Curr Treat Options Gastro DOI 10.1007/s11938-015-0059-6

Geriatrics (S Katz, Section Editor)

Challenges in the Diagnosis and Management of Inflammatory Bowel Disease in the Elderly Sasha Taleban, MD Address The University of Arizona Medical Center, 1501 N. Campbell Ave, Tucson, AZ 85724, USA Email: [email protected]

* Springer Science+Business Media, LLC 2015

This article is part of the Topical Collection on Geriatrics Keywords Elderly I Inflammatory bowel disease I Crohn’s disease I Ulcerative colitis I Older I Treatment

Opinion statement Among inflammatory bowel disease (IBD) patients, 4–12 % is diagnosed after the age of 60. Both the rates of elderly and IBD are increasing worldwide. In older patients, the diagnosis of Crohn’s disease (CD) and ulcerative colitis (UC) is made more difficult due to polypharmacy and multimorbidity along with disease processes that mimic IBD. The clinical presentation in older-onset IBD differs from younger patients, and there is minimal disease progression over time. The management of the older IBD patient involves a combination of medical and surgical strategies. Few treatment efficacy studies exist in elderly IBD as most authors have focused on the adverse events related to therapy. A vast number of incident CD and UC cases in elderly have been treated with 5-aminosalicylic acid agents and do not require the use of immune modifying agents or biologics. Many other older IBD patients are prescribed long-term corticosteroids despite guidelines recommending more effective and safer maintenance therapy regimens. Serious infections, malignancy, and drug interactions are the most concerning complications of medical therapy. There are particularly important health care maintenance issues in older IBD patients including vaccinations, colorectal cancer screening, and bone loss prevention.

Introduction Older-onset inflammatory bowel disease (IBD) has been identified as a unique entity going back well over half a century [1–3]. More recently, there has been

increased recognition of the disease in older patients with further characterization among the European population [4–8, 9••, 10•]. This increased attention

Geriatrics (S Katz, Section Editor) may in part be due to the rising population of elderly. By the year 2030, a fifth of the US population is expected to be 65 years and older [11]. At the same time, the rates of IBD are increasing [12]. Although traditionally IBD has been associated with the young, 4–12 % is diagnosed in the elderly [9••, 10•]. An aging population and the increasing incidence of Crohn’s disease (CD) and ulcerative colitis (UC) worldwide make elderly inflammatory bowel disease (IBD) an increasingly important issue. Patients who transition to old age with long-standing disease differ than those diagnosed at an older age. Difficulties associated with the diagnosis in the latter group may be due partly to a different disease pathophysiology and issues of polypharmacy and multimorbidity. Diagnostic tools, used to assess active intestinal disease, may vary with age and have not been validated in the elderly [13].

Since chronological age may not correlate with health status, management strategies vary between different elderly patients based on their physiologic age or frailty. Older patients may have more financial constraints and age-related functional capacity that limit management options [14]. The anti-TNF agents and immune modifying agents, commonly used for moderate to severe IBD, raise the concern for increased risk of adverse events in older patients, particularly serious infection and malignancy. Older age also has been associated with higher postoperative complications [15]. There are few medical and surgical studies to guide management of elderly IBD [7], leaving patients and providers to base treatment decisions on limited data and extrapolation from studies in younger adults. In this review, we will examine the difficulties in the diagnosis and management of IBD in the elderly.

