TNF-α 抑制剂
TNF-α 抑制剂已批准用于治疗强直性脊柱炎和银屑病关节炎,并显示了很好疗效,但并没有评价它在反应性关节炎 (ReA) 疗效的双盲安慰剂对照研究。一项小型的开放性回顾性研究和病例报告已表明,其对于治疗 ReA 具临床效益。[67]Flagg SD, Meador R, Hsia E, et al. Decreased pain and synovial inflammation after etanercept therapy in patients with reactive and undifferentiated arthritis: an open-label trial. Arthritis Rheum. 2005;53:613-617.http://www.ncbi.nlm.nih.gov/pubmed/16082643?tool=bestpractice.com[68]Oili KS, Niinisalo H, Korpilahde T, et al. Treatment of reactive arthritis with infliximab. Scand J Rheumatol. 2003;32:122-124.http://www.ncbi.nlm.nih.gov/pubmed/12737333?tool=bestpractice.com[69]Haibel H, Brandt J, Rudwaleit M, et al. Therapy of chronic enteral reactive arthritis with infliximab. Ann Rheum Dis. 2003;62:ABO380.[70]Meyer A, Chatelus E, Wendling D, et al. Safety and efficacy of anti-tumor necrosis factor α therapy in ten patients with recent-onset refractory reactive arthritis. Arthritis Rheum. 2011;63:1274-1280.http://onlinelibrary.wiley.com/doi/10.1002/art.30272/fullhttp://www.ncbi.nlm.nih.gov/pubmed/21538314?tool=bestpractice.com[71]Rihl M, Gu J, Baeten D, et al. Alpha beta but not gamma delta T cell clones in synovial fluids of patients with reactive arthritis show active transcription of tumour necrosis factor alpha and interferon gamma. Ann Rheum Dis. 2004;63:1673-1676.http://www.ncbi.nlm.nih.gov/pubmed/15547094?tool=bestpractice.com提示 TNF-α 抑制剂可能有效,但 ReA 更多的是 Th2 细胞驱动的疾病。[72]Braun J, Yin Z, Spiller I, et al. Low secretion of tumor necrosis factor alpha, but no other Th1 or Th2 cytokines, by peripheral blood mononuclear cells correlates with chronicity in reactive arthritis. Arthritis Rheum. 1999;42:2039-2044.http://www.ncbi.nlm.nih.gov/pubmed/10524674?tool=bestpractice.com[73]Thiel A, Wu P, Lauster R, et al. Analysis of the antigen-specific T cell response in reactive arthritis by flow cytometry. Arthritis Rheum. 2000;43:2834-2842.http://www.ncbi.nlm.nih.gov/pubmed/11145043?tool=bestpractice.com[74]Yin Z, Braun J, Neure L, et al. Crucial role of interleukin-10/interleukin-12 balance in the regulation of the type 2 T helper cytokine response in reactive arthritis. Arthritis Rheum. 1997;40:1788-1797.http://www.ncbi.nlm.nih.gov/pubmed/9336412?tool=bestpractice.com 在存在少量 TNF-α 分泌的 ReA 患者中观察到了较长的病程。[75]Colmegna I, Cuchacovich R, Espinoza LR. HLA-B27-associated reactive arthritis: pathogenetic and clinical considerations. Clin Microbiol Rev. 2004;17:348-369.http://www.ncbi.nlm.nih.gov/pubmed/15084505?tool=bestpractice.com此外,体外数据表明持续性衣原体生物体水平与 TNF-α 水平成反比。[76]Ishihara T, Aga M, Hino K, et al. Inhibition of Chlamydia trachomatis growth by human interferon-alpha: mechanisms and synergistic effect with interferon-gamma and tumor necrosis factor-alpha. Biomed Res. 2005;26:179-185.http://www.ncbi.nlm.nih.gov/pubmed/16152734?tool=bestpractice.com[77]Perry LL, Feilzer K, Caldwell HD. Immunity to Chlamydia trachomatis is mediated by T helper 1 cells through IFN-gamma-dependent and -independent pathways. J Immunol. 