Use of a baseline risk score to identify the risk of serious infectious events in patients with rheumatoid arthritis during certolizumab pegol treatment

Abstract

Background: The risk of serious infectious events (SIEs) is increased in patients with rheumatoid arthritis (RA). The aim of this study was to develop an age-adjusted comorbidity index (AACI) to predict, using baseline characteristics, the SIE risk in patients with RA treated with certolizumab pegol (CZP).

Methods: Data of CZP-treated patients with RA were pooled from the RAPID1/RAPID2 randomized controlled trials (RCT CZP) and their open-label extensions (All CZP). Predictors of the first SIE were examined using multivariate Cox models. The AACI was developed by assigning specific weights to patient age and comorbidities on the basis of relative SIE risk. SIE rates were predicted using AACI score and baseline glucocorticoid use, and they were compared with observed rates. The percentage of patients in each SIE risk group achieving low disease activity (LDA)/remission was examined at 1 year of treatment.

Results: Among 1224 RCT CZP patients, 40 reported ≥ 1 SIE (incidence rate [IR] 5.09/100 patient-years [PY]), and 201 of 1506 All CZP patients reported ≥ 1 SIE (IR 3.66/100 PY). Age ≥ 70 years, diabetes mellitus, and chronic obstructive pulmonary disease/asthma made the greatest contributions to AACI score. SIE rates predicted using AACI and glucocorticoid use at baseline showed good agreement with observed SIE rates across low-risk and high-risk groups. At 1 year, more high-risk All CZP patients than low-risk All CZP patients reported SIEs (IR 8.4/100 PY vs. IR 3.4/100 PY). Rates of LDA/remission were similar between groups.

Conclusions: AACI and glucocorticoid use were strong baseline predictors of SIE risk in CZP-treated patients with RA. Predicted SIE risk was not associated with patients' likelihood of clinical response. This SIE risk score may provide a valuable tool for clinicians when considering the risk of infection in individual patients with RA.

Trial registration: ClinicalTrials.gov, NCT00152386 (registered 7 September 2005); NCT00160602 (registered 8 September 2005); NCT00175877 (registered 9 September 2005); and NCT00160641 (registered 8 September 2005).

Keywords: Certolizumab pegol; Comorbidity; Global risk score; Safety; Serious infection.

Conflict of interest statement

Ethics approval and consent to participate

This is a secondary manuscript reporting post hoc analyses of data pooled from the RAPID1 and RAPID2 randomized controlled trials (NCT00152386 and NCT00160602, respectively) and their open-label extensions (NCT00175877 and NCT00160641, respectively). Information regarding ethics approval and patient consent can be found in the corresponding primary publications [–23].

Competing interests

JRC has received research grants and consultant fees from Roche, Genentech, UCB Pharma, Janssen, Corrona, Amgen, Pfizer, Bristol-Myers Squibb, Crescendo, and AbbVie. KW has received consultant fees from UCB Pharma, Pfizer, Bristol-Myers Squibb, Eli Lilly, AbbVie, and Roche. CO’B was an employee of UCB Pharma at the time of this work. ‘MNN is an employee of UCB Pharma. MdL is an employee of UCB Pharma. BH has received research grants and consultant fees from Abbott, Amgen, Bristol-Myers Squibb, Janssen, Pfizer, Roche, and UCB Pharma. UCB sponsored the study and the development of the manuscript/publication and reviewed the text to ensure that, from UCB’s perspective, the data presented in this article are scientifically, technically, and medically supportable; that they do not contain any information that has the potential to damage the intellectual property of UCB; and that the publication complies with applicable laws, regulations, guidelines, and good industry practice.

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Figures

Fig. 1

Rheumatoid Arthritis PreventIon of structural Damage 1 (RAPID1) and RAPID2 study design. Patients were randomized 2:2:1 to CZP 400 mg Q2W, CZP 200 mg Q2W, or placebo Q2W, respectively, in combination with MTX. The loading dose (LD) was CZP 400 mg at weeks 0, 2, and 4. aTwice the registered CZP dose. bRegistered CZP dose. cAt week 16, American College of Rheumatology 20% improvement nonresponders at weeks 12 and 14 were withdrawn from the RCTs; these patients, as well as those who completed the RCTs, were allowed to enter the OLEs, receiving CZP 400 mg Q2W + MTX for ≥ 6 months before being switched to CZP 200 mg Q2W + MTX. CZP Certolizumab pegol, Q2W Every 2 weeks, Q4W Every 4 weeks, MTX Methotrexate, RCT Randomized controlled trial, OLE Open-label extension

Fig. 2

Multivariate analysis of baseline predictors to the first SIE. a RCT CZP group. b All CZP group. A Cox proportional hazards model fitted with AACI categories was used to identify baseline covariates linked to SIE risk (p ≤ 0.25). Baseline covariates identified as risk factors (p ≤ 0.05) are highlighted in red. No other baseline covariates examined (BMI, disease duration, HAQ-DI, and MTX dose) were considered relevant to the outcome (p > 0.25). SIE Serious infectious event, RCT Randomized controlled trial, CZP Certolizumab pegol, AACI Age-adjusted comorbidity index, DAS28(CRP) 28-joint Disease Activity Score with C-reactive protein, BMI Body mass index, HAQ-DI Health Assessment Questionnaire Disability Index, MTX Methotrexate, RCT CZP Patients randomized to CZP in the RAPID1/RAPID2 randomized controlled trials, All CZP All patients treated with CZP during the RAPID1/RAPID2 randomized controlled trials and/or open label extensions

Fig. 3

Predicted time to first SIE, by baseline systemic glucocorticoid use and AACI. a RCT CZP. b All CZP. Predicted SIE-free survival curves correspond to Kaplan-Meier estimates for the indicated risk groups, based on the covariates selected by the Cox models. The c-indexes were 0.66 (95% CI 0.33–0.93) for the RCT CZP model and 0.85 (95% CI 0.73–0.93) for the All CZP model. aLow risk at baseline: AACI of 0, without systemic glucocorticoid use. bHigh risk at baseline: AACI ≥ 2, with systemic glucocorticoid use. SIE Serious infectious event, CZP Certolizumab pegol, AACI Age-adjusted comorbidity index, RCT CZP Patients randomized to CZP in the RAPID1/RAPID2 randomized controlled trials, All CZP All patients treated with CZP during the RAPID1/RAPID2 randomized controlled trials and/or open label extensions, CI Confidence interval

Fig. 4

Observed proportion of All CZP patients achieving LDA and remission at 1 year of treatment. a DAS28(CRP). b CDAI. c SDAI. LDA was defined as DAS28(CRP) ≤ 2.7, CDAI ≤ 10, and SDAI ≤ 11; remission corresponded to DAS28(CRP) < 2.3, CDAI ≤ 2.8, and SDAI ≤ 3.3. Missing data were imputed using nonresponder imputation. LDA Low disease activity, CZP Certolizumab pegol, AACI Age-adjusted comorbidity index, DAS28(CRP) 28-joint Disease Activity Score with C-reactive protein, REM Remission, CDAI Clinical Disease Activity Index, SDAI Simplified Disease Activity Index, All CZP All patients treated with CZP during the RAPID1/RAPID2 randomized controlled trials and/or open label extensions