研究者詳細 - 竹内　勤

論文 - 竹内　勤

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CHARACTERISTICS OF RECENT ELDERLY-ONSET RHEUMATOID ARTHRITIS PATIENTS

Oshige T., Kaneko Y., Takeuchi T.

ANNALS OF THE RHEUMATIC DISEASES 77 566 - 566 2018年06月

研究論文（学術雑誌）, 査読有り, ISSN 0003-4967

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BIOMARKERS FOR RELAPSE IN PATIENTS WITH ADULT ONSET STILL'S DISEASE TREATED WITH IL-6 INHIBITOR

Yamada H., Kaneko Y., Takeuchi T.

ANNALS OF THE RHEUMATIC DISEASES 77 853 - 853 2018年06月

研究論文（学術雑誌）, 査読有り, ISSN 0003-4967

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ARYL HYDROCARBON RECEPTOR EXPRESSION IS ASSOCIATED WITH LUNG INVOLVEMENT IN SYSTEMIC SCLEROSIS

Takei H., Yasuoka H., Yoshimoto K., Yamaoka K., Takeuchi T.

ANNALS OF THE RHEUMATIC DISEASES 77 738 - 738 2018年06月

研究論文（学術雑誌）, 査読有り, ISSN 0003-4967

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ANALYSIS OF SYMPTOMS IN VERY EARLY PHASE IN PATIENTS WITH ADULT-ONSET STILL'S DISEASE

Tamai H., Kaneko Y., Takeuchi T.

ANNALS OF THE RHEUMATIC DISEASES 77 1743 - 1744 2018年06月

研究論文（学術雑誌）, 査読有り, ISSN 0003-4967

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ACTIVATED PLATELETS ARE INCREASED IN CIRCULATION OF PATIENTS WITH SYSTEMIC SCLEROSIS AND ASSOCIATED WITH CLINICAL CHARACTERISTICS

Yasuoka H., Sakata K., Yoshimoto K., Yamaoka K., Kuwana M., Takeuchi T.

ANNALS OF THE RHEUMATIC DISEASES 77 1281 - 1281 2018年06月

研究論文（学術雑誌）, 査読有り, ISSN 0003-4967

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A PHASE 2B/3 RANDOMISED, PLACEBO-CONTROLLED, DOUBLE-BLIND STUDY OF UPADACITINIB, A SELECTIVE JAK1 INHIBITOR, IN JAPANESE PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS AND INADEQUATE RESPONSE TO CONVENTIONAL SYNTHETIC DMARDS

Tanaka Y., Takeuchi T., Yamaoka K., Oribe M., Kawano M., Zhou Y., Othman A. A., Pangan A. L., Kitamura S., Matsuda N., Meerwein S., Kameda H.

ANNALS OF THE RHEUMATIC DISEASES 77 991 - 992 2018年06月

研究論文（学術雑誌）, 査読有り, ISSN 0003-4967

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Interleukin-4 contributes to the shift of balance of IgG subclasses toward IgG4 in IgG4-related disease

竹内勤

Cytokine （Cytokine） 110 416 - 419 2018年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 10434666

© 2018 IgG4-related disease (IgG4-RD) is a systemic disorder characterized by elevated serum IgG4 level, which is mediated by T follicular helper 2 (Tfh2) cell. However, the cytokines responsible for enhancing IgG4 production remain unclear in IgG4-RD. The aim of this study was to identify responsible Tfh2-related cytokines (interleukin (IL)-4 and IL-21) for enhancing IgG4 production in IgG4-RD. Peripheral blood mononuclear cells obtained from consecutive patients with active, untreated IgG4-RD and healthy controls were examined. The production of both IgG and IgG4 were significantly increased by stimulation with IL-4 alone as well as IL-21 alone compared to background stimulation with anti-CD40 antibody in IgG4-RD. On the other hand, the IgG4/IgG ratio was statistically higher by stimulation with IL-4 alone compared to the other Tfh2-related cytokines including IL-21 in IgG4-RD. IgG4 production was not increased by stimulation with IL-4 in healthy controls. These results suggest that IL-4 can contribute to the shift of balance of IgG subclasses toward IgG4 compared to the other Tfh2-related cytokines in IgG4-RD.