Diagnosis Since other disease processes can mimic IBD, older patients with intestinal inflammation should be ruled out for infection, NSAID-induced intestinal injury, diverticular-associated disease, and ischemia. Stool studies for infectious organisms are essential in ruling out colitis secondary to microbial pathogens, particularly Clostridium difficile, which is associated with a 20 % rehospitalization rate and 9 % mortality in hospitalized elderly patients [16]. In 2012, approximately 98 million NSAID prescriptions were written and 29 million people were on chronic NSAIDs [17]. The elderly are particularly susceptible to the intestinal effects of NSAIDs like enterocolitis. A careful history of prescription and over-the-counter medications is key to identifying at-risk patients. Segmental associated colitis with diverticula (SCAD) spares the rectum and is isolated to areas of diverticular disease. In one study, 8 % of patients with SCAD were originally diagnosed with IBD [18]. Both SCAD and ischemia are histologically indistinguishable from IBD. Ischemic colitis is common in elderly occurring in regions of colon with decreased collateral vessels and increased susceptibility to changes in vascular flow. The splenic flexure, rectosigmoid, and right colon are the most common involved areas. Well-demarcated lesions that resolve on serial exams distinguish ischemic colitis. Establishing the diagnosis of older-onset IBD can be complicated by polypharmacy, multimorbidity, and cognitive impairment. On average, older IBD patients take 9.5 medications per day [19]. These medications are often being taken for cardiopulmonary disease, diabetes, and psychiatric disorders. Though typical risk factors for cardiovascular disease are not elevated in IBD patients, they are more prone to developing atherosclerosis [20]. Additionally, depression affects 23 % of older IBD patients [21]. Cognitive deficit is common

Challenges in Diagnosis and Management of IBD in the Elderly


among the elderly. After the age of 65, 17 % of patients have a cognitive decline often complicating diagnosis and management of IBD [22]. In IBD, objective assessment of intestinal inflammation is important for appropriate disease management. Biomarkers like fecal calprotectin and lactoferrin compliment diagnostic colonoscopy and imaging. However, the reference ranges for these biomarkers are age-related, and up to now, no reference range has been validated in older patients [23, 24]. Therefore, the current approach to the use of IBD biomarkers in the elderly may not accurately reflect disease activity. The etiology of IBD in the elderly differs from younger patients. Advanced age is associated with a gradual decline in immune function, termed immunosenescence. Pathophysiology of older-onset IBD is driven by aberrant immune pathways and gut dysbiosis rather than genetics [8]. This etiologic variability may play explain the unique disease distribution of CD and UC at an advanced age. In CD, older patients tend to have more isolated colonic disease and less small bowel or perianal disease, while in UC, left-sided colonic disease is more common with older age [9••]. Disease location explains the clinical presentation in older-onset IBD. CD patients often present with bloody diarrhea and less often weight loss [9••]. Rates of extraintestinal manifestations of disease are similar among all adult UC patients, while in CD, they occur less often among elderly [9••]. Some elderly patients may have atypical presentations of their disease adding to the diagnostic complexity [25].

Treatment The approach to IBD management involves a combination of medical and surgical therapy. The goal is to balance disease remission with the risks of ongoing active disease and its treatments. However, elderly are excluded from many of the larger studies examining drug efficacy, and when older patients are included, the results are not stratified according to age. In the medical management of adults, the goal of therapy is deep remission, defined as a combination of endoscopic healing and resolution of symptoms. It is unclear if clinical outcomes are best judged by subjective, objective, or a combination of these factors among elderly. Additionally, most studies in older patients have focused on potential adverse effects [26•]. Often, IBD providers are left with an incomplete and unbalanced standard in which to make complex management decisions regarding care of elderly IBD patients. In clinical trials of CD, the Crohn’s Disease Activity Index (CDAI) and the Harvey-Bradshaw Index (HBI) are often used as clinical endpoints. The HBI score correlates well with the CDAI [27]. CDAI takes into account subjective and objective findings to develop a score, classifying patients into one of four categories: remission, mild–moderate disease, and moderate–severe or fulminant disease. Among UC patients, the simple clinical colitis activity index (SCCAI) has been validated as a tool to stratify patients according to disease severity. For CD and UC patients, clinical trials determine quality of life through the IBD questionairre (IBDQ) or its abbreviated version, the short IBD questionairre (SIBDQ). None of these measures have been validated in older adults. It is vital to consider the natural history of disease with any intended treatment strategy. Older-onset CD patients have a more mild progression of disease extent and behavior. A similar pattern is found in extent of disease in

Geriatrics (S Katz, Section Editor) older-onset UC. One of the largest studies of older-onset IBD found that among CD patients, disease behavior (i.e., from inflammatory to stricturing/ penetrating or from stricturing to penetrating) remained unchanged after 10 years [10•]. A population-based study utilizing the EPIMAD registry of inhabitants in Northern France found that upon presentation, 78 % of patients had an uncomplicated inflammatory phenotype. Yet 91 % of older patients did not have progression of their disease behavior to more complicated stricturing/ penetrating disease [9••]. In UC, disease extension remained stable in 84–91 % of patients [9••, 10•]. A Btop-down^ treatment approach using immune modifying agents and biologics earlier in the course of therapy is now favored in most adults with IBD. However, based on the slow disease progression and concerns over adverse effects of medical treatment in the elderly, the preferred approach in older adults is Bstep-up^ therapy.

