SLE patients. A history of previous bone fracture was significantly associated with an increased risk of vertebral fractures among SLE patients (adjusted OR = 14.8, 95 % CI = 1.62-134; P = 0.017). Daily use of tea or coffee was marginally associated with a decreased risk of vertebral fractures among SLE patients (adjusted OR = 0.11, 95 % CI = 0.01-1.01; P = 0.051). Conclusion: The high prevalence of vertebral fracture in SLE patients (50 %) indicates that we need to assess the lateral spine radiograph in more female Japanese SLE patients regardless of BMD and use of corticosteroids, although additional studies are warranted to confirm the findings suggested in this study.

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)  

Objective. Identification of the association of killer cell immunoglobulin-like receptor (KIR) genes with SLE and accompanying infections. Methods. Presence or absence of all 14 KIR genes was studied for association with SLE by case-control studies. A total of 417 SLE cases, 72 RA cases and 256 controls, all of Japanese descent, were enrolled. Results. The carrier frequency of KIR2DL5 was significantly decreased in SLE patients compared with healthy controls [39.3 vs 50.4%; odds ratio (OR) = 0.64; 95% CI 0.36, 0.92; P = 0.005). When the prevalence of severe infections was analysed in 184 SLE patients, whose medical records were available, KIR2DL5 carriers were at an increased risk of overall infection and viral infection (crude OR = 2.66; 95% CI 1.43, 4.92; P = 0.017 and crude OR = 2.31; 95% CI 1.15, 4.62; P = 0.017, respectively). After adjusting for methylprednisolone pulse and/or cyclophosphamide pulse therapy, KIR2DL5 carriers were at significantly greater risk of infectious events overall (adjusted OR = 2.45; 95% CI 1.24, 4.81; P = 0.0095). However, KIR2DL5 carriers were marginally associated with an increased risk of viral infectious events (adjusted OR = 2.03; 95% CI 0.94, 4.41; P = 0.0718). Conclusion. KIR2DL5 was significantly associated with a decreased risk of SLE as well as an increased risk of infectious events overall in SLE patients. Our data suggest a further role of KIRs in the pathogenesis of autoimmune diseases and infection.

DOI： 10.1093/rheumatology/keq050

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

Objective. Accumulating evidence suggests that B-cell depletion therapy by rituximab may be effective for autoimmune disorders. However, an optimal dose of rituximab and a mechanism of its action remain to be established. We performed a dose-escalation study for treatment of Japanese patients with autoimmune diseases including eight with SLE and one with Evans' syndrome. Methods. Rituximab was infused intravenously, weekly 4 times in a dose-escalating fashion at three different doses of 100, 250 or 375 mg/m
²
to three patients each. Immunological parameters were monitored at certain points until 12 months after the treatment. Results. Rituximab was well tolerated and safe in these patients. Seven out of eight SLE patients and one with Evans' syndrome clinically responded completely or partially to the treatment. Four patients achieved long-term remission (18-30 months) without any additional treatment. In these patients, a significant decrease in circulating B cells continued for 6 months after the treatment. The mean fluorescence intensities of CD19, CD21, CD40 and BR3 on the residual B cells as well as the percentage of CD69+ CD4+ T cells decreased significantly. Serum TNF-α levels decreased significantly on day 2. The Th1/Th2 balance of CD4+ T cells gradually shifted towards a Th1 type by 6 months. Conclusion. In addition to B-cell depletion, modification of B-cell and T-cell phenotypes as well as cytokine profiles may be involved in the action of rituximab.

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

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

Objective. Identification of the genes responsible for systemic lupus erythematosus (SLE). Methods. All the exons and putative promoter regions of 53 candidate genes (TNFRSF6/Fas, TNFSF6/FasL, Fli1, TNFSF10/TRAIL, TNFSF12/TWEAK, Bcl-2, PTEN, FADD, TRADD, CDKN1A, TNFRSF1A/TNFR1, TNFRSF4/OX40, TNFSF4/OX40L, TNFSF5/CD40L, TNFSF13B/BAFF, ICOS, CTLA4, CD28, FYN, G2A, CR2, PTPRC/CD45, CD22, CD19, Lyn, PDCD1, PTPN6, TGFB1, TGFB2, TGFB3, TGFBR1, TGFBR2, TGFBR3, CD3Z, DNASE1, APCS, MERTK, C3, C1QA, C1QB, C1QG, C2, MBL2, IGHM, IL-2, IL-4, IL-10, IFNG, TNFA, MAN2A1, TNFRSF11A/RANK, TNFRSF11B/OPG, TNFSF11/OPGL) were screened for single nucleotide polymorphisms (SNPs) and their association with SLE was assessed by case-control studies. A total of 509 cases and 964 controls of Japanese descent were enrolled. Results. A total of 316 SNPs was identified. When analysed in the Japanese population, the allele frequencies of T at rs7951 and G at rs2230201 of the C3 gene were 0.110 and 0.626, respectively, in SLE patients; significantly higher than the frequencies of 0.081 and 0.584, respectively, in controls [odds ratio (OR) = 1.40, 95% confidence interval (CI) = 1.05-1.86, P = 0.016 and OR = 1.19, 95% CI = 1.01-1.41, P = 0.038, respectively]. The mean serum C3 level of carriers of the rs7951 T allele was significantly lower than that of non-carriers of the T allele in 87 SLE patients whose medical records were available (P = 0.0018). Conclusion. rs7951 T allele of the C3 gene was significantly associated with SLE, and decreased serum level of C3 seems to be correlated with this allele.

