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Language：English   Publishing type：Research paper (scientific journal)   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：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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DOI： 10.1182/blood-2023-181258

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DOI： 10.1016/j.eneco.2023.106809

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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)   Publisher：Rheumatology United Kingdom  

Objectives: To evaluate the long-term impact of immunosuppressive therapeutic agents on antibody response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) mRNA vaccination in patients with autoimmune rheumatic diseases (AIRD) in order to propose a strategy for annual vaccination. Methods: This prospective multicentre cohort study evaluated the humoral response to second and third BNT162b2 and/or mRNA-1273 vaccines in 382 Japanese AIRD patients classified into 12 different medication groups and in 326 healthy controls (HCs). The third vaccination was administered six months after the second vaccination. Antibody titres were measured using the Elecsys Anti-SARS-CoV-2 S assay. Results: The seroconversion rate and antibody titres were lower in AIRD patients than in HCs 3–6 weeks after the second vaccination and 3–6 weeks after the third vaccination. Seroconversion rates were <90% after the third vaccination in patients receiving mycophenolate mofetil and rituximab. Antibody levels after the third vaccination were significantly lower in the groups prescribed TNF inhibitor with or without methotrexate, abatacept and rituximab or cyclophosphamide than those of HCs in a multivariate analysis adjusting for age, sex, and glucocorticoid dosage. The third vaccination induced an adequate humoral response in patients treated with sulfasalazine, bucillamine, methotrexate monotherapy, iguratimod, interleukin-6 inhibitors or calcineurin inhibitors including tacrolimus. Conclusions: Repeated vaccinations in many immunosuppressed patients produced antibody responses similar to those observed in HCs. In contrast, annual vaccination in patients receiving TNF inhibitors, abatacept, mycophenolate mofetil and rituximab may require caution.

DOI： 10.1093/rheumatology/kead275

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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   Publishing type：Research paper (scientific journal)   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：Oxford University Press  

日本人成人Still病(AOSD)患者のアウトカム予測における重症度分類の有用性を検討した。2006年1月～2016年9月にAOSDと診断された患者の診療録を後方視的にレビューした。厚生労働省の重症度分類に基づいて軽症49例(35%)、中等症37例(26%)、重症56例(39%)に分類した。AOSD関連合併症の発症率と生物学的製剤の使用率は重症度に伴って上昇していた。AOSD関連生存率には重症度による有意差を認めなかったが(p=0.0776)、死亡例5例中4例は重症群であった。Drug-free寛解率については重症度による有意差を認めた(p=0.0125)。一方、systemic score(modified Pouchotスコア)による分類はAOSD関連生存率、drug-free寛解率のいずれとも関連しなかった。以上より、重症度分類はAOSD患者のアウトカム予測に有用であることが示された。

Language：English   Publisher：Modern Rheumatology  

Objectives: To investigate the usefulness of severity classification for predicting outcomes in patients with adult-onset Still’s disease (AOSD). Methods: This was a multi-centre retrospective cohort study. AOSD patients were classified into mild, moderate, and severe groups based on severity classification (Japanese Ministry of Health, Labour and Welfare) during the initial treatment, and clinical features were compared among these groups. The primary endpoints were the AOSD-related mortality and drug-free remission rate. For comparison, the same analysis was performed in parallel for patient groups stratified by the modified Pouchot systemic score. Results: According to severity classification, 49 (35%), 37 (26%), and 56 patients (39%) were classified into mild, moderate, and severe groups, respectively. Patients in the severe group showed higher frequency of severe complications and the use of biological agents. Although AOSD-related survival was not significantly different (p = .0776), four of the five fatal cases were classified into the severe group. The severe group showed a reduced rate of drug-free remission (p = .0125). Patient groups classified by systemic score did not correlate with survival or drug-free remission. Conclusions: Severity classification is useful for predicting outcomes in patients with AOSD.

