Background Differences in drug survival between anti-TNF agents (aTNF) have been attributed to variations in molecular structure leading to increased immunogenicity, in particular between chimeric and fully human monoclonal antibodies (MABs) and between MABs and soluble receptor antagonists (CEPTs). Synthetic DMARDs, such as methotrexate, have shown to delay the development of anti-drug antibodies and increase aTNF retention. Faced with secondary loss of effectiveness, clinicians may increase drug dosage, initiate new co-therapies (glucocorticoids, other DMARDs) or discontinue aTNF.
Objectives To investigate the time until aTNF drug adjustments attributable to secondary loss of effectiveness, such as drug discontinuation due to ineffectiveness, drug ‘dose creep’ (either by shortening of dosing intervals or increasing dosage) or significant increases in comedications.
Methods All patients who have received a first dose aTNF were retrieved from the SCQM cohort. The primary end point was drug adjustments attributable to aTNF secondary loss of effectiveness, which was operationally defined as a composite of (1.) aTNF discontinuation due to ineffectiveness, (2.) aTNF dose increase (in frequency or in total dose) or (3.) a major increase in co-therapy (initiation of - or doubling in the dose of - DMARD cotherapy or oral glucocorticoids) occurring after 6 months of aTNF therapy. The primary exposure of interest was the type of aTNF agent, specifically MAB aTNFs (Infliximab, Adalimumab, Golimumab) versus CEPTs (Etanercept). We performed a ‘time-to-event analysis’ using a Cox proportional hazards model, adjusting for potential confounders, such as concomitant use of DMARDs and oral glucocorticoids, calendar year, and various disease characteristics.
Results We identified 4796 treatment courses of aTNF therapy (3116 with MABs and 1680 with CEPTs), 1626 drug adjustments attributable to aTNF secondary loss of effectiveness (819 increases in co-therapy, 579 aTNF discontinuations, 180 aTNF dose increase) contributing a total of 7185 patient-years of aTNF use. No major differences existed in baseline characteristics, except for more patients on aTNF monotherapy in the CEPT group (28% vs 18%, p < 0.001) and more patients on MTX in the MAB group (64% vs 54%, p < 0.001).
The overall incidence of drug adjustments attributable to aTNF secondary loss of effectiveness was significantly higher in the MAB group (adjusted Hazard Ratio (HR) for MABs: 1.21 [95% CI: 1.09 – 1.34]) than in the CEPT group. The median crude drug survival was 30 months (IQR: 14 - 70) for MABs and 36 months (IQR: 15 – 88) on CEPTs.
Conclusions Drug adjustments attributable to secondary loss of effectiveness occur significantly more frequently with MAB than with CEPT aTNF agents.
Acknowledgements Unrestricted research grant from Pfizer
Disclosure of Interest S. Martin-du-Pan: None Declared, D. Neto: None Declared, P. Zufferey: None Declared, A. Ciurea: None Declared, H. Ziswiler: None Declared, C. Gabay: None Declared, A. Finckh Grant/research support from: unrestricted reserach grant from Pfizer