Alimentary Pharmacology and Therapeutics

Systematic review with meta-analysis: inflammatory bowel disease in the elderly J. P. Gisbert & M. Chaparro

Gastroenterology Unit, Centro de Investigaci on Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBEREHD), Hospital Universitario de La Princesa and Instituto de Investigaci on Sanitaria Princesa (IP), Madrid, Spain.

Correspondence to: Dr J. P. Gisbert, Playa de Mojacar 29. Urb. Bonanza, 28669 Boadilla del Monte. Madrid, Spain. E-mail: [email protected]

Publication data Submitted 14 October 2013 First decision 3 November 2013 Resubmitted 19 December 2013 Accepted 20 December 2013 EV Pub Online 9 January 2014 This uncommissioned systematic review was subject to full peer-review.

SUMMARY Background Elderly patients represent an increasing proportion of the inflammatory bowel disease (IBD) population. Aim To critically review available data regarding the care of elderly IBD patients. Methods Bibliographic searches (MEDLINE) up to June 2013. Results Approximately 10–15% of cases of IBD are diagnosed in patients aged >60 years, and 10–30% of the IBD population are aged >60 years. In the elderly, IBD is easily confused with other more common diseases, mainly diverticular disease and ischaemic colitis. The clinical features of IBD in older patients are generally similar to those in younger patients. Crohn’s disease (CD) in elderly patients is characterised by its predominantly colonic localisation and uncomplicated course. Proctitis and left-sided ulcerative colitis are more common in patients aged >60 years. Infections are associated with age and account for significant mortality in IBD patients. The treatment of IBD in the elderly is generally similar. However, the therapeutic approach in the elderly should be ‘start low-go slow’. The benefit of thiopurines in older CD patients remains debatable. Although the indications for anti-tumour necrosis factors in the elderly are generally similar to those for younger patients, lower response and higher adverse events have been reported in the elderly. Surgery in elderly patients does not generally differ. Ileal pouch-anal anastomosis can be successful, provided the patient retains good anal sphincter function. Conclusions Management of the older IBD patient differs from that of younger patients; therefore, conventional practice algorithms may have to be modified to account for advanced age. Aliment Pharmacol Ther 2014; 39: 459–477

ª 2014 John Wiley & Sons Ltd doi:10.1111/apt.12616

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J. P. Gisbert and M. Chaparro INTRODUCTION Inflammatory bowel disease (IBD), which comprises Crohn’s disease (CD) and ulcerative colitis (UC), is thought to be primarily a condition of young individuals. However, a significant proportion of new cases of IBD are diagnosed in elderly persons, and, given the negligible impact of IBD on mortality, younger patients with IBD will contribute to an increasing pool of ‘elderly’ IBD patients as they age.1 The prevalence of IBD is increasing worldwide, with the result that ageing of the population makes IBD in the elderly a growing problem. Recent estimations indicate that approximately 20% of the United States (US) population will be aged >65 years by the year 2030.2 At present, 10–15% of patients diagnosed with IBD are aged >60 years.3 Of these, 65% present in their 60s, 25% in their 70s and 10% in their 80s.4 Consequently, the number of elderly patients with IBD is expected to grow. Caring for older IBD patients who have either presented later in life or have had IBD for several decades presents the physician with unique challenges.5, 6 The characteristics of IBD in the elderly remain uncertain because data are scarce at the population level and come mainly from referral centres. Moreover, data from clinical trials cannot be extrapolated to this population, as older patients are excluded in the vast majority.1 Other recent trials did not set an upper age limit for eligibility, but the median age in most was the fourth decade.1 Since it was first reported in 1935, late-onset IBD has attracted much interest among clinical investigators.7 Despite advances in our knowledge of IBD, controversy remains concerning the epidemiology, clinical presentation, diagnosis, clinical course and management of IBD in the elderly.7 Management of late-onset IBD is complex because of problems with misdiagnosis, treatment of comorbid diseases, multiple drug interactions, impaired mobility and cognition, and difficult social and financial issues.1 The ageing population has a huge impact on the costs of health care delivery. For example, in Canada in 2005, individuals aged ≥65 years accounted for 14% of the population, but 60% of all acute care service spending. It is therefore important to study and optimise health care delivery to the elderly.8 Elderly patients with IBD can be divided into two groups: elderly patients with onset of IBD at a late age (late-onset IBD); and elderly patients with long-standing IBD, that is, those who had first been diagnosed as having IBD at a younger age (long-standing IBD). Most

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authors make no distinction between the age within each of the groups, although this, as will be reviewed, may be clinically relevant.9 In the present review, we address questions that commonly arise in the care of elderly IBD patients. No consensus has been reached on the definition of ‘elderly’. The World Health Organization defines elderly persons as those aged ≥65 years; however, we focus on patients aged ≥60 years, as most studies agree on this threshold and old-age colitis is generally considered to refer to patients aged >60 years.

SEARCH STRATEGY Bibliographical searches were performed in MEDLINE up to June 2013 using the following keywords: (inflammatory bowel disease OR Crohn’s disease OR ulcerative colitis) AND (elderly OR ageing OR older). Articles published in any language were included. Reference lists from the articles selected by electronic searching were manually reviewed to identify further relevant studies. Abstracts of the articles selected in each of these multiple searches were reviewed, and those meeting the inclusion criteria (that is, providing data regarding IBD in the elderly) were recorded. FREQUENCY OF IBD IN THE ELDERLY Onset of IBD in the elderly population (late-onset IBD) may not be as uncommon as previously suspected. Regional differences in the incidence of IBD in the elderly have been detected. For example, the incidence of CD and UC in the US was 4/100 000/year and 6–8/ 100 000/year, respectively, whereas in Europe, it was 8– 10/100 000/year for both UC and CD in persons aged >60 years.10–12 A population-based study indicated the incidence of CD to be 4/100 000 person-years at age 65 in 1469 European patients with CD.13 The annual incidence of CD in the elderly in France was 2.5/100 000.14 In a large cohort of 2509 patients from Sweden, the age-adjusted annual incidence was 8/100 000 person-years for UC at age 65, compared to a peak of 22/ 100 000 person-years at age 25.15 In relative terms (with respect to total IBD cases), in the largest population-based study of elderly onset IBD reported to date, 1/20 incident cases of CD and 1/8 incident cases of UC occurred in people aged >60 years.9 In summary, studies have shown that 10–15% of cases of IBD are diagnosed in patients aged ≥60 years.3, 4, 16–21 A bimodal age curve for the incidence of IBD has been suggested in epidemiological studies, with a second