Mild–moderate IBD Mesalamine or 5-aminosalicylic acids (5-ASAs) are the mainstay of induction and maintenance therapy in mild-moderate UC. Oral 5-ASAs, which include olsalazine and balsalazide, treat different parts of the small and large intestine based on the mechanism of drug release. Topical 5-ASAs include suppositories and enemas, address distal colonic inflammation, and are more effective in inducing endoscopic and histological improvement when compared to topical corticosteroids [28]. Combination of oral and topical 5-ASA therapies is more effective than only oral 5-ASA alone [29]. Among older-onset UC patients, 84 % have used at least one formulation of 5ASA after 10 years of disease [9••]. There are multiple challenges associated with 5ASA use in the elderly. Though they have a favorable adverse event profile, oral regimens may require four divided doses and upwards of 16 pills daily, decreasing compliance rates to 40 % [30]. Patients with at least four prescriptions have even lower adherence rates [30]. Single dosing formulations decrease the pill burden and improve compliance [31, 32]. Practical difficulties can impair the routine use of topical therapy. Many elderly have limitations on self-administration or retention of suppositories and enemas. When a prescription for topical therapy is being considered, a clear and open discussion and review of daily medication administration habits may help in developing an effective strategy for patients. While commonly prescribed in UC, 5-ASA use is more controversial in CD. While several studies have shown the efficacy of 5-ASAs in certain CD patients, most have shown that it is no better than placebo [33, 34]. Still, 80 % of olderonset CD patients have been exposed to these agents [9••]. This is in part due to the fact that in mild–moderate CD, there are few agents available for induction and maintenance. Budesonide is effective for induction therapy in ileitis and right-sided colitis in CD but is ineffective as a maintenance measure [35•]. Budesonide-multi-matrix system (MMX), a formulation that uses colonic release MMX to extend release of the drug to the colon, is effective for inductive therapy in UC [36]. Studies on antibiotic use in luminal CD and UC are inconsistent, but there may be a role in isolated colonic CD [37]. 5-ASAs have a very favorable safety profile, which in part explains the frequency with which they are prescribed in the elderly. There is a risk of nephrotoxicity especially in the elderly with underlying or predisposing factors to kidney disease like diabetes and hypertension. In one of the largest studies,

Challenges in Diagnosis and Management of IBD in the Elderly


the rate of kidney disease was 0.17 per 100 patients in 5-ASA users with IBD and 0.25 in IBD patients not on 5-ASAs, suggesting that IBD itself may be the culprit [38]. There appears to be no dose or duration-dependent effect on 5-ASAassociated nephrotoxicity [39]. 5-ASAs also may increase the risk of myelosuppression when used with thiopurines [40]. Concomitant NSAIDs also increase the risk of kidney injury. Budesonide, which does not have some of the systemic effects of other corticosteroids, has been associated with adrenal suppression and bone loss [41, 42].

