Initiation of Tumor Necrosis Factor-α Antagonists and the Risk of Hospitalization for Infection in Patients With Autoimmune Diseases

Division of Pharmacoepidemiology, Department of Preventive Medicine, Vanderbilt University School of Medicine, 1500 21st Ave S, Ste 2600, The Village at Vanderbilt, Nashville, TN 37212, USA.
JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 11/2011; 306(21):2331-9. DOI: 10.1001/jama.2011.1692
Source: PubMed


Although tumor necrosis factor (TNF)-α antagonists are increasingly used in place of nonbiologic comparator medications, their safety profile remains incomplete.
To determine whether initiation of TNF-α antagonists compared with nonbiologic comparators is associated with an increased risk of serious infections requiring hospitalization.
Within a US multi-institutional collaboration, we assembled retrospective cohorts (1998-2007) of patients with rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis, psoriatic arthritis, or ankylosing spondylitis (psoriasis and spondyloarthropathies) combining data from Kaiser Permanente Northern California, New Jersey and Pennsylvania Pharmaceutical Assistance programs, Tennessee Medicaid, and national Medicaid/Medicare. TNF-α antagonists and nonbiologic regimens were compared in disease-specific propensity score (PS)-matched cohorts using Cox regression models with nonbiologics as the reference. Baseline glucocorticoid use was evaluated as a separate covariate.
Infections requiring hospitalization (serious infections) during the first 12 months after initiation of TNF-α antagonists or nonbiologic regimens.
Study cohorts included 10,484 RA, 2323 IBD, and 3215 psoriasis and spondyloarthropathies matched pairs using TNF-α antagonists and comparator medications. Overall, we identified 1172 serious infections, most of which (53%) were pneumonia and skin and soft tissue infections. Among patients with RA, serious infection hospitalization rates were 8.16 (TNF-α antagonists) and 7.78 (comparator regimens) per 100 person-years (adjusted hazard ratio [aHR], 1.05 [95% CI, 0.91-1.21]). Among patients with IBD, rates were 10.91 (TNF-α antagonists) and 9.60 (comparator) per 100 person-years (aHR, 1.10 [95% CI, 0.83-1.46]). Among patients with psoriasis and spondyloarthropathies, rates were 5.41 (TNF-α antagonists) and 5.37 (comparator) per 100 person-years (aHR, 1.05 [95% CI, 0.76-1.45]). Among patients with RA, infliximab was associated with a significant increase in serious infections compared with etanercept (aHR, 1.26 [95% CI, 1.07-1.47]) and adalimumab (aHR, 1.23 [95% CI, 1.02-1.48]). Baseline glucocorticoid use was associated with a dose-dependent increase in infections.
Among patients with autoimmune diseases, compared with treatment with nonbiologic regimens, initiation of TNF-α antagonists was not associated with an increased risk of hospitalizations for serious infections.

