Clinical and Health Affairs
The Safety of Biologic Agents in the Treatment of Inflammatory Bowel Disease
By Chris Shepela, M.D.
Abstract
In the last decade, a new class of drugs referred to as biologics has been used successfully for treating patients with inflammatory bowel disease (IBD). Drugs such as infliximab, adalimumab, and certolizumab have been important treatment advancements because they allow the direct targeting of the inflammatory cytokine tumor necrosis factor alpha (TNF-α), which is elevated in the blood, stool, and tissue of patients with IBD. Evidence about the benefits of these drugs is accumulating. However, they are not risk-free, and evidence of their risks—primarily infection and malignancy—is also mounting. This article reviews that body of research and offers advice for physicians who must counsel patients about whether the benefits of these treatments outweigh the risks.
In most areas of medicine, advances lead to more refined, directed therapies. This is true in the case of inflammatory bowel disease (IBD), for which therapies have advanced from the use of widely active systemic corticosteroids to immunomodulators that inhibit T-lymphocytes (eg, azathioprine) to, most recently, biologics. Biologics are engineered monoclonal antibodies whose structure ranges from chimeric antibodies (infliximab) to humanized antibodies (adalimumab) to pegylated antibody fragments (certolizumab). These agents allow for the direct targeting of the inflammatory cytokine tumor necrosis factor alpha (TNF-α), which is elevated in the blood, stool, and tissue of patients with active IBD. TNF-α has 3 main functions: anti-tumor activity, control of intracellular infections, and mediation of the inflammatory response.
The current FDA-approved TNF-α antagonists for the treatment of IBD are infliximab, adalimumab, and certolizumab. By decreasing levels of circulating TNF-α, these drugs have been effective in decreasing inflammation, promoting mucosal healing, and healing fistulae, also sparing the use of steroids and leading to disease remission and possibly delaying disease progression. They have the potential to block not only the damaging effects of TNF-α such as inflammation but also the beneficial effects such as anti-tumor activity and control of cellular function.
These antagonists have been used not only in patients with IBD but also in those with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and other inflammatory conditions. Infliximab alone has been used in more than 900,000 individuals worldwide. TNF-α antagonists are an especially exciting treatment for individuals with rheumatoid arthritis, for whom this class of drugs has been proven effective in controlling symptoms and delaying disease progression. Historically, many anti-inflammatory agents used to treat rheumatoid arthritis were also found to be effective in treating IBD and have been adopted for such use. Although TNF-α antagonists have now become the standard of care for moderate-to-severe IBD, the financial costs and health risks associated with their use need to be considered on an individual basis. This article will examine the risks associated with TNF-α antagonist use in individuals with IBD.
Documented Downsides
Data from clinical TNF-α antagonist trials and multiple long-term registries of individuals using biologics have helped to determine the incidence of adverse events. The main complications of these therapies are infections and malignancies. Other adverse events associated with them—including neurologic, autoimmune, dermatologic, and cardiac complications—occur with much less frequency. In addition, administration-specific side effects such as infusion reactions, delayed hypersensitivity reactions, and local injection site reactions have been noted.
♦ Infectious Complications
Infections are the most common side effect of TNF-α antagonists. Postmarketing surveillance data suggest that up to 36% of patients receiving infliximab experience infections. The majority are upper respiratory infections that are not serious, although some patients experience more serious infections, including tuberculosis, pneumonia, sepsis, skin infections, invasive fungal infections, and Listeria monocytogenes infections.1,2
Tuberculosis (TB) reactivation is now a well-established risk of TNF-α antagonist therapy with the relative risk (RR) for reactivation ranging from 2- to 20-fold in the general population.3,4 It should be noted that recent reports about patients from the prebiologic era suggest that all individuals with IBD may be at a higher risk for TB (RR 2.36, 95% CI 1.17-4.74), most likely because of their use of steroids and immunomodulators.5 One study of patients taking adalimumab found that screening them with a tuberculin skin test led to a decline in the rate of TB cases from 1.2 to 0.08 per 100 patient-years.6 However, the effectiveness of screening can be affected by local disease incidence, prevalence of the BCG vaccination, and anergy to the tuberculin skin test, which has been reported in IBD patients on immunosuppressors.7 High-risk patients and patients on immunosuppressors should have a concomitant chest X-ray. A quantiferon-TB gold assay may be helpful for individuals vaccinated with BCG, but it is still controversial for persons taking immunosuppressants because of the high number of false-negatives in this group.8
In areas endemic for fungal infections such as histoplasmosis or coccidiomycosis, screening with a chest X-ray may be appropriate; but it is neither routinely helpful nor does it replace clinical vigilance after initiation of anti-TNF-α therapy.9
Infection from viruses such as herpes zoster and cytomegalovirus have been reported in patients taking biologics; however, the role of TNF-α antagonists in causing these diseases has not yet been determined.10 Use of biologic agents is not a cause for concern in individuals with chronic hepatitis C, but it is in patients with hepatitis B.11 Immunosuppression can enhance hepatitis B virus replication, and reactivation of hepatitis can occur after withdrawal of biologic agents, which can lead to liver failure and even death.12
In general, prior to their starting TNF-α antagonist therapy, patients should be screened for hepatitis B (HBV) with serology (HBV surface antigen, HBV surface antibody, HBV core antibody), undergo a tuberculin skin test and, if at high risk, a chest X-ray. Guidelines suggest that while on therapy, patients should have a yearly influenza vaccine, a one-time pneumococcal vaccine, and avoid any live vaccines (eg, varicella, typhoid).13 (It should be noted, however, that there is little evidence to support this.) In addition, the threshold for prescribing antibiotics or antivirals for suspected infections should be lower for these patients than for the general population.
