原文

译文

FRI0133

SERUM LEVELS OF TNF ANTAGONISTS IN RHEUMATOID ARTHRITIS: CAN WE ESTABLISH AN OPTIMAL CUT-OFF TO IDENTIFY PATIENTS IN REMISSION OR LOW DISEASE ACTIVITY?

R. Sanmarti^1,*, J. Inciarte-Mundo¹, P. Estrada Alarcón², M. García Manrique³, J. Narvaez², J. Rodríguez², T. Gómez Centeno³, M. Pascal⁴, J. Yagüe⁴

¹Rheumatology, Hospital Clinic I Provincial , Barcelona, ²Rheumatology, Hospital de Bellvitge, L'Hospitalet de Llobregat, ³Rheumatology, Hospital Parc Taulí, Sabadell, ⁴Immunology, Hospital Clinic I Provincial, Barcelona, Spain

Background: TNF antagonists (TNFα) are efficacious in controlling the signs and symptoms of rheumatoid arthritis (RA). Studies show low serum trough levels (STL) of TNFα are associated with worse therapeutic response.

Objectives: To determine STL of adalimumab (ADA) and etanercept (ETN) in RA patients and establish a cut-off to discriminate remission or low disease activity.

Methods: Cross-sectional study of 91 patients from the prospective multicenter INMUNOREMAR study, a cohort (all with DAS28 ≤3.2 at baseline) and 36 patients in whom immunogenicity was assessed due to active disease (all DAS28 >3.2) treated with ADA and ETN. Anti-drug antibodies (Abs) and STL were measured using Promonitor (Progenika Biopharma, Spain) ELISA kits. STL were compared by disease activity (Mann Whitney U test), and correlations between STL and DAS28 were analyzed (Spearman test). The accuracy and discriminatory capacity of ADA and ETN STL were assessed by ROC curves (AUC) for remission (DAS28≤2.6) and low disease activity (DAS28≤3.2).

Results: 127 patients (81.9% female, median age 61 years, median disease duration 13 years, TNF therapy 60 months, 57 patients receiving ADA and 73 ETN, 29.9% of patients on monotherapy and 27.6% on low doses of biological treatment) were included. 55.9% of patients were in remission and 71.7% in remission/low activity (DAS28≤3.2). Four ADA patients developed anti-drug antibodies. STL of ADA and ETN were significantly higher in patients in remission than in those not in remission (median (P25-P75) ADA. 6.9 (2.7-12) vs. 0.5 (0.1-1) p <0.001 ETN 2.3 (1.5- 3.1) vs. 0.8 (0.4-1.8) p <0.001). Similar results were obtained when comparing remission/low disease activity with patients with DAS28 >3.2. A significant inverse correlation was observed between STL and DAS28 (ADA: rho = 0.5 p <0.0001, ETN rho = 0.37 p <0.001). Accuracy analysis with remission by DAS28 as the reference variable showed an AUC for ADA of 0.81 (95% CI .68-.94), (s): 81.9%, (e): 81% and ETN of 0.747 (95% CI 0.68 to 0.85) (s): 71.1% (e) 71.4%. The STL with the greatest discriminative capacity for remission were 1,336 μg/mL for ADA and 1.56 μg/mL for ETN. Remission/low disease activity by DAS28 as the reference variable showed an AUC for ADA 0.863 (95% CI 0.73 to 0.99) (s): 78.9% (e): 93.8% and ETN 0.876 (0.80 to 0.95) (s): 81.1% (e): 80%. The cutoffs for remission/low activity (DAS28≤3.2) were: ADA 1,336 μg/mL and ETN 1.073 μg/mL.

Conclusions: RA patients in remission/low disease activity showed higher ADA and ETN STL compared to those with active disease. Cut-off values with a high discriminative capacity to identify remission or low disease activity were established.

References: Chen DY, Chen YM, Tsai WC, et al. Significant associations of antidrug antibody levels with serum drug trough levels and therapeutic response of adalimumab and etanercept treatment in rheumatoid arthritis.Ann Rheum Dis. 2014 Jan 17. doi: 10.1136/annrheumdis-2013-203893.

Disclosure of Interest: None declared

DOI: 10.1136/annrheumdis-2015-eular.3173

背景: TNF-α拮抗剂(TNFi)能有效控制类风湿关节炎(RA)患者的临床症状和体征。既往有研究提示血清低谷浓度(serum trough level, STL)的TNF-α与疗效较差有相关性。

目的: 确定阿达木单抗(ADL)和依那西普(ETN)在RA患者中的STL, 并建立能区分临床缓解和低活动度的的STL界值。

方法: 本研究分析对象来自2项研究。其一是一项前瞻性、多中心研究(INMUNOREMAR), 共91例。其二为某队列研究(患者基线时DAS28≤3.2), 这些患者接受ADL或ETN治疗, 其中有36例由于病情加重(DAS28均大于3.2)而接受免疫原性检查。本研究对这127例患者进行横断面分析。抗药抗体和STL的检测采用Promonitor ELISA试剂盒(Progenika Biopharma, 西班牙)。采用Mann Whitney U检验比较不同疾病活动度患者的STL。采用Spearman检查分析STL与DAS28之间相关性。阿达木单抗和依那西普STL对临床缓解(DAS28≤2.6)和低活动度(DAS28≤3.2)的判别准确性和分辨力, 通过ROC曲线下面积(ROC-AUC)加以分析。

结果: 127例患者中位数年龄为61岁, 女性比例为81.9%, 中位数病程为13年, TNFi平均疗程为60个月, 接受ADL、ETN治疗的分别为57例和73例, 单药治疗比例为29.9%, 生物制剂减量治疗的占27.6%。临床缓解的患者比例为55.9%, 临床缓解+低活动度的患者比例为71.7%。有4例ADL治疗患者检出抗药抗体。与未获临床缓解者相比, 获临床缓解者的ADL和ETN的STL明显较高(阿达木单抗的STL(中位数(P25-P75)): 6.9 (2.7-12) vs. 0.5 (0.1-1), p <0.001; 依那西普的STL: 2.3 (1.5- 3.1) vs. 0.8 (0.4-1.8); p <0.001)。比较DAS28≤3.2和DAS28>3.2的患者, 也获得相似结果。还观察到STL与DAS28之间呈显著的负相关(阿达木单抗: rho = 0.5, p <0.0001, 依那西普rho = 0.37, p <0.001)。以DAS28缓解为参考变量的准确性分析显示阿达木单抗的AUC界值为0.81(95%CI: 0.68-0.94), 敏感性为81.9%, 特异性为91%, 依那西普的AUC界值为0.747(95%CI: 0.68-0.85), 敏感性为71.1%, 特异性为71.4%。阿达木单抗STL对临床缓解的最大分辨力为1.336 mg/mL, 依那西普为1.56 mg/mL。以DAS28定义的临床缓解+低活动度为参考变量, 阿达木单抗的AUC界值为0.863(95%CI: 0.73-0.99), 敏感性为78.9%, 特异性为93.8%, 依那西普的AUC界值为0.876(95%CI: 0.80-0.95), 敏感性为81.1%, 特异性为80%。两药STL对临床缓解/低活动度的最大分辨力分别为阿达木单抗1.336 mg/mL、依那西普1.073 mg/mL。

结论: 与病情活动患者相比, 获临床缓解和低活动度的RA患者的阿达木单抗和依那西普的血药谷浓度较高。本研究确立了分辨力较高、能够区分RA临床缓解和低活动度的TNFi血药谷浓度的界值。