Decker Dima A, Higgins Paul, Hayes Kyle, Bollinger Chris, Becker Patrice, Wright Dale
Former employee of Mallinckrodt Pharmaceuticals, Bedminster, NJ, USA.
Mallinckrodt Pharmaceuticals, 675 McDonnell Blvd, Bedminster, NJ, 63042, USA.
BMC Musculoskelet Disord. 2020 Aug 31;21(1):586. doi: 10.1186/s12891-020-03609-3.
Melanocortin receptor (MCR) agonists have anti-inflammatory and immunomodulatory properties mediated by receptors expressed on cells relevant to arthritis. Repository corticotropin injection (RCI; Acthar® Gel), an MCR agonist preparation, is approved as adjunctive therapy for rheumatoid arthritis (RA), but its mechanism of action in RA is unclear. This study explored the efficacy of RCI as monotherapy or adjunctive therapy with etanercept (ETN) in an established animal model of collagen-induced arthritis (CIA).
After induction of CIA, rats (n = 10 per group) were randomized to receive subcutaneous RCI (40, 160, or 400 U/kg twice daily) alone or in combination with ETN (10 mg/kg 3 times daily), ETN alone, or vehicle (on days 13 through 19). Inflammation was assessed via changes in paw edema. Bone damage was determined by microfocal computed tomography histopathology, and immunohistochemistry. Statistical analyses were performed using a 2-way analysis of variance (ANOVA) followed by the Newman-Keuls, Dunn's, or Dunnett's multiple comparisons test or a 1-way ANOVA followed by the Dunnett's or Holm-Sidak multiple comparisons test.
RCI administration resulted in dose-dependent decreases in ankle edema and histopathologic measures of inflammation, pannus formation, cartilage damage, bone resorption, and periosteal bone formation. RCI and ETN showed combined benefits on all parameters measured. Radiographic evidence of bone damage was significantly reduced in rats that received RCI alone or in combination with ETN. This reduction in bone density loss correlated with decreases in the number of CD68-positive macrophages and cathepsin K-positive osteoclasts within the lesions.
As monotherapy or adjunctive therapy with ETN, RCI attenuated CIA-induced joint structural damage in rats. These data support the clinical efficacy of RCI as adjunctive therapy for patients with RA.
黑皮质素受体（MCR）激动剂具有抗炎和免疫调节特性，其作用由与关节炎相关的细胞上表达的受体介导。储存促肾上腺皮质激素注射液（RCI；Acthar® Gel），一种MCR激动剂制剂，被批准作为类风湿关节炎（RA）的辅助治疗药物，但其在RA中的作用机制尚不清楚。本研究在已建立的胶原诱导性关节炎（CIA）动物模型中探讨了RCI作为单药治疗或与依那西普（ETN）联合治疗的疗效。
诱导CIA后，将大鼠（每组n = 10）随机分组，分别接受皮下注射RCI（40、160或400 U/kg，每日两次）单独治疗或与ETN（10 mg/kg，每日三次）联合治疗、单独使用ETN或赋形剂（在第13至19天）。通过爪部水肿的变化评估炎症。通过微焦点计算机断层扫描组织病理学、免疫组织化学确定骨损伤情况。使用双向方差分析（ANOVA），随后进行纽曼-基尔斯、邓恩或邓尼特多重比较检验，或单向ANOVA，随后进行邓尼特或霍尔姆-西达克多重比较检验进行统计分析。
给予RCI导致踝关节水肿以及炎症、血管翳形成、软骨损伤、骨吸收和骨膜骨形成的组织病理学指标呈剂量依赖性降低。RCI和ETN在所有测量参数上均显示出联合益处。单独接受RCI或与ETN联合治疗的大鼠骨损伤的影像学证据显著减少。骨密度损失的减少与病变内CD68阳性巨噬细胞和组织蛋白酶K阳性破骨细胞数量的减少相关。
作为单药治疗或与ETN联合治疗，RCI减轻了CIA诱导的大鼠关节结构损伤。这些数据支持RCI作为RA患者辅助治疗的临床疗效。