Aliment Pharmacol Ther 2014; 39: 459-477 ª 2014 John Wiley & Sons Ltd

Systematic review with meta-analysis: IBD in the elderly peak occurring at 50–70 years.4, 20, 22, 23 However, this proposal remains open to debate and has not been confirmed in population studies using strict radiological and endoscopic diagnostic criteria.4, 17, 19, 20, 24 Thus, the traditional bimodal distribution of IBD was not uniformly seen in recent epidemiological studies.16 Misdiagnosis leads to confusion with acute self-limiting infectious colitis, ischaemia or bowel changes associated with nonsteroidal anti-inflammatory drugs (NSAIDs) and can therefore confound studies on the epidemiology of IBD in the elderly.1 The EPIMAD Registry covers a large area of Northern France with almost 6 million inhabitants (approximately 10% of the French population).25 The aim of this study was to review some of the most recent data obtained from this large population-based registry since its launch in 1988.25 From 1988 to 2008, 18 170 incident patients were recorded in the registry. The data included 8071 cases of incident CD, 5113 cases of incident UC and 591 cases of unclassified IBD. It was concluded that the percentage of late-onset IBD patients, now estimated at 5–11%, is on the rise.26 With respect to elderly patients with long-standing IBD, approximately 10–30% of the IBD population is aged >60 years.12, 19, 27, 28 The incidence of IBD decreases with advancing age: 65% of elderly cases are aged 60–70 years, 25% are aged 70–80 years and 10% are aged >80 years.4, 19

DIFFERENTIAL DIAGNOSIS The diagnosis of IBD in older patients is not as straightforward as it is in younger patients,5, 29 partially because IBD can easily be confused with other more common diseases.30

Katz and Pardi suggested that an appropriate differential diagnosis should be made before diagnosis can be confirmed, as several other conditions can present with symptoms that mimic those of IBD.1 The causes of chronic diarrhoea and bowel inflammation in patients aged >60 years are indicated in Table 1.17 The most frequent are complicated diverticular disease, ischaemic colitis, NSAID-associated diarrhoea, radiation colitis and infectious diarrhoea. Therefore, it is not unexpected that misdiagnosis at the initial presentation is more common in elderly IBD patients (60%) than in younger patients (15%).1, 31, 32 In addition, diagnostic delay is more common in elderly than in younger IBD patients (up to 6 years compared with 2 years).32–34 This delay may be due to the higher prevalence of IBD-like conditions in the elderly, although it could also be the result of unawareness of the possibility of a new diagnosis of IBD in an older patient.1 The most common conditions that can present with symptoms that mimic IBD are summarised below.

Diverticular disease Diverticulitis and diverticular bleeding are the most common complications of diverticular disease and both can mimic symptoms of IBD. Furthermore, diverticular disease coexists relatively frequently with IBD.35 Diverticulitis can be difficult to distinguish from CD, especially in cases of perforation, abscess formation and fistulisation.1 Diverticular colitis can mimic CD of the colon.36 Of particular relevance is the so-called ‘segmental colitis’ associated with diverticular disease, which involves an active inflammation site adjacent (and confined) to the segment containing the diverticula and can simulate IBD clini-

Table 1 | Differential diagnosis of colitis (that mimic inflammatory bowel disease) in patients aged >60 years Disease

Clinical characteristics

Endoscopic findings

Colitis associated with diverticulosis Ischaemic colitis

Rectal bleeding, abdominal pain, diarrhoea

Segmentary distribution, peridiverticular, sigma affected, rectum and proximal colon are normal Segmentary colitis (sigmoid/left colitis), most are non-obstructive

Microscopic colitis Infectious colitis NSAID colitis

Acute onset of abdominal pain and rectal bleeding. Inciting factors may not be found in elderly patients Watery diarrhoea, no rectal bleeding, no fever, frequent cause of diarrhoea in the elderly Dysentery-like diarrhoea, different agents, Clostridium difficile to be ruled out Recurrent abdominal pain, obstruction, perforation, haemorrhage, chronic anaemia

Normal endoscopy, multiple biopsies from colon, association with coeliac disease Diffuse effects on the colon Increased morbidity and mortality in elderly population Any part of the intestine, isolated lesions, aggravate previous ulcerative colitis and Crohn’s disease

NSAIDs, nonsteroidal anti-inflammatory drugs. Modified from Hinojosa del Val et al.17 Aliment Pharmacol Ther 2014; 39: 459-477 ª 2014 John Wiley & Sons Ltd

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J. P. Gisbert and M. Chaparro cally, endoscopically and histologically.17, 37, 38 A recent study in a German elderly IBD population showed that 8% of older patients diagnosed as having IBD in fact had segmental colitis associated with diverticular disease.39 This has clinically relevant consequences, as operations for suspected diverticulitis may be followed by major complications in patients with unrecognised CD.40

Ischaemic colitis Ischaemic colitis in the elderly IBD patient occurs with segmental involvement and can be confused with CD.41 The history, endoscopy, biopsy and subsequent course, as well as imaging studies (albeit less often), usually make it possible to distinguish this diagnosis from CD, although segmental Crohn’s colitis can mimic ischaemia.41, 42 Brandt et al. highlighted the importance of ischaemia as a cause of colitis in the elderly and found that nearly 50% of their patients were misdiagnosed as having IBD.43 Although onset of symptoms is usually abrupt in patients with ischaemic colitis, the course of ischaemic bowel disease may be indolent, making differentiation from IBD difficult.44 Rapid spontaneous improvement is more consistent with ischaemia than with IBD.42 NSAID-induced colitis NSAID-induced ulcerations, strictures and even perforation can mimic IBD.45 Radiation colitis Radiation-induced injury occurs most commonly with gynaecological, rectal and prostate cancers. The appearance of the mucosa may be similar to that observed in IBD, although these diagnoses can often be confirmed with biopsy.1 Infectious colitis Infectious colitis in the elderly patient can also be confused with IBD, mainly UC. For example, Clostridium difficile is no longer considered only a nosocomial infection but is now also recognised as a community-acquired infection. This is particularly true in patients aged >65 years who may be infected with a virulent strain that can lead to prolonged hospitalisation and greater mortality.1 It is important to perform stool studies to identify and distinguish infectious pathogens prior to initiating appropriate immunosuppressive therapy.46 Microscopic colitis Microscopic colitis causes diarrhoea, and occurs most commonly in middle-aged to elderly women.47 Given the 462

normal appearance of the mucosa, this diagnosis should not typically be confused with IBD.1 However, there are cases with proximal mucosal tears, which can sometimes mimic Crohn’s colitis. Diagnosis should be confirmed by biopsy to detect collagenous or lymphocytic colitis.47

