甲氨蝶呤治療類風濕性關節炎的不良反應及應對措施_《華西醫學》

作者：

王旻晉 ¹ ,  武永康 ¹ , 林輝 ²

四川大學華西醫院（成都，610041）1 實驗醫學科，2 風濕免疫科;

關鍵詞：

甲氨蝶呤類風濕性關節炎聯合用藥不良反應

DOI：

10.7507/1002-0179.20130296

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類風濕關節炎（rheumatoid arthritis，RA）是一種以累及周圍關節為主的多系統慢性炎癥性自身免疫疾病，其治療以減輕關節疼痛、腫脹癥狀并控制病情進展為主要目標。甲氨蝶呤（MTX）是治療RA的首選藥物，其價格低廉療效確鑿。但MTX敏感性及耐受性有明顯個體差異，部分藥物可在細胞內以多谷氨酸化形式存在，使其難以通過細胞膜而長期存留在細胞內，一般在腎、肝、胸腔、腹腔積液中潴留，個體清除率差異很大。因此，由于部分患者對MTX高敏或藥物蓄積，導致即使一次低劑量用藥，也可能誘發嚴重的不良反應。本文就以MTX為主的聯合用藥治療RA可能出現的不良反應及應對措施做一綜述。

引用本文： 王旻晉,武永康,林輝. 甲氨蝶呤治療類風濕性關節炎的不良反應及應對措施. 華西醫學, 2013, 28(6): 940-943. doi: 10.7507/1002-0179.20130296 復制

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, 楊岫巖. 甲氨蝶呤:安全、有效、價廉的抗風濕藥[J]. 新醫學, 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, 楊岫巖. 甲氨蝶呤:安全、有效、價廉的抗風濕藥[J]. 新醫學, 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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《華西醫學》

甲氨蝶呤治療類風濕性關節炎的不良反應及應對措施

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