Dow Medical College, Dow University of Health Sciences, Karachi, Pakistan.
Med Hypotheses. 2012 Sep;79(3):313-4. doi: 10.1016/j.mehy.2012.05.019. Epub 2012 Jun 2.
Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disorder involving mainly synovial joints. It can progress to a severely debilitating form with pulmonary, renal and cardiovascular involvement. Currently, disease-modifying antirheumatic drugs (DMARDs) remain the gold standard pharmacological therapy for RA (along with nonsteroidal anti-inflammatory drugs and corticosteroids). However, DMARDs are more or less ineffective in the late phase of the disease and adverse effects often limit their use. Studies show that serum levels of vascular endothelial growth factor (VEGF) remain elevated throughout the course of RA. In experimental models, the administration of pro-angiogenic cytokines, such as VEGF or FGF, has been shown to increase the severity of the disease. Therefore, anti-angiogenic drugs such as bevacizumab (which is already being used as an anti-tumor agent) may play a significant role in longstanding RA. However, adverse effects such as hypertension, gastro-intestinal perforation and the high cost of bevacizumab are major concerns. A recent study suggests that itraconazole, an antifungal drug, has a role in selectively inhibiting angiogenesis and growth of tumor in non-small cell lung cancer. Hence, this drug may be beneficial in the treatment of RA, especially in the later phase when other modalities have failed, or as an adjuvant. To test our hypothesis, we propose a randomized, double-blinded trial in patients with longstanding RA. The control group receives the standard DMARD therapy plus placebo, while the case group receives itraconazole in addition to DMARD therapy. Serum and synovial VEGF levels, in both the control group and the case group, are compared and their correlation with the symptoms is judged. If the VEGF levels are lower and/or the symptoms are less severe in the case group, our hypothesis will be confirmed. Multi-institutional efforts are needed to confirm this hypothesis, as it is relatively new and trial data is limited.
类风湿关节炎（RA）是一种慢性、炎症性、自身免疫性疾病，主要涉及滑膜关节。它可以发展为严重致残的形式，涉及肺部、肾脏和心血管。目前，疾病修饰抗风湿药物（DMARDs）仍然是 RA 的金标准药物治疗（与非甾体抗炎药和皮质类固醇一起）。然而，DMARDs 在疾病晚期或多或少无效，不良反应常常限制其使用。研究表明，血管内皮生长因子（VEGF）的血清水平在 RA 的整个过程中仍然升高。在实验模型中，给予促血管生成细胞因子，如 VEGF 或 FGF，已被证明会增加疾病的严重程度。因此，抗血管生成药物，如贝伐单抗（已被用作抗肿瘤药物），可能在长期 RA 中发挥重要作用。然而，不良反应如高血压、胃肠道穿孔和贝伐单抗的高成本是主要关注点。最近的一项研究表明，抗真菌药物伊曲康唑在选择性抑制非小细胞肺癌的血管生成和肿瘤生长方面具有作用。因此，这种药物可能对 RA 的治疗有益，尤其是在其他治疗方法失败或作为辅助治疗的晚期。为了验证我们的假设，我们提出了一项针对长期 RA 患者的随机、双盲试验。对照组接受标准 DMARD 治疗加安慰剂，而病例组除 DMARD 治疗外还接受伊曲康唑。比较对照组和病例组的血清和滑膜 VEGF 水平，并判断其与症状的相关性。如果病例组的 VEGF 水平较低且/或症状较轻，则我们的假设将得到证实。需要多机构努力来证实这一假设，因为它相对较新，试验数据有限。
