Anti-tumor necrosis factor (anti-TNF) agents have become an increasingly prominent option in the treatment of several immune-mediated inflammatory disorders. Infliximab, the first of these agents to receive Food and Drug Administration (FDA) approval, has largely revolutionized the management of inflammatory bowel disease (IBD) through its targeted inhibition of underlying inflammatory mediators. Increasingly recognized as first-line therapy for moderate-to-severe Crohn's disease (CD), infliximab has also demonstrated utility in moderate-to-severe ulcerative colitis (UC),1 which has led to its growing use in all aspects of IBD. More recent additions to the anti-TNF armamentarium include adalimumab and certolizumab pegol. All three anti-TNFs are now FDA-approved for the treatment of CD, although only infliximab is FDA-approved for UC.
While the TNF-α immune pathway can be inappropriately activated in IBD, it can also play a critical role in the control of certain infections. Shortly after the introduction of infliximab, numerous clinical reports documented the development of serious infections in patients receiving the drug.2–5 The most worrisome of these involved the reactivation of latent Mycobacterium tuberculosis (TB).6 TNF-α is central to the process of granuloma formation and its inhibition can result in reactivation of granulomatous disease.7, 8 While less well understood, but increasingly recognized, hepatitis B also has the potential to reactivate with anti-TNF treatment.9, 10 Reactivation of both TB and hepatitis B has resulted in substantial morbidity and mortality in patients receiving these agents.6, 11
In response to the potential infectious complications, a range of clinical guidelines for infection screening prior to the initiation of anti-TNF treatment have been developed by both national and international groups. The American College of Gastroenterology (ACG) recommends screening for latent TB with a tuberculin skin test (TST) and a chest x-ray.1, 12 The American Gastroenterological Association (AGA) recommends a TST prior to anti-TNF therapy.13 Both the ACG and the AGA emphasize the importance of a thorough risk factor assessment to TB given the high risk of anergy in this patient population.14 The American College of Rheumatology (ACR) recommends routine screening with a TST regardless of Bacille Calmette-Guérin (BCG) status combined with a thorough history and chest x-ray, as indicated.15 The European Crohn's and Colitis Organization (ECCO) guidelines differ in that there is less emphasis on TST given the high rate of BCG vaccination and more emphasis on obtaining a screening chest x-ray prior to anti-TNF initiation.16
In the most recent recommendation for UC management, the ACG recommends screening for hepatitis B prior to treatment with infliximab.12 While the ACR does not make a specific recommendation for screening for hepatitis B, they do recommend vaccination if risk factors are present.15 In 2009, the ECCO recommended baseline hepatitis B serologies and vaccination if not previously done.17 Testing for hepatitis B prior to initiation of chemotherapy in patients with underlying malignancies is advised and if the surface antigen is positive, prophylactic treatment with lamivudine is recommended. For patients who demonstrate hepatitis B core antibody, close monitoring with liver function tests and hepatitis B DNA titers are suggested.18
Data from British rheumatologists have indicated variable adherence to the recommendations for latent TB infection screening prior to anti-TNF therapy.19 It is unknown to what extent infection screening is practiced in the U.S. gastroenterology community. The aim of this study was to assess the level of adherence by gastroenterologists to recommended guidelines for screening for TB as well as hepatitis B prior to initiating anti-TNF therapy.
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- PATIENTS AND METHODS
It is well accepted that all patients should have appropriate screening for TB prior to initiating anti-TNF therapy. There is emerging evidence that patients should also be screened for hepatitis B prior to initiating anti-TNF therapy.9 To our knowledge, this is the first study to examine the adherence to latent infection screening in patients with IBD prior to starting anti-TNF therapy. In our study, 65% of patients were appropriately screened for latent TB, while only 25% were screened for hepatitis B infection. While the rates of screening have increased over time, assessing for potentially life-threatening complications prior to initiation of anti-TNF therapy should approach 100% compliance.
As there is a range of clinical guidelines for infection screening prior to initiation of an anti-TNF,1, 12, 13, 16 we chose to assess “obtaining a TST” as a simple surrogate for screening for latent TB. Even with this least stringent criterion, less than 80% of patients in our practice are currently being appropriately screened (Fig. 2). Both the ACG and the AGA emphasize the importance of a thorough assessment of risk factors for TB, including place of birth, travel history, known TB exposures, incarceration, and homelessness. Unfortunately, in our study we were only able to demonstrate that risk factors for TB were adequately assessed in 17% of patients. We agree that in addition to a TST or IGRA it is essential that a thorough history of TB risk factors should be ascertained for appropriate risk stratification and potential treatment of latent TB prior to the initiation of an anti-TNF. In our series, IGRAs were not used as a sole means for screening for latent TB. Interestingly, there is recent evidence that in patients on prednisone, IGRA may be superior to TST.20 However, both tests are still immune assays and subject to false-negative results when on immunosuppressive therapy. Even if not on immunosuppressive therapy, a substantial number of IBD patients are anergic prior to initiation of an anti-TNF.14 Because of this it is essential that a thorough history of TB risk factors should be ascertained for appropriate risk stratification and potential treatment of latent TB prior to the initiation of an anti-TNF.
