Immunogenicity of certolizumab pegol without concomitant methotrexate and clinical response in rheumatoid arthritis patients: post-hoc analysis of the HIKARI study

Background Immunogenicity and subsequent reduction in clinical response is an issue for biological agents in rheumatoid arthritis (RA) treatment. Objectives To assess immunogenicity and clinical response to certolizumab pegol (CZP), a PEGylated Fc‐free anti‐TNF, in RA patients (pts) without concomitant methotrexate (MTX). Methods Post‐hoc analysis of a 24���wk, double‐blind (DB) study of CZP 200mg without concomitant MTX (HIKARI study) and subsequent open‐label extension (OLE) in Japanese pts with active RA (116 pts).1 Results Anti‐CZP antibodies (Abs) were detected in 18 pts (15.5%) at any visit during the first 24 wks. Two anti‐CZP profiles were observed: 1) Abs peaked between Wk8‐Wk12 (early development, n=7); 2) Abs peaked at/after Wk24 (late development, n=11) (Figure). In 6 pts with early development, anti‐CZP Abs decreased to below threshold (<=2.4units/mL) at Wk24, and their plasma CZP level increased at Wk24 (median CZP concentration of 7.7mug/ml), following a drop at Wk8 (35.3 and 2.2mug/ml at Wk6 and Wk8, respectively). In contrast, in pts with late development, Abs appeared mostly at Wk24, and plasma CZP level slowly decreased from Wk8 (median CZP concentrations 27.5 and 2.4mug/ml at Wk8 and Wk24, respectively). ACR20/ACR50/ACR70 responses of early development pts (n=7) were greater than those with late development (n=11) (Table). These results suggest that early, transient development of anti‐CZP Abs was not associated with poor long‐term clinical response, whereas later development led to loss of response. This observation suggests that when anti‐CZP Abs with low affinity to CZP are developed early, they may be adsorbed by the high level of plasma CZP. In contrast, late‐developed anti‐CZP Abs may reside longer and lead to sustained drug clearance, similar to Abs against other anti‐TNF biologics. Conclusions Anti‐CZP Abs were detected in 15.5% of RA pts during 24 wks of treatment without concomitant MTX. Better long‐term clinical responses were observed in patients with early vs late anti‐CZP Abs development. (Table Presented).