4 The clinical relevance of immunogenicity in a long-term follow-up cohort of adalimumab treated rheumatoid arthritis patients

Context. Short term data on the immunogenicity of monoclonal antibodies showed associations between the development of anti-drug antibodies and diminished serum drug levels and a diminished treatment response. Little is known about the clinical relevance of anti-drug antibodies against these drugs during long-term follow-up. Objective. To examine the course of anti-drug 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. All two-hundred-seventy-two consecutive RA patients with active disease treated with adalimumab in an outpatient clinic were enrolled in a prospective observational cohort study between February 2004 and September 2008 at the initiation of treatment. Main Outcome Measures. The disease activity was monitored at baseline and 4, 16, 28, 40, 52, 78, 104, 130 and 156 weeks. Trough serum samples were obtained at all visits. Serum adalimumab concentrations and anti-adalimumab antibody titres were determined at the end of follow-up using an ELISA and RIA, respectively. Patients were defined as positive for anti-adalimumab antibodies if titres were above 12 AU/ml on at least one occasion, in combination with serum adalimumab levels below 5.0 mg/L. Treatment discontinuation and the achievement of minimal disease activity and clinical remission was compared for patients with and without anti-drug antibodies. Results. After three years 76 out of 272 patients (28%) developed antibodies against adalimumab (AAA), of whom 51 patients (67%) developed AAA during the first 28 weeks of treatment. Patients without AAA had significantly higher adalimumab concentrations compared to patients with both antibody titres from 13 to 100 AU/ml (p<0.0001) and higher than 100 AU/ml (p<0.0001). Patients with AAA more often dropped out of the study due to treatment failure (p<0.0001) and less often achieved minimal disease activity (DAS28<3.2; p<0.0001) and clinical remission (DAS28<2.6; p<0.0001) compared to patients without AAA. Conclusions. The development of anti-drug antibodies jeopardizes the long-term efficacy of adalimumab treatment in rheumatoid arthritis patients in clinical practice. Therefore, monitoring of serum drug levels and anti-drug antibody titres in daily routine practice is recommended to adjust treatment regimens towards achieving long-term treatment goals. The clinical relevance of immunogenicity