Practical Advice for the Management of Older Adults With Inflammatory Bowel Disease

There is an exponential rise in the number of older adults with inflammatory bowel disease (IBD), both Crohn's disease (CD) and ulcerative colitis (UC), likely due to more effective treatments, decreasing disease-related fatality, and an increasing incidence of disease at older ages (1). Currently, there are nearly 7 million people worldwide who have IBD; approximately one-third of people living with IBD in the Western world are 60 years or older (2,3). Although the rise in prevalence of older adults with IBD is a testament to our advances in care, years of life lived with disability has now doubled with a peak in the 7th decade of life (4). Early consideration of aging-related principles among individuals with IBD can shift this trajectory, improving not only mortality, but also clinical outcomes and thereby quality of life for this unique and rapidly growing cohort of people with IBD. EPIDEMIOLOGY & DIAGNOSTIC CONSIDERATIONS In the U.S., approximately 1% of individuals over the age of 60 years have IBD: the age cohort where IBD is the most prevalent (2). This is comprised of individuals who developed IBD early in life and are now aging, as well as the 15%–20% of individuals who develop IBD at 60 years of age or older (5). For the purposes of this review, when referencing older adults with IBD, this will refer to individuals ≥60 years old, consistent with prior literature. Diagnosing new-onset IBD in the older adult represents a unique challenge as a myriad of advanced age associated comorbidities can present with similar symptoms and endoscopic findings. These include segmental colitis associated with diverticulitis, colorectal cancer, radiation proctitis, ischemic and infectious colitis, as well as NSAID-induced enterocolitis (6,7). A detailed summary of potential mimickers, along with their clinical characteristics and distinguishing features, is provided in Table 1 of the paper by Taleban et al. (6) When evaluating an older adult with new onset gastrointestinal symptoms such as weight loss, rectal bleeding, abdominal pain, diarrhea and/or constipation, a careful review of medical history, family history (for presence of other immune-mediated conditions), and medications used (both prescribed and over the counter) must first be performed. This, in conjunction with laboratory tests (elevated C-reactive protein, anemia, thrombocytosis, etc.), stool tests (both infectious studies as well as inflammatory [fecal calprotectin and/or lactoferrin]), imaging, endoscopy and pathology can help confirm the potential diagnosis of IBD. Expedited and complete evaluation, recognizing that IBD can present for the first time later in life, can reduce diagnostic delays frequently experienced by older adults. In cases where the diagnosis remains uncertain, close follow-up with repeat labs, imaging, and/or endoscopy is warranted to assess for chronicity and disease extension, both of which may offer important clues supporting a diagnosis of IBD. Early diagnosis is critical, as prolonged inflammation and life-impairing symptoms may contribute to physical and cognitive decline (8,9).Table 1.: Treatment considerations for older adults with IBDaEnvironmental factors should be considered, as they are posited to play a greater role than genetic factors in the development of older-onset IBD. In 2 recent epidemiologic studies, antibiotics, particularly those with the greatest impact on the intestinal microbiome (e.g., fluoroquinolones, nitroimizadoles), and the presence of atherosclerotic-related diseases, were found to predispose older adults to develop IBD (10,11). Clinical presentations differ among older adults with incident IBD compared to younger adults who develop IBD. In particular, rectal bleeding is more common among older adults with new-onset CD as compared to younger adults (12). There are also differing phenotypes and areas of disease involvement in older adults with new-onset CD; they are more likely to have isolated ileal or colonic disease but less likely to have ileocolonic disease as compared to younger adults (13). Further, stricturing disease is more common among older adults with CD, with a lower incidence of penetrating disease. In older-onset UC, left-sided colitis is more common, with a lower incidence of isolated proctitis or pancolitis. DISEASE COURSE AMONG OLDER ADULTS WITH IBD A common misconception is that disease-severity is lower among older individuals. In a meta-analysis of population-based cohort studies, older adults who had new onset IBD, had similar clinical trajectories at 1, 5, and 10 years as compared to younger adults. More specifically, need for corticosteroids, IBD-related hospitalization, and IBD-related surgery were similar between the older-onset and younger-onset cohorts, when stratified by both UC and CD (14). Although immunosenescence is classically thought to reflect a reduced immune response, it may instead represent immune dysregulation, characterized by diminished T-cell diversity and loss of tolerance to self-antigens, which may in part explain the similar severity of IBD observed in older adults (15). In a survey-based study of individuals dating back to 1978, nearly one-quarter of adults had active disease even after 20 years of diagnosis (16). Among individuals whose IBD improves with advancing age, there are no clinical or molecular mechanisms to identify these patients. Summary: Introduction Older adults are the age cohort with the most prevalent IBD. Minimize diagnostic (and treatment) delays Perform a careful environmental and exposure history Some older adults may have less clinically significant IBD with advancing chronologic age, though many older adults still experience robust inflammation. TREATMENT CONSIDERATIONS The therapeutic armamentarium for IBD is rapidly expanding (17). Despite the number of steroid-sparing treatment options, older adults with IBD are significantly less likely to receive steroid-sparing therapy as compared to younger adults (14,18). This may in part explain why older adults with IBD have worse clinical outcomes as compared to younger adults; a finding which cannot be explained by differences in disease course. Older adults are more likely to be hospitalized, require surgical management, and have a disproportionately greater mortality from IBD as compared with younger adults (19–21). Further, advanced chronologic age is frequently used as an exclusion criterion in IBD clinical trials, resulting in a reluctance to use advanced therapies for older adults with IBD. Of the 46 randomized clinical trials (RCTs) reporting age, only 18 (39.1%) included individuals ≥ 65 years old (21). Moreover, of these 18 RCTs, individuals ≥ 65 years old only accounted for 0.6% of the 6,517 trial participants (22,23). Thus, while the management of IBD has advanced overall, older adults have not benefited due to a lack of data. Medical treatments