Moderate–severe disease Immune-modifying agents and biologics are corticosteroid-sparing therapies that treat moderate–severe CD and UC. Corticosteroids, used short-term for induction of remission, require an exit strategy when initiated. Azathioprine, 6mercaptopurine, infliximab, adalimumab, and vedolizumab are utilized for both CD and UC. Additionally, methotrexate, certolizumab, and natalizumab are used in CD, while golimumab has been approved in UC. Older IBD patients with multiple comorbidities and decreased functional status have a lower threshold for hospitalization, accounting for 25 % of all IBD-related hospitalizations [43]. Once hospitalized, patients 65 years and older are at increased risk of infection and malnutrition, require more blood transfusions, and have higher inpatient mortality [43]. Hospitalization can be prevented with adequate medical therapy and prevention of disease-related complications. In carefully selected older IBD patients, the use of immune suppressive therapy may be an important part of this strategy. No studies have evaluated the efficacy of using immune modifying agents specifically in the elderly and guidelines have not suggested that these medications are any more or less efficacious in this population [35•, 44•]. The scant data on anti-TNF use in elderly IBD is inconclusive. While one study showed that patients who transition to older age with their disease had similar clinical remission rates as younger adults, another described higher primary nonresponse rates and less sustained use among elderly [26•, 45•]. The use of natalizumab, an alpha-4-beta-1 anti-integrin antibody, has been limited by the risk of progressive multifocal leukoencephalopathy. Vedolizumab, an alpha-4-beta-7 antibody, which is a gutspecific protein, has been shown to be more effective in maintaining remission among older adults in both CD and UC [46, 47]. Currently, management of IBD in older patients may not be optimized and run counter to published guidelines, which limit corticosteroid use to induction therapy. In one retrospective observational study, over 30 % of patients ≥65 years old were maintained on long-term corticosteroid therapy, while 7 % were on thiopurines and 3 % were prescribed anti-TNFs [48]. Older-onset IBD patients were more frequently on corticosteroids than younger patients, had a higher average daily dose, and the percentage of older patients on corticosteroids increased over time [48]. Beyond its impact on bone disease, glucose metabolism, ocular manifestations, and psychiatric illness, corticosteroids are associated with serious infections, particularly in IBD patients [49]. A Canadian population-based study showed that incident IBD cases in patients 965 years old were threefold more likely to be hospitalized for serious infection. Corticosteroid use is a marker of active intestinal inflammation, which predisposes to infection. To make a more direct association between corticosteroids and infection, the authors showed a time-dependent risk of serious infection, with more recent corticosteroid use

Geriatrics (S Katz, Section Editor) associated with the highest vulnerability to infection [50]. In another study evaluating 100 consecutive IBD patients with opportunistic infections, increasing age was a risk factor for infection. Thiopurine and anti-TNF agent use were significantly associated with infection but the highest risk was among patients on two- or three-drug regimens that included corticosteroids [49]. This data is substantiated by the Crohn’s Therapy, Resource, Evaluation, and Assessment Tool (TREAT) registry data, which suggests that advanced age as well as the use of thiopurines and anti-TNFs are significantly associated with serious infection. However, corticosteroids and narcotics had the strongest association with infection and predicted mortality [51•]. In the TREAT registry, moderate to severe disease activity was associated with increased infection and mortality, suggesting that disease activity in part may have been driving the underlying risk [51•]. Older patients are more likely to have a history of malignancy and the risk of cancer increases with age. IBD patients 965 years old with a previous history of malignancy are at risk for new or recurrent malignancy, but this risk is not elevated with immune suppression [52]. With the exception of colon cancer and small bowel cancer in CD, IBD itself does not appear to predispose to cancer [53, 54•]. From the nationwide VA database, compared to thiopurinenaïve patients, the hazard ratio of non-Hodgkin’s lymphoma (NHL) in current thiopurine users was 4.2 and decreased to 0.5 when treatment was stopped. Age 965 was a risk factor for lymphoma development [53]. The data on methotrexate and the risk of lymphoma from the rheumatoid arthritis have not yet shown a significantly increased link to NHL [55, 56]. A prospective French study over 3 years did find that when compared to the general French population, methotrexate users were seven times more likely to develop Hodgkin’s disease [55]. The lymphoma risk tied to anti-TNF use appears less convincing. A metaanalysis, which followed CD patients for an average of 9.3 years found the risk of NHL was statistically increased in anti-TNF users compared to the general population, but the absolute risk was minimal at 6.1 per 10,000 patient years. The SIR and absolute risk increased dramatically with age among patients on anti-TNFs but was statistically significant only for men between the ages of 55– 64. However, 66 % of these patients were on concomitant immune modulating agents, making it difficult to decipher which medication was driving the elevated risk [57]. In the TREAT registry, when compared to data in the SEER database, there were more cases of lymphomas than expected in anti-TNF users, but the results were not statistically significant [54•]. Skin cancer has also been associated with immune suppression. The risk of nonmelanoma skin cancer (NMSC) has been tied to thiopurine use [58, 59], though not all studies have been consistent [54•]. Compared to thiopurinenaïve patients 965 years old, those exposed have a sixfold greater risk of NMSC [59]. This may be due to a decreased capability to repair photo-oxidative DNA damage in older adults [60]. Duration of exposure, typically not reported, plays a role. Anti-TNF monotherapy use in IBD appears to be associated with melanoma [61], but the rheumatology literature has not shown a statistically significant difference [62]. Dual therapy with biologics and thiopurines does not appear to increase the melanoma risk [63]. There are notable drug interactions with immune modulators and biologics among elderly. Allopurinol and ACE inhibitors can increase the risk of myelosuppression with thiopurines [64, 65]. While thiopurines can decrease the anticoagulation effects of warfarin, methotrexate may potentiate the action