CLINICAL PRESENTATION AND DISEASE COURSE The clinical features of older IBD patients are generally similar to those of younger patients, with notable exceptions.1, 3, 42 Furthermore, some reports have found no difference in disease location.32, 43, 48, 49 Nevertheless, elderly patients may have worse outcomes because of factors such as comorbid conditions and delayed presentation.3 Genetic factors seem to play a more prevalent role in paediatric patients with IBD than in older individuals.50, 51 In this respect, older patients are less likely to have a family history of IBD, perhaps reflecting greater environmental influence than in younger 12, 32, 52–54 patients. The clinical manifestations of the first disease flare, both in UC and in CD, are generally similar in patients aged >60 years and in younger age groups.17 Unexplained diarrhoea, weight loss and perianal disease in the elderly should arouse suspicions regarding CD.40, 55, 56 Reports of a more serious clinical course in older patients were not substantiated in some studies.57 In fact, some authors suggested that elderly IBD patients are less likely to present with symptoms of abdominal pain, diarrhoea and anaemia.31–33, 52, 58 With respect to extra-intestinal manifestations of IBD, no significant differences have been observed between elderly and younger patients in several studies,32, 48, 49, 59 although one report concluded that patients aged >40 years were more likely to have uveitis/ iritis than younger patients.60 As an example, 17% of patients aged >60 years of age were reported to have extra-intestinal manifestations in a recent sludy,39 which, in order of frequency, were peripheral arthritis, uveitis, spondylitis and erythema nodosum. The main differences between elderly patients and young patients with IBD are summarised in Table 2. In the following sections, the clinical presentation and disease course will be analysed separately for CD and UC. Crohn’s disease Several authors have reported that CD in elderly patients generally follows the same clinical pattern as in young people, with some exceptions, which are mainly related to the type of clinical onset and disease course.49 In this Aliment Pharmacol Ther 2014; 39: 459-477 ª 2014 John Wiley & Sons Ltd

Systematic review with meta-analysis: IBD in the elderly Table 2 | Inflammatory bowel disease: differences between elderly and young patients Clinical feature

Elderly

Young

Genetic factors Site of involvement

Play a minor role Colon in CD; distal colon in UC

Severity of first UC attack Severity of IBD disease course Behaviour of CD

More severe Less severe Less aggressive; less likely to have stricturing and penetrating CD; change in disease behaviour exceptional Infrequent More subtle Less diarrhoea, abdominal pain, weight loss, fever Less rectal bleeding and abdominal pain Constipation more frequent More frequent Sicker, malnourished, hypovolemic, and more anaemic with increased transfusion requirements; longer post-operative stay More frequent and severe; mainly Clostridium difficile and opportunistic infections Increased risk of several types of cancer; increased risk of non-Hodgkin’s lymphoma and nonmelanoma skin cancer associated with immunomodulators and anti-TNFs Very common Greater number of adverse events, mainly osteoporosis Potential benefit less clear Higher gastrointestinal, haematological and liver toxicity More likely to have contraindications Possibly lower response rate Possibly higher rate of adverse events Poorer results (although continues to be the technique of choice, provided the patient has good anal sphincter function) Still has indications

More relevant Ileum-colon in CD; extensive colonic involvement in UC Less severe More severe More aggressive; more likely to have penetrating CD; change in disease behaviour common Frequent More typical symptoms More apparent More apparent Less frequent Less frequent Less severe; shorter post-operative stay

Proximal UC extension over time Clinical IBD symptoms Clinical picture of CD Clinical picture of UC Atypical UC symptoms Hospitalisation Clinical situation at hospitalisation Infections Cancer

Polypharmacy Corticosteroids Thiopurines Methotrexate Cyclosporine Anti-TNF therapy efficacy Anti-TNF therapy toxicity Ileal pouch-anal anastomosis for UC Ileostomy and ileorectal anastomosis for UC

Less frequent and severe Lower risk of cancer

Less frequent Fewer adverse effects Clearer benefit Better tolerance Fewer adverse effects Possibly higher response rate Possibly lower rate of adverse events Better results

Mostly abandoned

CD, Crohn’s disease; UC, ulcerative colitis.

respect, some researchers have suggested that clinical symptoms on diagnosis are more subtle in elderly patients than in younger patients, with less diarrhoea, abdominal pain, weight loss, fever and extra-intestinal manifestations in CD.25 In a recent study, at the end of follow-up, only 30% of the elderly patients had complications (stricturing or penetrating) compared with more than 50% of the children;25 nevertheless, exceptions, such as CD presenting as toxic megacolon, are reported in elderly patients.61, 62 With respect to the location, colon disease is the most common form in elderly CD patients, whereas extensive Aliment Pharmacol Ther 2014; 39: 459-477 ª 2014 John Wiley & Sons Ltd

colon and diffuse small bowel disease is rare,14, 21, 32, 33, 52, 59, 63–68 although this has not been confirmed in all reports.4, 9, 40, 48 Thus, the proportion of patients with colonic involvement seems to increase with age at diagnosis. In a recent study, 48% of patients diagnosed after age 40 had isolated colonic involvement compared with 28% and 20% for those diagnosed at 20 and 40 years and before age 20 years, respectively.64 In a French population-based cohort (EPIMAD registry) comprising 841 IBD patients aged >60 years at diagnosis,9 the most frequent phenotype at diagnosis in patients 463

J. P. Gisbert and M. Chaparro with CD was pure colonic disease (65%). Because of the higher proportion with isolated colitis, elderly patients are less likely to present with abdominal pain and more likely to have diarrhoea and bleeding.3 In the case of CD, the Montreal classification considers three age groups, with age >40 years as the most advanced age group,69 although the proportion of patients with inflammatory (nonstricturing, nonpenetrating) behaviour also increases in patients after 40 years.14 Furthermore, no differences were found regardless of whether age was higher or lower than 60 years. In the aforementioned EPIMAD registry (IBD patients aged >60 at diagnosis), inflammatory disease (78%) was the most frequent phenotype.9 Consequently, the stricturing pattern (B2) and penetrating pattern (B3) are less common than in patients aged 18–60 years.4, 14, 33, 52 A change in the behaviour of CD is exceptional in the elderly, whereas in the paediatric and adult CD population, it is quite frequent after 5 years.9, 21, 54 In the study by Charpentier et al., only 30% of patients had B2/B3 behaviour at the end of follow-up as compared with more than 50% in younger patients.9 Regarding medical treatment, the cumulative probability of receiving corticosteroids, immunosuppressants and anti-tumour necrosis factor (TNF) a therapy in CD was, respectively, 47%, 27% and 9% at 10 years in the largest population-based study of late-onset IBD reported to date9 (see ‘Medical treatment’ section). Finally, several studies have reported a lower frequency of surgery in elderly patients with CD than in younger patients.52, 70