DOI： 10.1093/mr/roab083

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

Objectives: We aim to clarify the efficacy and safety of switching immunosuppressive drugs and to identify the predictive factors for treatment failure after switching in patients with systemic lupus erythematosus (SLE). Methods: We retrospectively evaluated patients with SLE who switched immunosuppressive drugs for any reason in our hospital between 2015 and 2020. The efficacy endpoints were the change in SLE Disease Activity Index 2000 score, prednisolone dose, and disease status over 12 months, as well as treatment continuation rates. The safety endpoint was the frequency of adverse events over 1 year before and after switching. Cox hazard regression analyses were used to identify the predictive factors for treatment failure. Results: Thirty-nine patients (age, 41.5 ± 12.6 years; 35 women and 4 men) were analysed. The SLE Disease Activity Index score and prednisolone dose were significantly reduced after switching, with few disease exacerbations over 12 months. The 1- and 2-year continuation rates were 71.4% and 62.3%, respectively. The frequency of adverse events was similar in the year before and after switching the drug. Drug switching due to inadequate efficacy was a predictive factor of less likely treatment failure. Conclusions: Immunosuppressive drug switching led to reduced disease activity and decreased glucocorticoid dose without disease exacerbations and severe adverse events.

DOI： 10.1093/mr/roac100

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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：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： 10.1177/1759720X221096367

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DOI： 10.1177/1759720X221096367

Language：English   Publishing type：Research paper (scientific journal)   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   Publishing type：Research paper (scientific journal)   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：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   Publisher：Arthritis Research and Therapy  

Background: To further improve rheumatoid arthritis (RA) treatment, it is necessary to understand each RA patient’s satisfaction and to identify the factors affecting their satisfaction. Despite the rise in medical costs for RA, little is known about the factors that influence patient satisfaction with the cost of treatment in RA patients. Methods: This is a multicenter observational study of Japanese RA patients from the FRANK Registry with data analyzed from March 2017 to August 2020. We collected data on demographic characteristics, clinical data, quality of life which was evaluated using the EuroQol 5-dimensional questionnaire (EQ5D), and patient satisfaction. The four categories of patient satisfaction were evaluated individually (i.e., cost, treatment efficacy, activities of daily living [ADL], and global treatment satisfaction). We analyzed the factors that affected each patient’s satisfaction, such as age, sex, EQ5D, disease duration, disease activity, and treatment. Results: This study included 2235 RA outpatients (406 males, 1829 females). In RA patients, “very satisfied” and “satisfied” were given for nearly half of each satisfaction aspect (cost 49%; efficacy 72%; ADL 58%; global treatment 66%) at the time of the initial registration. To investigate the factors influencing each satisfaction, multivariate analysis has revealed that the use of b/tsDMARDs increased satisfaction of treatment effect (odds ratio [OR] 0.66) and ADL (OR 0.78) but decreased cost satisfaction (OR 2.21). Age (50–64 years; OR 0.91; 65–74 years, 0.55: ≥ 75 years, 0.35), female (OR 0.81), and history of musculoskeletal surgery (OR 0.60) all increased cost satisfaction. Patients with lower disease activity and higher EQ5D scores had higher levels of satisfaction in all areas. Conclusions: In this study, patient satisfaction in terms of cost, treatment effect, ADL, and overall treatment was generally higher, but some patients were dissatisfied. The cost of satisfaction increased with age and a history of musculoskeletal surgery, while it decreased with a lower EQ5D score and the use of b/tsDMARDs.

DOI： 10.1186/s13075-022-02746-5

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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   Publisher：Clinical and Experimental Rheumatology  

Objective 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). Conclusion 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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DOI： 10.1177/09612033211031989

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DOI： 10.1186/s13075-021-02618-4

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DOI： 10.1038/s41598-021-95711-2

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DOI： 10.3389/fimmu.2021.713225

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DOI： 10.3389/fimmu.2021.654623

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DOI： 10.1016/j.cellimm.2020.104263

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DOI： 10.1111/cei.13477

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DOI： 10.3389/fimmu.2020.02042

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DOI： 10.1186/s12865-020-00361-0

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DOI： 10.4049/jimmunol.1901304

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DOI： 10.1371/journal.pone.0196368

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DOI： 10.1136/gutjnl-2015-309359

