Department of Clinical Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland.
Department of Rheumatology, St James' Hospital, Dublin, Ireland.
Rheumatol Int. 2022 Dec;42(12):2085-2095. doi: 10.1007/s00296-022-05174-5. Epub 2022 Aug 8.
Ankylosing spondylitis (AS) is a seronegative, chronic inflammatory arthritis with high genetic burden. A strong association with HLA-B27 has long been established, but to date its contribution to disease aetiology remains unresolved. Recent insights through genome wide studies reveal an increasing array of immunogenetic risk variants extraneous to the HLA complex in AS cohorts. These genetic traits build a complex profile of disease causality, highlighting several molecular pathways associated with the condition. This and other evidence strongly implicates T-cell-driven pathology, revolving around the T helper 17 cell subset as an important contributor to disease. This prominence of the T helper 17 cell subset has presented the opportunity for therapeutic intervention through inhibition of interleukins 17 and 23 which drive T helper 17 activity. While targeting of interleukin 17 has proven effective, this success has not been replicated with interleukin 23 inhibition in AS patients. Evidence points to significant genetic diversity between AS patients which may, in part, explain the observed refractoriness among a proportion of patients. In this review we discuss the impact of genetics on our understanding of AS and its relationship with closely linked pathologies. We further explore how genetics can be used in the development of therapeutics and as a tool to assist in the diagnosis and management of patients. This evidence indicates that genetic profiling should play a role in the clinician's choice of therapy as part of a precision medicine strategy towards disease management.
强直性脊柱炎（AS）是一种血清阴性、慢性炎症性关节炎，具有较高的遗传负担。长期以来，人们已经确立了它与 HLA-B27 的强烈关联，但迄今为止，其对疾病病因的贡献仍未得到解决。通过全基因组研究的最新发现揭示了在 AS 患者群体中，除了 HLA 复合体之外，免疫遗传风险变异体的数量不断增加。这些遗传特征构成了疾病因果关系的复杂图谱，突出了与该疾病相关的几个分子途径。这一证据以及其他证据强烈表明 T 细胞驱动的病理学，围绕 T 辅助 17 细胞亚群作为疾病的一个重要贡献者。T 辅助 17 细胞亚群的突出地位为通过抑制白细胞介素 17 和 23 来进行治疗干预提供了机会，白细胞介素 17 和 23 驱动 T 辅助 17 活性。虽然针对白细胞介素 17 的靶向治疗已被证明是有效的，但在 AS 患者中，白细胞介素 23 的抑制作用并未得到复制。有证据表明，AS 患者之间存在显著的遗传多样性，这在一定程度上可以解释一部分患者的观察到的耐药性。在这篇综述中，我们讨论了遗传学对我们理解 AS 及其与密切相关的病理之间关系的影响。我们进一步探讨了如何将遗传学用于治疗药物的开发，以及如何将其作为一种工具来协助患者的诊断和管理。这一证据表明，遗传分析应该在临床医生选择治疗方法时发挥作用，作为疾病管理的精准医学策略的一部分。
