FRI0109 Drug immunogenicity and the development of paradoxical adverse events with biologic therapies

Abstract

Background: Defined as De novo or exacerbation of pathologies that usually responds to biologic agents, paradoxical reactions encompass for a wide spectrum of manifestations (cutaneous, intestinal, ocular) reported during biological therapy (TNF and non-TNF medications) regardless of the underlying rheumatic or non-rheumatic disorder. Objectives: To assess drug levels (DL) and anti-drug antibodies (ADA) in patients with paradoxical reactions (de novo or exacerbation of psoriasis, uveitis, Crohn's disease) induced by biological drugs (bDMARS) in Rheumatoid Arthritis (RA), Ankylosing Spondylitis (AS) and Psoriatic Arthritis (PsA). Methods: We performed a retrospective observational study in cohorts of consecutive RA (267), PSA (65) and AS (145) undergoing TNF (i-TNF) or non-TNF biologics according to the local recommendations for initiation and monitoring, attending a single academic rheumatology department. All patients were assessed at every 24 weeks months for disease activity and outcomes; supplementary, drug immunogenicity (ADA and DL) was systematically evaluated in patients developing paradoxical adverse events. DL and ADA were measured with an ELISA assay and antibody binding test, respectively. Serum drug levels were considered positive for infliximab if >0.035 μg/mL, for adalimumab >0.024 μg/mL, for etanercept >0.035 μg/mL, rituximab >0.75 μg/mL, while the cut-offs for ADA positivity to infliximab was established at 5AU/ml, for adalimumab at 10AU/mL, etanercept at 142 AU/mL, rituximab 140 AU/mL (ELISA, Progenika) Results: 42 patients with paradoxical psoriasis (30 with De novo lesions, 18 with palmo-plantar pustulosis, 12 with exacerbation of pre-existent lesions), 12 with paradoxical uveitis (5 with a new onset uveitis) and 3 with paradoxical Crohn's were included in the final analysis. Paradoxical events related to abatacept, certolizumab (one De novo psoriasis per agent) or golimumab (2 new onset uveitis, one flare of Chron's disease) were excluded from the final analysis as no immunogenicity lab tests were provided. Drug induced paradoxical events were described not only with all TNF inhibitors but also with rituximab. DL was in normal range in all these patients; in addition, ADA were either negative, or, if present, had no impact on drug concentration. Furthermore, we found no significant differences in drug levels of TNF inhibitors for RA, PsA and AS. Moreover, no statistical significant differences were observed in the detection of ADA between the three groups. Conclusions: Patients who develop either true or borderline paradoxical AE have adequate drug levels, with normal ADA concentrations.