In this study, we found a time-dependent, higher risk of serious infections among infliximab initiators compared with etanercept initiators. The elevated risk associated with infliximab initiation appeared to vary by patient age, with an increased risk observed in patients aged <65 years, but not in those ≥65 years of age.
Infliximab is a chimeric monoclonal antibody targeting TNFα while etanercept is a soluble TNFα receptor. It has been hypothesized that infliximab and etanercept might have differential effects on granulomatous inflammatory conditions.17,32
Specifically, infliximab, but not etanercept, appears to disrupt established granulomas and increase infection risk of granulomatous diseases through 1) greater inhibition of TNF signaling events, 2) more complete blockade of TNF activity, 3) greater induction of apoptotic activity within granulomas, or 4) a combination of these pathways.17
This hypothesis is consistent with findings from a number of population-based observational studies.13,14,16–22
To our knowledge, this is the first study specifically designed to examine whether the differential risk of serious infections between the two anti-TNFα agents varies by important modifiable and non-modifiable patient characteristics.
Older age is a strong risk factor for acquiring infections in the general population33,34
and in RA patients.10,12,14,35–38
In our study, infliximab initiators were more likely to be aged ≥65 years, which might be due to a more generous coverage of the drug in Medicare.39
We found that patients ≥65 years had an approximately 3-fold higher incidence rate of serious infections than patients <65 years. Compared with initiation of etanercept, an increased risk associated with infliximab initiation was only observed in patients <65 years. We hypothesize that this may be due to a “ceiling effect”: the underlying risk was already high in older patients due to the presence of various risk factors, the effect of an additional risk factor (i.e., infliximab) may therefore be less pronounced when measured on a relative scale in these patients than in those without other risk factors. Alternatively, older age may be a proxy for other factors that modify the observed effect. Our finding may also be due to chance.
There was no strong evidence to suggest that the effect of infliximab on serious infections varied by sex, race/ethnicity, BMI, or smoking status. As shown in , the underlying risk at each sex, current smoking (but not past smoking), and BMI stratum was likely not great enough to lead to a ceiling effect. Although the incidence rate in Native Americans and African Americans was high, the estimate was based on a small number of cases.
Smoking is a risk factor for infection.40,41
Some have observed that RA patients who smoked might have a higher serious infection risk,36
but this finding was not found in other studies.35,38
The high incidence rate in past smokers is intriguing. A possible explanation is that patients who were at a higher risk of developing a serious infection might be more likely to stop smoking prior to the initiation of anti-TNFα therapy given the perceived infection risk associated with these medications. Alternatively, patients might quit smoking due to symptoms from the lung damage caused by smoking, which puts them at an increased risk of acquiring a serious infection. However, the precise timing of smoking cessation was not available in our cohort, limiting our ability to further investigate this issue and might have led to misclassification of smoking status. Alternatively, the results might be due to random error as the number of cases was small among past smokers.
Our study population was community-based, well characterized, and diverse. The depth of our database allowed us to adjust for multiple confounders and examine several effect modifiers that are often not available in other databases. We directly compared two anti-TNFα agents, thereby reducing confounding by underlying disease severity and potential bias introduced by disparate infection risk management between users of anti-TNFα drugs and non-biologic DMARDs.
On the other hand, the results should be interpreted in the context of the limitations of the study. As we did not have direct measures of disease severity, there might be residual confounding. However, it is reassuring that our results were consistent with other studies that had information on disease severity.14,18,20
We used a propensity score developed for the entire cohort for all analyses. It is possible that the propensity score might not perform equally well in all subgroups. A more ideal approach would be to estimate subgroup-specific propensity score, but limited sample size precluded us from doing so. In a sensitivity analysis, we used an alternative approach that included in the propensity score model potentially important interaction terms identified through a stepwise regression approach, and the results were similar.
The intention-to-treat analysis might be biased due to misclassification of exposure during follow-up, whereas the as-treated analysis might introduce bias due to selection of patients who were adherent to their initial therapy.30,31
However, it is reassuring that both analyses provided consistent results. As BMI and smoking status were determined partly from ICD-9-CM codes (48% for BMI and 66% for smoking), some patients might have been misclassified. However, restricting the analyses to patients whose BMI and smoking information were available in EMRs provided qualitatively similar results. Finally, the number of cases in certain subgroups was small, therefore the statistical power to detect an effect modification might be limited, and some findings might have been due to chance.
In conclusion, our study suggested that the higher risk of serious infections associated with infliximab initiation compared with etanercept initiation did not appear to be modified by patients’ sex, race/ethnicity, BMI, or smoking status. There was an indication that the increased risk might be limited to patients younger than 65 years. More studies are needed to verify or refute our findings.