ANTIBIOTIC THERAPY FOR RHEUMATOID ARTHRITIS (ATRA TRIAL)

类风湿性关节炎的抗生素治疗（ATRA 试验）

• 批准号: 6112749
• 负责人: Eugene William St. Clair
• 金额: $ 4.09万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6112749
• 关键词: antirheumatic agents; azithromycin; clinical research; collagenase; connective tissue disorder chemotherapy; drug screening /evaluation; enzyme activity; human subject; human therapy evaluation; rheumatoid arthritis; tetracyclines

Previous randomized, controlled clinical trials suggest that oral tetracyclines may reduce the symptoms of joint inflammation in rheumatoid arthritis (RA). This class of antibiotics has well-described antimicrobial effects as well as anti-collagenase activity. Collagenase is an enzyme that degrades cartilage and bone and is believed to be important in the pathogenesis of RA. This study evaluated the safety and potential clinical efficacy of I.V. doxycycline therapy in 31 patients with RA and explored whether any improvements in arthritis from the doxycycline were due to its antibacterial actions or ability to reduce the activity of collagenase. The three objectives of this study were: 1) To determine the feasibility, safety, and potential clinical efficacy of I.V. doxycycline therapy in RA and explore whether this agent ameliorates clinical manifestations of this disease by suppressing bacterial infection or matrix metalloproteinases (MMP) activity; 2) To determine whether daily and weekly treatment with I.V. doxycycline can reduce urinary excretion of collagen crosslinks in patients with RA and potentially retard joint damage; and 3) To explore the potential effects of daily and weekly I.V. doxcycline therapy on biochemical markers of cartilage proteoglycan degradation; and 4) to determine whether IV doxycycline can reduce expression of nitric oxide synthase type 2 expressed by circulatory monocytes. Patients were randomized into 3 groups: Group I received I.V. doxycycline and oral placebo, Group II will received I.V. placebo and oral azithromycin, and Group III received I.V. and oral placebo. The I.V. therapy was delivered through a peripheral long-line catheter. The initial treatment phase consisted of daily infusions and oral therapy for 21 days. The second treatment phase consisted of weekly infusions administered from week 4 through 11. Results: The study is closed and a Final Report was submitted to the NIH on December 29, 1998. Thirty-one patients were enrolled between April of 1995 and February 1998. The study population included various ethnic backgrounds, such as African- American, Caucasian, and Native American and was predominantly female (24/7). Only 4 patients withdrew from the trial before the day 112 visit. Three patients discontinued the study drug after day 28 because of worsening arthritis and one patient withdrew at day 56 when she was diagnosed with breast cancer. Thirteen (42%) of the patients experienced at least one infusion-related event during the trial. These events included catheter site tenderness/pain/redness, symptoms of burning during the infusion, site-related skin rash from adhesive tape, catheter infiltration, signs of localized infection at the catheter site, clotting of the catheter or line, and thrombophlebitis. None of these events were classified as serious. Most of the patients experienced at least 1 adverse event, which were most commonly gastrointestinal or neurologic in origin. The most frequent adverse events apart from the infusion-related complications included headache (8 patients), abdominal pain (6 patients), fatigue (6 patients), nausea/vomiting (5 patients, vaginitis (5 patients), loose stools/diarrhea 93 patients), dizziness/lightheadedness (3 patients), and decreased appetite (3 patients). The results of the present study do not provide evidence that i.v. doxycycline therapy reduces the signs or symptoms of RA. These data must be interpreted with caution because the study was not designed to provide adequate statistical power to answer this question. The present study does show that this treatment approach is feasible and does not cause unacceptable toxicities. However, no significant differences were noted among treatment groups in the primary endpoints. The tender joint count dropped only slightly in all of the 3 treatment groups. This result is compatible with little or no immediate clinical effect from the 3 weeks of i.v. doxycycline therapy. Significance: There are no future plans since doxycycline did not improve the primary endpoints.

先前的随机对照临床试验表明，口服四环素类药物可以减轻类风湿关节炎（RA）的关节炎症症状。这类抗生素具有良好的抗菌作用以及抗胶原酶活性。胶原酶是一种降解软骨和骨骼的酶，被认为在类风湿关节炎的发病机制中起重要作用。本研究评估了31例RA患者静脉注射强力霉素治疗的安全性和潜在临床疗效，并探讨强力霉素对关节炎的改善是否由于其抗菌作用或降低胶原酶活性的能力。本研究的三个目的是：1)确定静脉注射多西环素治疗类风湿关节炎的可行性、安全性和潜在临床疗效，探讨多西环素是否通过抑制细菌感染或基质金属蛋白酶（MMP）活性改善类风湿关节炎的临床表现；2)确定每日和每周静脉注射多西环素是否可以减少RA患者尿中胶原交联的排泄，并可能延缓关节损伤；3)探讨每日和每周静脉注射多环素治疗对软骨蛋白多糖降解生化指标的潜在影响；4)观察静脉注射强力霉素是否能降低循环单核细胞表达的2型一氧化氮合酶的表达。将患者随机分为3组，第一组静脉注射强力霉素并口服安慰剂，第二组静脉注射安慰剂并口服阿奇霉素，第三组静脉注射并口服安慰剂。静脉注射是通过外周长线导管进行的。初始治疗阶段包括每日输注和口服治疗21天。第二个治疗阶段包括从第4周到第11周每周输注。结果：研究结束，最终报告于1998年12月29日提交给美国国立卫生研究院。在1995年4月到1998年2月间，31名患者被纳入研究。研究人群包括不同的种族背景，如非裔美国人、高加索人和印第安人，主要是女性（24/7）。只有4名患者在第112天访问前退出了试验。三名患者在第28天因关节炎恶化而停药，一名患者在第56天因被诊断患有乳腺癌而停药。13例（42%）患者在试验期间经历了至少一次输注相关事件。这些事件包括导管部位压痛/疼痛/发红、输注过程中的灼烧症状、因胶带引起的部位相关皮疹、导管浸润、导管部位局部感染的迹象、导管或导管的凝血以及血栓性静脉炎。这些事件都没有被列为严重事件。大多数患者至少发生1次不良事件，最常见的是胃肠道或神经系统不良事件。除输液相关并发症外，最常见的不良事件包括头痛（8例）、腹痛（6例）、疲劳（6例）、恶心/呕吐（5例）、阴道炎（5例）、稀便/腹泻（93例）、头晕/头晕（3例）、食欲下降（3例）。目前的研究结果并没有提供证据表明静脉注射强力霉素治疗可以减轻类风湿性关节炎的症状或体征。这些数据必须谨慎解释，因为这项研究的目的不是提供足够的统计能力来回答这个问题。目前的研究确实表明，这种治疗方法是可行的，不会造成不可接受的毒性。然而，各治疗组在主要终点上没有显著差异。在所有3个治疗组中，压痛关节计数仅略有下降。这一结果与静脉注射强力霉素治疗3周后很少或没有立即临床效果相一致。意义：由于强力霉素没有改善主要终点，因此没有未来的计划。