Carter John D, Valeriano Joanne, Vasey Frank B
Division of Rheumatology, University of South Florida, Tampa, Florida 33612, USA.
J Rheumatol. 2004 Oct;31(10):1973-80.
Chlamydia is a known trigger of reactive arthritis (ReA). It may also be common cause of undifferentiated spondyloarthropathy (uSpA). Persistent, metabolically active, Chlamydiae have been observed in the synovial tissue of these patients years after their initial exposure. Trials with lymecycline and rifampin have shown benefit in early/acute Chlamydia-induced arthritis. In vitro data suggest that persistent Chlamydia become resistant to chronic monotherapy of tetracyclines or rifampin, whereas no such resistance is noted when rifampin is added to antimicrobials that are active against Chlamydia. Rifampin and doxycycline also show synergistic effect against Chlamydia. In addition, rifampin inhibits chlamydial production of heat shock proteins (HSP). HSP60 plays a key role in the chronic persistent state of Chlamydia. We conducted a prospective, randomized 9-month trial to evaluate the efficacy of doxycycline versus a combination of doxycycline and rifampin in the treatment of uSpA.
The study enrolled 30 patients with chronic inflammatory arthritis (average disease duration 10 yrs) who fulfilled the European Spondylarthropathy Study Group criteria, with no evidence of inflammatory bowel disease, psoriasis, ankylosing spondylitis, or preceding dysentery. Patients received doxycycline 100 mg po twice daily or a combination of doxycycline 100 mg po twice daily and rifampin 600 mg po daily. They received a 4-question self-questionnaire and a blinded joint examination at each visit. The questions include a visual analog scale (VAS) for their current amount of back pain, duration of morning stiffness, back pain at night, and peripheral joint pain. The blinded joint examination consisted of a swollen joint count (SJC) and a tender joint count (TJC). These 6 variables were assessed at baseline and at 1, 3, 6, and 9 months. Responders were defined as those who improved > or = 20% in at least 4 of the 6 variables at 9 months of therapy.
Comparing the doxycycline + rifampin arm (D/R) versus the doxycycline arm (D) at 9 months of therapy, all 6 variables improved more in D/R versus D, 4 of which were statistically significant. The mean VAS (scale of 100) decreased 24.4 points in D/R in contrast to 3 points in D (p < 0.03). Duration of morning stiffness decreased by 1.2 h in D/R, with a slight increase of 0.1 h in D (p < 0.003). The back pain at night and peripheral joint pain both improved in D/R group versus D (not statistically significant). Finally, the SJC and TJC also improved in D/R (-2.1 and -2.5) versus D (-0.4 and -0.6; p = 0.02, p = 0.03, respectively). Eleven of 15 patients in the D/R arm were responders, whereas only 2 of 15 D group patients were considered responders (p < 0.003).
The combination of doxycycline and rifampin for 9 months seemed to be effective in treatment of chronic uSpA. This is the first study to demonstrate therapeutic benefit with antimicrobials to a chronic inflammatory arthritis possibly secondary to persistent Chlamydia.
衣原体是反应性关节炎（ReA）的已知触发因素。它也可能是未分化脊柱关节炎（uSpA）的常见病因。在这些患者初次接触衣原体数年之后，仍可在其滑膜组织中观察到持续存在且具有代谢活性的衣原体。用赖甲环素和利福平进行的试验已显示出对早期/急性衣原体诱导的关节炎有益。体外数据表明，持续存在的衣原体对四环素或利福平的慢性单一疗法产生耐药性，而当利福平与对衣原体有活性的抗菌药物联合使用时则未观察到这种耐药性。利福平和多西环素对衣原体也显示出协同作用。此外，利福平可抑制衣原体热休克蛋白（HSP）的产生。HSP60在衣原体的慢性持续状态中起关键作用。我们进行了一项为期9个月的前瞻性随机试验，以评估多西环素与多西环素联合利福平治疗uSpA的疗效。
该研究纳入了30例慢性炎症性关节炎患者（平均病程10年），这些患者符合欧洲脊柱关节病研究组的标准，且无炎症性肠病、银屑病、强直性脊柱炎或先前痢疾的证据。患者接受每日两次口服100 mg多西环素或每日两次口服100 mg多西环素与每日口服600 mg利福平的联合治疗。每次就诊时，他们都要接受一份包含4个问题的自我调查问卷和一次盲法关节检查。这些问题包括用于评估其当前背痛程度、晨僵持续时间、夜间背痛及外周关节疼痛的视觉模拟量表（VAS）。盲法关节检查包括肿胀关节计数（SJC）和压痛关节计数（TJC）。在基线以及治疗1、3、6和9个月时对这6个变量进行评估。反应者定义为在治疗9个月时6个变量中至少4个变量改善≥20%的患者。
在治疗9个月时，比较多西环素联合利福平组（D/R）和多西环素组（D），D/R组的所有6个变量的改善均优于D组，其中4个变量具有统计学意义。D/R组的平均VAS（满分100分）下降了24.4分，而D组下降了3分（p<0.03）。D/R组的晨僵持续时间减少了1.2小时，而D组略有增加0.1小时（p<0.003）。D/R组的夜间背痛和外周关节疼痛相较于D组均有所改善（无统计学意义）。最后，D/R组的SJC和TJC也有所改善（分别为-2.1和-2.5），而D组分别为-0.4和-0.6（p分别为0.02和0.03）。D/R组15例患者中有11例为反应者，而D组15例患者中只有2例被视为反应者（p<0.003）。
多西环素与利福平联合使用9个月似乎对慢性uSpA有效。这是第一项证明抗菌药物对可能继发于持续存在的衣原体的慢性炎症性关节炎具有治疗益处的研究。
