长期应用阿达木单抗时所产生的抗抗体会影响疗效

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JAMA. 2011;305(14):1460-1468. doi: 10.1001/jama.2011.406   Development of Antidrug Antibodies Against Adalimumab and Association With Disease Activity and Treatment Failure During Long-term Follow-up 1.       Geertje M. Bartelds, MD; 2.       Charlotte L. M. Krieckaert, MD; 3.       Michael T. Nurmohamed, MD, PhD; 4.       Pauline A. van Schouwenburg, MSc; 5.       Willem F. Lems, MD, PhD; 6.       Jos W. R. Twisk, PhD; 7.       Ben A. C. Dijkmans, MD, PhD; 8.       Lucien Aarden, PhD; 9.       Gerrit Jan Wolbink, MD, PhD [+] Author Affiliations 1.       Author Affiliations: Jan van Breemen Research Institute (Drs Bartelds, Krieckaert, Nurmohamed, and Wolbink); VU Medical Center (Drs Nurmohamed, Lems, Twisk, and Dijkmans); and Sanquin Research and Landsteiner Laboratory Academic Medical Centre (Ms van Schouwenburg and Drs Aarden and Wolbink), Amsterdam, the Netherlands. Abstract Context 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. Objective 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. Main Outcome Measures 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. Results 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. Conclusion 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.	长期应用阿达木单抗时所产生的抗抗体会影响疗效 Bartelds GM, et al. JAMA. 2011;305:1460-8.     背景: 短期治疗数据显示单克隆抗体(单抗)免疫原性所致抗药物抗体(抗抗体)与血药浓度和疗效降低有关联。而目前缺乏长期治疗时抗药物抗体的临床意义。 目的: 检验全人化单抗阿达木治疗类风湿关节炎(RA)达3年时抗抗体的形成及其临床意义。 研究设计和病人: 在2004年2月至2008年9月开展前瞻性研究，随访结束于2010年9月。确诊为RA的所有272例病人在门诊接受阿达木单抗治疗。 重要观察结局: 在基线及整个156周观察期内8个随访时间点，评估病情活动度，采集血样以备随访结束后检测阿达木单抗血液波谷浓度和抗抗体水平。治疗结束后，比较有和无抗抗体病人的最小疾病活动度(MDA)以及临床缓解情况。 结果: 3年治疗后，272例病人中被检出抗抗体的病人有76例(28%)，其中51例出现于头28周。无抗抗体的病人的阿达木单抗血药水平 (中位数: 12 mg/L; IQR: 9～16 mg/L)高于抗抗体滴度为13至100 AU/mL的病人(中位数: 5 mg/L; IQR: 3～9 mg/L; 回归系数: −4.5; 95% CI: −6.0～−2.9; P < .001)，也高于抗抗体滴度超过100 AU/mL的病人(中位数: 0 mg/L; IQR: 0～3 mg/L; 回归系数: −7.1; 95% CI: −8.4～-5.8; P < .001)。抗抗体阳性病人常常由于治疗无效而停用药物(n = 29 [38%]; 风险比[HR]: 3.0; 95% CI: 1.6～5.5; P < .001)，而无抗抗体的病人中因无效而停用的仅有28例(14%)。无抗抗体的196例病人中有95例(48%)达到MDA，而抗抗体阳性病人获得MDA的病例数为10/76(13%)。抗抗体阳性患者获得持续低活动(DAS28<3.2)的病人数较少(HR: 3.6, 95%CI: 1.8～7.2, P<.001)。 抗抗体阳性者中仅有3 / 76 (4%)获得临床持续缓解，而抗抗体阴性者有67 / 196 (34%)。达到临床缓解(DAS28<2.6)的抗抗体阳性病人病例较低( HR: 7.1; 95%CI: 2.1～23.4; P<.001)。 结论: 门诊接受阿达木单抗治疗3年期间，抗药物抗体的产生与阿达木单抗血药浓度下降以及获得低活动度或临床缓解的可能性降低有关联性。       `