Our findings indicate that among RA patients enrolled in TennCare, initiation of TNF-α antagonists was not associated with a large increase in the risk of serious infections requiring hospitalization compared with initiation of MTX. However, compared with MTX, the initiation of glucocorticoid regimens increased the risk of serious infections.
Although most randomized clinical trials reported effects of TNF-α antagonists compared with placebo in patients who continue traditional DMARDs, few trials provided information on the risk of serious infections comparing initiation of TNF-α antagonists with initiation of MTX. Available data suggested that infliximab increased the risk of serious infections compared with initiation of MTX [11
], whereas initiation of either adalimumab [12
] or etanercept [13
] did not. A pooled estimate of these three randomized trials comparing initiation of TNF-α antagonists with initiation of MTX yielded an overall risk ratio of 1.48 (95% CI 0.93, 2.35), encompassing the estimates reported in this study.
We considered some of the methodological challenges that could explain differences in results of observational studies in this area [35
]. Previous research suggested a time-dependent risk of infections after initiation of TNF-α antagonists [5
]. To assure comparability of exposure groups, we applied a new-user design and focused on the period immediately after treatment initiation [17
]. We reduced exposure misclassification by using pharmacy data to classify each day of follow-up during the new episodes of medication use. To reduce outcome misclassification, we identified infections using algorithms that had previously shown high positive predictive values in our population [24
]. Furthermore, although direct measurements of disease severity were not available, adjustment for measured covariates (including surrogates for disease severity) was performed and the potential role of unmeasured confounders was examined.
In our study, patients initiating TNF-α antagonists had an increased prevalence of surrogates for severe RA, suggesting channeling of patients with severe disease to these medications. However, TNF-α antagonists initiators were younger and had more baseline exposure to DMARDs than MTX initiators, suggesting that TNF-α antagonist initiators were less frail than MTX initiators. Adjustment for these latter factors resulted in increased HRs for TNF-α antagonists initiators. Although residual confounding could not be ruled out, our sensitivity analyses indicated that improving our imperfect adjustment for disease severity would reduce our HR within the confidence intervals of our estimate (see supplementary data
available at Rheumatology
Glucocorticoid use increased the risk of serious infections requiring hospitalizations consistently and in a dose-dependent manner, compared with MTX initiation. Although glucocorticoid use could also be a surrogate for severe RA, these associations persisted after adjustment for measured confounders and in a number of sensitivity analyses. Furthermore, these findings are consistent with results from randomized clinical trials and from previous observational studies [5–7
A retrospective cohort study of 609 RA patients reported 3.1 pneumonia hospitalizations per 100 person-years, but was not restricted to patients exposed to DMARDs [37
]. Although our crude pneumonia hospitalization rate was 5/100 person-years, this likely reflects a sicker population of RA patients enrolled in a Medicaid plan and initiating DMARDs or glucocorticoids and observed during the initial months of medication use, when the risk for infections is considered to be the highest [5
Since several DMARD therapies require months to achieve a satisfactory response, we hypothesized that studying medication effects during a short, defined follow-up time after initiation would maximize the potential for complete persistence. However, both stopping and switching were common shortly after initiation of a new DMARD [19
]. We reduced the potential effects of changes in exposure categories by studying new episodes of medication use and by truncating the exposure follow-up when an original study regimen was changed. A sensitivity analysis based on initiation of regimens ignoring subsequent regimen changes showed results consistent with our main findings.
Our study has several limitations. First, although pharmacy files provide excellent information on medications dispensed through TennCare and they are virtually free of information bias [38
], the actual use of these medications is unknown. Even though use of medications filled outside the system could not be ruled out, we consider this unlikely because cohort members had full access to TennCare pharmacy benefits and because some medications, such as TNF-α antagonists, are expensive. Secondly, we relied on coded information to identify study outcomes. Misclassification makes it more difficult to demonstrate true associations [5
]. However, we minimized outcome misclassification by using computerized definitions that were previously validated in our population [24
]. Thirdly, we had insufficient numbers to evaluate the role of specific TNF-α antagonists on serious infections. Furthermore, the relatively short, exposed person-time during episodes of medication use limited our power to detect small increases in the risk of serious infections. Indeed, our findings are also consistent with up to a 2-fold increased risk of serious infections hospitalization. Finally, TennCare enrollees may not be representative of the general population.
In conclusion, we found no increased risk of hospitalizations due to serious infections among initiators of TNF-α antagonists compared with initiators of MTX. Although we could not rule out small increases in risk or differences between TNF-α antagonists, our results were robust to a number of sensitivity analyses and we did not observe significant increases in the risk of infections among other DMARD regimens commonly used in our population. However, our study demonstrated a strong association between glucocorticoid use (especially at high doses) and the risk of serious infections requiring hospitalization among RA patients.