Manivel Vivek Anand, Mullazehi Mohammed, Padyukov Leonid, Westerlind Helga, Klareskog Lars, Alfredsson Lars, Saevarsdottir Saedis, Rönnelid Johan
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala Sweden.
Rheumatology Unit, Department of Medicine, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden.
Ann Rheum Dis. 2017 Sep;76(9):1529-1536. doi: 10.1136/annrheumdis-2016-210873. Epub 2017 Mar 23.
Antifibrillar collagen type II (anti-CII) antibody-positive patients with rheumatoid arthritis (RA) have early but not late signs of increased inflammation and joint erosions. We wanted to replicate this in a large RA cohort, and to relate to human leukocyte antigen (HLA)-DRB1* alleles.
Anti-CII and anti-cyclic citrullinated peptide (CCP)2 were measured at baseline in 773 patients with RA from the Swedish Epidemiological Investigation in Rheumatoid Arthritis (EIRA) study with clinical follow-up data from the Swedish Rheumatology Quality Register (SRQ) registry, and 1476 with HLA-DRB1* information. Comparisons were done concerning C reactive protein (CRP), erythrocyte sedimentation rate (ESR), tender joint count (TJC), swollen joint count (SJC), Disease Activity Score encompassing 28 joints based on ESR (DAS28), DAS28CRP, pain-Visual Analogue Scale (VAS), global-VAS and Health Assessment Questionnaire Score (HAQ) at eight occasions during 5 years, and association with HLA-DRB1* alleles.
Anti-CII associated with elevated CRP, ESR, SJC, DAS28 and DAS28CRP at diagnosis and up to 6 months, whereas anti-CCP2 associated with SJC and DAS28 from 6 months to 5 years, but not earlier. The anti-CII-associated phenotype was strong, and predominated in anti-CII/anti-CCP2 double-positive patients. Anti-CII was associated with improvements in CRP, ESR, SJC, TJC and DAS28, whereas anti-CCP2 was associated with deteriorations in SJC and DAS28 over time. Anti-CII-positive patients achieved European League Against Rheumatism good or moderate response more often than negative patients. Anti-CII was positively associated with HLA-DRB101 and HLA-DRB103, with significant interaction, and double-positive individuals had >14 times higher mean anti-CII levels than HLA double negatives. Whereas smoking was associated with elevated anti-CCP2 levels, smokers had lower anti-CII levels.
Anti-CII seropositive RA represents a distinct phenotype, in many respects representing the converse to the clinical, genetic and smoking associations described for anticitrullinated protein peptide autoantibodies. Although not diagnostically useful, early anti-CII determinations predict favourable inflammatory outcome in RA.
类风湿关节炎（RA）患者中抗II型纤维状胶原（抗CII）抗体阳性者具有炎症增加和关节侵蚀的早期而非晚期体征。我们希望在一个大型RA队列中重现这一现象，并将其与人类白细胞抗原（HLA）-DRB1*等位基因相关联。
在瑞典类风湿关节炎流行病学调查（EIRA）研究的773例RA患者中，于基线时检测抗CII和抗环瓜氨酸肽（CCP）2，并获取来自瑞典风湿病质量登记册（SRQ）登记处的临床随访数据，另外1476例患者有HLA-DRB1信息。对5年期间8个时间点的C反应蛋白（CRP）、红细胞沉降率（ESR）、压痛关节计数（TJC）、肿胀关节计数（SJC）、基于ESR的包含28个关节的疾病活动评分（DAS28）、DAS28CRP、疼痛视觉模拟量表（VAS）、整体VAS和健康评估问卷评分（HAQ）进行比较，并分析与HLA-DRB1等位基因的关联。
抗CII在诊断时及诊断后6个月内与CRP、ESR、SJC、DAS28和DAS28CRP升高相关，而抗CCP2在6个月至5年期间与SJC和DAS28相关，但在更早阶段无此关联。抗CII相关的表型较强，且在抗CII/抗CCP2双阳性患者中占主导。抗CII与CRP、ESR、SJC、TJC和DAS28的改善相关，而抗CCP2随时间推移与SJC和DAS28的恶化相关。抗CII阳性患者比阴性患者更常达到欧洲抗风湿病联盟良好或中等反应。抗CII与HLA-DRB101和HLA-DRB103呈正相关，存在显著相互作用，双阳性个体的平均抗CII水平比HLA双阴性个体高14倍以上。虽然吸烟与抗CCP2水平升高相关，但吸烟者的抗CII水平较低。
抗CII血清阳性RA代表一种独特的表型，在许多方面与抗瓜氨酸化蛋白肽自身抗体所描述的临床、遗传和吸烟关联相反。尽管抗CII对诊断无帮助，但早期检测抗CII可预测RA患者良好的炎症转归。
