Inhibitors of tumor necrosis factor (TNF)-alpha offer a way to target pathologic inflammation in a number of conditions such as rheumatoid arthritis, spondyloarthropathy, and inflammatory bowel disease.
However, the use of TNF inhibitors is associated with an increased risk for a variety of serious infections,1 including bacterial, viral, and fungal infections, because TNF-alpha plays a key role in macrophage and phagosome activation, monocyte differentiation into macrophages, and neutrophil recruitment.2
The presence of TNF-alpha is critical to contain infection caused by pathogens including Mycobacterium tuberculosis, M avium, M bovis, Bacillus Calmette-Guerin (BCG), Aspergillus fumigatus, Histoplasma capsulatum, Toxoplasma gondii, Cryptococcus neoformans, and Candida albicans as these organisms require sequestration within granulomas consisting of macrophages and lymphocytes.1
The American College of Rheumatology recommends that TNF-alpha inhibitors not be administered to patients with active bacterial infection, active or untreated latent tuberculosis, active herpes zoster infection, nonhealed infected skin ulcer, acute hepatitis B or C infection, life-threatening fungal infection, or severe respiratory tract infection.3
A variety of recommendations exist regarding screening for certain infections, including tuberculosis, hepatitis B, and hepatitis C, prior to the administration of TNF-alpha inhibitors.4 Possible exposure to regional endemic fungi should also be considered prior to initiation of TNF inhibitor therapy. Appropriate screening includes a full medical history, physical examination, tuberculin skin test or interferon-gamma release assay, and a chest radiograph for those with positive tuberculin skin test or interferon-gamma release assay or a history or physical examination suggestive of tuberculosis.4
To study the incidence and risk factors for the development of bacterial and fungal infections among patients taking TNF inhibitors, Elizabeth Salt, PhD, APRN, and colleagues from the University of Kentucky designed a case-control study using de-identified commercial US health claim information from January 1, 2007, to December 31, 2009.5 The information assessed included patient age, sex, prescription drug codes, procedure and diagnosis codes, and laboratory test results.
Of the 30,772 persons identified as having received TNF inhibitor therapy for any indication, 183 were identified as having been treated for mycobacterial infection, blastomycosis, coccidioidomycosis, cryptococcal infection, histoplasmosis, pneumocystosis, tuberculosis, or unspecified fungal infection. Of these, 25 patients were excluded from analysis because of cancer diagnosis, as inclusion of these patients might confound results because of the multifactorial and complicated clinical histories of the patients. The remaining 158 people were found to have been prescribed 1 of 4 TNF inhibitors: adalimumab, etanercept, infliximab, or certolizumab.
The minimum duration of follow up (from initiation of inhibitor therapy) was defined as 97 days. Those who did not seek medical care for fungal or mycobacterial infection but were followed for 97 days were used as controls, at a control-to-case sampling ratio of 3:1 for a total of 474 controls.
No difference was found in age, sex, race, or education between patients who received treatment for fungal or mycobacterial infection and those who did not (control cases). Of the 30,772 patients prescribed TNF inhibitors, fungal or mycobacterial infection developed in 150 (0.51%), consistent with the previously reported low rate for these types of infections.6
After multivariate logistic regression, researchers found that predrug screening, TNF inhibitor type, diabetes mellitus, race, education, and concomitant prescription use were not associated with increased likelihood for the development of fungal or mycobacterial infection requiring medical attention. Those who resided in the western United States (odds ratio 1.77, P = .03) or who had prior prednisone prescription (odds ratio 2.08, P < .001), on the other hand, were more likely to receive treatment for fungal or mycobacterial infection.
Summary and Clinical Applicability
This case-control study found that the development of a fungal or mycobacterial infection among patients taking TNF inhibitors was low (0.51%). Among the risk factors for seeking treatment for fungal or mycobacterial infection, prednisone use was most predictive.
This finding was limited by the case-control design of the study, which made data collection by definition retrospective. Additionally, the source from which the study extracted data was a commercial insurance database and, as such, the reported diagnostic procedures, medications, and further treatment received by patients consisted only of those recognized and billed for by the insurance company according to International Classification of Diseases and Current Procedural Terminology diagnosis codes.
“The question remains whether increased infection rates are related solely to the use of glucocorticoids or also to the active disease for which the medication is being prescribed,” the authors state.
1. Koo S, Marty FM, Baden LR. Infectious complications associated with immunomodulating biologic agents. Hematol Oncol Clin North Am. 2011;25(1):117-138.
2. Mootoo A, Stylianou E, Arias MA, Reljic R. TNF-alpha in tuberculosis: a cytokine with a split personality. Inflamm Allergy Drug Targets. 2009;8(1):53-62.
3. Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012;64(5):625-639.
4. Chirch LM, Cataline PR, Dieckhaus KD, Grant-Kels JM. Proactive infectious disease approach to dermatologic patients who are taking tumor necrosis factor-alfa antagonists: Part II. Screening for patients on tumor necrosis factor-alfa antagonists. J Am Acad Dermatol. 2014;71(1):11.e1-7.
5. Salt E, Wiggins AT, Rayens MK, et al. Risk factors for targeted fungal and mycobacterial infections in patients taking tumor necrosis factor inhibitors. Arthritis Rheumatol. 2016;68(3):597-603.
6. Singh JA, Cameron C, Noorbaloochi S, et al. Risk of serious infection in biological treatment of patients with rheumatoid arthritis: a systematic review and meta-analysis. Lancet. 2015;386(9990):258-265.