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Management of inflammatory bowel disease in the elderly: A review

Open AccessPublished:January 19, 2023DOI:https://doi.org/10.1016/j.dld.2022.12.024

      Abstract

      The burden of Inflammatory Bowel Disease (IBD) is increasing worldwide, with a particular increase in the prevalence in the elderly population, due to the ageing of young-onset IBD as well as to the increasing incidence in elderly patients.
      Elderly IBD patients present specific challenges to the treating physician, as they have comorbidities, lower functional reserves, and higher risk of treatment-related complications. The diagnosis of IBD in the elderly may be difficult due to a more subtle disease presentation and to a wide range of differential diagnosis. Moreover, as these patients are often excluded from clinical trials, there is a lack of high-quality evidence to inform on the most appropriate management.
      Despite an increasing prevalence, the management of IBD in the elderly is still hindered by frequent misconceptions by physicians treating these patients. Due to a erroneous notion of a milder disease course and fear of adverse events, elderly IBD-patients are managed with frequent and continuous use of steroids and undertreated with effective medical therapies.
      In this review, we describe the principles of management of IBD in the elderly, which is a topic of increasing importance to IBD clinics, that will have to progressively adapt to care for an ageing population.

      Keywords

      1. Introduction

      Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC) is a global disease with an increasing burden worldwide [
      • Kaplan G.G.
      • Windsor J.W.
      The four epidemiological stages in the global evolution of inflammatory bowel disease.
      ].
      While newly industrialized countries in Latin America and Asia are currently experiencing a rapidly rising incidence of IBD but still have a low prevalence, in the Western world IBD is in the “Compounding Prevalence” epidemiological stage. The incidence of the disease is stabilizing, but prevalence is increasing [
      • Kaplan G.G.
      • Windsor J.W.
      The four epidemiological stages in the global evolution of inflammatory bowel disease.
      ,
      • Ng S.C.
      • Shi H.Y.
      • Hamidi N.
      • et al.
      Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies.
      ], which is explained by the chronic and, for now, incurable nature of IBD associated with a relatively low mortality rate [
      • Bitton A.
      • Vutcovici M.
      • Sewitch M.
      • Suissa S.
      • Brassard P.
      Mortality trends in Crohn's disease and ulcerative colitis: a population-based study in Québec, Canada.
      ]. This means that, while IBD is typically thought of as a disease of the young, soon IBD populations will be increasingly comprised of an ageing population with longstanding disease [
      • Kaplan G.G.
      • Windsor J.W.
      The four epidemiological stages in the global evolution of inflammatory bowel disease.
      ]. In fact, presently, approximately 25 to 30% of the IBD population consists of patients >60 years [
      • Sturm A.
      • Maaser C.
      • Mendall M.
      • et al.
      European Crohn's and colitis organisation topical review on IBD in the elderly.
      ] and in a recent nationwide study conducted in Canada, Coward et al. estimated an increase in prevalence from 0.7% to 1.0% in 2030, most evident in the elderly population [
      • Coward S.
      • Clement F.
      • Benchimol E.I.
      • et al.
      Past and future burden of inflammatory bowel diseases based on modeling of population-based data.
      ].
      Besides patients diagnosed earlier in life who later transition to old-age (“non-elderly onset IBD”) one should consider a specific group diagnosed at an older ager (“late-onset” or “elderly-onset” IBD) [
      • Gisbert J.P.
      • Chaparro M.
      Systematic review with meta-analysis: inflammatory bowel disease in the elderly.
      ,
      • Amano T.
      • Shinzaki S.
      • Asakura A.
      • et al.
      Elderly onset age is associated with low efficacy of first anti-tumor necrosis factor treatment in patients with inflammatory bowel disease.
      ]. There is no consensus on the definition of “elderly”, and definitions vary between studies from patients over the age of 60, 65, 70 or even 75 [
      • Sturm A.
      • Maaser C.
      • Mendall M.
      • et al.
      European Crohn's and colitis organisation topical review on IBD in the elderly.
      ,
      • Gisbert J.P.
      • Chaparro M.
      Systematic review with meta-analysis: inflammatory bowel disease in the elderly.
      ,
      • Higashiyama M.
      • Komoto S.
      • Suzuki Y.
      • et al.
      Relation of geriatric nutritional risk index with clinical risks in elderly-onset ulcerative colitis.
      ]. In a recent European Crohn's and Colitis (ECCO) Topical Review [
      • Sturm A.
      • Maaser C.
      • Mendall M.
      • et al.
      European Crohn's and colitis organisation topical review on IBD in the elderly.
      ], elderly-onset IBD was defined as disease-onset at an age of 60 years or older. Approximately 10 to 20% of new IBD diagnosis are reported in this group of patients, and these numbers are expected to be greater with progressive ageing societies [
      • Sturm A.
      • Maaser C.
      • Mendall M.
      • et al.
      European Crohn's and colitis organisation topical review on IBD in the elderly.
      ,
      • Gisbert J.P.
      • Chaparro M.
      Systematic review with meta-analysis: inflammatory bowel disease in the elderly.
      ,
      • Rozich J.J.
      • Dulai P.S.
      • Fumery M.
      • Sandborn W.J.
      • Singh S.
      Progression of elderly onset inflammatory bowel diseases: a systematic review and meta-analysis of population-based cohort studies.
      ,
      • Mañosa M.
      • Calafat M.
      • de Francisco R.
      • et al.
      Phenotype and natural history of elderly onset inflammatory bowel disease: a multicentre, case-control study.
      ,
      • Everhov Å.H.
      • Halfvarson J.
      • Myrelid P.
      • et al.
      Incidence and treatment of patients diagnosed with inflammatory bowel diseases at 60 years or older in Sweden.
      ,
      • Mak J.W.Y.
      • Lok Tung Ho C.
      • Wong K.
      • et al.
      Epidemiology and natural history of elderly-onset inflammatory bowel disease: results from a territory-wide Hong Kong IBD registry.
      ] (Fig. 1). According to a recent systematic review of 68 population-based studies evaluating the worldwide incidence of elderly-onset IBD, one in 8600 older adults are diagnosed annually with UC and one in 22.000 with CD, on average, in the Western world [
      • Singh S.
      • Underwood F.E.
      • Loftus E.V.
      • et al.
      Sa1769: worldwide incidence of older-onset inflammatory bowel diseases in the 21STCentury: a systematic review of population-based studies.
      ].
      Fig 1
      Fig. 1Compounding Prevalence and Ageing of the Inflammatory Bowel Disease (IBD) population. Elderly IBD patients, who constitute 25 to 30% of the IBD population, include elderly-onset IBD patients (∼10–20% of new IBD diagnosis) and patients diagnosed earlier in life that later transition into old age. In the Western World, IBD is in the "Compounding Prevalence" epidemiological stage, as the incidence of the disease is stabilizing but prevalence is increasing due to a low mortality rate. As such, the number of elderly-IBD patients is expected to increase, also as a result of ageing of the population.
      Even though elderly-onset and non-elderly-onset are often grouped together in studies evaluating older IBD patients, the distinction between these two groups is important, as they might have different epidemiology, phenotypes, outcomes, and specific safety concerns with the available treatments. One aspect that emphasizes the differences between these groups is the likely weight of genetic factors on the pathophysiology of IBD, which seem to be greater in non-elderly onset IBD [
      • Gisbert J.P.
      • Chaparro M.
      Systematic review with meta-analysis: inflammatory bowel disease in the elderly.
      ]. This is derived from the observation that older patients are less likely to have a family history of IBD [
      • Quezada S.M.
      • Steinberger E.K.
      • Cross R.K.
      Association of age at diagnosis and Crohn's disease phenotype.
      ,
      • Charpentier C.
      • Salleron J.
      • Savoye G.
      • et al.
      Natural history of elderly-onset inflammatory bowel disease: a population-based cohort study.
      ], with a possible higher importance of environmental factors on its aetiology [
      • Moon J.M.
      • Kang E.A.
      • Han K.
      • et al.
      Trends and risk factors of elderly-onset Crohn's disease: a nationwide cohort study.
      ]. On the other hand, overall risk factors seem to be the same as in non-elderly-onset IBD, with the caveat of limited data, as most results were obtained in younger patients [
      • Sturm A.
      • Maaser C.
      • Mendall M.
      • et al.
      European Crohn's and colitis organisation topical review on IBD in the elderly.
      ,
      • Moon J.M.
      • Kang E.A.
      • Han K.
      • et al.
      Trends and risk factors of elderly-onset Crohn's disease: a nationwide cohort study.
      ].
      In the past, the recognition of the particularities of paediatric-onset IBD led to the subcategorization of the age of onset of CD with an A1 category for those with an age of diagnosis of 16 or younger [
      • Silverberg M.S.
      • Satsangi J.
      • Ahmad T.
      • et al.
      Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a working party of the 2005 montreal world congress of gastroenterology.
      ]. The current A3 category includes a broad group of patients diagnosed over the age of 40 which does not consider the specificities and challenges of elderly-onset IBD. In this review, we discuss the particularities of the management of IBD in the elderly, as IBD clinics will have to adapt and evolve their models of care to an ageing IBD population.