We demonstrated that previous exposure to an anti-TNF was a strong predictor of failure to screen adequately for TB. This is potentially due to providers assuming the patient had previously been screened or that the patient's lack of reactivation of TB during their prior anti-TNF course infers an absence of latent TB. Regardless, patients should still be assessed for latent TB prior to reinitiating anti-TNF therapy. In our series, one patient was documented to have latent TB in this situation.
There was no documented clinical reason for a failure to screen for latent TB in the majority of cases (Fig. 1). However, in 21% of cases it was noted that a TST was placed, but no documented result. In one instance a positive TST was noted by an infusion nurse prior to initiation of infliximab. A number of patients were instructed to get a TST but the results were never documented, or the physician accepted a verbal report by a patient of a negative TST. As care for IBD patients can be complex and multiple healthcare specialists are often involved, there may be confusion with regard to responsibility for screening. We feel that it is the responsibility of the provider initiating treatment to ensure that appropriate screening has occurred. Methods to ensure patient and physician follow-through need to be examined.
Only recently has the ACG and ECCO incorporated screening for hepatitis B into their practice guidelines. In our population, screening for hepatitis B was low. Although the rates of screening for hepatitis B are increasing, even in 2010 they are below 50% (Fig. 2). Prior exposure to an anti-TNF was associated with not screening likely for similar reasons as TB.
Currently, screening for hepatitis B generally only includes a surface antigen. However, patients on chemotherapy who are antigen-negative but core antibody-positive have been known to reactivate.18 While it is unclear at this time what implications hepatitis B core antibody positivity has for IBD patients, we found that hepatitis B surface antigen and viral load were routinely followed. To date, none of our patients have reactivated, but long-term follow-up is necessary. Negative hepatitis B antibody titers can be useful and should prompt hepatitis B vaccination. For these reasons, we think it is reasonable to screen for hepatitis B prior to initiating treatment with a surface antigen, surface antibody, and core antibody.
As with all guidelines, dissemination of recommendations and education of physicians is paramount. The AGA mentioned screening for latent TB as early as 2003,21 although significantly elaborated on those guidelines in 2006.13 Recently, in 2010 the ACG recommended screening for hepatitis B prior to treatment of UC with infliximab.12 Our data show that screening has been increasing over time (Fig. 2). While screening increased over time, independent of the guidelines, we hypothesize that further support from societies and dissemination of these guidelines may help gastroenterologists create practice standards and increase adherence to accepted screening. However, further study is needed to assess this effect.
Our study has several limitations. First, this is a retrospective analysis of medical records. As a result, it may underestimate the true prevalence of screening. This is most likely for the TB risk factor assessment, which was not formalized, and less likely with hepatitis B screening, which was an objective lab value. As no paper charts were reviewed, it is possible that nonelectronic communications were missed. However, while the true prevalence of screening may be higher, the importance of documentation should not be understated, as it is vital to the multidisciplinary care of these complicated patients. Second, our outcome was a documented result in the electronic medical record. At the start of the study period there was a gradual transition to electronic medical records, which may account for “missing” results. In the middle of our study period electronic medical records were required for billable encounters, which certainly caused some of the increase in documentation over time. Third, this study only examined the records of one medical center. While many patients had all of their care at this center, others had only a GI provider at the center. As the responsibility of appropriate screening relies on the provider prescribing the medication, this should not have affected the primary outcome of adherence to screening. A final limitation is generalizability. In our population the rate of latent TB was low and there were no cases of reactivation of latent TB or reactivation hepatitis B. In a population where latent TB and hepatitis B are more common, screening habits may be different based on provider experience.
Adherence to screening for TB and hepatitis B, although improving over time, was not adequate in this study. Prior anti-TNF exposure is frequently associated with a failure to rescreen for latent TB and hepatitis B. In addition to screening with a TST or an IGRA, more emphasis needs to be placed on a TB risk factor assessment of patients prior to treatment with an anti-TNF. Although screening rates have improved over time, all patients starting anti-TNF therapy should be screened for evidence of latent infections. Further study is warranted to assess the optimal mechanism to improve screening.
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- PATIENTS AND METHODS
Disclosures: Dr. Adam Cheifetz has served as an advisory board participant for UCB and Abbott. Dr Alan Moss has been an advisor and received honoraria from Abbott and UCB. Dr. Glen Doherty has served as an advisory board participant for Abbott and MSD. There are no other potential conflicts of interest to disclose. Contributions: Byron Vaughn: Study concept and design, acquisition and interpretation of data, statistical analysis, drafting the article, and critical revision of the article. Glen Doherty: Study concept and design, interpretation of data, and critical revision of article. Shiva Gautam: Statistical analysis, interpretation of results and critical revision of article. Alan Moss: Study concept and design, interpretation of data, and critical revision of article. Adam Cheifetz: Study concept and design, interpretation of data, and critical revision of article.