The influence of smoking on biologics treatment in rheumatoid arthritis and its possible molecular mechanism.

• Project/Area Number: 15K09544
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: National Hospital Organization Osaka-Minami Medical Center
• Principal Investigator: Saeki Yukihiko 独立行政法人国立病院機構(大阪南医療センター臨床研究部), その他部局等, 臨床研究部長 (40240840)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 関節リウマチ / ＴＮＦ阻害薬 / 喫煙 / NF-ｋB / ＡｈＲ / クロストーク / TNF阻害薬 / AhR / NF-kB / 生物学的製剤 / TNF

Outline of Final Research Achievements

To investigate the influence of smoking on biologics treatment in RA, the association between discontinuation due to poor therapeutic response and smoking status was analyzed in a cross-sectional way by using the“NinJa” Registry of Japanese patients with RA, by a multivariable logistic regression analysis. The rate of discontinuation due to poor therapeutic response was significantly higher in the patients with current smoking compared to those with either never- or ever-smoking in the TNF-inhibitor (TNF-i)treatment group. Using an immortalized rheumatoid synovial cell line, MH7A, cigarette chemical compounds known as AhRligands, themselves activated NF-kB and induced proinflammatory cytokines.They enhanced both TNFa-induced NF-kB activation and proinflammatory cytokine production. This enhancement was diminished significantly by a NF-kB inhibitor, suggesting a crosstalk between TNFa and smoke signalings in NF-kB activation.This may cause treatment failure of TNF-iin RA.