      2. Challenges in the elderly population

      Older patients with IBD are a real challenge to the clinician throughout all phases of the disease, as there are still uncertainties regarding clinical presentation, diagnosis, disease course, and treatment considerations in this population (Fig. 2). In the following sections, we review the main challenges and points to consider in the management of elderly IBD patients.
      Fig 2
      Fig. 2Specific patient and disease-related challenges of the management of Inflammatory Bowel Disease in the elderly.

      2.1 Clinical presentation and diagnosis

      Establishing a diagnosis of IBD in the elderly is hampered by a wide list of differential diagnosis of disorders that may be more frequent in this age group than IBD. As a practical exercise, faced with a patient with rectal bleeding and anaemia, IBD would have a very different likelihood of diagnosis in a 30-year-old as opposed to a 70-year-old patient. The differentials list includes, amongst others, infections, cancer, diverticular disease, ischaemic colitis, and drug-induced colitis [
      • Sturm A.
      • Maaser C.
      • Mendall M.
      • et al.
      European Crohn's and colitis organisation topical review on IBD in the elderly.
      ]. Due to the possible confusion with more common disorders, the rate of misdiagnosis at presentation is greater in this population (60%) when compared to younger-onset IBD (15%) [
      • Gisbert J.P.
      • Chaparro M.
      Systematic review with meta-analysis: inflammatory bowel disease in the elderly.
      ,
      • Wagtmans M.J.
      • Verspaget H.W.
      • Lamers C.B.
      • van Hogezand R.A.
      Crohn's disease in the elderly: a comparison with young adults.
      ,
      • Foxworthy D.M.
      • Wilson J.A.
      Crohn's disease in the elderly. Prolonged delay in diagnosis.
      ]. The unawareness of the possibility of IBD diagnosis in the elderly may also account for the diagnostic delay which is significantly greater in this age group (6 years vs 2 years in the younger population) [
      • Gisbert J.P.
      • Chaparro M.
      Systematic review with meta-analysis: inflammatory bowel disease in the elderly.
      ,
      • Wagtmans M.J.
      • Verspaget H.W.
      • Lamers C.B.
      • van Hogezand R.A.
      Crohn's disease in the elderly: a comparison with young adults.
      ]. Despite the difficulties, clinicians should have the same approach in the diagnostic work-up in the elderly with an appropriate anamnesis, ileocolonoscopy and histology [
      • Sturm A.
      • Maaser C.
      • Mendall M.
      • et al.
      European Crohn's and colitis organisation topical review on IBD in the elderly.
      ].
      The literature on the clinical presentation of elderly-onset IBD is limited and heterogeneous, but most reports describe a different phenotypic pattern in elderly onset-IBD. Patients with CD may have a more subtle presentation, with symptoms of abdominal pain, weight loss and fever reported as less likely. In opposition, rectal bleeding may be more frequent, which is likely associated to the different disease location in the elderly. More frequently, elderly-onset CD seems to have an isolated colonic distribution and a predominantly inflammatory behaviour, while perianal involvement is less common [
      • Gisbert J.P.
      • Chaparro M.
      Systematic review with meta-analysis: inflammatory bowel disease in the elderly.
      ,
      • Mak J.W.Y.
      • Lok Tung Ho C.
      • Wong K.
      • et al.
      Epidemiology and natural history of elderly-onset inflammatory bowel disease: results from a territory-wide Hong Kong IBD registry.
      ,
      • Keyashian K.
      • Dehghan M.
      • Sceats L.
      • Kin C.
      • Limketkai B.N.
      • Park K.T.
      Comparative incidence of inflammatory bowel disease in different age groups in the United States.
      ,
      • Ananthakrishnan A.N.
      • Shi H.Y.
      • Tang W.
      • et al.
      Systematic review and meta-analysis: phenotype and clinical outcomes of older-onset inflammatory bowel disease.
      ]. However, these reports are not consistent between studies, and a population-based study described a higher proportion of ileal CD and stricturing phenotype in elderly-onset CD in China [
      • Mak J.W.Y.
      • Lok Tung Ho C.
      • Wong K.
      • et al.
      Epidemiology and natural history of elderly-onset inflammatory bowel disease: results from a territory-wide Hong Kong IBD registry.
      ]. Other reports from Asia also describe a higher frequency of ileal location across all age groups, including the elderly, suggesting the possibility of different phenotypes between Western and Asian populations [
      • Hwang S.W.
      • Kim J.H.
      • Im J.P.
      • et al.
      Influence of age at diagnosis on the clinical characteristics of Crohn's disease in Korea: results from the CONNECT study.
      ]. On the other hand, elderly-onset UC seems to be more like younger-onset IBD in terms of both symptoms and location, notwithstanding a more subtle clinical presentation and a slightly higher probability of left-side colitis as opposed to extensive colitis [
      • Gisbert J.P.
      • Chaparro M.
      Systematic review with meta-analysis: inflammatory bowel disease in the elderly.
      ,
      • Mañosa M.
      • Calafat M.
      • de Francisco R.
      • et al.
      Phenotype and natural history of elderly onset inflammatory bowel disease: a multicentre, case-control study.
      ,
      • Ananthakrishnan A.N.
      • Shi H.Y.
      • Tang W.
      • et al.
      Systematic review and meta-analysis: phenotype and clinical outcomes of older-onset inflammatory bowel disease.
      ,
      • Jeuring S.F.
      • van den Heuvel T.R.
      • Zeegers M.P.
      • et al.
      Epidemiology and long-term outcome of inflammatory bowel disease diagnosed at elderly age-an increasing distinct entity?.
      ].