1997;158:3344-3352.http://www.ncbi.nlm.nih.gov/pubmed/9120292?tool=bestpractice.com[78]Takano R, Yamaguchi H, Sugimoto S, et al. Cytokine response of lymphocytes persistent infected with Chlamydia pneumoniae. Curr Microbiol. 2005;50:160-166.http://www.ncbi.nlm.nih.gov/pubmed/15883875?tool=bestpractice.comTNF-α 抑制剂需谨慎的用于难以控制的 ReA。但是,在 ReA 中使用 TNF-α 拮抗剂仍可能再次激活感染源,特别是对于衣原体诱发的 ReA。[54]British Association for Sexual Health and HIV. United Kingdom national guideline on the management of sexually acquired reactive arthritis. January 2008. http://www.bashh.org (last accessed 21 March 2016).http://www.bashh.org/documents/1772.pdf因此,TNF-α 抑制剂在这些患者中的治疗地位仍未确定。
抗生素
抗生素在 ReA 中的确切作用仍在研究中。一项在 ReA 患者中使用赖甲环素的为期 3 个月的研究发现,与安慰剂相比,其在性交后 ReA (而不是肠道型 ReA)中显示出统计学意义上的改善。[64]Lauhio A, Leirisalo-Repo M, Lahdevirta J, et al. Double-blind, placebo-controlled study of three-month treatment with lymecycline in reactive arthritis, with special reference to Chlamydia arthritis. Arthritis Rheum. 1991;34:6-14.http://www.ncbi.nlm.nih.gov/pubmed/1670621?tool=bestpractice.com一项类似的使用环丙沙星的研究发现,与安慰剂相比,对于任何形式的 ReA 均未显示出统计学差异;然而,在沙眼衣原体亚组中可看到一些改进。[79]Sieper J, Fendler C, Laitko S, et al. No benefit of long-term ciprofloxacin in patients with reactive arthritis and undifferentiated oligoarthritis: a three-month, multicenter, double-blind, randomized, placebo-controlled study. Arthritis Rheum. 1999;42:1386-1396.http://www.ncbi.nlm.nih.gov/pubmed/10403266?tool=bestpractice.com其他研究已显示,使用抗生素并无益处。[80]Putschky N, Pott HG, Kuipers JG, et al. Comparing 10-day and 4-month doxycycline courses for treatment of Chlamydia trachomatis-reactive arthritis: A prospective, double-blind trial. Ann Rheum Dis. 2006;65:1521-1524.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1798345/?tool=pubmedhttp://www.ncbi.nlm.nih.gov/pubmed/17038453?tool=bestpractice.com体外数据表明,长期几种抗生素单一治疗可使衣原体在细胞内持久存在。[81]Dreses-Werringloer U, Padubrin I, Jurgens-Saathoff B, et al. Persistence of Chlamydia trachomatis is induced by ciprofloxacin and ofloxacin in vitro. Antimicrob Agents Chemother. 2000;44:3288-3297.http://www.ncbi.nlm.nih.gov/pubmed/11083629?tool=bestpractice.com[82]Dreses-Werringloer U, Padubrin I, Zeidler H, et al. Effects of azithromycin and rifampin on Chlamydia trachomatis infection in vitro. Antimicrob Agents Chemother. 2001;45:3001-3008.http://www.ncbi.nlm.nih.gov/pubmed/11600348?tool=bestpractice.com[83]Morrissey I, Salman H, Bakker S, et al. Serial passage of Chlamydia spp. in sub-inhibitory fluoroquinolone concentrations. J Antimicrob Chemother. 