FM - Teses de Doutoramento
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Browsing FM - Teses de Doutoramento by advisor "Aarden, Lucien"
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- The clinical relevance of drug immunogenicityPublication . Gama, Sandra Pinheiro Garcês da, 1977-; Demengeot, Jocelyne; Graça, Luís, 1971-; Aarden, LucienThe introduction of biologic therapies into clinical practice has greatly improved the treatment of chronic disabling inflammatory diseases, such as Rheumatoid Arthritis, Spondylarthritis or Inflammatory Bowel Diseases, among others. However, a sizeable fraction of patients never achieve therapeutic response or, more often, cannot maintain therapeutic response over time. Among the pitfalls of biologicals is their potential immunogenicity and the associated anti-drug antibodies (ADAb) produced by the patients, which promote faster clearance/neutralization of the drug in circulation and thus interfere with drug efficacy. Moreover, ADAb have also been associated with adverse events. In this work we aimed at formally document the impact of ADAb in clinical outcomes, and use this analysis to construct and test an algorithm for therapeutic decisions based on explicit biomarkers of immunogenicity. To evaluate the clinical relevance of biological drug’s immunogenicity, we first performed a systematic review of the literature coupled with a meta-analysis. We evidenced that in the presence of detectable ADAb therapeutic response may be reduced by as much as 80%. Such impact is attenuated, although not abrogated, by concomitant immunosuppression, particularly with methotrexate that associates with reduced ADAb production. Differences in the immunogenic profile of specific biologics were also verified, with monoclonal antibodies exhibiting higher immunogenicity than fusion proteins. We next assessed the impact of immunogenicity on drug’s safety profile by following a cohort of patients receiving intravenous infliximab, a TNF-inhibitor. Infusion-related adverse events occurred exclusively in ADAb-positive patients and nearly half of the ADAb-positive patients developed an acute reaction during or immediately after the infusion, requiring medical intervention. To evaluate the relevance of drug immunogenicity assessment for therapeutic decisions, we first defined a convenient method to assess immunogenicity on a routine basis. We verified that a newly developed Bridging ELISA performed as well as antigen-binding radio-immuno assay, currently considered by many as the “gold-standard” to assess ADAb. Next, we designed an algorithm for the management of patients receiving biologic therapies, which combines the usual clinical evaluation with immunogenicity assessment at every three months. This algorithm was tested in a cohort of RA patients treated with one of the three most commonly used biologics. We evidenced that patients who followed therapeutic strategies concordant with the proposed algorithm had close to 10-times higher probability of achieving low disease activity, when compared to those who followed other strategies commonly adopted in current clinical practice. Our work demonstrates that a personalized, evidence-based approach for the management of patients receiving biologic therapies will lead to safer and most cost-effective strategies. These findings have important clinical, societal and economic consequences.