      2.2 Natural history

      Data on disease course of IBD in the elderly is scarce, heterogeneous and limited by several factors, since, as opposed to disease phenotype, the definition of natural history may be affected by variables other than the biological evolution of the disease. A lower use of immunomodulators and biologics in the elderly is frequently reported [
      • Gisbert J.P.
      • Chaparro M.
      Systematic review with meta-analysis: inflammatory bowel disease in the elderly.
      ,
      • Rozich J.J.
      • Dulai P.S.
      • Fumery M.
      • Sandborn W.J.
      • Singh S.
      Progression of elderly onset inflammatory bowel diseases: a systematic review and meta-analysis of population-based cohort studies.
      ,
      • Mañosa M.
      • Calafat M.
      • de Francisco R.
      • et al.
      Phenotype and natural history of elderly onset inflammatory bowel disease: a multicentre, case-control study.
      ,
      • Mak J.W.Y.
      • Lok Tung Ho C.
      • Wong K.
      • et al.
      Epidemiology and natural history of elderly-onset inflammatory bowel disease: results from a territory-wide Hong Kong IBD registry.
      ,
      • Ananthakrishnan A.N.
      • Shi H.Y.
      • Tang W.
      • et al.
      Systematic review and meta-analysis: phenotype and clinical outcomes of older-onset inflammatory bowel disease.
      ,
      • Fries W.
      • Viola A.
      • Manetti N.
      • et al.
      Disease patterns in late-onset ulcerative colitis: results from the IG-IBD “AGED study”.
      ,
      • Viola A.
      • Monterubbianesi R.
      • Scalisi G.
      • et al.
      Late-onset Crohn's disease: a comparison of disease behaviour and therapy with younger adult patients: the Italian Group for the Study of Inflammatory Bowel Disease ‘AGED’ study.
      ,
      • Barnes E.L.
      • Hanson J.S.
      • Regueiro M.D.
      • et al.
      Older adult patients use more aminosalicylate monotherapy compared with younger patients with inflammatory bowel disease: TARGET-IBD.
      ] and often used as a marker of a milder severity of the disease. Still, this is contraposed by a higher rate of hospitalisations [
      • Gisbert J.P.
      • Chaparro M.
      Systematic review with meta-analysis: inflammatory bowel disease in the elderly.
      ,
      • Mak J.W.Y.
      • Lok Tung Ho C.
      • Wong K.
      • et al.
      Epidemiology and natural history of elderly-onset inflammatory bowel disease: results from a territory-wide Hong Kong IBD registry.
      ] and surgery (particularly for UC) [
      • Everhov Å.H.
      • Halfvarson J.
      • Myrelid P.
      • et al.
      Incidence and treatment of patients diagnosed with inflammatory bowel diseases at 60 years or older in Sweden.
      ,
      • Ananthakrishnan A.N.
      • Shi H.Y.
      • Tang W.
      • et al.
      Systematic review and meta-analysis: phenotype and clinical outcomes of older-onset inflammatory bowel disease.
      ,
      • Nguyen G.C.
      • Bernstein C.N.
      • Benchimol E.I.
      Risk of surgery and mortality in elderly-onset inflammatory bowel disease: a population-based cohort study.
      ] than non-elderly IBD patients. Using rates of medical treatment as a proxy for disease course in the elderly is misleading, as it may reflect physician's reluctance to start immunosuppressants or patient acceptance of treatment rather than a true benign course of the disease [
      • Everhov Å.H.
      • Halfvarson J.
      • Myrelid P.
      • et al.
      Incidence and treatment of patients diagnosed with inflammatory bowel diseases at 60 years or older in Sweden.
      ,
      • Ananthakrishnan A.N.
      • Shi H.Y.
      • Tang W.
      • et al.
      Systematic review and meta-analysis: phenotype and clinical outcomes of older-onset inflammatory bowel disease.
      ]. In fact, in two multicentre retrospective Italian studies that evaluated medical treatment in the elderly based on disease patterns and behaviour, the authors reported a frequent undertreatment of elderly-onset UC and CD with a more aggressive course, suggesting that treatment decisions may be more influenced by comorbidities rather than disease severity [
      • Fries W.
      • Viola A.
      • Manetti N.
      • et al.
      Disease patterns in late-onset ulcerative colitis: results from the IG-IBD “AGED study”.
      ,
      • Viola A.
      • Monterubbianesi R.
      • Scalisi G.
      • et al.
      Late-onset Crohn's disease: a comparison of disease behaviour and therapy with younger adult patients: the Italian Group for the Study of Inflammatory Bowel Disease ‘AGED’ study.
      ].
      Another limiting factor when evaluating natural history of IBD in the elderly is that patients with elderly-onset IBD are often grouped together with younger-onset IBD as they progress into old age [
      • Ananthakrishnan A.N.
      • Shi H.Y.
      • Tang W.
      • et al.
      Systematic review and meta-analysis: phenotype and clinical outcomes of older-onset inflammatory bowel disease.
      ]. Rozich et al. hypothesize that the latter group, with a longer standing diagnosis, may have already adapted to cope with IBD as they age, building up adequate biological and functional reserve [
      • Rozich J.J.
      • Luo J.
      • Dulai P.S.
      • et al.
      Disease- and treatment-related complications in older patients with inflammatory bowel diseases: comparison of adult-onset vs elderly-onset disease.
      ]. On the contrary, as IBD is often more aggressive within the first year of onset [
      • Solberg I.C.
      • Lygren I.
      • Jahnsen J.
      • et al.
      Clinical course during the first 10 years of ulcerative colitis: results from a population-based inception cohort (IBSEN Study).
      ], and the risk of treatment-related infections is highest within the first months of treatment [
      • Nyboe Andersen N.
      • Pasternak B.
      • Friis-Møller N.
      • Andersson M.
      • Jess T.
      Association between tumour necrosis factor-α inhibitors and risk of serious infections in people with inflammatory bowel disease: nationwide Danish cohort study.
      ], diagnosis at an older age may contribute to frailty and worse outcomes [
      • Rozich J.J.
      • Luo J.
      • Dulai P.S.
      • et al.
      Disease- and treatment-related complications in older patients with inflammatory bowel diseases: comparison of adult-onset vs elderly-onset disease.
      ]. As such, disease course and prognosis in these two groups may be very different. In a retrospective comparison of patients over 60 years with adult-onset IBD with patients with elderly-onset IBD, disease-related complications (assessed by a composite variable incorporating IBD-related surgery, all cause hospitalization, treatment escalation, clinical flare or disease complications) were similar between these groups [
      • Rozich J.J.
      • Luo J.
      • Dulai P.S.
      • et al.
      Disease- and treatment-related complications in older patients with inflammatory bowel diseases: comparison of adult-onset vs elderly-onset disease.
      ]. However, risk of IBD-related surgery was higher in the elderly-onset population, as were treatment-related complications (a composite of malignancy, death, and serious infections).
      Finally, data on the natural history of elderly patients with IBD are often derived from studies from referral centres or single regions, which may not be truly representative of elderly-onset IBD. In many of these studies, IBD in the elderly is described as having a milder course [
      • Charpentier C.
      • Salleron J.
      • Savoye G.
      • et al.
      Natural history of elderly-onset inflammatory bowel disease: a population-based cohort study.
      ,
      • Ananthakrishnan A.N.
      • Shi H.Y.
      • Tang W.
      • et al.
      Systematic review and meta-analysis: phenotype and clinical outcomes of older-onset inflammatory bowel disease.
      ,
      • Jeuring S.F.
      • van den Heuvel T.R.
      • Zeegers M.P.
      • et al.
      Epidemiology and long-term outcome of inflammatory bowel disease diagnosed at elderly age-an increasing distinct entity?.
      ]. In this regard, data from population-based studies from unselected cohorts may be more illustrative of the phenotype and clinical course of the elderly IBD population. A recent systematic review based on population-based cohorts that compared the natural history and outcomes of elderly-onset IBD to adult-onset IBD found similar risks of surgery, hospitalization and corticosteroid exposure between these groups, suggesting a similar disease course [
      • Rozich J.J.
      • Dulai P.S.
      • Fumery M.
      • Sandborn W.J.
      • Singh S.
      Progression of elderly onset inflammatory bowel diseases: a systematic review and meta-analysis of population-based cohort studies.
      ]. A population-based study from China reported similar results, suggesting that elderly-onset IBD is at least as complicated as adult-onset IBD [
      • Mak J.W.Y.
      • Lok Tung Ho C.
      • Wong K.
      • et al.
      Epidemiology and natural history of elderly-onset inflammatory bowel disease: results from a territory-wide Hong Kong IBD registry.
      ].
      Even with the limitations of the available data, it seems likely that elderly-onset IBD is not milder than younger-onset disease. Both patients and physicians should be aware of the possibility of an aggressive behaviour even later in life, and should make appropriate treatment decisions based on the potential implications of active disease on health-related quality of life, associated comorbidities and disease complications.