Ulcerative colitis The clinical course of UC in elderly patients is similar to or more favourable than that observed in younger patients.21, 68, 71–73 As was the case with CD, clinical symptoms on diagnosis seem to be more subtle in elderly than in younger patients, with less rectal bleeding, diarrhoea and abdominal pain in UC.25, 68, 74 However, initial UC attacks in the elderly may be more severe.4, 34, 59, 68 As for location, according to the Montreal classification, proctitis and left-sided UC are more common in patients aged >60 years than in younger patients.17, 21, 34, 59, 68 A World Gastroenterology Organisation survey reported proctitis in 42% of UC patients aged >60 years, compared to 33% in those aged 60 years at diagnosis), 29% of patients had proctitis, 45% left-sided colitis and 26% extensive colitis, with no extension during follow-up in most cases (84%).9 Thus, in UC, location tends to remain stable, with only about 15% of patients showing progression over time;9, 75 this observation is in sharp contrast with the 50% rate of extension reported in the paediatric population.76 An inverse correlation was found between age at onset of UC and the risk of relapse7 (i.e. a lower incidence of relapse among older patients). However, some authors have reported that severity of recurrence is usually higher in elderly patients.34, 77 Paediatric and adult patients more often require systemic corticosteroids during follow-up than elderly patients (17%)21 (see ‘Medical treatment’ section). Finally, as for surgery, colectomy rates in UC seem to be lower in the elderly.1 In the EPIMAD registry, only 16% of elderly onset patients were operated on at 10 years from diagnosis.9

DISEASE SEVERITY AND HOSPITALISATION REQUIREMENTS Older patients tend be hospitalised more often than younger patients.78 In a recent study, more patients aged >65 years were hospitalised than younger patients (25% of all admissions for IBD occurring in the US, 33% of hospitalisations for UC and 20% for CD).78 Most of the health care burden associated with IBD consists of direct and indirect costs of hospitalisation, particularly surgical costs.78, 79 Once hospitalised, older patients tend to be sicker, malnourished, hypovolemic and more anaemic, with increased transfusion requirements; however, they are less likely to be hospitalised with fistulising and stricturing complications. Among IBD patients who undergo surgery, older patients also have a longer post-operative stay.78 As in the general population, increased age is an independent risk factor for in-hospital mortality among IBD patients;78, 80–82 importantly, even after adjusting for comorbidity, in-hospital mortality is higher in older patients.59, 71, 78 Findings on the spectrum of infection-related hospitalisations in patients with IBD show that infections have been independently associated with age, account for significant morbidity and mortality in patients with IBD, and disproportionately impact older IBD patients with greater comorbidity.78 Thus, some researchers have demonstrated that the relative risk of acquiring an Aliment Pharmacol Ther 2014; 39: 459-477 ª 2014 John Wiley & Sons Ltd

Systematic review with meta-analysis: IBD in the elderly opportunistic infection was greatest in IBD patients aged >50 years of age.83, 84 In particular, older patients are more susceptible to C. difficile, opportunistic infections and venous thromboembolic events, with a 20% increased risk of this complication per decade in age.83, 85, 86 Finally, older age is also associated with increased endoscopic complications. In particular, perforations during colonoscopy were reported in 1% of hospitalised IBD patients compared to 0.6% of non-IBD hospitalised controls.87

CANCER RISK Compared with the general population, older patients diagnosed with CD have an increased risk for several types of cancer (e.g. small intestine carcinoma, pancreatic cancer, cancer of the endocrine glands, kidney cancer, stomach cancer and lung cancer).88 These findings emphasise the importance of excluding malignancy before beginning therapy with immunosuppressants or biologics in the elderly.89 In patients with IBD, thiopurines have been associated with a higher risk of non-Hodgkin’s lymphoma90, 91 and nonmelanoma skin cancer,92 while anti-TNF drugs seem to increase the risk of melanoma.93 With increasing age, there is also an increased risk of non-Hodgkin’s lymphoma and nonmelanoma skin cancer associated with immunomodulators and anti-TNF agents.91–94 A Danish study of IBD patients identified older age at diagnosis as a risk factor for early development of colorectal cancer (CRC).95 Similarly, a Canadian study described earlier progression to CRC among IBD patients diagnosed after the age of 40, with 30% of patients diagnosed with cancer prior to the recommended 8 years of post-diagnosis surveillance.96 Using data from the ‘Surveillance, Epidemiology and End Results’ Program, the calculated incidence of CRC among IBD patients over the age of 65 was 8.2 cancers per 10 000 person-years compared to 6.1 cancers per 10 000 person-years for the non-IBD controls.97 Therefore, revised surveillance strategies may need to consider older age at diagnosis of IBD. MORTALITY Patients with IBD (all ages) have an overall survival comparable to or only slightly lower than that of the general population,98–100 and both higher19 and lower59 mortality than younger patients have been reported by different authors. However, most studies suggest that increased age is an independent risk factor for mortality Aliment Pharmacol Ther 2014; 39: 459-477 ª 2014 John Wiley & Sons Ltd

among IBD patients, even after adjusting for comorbidity.59, 71, 78 As previously stated, infections have been independently associated with age and account for significant mortality in patients with IBD.78

MEDICAL TREATMENT The principles of medical management of IBD in patients aged >60 years are generally the same as in other age groups.17 Elderly IBD patients are candidates for treatment with all of the therapeutic options available for younger IBD patients. In fact, IBD responds well to medical treatment in most elderly patients.101 However, a recent study found a significant variation in medication prescription rates between countries when elderly patients with IBD were analysed.102 Treatment with immunomodulators and biologics confers a risk of infection and malignancy that may be even more pertinent in older patients. However, underuse of these agents could be associated with poorer outcomes in the elderly.103 In this respect, more research is necessary to clarify whether the natural history of IBD in the elderly onset IBD is less aggressive (as some authors have suggested) or, in truth, it is similarly aggressive, but not as progressive (stricturing or penetrating complications) as in early-onset IBD. On average, geriatric patients are treated with five drugs, and 25% regularly take more than six different medications.89, 104 In a study of 150 elderly CD patients (mean age 73 years), polypharmacy was common, with a mean of seven drugs per patient.103 Polypharmacy and the complex regimens often required to achieve clinical response or remission in IBD increase the likelihood of non-adherence105 and medication-related errors.2 Thus, forgetting to take the medication owing to frequent dosing is reported to be the most common reason for non-adherence.106 Elderly patients with underlying cognitive defects or with limited functional ability may be especially prone to non-adherence with regimens involving multiple pills taken several times a day. Daily single dosing could improve adherence and reduce the probability of recurrence in IBD patients in general and in older IBD patients in particular.3 Visiting nurse programmes and other social support mechanisms could play an important role in ensuring adherence and optimal outcomes in this cohort.46 Finally, given the risk of serious side effects in elderly patients receiving several drugs, it is important to investigate possible interactions before starting therapy.89 Difficulty using topical therapy can result from physical limitations and anal sphincter incompetence in the 465