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Tocilizumab discontinuation after attaining remission in patients with rheumatoid arthritis who were treated with tocilizumab alone or in combination with methotrexate

Kaneko Yuko, Kato Masaru, Tanaka Yoshiya, Inoo Masayuki, Kobayashi-Haraoka Hitomi, Amano Koichi, Miyata Masayuki, Murakawa Yohko, Yasuoka Hidekara, Hirata Shintaro, Tanaka Eiichi, Miyasaka Nobuyuki, Yamanaka Hisashi, Yamamoto Kazuhiko, Takeuchi Tsutomu

Annals of the Rheumatic Diseases 77 1268 2018年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0003-4967

Objective: To evaluate the sustained remission and low disease activity after discontinuation of tocilizumab in patients with rheumatoid arthritis who were treated with tocilizumab alone or in combination with methotrexate. Methods: The SURPRISE study was a 2-year, open-label randomised controlled study. Among patients who had been randomised to additional tocilizumab (ADD-ON) or switch to tocilizumab (SWITCH) in the first year, those who achieved remission based on the disease activity score for 28 joints (DAS28-ESR<2.6) discontinued tocilizumab at week 52 and were observed for the following 52 weeks. The endpoint of the second year included tocilizumab-free remission and low disease-Activity rates, functional outcome, radiological outcomes assessed with the modified total Sharp score (mTSS) and safety. The efficacy of reinstituted tocilizumab/methotrexate was also evaluated. Results: A total of 105 patients who achieved remission at week 52 discontinued tocilizumab; 51 in ADD-ON continued methotrexate and 54 in SWITCH received no disease-modifying antirheumatic drugs. Sustained DAS28 low disease-Activity rates were significantly higher in ADD-ON than in SWITCH (55%vs27%, p=0.005). Sustained remission rates at week 104 were 24% for ADD-ON and 14% for SWITCH (p=0.29). Radiological progression was comparable between both groups (mTSS; 0.37vs0.64, p=0.36). The restart of tocilizumab induced remission in all except two patients after 36 weeks, irrespective of concomitant methotrexate. Conclusion: Sustained low disease activity after tocilizumab discontinuation could be maintained with continued methotrexate in more than half of the patients. Retreatment with tocilizumab led to remission in more than 90% of patients. Trial registration number: NCT01120366; Results.

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Clinical practice guideline for Sjögren’s syndrome 2017

Sumida T., Azuma N., Moriyama M., Takahashi H., Asashima H., Honda F., Abe S., Ono Y., Hirota T., Hirata S., Tanaka Y., Shimizu T., Nakamura H., Kawakami A., Sano H., Ogawa Y., Tsubota K., Ryo K., Saito I., Tanaka A., Nakamura S., Takamura E., Tanaka M., Suzuki K., Takeuchi T., Yamakawa N., Mimori T., Ohta A., Nishiyama S., Yoshihara T., Suzuki Y., Kawano M., Tomiita M., Tsuboi H.

Modern Rheumatology （Modern Rheumatology） 28 （ 3 ） 383 - 408 2018年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

© 2018 Japan College of Rheumatology. Published by Informa UK Limited, trading as Taylor & Francis Group. Objectives: The objective of this study is to develop clinical practice guideline (CPG) for Sjögren’s syndrome (SS) based on recently available clinical and therapeutic evidences. Methods: The CPG committee for SS was organized by the Research Team for Autoimmune Diseases, Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW), Japan. The committee completed a systematic review of evidences for several clinical questions and developed CPG for SS 2017 according to the procedure proposed by the Medical Information Network Distribution Service (Minds). The recommendations and their strength were checked by the modified Delphi method. The CPG for SS 2017 has been officially approved by both Japan College of Rheumatology and the Japanese Society for SS. Results: The CPG committee set 38 clinical questions for clinical symptoms, signs, treatment, and management of SS in pediatric, adult and pregnant patients, using the PICO (P: patients, problem, population, I: interventions, C: comparisons, controls, comparators, O: outcomes) format. A summary of evidence, development of recommendation, recommendation, and strength for these 38 clinical questions are presented in the CPG. Conclusion: The CPG for SS 2017 should contribute to improvement and standardization of diagnosis and treatment of SS.

