IBD in the elderly - beware of pitfalls!

Abstract

See accompanying article on page 212 Inflammatory bowel diseases (IBD), Crohn’s disease (CD), and ulcerative colitis (UC) typically affect people between the ages of 15 and 30, but there is a second smaller peak in the elderly, referred to as elderly-onset IBD.[1] Typically, patients diagnosed over the age of 60 are referred to as elderly-onset IBD patients. Recent studies have reported a marked increase in IBD incidence in the elderly.[2] The reasons for this are unclear but likely to include a combination of improved diagnosis, increased life expectancy, and, finally, a more pronounced effect of environmental factors on the risk of IBD in the elderly. For instance, the magnitude of risk for IBD with antibiotic exposure is higher with increasing age.[3] In addition to the increased incidence of IBD in the elderly, prevalence rates have also increased due to an aging population. Approximately 15% of the world’s population is currently aged 60 or over, and thus clinicians are increasingly likely to be confronted with managing elderly IBD patients. Furthermore, it is estimated that elderly patients comprise 25–30% of the current overall IBD population, and this is set to increase.[4] Therefore, clinicians must be fully familiar with the unique challenges surrounding the diagnosis and management of IBD in the elderly. The diagnosis of IBD in the elderly is often delayed due to a combination of factors such as reluctance to seek healthcare and a higher prevalence of diagnostic mimics. For instance, segmental colitis associated with diverticular disease, ischemic, and infective colitis all share several common features with IBD in this patient group. Thus, careful consideration should be given to exclude them. In addition, there are some intriguing phenotypic differences among elderly-onset IBD patients compared to a standard cohort. In CD, elderly-onset patients are more likely to have the colonic disease and inflammatory behavior and less likely to have penetrating disease or perianal involvement.[5] In UC, elderly-onset patients are more likely to have left-sided colitis and less likely to have proximal extension over time.[5] The medical management of elderly IBD patients poses unique challenges for several reasons. First, with immunomodulatory therapy, age-related immune senescence may increase the risk of infections and malignancies. In keeping with this, older patients are at greater risk of opportunistic infections compared to younger IBD patients.[6] Furthermore, the higher prevalence of comorbidities, polypharmacy, and frailty among elderly patients increases the risk of infections and drug interactions. Finally, a limited number of elderly patients are enrolled in clinical trials due to age restrictions for inclusion. Hence, much of the limited evidence for the safety and efficacy of medications among elderly IBD patients is derived from uncontrolled, real-world cohort studies. Consequently, there is often reluctance among IBD clinicians to prescribe immunomodulatory and biologic therapy to elderly IBD patients, with fewer elderly patients receiving such therapies.[7] In addition, much of the published data on elderly IBD came from the Western world with predominantly Caucasian patients. There is relatively little data from other parts of the world with ethnically diverse populations. In this current issue of the Saudi Journal of Gastroenterology, Mosli and colleagues try to address this gap by conducting a retrospective single-center study of elderly IBD patients treated in Saudi Arabia.[8] The study’s primary objectives were to describe disease phenotype and treatment patterns among elderly IBD patients. The predominance of left-sided colitis and a lower prevalence of perianal disease and penetrating phenotype largely align with previously published literature.[5] In addition, there was a high prevalence of co-morbidities and polypharmacy, consistent with previous findings. Around 40% of patients were treated with corticosteroids and immunomodulators, and approximately 25% were treated with biologicals, mostly with anti-tumor necrosis factor (TNF) agents. However, the study was limited by the lack of a comparator group (i.e., a standard cohort of IBD patients <60 years), and it is, therefore, difficult to establish if the biologic prescription rate in the elderly is reflective of prescription rates in a younger cohort in Saudi Arabia. Moreover, the study did not provide data on other important aspects, such as the prevalence of frailty among the cohort and the frequency of treatment-related adverse events. Such data are essential to inform further treatment choices in this difficult-to-treat cohort. Current evidence suggests that many of the commonly used treatments for IBD are associated with worse outcomes among elderly patients. For instance, in a large cohort of elderly IBD patients, current steroid use and exposure within the previous 90 days were associated with an increased risk of serious infections.[9] Steroid use also worsens pre-existing conditions such as diabetes and heart failure in the elderly. Similarly, the use of immunomodulatory therapy is associated with an increased risk of infections and malignancies among the elderly. In the pivotal French study (CESAME), the risk of lymphoma[10] and urothelial cancers[11] were all increased among older patients treated with thiopurines. Various cohort studies have reported an increased risk of infections and mortality with anti-TNF agents in the elderly.[12] In particular, the risk of opportunistic infections in the elderly is higher with a combination of anti-TNF agents and immunosuppressants. Thus, newer alternative biologics, which can more often be prescribed as monotherapy, may be preferred among the elderly. Vedolizumab, an α4β7 antibody, which blocks gut lymphocyte trafficking, is generally perceived to be safer among elderly patients due to its gut selectivity. Indeed, a recent Italian study reported comparable safety and efficacy for vedolizumab in the elderly compared to a younger cohort.[13] Ustekinumab was similarly found to be equally safe and effective in an elderly IBD cohort compared to a younger cohort.[14] However, these findings have not been consistently replicated, and a recent study reported a significantly higher infection rate among elderly patients treated with vedolizumab.[15] Comparative effectiveness and safety studies, performed appropriately with propensity adjustment, may help inform biological treatment choices in the elderly in the absence of head-to-head comparative studies. However, these studies have also produced inconsistent results. For instance, a recent nationwide Danish study did not show a difference in the risk of serious infections between vedolizumab and anti-TNF, but the risk of treatment failure was higher in vedolizumab-treated CD patients.[16] However, a US Medicare claims database study showed a lower serious infection risk with vedolizumab compared to anti-TNF treated older adults, but similar effectiveness between the two groups.[17] There are even fewer comparative data on the efficacy and safety in the elderly for ustekinumab, which targets the p40 subunit of interleukins-12 and 23 signaling with anti-TNF agents. A recent study in the elderly (in abstract form alone) suggested equivalent safety of anti-TNF agents compared to vedolizumab or ustekinumab.[18] However, this study did not analyze vedolizumab and ustekinumab separately. We recently reported comparable safety and effectiveness between vedolizumab and ustekinumab in an elderly cohort.[19] Some of the discrepant findings could be related to population differences across the studies. In particular, frailty has recently emerged as a significant predictor of adverse outcomes in IBD patients. Recent studies have shown that comorbidities[20] and frailty,[21] rather than age, dictate infection risk with biological therapy. Finally, clinicians need to be aware of worse outcomes among elderly IBD patients during hospitalization and emergency surgery. In-hospital mortality is higher among elderly IBD patients,[22] likely driven by an increased risk of venous thromboembolism and Clostridium difficile in this cohort. Emergency surgery is likewise associated with a higher mortality rate among elderly IBD patients.[23] Particular attention to preventive strategies such as thromboprophylaxis, preoperative nutritional optimization, and optimal use of antibiotics should be employed to mitigate these risks. In summary, patients with elderly IBD represent a heterogenous group, and clinicians should adopt individualized management strategies. Frailty is an important emerging metric which may predict worse outcomes with medical and surgical treatments, but optimal, validated tools are required to assess frailty in this cohort. The study by Mosli and colleagues adds further interesting data from a non-Cacucasian elderly IBD cohort, albeit with significant limitations. Further prospective, well-designed observational and randomized studies from diverse cohorts are required to inform ideal treatment strategies in elderly IBD patients.