Table_1_Synovial Tissue: Turning the Page to Precision Medicine in Arthritis.DOCX

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease targeting the joints. Current treatment strategies are based on clinical, biological and radiological features, yet still fail to reach the goal of early low disease activity in a significant number of cases. Hence, there is a need for refining current treatment algorithms, using accurate markers of response to therapy. Because RA induces histological and molecular alterations in the synovium even before apparition of clinical symptoms, synovial biopsies are a promising tool in the search of such new biomarkers. Histological and molecular characteristics of RA synovitis are heterogeneous. Variations in synovial lining layer hyperplasia, in cellular infiltration of the sublining by immune cells of myeloid and lymphoid lineages, and in molecular triggers of these features are currently categorized using well-defined pathotypes: myeloid, lymphoid, fibroid and pauci-immune. Here, we first bring the plasticity of RA synovitis under scrutiny, i.e., how variations in synovial characteristics are associated with relevant clinical features (disease duration, disease activity, effects of therapies, disease severity). Primary response to a specific drug could be, at least theoretically, related to the representation of the molecular pathway targeted by the drug in the synovium. Alternatively, absence of primary response to a specific agent could be due to disease severity, i.e., overrepresentation of all synovial molecular pathways driving disease activity overwhelming the capacity of any drug to block them. Using this theoretical frame, we will highlight how the findings of previous studies trying to link response to therapy with synovial changes provide promising perspectives on bridging the gap to personalized medicine in RA.

类风湿关节炎（Rheumatoid arthritis, RA）是一种以关节为主要受累靶标的慢性全身性炎症性疾病。当前治疗策略基于临床、生物学及影像学特征制定，但仍有大量病例无法达成早期低疾病活动度的治疗目标。因此，亟需优化现有治疗方案，寻找精准的治疗应答标志物。由于RA甚至在临床症状出现前即可诱导滑膜发生组织学与分子改变，滑膜活检（synovial biopsy）成为探索此类新型生物标志物的极具前景的技术手段。RA滑膜炎的组织学与分子特征具有显著异质性：滑膜衬里层增生、滑膜下层组织中髓系与淋巴系免疫细胞浸润，以及上述特征的分子触发因素，目前均通过明确的病理亚型（pathotype）进行分类，包括髓系型、淋巴系型、纤维型与寡免疫型。
本文首先深入探讨RA滑膜炎的可塑性，即滑膜特征的变化如何与相关临床指标相关联，包括病程、疾病活动度、治疗应答效果及疾病严重程度。从理论层面而言，特定药物的原发应答可能与滑膜中该药物靶向的分子通路的表达丰度相关；反之，特定药物出现原发无应答的情况，可能源于疾病严重程度过高——即驱动疾病活动的所有滑膜分子通路过度表达，远超任何单一药物的阻断能力。基于这一理论框架，我们将阐明此前探索治疗应答与滑膜改变关联的研究成果，如何为弥合类风湿关节炎个体化医疗的实践差距提供极具前景的发展方向。