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    • "Contradictory results are probably, at least in part, a consequence of the different events studied, including overall, non-serious, serious or opportunistic infections, different patient groups or different statistical pmeters [8]. Moreover, the high statistical power obtained from large patient populations is frequently counterbalanced by possible bias linked to the scarce availability of detailed clinical information [9,10], which may eventually compromise the outcome. Finally, also the type of study, randomized controlled trial or observational study, may make a difference, particularly in relation to the patient selection criteria. "
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    ABSTRACT: Infections which complicate rheumatic diseases such as Rheumatoid Arthritis (RA) and Spondyloarthropathy (SpA) (Psoriatic Arthritis [PA] and Ankylosing Spondylitis [AS]), may cause significant morbidity and mortality. However, among the studies on the incidence rate (IR) of infections in such patients, very few have involved controls and the results have been controversial, probably due to methodological difficulties.To estimate infection rates in RA and SpA patients under disease-modifying anti-rheumatic drugs (DMARDs), corticosteroids (CS) and tumor necrosis factor (TNF)alpha antagonists, alone or combined, a single-centre retrospective observational cohort study has been performed. Incidence rates/100 patient-years of any infections were evaluated in RA and SpA outpatients observed in the period November 1, 2003 through December 31, 2009 and stratified according to therapy. Infection incidence rate ratios (IRR) were calculated using Poisson regression models which adjusted for demographic/clinical characteristics of the patients. Three hundred and thirtyone infections [318 (96.1%) non-serious and 13 (3.9%) serious] have been registered among 176 of the 341 patients (52%). The IR/100 patient-years of all infections was 36.3 ranging from 12.4 (DMARDs + CS) to 62.7 (anti-TNFalpha + CS). The most frequent infection site was respiratory tract, and bacteria were responsible for three quarters of all infections. In the multivariate analysis, adding anti-TNFalpha to DMARDs doubled the IRR compared to DMARDs alone, anti-TNFalpha + CS significantly tripled it, whereas anti-TNFalpha + CS + DMARDs only increased the risk 2.5 times. The degree of disease activity was strongly and significantly associated with the infection risk (severe or moderate versus mild, IRR = 4). Female sex was significantly associated with increased infection risk, while duration of disease and anti-influenza vaccination were protective, the latter even for cutaneous/soft-tissue (mainly herpetic) infections. The combination anti-TNFalpha with CS was found to be the most pro-infective treatment, whereas DMARDs alone were relatively safe. Physicians, therefore, should be aware that there may be an increased risk of infection when using anti-TNFalpha and CS therapy together. Anti-influenza vaccination appears to provide broad protection, adding evidence to support its use in these patients, and deserves further study.
    Full-text · Article · Mar 2014 · Journal of Translational Medicine
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    • "In relation to existing research, our findings differ from earlier studies that reported an association between anti-TNF drug treatment and an increase in all serious infections in RA patients [19,20]. Conversely, recent studies reported similar results to ours, and found no association between anti-TNF therapy and increased risk of infection in RA patients [22]. Another large retrospective study conducted among elderly RA patients, using data from 1995 to 2003, also did not find an increase in serious infections when comparing patients receiving anti-TNF therapy to those receiving methotrexate [26]. "
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    ABSTRACT: Anti-tumor necrosis factor alpha (anti-TNF) drugs are very effective for the treatment of rheumatoid arthritis but may increase the risk of serious bacterial infections. We assessed the association between the risk of serious skin and soft tissue infections (SSSTI) and the use of these agents in rheumatoid arthritis patients (RA). We conducted a nested case-control study among rheumatoid arthritis patients in the Veterans Integrated Service Network 20 from 2000-2008. We identified rheumatoid arthritis patients with SSSTI, matched them to three sets of RA controls and used conditional logistic regression to compare the risk of SSSTI between patients treated and those not treated with an anti-TNF drug, after adjusting for known confounders and important covariates. Limited by the design, we could not assess (absolute) risk but only relative risk in terms of association. Among the 97 cases and 291 controls, 90 percent were male, 62 percent white, with a mean age of 63 years. Twenty percent received anti-TNF drugs during the study period. Thirty-nine percent of cases and 15 percent of controls died, (OR 3.5, 95% CI: 2.033, 6.11, p <0.01). Diabetes mellitus (37%), kidney disease (16%) and a history of skin infections (27%) were common among cases. Based on conditional logistic regression, anti-TNF use was not significantly associated with skin and soft tissue infections (OR 1.1, 95% CI: 0.61-2.03, p = 0.92). However, patients with diabetes mellitus (OR 2.5, 95% CI: 1.53-4.13, p = 0.01) or a prior history of skin infection (OR 5.7, 95% CI: 2.87-11.43, p <0.01) were more likely to have skin and soft tissue infections. Use of anti-TNF therapy among RA patients was not associated with an increased risk of SSSTI, but patients with diabetes mellitus and those with a history of prior skin infection were significantly more likely to have SSSTI and mortality was higher among cases than controls in this veteran cohort.
    Full-text · Article · Nov 2013 · BMC Infectious Diseases
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    • "Bacterial pneumonias have been shown to be more common in IBD patients.7 Furthermore, bacterial pneumonias have been identified in several cohort studies as one of the commonest infections resulting in hospitalization in IBD patients on immunomodulators and/or TNF-α inhibitors.8,9Streptococcus pneumoniae (S. pneumoniae) as well as influenza virus have been identified as vaccine preventable causes of pneumonia among IBD patients and vaccinations against these have been advocated since 2004.10,11 "
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    ABSTRACT: Background: Pneumonias are among the most common causes of hospitalization among inflammatory bowel disease (IBD) patients. Guidelines published in 2004 advocate vaccina-tion against Streptococcus pneumoniae and influenza virus. We sought to examine trends in hospitalizations for vaccine preventable pneumonias among IBD patients since the availability of published guidelines, and to identify whether Haemophilus influenzae is a causative organism for pneumonia hospitalizations among IBD patients. Methods: This cross-sectional study on the Nationwide Inpatient Sample was used to iden-tify admissions for pneumonias in patients with IBD between 2004 and 2009. A multivariate logistic regression analysis was performed comparing IBD patients to controls, accounting for potential confounders. Results: There were more admissions for S. pneumoniae pneumonia than influenza virus or H. influenzae (787, 393, and 183 respectively). Crohn's disease (CD) as well as ulcerative colitis (UC) patients did not demonstrate increased adjusted odds of hospitalization for S. pneumoniae pneumonia (1.08; confidence interval [CI] 0.99–1.17 compared to 0.93; CI 0.82–1.06 respectively). Increased adjusted odds for hospitalization for pneumonias due to influenza virus were seen among UC patients in the bottom quartile of income (1.86; CI 1.46–2.37). Adjusted odds for H. influenzae pneumonia admission in patients with UC and CD patients were increased compared to controls (1.42; CI 1.13–1.79 and 1.28; CI 1.06–1.54, respectively). Conclusion: The study identified lowest income UC patients as having higher adjusted odds, and these patients should be targeted for influenza virus vaccination. Additionally, H. influenzae may be another vaccine preventable cause for pneumonia among IBD patients.
    Full-text · Article · May 2013 · Clinical and Experimental Gastroenterology
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