甲氨蝶呤治疗类风湿性关节炎的不良反应及应对措施_《华西医学》

作者：

王旻晋 ¹ ,  武永康 ¹ , 林辉 ²

四川大学华西医院（成都，610041）1 实验医学科，2 风湿免疫科;

关键词：

甲氨蝶呤类风湿性关节炎联合用药不良反应

DOI：

10.7507/1002-0179.20130296

视频：

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摘要 全文 图表 视频 参考文献 施引文献 补充材料

类风湿关节炎（rheumatoid arthritis，RA）是一种以累及周围关节为主的多系统慢性炎症性自身免疫疾病，其治疗以减轻关节疼痛、肿胀症状并控制病情进展为主要目标。甲氨蝶呤（MTX）是治疗RA的首选药物，其价格低廉疗效确凿。但MTX敏感性及耐受性有明显个体差异，部分药物可在细胞内以多谷氨酸化形式存在，使其难以通过细胞膜而长期存留在细胞内，一般在肾、肝、胸腔、腹腔积液中潴留，个体清除率差异很大。因此，由于部分患者对MTX高敏或药物蓄积，导致即使一次低剂量用药，也可能诱发严重的不良反应。本文就以MTX为主的联合用药治疗RA可能出现的不良反应及应对措施做一综述。

引用本文： 王旻晋,武永康,林辉. 甲氨蝶呤治疗类风湿性关节炎的不良反应及应对措施. 华西医学, 2013, 28(6): 940-943. doi: 10.7507/1002-0179.20130296 复制

1.	Shergy WJ, Polisson RP, Caldwell DS, et al. Methotrexate associated hepatotoxicity: retrospective analysis of 210 patients with rheumatoid arthritis[J]. Am J Med, 1988, 85(6): 771-774.
2.	Diouf ML, Diallo S, Mbengue M, et al. Methotrexate, liver and rheumatoid arthritis in tropical areas[J]. Sante, 2001, 11(3): 195-200.
3.	Kalden JR, Schattenkirchner M, Sorensen H, et al. The efficacy and safety of leflunomide in patients with active rheumatoid arthritis: a five-year follow up study[J]. Arthritis Rheum, 2003, 48(6): 1513-1520.
4.	The European Agency for the Evaluation of Medicinal Products. EMEA issues public statement on leflunomide[J]. Reactions Weekly, 2001, 844(6): 2.
5.	Health Canada. Leflunomide (Arava): hematologic, hepatic and respiratory reactions[J]. Can Newsletter, 2002, 12(1): 2-3.
6.	Curtis JR, Beukelman T, Onofrei A, et al. Elevated liver enzyme tests among patients with rheumatoid arthritis or psoriatic arthritis treated with methotrexate and/or leflunomide[J]. Ann Rheum Dis, 2010, 69(1): 43-47.
7.	Weinblatt ME, Kremer JM, Coblyn JS, et al. Pharmacokinetics, safety and efficacy of combination treatment with methotrexate and leflunomide in patients with active rheumatoid arthritis[J]. Arthritis Rheum,1999, 42(6): 1322-1328.
8.	Visser K, Katchamart W, Loza E, et al. Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E initiative[J]. Ann Rheum Dis, 2009, 68(7): 1086-1093.
9.	Yazici Y, Erkan D, Paget SA. Monitoring methotrexate hepatic toxicity in rheumatoid arthritis: is it time to update the guidelines?[J].J Rheumatol, 2002, 29(8): 1586-1589.
10.	梁柳琴, 杨岫岩. 甲氨蝶呤:安全、有效、价廉的抗风湿药[J]. 新医学, 2001, 32(5): 309-311.
11.	Arena U, Stasi C, Mannoni A, et al. Liver stiffness correlates with methotrexate cumulative dose in patients with rheumatoid arthritis[J]. Dig Liver Dis, 2012, 44(2): 149-153.
12.	Hassan W. Methotrexate and liver toxicity: role of surveillance liver biopsy, Conflict between guidelines for rheumatologists and dermatologists[J]. Ann Rheum Dis, 1996, 55(5): 273-275.
13.	Merino-Sanjuán M, Carrera A, Monte E, et al. Adsorption of methotrexate and calcium leucovorin onto cholestyramine in vitro[J]. Int J Pharm, 2004, 278(2): 283-291.
14.	Fernández Megía MJ, Alós Almiñana M, Terol Castera MJ. Managing methotrexate toxicity: a case report[J]. Farm Hosp, 2004, 28(5): 371-374.
15.	Sotoudehmanesh R, Anvari B, Akhlaghi K, et al. Methotrexate hepatotoxicity in patients with rheumatoid arthritis[J]. Middle East Journal of Digestive Diseases, 2010, 2(2): 104-109.
16.	Tugwell P, Pincus T, Yocum D, et al. Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. The Methotrexate-Cyclosporine Combination Study Group [J]. N Engl J Med, 1995, 333(3): 137-141.
17.	Ferraccioli GF, Gremese E, Tomoetto P, et al. Analysis of improvements, full responses, remission and toxicity in rheumatoid patients treated with step-up combination therapy (methotrexate, cyclosporin A, sulphasalazine) or monotherapy for three years[J]. Rheumatology (Oxford), 2002, 41(8): 892-898.
18.	Pavy S, Constantin A, Pham T, et al. Methotrexate therapy for rheumatoid arthritis: clinical practice guidelines based on published evidence and expert opinion[J]. Joint Bone Spine, 2006, 73(4): 388-395.
19.	Katchamart W, Trudeau J, Phumethum V, et al. Efficacy and toxicity of methotrexate (MTX) monotherapy versus MTX combination therapy with non-biological disease-modifying antirheumatic drugs in rheumatoid arthritis: a systematic review and meta-analysis[J]. Ann Rheum Dis, 2009, 68(7): 1105-1112.
20.	Grove ML, Hassell AB, Hay EM, et al. Adverse reactions to disease-modifying anti-rheumatic drugs in clinical practice[J]. QJM, 2001, 94(6): 309-319.
21.	Hoekstra M, Haagsma CJ, Doelman CJ, van de Laar MA, et al. Intermittent rises in plasma homocysteine in patients with rheumatoid arthritis treated with higher dose methotrexate[J]. Ann Rheum Dis, 2005, 64(1):141-143.