J. P. Gisbert and M. Chaparro elderly.1 Older patients may be less responsive than younger patients to topical therapy, particularly if they are unable to retain the drug long enough for its effects to occur.107 Hence, anal sphincter competence (as determined based on a history of faecal incontinence and rectal examination) and the coordination skills necessary to self-administer topical therapy will determine whether this therapy is used.42 An important consideration in the management of elderly UC patients is the loss of physical reserve, which accompanies ageing.46 Elderly patients who present who experience severe colitis flare should be managed earlier as in-patients, as the ability to handle faecal urgency and multiple nocturnal trips to the bathroom may not be readily handled by an elderly individual without assistance.46 Overall, the benefits of using highly potent agents earlier in IBD treatment, especially in CD, are becoming more widely accepted. However, this strategy has yet to be formally assessed in elderly patients.3 In a French population-based cohort (EPIMAD registry), 841 IBD patients aged >60 years at diagnosis were studied.9 Remarkably, in the elderly onset cohort, only 27% of CD patients and 16% of UC patients were receiving immunosuppressors after 10 years of follow-up (half of the percentages reported for the whole IBD population), and only 3% had received anti-TNF therapy.9 In another study of 393 geriatric IBD patients, up to 32% were receiving long-term corticosteroids with only 6% receiving immunomodulators and 3% biologics.103 Finally, a Veteran’s Administration Hospital survey found that biologic use varied inversely with age at diagnosis, with no patient over the age of 70 years at diagnosis receiving anti-TNF therapy compared to 67% of patients diagnosed before the age of 40.108 In summary, current approach to drug therapy in the elderly is to ‘start low go slow’ before reassessing more aggressive therapy (immunomodulators, biologics, surgery).12

Antibiotics Metronidazole is one of the most commonly used antibiotics in IBD patients; however, its side effects include neuropathy, which may be particularly marked in the elderly, and nausea and metallic taste.1, 109, 110 The drugs that can interact with metronidazole and which are of special interest in elderly patients are simvastatin, sildenafil, calcium channel blockers, phenytoin and warfarin (in patients with a prolonged international normalised ratio, INR).1, 110 Ciprofloxacin decreases theophylline clearance and has the potential for significant 466

central nervous system adverse effects; it may also alter serum phenytoin levels and increase warfarin levels, resulting in an increased INR1, 12, 111.

5-aminosalicylates 5-Aminosalicylates have comparable efficacy in both young and elderly patients.112 Elimination of sulfasalazine in the elderly is considerably slower and has been associated with a decreased glomerular filtration rate and lower renal clearance.112 It is unknown whether the risk of nephrotoxicity in 5-aminosalicylate users is related to age.113 Patients receiving digoxin for congestive heart failure or atrial fibrillation should be closely monitored when on concomitant medication with 5-aminosalicylates.89 5-Aminosalicylates can also interact with the tuberculostatic drug isoniazid.89 The most clinically relevant effects of interactions with 5-aminosalicylates include an increase in the INR when administered with warfarin (particularly with olsalazine)11, 114 and increased levels of thiopurines.115, 116 Several in vitro and in vivo pharmacological studies have reported inhibition of thiopurine methyltransferase (TPMT) enzyme and an increase in 6-tioguanine (thioguanine) nucleotides due to administration of sulfasalazine or 5-aminosalicylates.117 However, modifications in TPMT or 6-tioguanine nucleotide levels do not seem to be clinically relevant.117 Therefore, the theoretical synergism between azathioprine or mercaptopurine and 5-aminosalicylates has not been confirmed, and its clinical significance is presumably minimal.118, 119 Corticosteroids Corticosteroids are associated with a greater number of more severe adverse events in elderly IBD patients.120–122 Thomas et al. reviewed the complications of long-term corticosteroid use in 100 elderly patients and found dose-related adverse effects in 40%, including osteoporosis in 16%.120 In other studies, osteoporotic-related fractures and osteonecrosis were found to be especially common (prevalence of almost 15%) in elderly IBD patients.123 Early bone density testing with repeated annual examinations, limited corticosteroid use in both duration and dosage, and an exit strategy are considered mandatory.124 Concomitant malabsorption and nutritional deprivation of vitamin D and calcium frequently affects the elderly.125 Therefore, elderly patients receiving long-term corticosteroid therapy should undergo baseline assessment of bone density, and use of bisphosphonates should be considered along with vitamin D and calcium supplementation.16 Aliment Pharmacol Ther 2014; 39: 459-477 ª 2014 John Wiley & Sons Ltd

Systematic review with meta-analysis: IBD in the elderly Elderly patients treated with corticosteroids frequently have altered mental status, including depression.120–122 In addition, the elderly are especially prone to hypertension, hypokalaemia, hyperglycaemia, precipitating or exacerbating diabetes mellitus, and reduced control of diabetes.120, 121 Administration of corticosteroids can also be associated with fluid retention, which can be significant in patients with underlying hypertension, congestive heart failure or renal disease.120, 121 Finally, elderly patients may also have underlying ocular problems such as glaucoma, which could be worsened by corticosteroids.120, 121 Corticosteroid clearance is decreased in the elderly.126 Corticosteroid drug interactions include phenytoin, phenobarbital, ephedrine and rifampin, all of which accelerate corticosteroid metabolism and thereby decrease the systemic activity of these drugs.1, 11 The combination of corticosteroids and anticoagulants may be accompanied by an increase or decrease in the effectiveness of the anticoagulants, and more frequent control of coagulation parameters is recommended.89 In elderly patients, increased dependence on corticosteroids leads to an increased need for immunosuppressive therapy.127 However, paradoxically, immunomodulator and biologic agents are infrequently used in geriatric IBD patients, whereas corticosteroids continue to be frequently prescribed (even more than in young patients).103 Juneja et al. reviewed the medical records of 393 geriatric IBD patients and found that as many as 32% were receiving maintenance prednisone (treatment duration >6 months).103

