PILOT INVESTIGATION OF SAFETY AND EFFICACY OF THALIDOMIDE IN SARCOIDOSIS

结节病是一种病因不明的多系统疾病，以非干酪化性肉芽肿的形成为特征。 疾病累及可以是自限性的或慢性的，范围从无症状到终末器官衰竭。 这种疾病可能会影响肺，胸部淋巴结，皮肤，眼睛和其他器官。 皮质类固醇仍然是结节病的主要治疗方法。 然而，类固醇治疗有多种副作用，可能无法改变疾病进程。 促炎细胞因子TNF-α可能在介导结节病活动中起重要作用。 由活化的巨噬细胞产生的TNF-α是导致肉芽肿形成的细胞介导的免疫应答中的重要因素。 结节病患者血清TNF-α和可溶性TNF-α受体水平升高，并与疾病活动性相关。 沙利度胺是一种TNF-α产生的抑制剂，已被证明在许多自身免疫性疾病中具有抗炎和免疫调节作用，包括盘状狼疮、阿弗他溃疡形成、麻风结节性红斑等。在抗生素治疗方案中加入沙利度胺也改善了M.肺和中枢神经系统的结核感染。 本研究将使用临床和实验室疾病活动性指标，评价沙利度胺每日给药对结节病患者的影响，为期4个月。 连续记录的临床疾病活动测量包括肺量测定、皮肤照片、红细胞沉降率、健康评估量表和关节计数。 将在几个规定的时间点进行胸部X线检查和几次皮肤活检。 基于实验室的疾病活动性测量包括血浆TNF-α和可溶性TNF-α受体、可溶性白细胞介素2受体和细胞间细胞粘附分子-1。 还将测定γ干扰素血浆水平。 将测量T淋巴细胞亚群和抗原刺激的淋巴细胞增殖。 将通过血液化学和细胞计数、病史和体格检查以及每月患者访视期间进行的肾功能评估监测该患者组的药物安全性。

Sarcoidosis is a multisystem disease of unknown etiology characterized by the formation of noncaseating granulomas. Disease involvement can be self limited or chronic, ranging from asymptomatic to end organ failure. The disease may affect lungs, thoracic lymph nodes, skin, eyes, and other organs. Corticosteroids remain the primary sarcoidosis therapy. However, steroid treatment has multiple side effects and may fail to alter the disease course. The proinflammatory cytokine TNF-alpha may play an important role in mediating sarcoid disease activity. TNF-alpha production by activated macrophages is an important element in the cell mediated immune response leading to granuloma formation. Serum levels of TNF-alpha and soluble TNF-alpha receptors are elevated in sarcoidosis patients and correlate with disease activity. Thalidomide, an inhibitor of TNF-alpha production, has been shown to have both anti-inflammatory and immune modulating effects in a number of autoimmune diseases, including discoid lupus, aphthous ulcer formation, erythema nodosum leprosum, and others. The addition of thalidomide to antibiotic regimens has also improved morbidity and mortality in animal models of M. tuberculosis infection of the pulmonary and central nervous systems. This study will evaluate the effect of daily thalidomide administration in sarcoidosis patients over a 4 month period, using clinical and laboratory based disease activity measures. Serially recorded clinical disease activity measures include spirometry, skin photographs, erythrocyte sedimentation rates, Health Assessment Questionnaires, and joint counts. Chest x-rays and several skin biopsies will be performed at several defined time points. Laboratory based disease activity measures include plasma TNF-alpha and soluble TNF-alpha receptor, soluble interleukin 2 receptor, and intercellular cell adhesion molecule-1. Interferon gamma plasma levels will also be determined. T-lymphocytes subsets and antigen-stimulated lymphocyte proliferation will be measured. Drug safety in this patient group will be monitored by blood chemistries and cell counts, history and physical exams, and renal function assessments performed during monthly patient visits.