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A Low molecular weight BAFF receptor antagonist inhibits differentiation of human peripheral B cells into plasma blasts/plasma cells in vitro.

Yoshimoto Keiko, Seki Noriyasu, Suzuki Katsuya, Sugahara Kunio, Takeuchi Tsutomu

JOURNAL OF IMMUNOLOGY 200 （ 1 ） 2018年05月

研究論文（学術雑誌）, 査読有り, ISSN 0022-1767

Clinicopathologic investigation of methotrexate-induced lymphoproliferative disorders, with a focus on regression

竹内勤

Leukemia and Lymphoma （Leukemia and Lymphoma） 59 （ 5 ） 1143 - 52 2018年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 10428194

© 2017 Informa UK Limited, trading as Taylor & Francis Group. Although recent accumulative data reveal the clinicopathogenesis of regression in methotrexate-induced lymphoproliferative disorders (MTX-LPDs), the precise understanding including this category remains controversial. In this study, we analyzed 62 patients with MTX-LPD. Forty-three patients showed regression (Reg group), with high rates of Hodgkin lymphoma (HL) and LPD (90 and 88%, respectively). Among the 43 patients of the Reg group, 14 patients (33%) relapsed. The median duration before relapse in the Reg group was 10.6 months. Although the difference of OS between the Reg and Non-Reg groups was not significantly different, relapse-free patients in the Reg group had a superior overall survival (OS). MTX duration had a significant impact on Epstein–Barr virus (EBV) infection (p =.00131). Furthermore, EBV infection was significantly related to clinical manifestations, including spleen invasion, in the regression phenomenon. Some human leukocyte antigens (HLA) alleles might affect MTX-LPD development via EBV infection, although A*2402 and DRB1*0405 might be affected as fundamental factors.

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DURABILITY, MAINTENANCE AND EFFECTS OF DOSE REDUCTION FOLLOWING PROLONGED TREATMENT WITH BARICITINIB

Smolen J., Dougados M., Takeuchi T., Genovese M., Haraoui B., Klar R., Kavanaugh A., Alonso R. B., Dudler J., Taylor P., Nash P., Zerbini C., Durez P., Pum G., Arthanari S., De Leonardis F., van Vollenhoven R.

INTERNAL MEDICINE JOURNAL 48 43 - 43 2018年05月

研究論文（学術雑誌）, 査読有り, ISSN 1444-0903

Efficacy and safety of sirukumab in Japanese patients with active rheumatoid arthritis who were refractory or intolerant to anti-tumor necrosis factor therapy

Tanaka Yoshiya, Takeuchi Tsutomu, Harigai Masayoshi, Yamanaka Hisashi, Nakano Toshikazu, Akagi Koshiro, Ukyo Yoshifumi, Hsu Benjamin

Modern Rheumatology 1 - 8 2018年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Objective: To evaluate the efficacy and safety of sirukumab, a human anti-interleukin six monoclonal antibody, in Japanese patients with rheumatoid arthritis who were refractory to anti-tumor necrosis factor therapy. Methods: This subgroup analysis, based on a double-blind, placebo-controlled, 52-week phase 3, global study (SIRROUND-T) assessed the American College of Rheumatology (ACR) 20 response at week 16 (primary endpoint). Secondary endpoints: ACR 50, Disease Activity Score in 28 joints-C reactive protein, Health Assessment Questionnaire-Disability Index and safety were assessed. Results 116/878 patients received sirukumab 50 mg/4 weeks (q4w, n = 35), 100 mg/2 weeks (q2w, n = 44) or placebo (n = 37) subcutaneously. Significantly more patients achieved ACR 20 response at week 16 with sirukumab (50 mg q4w:20 [57.1%]; p < .001, 100 mg q2w:24 [54.5%]; p = .001) versus placebo (7 [18.9%]); consistent significant improvement in secondary endpoints at week 24 and 52 was observed. At week 24, incidence of treatment-emergent adverse events (TEAEs) was numerically higher with sirukumab groups (50 mg q4w:29 [82.9%]; 100 mg q2w:38 [86.4%] versus placebo (28 [75.7%]); however, at week 52, sirukumab combined groups had comparable incidence of TEAEs. Conclusion: Efficacy findings through 52 weeks were comparable between sirukumab doses in Japanese patients and consistent with primary SIRROUND-T study results. No new safety signals were observed.