2002;49:757-761.http://www.ncbi.nlm.nih.gov/pubmed/12003968?tool=bestpractice.com[84]Khan MA. Update on spondyloarthropathies. Ann Intern Med. 2002;136:896-907.http://www.ncbi.nlm.nih.gov/pubmed/12069564?tool=bestpractice.com然而,多种抗生素联合使用可清除体内持久存在的衣原体,从而治愈疾病。一项评估利福平和阿奇霉素联合使用的体外实验成功清除了持久存在的衣原体。[82]Dreses-Werringloer U, Padubrin I, Zeidler H, et al. Effects of azithromycin and rifampin on Chlamydia trachomatis infection in vitro. Antimicrob Agents Chemother. 2001;45:3001-3008.http://www.ncbi.nlm.nih.gov/pubmed/11600348?tool=bestpractice.com一项体内研究显示,将利福平和多西环素联用于治疗据认为由衣原体诱发的脊柱关节病大有裨益。[45]Carter JD, Valeriano J, Vasey FB. Doxycycline versus doxycycline and rifampin in undifferentiated spondyloarthropathy with special reference to chlamydia-induced arthritis. A prospective, randomized 9-month comparison. J Rheumatol. 2004;31:1973-1980.http://www.ncbi.nlm.nih.gov/pubmed/15468362?tool=bestpractice.com现有数据表明,联合应用抗生素对于肠后 ReA 无潜在益处,但在衣原体诱发的 ReA 中可能发挥作用。这支持衣原体感染后的反应性关节炎滑膜组织中存在可变的衣原体而肠道感染后的反应性关节炎 (ReA) 滑膜组织中存在不可变的微生物这一现象。需更多的研究以确定抗生素在 ReA 中的确切作用。一项为期 9 月将多西环素单药治疗与多西环素联合利福平治疗的一对一研究表明,联用明显优于单药治疗。[45]Carter JD, Valeriano J, Vasey FB. Doxycycline versus doxycycline and rifampin in undifferentiated spondyloarthropathy with special reference to chlamydia-induced arthritis. A prospective, randomized 9-month comparison. J Rheumatol. 2004;31:1973-1980.http://www.ncbi.nlm.nih.gov/pubmed/15468362?tool=bestpractice.com长疗程(4 个月)的应用多西环素单药治疗并没有比短期(10 天)联合用药在治疗衣原体诱发的反应性关节炎 (ReA) 中显示出更好的疗效。[80]Putschky N, Pott HG, Kuipers JG, et al. Comparing 10-day and 4-month doxycycline courses for treatment of Chlamydia trachomatis-reactive arthritis: A prospective, double-blind trial. Ann Rheum Dis. 2006;65:1521-1524.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1798345/?tool=pubmedhttp://www.ncbi.nlm.nih.gov/pubmed/17038453?tool=bestpractice.com一项前瞻性、双盲、安慰剂对照试验比较了 6 个月联用阿奇霉素和利福平或强力霉素和利福平与安慰剂对比在治疗衣原体诱发的反应性关节炎 (ReA) 中的疗效。这项研究显示,这两种联合用药方案疗效均好于安慰剂对照组,且联合用药组患者体内的衣原体更容易被清除。[65]Carter JD, Espinoza LR, Inman RD, et al. Combination antibiotics as a treatment for chronic Chlamydia-induced reactive arthritis: a double-blind, placebo-controlled, prospective trial. Arthritis Rheum. 2010;62:1298-1307.http://www.ncbi.nlm.nih.gov/pubmed/20155838?tool=bestpractice.com一项动物模型研究表明,树枝形的功能性叶酸可用于反应性关节炎 (ReA) 中特定的衣原体感染的组织。[85]Benchaala I, Mishra MK, Wykes SM, et al. Folate-functionalized dendrimers for targeting Chlamydia-infected tissues in a mouse model of reactive arthritis. Int J Pharm. 2014;466:258-265.http://www.ncbi.nlm.nih.gov/pubmed/24607214?tool=bestpractice.com[35]Baillet AC, Rehaume L, Benham H, et al. High Chlamydia burden promotes TNF-dependent reactive arthritis in SKG mice. Arthritis Rheumatol. 2015;67:1535-1547.http://www.ncbi.nlm.nih.gov/pubmed/25624153?tool=bestpractice.com在 ReA 小鼠模型中衣原体感染后的炎性关节炎对抗 TNF-α 治疗有反应,并且在接种后 1 天联用抗生素可预防疾病。这给特定类型的反应性关节炎 (ReA) 的治疗带来了希望。