Pediatric Rheumatology Unit, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, SP, Brazil.
Division of Rheumatology, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Av. Dr. Arnaldo, 455, 3rd floor, room 3190 - Cerqueira Cesar, São Paulo, SP, 05403010, Brazil.
Clin Rheumatol. 2020 Feb;39(2):515-521. doi: 10.1007/s10067-019-04798-6. Epub 2019 Nov 9.
To assess the longitudinal production of anti-adalimumab antibody (AAA) and baseline risk factors for this antibody development in juvenile idiopathic arthritis (JIA) patients initiating adalimumab (ADA).
Thirty consecutive JIA patients under ADA therapy were prospectively followed. JIA clinical/laboratorial/treatment data and sera for ADA and AAA assays (ELISA and bridging ELISA) were obtained at baseline (BL), 2 months (2M), 3 months (3M), 6 months (6M), 12 months (12M), and 24 months (24M). Patients with therapy failure requiring ADA withdrawn had their sera evaluated at their last medical visit prior to biologic switch (blinded to ADA and AAA levels).
AAA was absent at BL, first detected at 2M after ADA initiation in 2/30 (7%) patients with a significant increase at 3M (10/29 (34%), p = 0.013) and no major change in 6M (11/30 (37%)) and 12M (9/26 (35%)). Of note, at 3M, AAA levels correlated negatively with ADA levels (r = - 0.781, p = 0.0001). Analysis of BL predictors revealed a significantly higher risk of developing AAA in patients with female gender (OR 21; 95% CI 1.08-406.57; p = 0.044), ESR > 30 mm/1st hour (OR 5.44; 95% CI 1.04-28.53; p = 0.045), and leflunomide use (OR 9.33; 95% CI 1.51-57.66; p = 0.016). In contrast, concomitant use of methotrexate was protective for AAA appearance (OR 0.08; 95% CI 0.01-0.53; p = 0.009). After 12M of ADA, 60% of AAA-positive patients required drug switch for drug failure compared with 15% in AAA-negative group (p = 0.03).
This study provides novel evidence of AAA production kinetics demonstrating a timely significant increase starting at 3M and stable throughout 24M. We also identified female gender, increased ESR, and leflunomide use as relevant risk factors for AAA production at BL, whereas methotrexate was protective. Early systematic monitoring of AAA at 3M may, therefore, guide drug switching in these patients.Key Points• Anti-adalimumab antibodies (AAA) production kinetics demonstrated a timely significant increase starting at 3M in juvenile idiopathic arthritis (JIA) patients under adalimumab therapy• Female gender, increased ESR, and leflunomide use were identified as relevant risk factors for AAA production in JIA, whereas methotrexate was protective.
评估接受阿达木单抗（ADA）治疗的幼年特发性关节炎（JIA）患者中抗阿达木单抗抗体（AAA）的纵向产生情况，以及该抗体产生的基线风险因素。
连续前瞻性随访 30 例接受 ADA 治疗的 JIA 患者。在基线（BL）、2 个月（2M）、3 个月（3M）、6 个月（6M）、12 个月（12M）和 24 个月（24M）时获得 JIA 临床/实验室/治疗数据以及 ADA 和 AAA 检测（ELISA 和桥接 ELISA）的血清。在需要停用 ADA 的治疗失败的患者中，在进行生物转换之前的最后一次就诊时评估他们的血清（对 ADA 和 AAA 水平进行盲法评估）。
AAA 在 BL 时不存在，在 ADA 起始后 2M 首次检测到 2/30（7%）例患者中存在，在 3M 时显著增加（10/29（34%），p=0.013），在 6M（11/30（37%））和 12M（9/26（35%））时无明显变化。值得注意的是，在 3M 时，AAA 水平与 ADA 水平呈负相关（r=-0.781，p=0.0001）。BL 预测因素分析显示，女性（OR 21；95%CI 1.08-406.57；p=0.044）、ESR＞30mm/1h（OR 5.44；95%CI 1.04-28.53；p=0.045）和使用来氟米特（OR 9.33；95%CI 1.51-57.66；p=0.016）的患者发生 AAA 的风险显著更高。相比之下，同时使用甲氨蝶呤对 AAA 出现具有保护作用（OR 0.08；95%CI 0.01-0.53；p=0.009）。ADA 治疗 12M 后，AAA 阳性患者中有 60%因药物失效需要药物转换，而 AAA 阴性组为 15%（p=0.03）。
本研究提供了 AAA 产生动力学的新证据，表明从 3M 开始及时出现显著增加，并在 24M 时保持稳定。我们还发现女性、ESR 升高和使用来氟米特是 BL 时 AAA 产生的相关风险因素，而甲氨蝶呤具有保护作用。因此，早期在 3M 时系统监测 AAA 可能有助于指导这些患者的药物转换。
ADA 治疗的幼年特发性关节炎（JIA）患者中，抗阿达木单抗抗体（AAA）的产生动力学显示从 3M 开始及时出现显著增加。
女性、ESR 升高和使用来氟米特是 JIA 中 AAA 产生的相关风险因素，而甲氨蝶呤具有保护作用。