Challenges in Diagnosis and Management of IBD in the Elderly


of warfarin [66, 67]. NSAIDs and loop diuretics can increase the concentrations of methotrexate while concentration of loop diuretics can also be altered by methotrexate [66, 67]. Finally, anti-TNF agents should not be used concomitantly with other biologics due to concerns for increased immunosuppression and infection [68]. Patients refractory or unable to tolerate medical therapy and those with dysplasia or cancer require surgery. Patients 955 years old undergo at least 25 % of intestinal surgeries in IBD [69]. The rate of surgery appears to be similar regardless of age [10•, 70, 71]. Timing of surgery is an important determinant of outcome [15, 72, 73]. A single-center study reported that among patients 960 years old undergoing emergent colectomy, there was significantly higher mortality rates compared to elective operations (27 versus G1 %). The most common causes of death were pneumonia and sepsis [73]. The largest series of patients 965 undergoing colectomy for UC revealed that urgent surgery and low albumin were associated with worse outcomes [72]. Patients requiring urgent surgery would be expected to have more fulminant disease and at higher risk for poor outcomes. Surgery in IBD patients ≥60 years old is associated with higher complication rates, hospital length of stays, and operating room time. However, when comparing this older group to their younger counterparts, age ≥60 was associated with higher rates of immune suppression use suggesting more advanced disease [15]. Surgery often is delayed in older patients and close collaboration between medical and surgical providers can optimize outcomes. Ileal pouch-anal anastomosis (IPAA) is the operation of choice in older UC patients undergoing restorative proctocolectomy. Daytime and nighttime bowel frequency, bowel incontinence, and pouch failure rates are similar between older and younger patients [74, 75]. Overall, quality of life was very good, with 89 % of patients willing to undergo the surgery again [75]. Patients with decreased anal sphincter function may have better health outcomes with colectomy and ileorectal anastomosis or end-ileostomy (EI) surgery. A population-based national VA study found no difference in morbidity and mortality in older patients undergoing permanent EI versus IPAA [76].

Health care maintenance Smoking Smoking, one of the best studied lifestyle factors in IBD, is associated with exacerbation of CD and a protective effect in UC [77]. Smokers respond less well to anti-TNF agents, and this may occur in a dose-dependent manner [78]. Though smoking rates decrease with aging, a European study revealed that among patients between 60 and 64 years old, roughly 30 % of CD and 20 % of UC patients were active smokers [77]. Cigarette use has deleterious effects on other important aspects of care in elderly IBD such as bone health, venous thromboembolism, and cardiovascular disease. Smoking cessation must be a point of discussion between providers and older patients.

NSAIDs NSAIDS are among the most frequently used medications in the elderly to treat osteoarthritis and CVD prevention, but they may exacerbate IBD. The only study to evaluate IBD patients and the risk of relapse between groups taking and not taking

Geriatrics (S Katz, Section Editor) NSAIDs revealed an OR of 6.31 associated with NSAID use. However, the study had incomplete data for smoking status among patients and did not control for disease activity prior to NSAID exposure [79]. Some studies have suggested the use of selective COX inhibitors to avoid exacerbation of IBD and potential adverse events. A recent Cochrane evaluation included only two studies and found no association between COX-2 inhibitors and increased IBD activity or adverse events. No definitive conclusions could be made due to the small size and short duration of the studies [80]. Overall, studies linking NSAIDs to increasing IBD activity are inconsistent and further work is necessary to clarify this relationship [81]. Both the American College of Gastroenterology and British Society of Gastroenterology guidelines indicate that IBD may be exacerbated by NSAID use [44•, 82]. In older IBD patients in remission, it is considered reasonable to use low-dose aspirin and short-term COX-2 inhibitors. Whenever possible, alternative therapies including acetaminophen, intraarticular corticosteroids, and nonpharmacological methods (i.e., physical therapy, exercise) should be utilized.