♦ Malignancy
It has long been suspected that patients with IBD are at greater risk for developing lymphoma. The data taken as a whole, however, does not support the idea that IBD alone is a risk factor for lymphoma.14 Specific agents used to treat IBD such as azathioprine/6MP have been found to increase the risk for lymphoma up to 4-fold.15 The case for TNF-α antagonists is less clear.
Multiple TNF-α antagonist trials and registries of patients with rheumatoid arthritis have yielded conflicting results. In a large Swedish register, the standardized incidence ratio (SIR) for any tumor was lower with TNF-α antagonist use, but the unadjusted RR for lymphoma was higher (RR 11.5, 95% CI 3.7-26.9).16 However, when adjusted for disease severity, the risk was no longer statistically significant (RR 5.0, 95% CI 0.9-27.9). A U.S. study of rheumatoid arthritis patients using infliximab, etanercept, and methotrexate and cancer risk demonstrated an SIR for lymphoma with any biologic use of 2.9 (95% CI 1.7-4.9) but no increased risk with methotrexate.17 Because studies have suggested that the incidence of lymphoma is higher and long-standing high levels of disease activity may actually increase the risk of lymphoma in patients with rheumatoid arthritis, it is not known if these findings can be applied directly to patients with IBD.18
In individuals with IBD, there is likely a small-but-increased risk of malignancies (lymphoma and possibly some skin cancers) with TNF-α antagonists, but the magnitude of that risk is not known. The TREAT registry, which was established to track the long-term safety of infliximab use in patients with Crohn’s disease, has not shown an increase in the incidence of malignancies: 0.53 per 100 patient-years in the infliximab group vs. 0.49 in the noninfliximab group (OR 1.05, 95% CI 0.53-2.08).19 However, in May 2006, a black-box warning was issued for infliximab that includes information about the risk for a rare type of lymphoma seen in adolescents and young adults called hepatosplenic T-cell lymphoma. As many as 150 cases have been reported worldwide since the 1990s, and 13 cases have been reported to the FDA in adolescents with Crohn’s disease who had been treated with infliximab and thiopurines.20 This has led gastroenterologists to reevaluate treating adolescents with concomitant azathioprine/6MP and TNF-α antagonists.
♦ Other Reported Adverse Events
Although rare, neurological events in patients receiving TNF-α antagonists have been reported. These include demyelinating disease, seizures, optic neuritis, aseptic meningitis, and motor neuropathy. Autoimmune antibody formation, including ANA, anti-double-stranded DNA in patients with Crohn’s disease, and anti-cardiolipin in patients with systemic lupus erythematosus, has also been seen following treatment.21 Finally, in addition to local injection reactions, psoriasiform and bullous skin lesions and Behcet’s disease have been reported in patients taking TNF-α antagonists.22
Patient Perceptions and Preferences
It is helpful to consider patients’ perceptions and preferences when counseling them about the risks and benefits of any therapy. To set the stage, the current and evolving paradigm of treatment should be discussed first. Typically, a step-up approach would be advised. Agents that have an excellent safety profile but may be less efficacious are used early; medications that are more efficacious yet riskier are reserved for advanced disease or disease progression. The natural history of Crohn’s disease is such that individuals progress from a milder inflammatory state to a more severe one, with scarring, structuring, or even perforating over time. The pros and cons of introducing immunosuppressives and TNF-α antagonists earlier in the course of the disease, with the hope of altering its natural history, are currently being debated. D’Haens et al. performed a 1-year, prospective randomized controlled trial of the traditional step-up approach versus a top-down approach, in which patients with Crohn’s disease received combined infliximab and azathioprine during their first flare up.23 At 6 and 12 months, the remission rates for the top-down group were 60% and 61.5% respectively, while those of the step-up group were 35.9% and 42.2%. The rate of serious adverse events was numerically but not statistically different in the top-down group (30.8%) as compared with the step-up group (25.3%).
