Background Anti-TNF drugs are an effective treatment option for rheumatoid arthritis (RA) patients (pts) but have been associated with an increased incidence of serious infectious events (SIEs).1,2 Using only baseline (BL) data, we previously identified pharmacologically-treated comorbidity and systemic steroid use (regardless of dose) as risk factors for SIEs in RA pts treated with certolizumab pegol (CZP).3 Because RA disease activity, flare patterns, systemic inflammation and disability status may change over time, it is important to assess static and dynamic risk factors for the incidence of SIEs.
Objectives To identify time-dependent risk factors for SIEs in CZP-treated RA pts, using data pooled from the RAPID1 and RAPID2 randomized controlled trials (RCTs; NCT00152386/NCT00160602)4,5 and respective open-label extensions (OLEs; NCT00175877/NCT00160641).6
Methods Statistical analyses were performed on anti-TNF/biologic-naïve pts using data recorded between first CZP dose and up to 84 days after last CZP dose or pt withdrawal. A non-sequential stepwise multivariate Cox proportional hazards model (selection criteria: entry p≤0.2, stay p≤0.25)7 was used to estimate the relative risk of pt covariates to all SIEs.2 BL covariates included age (<65;≥65 yrs), BMI (<20;20–30;>30 kg/m2), disease duration (<2;≥2 yrs), log(mTSS), pharmacologically-treated comorbidity (diabetes, COPD or cardiac disorder), MTX dose (≤15;>15 mg/week) and systemic steroid dose (0;≤5;>5 mg/day). During the CZP exposure period, time-dependent (TD) covariates recorded at each pt visit (≤12 wk intervals) included DAS28(CRP;ESR), HAQ-DI and flare >1.2 in DAS28(CRP) compared to the previous visit (yes/no). Each TD covariate was added to the Cox model separately, while keeping BL covariates that satisfied the selection criteria. The final Cox model included all covariates that satisfied the selection criteria.
Results 201/1506 CZP-treated pts reported ≥1 SIE; 29 pts experienced >1 SIE. Over time (max: 6.40 pt-yrs; median: 4.79 pt-yrs), the occurrence of flare in DAS28(CRP) or a unit increase in HAQ-DI, DAS28(CRP) or DAS28(ESR) scores were individually associated with a greater risk of SIEs (Figure A). In the final Cox model, age ≥65 yrs, treated comorbidity, flare and HAQ-DI were identified as risk factors for SIEs (Figure B). No other covariates examined were clinically relevant to the outcome.
Conclusions In CZP-treated RA pts, age ≥65 yrs and a treated comorbidity increased the risk of SIEs by ∼50% and ∼80%, respectively. Over time, higher disease activity increased the risk of SIEs as shown by concomitant measurement of DAS28(CRP;ESR) and HAQ-DI. Notably, pts experiencing a flare had more than double the risk of SIEs. Results suggest that reducing disease activity with optimal treatment may help to decrease the long-term risk of SIEs in CZP-treated RA pts.
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Acknowledgements The authors acknowledge Costello Medical Consulting for writing and editorial assistance which was funded by UCB Pharma.
Disclosure of Interest J. R. Curtis Grant/research support from: AbbVie, Amgen, BMS, CORRONA, Crescendo, Genentech, Janssen, Pfizer, Roche, UCB Pharma, Consultant for: AbbVie, Amgen, BMS, CORRONA, Crescendo, Genentech, Janssen, Pfizer, Roche, UCB Pharma, M. de Longueville Employee of: UCB Pharma, C. O'Brien Employee of: UCB Pharma, B. Haraoui Grant/research support from: Abbott, Amgen, BMS, Janssen, Pfizer, Roche and UCB Pharma, Consultant for: Abbott, Amgen, BMS, Janssen, Pfizer, Roche and UCB Pharma, Speakers bureau: Abbott, Amgen, BMS, Janssen, Pfizer, Roche and UCB Pharma
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