      2.3 Patient-related challenges

      Other than disease-specific factors, there are unique characteristics of elderly patients that influence their management, which include comorbidities, drug interactions, immunological dysfunction, and somatic, cognitive, and social abilities [
      • Gisbert J.P.
      • Chaparro M.
      Systematic review with meta-analysis: inflammatory bowel disease in the elderly.
      ,
      • Asscher V.E.R.
      • Waars S.N.
      • van der Meulen-de Jong A.E.
      • et al.
      Deficits in geriatric assessment associate with disease activity and burden in older patients with inflammatory bowel disease.
      ].
      Ageing is associated with progressive physiological and pharmacokinetic changes that can complicate drug metabolism, efficacy, and safety [
      • Klotz U.
      Pharmacokinetics and drug metabolism in the elderly.
      ,
      • Calafat M.
      • Mañosa M.
      • Cañete F.
      • et al.
      Increased risk of thiopurine-related adverse events in elderly patients with IBD.
      ]. Impaired mobility, incontinence and coordination skills may also hinder the administration of rectal therapies [
      • Sturm A.
      • Maaser C.
      • Mendall M.
      • et al.
      European Crohn's and colitis organisation topical review on IBD in the elderly.
      ].
      Additionally, the occurrence of other chronic conditions is common in the elderly [
      • Mesonero F.
      • Fernández C.
      • Sánchez-Rodríguez E.
      • et al.
      Polypharmacy in patients with inflammatory bowel disease: prevalence and outcomes in a single-center series.
      ,
      • Juneja M.
      • Baidoo L.
      • Schwartz M.B.
      • et al.
      Geriatric inflammatory bowel disease: phenotypic presentation, treatment patterns, nutritional status, outcomes, and comorbidity.
      ,
      • Argollo M.
      • Gilardi D.
      • Peyrin-Biroulet C.
      • Chabot J.F.
      • Peyrin-Biroulet L.
      • Danese S.
      Comorbidities in inflammatory bowel disease: a call for action.
      ]. In an American study, more than half of geriatric IBD patients had a Charlson comorbidity index equal or superior to 4 [
      • Juneja M.
      • Baidoo L.
      • Schwartz M.B.
      • et al.
      Geriatric inflammatory bowel disease: phenotypic presentation, treatment patterns, nutritional status, outcomes, and comorbidity.
      ]. The most frequent comorbidities were cardiovascular, respiratory, and diabetes mellitus. Kariywasam et al. [
      • Kariyawasam V.C.
      • Kim S.
      • Mourad F.H.
      • et al.
      Comorbidities rather than age are associated with the use of immunomodulators in elderly-onset inflammatory bowel disease.
      ] reported that comorbidities rather than age at diagnosis were the main drivers of delayed immunomodulator use in both CD and UC. As comorbidities were more frequent in elderly-onset IBD patients, immunomodulator use was lower in this age group. Indeed, comorbidities may increase the risk of treatment-related complications [
      • Rozich J.J.
      • Luo J.
      • Dulai P.S.
      • et al.
      Disease- and treatment-related complications in older patients with inflammatory bowel diseases: comparison of adult-onset vs elderly-onset disease.
      ] and preclude the use of certain treatments, as it is the case of anti-TNF and advanced heart failure [
      • Barnes E.L.
      • Hanson J.S.
      • Regueiro M.D.
      • et al.
      Older adult patients use more aminosalicylate monotherapy compared with younger patients with inflammatory bowel disease: TARGET-IBD.
      ]. Cognitive deficit and depression, which are common disorders in the elderly, may also complicate the management of IBD patients [
      • Sturm A.
      • Maaser C.
      • Mendall M.
      • et al.
      European Crohn's and colitis organisation topical review on IBD in the elderly.
      ].
      In accordance with frequent comorbidities, polypharmacy (defined as the simultaneous use of ≥5 drugs) is common in IBD patients, particularly in those older than 62 years old where the prevalence may reach 48% [
      • Mesonero F.
      • Fernández C.
      • Sánchez-Rodríguez E.
      • et al.
      Polypharmacy in patients with inflammatory bowel disease: prevalence and outcomes in a single-center series.
      ]. On average, older IBD patients were regularly taking 7 drugs in a retrospective observational study [
      • Juneja M.
      • Baidoo L.
      • Schwartz M.B.
      • et al.
      Geriatric inflammatory bowel disease: phenotypic presentation, treatment patterns, nutritional status, outcomes, and comorbidity.
      ]. Polypharmacy may have a potential impact on drug adherence and drug interactions, and should be a variable to consider when selecting a treatment for an IBD patient [
      • Sturm A.
      • Maaser C.
      • Mendall M.
      • et al.
      European Crohn's and colitis organisation topical review on IBD in the elderly.
      ,
      • Lakatos P.L.
      Prevalence, predictors, and clinical consequences of medical adherence in IBD: how to improve it?.
      ]. For example, steroids can interfere with the efficacy of antiepileptics. Moreover, not only steroids, but also azathioprine and 5-aminosalycilates alter the action of anticoagulants [
      • Sturm A.
      • Maaser C.
      • Mendall M.
      • et al.
      European Crohn's and colitis organisation topical review on IBD in the elderly.
      ].
      Immunosenescence is an impairment of the innate and adaptive immune systems that occurs with age, and that may promote an aberrant immune response to environmental antigens [
      • Hong S.J.
      • Galati J.
      • Katz S.
      Crohn's disease of the elderly: unique biology and therapeutic efficacy and safety.
      ]. The relative immunodeficiency of the elderly may be responsible for an increased infection risk, and older patients are more vulnerable to opportunistic infections and C. difficile [
      • Gisbert J.P.
      • Chaparro M.
      Systematic review with meta-analysis: inflammatory bowel disease in the elderly.
      ]. Along with cardiovascular complications, serious infections are one of the most common reasons for hospitalization in the elderly with IBD [
      • Mak J.W.Y.
      • Lok Tung Ho C.
      • Wong K.
      • et al.
      Epidemiology and natural history of elderly-onset inflammatory bowel disease: results from a territory-wide Hong Kong IBD registry.
      ,
      • Nguyen N.H.
      • Ohno-Machado L.
      • Sandborn W.J.
      • Singh S.
      Infections and cardiovascular complications are common causes for hospitalization in older patients with inflammatory bowel diseases.
      ]. Hospitalized older IBD patients are at higher risk of in-hospital mortality, and age is an independent risk factor for mortality even after adjusting for comorbidity [
      • Gisbert J.P.
      • Chaparro M.
      Systematic review with meta-analysis: inflammatory bowel disease in the elderly.
      ,
      • Schwartz J.
      • Stein D.J.
      • Lipcsey M.
      • Li B.
      • Feuerstein J.D.
      High rates of mortality in geriatric patients admitted for inflammatory bowel disease management.
      ,
      • Ananthakrishnan A.N.
      • McGinley E.L.
      • Binion D.G.
      Inflammatory bowel disease in the elderly is associated with worse outcomes: a national study of hospitalizations.
      ]. In comparison with the general population, older IBD patients may have an increased risk of several types of cancer [
      • Gisbert J.P.
      • Chaparro M.
      Systematic review with meta-analysis: inflammatory bowel disease in the elderly.
      ,
      • Mak J.W.Y.
      • Lok Tung Ho C.
      • Wong K.
      • et al.
      Epidemiology and natural history of elderly-onset inflammatory bowel disease: results from a territory-wide Hong Kong IBD registry.
      ,
      • Khan N.
      • Vallarino C.
      • Lissoos T.
      • Darr U.
      • Luo M.
      Risk of malignancy in a nationwide cohort of elderly inflammatory bowel disease patients.
      ], which underline the importance of excluding malignancy before starting immunosuppressive treatments.

