Jan van Breemen Research Institute, Amsterdam, The Netherlands.
JAMA. 2011 Apr 13;305(14):1460-8. doi: 10.1001/jama.2011.406.
Short-term data on the immunogenicity of monoclonal antibodies showed associations between the development of antidrug antibodies and diminished serum drug levels, and a diminished treatment response. Little is known about the clinical relevance of antidrug antibodies against these drugs during long-term follow-up.
To examine the course of antidrug antibody formation against fully human monoclonal antibody adalimumab and its clinical relevance during long-term (3-year) follow-up of patients with rheumatoid arthritis (RA).
DESIGN, SETTING, AND PATIENTS: Prospective cohort study February 2004-September 2008; end of follow-up was September 2010. All 272 patients were diagnosed with RA and started treatment with adalimumab in an outpatient clinic.
Disease activity was monitored and trough serum samples were obtained at baseline and 8 time points to 156 weeks. Serum adalimumab concentrations and antiadalimumab antibody titers were determined after follow-up. Treatment discontinuation, minimal disease activity, and clinical remission were compared for patients with and without antiadalimumab antibodies.
After 3 years, 76 of 272 patients (28%) developed antiadalimumab antibodies--51 of these (67%) during the first 28 weeks of treatment. Patients without antiadalimumab antibodies had much higher adalimumab concentrations (median, 12 mg/L; IQR, 9-16 mg/L) compared with patients with antibody titers from 13 to 100 AU/mL (median, 5 mg/L; IQR, 3-9 mg/L; regression coefficient, -4.5; 95% CI, -6.0 to -2.9; P < .001) and also those greater than 100 AU/mL (median, 0 mg/L; IQR, 0-3 mg/L; regression coefficient, -7.1; 95% CI, -8.4 to -5.8; P < .001). Patients with antiadalimumab antibodies more often discontinued participation due to treatment failure (n = 29 [38%]; hazard ratio [HR], 3.0; 95% CI, 1.6-5.5; P < .001) compared with antiadalimumab antibody-negative ones (n = 28 [14%]). Ninety-five of 196 patients (48%) without antiadalimumab antibodies had minimal disease activity vs 10 of 76 patients (13%) with antiadalimumab antibodies; patients with antiadalimumab antibodies less often had sustained minimal disease activity score in 28 joints (DAS28) (< 3.2; HR, 3.6; 95% CI, 1.8-7.2; P < .001) compared with antiadalimumab antibody-negative ones. Three of 76 patients (4%) with antiadalimumab antibodies achieved sustained remission compared with 67 of 196 (34%) antiadalimumab antibody-negative ones; patients with antiadalimumab antibodies less often achieved remission (DAS28 < 2.6; HR, 7.1; 95% CI, 2.1-23.4; P < .001) compared with antiadalimumab antibody-negative ones.
Among outpatients with RA in whom adalimumab was started over 3 years, the development of antidrug antibodies was associated with lower adalimumab concentration and lower likelihood of minimal disease activity or clinical remission.
单克隆抗体的短期免疫原性数据表明，抗药物抗体的产生与血清药物水平降低和治疗反应减弱有关。关于这些药物的长期（3 年）随访中抗药物抗体的临床相关性知之甚少。
检查类风湿关节炎（RA）患者在阿达木单抗的完全人源单克隆抗体的长期（3 年）随访中抗药物抗体形成的过程及其临床相关性。
设计、设置和患者：2004 年 2 月至 2008 年 9 月的前瞻性队列研究；随访结束时间为 2010 年 9 月。所有 272 例患者均被诊断为 RA，并在门诊接受阿达木单抗治疗。
疾病活动度监测，在基线和 8 个时间点至 156 周时获得最低血清样本。随访后确定血清阿达木单抗浓度和抗阿达木单抗抗体滴度。比较有无抗阿达木单抗抗体患者的停药、最小疾病活动度和临床缓解情况。
3 年后，272 例患者中有 76 例（28%）产生了抗阿达木单抗抗体，其中 51 例（67%）在治疗的前 28 周内产生。无抗阿达木单抗抗体的患者阿达木单抗浓度明显更高（中位数，12 mg/L；IQR，9-16 mg/L），与抗体滴度为 13 至 100 AU/mL 的患者相比（中位数，5 mg/L；IQR，3-9 mg/L；回归系数，-4.5；95%CI，-6.0 至-2.9；P<0.001），以及抗体滴度大于 100 AU/mL 的患者相比（中位数，0 mg/L；IQR，0-3 mg/L；回归系数，-7.1；95%CI，-8.4 至-5.8；P<0.001）。与抗阿达木单抗抗体阴性患者相比（n=28，14%），有抗阿达木单抗抗体的患者因治疗失败而更常停止参与研究（n=29，38%；HR，3.0；95%CI，1.6-5.5；P<0.001）。196 例无抗阿达木单抗抗体的患者中有 95 例（48%）达到最小疾病活动度，而 76 例有抗阿达木单抗抗体的患者中有 10 例（13%）达到最小疾病活动度；与抗阿达木单抗抗体阴性患者相比，有抗阿达木单抗抗体的患者在 28 个关节中较少出现持续的最小疾病活动度评分（<3.2；HR，3.6；95%CI，1.8-7.2；P<0.001）。有 3 例（4%）有抗阿达木单抗抗体的患者达到持续缓解，而 196 例（34%）抗阿达木单抗抗体阴性的患者有 67 例达到缓解；与抗阿达木单抗抗体阴性患者相比，有抗阿达木单抗抗体的患者较少达到缓解（DAS28<2.6；HR，7.1；95%CI，2.1-23.4；P<0.001）。
在接受阿达木单抗治疗 3 年以上的 RA 门诊患者中，抗药物抗体的产生与阿达木单抗浓度降低和最小疾病活动度或临床缓解的可能性降低有关。