1. 　Shergy WJ, Polisson RP, Caldwell DS, et al. Methotrexate associated hepatotoxicity: retrospective analysis of 210 patients with rheumatoid arthritis[J]. Am J Med, 1988, 85(6): 771-774.
2. 　Diouf ML, Diallo S, Mbengue M, et al. Methotrexate, liver and rheumatoid arthritis in tropical areas[J]. Sante, 2001, 11(3): 195-200.
3. 　Kalden JR, Schattenkirchner M, Sorensen H, et al. The efficacy and safety of leflunomide in patients with active rheumatoid arthritis: a five-year follow up study[J]. Arthritis Rheum, 2003, 48(6): 1513-1520.
4. 　The European Agency for the Evaluation of Medicinal Products. EMEA issues public statement on leflunomide[J]. Reactions Weekly, 2001, 844(6): 2.
5. 　Health Canada. Leflunomide (Arava): hematologic, hepatic and respiratory reactions[J]. Can Newsletter, 2002, 12(1): 2-3.
6. 　Curtis JR, Beukelman T, Onofrei A, et al. Elevated liver enzyme tests among patients with rheumatoid arthritis or psoriatic arthritis treated with methotrexate and/or leflunomide[J]. Ann Rheum Dis, 2010, 69(1): 43-47.
7. 　Weinblatt ME, Kremer JM, Coblyn JS, et al. Pharmacokinetics, safety and efficacy of combination treatment with methotrexate and leflunomide in patients with active rheumatoid arthritis[J]. Arthritis Rheum,1999, 42(6): 1322-1328.
8. 　Visser K, Katchamart W, Loza E, et al. Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E initiative[J]. Ann Rheum Dis, 2009, 68(7): 1086-1093.
9. 　Yazici Y, Erkan D, Paget SA. Monitoring methotrexate hepatic toxicity in rheumatoid arthritis: is it time to update the guidelines?[J].J Rheumatol, 2002, 29(8): 1586-1589.
10. 　梁柳琴, 杨岫岩. 甲氨蝶呤:安全、有效、价廉的抗风湿药[J]. 新医学, 2001, 32(5): 309-311.
11. 　Arena U, Stasi C, Mannoni A, et al. Liver stiffness correlates with methotrexate cumulative dose in patients with rheumatoid arthritis[J]. Dig Liver Dis, 2012, 44(2): 149-153.
12. 　Hassan W. Methotrexate and liver toxicity: role of surveillance liver biopsy, Conflict between guidelines for rheumatologists and dermatologists[J]. Ann Rheum Dis, 1996, 55(5): 273-275.
13. 　Merino-Sanjuán M, Carrera A, Monte E, et al. Adsorption of methotrexate and calcium leucovorin onto cholestyramine in vitro[J]. Int J Pharm, 2004, 278(2): 283-291.
14. 　Fernández Megía MJ, Alós Almiñana M, Terol Castera MJ. Managing methotrexate toxicity: a case report[J]. Farm Hosp, 2004, 28(5): 371-374.
15. 　Sotoudehmanesh R, Anvari B, Akhlaghi K, et al. Methotrexate hepatotoxicity in patients with rheumatoid arthritis[J]. Middle East Journal of Digestive Diseases, 2010, 2(2): 104-109.
16. 　Tugwell P, Pincus T, Yocum D, et al. Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. The Methotrexate-Cyclosporine Combination Study Group [J]. N Engl J Med, 1995, 333(3): 137-141.
17. 　Ferraccioli GF, Gremese E, Tomoetto P, et al. Analysis of improvements, full responses, remission and toxicity in rheumatoid patients treated with step-up combination therapy (methotrexate, cyclosporin A, sulphasalazine) or monotherapy for three years[J]. Rheumatology (Oxford), 2002, 41(8): 892-898.
18. 　Pavy S, Constantin A, Pham T, et al. Methotrexate therapy for rheumatoid arthritis: clinical practice guidelines based on published evidence and expert opinion[J]. Joint Bone Spine, 2006, 73(4): 388-395.
19. 　Katchamart W, Trudeau J, Phumethum V, et al. Efficacy and toxicity of methotrexate (MTX) monotherapy versus MTX combination therapy with non-biological disease-modifying antirheumatic drugs in rheumatoid arthritis: a systematic review and meta-analysis[J]. Ann Rheum Dis, 2009, 68(7): 1105-1112.
20. 　Grove ML, Hassell AB, Hay EM, et al. Adverse reactions to disease-modifying anti-rheumatic drugs in clinical practice[J]. QJM, 2001, 94(6): 309-319.
21. 　Hoekstra M, Haagsma CJ, Doelman CJ, van de Laar MA, et al. Intermittent rises in plasma homocysteine in patients with rheumatoid arthritis treated with higher dose methotrexate[J]. Ann Rheum Dis, 2005, 64(1):141-143.

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甲氨蝶呤治疗类风湿性关节炎的不良反应及应对措施

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《华西医学》

甲氨蝶呤治疗类风湿性关节炎的不良反应及应对措施

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