Abstract

Rheumatoid arthritis (RA) is immune-mediated, inflammatory disease that affects synovial joints, and characterized by inflammatory changes in synovial tissue, cartilage, bone, and less commonly in extra-articular structures. Docetaxel (DTX) is a semi-synthetic anti-neoplastic medication. Peptidyl-arginine deiminase type 4 (PAD4) is expressed in macrophages and neutrophils in RA synovial membrane. Their effectiveness is in producing anti-cyclic citrullinated peptide antibodies (ACPA)-targeted citrullinated neoepitopes.

Aim

To evaluate the anti-inflammatory effects of DTX in RA and the effect of methotrexate on PAD4 to investigate its potential as an RA biomarker.

Methods

Forty male Wistar rats were divided into five groups of eight rats. Healthy rats formed the control group. The Second Group to Fifth group were induced with Complete Freund’s adjuvant. The third group received DTX at a dosage of 1 mg/kg on alternate days, as determined by a preliminary experiment. The fourth group was given 1 mg/kg/week of methotrexate intraperitoneally. The fifth group was treated with a half dose of DTX and methotrexate simultaneously.

Results

Significant Arthritis index and knee joint circumference decrease in the DTX group. No significant difference in body weight, platelet–lymphocyte ratio, and white blood cell count between the groups. Neutrophile lymphocyte ratio showed weak correlation with ACPA, while PAD4 showed good correlation with RA markers. Level of ACPA, PAD4, TNF-α, IL-1β, and VEGF significantly decreased in the DTX group than induction group (p < 0.05).

Conclusion

DTX reduces the progression and joint destruction in rats induced by Complete Freund’s Adjuvant which may due to inhibition of PAD4, TNF-α, IL-1β, VEGF, and ACPA. Also, methotrexate exhibited anti PAD4 effect.

中文翻译：

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评估多西紫杉醇在多关节炎动物模型中的作用

摘要

类风湿性关节炎 (RA) 是一种免疫介导的炎症性疾病，影响滑膜关节，其特征是滑膜组织、软骨、骨的炎症变化，但关节外结构的炎症变化较少见。多西他赛（DTX）是一种半合成抗肿瘤药物。肽基精氨酸脱亚胺酶 4 型 (PAD4) 在 RA 滑膜的巨噬细胞和中性粒细胞中表达。它们的功效在于产生抗环瓜氨酸肽抗体（ACPA）靶向瓜氨酸新表位。

目的

评估 DTX 在 RA 中的抗炎作用以及甲氨蝶呤对 PAD4 的影响，以探讨其作为 RA 生物标志物的潜力。

方法

将四十只雄性 Wistar 大鼠分为五组，每组八只。健康大鼠作为对照组。第二组至第五组均采用弗氏完全佐剂诱导。第三组根据初步实验确定，隔日接受 1 mg/kg 剂量的 DTX。第四组腹膜内给予甲氨蝶呤 1 mg/kg/周。第五组同时接受一半剂量的DTX和甲氨蝶呤治疗。

结果

DTX 组的关节炎指数和膝关节周长显着下降。各组之间的体重、血小板-淋巴细胞比值和白细胞计数没有显着差异。中性粒细胞比值与 ACPA 相关性较弱，而 PAD4 与 RA 标志物相关性较好。 DTX 组 ACPA、PAD4、TNF-α、IL-1β 和 VEGF 水平较诱导组显着降低（p  < 0.05）。

结论

DTX 可减少弗氏完全佐剂诱导的大鼠的进展和关节破坏，这可能是由于抑制 PAD4、TNF-α、IL-1β、VEGF 和 ACPA 所致。此外，甲氨蝶呤还表现出抗 PAD4 作用。