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Restoration of decreased T helper 1 and CD8+ T cell subsets is associated with regression of lymphoproliferative disorders developed during methotrexate treatment

Saito S., Suzuki K., Yoshimoto K., Kaneko Y., Yamaoka K., Shimizu T., Mori T., Okamoto S., Kameyama K., Amano K., Tamaru J., Tokuhira M., Takeuchi T.

Frontiers in Immunology （Frontiers in Immunology） 9 （ APR ） 621 2018年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1664-3224

© 2018 Saito, Suzuki, Yoshimoto, Kaneko, Yamaoka, Shimizu, Mori, Okamoto, Kameyama, Amano, Tamaru, Tokuhira and Takeuchi. Background: Lymphoproliferative disorder (LPD), including malignant lymphoma, is a relatively rare but life-threatening complication in RA patients under methotrexate (MTX) therapy. Spontaneous regression of LPD after MTX withdrawal is regarded as a distinct characteristic in part of such LPDs. Objective: The present study aimed to investigate the immunological difference in regressive LPD and persistent LPD. Methods: We studied RA patients who developed LPD during MTX administration (n = 35) and clinically matched controls (n = 35). The time of MTX cessation was defined as week 0, and LPD patients were divided into two groups according to LPD status at week 12: regressive group (n = 22) and persistent group (n = 13). Flow cytometric analysis of whole blood samples and serum cytokine assays were conducted for LPD (n = 10) and control patients (n = 10) at weeks 0, 4, and 12. Results: There was a significant decrease in peripheral lymphocytes and the proportion of T helper 1 cells (Th1 cells), effector memory CD8+ T cells (EMCD8+ T) and Epstein-Barr virus (EBV)-specific CD8+ T cells at the time of LPD diagnosis, and a significant increase after MTX cessation was observed in the regressive group but not in the persistent group. The expansion of Th1 cells and EMCD8+ T cells significantly correlated with an increase in serum interferon (IFN)-γ concentration. Conclusion: Changes in Th1 cells, EMCD8+ T cells and EBV-specific CD8+ T cells, which coincided with an increase in IFN-γ, were significantly different between regressive LPD and persistent LPD after MTX cessation.

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Splicing variant of WDFY4 augments MDA5 signalling and the risk of clinically amyopathic dermatomyositis

Kochi Y., Kamatani Y., Kondo Y., Suzuki A., Kawakami E., Hiwa R., Momozawa Y., Fujimoto M., Jinnin M., Tanaka Y., Kanda T., Cooper R., Chinoy H., Rothwell S., Lamb J., Vencovský J., Mann H., Ohmura K., Myouzen K., Ishigaki K., Nakashima R., Hosono Y., Tsuboi H., Kawasumi H., Iwasaki Y., Kajiyama H., Horita T., Ogawa-Momohara M., Takamura A., Tsunoda S., Shimizu J., Fujio K., Amano H., Mimori A., Kawakami A., Umehara H., Takeuchi T., Sano H., Muro Y., Atsumi T., Mimura T., Kawaguchi Y., Mimori T., Takahashi A., Kubo M., Kohsaka H., Sumida T., Yamamoto K.