Thiopurines No consensus has been reached on the frequency of immunomodulator use in the elderly, and some authors report no differences between young adults and the elderly;73 however, other authors suggest that a higher incidence of corticosteroid dependence leads to increased need for immunosuppressive therapy in elderly patients.127 Finally, other authors report a low use of immunomodulators in geriatric IBD patients.103 In the study by Juneja et al.103 (almost 400 geriatric IBD patients), only 6% were using thiopurines.103 No differences in efficacy, metabolism and toxicity of thiopurine agents have been found between patients aged >60 years and younger patients.17 Thiopurine agents are generally well tolerated with a relatively low incidence of adverse effects in this age group.120, 128 Allopurinol is commonly prescribed in the elderly for gout and may result in significant bone marrow toxicity Aliment Pharmacol Ther 2014; 39: 459-477 ª 2014 John Wiley & Sons Ltd

when combined with azathioprine or mercaptopurine.117, 129 The enzyme xanthine oxidase metabolises mercaptopurine into 6-thiouric acid (an inactive metabolite), and allopurinol is a competitive inhibitor of this enzyme.130 Other important drug interactions with thiopurines include a decrease in the anticoagulation effect of warfarin.131 As decreased INR has been reported in patients taking additional doses of azathioprine during therapy with oral anticoagulants, prothrombin time, INR and clinical status should be strictly monitored if azathioprine is started during oral anticoagulant therapy or discontinued.132 The use of thiopurines in IBD seems to increase the risk of lymphoma compared with the general population.90, 91 A recent prospective observational cohort study of 19 486 patients with IBD from the French CESAME group identified older age, male sex and longer duration of IBD as the main risk factors of developing a lymphoproliferative disorder.94 Regarding age, the hazard ratio per 1-year increase was 1.06 (95% confidence interval, 1.03–1.09). From the 23 patients that were diagnosed with incident lymphoproliferative disorders, 12 (that is, approximately 50% of the patients) were >60 years. This risk was further elevated for patients with ongoing therapy combining thiopurines and anti-TNF-a agents.94 Life expectancy and potential benefits of treatment with azathioprine are greater in younger patients; however, the potential benefit of azathioprine in older CD patients remains debatable.89 This question was assessed by Lewis et al. using a Markov model.133 Gain in quality-adjusted life years (QALYs) decreased with age upon initiation of azathioprine therapy: an assumed 4-year course of azathioprine would yield an increase of 0.09 QALYs for a 15-year-old patient, but only 65 years would provide no benefit.89

Methotrexate Although methotrexate has not been specifically studied in the elderly, it is widely used in older patients with rheumatoid arthritis or psoriasis.120 There is no evidence for differences in efficacy between older and younger age groups. Metabolism and renal or biliary excretion of methotrexate may be affected by age and should be considered when using this drug.11 Gastrointestinal and haematological toxicity are more frequent in older patients.134 Regarding interactions, NSAIDs inhibit renal excretion of methotrexate and may increase its toxicity.11 Tetracycline inhibits methotrexate absorption, and peni467

J. P. Gisbert and M. Chaparro cillin decreases renal clearance.11 Finally, methotrexate also alters the clearance of theophylline.11

Ciclosporin The risk of adverse effects with ciclosporin is probably significantly higher in older patients than in younger patients. In general, contraindications to ciclosporin (e.g. renal insufficiency, hypertension) are more likely in elderly patients, who may be unable to tolerate the drug. Thus, the elderly are not considered ideal candidates for cyclosporine.42 Older patients in particular are more likely to have impaired renal function; therefore, creatinine clearance must be accurately assessed before ciclosporin therapy is started.135 Anti-TNF agents Little is known about the efficacy and safety profile of anti-TNF agents in the elderly, as most of the published trials do not include IBD patients >60 years. Their indications are generally similar to those for patients aged 65 years) and younger (60 years was associated with an increased risk of severe adverse effects and higher mortality. Severe infections occurred in 11% of elderly patients compared with 2% in the clinical trials and post-marketing studies,146 2.6% in the control population of adult patients aged 60 years.140 Seventy per cent discontinued anti-TNF therapy after a mean of 24 months. Compared with older azathioprine users, older anti-TNF users who started therapy beyond the age of 60 years were three-

Aliment Pharmacol Ther 2014; 39: 459-477 ª 2014 John Wiley & Sons Ltd

Systematic review with meta-analysis: IBD in the elderly fold more likely to discontinue therapy than younger users. Clinical studies on anti-TNF agents have disclosed the potential aggravation of severe heart failure, with excess mortality in patients with heart failure and worsening lipid profile.147 Therefore, the use of anti-TNF agents in heart failure (NYHA class III and IV), a common comorbid condition in the elderly population, is contraindicated.147 Anti-TNF–induced thrombocytopaenia in elderly patients with CD has been reported after therapy with infliximab148 and adalimumab.149 Finally, as for mortality, one study points out that three of four deaths attributable to infliximab treatment were patients aged >65 years.141 However, these patients had a longer disease course (15–26 years), severe disease and comorbid conditions, and they were on concomitant immunomodulator therapy; therefore, the independent contribution of age was not clear. Although it is evident that more safety data are required on the use of biologics in patients aged >60 years, caution should be exercised when treating elderly patients with these drugs. The recommendations of guidelines should be followed and the necessary tests performed.17 Accurate screening for infections is needed before starting therapy.139 It should be borne in mind that in this age group, and particularly in countries where the prevalence of tuberculosis is higher, latent tuberculosis is likely to be more common.17 In summary, a gentler approach should be used in patients older than 60 years, and a combination of immunosuppressive agents should probably be avoided because of the increased risk of infectious and neoplastic complications.89 Nevertheless, when taking the decision to initiate anti-TNF therapy in older individuals, clinicians must also take into account the consequences of untreated disease and potential risks associated with alternative treatments such as surgery and the likelihood of post-operative complications.