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Interleukin-33 (IL-33) induces T helper type 2 (Th2) cytokine production and eosinophilia independently of acquired immunity, leading to innate immunity-mediated allergic inflammation. Allergy-related innate myeloid cells such as eosinophils, basophils and mast cells express the IL-33 receptor (IL-33R), but it is still unknown how IL-33 regulates allergic inflammation involving these cells and their progenitors. Here, we revealed that the functional IL-33R was expressed on eosinophil progenitors (EoPs), basophil progenitors (BaPs) and mast cell progenitors (MCPs). In the presence of IL-33, these progenitors did not expand, but produced a high amount of Th2 and pro-inflammatory cytokines such as IL-9, IL-13, IL-1β and IL-6. The amount of cytokines produced by these progenitors was greater than that by mature cells. In vivo, IL-33 stimulated the expansion of EoPs, but it was dependent upon the elevated serum IL-5 that is presumably derived from type 2 innate lymphoid cells that express functional IL-33R. These data collectively suggest that EoPs, BaPs and MCPs are not only the sources of allergy-related granulocytes, but can also be sources of allergy-related cytokines in IL-33-induced inflammation. Because such progenitors can differentiate into mature granulocytes at the site of inflammation, they are potential therapeutic targets in IL-33-related allergic diseases.

DOI： 10.1111/imm.12667

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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

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DOI： 10.1186/s13075-016-0957-6

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DOI： 10.4049/jimmunol.1403046

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DOI： 10.1186/s13075-015-0547-z

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DOI： 10.1073/pnas.1412487111

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DOI： 10.4049/jimmunol.1401448

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DOI： 10.1073/pnas.1400139111

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DOI： 10.1097/MIB.0b013e318280b169

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Tumor necrosis factor (TNF)-α is a potent pro-inflammatory and pathological cytokines in inflammatory diseases such as rheumatoid arthritis and inflammatory bowel diseases. Anti-TNF-α therapy has been established as an efficacious therapeutic strategy in these diseases. In clinical settings, three monoclonal anti-TNF-α full IgG1 antibodies infliximab, adalimumab, and golimumab, PEGylated Fab’ fragment of anti-TNF-α antibody certolizumab pegol, extracellular domain of TNF receptor 2/IgG1-Fc fusion protein etanercept, are almost equally effective for rheumatoid arthritis. Although monoclonal full IgG1 antibodies are able to induce clinical and endoscopic remission in inflammatory bowel diseases, certolizumab pegol without Fc portion has been shown to be less effective for inflammatory bowel diseases compared to full IgG1 antibodies. In addition, there are no evidences that etanercept leads clinical remission in inflammatory bowel diseases. Besides the common effect of anti-TNF-α agents on neutralization of soluble TNF-α, each anti-TNF-α agent has its own distinctive pharmacological properties which cause the difference in clinical efficacies. Here we focus on the distinctions of action of anti-TNF-α agents especially in following points; (1) blocking ability against ligands, transmembrane TNF-α and lymphotoxin, (2) effects toward transmembrane TNF-α-expressing cells, (3) effects toward Fcγ receptor-expressing cells, (4) degradation and distribution in inflamed tissue. Accumulating evidence will give us the idea how to modify anti-TNF-α agents to enhance the clinical efficacy in inflammatory diseases.

DOI： 10.1016/j.cyto.2016.08.014

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Systemic sclerosis (SSc) is an intractable multifaceted disease with high mortality. Although its pathogenesis is not fully understood, recent studies have advanced our knowledge on SSc. The cardinal pathological features of SSc are autoimmunity, vasculopathy, and fibrosis. The B cells in SSc are constitutively activated and lead to the production of a plethora of autoantibodies, such as anti-topoisomerase I and anti-centromere antibodies. In addition to these autoantibodies, which are valuable for diagnostic criteria or biomarkers, many other autoantibodies targeting endothelial cells, including endothelin type A receptor and angiotensin II type I receptor, are known to be functional and induce activation or apoptosis of endothelial cells. The autoantibody-mediated endothelial cell perturbation facilitates inflammatory cell infiltration, cytokine production, and myofibroblastic transformation of fibroblasts and endothelial cells. Profibrotic cytokines, such as transforming growth factor β, connective tissue growth factor, interleukin 4/interleukin 13, and interleukin 6, play a pivotal role in collagen production from myofibroblasts. Specific treatments targeting these causative molecules may improve the clinical outcomes of patients with SSc. In this review, we summarize recent topics on the pathogenesis (autoantibodies, vasculopathy, and fibrosis), animal models, and emerging treatments for SSc.

DOI： 10.1007/s12026-017-8926-y

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

Type：Peer review 

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

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

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Number of peer-reviewed articles in foreign language journals：3

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Number of peer-reviewed articles in foreign language journals：3

Type：Peer review 

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

Number of peer-reviewed articles in Japanese journals：1

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Type：Competition, symposium, etc. 

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：1

Type：Competition, symposium, etc. 

Type：Peer review 

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

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：3