Narrative Reviews
Balancing Benefit vs Risk of Immunosuppressive Therapy for Individual Patients With Inflammatory Bowel Diseases

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Inflammatory bowel diseases (IBD) and their treatments, particularly immunosuppressive drugs, increase risk of infections and cancers. However, by promoting mucosal healing, these agents should reduce risks of infections related to intestinal lesions, malnutrition, intravenous devices, and IBD surgeries and reduce risk of cancers associated with chronic mucosal inflammation—although there are few data to support this concept. Corticosteroids increase the risk of vascular thromboembolic events, yet other immunosuppressive drugs that induce deep remission from IBD could decrease the incidence of cardiovascular events attributable to systemic inflammation and IBD-related hospitalizations and/or surgeries. The nature and magnitude of the risks of infections and cancers vary with immunosuppressive drug class and patient sex and age. For example, thiopurines increase risk of viral infections that might be fatal in young patients, whereas tumor necrosis factor antagonists increase risk of bacterial and intracellular infections that can be fatal in patients of any age, but particularly in older patients. The ability of drugs to prevent IBD-associated colorectal cancer varies with IBD location and duration. Models to assess the benefit:risk ratio of long-term use of immunosuppressive drugs for patients with IBD should be adapted based on patients’ age, sex, and IBD phenotype, to properly guide patient management. The decision-making process should begin with a clear explanation of treatment risks and then integrate the patient’s emotional perception of risks.

Section snippets

Potential Impact of Immunosuppressive Therapy on Morbidity and Mortality in Inflammatory Bowel Diseases

In westernized countries, the 2 primary causes of death are cardiovascular disease and cancer.1 This is also true for individuals living with IBD.2 In developed countries, death by infection (mainly influenza and pneumonia) is 20 times less frequent than death by cancer.3

Patients with IBD may develop cancers, cardiovascular events, and infections that are not related to IBD or IBD treatment, are attributable to IBD itself, or are attributable to IBD treatment. Immunosuppressive drugs have been

Expression of the Magnitude of Risks Attributable to Inflammatory Bowel Disease or Inflammatory Bowel Disease Drugs

The association between treatment exposure and outcomes of interest may be expressed in relative terms, such as relative risks or odds ratios. The absolute risk is the probability of the occurrence of a specified outcome within a period of time (incidence rate). Incidence rates are generally expressed as the number of events per patient-years. The denominator of 1000 persons-years is increasingly used in the IBD literature. The number of events per 1000 years represents the risk percentage of

Data Sources for Assessing the Magnitude of Risks Associated With Inflammatory Bowel Disease or Inflammatory Bowel Disease Treatment

The incidence of frequent events in IBD may be adequately estimated in reports from IBD centers or meta-analyses of randomized controlled trials. To estimate the risks of rare events, such as opportunistic infections or cancers, the minimum time of observation needed often exceeds 30,000 patient-years. This power may be attained in studies from medicoadministrative databases or observational cohorts. Subgroup assessment of the risks according to age-class and gender is possible in all studies.

Infections

Infections are extremely frequent in everyday life and can be categorized according to their clinical impact (Table 1). Serious infections are generally defined as infections that require hospitalization and may be life-threatening or result in permanent disability. In the IBD population, the incidence of serious infections ranges from 10 to 100 events per 1000 patient-years according to study designs and care pathway specificities.5, 6, 7

Opportunistic infections occur selectively or are

Cancers Promoted by Immunosuppressive Therapy

The excess risk of cancer in patients with IBD exposed to corticosteroids, thiopurines, and anti-TNF agents varies among organs and drug classes (Table 3). Patients with IBD exposed to thiopurines exhibit a mild overall excess risk of cancers.26 All patients with IBD treated with thiopurines are at increased risk of Epstein-Barr virus–associated lymphoma.27 Young patients, particularly males, are at risk of postmononucleosis lymphomas and hepatosplenic T-cell lymphomas.28, 29 Patients with IBD

