High frequency of antidrug antibodies and association of random drug levels with efficacy in certolizumab pegol-treated patients with rheumatoid arthritis: results from the BRAGGSS cohort

Abstract

ObjectivesTo evaluate (i) the association between random certolizumab drug levels, antidrug antibodies (ADAbs) and treatment response in patients with rheumatoid arthritis (RA); (ii) longitudinal factors associated with ADAbs and certolizumab drug levels.MethodsThis prospective cohort included 115 patients with RA treated with certolizumab. Serum samples were collected at 3, 6 and 12 months following treatment initiation. Drug levels and ADAbs were measured using ELISA and radioimmunoassay, respectively, at 3, 6 and 12 months. Disease Activity Score in 28 joints (DAS28) were measured at each visit and 12 months European League Against Rheumatism (EULAR) response was calculated. Patient self-reported adherence was collected longitudinally. Ordinal logistic regression and generalised estimating equation were used to test the association: (i) between drug levels, from serum sampled and treatment response; (ii) between ADAbs and drug levels; (iii) patient-centred factors and drug levels.ResultsADAbs were detected in 37% (42/112 patients by 12 months). The presence of ADAbs were significantly associated with lower drug levels over 12 months (β=−0.037, 95% CI −0.055 to 0.018, p<0.0001) but not independently with 12 months EULAR response (β=0.0013 (95% CI −0.0032 to 0.00061), p=0.18). Drug level was associated with 12 months EULAR response (β=0.032 (95% CI 0.0011 to 0.063), p=0.042). In the multivariate model, ADAb level and adherence were significantly associated with drug concentrations.ConclusionsThis is the first study to demonstrate that higher certolizumab drug levels are associated with better 12 months EULAR response. ADAbs in certolizumab-treated patients with RA were detected at higher levels than previous studies and help determine the aetiology of a low drug level.

Practical recommendations for the use of therapeutic drug monitoring of biopharmaceuticals in inflammatory diseases

“…The impact of ADA on exposure and response has been reported for infliximab, adalimumab and golimumab 49,90,94. ADA toward certolizumab pegol were associated with lower drug concentration but not with a lower clinical response 92. Furthermore, ADA have been detected toward etanercept (although non-neutralizing antibodies), rituximab, tocilizumab and abatacept, but no impact on drug exposure and response has been observed 18,31,91,95,96.…”

What Is the Clinical Relevance of TNF Inhibitor Immunogenicity in the Management of Patients With Rheumatoid Arthritis?

“…Trough TNFi drug levels exhibit a "concentration-response" relationship (4) (an inverse correlation with clinical outcomes), which forms the basis for the rationale for TDM in RA. This has been observed in studies of the key TNFis used in clinical practiceincluding infliximab (5-10), adalimumab (11), etanercept (12,13), golimumab (14), and certolizumab (15,16).…”

The Potential Benefits of Certolizumab Pegol in Patients with Concurrent Psoriatic Arthritis and Chronic Plaque Psoriasis: A Case Series and Review of the Literature

“…We were able to demonstrate efficacy with certolizumab in one patient who we showed low adalimumab drug levels associated with ADAbs to adalimumab, but no other patients in this case series had this additional testing. The presence of ADAbs has been associated with decreased treatment efficacy with both infliximab and adalimumab although not etanercept [ 22 – 26 ]. In certolizumab, the presence of ADAbs and the impact on clinical efficacy remain uncertain as several papers have identified higher levels of circulating antibody than would be expected; however, it has been postulated that this may be secondary to the presence of the Fab fragment which is monovalent; thus, drug–ADAb complexes easily dissociate and can therefore be more easily detected [ 26 ].…”