      2.4 Impact of functional status

      Despite the focus on chronological age to define IBD in the elderly, there is an increased recognition that biological age and functional status may be a more important determinant of health outcomes and more appropriate as clinical risk stratification tools [
      • Sturm A.
      • Maaser C.
      • Mendall M.
      • et al.
      European Crohn's and colitis organisation topical review on IBD in the elderly.
      ,
      • Kochar B.D.
      • Cai W.
      • Ananthakrishnan A.N.
      Inflammatory bowel disease patients who respond to treatment with anti-tumor necrosis factor agents demonstrate improvement in pre-treatment frailty.
      ,
      • Kochar B.
      • Cai W.
      • Cagan A.
      • Ananthakrishnan A.N.
      Frailty is independently associated with mortality in 11 001 patients with inflammatory bowel diseases.
      ,
      • Faye A.S.
      • Wen T.
      • Soroush A.
      • et al.
      Increasing prevalence of frailty and its association with readmission and mortality among hospitalized patients with IBD.
      ].
      Frailty is a state of increased vulnerability where a relatively minor insult may cause a dramatic and disproportionate change in health status, with a poor resolution of homoeostasis [
      • Clegg A.
      • Young J.
      • Iliffe S.
      • Rikkert M.O.
      • Rockwood K.
      Frailty in elderly people.
      ]. It is related to an accelerated decline in physiological reserve as a consequence of a deterioration in multiple physiological systems [
      • Clegg A.
      • Young J.
      • Iliffe S.
      • Rikkert M.O.
      • Rockwood K.
      Frailty in elderly people.
      ]. The first formal frailty score was the “Frailty phenotype” [
      • Fried L.P.
      • Tangen C.M.
      • Walston J.
      • et al.
      Frailty in older adults: evidence for a phenotype.
      ], which determined the presence or absence of five physical criteria (unintentional weight loss, self-reported exhaustion, weakness, slow walking speed, and low physical activity). Later, a model based on an accumulation of deficits was developed, including both physical and psychosocial elements of frailty [
      • Thompson C.
      • Taleban S.
      Incorporating frailty in the treatment program of elderly patients with gastrointestinal disease.
      ,
      • Mitnitski A.B.
      • Mogilner A.J.
      • Rockwood K.
      Accumulation of deficits as a proxy measure of aging.
      ]. In addition to these scores, surrogate markers of frailty have also been evaluated. These include sarcopenia (defined as the reduction of lean muscle mass), malnutrition and disability. While these entities are associated with frailty, these terms are not interchangeable [
      • Thompson C.
      • Taleban S.
      Incorporating frailty in the treatment program of elderly patients with gastrointestinal disease.
      ].
      In IBD, at least 10% of patients over the age of 65 years have a frailty associated diagnosis [
      • Kochar B.
      • Cai W.
      • Cagan A.
      • Ananthakrishnan A.N.
      Frailty is independently associated with mortality in 11 001 patients with inflammatory bowel diseases.
      ]. Frailty was demonstrated to be an important determining factor of outcomes such as hospital readmission, length of hospital-stay, treatment-related complications, perioperative IBD outcomes and mortality, independently of age, comorbidity, and disease severity [
      • Higashiyama M.
      • Komoto S.
      • Suzuki Y.
      • et al.
      Relation of geriatric nutritional risk index with clinical risks in elderly-onset ulcerative colitis.
      ,
      • Kochar B.
      • Cai W.
      • Cagan A.
      • Ananthakrishnan A.N.
      Frailty is independently associated with mortality in 11 001 patients with inflammatory bowel diseases.
      ,
      • Faye A.S.
      • Wen T.
      • Soroush A.
      • et al.
      Increasing prevalence of frailty and its association with readmission and mortality among hospitalized patients with IBD.
      ,
      • Kochar B.
      • Cai W.
      • Cagan A.
      • Ananthakrishnan A.N.
      Pretreatment frailty is independently associated with increased risk of infections after immunosuppression in patients with inflammatory bowel diseases.
      ,
      • Qian A.S.
      • Nguyen N.H.
      • Elia J.
      • Ohno-Machado L.
      • Sandborn W.J.
      • Singh S.
      Frailty is independently associated with mortality and readmission in hospitalized patients with inflammatory bowel diseases.
      ,
      • Pedersen M.
      • Cromwell J.
      • Nau P.
      Sarcopenia is a predictor of surgical morbidity in inflammatory bowel disease.
      ]. In geriatric assessment, deficits in various domains are highly prevalent in elderly IBD patients and are associated with lower health-related quality of life [
      • Asscher V.E.R.
      • Waars S.N.
      • van der Meulen-de Jong A.E.
      • et al.
      Deficits in geriatric assessment associate with disease activity and burden in older patients with inflammatory bowel disease.
      ]. This underlines the importance of systematic assessment of frailty in IBD patients. Despite the existence of numerous frailty indexes for both clinical and research purposes [
      • Rasiah J.
      • Gruneir A.
      • Oelke N.D.
      • Estabrooks C.
      • Holroyd-Leduc J.
      • Cummings G.G.
      Instruments to assess frailty in community dwelling older adults: a systematic review.
      ], a simple and validated IBD-specific frailty score useful for clinical practice is not yet available [
      • Kochar B.D.
      • Cai W.
      • Ananthakrishnan A.N.
      Inflammatory bowel disease patients who respond to treatment with anti-tumor necrosis factor agents demonstrate improvement in pre-treatment frailty.
      ].

      3. Management of IBD in the elderly

      3.1 General principles

      Although no specific guidelines are currently available, the principles of IBD treatment in the elderly should be similar to the younger population, with the consideration of the specific challenges aforementioned [
      • Sturm A.
      • Maaser C.
      • Mendall M.
      • et al.
      European Crohn's and colitis organisation topical review on IBD in the elderly.
      ] (Fig. 3). According with this view, therapy should be focused on inducing and maintaining remission, preventing disease-related complications and improving quality of life. Endoscopic remission should be considered the ideal treatment target according to current guidelines [
      • Peyrin-Biroulet L.
      • Sandborn W.
      • Sands B.E.
      • et al.
      Selecting therapeutic targets in inflammatory bowel disease (STRIDE): determining therapeutic goals for treat-to-target.
      ,
      • Turner D.
      • Ricciuto A.
      • Lewis A.
      • et al.
      STRIDE-II: an update on the selecting therapeutic targets in inflammatory bowel disease (STRIDE) initiative of the international organization for the study of IBD (IOIBD): determining therapeutic goals for treat-to-target strategies in IBD.
      ], but in elderly population, physicians may opt to tolerate mild endoscopic activity in view of the perceived lower long-term risks of IBD-related complications, resulting from a relatively shorter lifespan compared to the younger population [
      • LeBlanc J.F.
      • Wiseman D.
      • Lakatos P.L.
      • Bessissow T.
      Elderly patients with inflammatory bowel disease: updated review of the therapeutic landscape.
      ,
      • Butter M.
      • Weiler S.
      • Biedermann L.
      • et al.
      Clinical manifestations, pathophysiology, treatment and outcome of inflammatory bowel diseases in older people.
      ]. Still, one of the most important factors to evaluate in elderly-IBD is patients’ desires and treatment expectations. With patient-reported outcomes, which are more often used in the elderly, patients are directly involved in choosing the management strategy with their physician [
      • Arnott I.
      • Rogler G.
      • Halfvarson J.
      The management of inflammatory bowel disease in elderly: current evidence and future perspectives.
      ].
      Fig 3
      Fig. 3Common mistakes and principles of management of Inflammatory Bowel Disease in the elderly.
      The choice of the most appropriate therapeutic approach in older patients should be driven by balancing potential benefits and risks on an individual basis [
      • Arnott I.
      • Rogler G.
      • Halfvarson J.
      The management of inflammatory bowel disease in elderly: current evidence and future perspectives.
      ]. If the risks of IBD-related complications prevail, or in case of a fit old patient, a top-down approach could be cautiously considered, as it has been demonstrated that early combined immunosuppression had similar efficacy in older and younger CD patients, and was more effective than conventional treatment in lowering disease-related complications [
      • Singh S.
      • Stitt L.W.
      • Zou G.
      • et al.
      Early combined immunosuppression may be effective and safe in older patients with Crohn's disease: post hoc analysis of REACT.
      ]. Conversely, in a frail patient, the risks of treatment-related complications could induce clinicians to opt for a more conservative step-up approach. Still, one should consider that a flare of IBD in a frail patient with diminished functional reserves may have very deleterious effects on the patient health status [
      • Sturm A.
      • Maaser C.
      • Mendall M.
      • et al.
      European Crohn's and colitis organisation topical review on IBD in the elderly.
      ,
      • Ananthakrishnan A.N.
      • McGinley E.L.
      • Binion D.G.
      Inflammatory bowel disease in the elderly is associated with worse outcomes: a national study of hospitalizations.
      ] and that refraining from the use of the most effective drugs may induce an increased risk of surgery [
      • Arnott I.
      • Rogler G.
      • Halfvarson J.
      The management of inflammatory bowel disease in elderly: current evidence and future perspectives.
      ]. Additionally, both severe disease activity and steroids use are factors greatly associated with serious infections in IBD [
      • Singh S.
      • Stitt L.W.
      • Zou G.
      • et al.
      Early combined immunosuppression may be effective and safe in older patients with Crohn's disease: post hoc analysis of REACT.
      ]. Notably, a recent study showed that an effective use of anti-TNF drugs was able to improve frailty in elderly IBD patients, with a greater impact on patients with higher pre-treatment frailty [
      • Kochar B.D.
      • Cai W.
      • Ananthakrishnan A.N.
      Inflammatory bowel disease patients who respond to treatment with anti-tumor necrosis factor agents demonstrate improvement in pre-treatment frailty.
      ]. As such, treating physicians should consider the possibility of frailty improvement with IBD treatment during the risk-benefit assessment for each individual patient.
      A key principle of management is to avoid undertreating patients, a common mistake in clinical practice, where physicians rely on the frequent use of steroids and delay treatment escalation. The underuse of the most effective therapies in elderly IBD could have several explanations including, (i) the misperception of a milder course of disease in this population [
      • Ananthakrishnan A.N.
      • Shi H.Y.
      • Tang W.
      • et al.
      Systematic review and meta-analysis: phenotype and clinical outcomes of older-onset inflammatory bowel disease.
      ]; (ii) a false perception of the safety and convenience of steroids instead of steroid-sparing therapies [
      • Beaugerie L.
      • Rahier J.F.
      • Kirchgesner J.
      Predicting, preventing, and managing treatment-related complications in patients with inflammatory bowel diseases.
      ,
      • Lin E.
      • Lin K.
      • Katz S.
      Serious and opportunistic infections in elderly patients with inflammatory bowel disease.
      ]; (iii) the fear of adverse events (as suggested by an international survey) [
      • Chan W.
      • Kariyawasam V.C.
      • Kim S.
      • et al.
      Gastroenterologists' preference and risk perception on the use of immunomodulators and biological therapies in elderly patients with ulcerative colitis: an international survey.
      ]; or (iv) concerns about a reduced efficacy of immune-modulating therapies due to immunosenescence, although no clear data are currently available [
      • LeBlanc J.F.
      • Wiseman D.
      • Lakatos P.L.
      • Bessissow T.
      Elderly patients with inflammatory bowel disease: updated review of the therapeutic landscape.
      ].
      A major limitation in choosing an appropriate treatment strategy and target in the elderly with IBD is that elderly patients are often excluded from clinical trials as many factors serving as barriers for recruitment are more likely to affect this age group (such as comorbidities and malignancies) [
      • Kochar B.
      • Kalasapudi L.
      • Ufere N.N.
      • Nipp R.D.
      • Ananthakrishnan A.N.
      • Ritchie C.S.
      Systematic review of inclusion and analysis of older adults in randomized controlled trials of medications used to treat inflammatory bowel diseases.
      ]. This limits the generalization of their RCT results to guide treatment in the elderly. In a systematic review of inclusion of older adults in the randomized controlled trials (RCT) of approved drugs to treat IBD, Kochar et al. found that less than 1% of participants were ≥ 65 years [
      • Kochar B.
      • Kalasapudi L.
      • Ufere N.N.
      • Nipp R.D.
      • Ananthakrishnan A.N.
      • Ritchie C.S.
      Systematic review of inclusion and analysis of older adults in randomized controlled trials of medications used to treat inflammatory bowel diseases.
      ].