Research Products

• [Journal Article] Safety and efficacy of CT-P13 in Japaneses patients with rheumatoid arthritis in an extension phase or after switching from infliximab. (2017)
  • Author(s): Tanaka Y, Yamanaka H, Takeuchi T, Inoue M, Saito K, Saeki Y, Lee SJ, Nambu Y.
  • Journal Title: Modern Rheumatology Volume: 27 (2) Pages: 237-45
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Elevated soluble CD14-subtype (PRESEPSIN; P-SEP) levels in rheumatoid arthritis (RA) patients with bacterial infection. (2016)
  • Author(s): Tsuji S, Kitatoube A, Kikuchi-Taura A, Oguro E, Shigesaka M, Okita Y, Shimizu T, Nii T, Teshigawara S, Tanaka E, Harada Y, Matsushita M, Hashimoto J, Ohshima S, Takahashi G, Endo S, Saeki Y.
  • Journal Title: Modern Rheumatology Volume: Oct27 Pages: 1-3
  • Peer Reviewed / Open Access
• [Journal Article] Dysbiosis contributes to arthritis development via activation of autoreavtive T cells in the intestine. (2016)
  • Author(s): Maeda Y, Kurakawa T, Umemoto E, Motooka D, Ito Y, Gotoh K, Hirota K, Matsushita M, Furuta Y, Narazaki M, Sakaguchi N, Kayama H, Nakamura S, Iida T, Saeki Y, Kumanogoh A, Sakaguchi S, Takeda K.
  • Journal Title: Arthritis Rheumatology Volume: 68 (11) Pages: 2646-61
  • Peer Reviewed / Open Access
• [Journal Article] Hemophagocytic lymphohistiocytosis with leucoencephalopathy in a aptient with dermatomyosiyis accompanied with peripheral T-cell lymphoma: a cse report. (2016)
  • Author(s): Teshigawara S, Katada Y, Maeda Y, Yoshimura M, Kudo-Tanaka E, Tsuji S, Harada Y, Matsushita M, Ohshima S, Watanabe K, Kumode T, Hoshida Y, Saeki Y.
  • Journal Title: J Med Case Rep Volume: 4 (10)
  • Peer Reviewed / Open Access
• [Journal Article] Low rates of biologic-free clinical disease activity index remission maintenance after biologic disease-modifying anti-rheumatic drug discontinuation while in remission in a Japanisese multicenter rheumatoid arthritis registry. (2016)
  • Author(s): Yoshida K, Kishimoto M, Radner H, Matsui K, Okada M, Saeki Y, Solomon DH, Tohma S.
  • Journal Title: Rheumatology (Oxford) Volume: 55(2) Issue: 2 Pages: 286-90
  • DOI: 10.1093/rheumatology/kev329
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Incidence and predictors of biological antirheumatic drugs discontinuation attempts among patinets with rheumatoid arthritis in remission: A CORRONA and NinJa collaborative cohort study. (2015)
  • Author(s): Yoshida K, Radner H, Mjaavatten MD, Greenberg JD, Kavanaugh A, Kishimoto M, Matsui K, Okada M, Reed G, Saeki Y, Tohma S, Kremer J, Solomon DH.
  • Journal Title: J Rheumatol Volume: 42(12) Issue: 12 Pages: 2238-46
  • DOI: 10.3899/jrheum.150240
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Monocyte CD64 expression as a novel biomarker for the disease activity of systemic lupus erythematosus. (2015)
  • Author(s): Kikuchi-Taura A, Yura A, Tsuji S, Ohshima S, Kitatoube A, Shimizu T, Nii T, Katayama M, Teshigawara S, Yoshimura M, Kudo-Tanaka E, Harada Y, Matsushita M, Hashimoto J, Saeki Y
  • Journal Title: Lupus Volume: 24(10) Issue: 10 Pages: 1076-80
  • DOI: 10.1177/0961203315579093
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Early therapeutic intervention with methotrexate prevents the development of rheumatoid arthritis in patients with recent-onset undifferentiated arthritis: A prospective cohort study. (2015)
  • Author(s): Kudo-Tanaka E, Shimizu T, Nii T, Teshigawara S, Yoshimura M, Watanabe A, Tsuji S, Tsuboi H, Hirao M, Yura A, Harada Y, Sueishi M, Suenaga Y, Chiba N, Tonai T, Saisho K, Ogata A, Matsushita M, Hashimoto J, Ohshima S, Tohma S, Saeki Y.
  • Journal Title: Mod Rheumatol Volume: 25(6) Issue: 6 Pages: 831-6
  • DOI: 10.3109/14397595.2015.1031364
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] 1.Semaphorin 4D contributes to rheumatoid arthritis by inducing inflammatory cytokine production: Pathogenic and therapeutic implications (2015)
  • Author(s): Yoshida Y, Ogata A, Kang S, Ebina K, Shi K, Nojima S, Kimura T, Ito D, Morimoto K, Nishide M, Hosokawa T, Hirano T, Shima Y, Narazaki M, Tsuboi H, Saeki Y, Tomita T, Tanaka T, Kumanogoh A.
  • Journal Title: Arthritis Rheumatol Volume: none Issue: 6 Pages: 1481-1490
  • DOI: 10.1002/art.39086
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] SMOKING HABITS INCREASE THERAPEUTIC FAILURE OF BIOLOGICS, SPECIFICALLY TNF-INHIBITORS IN RHEUMATOID ARTHRIIS: A POSSIBLE CROSS-TALK BETWEEN TNFa AND SMOKING (AhR) SIGNALINGS. (2018)
  • Author(s): Y. Saeki, et al.
  • Organizer: 11th International Congress on Autoimmunity
  • Int'l Joint Research
• [Presentation] Smoking signaling enhances TNFa-induced pro-inflammatory cytokine production on a rheumatoid synovial cell line, MH7A. (2017)
  • Author(s): Nii T, Oguro E, Okita T, Shimizu T, Matsuoka H, Tsuji S, Tanaka-Kudo E, Teshigawara S, Harada Y, Matsushita M, Ohshima S, Saeki Y.
  • Organizer: The 4th International Congress on Controversies in Rheumatology & Autoimmunity. 9-11 March, 2017, Bologna, Italy.
  • Place of Presentation: Bologna, Italy
  • Year and Date: 2017-03-09
  • Int'l Joint Research