Patient perceptions of the risks and benefits of infliximab for treating IBD were recently evaluated by Siegel et al.24 They found that patients and parents of patients tended to overestimate the benefit of infliximab while underestimating its risk. Interestingly, when a theoretical new drug with all the characteristics of infliximab was presented to the subjects, 64% indicated that they would not take the medication, although 30% were currently receiving or had previously received infliximab for the treatment of their IBD. A web-based survey evaluating the risk-benefit preferences of patients with Crohn’s disease attempted to determine the maximum acceptable annual risk of several hypothetical treatments.25 Three serious adverse events associated with these treatments were evaluated: serious infection, lymphoma, and progressive multifocal leukoencephalopathy. Daily symptom severity played the largest role in determining treatment preferences, and higher levels of clinical benefit were associated with greater risk tolerance. The weighted means for the maximum acceptable annual risk were 0.38% for progressive multifocal leukoencephalopathy, 0.49% for serious infection, and 0.52% for lymphoma. In comparison, the annual mortality risk associated with infliximab is estimated to be 0.4% for serious infections and 0.06% for lymphoma.26 For azathioprine/6MP, the annual mortality risks for IBD patients are 0.15% for serious infection and 0.009% for lymphoma.26 Thus, even when adjusted for these observed rates, patients’ risk tolerance is well-above the actual observed risks. That is, they are willing to tolerate risk if they receive clinical benefit. Patients’ perspectives about the benefits versus the risks of a drug can assist in making treatment and regulatory decisions.
New Agents, New Mechanisms, Similar Risk
Finally, nearly all evolving therapies for IBD involve some degree of immunosuppression as a mechanism of action, and concern about the risks and benefits of treatment will continue. The latest addition to the armamentarium is no exception: Natalizumab is a humanized IgG4 monoclonal antibody that blocks adhesion and migration of leukocytes into the gut by binding to α4 integrin. This agent has been approved for use for treatment of both multiple sclerosis and Crohn’s disease. The Phase 3 induction trial for Crohn’s disease failed to show a significant benefit except in certain subgroups; however, the maintenance trial did show a sustained clinical response.27 In addition to serious infections, 1 case of progressive multifocal leukoencephalopathy (PML) was seen in the Crohn’s disease trials, while 2 cases were observed in the multiple sclerosis trials. Progressive multifocal leukoencephalopathy is a rare-but-devastating neurological disease that is usually associated with profound immunosuppression. It is caused by reactivation of latent JC virus, leading to the death of myelin-producing oligodendrocytes and, typically, the death of the patient.28 Natalizumab was approved for patients with moderate-to-severe Crohn’s disease who have failed or lost response to TNF-α antagonists. But it carries a safety warning and is available only through a prescribing program at selected centers. This program prevents concomitant immunosuppression and limits prednisone exposure in an effort to prevent PML or other opportunitistic infections. To date, approximately 26,000 individuals have been treated with natalizumab; no further cases of PML have been identified.
Conclusion
The evolution of and improvement in treatment strategies for individuals with IBD during the last decade has been remarkable. However, with the increase in efficacy has come an increase in risk. Thus, any treatment plan for patients with IBD should start with an open discussion about the risks and benefits of the drugs to be used.
Although some risks are modifiable, others are unavoidable, and physicians need to be vigilant about monitoring patients. The use of biologic agents for treating disease is increasing each year. Responsibility for the recognition and treatment of adverse events associated with use of biologic agents will be spread among prescribing specialists, primary care providers, and emergency medicine providers alike. MM
Chris Shepela is a gastroenterologist and assistant professor in the department of medicine at the University of Minnesota.
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