      3.2 Drug efficacy in the elderly

      Overall, current literature did not demonstrate differences of efficacy of medical treatment in elderly patients [
      • Sturm A.
      • Maaser C.
      • Mendall M.
      • et al.
      European Crohn's and colitis organisation topical review on IBD in the elderly.
      ], as it was shown for corticosteroids [
      • Gisbert J.P.
      • Marin A.C.
      • Chaparro M.
      Systematic review: factors associated with relapse of inflammatory bowel disease after discontinuation of anti-TNF therapy.
      ] and thiopurines [
      • Chaparro M.
      • Ordas I.
      • Cabre E.
      • et al.
      Safety of thiopurine therapy in inflammatory bowel disease: long-term follow-up study of 3931 patients.
      ]. Methotrexate is not widely used in elderly patients, but a retrospective study showed similar outcomes in these patients compared to a younger cohort [
      • Gonzalez-Lama Y.
      • Taxonera C.
      • Lopez-Sanroman A.
      • et al.
      Methotrexate in inflammatory bowel disease: a multicenter retrospective study focused on long-term efficacy and safety. The Madrid experience.
      ].
      Biological agents in the elderly IBD population are rarely utilized, with rates as low as 2% in UC patients and 6% in CD patients at 5 years following date of diagnosis, compared to 7% and 20% in the adult population [
      • Kim M.
      • Katz S.
      • Green J.
      Drug management in the elderly IBD patient.
      ]. Data from the large TARGET-IBD multicenter cohort indicated that older patients with IBD were prescribed more aminosalicylate monotherapy and less anti-TNF therapy compared with younger patients [
      • Barnes E.L.
      • Hanson J.S.
      • Regueiro M.D.
      • et al.
      Older adult patients use more aminosalicylate monotherapy compared with younger patients with inflammatory bowel disease: TARGET-IBD.
      ]. The underuse of biological therapies in elderly-onset IBD may lead to increasing rates of surgery in UC [
      • Everhov Å.H.
      • Halfvarson J.
      • Myrelid P.
      • et al.
      Incidence and treatment of patients diagnosed with inflammatory bowel diseases at 60 years or older in Sweden.
      ,
      • Manosa M.
      • Calafat M.
      • de Francisco R.
      • et al.
      Phenotype and natural history of elderly onset inflammatory bowel disease: a multicentre, case-control study.
      ].
      Concerning the efficacy of anti-TNF drugs in the elderly, available data is conflicting. A pooled analysis of RCT comparing patients >60 years with younger ones showed that they had similar rates of clinical remission after both induction (OR, 0.78; 95% CI, 0.51–1.19) and maintenance (OR, 0.65; 95% CI, 0.41–1.06) [
      • Cheng D.
      • Cushing K.C.
      • Cai T.
      • Ananthakrishnan A.N.
      Safety and efficacy of tumor necrosis factor antagonists in older patients with ulcerative colitis: patient-level pooled analysis of data from randomized trials.
      ]. These results were confirmed in a real-life setting [
      • Adar T.
      • Faleck D.
      • Sasidharan S.
      • et al.
      Comparative safety and effectiveness of tumor necrosis factor alpha antagonists and vedolizumab in elderly IBD patients: a multicentre study.
      ]. There are, however, other reports demonstrating a lower efficacy of anti-TNF treatment in bio-naïve elderly IBD patients [
      • Amano T.
      • Shinzaki S.
      • Asakura A.
      • et al.
      Elderly onset age is associated with low efficacy of first anti-tumor necrosis factor treatment in patients with inflammatory bowel disease.
      ], and higher risk of anti-TNF treatment discontinuation, due to both the increased risk of adverse events and the lower rate of response [
      • Desai A.
      • Zator Z.A.
      • de Silva P.
      • et al.
      Older age is associated with higher rate of discontinuation of anti-TNF therapy in patients with inflammatory bowel disease.
      ]. However, elderly patients may need more time to obtain remission after starting anti-TNF treatment, suggesting that pharmacokinetic mechanisms could play a role [
      • Lobaton T.
      • Ferrante M.
      • Rutgeerts P.
      • Ballet V.
      • Van Assche G.
      • Vermeire S.
      Efficacy and safety of anti-TNF therapy in elderly patients with inflammatory bowel disease.
      ,
      • Paul S.
      • Roblin X.
      Letter: immunogenicity of anti-TNF in elderly IBD patients.
      ].
      Regarding vedolizumab, data are more homogeneous, indicating that drug efficacy is similar in elderly and in young patients [
      • Yajnik V.
      • Khan N.
      • Dubinsky M.
      • et al.
      Efficacy and safety of vedolizumab in ulcerative colitis and crohn's disease patients stratified by age.
      ,
      • Khan N.
      • Pernes T.
      • Weiss A.
      • et al.
      Efficacy of vedolizumab in a nationwide cohort of elderly inflammatory bowel disease patients.
      ,
      • Pugliese D.
      • Privitera G.
      • Crispino F.
      • et al.
      Effectiveness and safety of vedolizumab in a matched cohort of elderly and nonelderly patients with inflammatory bowel disease: the IG-IBD LIVE study.
      ]. Interestingly, a large multicenter Italian study showed that vedolizumab effectiveness in elderly UC patients may be reduced in terms of treatment persistence, clinical and biochemical remission, while no age-dependant effect on effectiveness was observed in CD [
      • Pugliese D.
      • Privitera G.
      • Crispino F.
      • et al.
      Effectiveness and safety of vedolizumab in a matched cohort of elderly and nonelderly patients with inflammatory bowel disease: the IG-IBD LIVE study.
      ].
      Limited data are available for ustekinumab, with only one study in IBD setting showing a similar rate of clinical response in elderly and young patients, but the first group was less likely to achieve complete clinical remission [
      • Garg R.
      • Aggarwal M.
      • Butler R.
      • et al.
      Real-world effectiveness and safety of ustekinumab in elderly Crohn's disease patients.
      ].
      An early identification of patients responding to biological therapies could have a significant impact in clinical management of elderly IBD patients. Unfortunately, the most used biomarkers in IBD setting, such as C-reactive protein (CRP) or faecal calprotectin (FC) have a significantly lower reliability in the elderly population, mainly due to their low specificity [
      • Bertani L.
      • Mumolo M.G.
      • Tapete G.
      • et al.
      Fecal calprotectin: current and future perspectives for inflammatory bowel disease treatment.
      ,
      • Alsoud D.
      • Vermeire S.
      • Verstockt B.
      Biomarker discovery for personalized therapy selection in inflammatory bowel diseases: challenges and promises.
      ]. Indeed, both CRP and FC could be increased by several non-IBD conditions and by several drugs, such as proton pump inhibitors and nonsteroidal anti-inflammatory drugs, which are commonly used in the elderly population [
      • LeBlanc J.F.
      • Wiseman D.
      • Lakatos P.L.
      • Bessissow T.
      Elderly patients with inflammatory bowel disease: updated review of the therapeutic landscape.
      ,
      • Bertani L.
      • Mumolo M.G.
      • Tapete G.
      • et al.
      Fecal calprotectin: current and future perspectives for inflammatory bowel disease treatment.
      ]. A recent study pointed out that the serum triiodothyronine-to-thyroxine (T3/T4) ratio before starting a biological therapy in elderly IBD patients could predict therapeutic outcome in terms of mucosal healing at one year [
      • Bertani L.
      • Tricò D.
      • Pugliese D.
      • et al.
      Serum triiodothyronine-to-thyroxine (T3/T4) ratio predicts therapeutic outcome to biological therapies in elderly IBD patients.
      ]. Interestingly, T3/T4 ratio could be considered as an independent biomarker of frailty in elderly patients regardless of disease [
      • Pasqualetti G.
      • Calsolaro V.
      • Bernardini S.
      • et al.
      Degree of peripheral thyroxin deiodination, frailty, and long-term survival in hospitalized older patients.
      ]. If the results of this study would be confirmed in future larger studies, the assessment of T3/T4 ratio could help clinicians in identifying patients with higher probability of therapeutic response, maximizing the results, and reducing the rate of treatment-related complications.

