Development of Antidrug Antibodies Against Adalimumab and Association With Disease Activity and Treatment Failure During Long-term Follow-up

TLDR

Abstract

<h3>Context</h3>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.<h3>Objective</h3>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).<h3>Design, Setting, and Patients</h3>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.<h3>Main Outcome Measures</h3>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.<h3>Results</h3>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 &lt; .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 &lt; .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 &lt; .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) (&lt; 3.2; HR, 3.6; 95% CI, 1.8-7.2; P &lt; .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 &lt; 2.6; HR, 7.1; 95% CI, 2.1-23.4; P &lt; .001) compared with antiadalimumab antibody–negative ones.<h3>Conclusion</h3>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.