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Biologic Therapies for Inflammatory Bowel Disease
Q: What Necessary Testing Should Be Performed Before Initiating Biologic Therapy?
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A: Current biologic therapies for inflammatory bowel disease include infliximab and adalimumab, which were approved in North America, Australia and Western Europe. Certolizumab pegol was approved in the United States and Switzerland, and natalizumab was approved in the United States.
Although these therapies have demonstrated efficacy for induction and maintenance of response and remission in patients with inflammatory bowel disease (IBD), the treatments are also associated with a four-fold increased risk of opportunistic infection, and certain testing is recommended prior to treatment (Table).
Anti-TNF-Alpha Therapies
In particular, the reactivation of latent tuberculosis infection (LTBI) poses a potentially life-threatening, treatment-related adverse event, often presenting as extrapulmonary and disseminated disease. Thus, screening for LTBI is mandatory in IBD patients prior to initiation of therapy with tumor necrosis factor-alpha (TNF-α) blockers.
Standard testing for LTBI consists of careful evaluation of medical history and physical examination with aims to investigate any signs and symptoms that can suspect tuberculosis (TB), chest radiograph (CXR) and tuberculin skin test (TST) or purified protein derivative (PPD) test or interferon-gamma release assays (IGRAs). Interferon-gamma release assays measure the release of interferon-gamma from whole blood (QuantiFERON-TB Gold; Quest Diagnostics and QuantiFERON-TB Gold In-Tube; Quest Diagnostics) or peripheral blood lymphocytes (T-SPOT.TB; Oxford Immunotec) after stimulation by tuberculosis antigens. Either the IGRAs or the TST can be used to screen for LTBI in IBD as first-line diagnostic tests for LTBI. For patients who are Bacillus Calmette–Guérin (BCG) vaccinated, IGRAs may be a more favorable choice, as BCG increases false TST positivity. Results from both PPD test and IGRA are influenced by immunosuppressive therapy, including steroids, thiopurines and TNF-α inhibitors, leading to a lower rate of positive tests. In individuals at high risk of LTBI, the European Crohn’s and Colitis Organization suggests screening at diagnosis of IBD (before any immunosuppressive treatment, including steroids, is offered). This particularly applies to patients with risk factors for a disabling course of disease who are likely to receive immunosuppressive therapy early in the course of their disease.
All patients who have a TST result of greater than or equal to 5 mm in duration or a positive IGRA and who are planning to receive anti-TNF-α agents should undergo TB chemoprophylaxis with isoniazid for 9 months. Anti-TNF-α therapy should be delayed for at least 4 weeks after starting chemoprophylaxis. This arbitrary period could be subjected to variability with respect to disease severity. Patients with a negative TST (less than 5 mm) or IGRA also should be treated for LTBI if there is any evidence on a chest radiograph of a remote TB disease or if there is positive history of prior TB exposure. Empiric treatment of latent TB should also be considered in high-risk groups (such as prisoners, homeless people or birth in a high incidence country), even if the tuberculin skin test is negative.
During anti-TNF-α therapy, there is also an increased risk of reactivation in patients with previous and occult hepatitis B virus (HBV) infections. Before starting anti-TNF-α agents, screening for HBV should be performed. Appropriate screening includes transaminases, hepatitis B surface antigen (HBsAg) and anti-hepatitis B core (anti-HBc). If the anti-HBc is positive, then HBV DNA is required. Hepatitis B surface antigen-positive patients should be treated with nucleoside analogues and HBsAg negative patients with positive anti-HBc (+/-anti-HBs) should be carefully monitored during anti-TNF-α therapy and nucleoside analogues beginning with the appearance of HBsAg or HBV DNA.
As far as hepatitis C virus (HCV) infection is concerned, there are sporadic reports showing infliximab does not cause viral reactivation. Screening for an Epstein-Barr virus infection or a latent or subclinical cytomegalovirus virus infection is not necessary before starting anti-TNF-α therapy. Clostridium difficile infection must be ruled out in a patient with active IBD before starting anti-TNF-α therapy. A previous varicella-zoster infection is not a contraindication to anti-TNF-α therapy, but biologics should not be started during an active infection with chickenpox or herpes zoster, as well as any active infection including abscess. Active sepsis is an absolute contraindication. Influenza vaccination with inactivated vaccine and pneumococcal vaccination are both recommended before and during anti-TNF-α therapy.
Natalizumab
As of October 2013, there have been 410 worldwide confirmed progressive multifocal leukoencephalopathy (PML) cases in natalizumab-treated patients for either multiple sclerosis or Crohn’s disease. Natalizumab treatment duration, prior use of immunosuppressive therapies and serologic status for John Cunningham virus (JCV) are established risk factors for development of PML in natalizumab-treated patients. Approximately 55% of the population tests positive for JCV antibodies, while the overall incidence of PML is approximately one in 1,000 natalizumab-treated patients. Patients with all three known risk factors and in treatment for more than 24 months have an estimated risk of PML of 11/1,000. Even if the presence of anti-JCV antibodies is not a contraindication for use of natalizumab, seropositivity for anti-JCV antibodies should be verified prior to treatment or during treatment in case of unknown antibody status.
Anti-JCV antibody-negative patients may potentially be treated with minimal risk, but they may still develop PML due to the potential for a new JCV infection on natalizumab or a false-negative test result (approximately 3%). Therefore, patients with a negative anti-JCV antibody test result should be retested every 6 months to 12 months.
Once a patient tests positive for anti-JCV antibodies, the patient should be considered exposed to the JCV with regard to risk stratification and no further testing is recommended. Anti-JCV antibody testing should not be performed for at least 2 weeks following plasma exchange due to the removal of antibodies from the serum.
The risk of developing PML is low during the first 12 months of natalizumab therapy and, therefore, any patient independent of anti-JCV antibody serostatus or prior immunosuppressant use may potentially be safely treated with natalizumab for 12 months. The decision whether to continue natalizumab or switch to another available therapy should be based on a benefit vs. risk evaluation in every patient.
Excerpt From
Rubin DT, et al. Curbside Consultation in IBD: 49 Clinical Questions. Second Edition (pp 25-27). © 2015 SLACK Incorporated.
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