根据“目标治疗”原则治疗的高炎症活动度早期类风湿关节炎患者中，HLA - DRB1多态性和TNF - 308 G/A与关节影像学损伤的相关性（REMARKA研究）

Association of polymorphisms of HLA-DRB1 and TNF-308 G/A with radiographic joint damage in patients with early rheumatoid arthritis with high inflammatory activity, treated according to the principle of "Treat to target" (REMARKA study).

作者信息

Guseva I A, Smirnov A V, Demidova N V, Krylov M Yu, Avdeeva A S, Samarkina E Yu, Luchikhina E L, Karateev D E, Abramov D D, Nasonov E L

机构信息

Federal State Budgetary Scientific Institution «Research Institute of Rheumatology named after V.A. Nasonova», Moscow, Russia.

Moscow Regional Research and Clinical Institute (MONIKI), Moscow, Russia.

出版信息

Ter Arkh. 2018 May 11;90(5):38-43. doi: 10.26442/terarkh201890538-43.

DOI:10.26442/terarkh201890538-43

PMID:30701887

Abstract

AIM

To clarify the association between HLA-DRB1 and TNFα (-308G>A) genes polymorphism and joint destruction/further progression during 12 months of the follow-up period (FUP) in patients with early (<6 months), active, predominantly antibodies to cyclic citrullinated peptide (ACCP) and rheumatoid factor (RF)-positive rheumatoid arthritis (RA) treated according to "Treat to target" strategy.

MATERIALS AND METHODS

The study included 85 patients with early RA and duration of symptoms <6 months. All patients were initially assigned to subcutaneous methotrexate (MTX) with rapid dose escalation to 20-25 mg/week. Combination MTX + biological therapy, mainly adalimumab, was used when MTX was ineffective. Joint destruction was assessed by Sharp-Van der Heijde modification scoring method at baseline and after 12 months FUP. Real time polymerase chain reaction (PCR-RT) was used for TNFα gene polymorphism (-308G>A) genotyping. Low resolution PCR-RT with subsequent sequence-based typing of 04 were performed to study HLA-DRB1 gene polymorphism. The HLA-DRB101, *04:01, *04:04, *04:05, *04:08, *10 alleles were categorized as SE+ (Shared Epitope) alleles.

RESULTS

As for TNFα gene polymorphism, it was demonstrated that the number of narrowings and total Sharp score values were almost twice as high at baseline in GG genotype carriers as compared to GA genotype carriers (р<0,005, and р<0,004 respectively). Similar association was found after 12mo FUP. The progression of joint destruction, assessed as the change (∆) in the number of erosions, joint space narrowings and the total score, was statistically significantly associated with HLA-DRB1*(SE) genotypes: the carriers of SE (SE+/SE+) double-dose had more advanced progression as compared to (SE+/SE-)/(SE-/SE-) carriers (р<0,028, р<0,019, р<0,035 respectively).

CONCLUSION

Our data suggest that HLA-DRB1 (SE+) gene and TNFα (-308G>A) polymorphisms are associated with the progression of radiographic joint destruction in early, active RA patients managed according to "Treat to target" stratagy.

摘要

目的

明确 HLA - DRB1 和 TNFα（-308G>A）基因多态性与采用“治疗到靶目标”策略治疗的早期（<6 个月）、活动期、以抗环瓜氨酸肽抗体（ACCP）和类风湿因子（RF）阳性为主的类风湿关节炎（RA）患者在 12 个月随访期（FUP）内关节破坏/病情进一步进展之间的关联。

材料与方法

该研究纳入 85 例症状持续时间<6 个月的早期 RA 患者。所有患者初始均给予皮下注射甲氨蝶呤（MTX），并迅速将剂量增至 20 - 25mg/周。当 MTX 无效时，采用 MTX + 生物治疗联合方案，主要为阿达木单抗。在基线和随访 12 个月后，采用 Sharp - Van der Heijde 改良评分法评估关节破坏情况。采用实时聚合酶链反应（PCR - RT）对 TNFα 基因多态性（-308G>A）进行基因分型。采用低分辨率 PCR - RT 及后续基于序列的 04 分型来研究 HLA - DRB1 基因多态性。将 HLA - DRB101、*04:01、*04:04、*04:05、*04:08、*10 等位基因归类为 SE +（共享表位）等位基因。

结果

关于 TNFα 基因多态性，结果显示，在基线时，GG 基因型携带者的狭窄数量和 Sharp 总分值几乎是 GA 基因型携带者的两倍（分别为 p<0.005 和 p<0.004）。在随访 12 个月后发现了类似的关联。以侵蚀数量、关节间隙狭窄和总分的变化（∆）评估的关节破坏进展与 HLA - DRB1*（SE）基因型在统计学上显著相关：与（SE + / SE -）/（SE - / SE -）携带者相比，SE（SE + / SE +）双剂量携带者的病情进展更严重（分别为 p<0.028、p<0.019、p<0.035）。