      3.3 Drug safety in the elderly

      Safety profile should be considered as a significant issue in the elderly IBD population for almost all therapeutic agents, as elderly IBD patients seem to have higher risks of treatment-related complications, especially those with elderly-onset IBD [
      • Rozich J.J.
      • Luo J.
      • Dulai P.S.
      • et al.
      Disease- and treatment-related complications in older patients with inflammatory bowel diseases: comparison of adult-onset vs elderly-onset disease.
      ].
      Aminosalicylates and sulfasalazine are undoubtedly drugs with a good safety profile, but they are associated with an increased risk of nephrotoxicity, particularly in patients with concomitant renal dysfunction or heart failure [
      • Gisbert J.P.
      • Gonzalez-Lama Y.
      • Mate J.
      5-Aminosalicylates and renal function in inflammatory bowel disease: a systematic review.
      ], comorbidities that are more frequent in elderly patients [
      • Argollo M.
      • Gilardi D.
      • Peyrin-Biroulet C.
      • Chabot J.F.
      • Peyrin-Biroulet L.
      • Danese S.
      Comorbidities in inflammatory bowel disease: a call for action.
      ].
      Corticosteroid treatment is clearly associated with higher risks of complications in elderly patients as compared with younger ones, especially in case of a prolonged use [
      • Sturm A.
      • Maaser C.
      • Mendall M.
      • et al.
      European Crohn's and colitis organisation topical review on IBD in the elderly.
      ]. The TREAT registry highlighted that age, use of corticosteroids and narcotics were independent predictors of mortality, whereas mortality rates were similar between infliximab- and non-infliximab-treated patients [
      • Lichtenstein G.R.
      • Feagan B.G.
      • Cohen R.D.
      • et al.
      Serious infections and mortality in association with therapies for Crohn's disease: TREAT registry.
      ]. In fact, most studies agree that infections, and particularly serious infections, are more common in elderly IBD patients, especially in those receiving corticosteroids [
      • Gisbert J.P.
      • Chaparro M.
      Systematic review with meta-analysis: inflammatory bowel disease in the elderly.
      ,
      • Lichtenstein G.R.
      • Feagan B.G.
      • Cohen R.D.
      • et al.
      Serious infections and mortality in association with therapies for Crohn's disease: TREAT registry.
      ,
      • Brassard P.
      • Bitton A.
      • Suissa A.
      • Sinyavskaya L.
      • Patenaude V.
      • Suissa S.
      Oral corticosteroids and the risk of serious infections in patients with elderly-onset inflammatory bowel diseases.
      ,
      • Stuck A.E.
      • Minder C.E.
      • Frey F.J.
      Risk of infectious complications in patients taking glucocorticosteroids.
      ]. Corticosteroids are also associated with other complications, such as osteoporosis, alteration in mental status, fluid retention, ocular problems, and drug interactions [
      • Akerkar G.A.
      • Peppercorn M.A.
      • Hamel M.B.
      • Parker R.A.
      Corticosteroid-associated complications in elderly Crohn's disease patients.
      ]. Given all of these risks, corticosteroids in the elderly should be initiated with an appropriate ‘exit strategy’, planning a transition to a safer maintenance therapy [
      • Hong S.J.
      • Katz S.
      The elderly IBD patient in the modern era: changing paradigms in risk stratification and therapeutic management.
      ].
      Safety problems are significant in case of immunosuppressive treatment with thiopurines. Their use increases the risk of infections, nonmelanoma skin cancers and lymphoproliferative disorders, particularly in elderly patients [
      • Kandiel A.
      • Fraser A.G.
      • Korelitz B.I.
      • Brensinger C.
      • Lewis J.D.
      Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine.
      ,
      • Beaugerie L.
      • Brousse N.
      • Bouvier A.M.
      • et al.
      Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study.
      ,
      • Siegel C.A.
      • Marden S.M.
      • Persing S.M.
      • Larson R.J.
      • Sands B.E.
      Risk of lymphoma associated with combination anti-tumor necrosis factor and immunomodulator therapy for the treatment of Crohn's disease: a meta-analysis.
      ,
      • Lemaitre M.
      • Kirchgesner J.
      • Rudnichi A.
      • et al.
      Association between use of thiopurines or tumor necrosis factor antagonists alone or in combination and risk of lymphoma in patients with inflammatory bowel disease.
      ,
      • Peyrin-Biroulet L.
      • Khosrotehrani K.
      • Carrat F.
      • et al.
      Increased risk for nonmelanoma skin cancers in patients who receive thiopurines for inflammatory bowel disease.
      ]. The CESAME study [
      • Beaugerie L.
      • Brousse N.
      • Bouvier A.M.
      • et al.
      Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study.
      ] indicated that older age is an independent risk factor for the development of lymphomas. Even though azathioprine therapy increases life expectancy in patients with CD, the incremental gain in life expectancy decreases with increasing patients’ age due to the increasing risk of lymphoma [
      • Lewis J.D.
      • Schwartz J.S.
      • Lichtenstein G.R.
      Azathioprine for maintenance of remission in Crohn's disease: benefits outweigh the risk of lymphoma.
      ]. Notably, the risk of malignancies seems to be significant even after the discontinuation of thiopurine therapy [
      • Jorissen C.
      • Verstockt B.
      • Schils N.
      • Sabino J.
      • Ferrante M.
      • Vermeire S.
      Long-term clinical outcome after thiopurine discontinuation in elderly IBD patients.
      ], suggesting a long-term monitoring of elderly IBD patients treated with these drugs. Moreover, the ENEIDA registry showed that patients starting thiopurines after 60 years had higher rates of myelotoxicity, digestive intolerance and hepatotoxicity [
      • Calafat M.
      • Manosa M.
      • Canete F.
      • et al.
      Increased risk of thiopurine-related adverse events in elderly patients with IBD.
      ]. For these reasons, ECCO suggests that the use of thiopurines in the elderly needs careful consideration and monitoring [
      • Sturm A.
      • Maaser C.
      • Mendall M.
      • et al.
      European Crohn's and colitis organisation topical review on IBD in the elderly.
      ]. Thiopurines should be avoided in the case of chronic renal disease and lower renal clearance, in those with a history of neoplasms or lymphoma, and in patients requiring the use of xanthine oxidase inhibitors [
      • Calafat M.
      • Manosa M.
      • Canete F.
      • et al.
      Increased risk of thiopurine-related adverse events in elderly patients with IBD.
      ].
      Biological agents seem to have a safer profile in comparison with thiopurines, although all the immune-suppressive therapies could increase the risks of infections and cancer [
      • Beaugerie L.
      • Kirchgesner J.
      Balancing benefit vs risk of immunosuppressive therapy for individual patients with inflammatory bowel diseases. Clinical gastroenterology and hepatology: the official clinical practice journal of the American.
      ]. The ENEIDA registry showed that elderly patients with IBD have a similar risk of developing infliximab-related adverse events in comparison with younger patients [
      • Calafat M.
      • Manosa M.
      • Ricart E.
      • et al.
      Risk of immunomediated adverse events and loss of response to infliximab in elderly patients with inflammatory bowel disease: a cohort study of the ENEIDA registry.
      ]. In a pooled analysis of data from RCT, even though elderly UC patients had an increased baseline risk of serious adverse events, no increase in risk could be attributed to anti-TNF therapy [
      • Cheng D.
      • Cushing K.C.
      • Cai T.
      • Ananthakrishnan A.N.
      Safety and efficacy of tumor necrosis factor antagonists in older patients with ulcerative colitis: patient-level pooled analysis of data from randomized trials.
      ]. Conversely, Desai et al. [
      • Desai A.
      • Zator Z.A.
      • de Silva P.
      • et al.
      Older age is associated with higher rate of discontinuation of anti-TNF therapy in patients with inflammatory bowel disease.
      ] observed a threefold risk of discontinuation of anti-TNF treatment in patients starting the therapy over the age of 60. On the same line, an Italian multicenter study showed that elderly IBD patients treated with anti-TNFs displayed an increased risk of infections (particularly respiratory infections) malignancy and mortality when compared to a younger group or to elderly patients treated with other drugs [
      • Cottone M.
      • Kohn A.
      • Daperno M.
      • et al.
      Advanced age is an independent risk factor for severe infections and mortality in patients given anti-tumor necrosis factor therapy for inflammatory bowel disease.
      ]. These findings were confirmed by a more recent study that took into consideration all serious adverse events, which were significantly higher in patients >65 years treated with anti-TNF as compared to younger ones [
      • Lobaton T.
      • Ferrante M.
      • Rutgeerts P.
      • Ballet V.
      • Van Assche G.
      • Vermeire S.
      Efficacy and safety of anti-TNF therapy in elderly patients with inflammatory bowel disease.
      ]. The IBDREAM registry confirmed these data, indicating that older patients treated with anti-TNF have higher rates of treatment discontinuation, although the concomitant use of thiopurines at baseline was associated with lower failure rates, but with higher risk of serious adverse events and infections [
      • de Jong M.E.
      • Smits L.J.T.
      • van Ruijven B.
      • et al.
      Increased discontinuation rates of anti-TNF therapy in elderly inflammatory bowel disease patients.
      ].
      A recent survey indicated that vedolizumab is the preferred treatment option of the gastroenterologists in elderly IBD patients [
      • Chan W.
      • Kariyawasam V.C.
      • Kim S.
      • et al.
      Gastroenterologists' preference and risk perception on the use of immunomodulators and biological therapies in elderly patients with ulcerative colitis: an international survey.
      ]. This could be related to its gut-selectivity, which a perceived lower risk of adverse events. Indeed, a post-hoc analysis of GEMINI trials showed no age-related differences in the incidence of adverse haematological events, malignancy, or death [
      • Yajnik V.
      • Khan N.
      • Dubinsky M.
      • et al.
      Efficacy and safety of vedolizumab in ulcerative colitis and crohn's disease patients stratified by age.
      ]. These results were confirmed in a recent, large real-life study [
      • Pugliese D.
      • Privitera G.
      • Crispino F.
      • et al.
      Effectiveness and safety of vedolizumab in a matched cohort of elderly and nonelderly patients with inflammatory bowel disease: the IG-IBD LIVE study.
      ]. Accordingly, Kochar et al. observed that older IBD patients treated with vedolizumab had a lower risk of infection-related hospitalization compared with those initiating anti-TNF therapies [
      • Kochar B.
      • Pate V.
      • Kappelman M.D.
      • et al.
      Vedolizumab is associated with a lower risk of serious infections than anti-tumor necrosis factor agents in older adults.
      ]. Conversely, Adar et al. [
      • Adar T.
      • Faleck D.
      • Sasidharan S.
      • et al.
      Comparative safety and effectiveness of tumor necrosis factor alpha antagonists and vedolizumab in elderly IBD patients: a multicentre study.
      ] reported an increased risk of pneumonia in elderly IBD patients treated with vedolizumab, similar to the rates obtained in patients treated with anti-TNF. A larger subsequent study of 3 population-based cohorts confirmed that the risk of serious infections was not decreased with vedolizumab versus anti-TNF in patients with CD, whereas it decreased of 32% in patients with UC, suggesting that the disease phenotype could play a role in the development of infections in vedolizumab-treated patients [
      • Kirchgesner J.
      • Desai R.J.
      • Beaugerie L.
      • Schneeweiss S.
      • Kim S.C.
      Risk of serious infections with vedolizumab versus tumor necrosis factor antagonists in patients with inflammatory bowel disease.
      ].
      Fewer data are currently available for ustekinumab. UNITI-1 and UNITI-2 registration trials found that the proportion of patients who developed infections was similar between those treated with ustekinumab and those treated with placebo [
      • Feagan B.G.
      • Sandborn W.J.
      • Gasink C.
      • et al.
      Ustekinumab as induction and maintenance therapy for Crohn's disease.
      ,
      • Sands B.E.
      • Sandborn W.J.
      • Panaccione R.
      • et al.
      Ustekinumab as induction and maintenance therapy for ulcerative colitis.
      ], and a recent meta-analysis confirmed these reassuring findings, but patients were not stratified by age [
      • Rolston V.S.
      • Kimmel J.
      • Popov V.
      • et al.
      Ustekinumab does not increase risk of adverse events: a meta-analysis of randomized controlled trials.
      ]. However, a real-life study showed no significant differences in infusion reactions, infection, or postsurgical complications in patients stratified by age category (>65 vs <65 years old) [
      • Garg R.
      • Aggarwal M.
      • Butler R.
      • et al.
      Real-world effectiveness and safety of ustekinumab in elderly Crohn's disease patients.
      ].
      Despite the notion that newer biologics may have better safety profiles, in a recent meta-analysis evaluating safety of biologics in elderly-IBD, the rate of adverse events and infections was not different between the investigated biologics [
      • Hahn G.D.
      • Golovics P.A.
      • Wetwittayakhlang P.
      • et al.
      Safety of biological therapies in elderly inflammatory bowel diseases: a systematic review and meta-analysis.
      ]. The authors concluded that data was still lacking to propose sequencing of biologics in the elderly based on safety, and that larger studies are needed.
      Tofacitinib is a Janus kinase (JAK) inhibitor, a small molecule with proven efficacy in IBD. However, as increasing age seems to be a risk factor for adverse events reported with this drug (namely a higher risk of infections and of thrombotic events), its use in the elderly should be carefully considered [
      • Deepak P.
      • Alayo Q.A.
      • Khatiwada A.
      • et al.
      Safety of tofacitinib in a real-world cohort of patients with ulcerative colitis.
      ].

