Anxiety disorders and cognitive decline are highly prevalent in rheumatic diseases, including Juvenile Idiopathic Arthritis (JIA). In this study, we investigated the effect of long-term treatment with infliximab and tocilizumab on anxiety-like behaviour and cognitive performance in a juvenile collagen–induced arthritis (CIA) rat model. Forty-nine rats with established moderate arthritis were randomly allocated into 7 equal groups: negative control, vehicle, methotrexate, infliximab, tocilizumab, methotrexate + infliximab and methotrexate + tocilizumab groups. Behavioural tests were performed to evaluate anxiety-like behaviour and cognitive function. Neuropathological changes were investigated by histological examination at the level of the hippocampus, the amygdala and the prefrontal cortex. Also, the expression of Brain-Derived Neurotrophic Factor (BDNF), a biomarker associated with neuronal survival and plasticity, was determined in the hippocampus and the amygdala by RT-qPCR. We found that both infliximab and tocilizumab reduced anxiety-like behaviour in the elevated-plus and elevated-zero maze tests. Tocilizumab, also, improved cognitive function in the olfactory social memory and passive avoidance tests. Anti-cytokine treatment reversed the histopathological changes in the brain induced by CIA. BDNF expression was higher in all treatment groups and especially those receiving monoclonal antibodies combined with methotrexate. Our data provide evidence that chronic infliximab and tocilizumab treatment reduces anxiety-like behaviour, improves cognitive function, reverses neuropathological changes and increases central BDNF expression in a juvenile arthritis rat model. These findings may be translated to humans to address behavioural comorbidities associated with JIA.

焦虑症和认知能力下降在风湿性疾病中非常普遍，包括幼年特发性关节炎 (JIA)。在这项研究中，我们调查了英夫利昔单抗和托珠单抗长期治疗对幼年胶原诱导关节炎 (CIA) 大鼠模型中焦虑样行为和认知表现的影响。49 只已确诊的中度关节炎大鼠随机分为 7 个相等的组：阴性对照组、载体组、甲氨蝶呤组、英夫利昔单抗组、托珠单抗组、甲氨蝶呤 + 英夫利昔单抗组和甲氨蝶呤 + 托珠单抗组。进行行为测试以评估焦虑样行为和认知功能。通过海马、杏仁核和前额叶皮层水平的组织学检查来研究神经病理学变化。还，通过 RT-qPCR 在海马和杏仁核中测定脑源性神经营养因子 (BDNF) 的表达，这是一种与神经元存活和可塑性相关的生物标志物。我们发现英夫利昔单抗和托珠单抗在升高的正和升高的零迷宫测试中都减少了焦虑样行为。托珠单抗还改善了嗅觉社会记忆和被动回避测试中的认知功能。抗细胞因子治疗逆转了由 CIA 诱导的大脑组织病理学变化。所有治疗组的 BDNF 表达均较高，尤其是接受单克隆抗体联合甲氨蝶呤的治疗组。我们的数据提供证据表明，长期使用英夫利昔单抗和托珠单抗治疗可减少焦虑样行为，改善认知功能，在幼年关节炎大鼠模型中逆转神经病理学变化并增加中枢 BDNF 表达。这些发现可能会转化为人类，以解决与 JIA 相关的行为合并症。