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: 6415282
• 负责人: Eugene William St. Clair
• 金额: $ 29.31万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-12-01 至 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6415282
• 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减轻类风湿性关节炎（RA）的关节炎症症状。这类抗生素具有充分描述的抗微生物作用以及抗胶原酶活性。胶原酶是降解软骨和骨的酶，并且被认为在RA的发病机制中是重要的。本研究评估了静脉注射多西环素治疗31例RA患者的安全性和潜在临床疗效，并探讨了多西环素对关节炎的任何改善是否是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）确定静脉注射强力霉素治疗RA的可行性、安全性和潜在的临床疗效，并探讨该药物是否通过抑制细菌感染或基质金属蛋白酶（MMP）活性来改善这种疾病的临床表现;（二）确定每天和每周静脉注射多西环素治疗是否可以减少RA患者胶原交联的尿排泄，并可能延缓关节炎的发生。损害;和3）探索每日和每周静脉内多西环素治疗对软骨蛋白聚糖降解的生化标志物的潜在影响;和4）确定静脉内多西环素是否可以降低由循环单核细胞表达的一氧化氮合酶2型的表达。患者被随机分为3组：I组接受静脉注射强力霉素和口服安慰剂，II组接受静脉注射安慰剂和口服阿奇霉素，III组接受静脉注射和口服安慰剂。通过外周长线导管进行静脉注射治疗。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周至第11周每周输注一次。结果：研究结束，最终报告于1998年12月29日提交给NIH。1995年4月至1998年2月期间入组了31例患者。研究人群包括各种种族背景，例如非裔美国人、高加索人和美洲原住民，并且主要是女性（24/7）。仅4例患者在第112天访视前退出试验。3名患者在第28天后因关节炎恶化而停用研究药物，1名患者在第56天被诊断出患有乳腺癌时退出研究药物。13例（42%）患者在试验期间至少发生1起输注相关事件。这些事件包括导管部位压痛/疼痛/发红、输注期间烧灼症状、胶带引起的部位相关皮疹、导管浸润、导管部位局部感染体征、导管或管路凝血和血栓性静脉炎。这些事件均未归类为严重事件。大多数患者至少发生1起不良事件，最常见的是胃肠道或神经系统。除输注相关并发症外，最常见的不良事件包括头痛（8例患者）、腹痛（6例患者）、疲乏（6例患者）、恶心/呕吐（5例患者）、阴道炎（5例患者）、稀便/腹泻（93例患者）、头晕/头晕（3例患者）和食欲下降（3例患者）。本研究的结果并没有提供证据表明静脉注射强力霉素治疗减少了RA的体征或症状。必须谨慎解释这些数据，因为本研究的设计不足以提供足够的统计功效来回答这个问题。目前的研究确实表明这种治疗方法是可行的，不会引起不可接受的毒性。然而，在主要终点方面，未观察到治疗组间的显著差异。所有3个治疗组的压痛关节计数仅略微下降。这一结果与静脉注射多西环素治疗3周后几乎没有或没有立即临床效果相一致。意义：由于多西环素没有改善主要终点，因此没有未来的计划。