ANTICOAGULATION AND ANTIPLATELET THERAPY The issue of anticoagulation and anti-platelet treatment in the elderly has been comprehensively reviewed by Katz and Pardi.1 Despite the fear of worsening IBD in patients given anti-platelet or anticoagulation therapy, a study of this issue in 90 elderly CD patients showed that therapy with aspirin and warfarin was not associated with increased activity of CD.103 Similarly, the Lenox Hill Hospital experience with 41 IBD patients taking aspirin and clopidogrel for coronary artery disease showed no change in the frequency of IBD flares in most Aliment Pharmacol Ther 2014; 39: 459-477 ª 2014 John Wiley & Sons Ltd

patients on antiplatelet therapy when compared with a control group not on antiplatelet therapy.150 On the contrary, a reduction of approximately 10% in IBD flares was recorded in patients on anti-platelet therapy.150 Another study of aspirin use in older CD patients with vascular disease showed no differences in hospitalisation rates regardless of whether the patient was taking aspirin or not.103 Finally, as previously mentioned, many of the drugs used in treating IBD can interfere with the metabolism of warfarin,114 and potential interactions should be considered in any patient taking warfarin when a new IBD medication is begun.1

SCREENING FOR COLON CANCER While UC and CD are thought to predispose to CRC,151 the association has not been well studied in elderly patients.152 Some authors have suggested that the risk of CRC is much higher in elderly UC patients, and every effort should be made to monitor this cancer in these patients.153 Others consider that older IBD patients have an increased risk of CRC that is proportional to the duration of colitis.154 Finally, one study concluded that the risk of CRC in elderly patients with IBD may be lower than previously thought;97 the incidence rate ratio of CRC was only 1.34 in the older population. There are several explanations for this modest association between UC and CRC.97 First, as a cohort with UC reaches advanced age, most of the patients who have already developed CRC or have undergone colectomy are excluded. Second, individuals who develop UC at an older age may have milder and more limited disease, and disease duration may not be long enough to have an effect on the relative risk of CRC. Third, although the cumulative risk of CRC complicating UC increases with age, the age-specific relative risk of CRC decreases with age because of the marked rise in the incidence of CRC in the ageing background population.71 In any case, it may well be that advanced age per se does not constitute an additional risk for cancer in UC beyond that associated with the extent and duration of disease. Current surveillance guidelines are based on duration and extension of colitis, and recommendations are no different for the elderly, with the exception that surveillance should only be applied in patients whose life expectancy is such that they would be expected to benefit and in those who are healthy enough to undergo colectomy should dysplasia be found.1 Some authors have compared the rate of early/missed CRCs after colonoscopy in IBD and non-IBD patients.155 Compared with older non-IBD patients, early/missed 469

J. P. Gisbert and M. Chaparro CRCs among older IBD patients were less likely rightsided. Multivariate logistic regression analysis showed that the risk of early/missed CRCs was three times higher for IBD patients, thus supporting intensive surveillance colonoscopy for older IBD patients, as recommended by guidelines. Little is known about effects of age on the risks associated with colonoscopy. In a large retrospective study of the safety of ileocolonoscopy in IBD patients,156 few severe complications were detected (0.3–0.8%), and none were related to the patients’ advanced age. Finally, some studies report better survival in patients with UC and CRC than in those with sporadic CRC, while others show no difference. Shaukat et al. assessed all cases of CRC in persons aged 67 years and older and concluded that CRC tends to be diagnosed at earlier stages in persons with UC; however, the authors found no differences in 3-year survival rates for CRC among individuals with and without UC.157

SURGICAL TREATMENT Although the primary treatment of patients with IBD is usually medical, a significant proportion of patients undergo surgery. In older patients, failure of medical treatment is the most common reason for surgery.158 Surgery has often been avoided in elderly patients with IBD in favour of medical management because of a perceived increase in surgical risk. Ikeuchi et al. reviewed the surgical experience of elderly patients with UC treated at their hospital.159 The prognosis of elderly patients who underwent emergency surgery was extremely poor: 27% of patients died within 30 days. Respiratory tract infection and sepsis resulting from infection by methicillin-resistant Staphylococcus aureus or fungus were the most common causes of death after emergency surgery. Other authors have reported that elderly patients with IBD have an increased rate of post-operative complications, along with an increased length of hospital stay and increased operating room time.78, 160, 161 A reported increase in surgical complication rates has been attributed to the presence of comorbid conditions in elderly patients.161 However, the increased rate of post-operative complications and the increased length of hospital stay remain unchanged after adjustment for comorbidity.161 These data indicate that physicians and surgeons should collaborate to treat severe and fulminant disease to optimise timing of surgery. Other authors have suggested that surgery to treat elderly patients should not differ from that used in younger patients with IBD.162 This advice is based on 470

recent reports, which reveal no increase in surgical morbidity and mortality among older patients with UC (undergoing restorative proctocolectomy)163 or with CD.49, 162 Furthermore, in the largest series of elderly patients with UC who underwent surgery, Almogy et al. showed that the mortality rate was lower than 3%.164 The authors found that the frequency of surgery-associated adverse outcomes decreased significantly from 50% during 1960–1984 to 27% in recent years.164 Age is currently not considered a contraindication for performing ileal pouch-anal anastomosis (IPAA).17 The dogma ‘no pouch anal anastomosis in those over 50’ established by some authors in the early 1990s can now be abandoned.165 In UC, restorative proctocolectomy with IPAA continues to be the surgical technique of choice.165– 168 The American Society of Colon and Rectal Surgeons has recommended that ‘chronologic age should not itself be an exclusion criterion for IPAA’.169 Thus, IPAA is safe and has acceptable results in elderly UC patients; in fact, most elderly UC patients (89%) stated that they would opt to undergo IPAA again, and 96% would recommend the procedure to others.165 Nevertheless, the results are generally not as good in older patients as in younger patients, although in both cases, they are reasonably good in terms of efficacy and morbidity.17 The only complications are increased frequency of diurnal incontinence and nocturnal leakage among patients aged >65 years.17 Interestingly, pouch failure rates and the incidence of anastomotic leaks are comparable to those seen in younger patients.170 However, an increased frequency of long-term complications such as pouchitis or anastomotic stricture in elderly patients undergoing IPAA has been reported.170 Deterioration in pouch function with advancing age applies to all patients undergoing IPAA and faecal incontinence in particular, with evidence that this may be more pronounced in the elderly.171 Ileal pouch-anal anastomosis can be successful in the elderly, provided the patient retains good anal sphincter function.165, 172 Thus, a history of pre-operative incontinence would ordinarily contraindicate pouch surgery.173 Careful patient selection with good anal sphincter function and adequate cognitive ability will lead to greater tolerance of IPAA. Patients with a pre-existing diagnosis of anorectal dysfunction or incontinence may not be candidates for such reconstructive surgery and may have better function and quality of life with permanent ileostomy.46, 89, 174 One study indicated that older veterans were less likely to have problems such as leakage or adjusting to the ileostomy than younger veterans.175 Another study showed Aliment Pharmacol Ther 2014; 39: 459-477 ª 2014 John Wiley & Sons Ltd

