Clinic of Pediatrics, Department of Pediatric Rheumatology, University Clinic Center, Nis, Serbia.
Mol Med. 2011 May-Jun;17(5-6):397-403. doi: 10.2119/molmed.2011.00030. Epub 2011 Feb 4.
Rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) are heterogeneous autoimmune diseases characterized by chronic joint inflammation. Methotrexate is used as the gold standard to treat rheumatoid arthritis, yet there are many patients in whom the disease cannot be controlled or who experience unacceptable intolerance. Most of the biologics currently used are effective, but mostly if combined with methotrexate. Long-term possible side effects, such as impaired host defense mechanisms against infection and lymphoma, are distinct disadvantages and a major concern of anticytokine therapies. Parenteral administration is a problem, particularly in children. Thus, there is a need to explore new treatment options. Here we review the properties of histone deacetylase inhibitors (HDACi) as they apply to rheumatoid arthritis by looking at effects on cytokine production, T-cell differentiation and the function of macrophages, dendritic cells, osteoblasts, osteoclasts and synovial fibroblasts. We also review the safety and efficacy of givinostat (ITF 2357) in the treatment of systemic onset juvenile idiopathic arthritis (SOJIA) and its influence on the cytokine networks in SOJIA. Givinostat is an orally active HDACi which was given to children with SOJIA. After 12 wk of treatment, there were significant benefits, particularly in reducing the pain and arthritic component of the disease and decreasing the neutrophilia. CD40L, IL-1α and IFNγ in whole blood lysates decreased at wks 2 and 4 compared with baseline levels. The clinical data are consistent with those from animal models of rheumatoid arthritis and suggest that trials with HDACi are promising as a safe oral alternative to anticytokines and methotrexate.
类风湿关节炎（RA）和幼年特发性关节炎（JIA）是异质性自身免疫性疾病，其特征为慢性关节炎症。甲氨蝶呤被用作治疗类风湿关节炎的金标准，但许多患者的疾病无法得到控制，或者无法耐受。目前使用的大多数生物制剂都有效，但主要是与甲氨蝶呤联合使用。长期可能出现的副作用，如宿主抗感染和淋巴瘤的防御机制受损，是明显的劣势，也是抗细胞因子治疗的主要关注点。肠外给药是一个问题，尤其是在儿童中。因此，需要探索新的治疗选择。在这里，我们通过观察对细胞因子产生、T 细胞分化以及巨噬细胞、树突状细胞、成骨细胞、破骨细胞和滑膜成纤维细胞功能的影响，综述了组蛋白去乙酰化酶抑制剂（HDACi）在类风湿关节炎中的特性。我们还回顾了givinostat（ITF 2357）在治疗全身型幼年特发性关节炎（SOJIA）中的安全性和疗效及其对 SOJIA 中细胞因子网络的影响。givinostat 是一种口服活性的 HDACi，用于治疗 SOJIA 患儿。治疗 12 周后，显著获益，特别是在减轻疾病的疼痛和关节炎成分以及减少中性粒细胞方面。与基线水平相比，在第 2 和第 4 周时，全血裂解物中的 CD40L、IL-1α 和 IFNγ 降低。临床数据与类风湿关节炎动物模型一致，表明 HDACi 试验具有作为安全的口服替代抗细胞因子和甲氨蝶呤的前景。
