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Comparative Safety of Infliximaband Etanercept on the Risk of Serious Infections TOH
1. Comparative safety of infliximab and
etanercept on the risk of serious infection
Does the association vary by patient
characteristics?
Darren Toh, ScD
Lingling Li, PhD
Leslie R. Harrold, MD, MPH
Elizabeth A. Bayliss, MD, MSPH
Jeffrey R. Curtis, MD, MS, MPH
Liyan Liu, MS
Lang Chen, PhD
Carlos G. Grijalva, MD, MPH
Lisa J. Herrinton, PhD
2. Background
• Infliximab, a chimeric monoclonal anti-TNF antibody,
has been found to increase the risk of serious
infections compared to etanercept (a TNF receptor
fusion protein)
• It is unclear whether the risk varies by patient
characteristics
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3. Objective
• To assess if the relative risk of serious infections
comparing infliximab and etanercept varies by five
patient characteristics (age, sex, race/ethnicity, and
body mass index, smoking status)
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5. Exposure
• Infliximab: Administered through infusion; each
infusion covers 56 days
• Etanercept: Self-administered via injection; each
injection covers 7 days and each dispensing
containing 4 injections
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6. Outcome
• Serious infections, defined as infections requiring
hospitalization or opportunistic infections
• Used previously validated algorithms to identify
serious infection cases (PPV of ≥80%)
Grijalva et al, JAMA 2011;306: 2331-2339 6
7. Potential confounders & effect modifiers
• Age; sex; race/ethnicity; body mass index; smoking status
• Type of insurance; proportion of household below the poverty
line in the census block in which the patient lived
• Charlson comorbidity score; diagnosis of rheumatoid arthritis,
psoriatic arthritis, psoriasis, ankylosing spondylitis, diabetes, or
COPD
• Use of methotrexate, hydroxychloroquine, leflunomide,
sulfasalazine, NSAIDs, opioids, corticosteroids, or antibiotics
• Number of inpatient visits, outpatient visits, and unique
medications dispensed
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8. Statistical analysis
• Calculated the incidence rate and 95% CI
• Propensity score stratified (by quintiles) Cox model to
adjust for potential confounders
• HRs and 95% CIs comparing infliximab vs. etanercept
• An “intention-to-treat” analysis
• Follow-up started from treatment initiation to the earliest
occurrence of the outcome, death, disenrollment,
12/31/2007, or 365 days after treatment initiation
• 0-3, 0-6, and 0-12 months after treatment initiation
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9. Statistical analysis (cont)
• Stratified the analysis by
• Age: <65 vs. ≥65 years
• Sex: male vs. female
• Race/ethnicity: Non-Hispanic White, African-American,
Hispanic, Asian American, Native American, and other or
unknown
• BMI: <25 vs. ≥25 kg/m2
• Smoking status: non, past, and current smoker
• Likelihood ratio test to assess effect modification
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15. Discussion
• The relation between infliximab and serious infections
may be modified by age
• Increased risk observed only among patients <65 years
• No increased risk among patients ≥65 years
• Ceiling effect?
• No strong evidence to suggest that the effect is
modified by other patient characteristics examined
• Need to be confirmed or refuted by other studies
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16. Discussion (cont)
• Limitations
• Residual confounding by disease severity
• Residual confounding by non-specific propensity score
• ITT analysis may be biased due to exposure misclassification
• 48% BMI and 66% smoking determined by ICD-9 codes
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