Rheumatoid arthritis (RA) is a potentially devastating autoimmune disease. The great majority of patients with RA are seropositive for anti-citrullinated protein antibodies (ACPAs), rheumatoid factors, or other autoantibodies. The onset of clinically apparent inflammatory arthritis meeting classification criteria (clinical RA) is preceded by ACPA seropositivity for an average of 3–5 years, a period that is designated as ‘at-risk’ of RA for ACPA-positive individuals who do not display signs of arthritis, or ‘pre-RA’ for individuals who are known to have progressed to developing clinical RA. Prior studies of individuals at-risk of RA have associated pulmonary mucosal inflammation with local production of ACPAs and rheumatoid factors, leading to development of the ‘mucosal origins hypothesis’. Recent work now suggests the presence of multiple distinct mucosal site-specific mechanisms that drive RA evolution. Indicatively, subsets of individuals at-risk of RA and patients with RA harbour a faecal bacterial strain that has exhibited arthritogenic activity in animal models and that favours T helper 17 (T_H17) cell responses in patients. Periodontal inflammation and oral microbiota have also been suggested to promote the development of arthritis through breaches in the mucosal barrier. Herein, we argue that mucosal sites and their associated microbial strains can contribute to RA evolution via distinct pathogenic mechanisms, which can be considered causal mucosal endotypes. Future therapies instituted for prevention in the at-risk period, or, perhaps, during clinical RA as therapeutics for active arthritis, will possibly have to address these individual mechanisms as part of precision medicine approaches.

类风湿性关节炎 （RA） 是一种具有潜在破坏性的自身免疫性疾病。绝大多数 RA 患者的抗瓜氨酸蛋白抗体 （ACPA）、类风湿因子或其他自身抗体血清反应阳性。在符合分类标准（临床 RA）的临床明显炎症性关节炎发作之前，ACPA 血清阳性平均持续 3-5 年，对于没有关节炎迹象的 ACPA 阳性个体，这段时间被指定为 RA 的“风险”，或对于已知已发展为临床 RA 的个体，被指定为“RA 前”。先前对 RA 风险个体的研究将肺粘膜炎症与 ACPA 和类风湿因子的局部产生联系起来，导致“粘膜起源假说”的发展。最近的研究表明，存在多种不同的粘膜部位特异性机制来驱动 RA 进化。指示性地，有 RA 风险的个体和 RA 患者亚群携带一种粪便细菌菌株，该菌株在动物模型中表现出致节活性，并且有利于患者的辅助性 T 细胞反应 17 （T_H17）。牙周炎和口腔微生物群也被认为通过破坏粘膜屏障来促进关节炎的发展。在此，我们认为粘膜部位及其相关微生物菌株可以通过不同的致病机制促进 RA 进化，这可以被认为是因果粘膜内型。未来为在高危时期或临床 RA 期间作为活动性关节炎的治疗方法而制定的预防疗法可能必须解决这些个体机制，作为精准医学方法的一部分。