Vaccinations The immune system’s ability to detect and defend against infection wanes with aging. T cells, critical to the adaptive immune system response to gut antigens, are less effective in older age, and the elderly are more susceptible to infection [83]. Immune suppression therapy can further elevate this risk. Respiratory infections, including pneumonias and flu, are the most common infections in the elderly. These respiratory ailments are preventable with vaccinations [84]. The recommended vaccinations in the older IBD are the same as those without CD or UC. Live vaccines are typically avoided with immune suppression use. The use of the live herpes zoster vaccine is controversial with careful consideration given to its benefits and potential adverse events before administration. The indicated vaccinations in older IBD patients include the annual influenza flu vaccine, the pneumococcal vaccine administered at the age of 65, and the zoster vaccine after age 60. Importantly, vaccination is more likely to be associated with a suboptimal response in the elderly, especially in the setting of immune suppression [84–86].

Colorectal cancer screening There is variability among IBD studies regarding the degree of colorectal cancer risk which makes up 10–15 % of IBD deaths [87]. A population-based study showed similar rates of dysplasia and cancer between older age onset and younger UC patients [10•]. Colorectal cancer screening in the elderly can prevent poor outcomes. However the risk of colonoscopic complications including intestinal perforation increase with advanced age though this finding has not been consistent [88–90]. The number of patient comorbidities is also associated with increased complication risk. Whether aging or multimorbidities is driving the association is unclear [89]. Chronological age may not predict the overall well-being of an individual, and the approach to decisions regarding continuing colorectal cancer surveillance should be based on the patient’s life expectancy and the patients’ desires.

Bone health Between 26 and 48 % of CD and UC patients have decreased bone density when compared to a non-IBD population with a risk of fracture that is 40 % higher [91, 92]. The lifetime risk of a hip fracture is 17 %

Challenges in Diagnosis and Management of IBD in the Elderly


in Caucasian women and 6 % in men over age 60, with significant impact on morbidity and mortality [93]. Older age is a risk factor for the development of osteoporosis, but establishing the degree to which IBD affects bone loss is difficult because of confounding factors like corticosteroids, poor nutrition, duration of disease and ongoing active inflammation, and body habitus [94]. The American Gastroenterological Association (AGA) guidelines suggest bone density tests be performed in postmenopausal women and males 950 years of age along with patients with a history of fractures, 93 months of corticosteroid use, or hypogonadism [94]. Multiple studies reveal inadequate vitamin D levels in 40–100 % of community-dwelling older adults, even those taking supplements [95]. One approach would encompass following vitamin D levels ensuring that patients are receiving optimal dosing of calcium and vitamin D.

Conclusion An increasing population of older IBD patients creates challenging issues. IBD is a diagnosis of exclusion in the elderly requiring careful verification of the disease. The lack of efficacy studies in elderly IBD and the concern for adverse events such as infection and malignancy has led to suboptimal medical and surgical management of patients. When immune suppression or surgery is indicated, it has to be individualized to each patient to ensure maximal clinical benefit and minimize the risk of complications. Comprehensive management of older IBD patients entails minimizing factors that exacerbate active disease, updating vaccinations, appropriate colorectal surveillance, and maintenance of bone health.

Compliance with Ethics Guidelines Conflict of Interest Sasha Taleban declares that he has no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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Challenges in the Diagnosis and Management of Inflammatory Bowel Disease in the Elderly.

Among inflammatory bowel disease (IBD) patients, 4-12 % is diagnosed after the age of 60. Both the rates of elderly and IBD are increasing worldwide. ...
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