Annals of the Rheumatic Diseases （Annals of the Rheumatic Diseases） 77 （ 4 ） 602 - 611 2018年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0003-4967

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted. Objectives Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare autoimmune diseases in which both genetic and environmental factors play important roles. To identify genetic factors of IIM including polymyositis, dermatomyositis (DM) and clinically amyopathic DM (CADM), we performed the first genome-wide association study for IIM in an Asian population. Methods We genotyped and tested 496 819 single nucleotide polymorphism for association using 576 patients with IIM and 6270 control subjects. We also examined the causal mechanism of disease-associated variants by in silico analyses using publicly available data sets as well as by in in vitro analyses using reporter assays and apoptosis assays. Results We identified a variant in WDFY4 that was significantly associated with CADM (rs7919656; OR=3.87; P=1.5×10 -8). This variant had a cis-splicing quantitative trait locus (QTL) effect for a truncated WDFY4isoform (tr-WDFY4), with higher expression in the risk allele. Transexpression QTL analysis of this variant showed a positive correlation with the expression of NF-ΚB associated genes. Furthermore, we demonstrated that both WDFY4 and tr-WDFY4 interacted with pattern recognition receptors such as TLR3, TLR4, TLR9 and MDA5 and augmented the NF-ΚB activation by these receptors. WDFY4 isoforms also enhanced MDA5-induced apoptosis to a greater extent in the tr-WDFY4-transfected cells. Conclusions As CADM is characterised by the appearance of anti-MDA5 autoantibodies and severe lung inflammation, the WDFY4 variant may play a critical role in the pathogenesis of CADM.

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Adolescent PR3-ANCA-positive hypertrophic pachymeningitis

Matsumoto K., Akiyama M., Kajio N., Otomo K., Suzuki K., Nishina N., Kasuya K., Oishi N., Kameyama K., Takeuchi T.

Medicine (United States) （Medicine (United States)） 97 （ 17 ） 17 2018年04月

研究論文（学術雑誌）, 査読有り, ISSN 0025-7974

© 2018 the Author(s). Published by Wolters Kluwer Health, Inc. Rationale: Hypertrophic pachymeningitis (HP) is an uncommon, life-threatening disease that is seen in elderly patients with antineutrophil cytoplasmic antibody (ANCA) positivity. Proteinase-3 (PR3)-ANCA-positive HP has not been reported in adolescents. Here, we report the first case of adolescent PR3-ANCA-positive HP successfully treated with immunosuppressive therapy. Patient concerns: A 14-year-old female presented with fullness and pain in her right ear unresponsive to antibiotics. Laboratory tests showed an elevated C-reactive protein and PR3-ANCA positivity. Computed tomography and magnetic resonance imaging revealed mastoiditis in the right temporal bone. Surgical biopsy revealed severe fibrosis and prominent inflammatory-cell infiltration. She received prednisolone and methotrexate therapy, and then underwent a right mastoidectomy. Five months later, she developed headache, dysarthria, and multiple cranial nerve palsies. Further imaging revealed enhancement and thickening of the right hemispheric dura. Diagnosis: PR3-ANCA-positive HP. Interventions: She was successfully treated with steroid pulse therapy for 3 days, followed by high doses of prednisolone and intravenous cyclophosphamide. Outcome: The treatment resulted in significant improvement of her symptoms, laboratory data, and radiologic findings. Lessons: PR3-ANCA-positive HP can present not only in the elderly, but also in adolescence, and prompt diagnosis and treatment with immunosuppressive therapy is vital.

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Akiyama M., Takeuchi T.

Drugs and Aging （Drugs and Aging） 35 （ 4 ） 275 - 287 2018年04月

研究論文（学術雑誌）, 査読有り, ISSN 1170229X

© 2018, Springer International Publishing AG, part of Springer Nature. IgG4-related disease is a heterogeneous immune-mediated fibroinflammatory condition that can affect every single organ. This disease is more prevalent in the elderly (the mean age of patients is above 60 years) and the prevalence rate is estimated to be over 4.6 per 100,000 population. Before making a diagnosis, the exclusion of malignancies, lymphoma, anti-neutrophil cytoplasmic antibody-associated vasculitis, multicentric Castleman disease, and other mimickers is crucial for appropriate treatment. Broad management guidelines have been published emphasizing the need for prompt treatment and the use of glucocorticoids as first-line drug therapy for induction of remission. However, the toxic effects of glucocorticoids are problematic because IgG4-related disease is more prevalent in patients above 60 years of age, a population with frequent comorbid conditions and polypharmacy. Immunosuppressants (cyclophosphamide, methotrexate, leflunomide, and tacrolimus) and targeted immunomodulators (rituximab, XmAb5871, and abatacept) are appealing to overcome potential toxic effects of glucocorticoids and as emerging glucocorticoid-sparing and/or maintenance treatments. In this review, we provide an overview of our understanding of the pathophysiology of the disease (T follicular helper cells, CD4+ cytotoxic T cells, plasmablasts, and alternatively activated M2 macrophages) and clinical characteristics, and highlight the potential targets for treatment intervention.