DOI： 10.1093/rheumatology/kem321

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

DOI： 10.1136/ard.2006.065961

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

Objectives: To perform a case-control study of a functional M196R polymorphism of tumour necrosis factor receptor type 2 (TNF-RII) in a Japanese population and a meta-analysis of all published reports on the polymorphism to investigate the association of the M196R polymorphism of TNF-RII with systemic lupus erythematosus (SLE). Methods: The functional M196R polymorphism of TNF-RII was genotyped by using polymerase chain reaction combined with the subsequent single-strand conformation polymorphism (PCR-SSCP) analysis for screening, followed by nucleotide sequencing for confirmation. A total of 331 patients and 359 controls were subjected to a case-control study. A meta-analysis of the available case-control studies including all published data as well as our own data was performed to investigate the association of the functional M196R polymorphism of TNF-RII with SLE. Results: Our case-control study did not show any significant association of a functional M196R polymorphism of TNF-RII with SLE, although there was a trend towards association. A meta-analysis of seven case-control studies in eight different ethnic populations including our own showed that 196M/R and 196R/R genotypes combined was significantly associated with an increased risk of SLE (odds ratio (OR) 1.29, 95% confidence interval (CI) 1.04 to 1.60; p = 0.02). Stratification by ethnicity showed a more significant association in Asians, including Japanese, Korean and Vietnamese (OR 1.40, 95% CI 1.10 to 1.78; p = 0.006). The effect of the 196R allele on SLE was not clear in Caucasians. Conclusions: The 196R allele of the functional M196R polymorphism of TNF-RII is a risk factor for SLE, especially in the Asian population.

DOI： 10.1136/ard.2006.058917

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

DOI： 10.1016/j.bbrc.2005.02.159

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

Interleukin-21 (IL-21) is the most recent member of the common gamma-chain-dependent cytokine family. We studied the expression of the IL-21 receptor (IL-21R) on peripheral B lymphocytes in patients with systemic lupus erythematosus (SLE) or primary Sjögren's syndrome (pSjS), and healthy controls. Naive B lymphocytes expressed higher levels of IL-21R than memory B lymphocytes and plasmablasts, both in SLE patients and healthy controls. The proportion of IL-21R+ cells in the total peripheral B lymphocytes, as well as those in the respective B lymphocyte subsets, was significantly lower in SLE compared with those of pSjS or healthy controls (p=0.0002 and p<0.0001, respectively, in total B lymphocytes). The decreased expression of IL-21R in SLE was significantly associated with nephritis and high titer anti-double-strand DNA antibody. In some SLE patients, IL-21-induced proliferation of CD19+ B lymphocytes, in the presence of CD40 stimulation, was impaired. The abnormalities of IL-21R signaling might contribute to the pathological features of SLE, such as B lymphocytopenia.

Event date： 2022.4

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

Venue：パシフィコ横浜   Country：Japan  

Event date： 2021.8

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

Venue：Kyoto International Conference Center   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。

Language：Japanese  

Venue：大阪  

Event date： 2025.7

Venue：web  

Event date： 2025.6

Event date： 2025.3

Event date： 2024.9

Event date： 2024.4

Event date： 2024.1

Event date： 2023.10

Event date： 2023.8

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

Venue：別府市   Country：Japan  

Event date： 2023.8

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

Venue：別府市   Country：Japan  

Event date： 2023.8

Event date： 2023.7

Event date： 2023.4 - 2024.4

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

Venue：福岡市   Country：Japan  

Event date： 2023.4

Language：Japanese  

Venue：福岡国際会議場   Country：Japan  

Event date： 2023.4

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

Venue：福岡国際会議場   Country：Japan  

Event date： 2023.4

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

Venue：福岡国際会議場   Country：Japan  

Event date： 2023.4

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

Venue：福岡国際会議場   Country：Japan  

Event date： 2023.4

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

Venue：福岡国際会議場   Country：Japan  

Event date： 2023.4

Language：Japanese  

Venue：福岡国際会議場   Country：Japan  

Event date： 2023.4

Language：Japanese  

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

Language：Japanese  

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： 2022.4

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

Venue：パシフィコ横浜   Country：Japan  

Event date： 2022.3

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

Venue：久留米シティプラザ   Country：Japan  

Event date： 2022.3

Language：Japanese  

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

Language：Japanese  

Country：Japan  

Event date： 2021.4

Language：Japanese  

Country：Japan  

Event date： 2021.4

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

Country：Japan  

Event date： 2021.3

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

Country：Japan  

Event date： 2021.2

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2020.4

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

Country：Japan  

Event date： 2020.4

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

Country：Japan  

Event date： 2020.4

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

Country：Japan  

Event date： 2019.11

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2019.10

Language：Japanese   Presentation type：Oral presentation (general)  

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

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：別府市医師会館   Country：Japan  

Event date： 2018.11

Language：Japanese   Presentation type：Oral presentation (general)  

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

Language：Japanese  

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

Language：Japanese  

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

Language：Japanese   Presentation type：Oral presentation (general)  

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

Language：Japanese   Presentation type：Oral presentation (general)  

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  

A case of follicular bronchiolitis associated with RA, which needed to differentiate from HTLV-1 associated bronchiolo-alveolar disorder and pulmonary MTX associated LPD.

Language：Japanese  

Venue：福岡  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

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Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

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

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

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

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

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

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

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

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

Umbilical cord mesenchymal stem cell transplantation in systemic lupus erythematosus

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. 

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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. 

Type：Seminar, workshop

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Type：Visiting lecture

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Type：Other

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