类风湿关节炎患者的滑膜免疫表型与抗瓜氨酸化肽抗体：与治疗反应和放射学预后的关系。

Synovial Immunophenotype and Anti-Citrullinated Peptide Antibodies in Rheumatoid Arthritis Patients: Relationship to Treatment Response and Radiologic Prognosis.

机构信息

University College Dublin, Dublin, Ireland.

Trinity College Dublin, Dublin, Ireland.

出版信息

Arthritis Rheumatol. 2017 Nov;69(11):2114-2123. doi: 10.1002/art.40218.

DOI:10.1002/art.40218

PMID:28732135

Abstract

OBJECTIVE

Serum anti-citrullinated peptide antibodies (ACPAs) may be present before the development of rheumatoid arthritis (RA) and may be predictive of more severe, erosive disease. This study was undertaken to examine the synovial tissue immunophenotype according to ACPA status in patients with RA, as well as the response to treatment and erosion status.

METHODS

Consecutive RA patients were prospectively recruited and underwent clinical and serologic assessments before and after treatment. Radiologic assessment was performed at the time of clinical follow-up. Synovial tissue was immunostained for specific markers of B cells (CD19), T cells (CD3, CD4, and CD8), macrophages (CD68), and blood vessels (factor VIII). Serum CXCL13 levels were quantified by enzyme-linked immunosorbent assay. Synovial tissue sections were analyzed for immunophenotype according to ACPA status, using a validated semiquantitative scoring method, and also analyzed for the presence of lymphoid aggregates. Response to treatment with nonbiologic or biologic disease-modifying antirheumatic drugs was assessed using the European League Against Rheumatism (EULAR) response criteria.

RESULTS

In total, 123 subjects (78 ACPA+) were included. Compared to ACPA- RA patients, synovium from ACPA+ RA patients was characterized by significantly higher levels of CD19+ B cells and CD3+ and CD8+ T cells (each P < 0.05), and CD19+ B cell levels were significantly higher in patients who were naive to treatment. The CD19+ B cell infiltrate level was higher in patients with erosions at follow-up (P = 0.0128). Levels of lymphoid aggregates of CD19+ B cells were significantly higher in ACPA+ patients (P < 0.05), and this was associated with increased serum CXCL13 levels. The EULAR response was significantly associated with the level of CD3+ T cell infiltrates (P < 0.05), while CD68+ macrophage and CD8+ T cell levels were predictive of the response to tumor necrosis factor inhibitors (P < 0.05).

CONCLUSION

The results of this prospective study demonstrate that the levels of synovial B cell infiltrates and lymphoid aggregates were significantly higher in ACPA+ RA patients, especially those who were naive to treatment. In addition, ACPA+ subjects developed more erosions during progression of the disease and had higher serum levels of CXCL13. The EULAR response to therapy in ACPA+ RA patients was associated with increased levels of T cell and macrophage markers.

摘要

目的

血清抗瓜氨酸化肽抗体（ACPAs）可能在类风湿关节炎（RA）发病前出现，并且可能预测更严重、侵蚀性疾病。本研究旨在检查 RA 患者根据 ACPA 状态的滑膜组织免疫表型，以及治疗反应和侵蚀状态。

方法

连续招募 RA 患者，在治疗前后进行临床和血清学评估。在临床随访时进行放射学评估。滑膜组织用特定的 B 细胞标志物（CD19）、T 细胞（CD3、CD4 和 CD8）、巨噬细胞（CD68）和血管（VIII 因子）进行免疫染色。通过酶联免疫吸附试验定量测定血清 CXCL13 水平。根据 ACPA 状态，使用经过验证的半定量评分方法分析滑膜组织切片的免疫表型，并分析淋巴样聚集物的存在。使用欧洲抗风湿病联盟（EULAR）反应标准评估非生物或生物疾病修饰抗风湿药物的治疗反应。

结果

共纳入 123 例患者（78 例 ACPA+）。与 ACPA-RA 患者相比，ACPA+RA 患者的滑膜组织中 CD19+B 细胞和 CD3+和 CD8+T 细胞的水平明显更高（均 P<0.05），且在初治患者中 CD19+B 细胞水平更高。在随访时出现侵蚀的患者的 CD19+B 细胞浸润水平更高（P=0.0128）。ACPA+患者的 CD19+B 细胞淋巴样聚集物水平明显更高（P<0.05），且与血清 CXCL13 水平升高相关。EULAR 反应与 CD3+T 细胞浸润水平显著相关（P<0.05），而 CD68+巨噬细胞和 CD8+T 细胞水平是对肿瘤坏死因子抑制剂反应的预测指标（P<0.05）。