Systematic review with meta-analysis: IBD in the elderly that older patients were more likely to have difficulty in the daily management of their stoma, although quality of life overall was equal to or better than that of younger patients who had undergone ileostomy.176 Finally, ileorectal anastomosis, which is mostly abandoned in young UC patients, still has indications in the elderly.89 Recurrence after bowel resection is quite frequent in CD patients. Disparate reports in the literature have noted recurrence rates in the elderly after CD surgery ranging anywhere from five times greater than to equal to the recurrence rates in younger patients.12, 65, 177 Some authors have even reported that in elderly CD patients, recurrence after bowel resection was less common than in younger patients (43% vs. 64%); however, when it did occur, the time to recurrence was significantly shorter in the elderly patients (3.7 vs. 5.8 years).32 It is important for physicians and surgeons involved in the management of elderly IBD patients to discuss the risks and benefits of these procedures, so that a fully informed decision may be taken prior to reconstructive surgery. Some of the data reviewed above clearly argue against performing surgery in older IBD patients. However, arguments for early surgery should also be taken into account. For example, in severe UC, early surgery has been recommended for elderly patients, because complications such as toxic megacolon, perforation, massive haemorrhage and mortality are more common in the elderly when surgery is delayed, and outcomes are worse if surgery is performed when patients are critically ill.3, 7, 74, 101 Furthermore, as previously mentioned, elderly patients with severe IBD have prolonged, complicated post-operative clinical courses with worse hospital outcomes; therefore, early surgical intervention for elderly patients may be recommended.89 In summary, the most important determinants of surgical outcome after colectomy for UC are severity of the episode and promptness of the surgical intervention. As morbidity of severe UC results from prolonged ineffective medical treatment, surgery should be performed as soon as possible.178 Postponing surgery on the basis of advanced age alone could increase mortality, whereas prompt intervention has been associated with dramatic reductions in mortality in elderly patients with severe colitis.71, 178

VACCINATION The vaccination status of elderly IBD patients is often neglected,1 probably because, at least in part, vaccination strategies were not considered to be as relevant a few decades ago as they are now. Therefore, the older patient’s Aliment Pharmacol Ther 2014; 39: 459-477 ª 2014 John Wiley & Sons Ltd

vaccination schedule or antibody titres should be reviewed, and appropriate vaccines administered.1, 179, 180 The response to vaccine may be reduced in elderly persons; in fact, some authors have assessed the effectiveness of hepatitis B virus vaccine in IBD patients and found that older age was associated with a worse response.181

THROMBOTIC COMPLICATIONS The incidence of deep vein thrombosis is greater in elderly patients, presumably because of the hypercoagulability of IBD patients, together with dehydration, decreased mobility and coexistence of CRC, all of which are more common in older patients.1, 33 In a recent review of clotting complications in IBD patients, Nguyen et al. demonstrated that elderly IBD patients were at significant risk of developing venous clotting complications, which was more frequent with age.85 According to the Nationwide Inpatient Sample data set, elderly UC patients demonstrated the highest rates of venous thromboembolism, which occurred in 25% or more of hospitalisations in patients who were 50 years and older; approximately one third of the UC patients who were older than age 80 experienced a venous clotting complication during hospitalisation in the year 2004. These high rates indicate that heparin-based prophylaxis strategies should be implemented in hospitalised elderly patients with UC.46 CONCLUSIONS Although IBD is generally considered to affect young individuals, elderly patients represent an increasing proportion of the IBD population. Approximately 10–15% of cases of IBD are diagnosed in patients aged >60 years, and 10–30% of the IBD population are aged >60 years. In the elderly, IBD is easily confused with other more common diseases, mainly diverticular disease and ischaemic colitis. The clinical features in older patients with IBD are generally similar to those in younger patients, with some notable exceptions. Genetic factors seem to play a greater role in paediatric patients with IBD than in older individuals. The symptoms of CD at diagnosis are more subtle in the elderly. CD in the elderly patient is characterised by a predominantly colonic location and uncomplicated behaviour with slower progression (less change in disease behaviour) over time than in younger patients. Similarly, in elderly patients with UC, symptoms seem to be more subtle, and proctitis and left-sided UC are more common. Compared with the general population, older patients diagnosed with CD are at increased risk for several types 471

J. P. Gisbert and M. Chaparro of cancer. The risk of non-Hodgkin’s lymphoma and nonmelanoma skin cancer associated with immunomodulators and anti-TNF agents increases with age. Increased age is an independent risk factor for mortality among IBD patients. Infections (including C. difficile and opportunistic infections) have been independently associated with age and account for significant mortality in patients with IBD. In general, the treatment of IBD in the elderly is similar to that administered to younger patients, with a few relevant exceptions. A clinical distinction must be made between fit elderly and frail elderly. The former should not be excluded from newer therapies or clinical trials simply because of age. Polypharmacy, which is very common among elderly patients, and complex regimens increase the likelihood of non-adherence. Once-daily dosing can improve adherence, particularly in older IBD patients. When polymedication is used for elderly patients, it is important to consider possible interactions. One approach to drug therapy in the elderly IBD patient is the ‘start low-go slow’ approach, by which patients are regularly reassessed for progression to more aggressive therapy if their response is inadequate. Corticosteroids are associated with a greater number of adverse events, mainly osteoporosis, in the elderly. The potential benefit of azathioprine in older CD patients remains debatable. No differences in the toxicity of thiopurine agents have been found between patients aged

>60 years and younger patients. However, a higher frequency of toxicity occurs in elderly patients treated with methotrexate. Although the indications for anti-TNFs in the elderly are generally similar to those for younger patients, lower response and higher adverse events have been reported in the elderly. Thus, in patients older than 60 years, a gentler approach may be used, and a combination of immunosuppressive agents should probably be avoided because of an increased risk of infectious and neoplastic complications. Surgical treatment in elderly patients should not differ from that of younger patients with IBD. Age is currently not considered a contraindication for performing IPAA, which can be successful, provided the patient retains good anal sphincter function.

AUTHORSHIP Guarantor of the article: Javier P. Gisbert Author contributions: JP Gisbert had the original idea for the study, performed the bibliographical search and wrote the manuscript. M Chaparro critically reviewed the paper. All authors approved the final version of the manuscript. ACKNOWLEDGEMENT Declaration of personal and funding interests: None.

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