Rheumatoid arthritis (RA) is the most common chronic autoimmune arthropathy. If the disease is aggressive or left untreated, it becomes debilitating, affects a patient’s functionality, and reduces the quality of life. Disease-modifying anti-rheumatic drugs (DMARDs), both conventional, targeted, and biological, decrease the disease progression and are key components of effective treatment. Recently, there has been a continuous debate about the possible carcinogenicity of various DMARDs. Lung cancer is a leading cause of cancer death worldwide. The available data show an increased risk of lung cancer in RA patients, but the link between RA and cancer is poorly understood. Carcinogenesis in RA seems to be related to chronic inflammation, familial predisposition, risky behaviors (e.g., smoking), and iatrogenic complications. The main mechanisms of carcinogenic processes in patients with RA are the up-regulation of interleukin-6 (IL-6) cytokine production and wingless/integrated WNT signaling. Up-regulation of WNT5A is an important mechanism that links chronic inflammatory pathways to carcinogenesis observed in RA patients. Concomitant up-regulation of transcription factor STAT3 promotes cell proliferation and inhibits apoptosis. Conversely, suppressed inflammatory processes by DMARDs may decrease the risk of lung cancer. In this article, we discuss the molecular mechanisms of lung cancer in RA and the role of DMARDs in this process. Furthermore, we analyze the molecular effect of drug-induced cancer, which affects transcription factors and thus modulates carcinogenic processes. Finally, we describe risk factors and present preventive and therapeutic approaches.
类风湿关节炎是最常见的慢性自身免疫性关节病。若疾病呈侵袭性发展或未经治疗，会导致患者功能受损、活动能力下降，并严重影响生活质量。改善病情抗风湿药（包括传统合成、靶向及生物制剂）能有效延缓疾病进展，是治疗体系的核心组成部分。近年来，关于各类改善病情抗风湿药潜在致癌风险的争议持续存在。肺癌是全球癌症致死的主要原因，现有数据显示类风湿关节炎患者肺癌风险升高，但二者关联机制尚未明确。类风湿关节炎的致癌机制可能与慢性炎症、家族易感性、高危行为（如吸烟）及医源性并发症相关。其核心致癌机制涉及白细胞介素-6细胞因子分泌上调及Wnt信号通路异常激活，其中WNT5A的上调是连接慢性炎症通路与类风湿关节炎患者致癌过程的重要机制。同时，转录因子STAT3的上调会促进细胞增殖并抑制细胞凋亡。反之，改善病情抗风湿药对炎症过程的抑制可能降低肺癌风险。本文系统探讨类风湿关节炎相关肺癌的分子机制及改善病情抗风湿药在此过程中的作用，分析药物诱导癌症影响转录因子进而调控致癌过程的分子效应，最后阐述相关风险因素并提出预防与治疗策略。
Inflammatory Pathways to Carcinogenesis: Deciphering the Rheumatoid Arthritis–Lung Cancer Connection
肿瘤(癌症)患者之家