Prospective Observational Evaluation of Time-Dependency of Adalimumab Immunogenicity and Drug Concentrations: The Poetic Study

Bella Ungar, Tal Engel, Doron Yablecovitch, Adi Lahat, Alon Lang, Benjamin Avidan, Ofir Har-Noy, Dan Carter, Nina Levhar, Limor Selinger, Sandra Neuman, Ola Haj Natour, Miri Yavzori, Ella Fudim, Orit Picard, Uri Kopylov, Yehuda Chowers, Timna Naftali, Efrat Broide, Eyal ShacharRami Eliakim, Shomron Ben-Horin

Research output: Contribution to journalArticlepeer-review

Abstract

Objectives: Adalimumab is usually self-injected at home, making prospective serial-sampling studies challenging and scarce. This has led to a gap in knowledge about evolution of anti-adalimumab antibodies (AAAs) over time and its correlation with clinical and inflammatory outcomes. Methods: A program for home visits by physicians at induction, every 3 months and at event of relapse, was established prospectively for Crohn's disease (CD) patients. At each visit, patients' clinical scores were determined and sera were obtained for C-reactive protein, drug, and AAA levels. This cohort was compared to a parallel prospective cohort of infliximab-treated CD patients. In a subgroup of 29 patients, trough and in-between-trough levels were compared, to elucidate the importance of timing of sampling during the injection cycle. Results: Ninety-eight CD patients starting adalimumab were prospectively followed (median follow-up 44 weeks) and 621 serum samples were analyzed. Thirty-three patients (32%) developed AAA; 18/33 (55%) of them as early as week 2, and 26/33 (79%) by week 14. Induction period AAAs were strongly associated with primary non-response (odds ratio (OR) = 5.4, 95% confidence interval (CI): 1.6-17.8, p = 0.005). As compared to antibodies-to-infliximab (ATI), AAA formation rate over time was significantly lower (p = 0.01) and AAA were much more specific - 85% of AAA events were associated with loss-of-response compared with 58% rate for ATI (p = 0.01). In 29 patients sampled serially during an injection cycle, levels of drug and AAA seemed comparable between four time-points during a single cycle both in patients with or without AAA (n = 8, n = 21, respectively). Conclusions: When followed prospectively and serially, AAAs are found to arise earlier than previously appreciated and their impact may be more pronounced for primary rather than secondary, non-response. Drug and AAA levels were similar both at trough and in-between injections, enabling to simplify therapeutic drug monitoring of adalimumab.

Original languageEnglish
Pages (from-to)890-898
Number of pages9
JournalAmerican Journal of Gastroenterology
Volume113
Issue number6
DOIs
StatePublished - 1 Jun 2018

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