Cardiovascular Events

The increased risk of venous thromboembolism (VTE) is established in patients with IBD. Deep vein thrombosis and pulmonary embolism are the most common types of VTE. Population-based cohorts revealed a 1.5- to 3-fold higher risk for the development of VTE in patients with IBD compared with non-IBD control subjects.41 The highest risks are reported in patients with IBD flare, outside the hospital and without thromboprophylaxis.42

Patients with IBD exposed to systemic corticosteroids exhibit an

Assessment of the Benefit-Risk Balance of Immunosuppressive Therapy in Inflammatory Bowel Disease

Merging all of the findings on the benefits and risks of IBD immunosuppressive therapy is difficult for clinicians. Treatment benefits are reported in randomized controlled trials, and treatment risks or indirect treatment benefits (eg, chemoprevention, cardiovascular protection) are reported in observational studies. One unique tool is adapted to combine all findings and aid clinical decision-making. Clinical decision models were developed initially in the field of cost-effectiveness analyses.

Time-Scale to Assess the Benefit-Risk Balance of Immunosuppressive Therapy

The time-scale over which outcomes are assessed is the time horizon.51 Guidelines recommend a time horizon that is sufficiently long to capture differences in outcomes across treatment strategies.51 Because IBDs are lifetime diseases, the time horizon may be a lifetime. However, the time horizon that may be considered clinically relevant in IBD is the period of drug exposure because treatment-related benefits and risks generally do not persist after drug withdrawal. The concept of treatment

Outcomes of Interest

The highest priority in the overall management of individuals with IBD is to avoid death caused by IBD or IBD drugs. Therefore, the primary health outcome is life expectancy. However, events that are not at risk of death are not considered in this model, but some events, such as permanent stomas, highly affect patients’ lives.

Alternatively, quality of life may be used as the health outcome. The utility associated with health states was introduced to estimate gains in quality-adjusted life-years.

Key Parameters to be Included in the Benefit-Risk Assessment

Personalized information on all risks and benefit parameters should become the standard of quality for guiding individual decision-making processes of treatment strategy. The historical evolution of decision models to assess the risk of lymphoma in patients with IBD exposed to thiopurines may illustrate this point. One of the first decision models published assessed the impact of thiopurines in patients with CD who achieved remission with corticosteroids.53 This study provided subgroups

Special Situations That Deserve Specific Assessments of the Benefit-Risk Balance of Immunosuppressive Therapy

Patients older than the age of 65 years have the highest risks of morbidity and mortality caused by uncontrolled IBD, such as VTE59 or perioperative death in UC.60 Older patients are also at maximal risk of cancers attributable to thiopurines,27 and serious and opportunistic infections caused by corticosteroids, thiopurines, and anti-TNF agents.5, 18 In this context, the use of new biologics (vedolizumab and ustekinumab) and small molecules (JAK inhibitors) is attractive as long as no

Communication on Risks

When 2 or more alternative therapeutic strategies may be considered in a given individual with IBD, the first step of the shared decision-making process is to explain the risks of IBD and IBD drugs to patients. Some general recommendations have been proposed66 based on the results of dedicated surveys. Descriptive words (rare, very rare) should be avoided because absolute numbers associated with these adjectives vary considerably among individuals. Relative risks are difficult to conceptualize.

Conclusions

In patients with severely active IBD, potential complications of IBD generally outweigh the potential complications of IBD drugs on a short-term basis, which results in a favorable benefit-risk balance of most IBD drugs. In contrast, in patients with sustained deep remission thanks to immunosuppressive therapy, the long-term cumulative risks of IBD drugs may outweigh the risks associated with disease relapse. Long-term risks of immunosuppressive drugs are strongly age- and gender-dependent. For

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    Conflicts of interest This author discloses the following: Laurent Beaugerie received consulting fees from Janssen, Pfizer, and Allergan; lecture fees from Abbvie, Janssen, MSD, Ferring Pharmaceuticals, Mayoly-Spendler, Takeda, and Tillots; and research support from Abbott, Ferring Pharmaceuticals, Hospira-Pfizer, Janssen, MSD, Takeda, and Tillots. The remaining author discloses no conflicts. The English of the article was revised via the Springer Nature language editing system. This was funded by the authors.

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