Corticosteroids Over the past century, corticosteroids have been the mainstay of treatment for IBD. However, due to the high-risk of both short- and long-term side-effects, including but not limited to thrombosis, fractures, insulin resistance, adrenal insufficiency and infections, corticosteroid-sparing options have replaced them as the standard of care (24). Additionally, older adults are at higher risk for adverse outcomes due to corticosteroids compared to younger adults (25). Despite this, older adults are often prescribed prolonged courses of corticosteroids for the treatment of IBD (26). We recommend that corticosteroid use should be limited to the induction period and minimized in the maintenance period, with consideration of switching strategies if corticosteroids are needed frequently. If needed, we recommend a trial of budesonide over systemic corticosteroids if appropriate. Mesalamines Mesalamine agents can be effective for the treatment of mild to moderate UC. However, mesalamine monotherapy is not recommended for maintenance in the setting of moderate to severe UC-related inflammation. Similarly, although data are limited regarding mesalamine use in mild CD, high-quality evidence demonstrates that it is not effective for moderate to severe CD (27,28). Despite this, in a French population-based study of older adults with new-onset IBD, more than 90% of individuals with both UC and CD were prescribed mesalamines, whereas fewer than 20% with UC and 33% with CD were prescribed anti-TNF or immunomodulator therapy within 10 years of diagnosis (29). This pattern is consistent with findings from a Danish national registry study, which reported that individuals with IBD onset at or after age 70 had markedly lower use of immunomodulating therapy and surgery, even compared to those aged 60 and above (30). These low rates likely reflect hesitancy in prescribing immune-modulating therapies due to concerns about adverse events, rather than an accurate reflection of disease severity distribution in older adults. Additionally, since renal function declines with advancing age, kidney function should be monitored at least annually when using mesalamine to ensure prompt recognition of the rare but serious side effect of interstitial nephritis. Immunomodulators Immunomodulators are older medications with a less established safety profile among older adults. Methotrexate is primarily renally excreted, which should be kept at the forefront when prescribing it for the older adult. Furthermore, methotrexate toxicity is often quite subtle and occurs more commonly in the older adult, with presentation most notable for fatigue and myalgias (31). Thiopurines also carry greater risks with advancing chronologic age (32–34). This is especially the case given the elevated baseline risk of lymphoma that is present among individuals >55 years old, with 1 model suggesting a 9 fold increase in lymphoma incidence between the 4th decade of life and 8th decade of life with thiopurine use (34,35). Additionally, thiopurine use is associated with nearly a twofold increased risk of non-melanoma skin cancer (NMSC), an especially important consideration in older adults who may already have a history of recurrent skin cancers (36). Despite the potential increase in risk of lymphoma, NMSC, and infection, combination therapy may still be appropriate in select older adults; particularly those with ongoing perianal disease or at high risk of developing anti-TNF antibodies. In a post-hoc analysis of the REACT trial, combination therapy was not associated with a higher risk of serious complications or death compared to conventional therapy in older adults (37). However, in those with a history of lymphoma or NMSC, these risks may outweigh potential benefits and should prompt careful consideration of combination therapy. Notably, no dedicated studies of thiopurine withdrawal or replacement among the older adult who has maintained endoscopic remission has been assessed. Biologics Biologic agents have an established safety profile in older adults, with studies demonstrating the safety of anti-TNF agents, vedolizumab and ustekinumab (38–41). While many studies conclude that biologic agents confer a higher rate of adverse events, including infections and hospitalizations, among older adults as compared to younger adults, it is imperative to understand the drug-attributable risk vs the disease-attributable risk (42,43). In a post-hoc analysis of randomized clinical trial data for older adults with moderate-to-severe UC, effective IBD treatment with an anti-TNF agent resulted in numerically lower rates of serious adverse events, hospitalizations, and severe infections as compared with older adults who were treated with placebo (44). These results support the notion that treatment of disease with anti-TNF therapy does not worsen clinical outcomes, and may in fact, improve clinical outcomes among older adults with IBD. It is therefore paramount to consider both the safety and efficacy of a therapy when choosing a biologic. Further, comorbidities should be considered, as they can both determine the appropriateness of a therapy as well as therapy related risks (45). When using anti-TNF therapy among older adults with IBD, it is critical to ensure adequate dosing based upon albumin and clinical characteristics. In an analysis of more than 20,000 samples, older adults were more likely to develop antibodies to anti-TNF therapy, and were less likely to receive dose escalation compared to younger adults with IBD (46). This underscores the importance of close therapeutic drug monitoring in this population, particularly in the setting of ongoing symptoms. There is a lack of data demonstrating an association between serum level of anti-TNF and risk of an adverse outcome, thus dosing should be based upon clinical characteristics, and should be determined independent of chronological age. Small molecule inhibitors In the ORAL surveillance study, individuals with rheumatoid arthritis who were ≥50 years old with at least 1 additional cardiovascular risk factor failed to demonstrate non-inferiority for JAKi as compared to anti-TNF therapy for the outcomes of a major adverse cardiovascular event or malignancy. Venous thromboembolism (VTE) events were also higher for the tofacitinib group as compared to the anti-TNF group, with a dose dependent effect seen (47). However, the safety of small molecule therapy among older adults with IBD has been less well studied. In 1 retrospective study of 123 individuals ≥50 years old on tofacitinib, there was no increased risk of venous thromboembolism or cardiovascular events, as compared to those on anti-TNF therapy (48). Additional studies have suggested the long-term safety of JAK inhibitors, though their applicability is limited by the underrepresentation of older adults and individuals with established cardiovascular or thromboembolic comorbidities (49). 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