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DURABILITY, MAINTENANCE AND EFFECTS OF DOSE REDUCTION FOLLOWING PROLONGED TREATMENT WITH BARICITINIB

Smolen Josef S., Dougados Maxime, Takeuchi Tsutomu, Genovese Mark C., Haraoui Boulos, Klar Rena, Kavanaugh Arthur, Alonso Ricardo B., Dudler Jean, Taylor Peter C., Nash Peter, Zerbini Cristiano A., Durez Patrick, Pum Georg, Arthanari Subhashini, De Leonardis Francesco, van Vollenhoven Ronald

RHEUMATOLOGY 57 2018年04月

研究論文（学術雑誌）, 査読有り, ISSN 1462-0324

IgG4-Related Disease

Akiyama Mitsuhiro, Takeuchi Tsutomu

Drugs and Aging 35 275 - 287 2018年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1170-229X

IgG4-related disease is a heterogeneous immune-mediated fibroinflammatory condition that can affect every single organ. This disease is more prevalent in the elderly (the mean age of patients is above 60 years) and the prevalence rate is estimated to be over 4.6 per 100,000 population. Before making a diagnosis, the exclusion of malignancies, lymphoma, anti-neutrophil cytoplasmic antibody-associated vasculitis, multicentric Castleman disease, and other mimickers is crucial for appropriate treatment. Broad management guidelines have been published emphasizing the need for prompt treatment and the use of glucocorticoids as first-line drug therapy for induction of remission. However, the toxic effects of glucocorticoids are problematic because IgG4-related disease is more prevalent in patients above 60 years of age, a population with frequent comorbid conditions and polypharmacy. Immunosuppressants (cyclophosphamide, methotrexate, leflunomide, and tacrolimus) and targeted immunomodulators (rituximab, XmAb5871, and abatacept) are appealing to overcome potential toxic effects of glucocorticoids and as emerging glucocorticoid-sparing and/or maintenance treatments. In this review, we provide an overview of our understanding of the pathophysiology of the disease (T follicular helper cells, CD4⁺ cytotoxic T cells, plasmablasts, and alternatively activated M2 macrophages) and clinical characteristics, and highlight the potential targets for treatment intervention.

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Risk factors of relapse following glucocorticoid tapering in IgG4-related disease

竹内勤

Clinical and Experimental Rheumatology （Clinical and Experimental Rheumatology） 36 （ 3 ） S157 - S164 2018年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0392856X

© Copyright CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 2018. Objective. To identify risk factors of relapse in IgG4-related disease (IgG4-RD) during glucocorticoid (GC) tapering. Methods. A total of 27 consecutive patients with IgG4-RD (7 with and 20 without relapse) treated with GC for more than 6 months were enrolled. Baseline characteristics were compared in patients with and without relapse. Longitudinal analysis was also performed. Results. Patients with relapse had significantly higher levels of serum IgG4 (816.0 vs. 346.5 mg/dL, p=0.048) and number of organs involved (5 vs. 3, p=0.008) and lower levels of serum IgA (82 vs. 176 mg/dL, p=0.002) at baseline, compared to patients without relapse. The most useful cut-off value of baseline serum IgG4 to predictive relapse was 813 mg/dl with a sensitivity of 57.1% and a specificity of 95.0%. In longitudinal analysis, serum IgG4 decreased at 6 months after treatment in both groups, but was elevated at relapse in patients with relapse, while remaining low in those without relapse. Conclusion. Higher levels of serum IgG4 at baseline were associated with relapse in IgG4-RD. Re-elevation of serum IgG4 levels during GC treatment reflected disease relapse.

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