      3.4 Surgery in the elderly

      Elderly IBD patients seem to have increased rates of surgery, mainly shortly after diagnosis [
      • Mañosa M.
      • Calafat M.
      • de Francisco R.
      • et al.
      Phenotype and natural history of elderly onset inflammatory bowel disease: a multicentre, case-control study.
      ,
      • Everhov Å.H.
      • Halfvarson J.
      • Myrelid P.
      • et al.
      Incidence and treatment of patients diagnosed with inflammatory bowel diseases at 60 years or older in Sweden.
      ,
      • Ananthakrishnan A.N.
      • Shi H.Y.
      • Tang W.
      • et al.
      Systematic review and meta-analysis: phenotype and clinical outcomes of older-onset inflammatory bowel disease.
      ,
      • Nguyen G.C.
      • Bernstein C.N.
      • Benchimol E.I.
      Risk of surgery and mortality in elderly-onset inflammatory bowel disease: a population-based cohort study.
      ,
      • Ananthakrishnan A.N.
      • McGinley E.L.
      • Binion D.G.
      Inflammatory bowel disease in the elderly is associated with worse outcomes: a national study of hospitalizations.
      ,
      • Manosa M.
      • Calafat M.
      • de Francisco R.
      • et al.
      Phenotype and natural history of elderly onset inflammatory bowel disease: a multicentre, case-control study.
      ,
      • Komoto S.
      • Higashiyama M.
      • Watanabe C.
      • et al.
      Clinical differences between elderly-onset ulcerative colitis and non-elderly-onset ulcerative colitis: a nationwide survey data in Japan.
      ]. This may be caused by an underuse of effective medical therapies with subsequent complications needing a surgical procedure, as previously mentioned. However, it may also be a conscious decision by the physician to avoid medical therapy, as surgery may be seen as a safer alternative to immunosuppressive treatment in patients with comorbidities [
      • Everhov Å.H.
      • Halfvarson J.
      • Myrelid P.
      • et al.
      Incidence and treatment of patients diagnosed with inflammatory bowel diseases at 60 years or older in Sweden.
      ,
      • Ananthakrishnan A.N.
      • Shi H.Y.
      • Tang W.
      • et al.
      Systematic review and meta-analysis: phenotype and clinical outcomes of older-onset inflammatory bowel disease.
      ]. In fact, in a recent survey [
      • Chan W.
      • Kariyawasam V.C.
      • Kim S.
      • et al.
      Gastroenterologists' preference and risk perception on the use of immunomodulators and biological therapies in elderly patients with ulcerative colitis: an international survey.
      ], the presence of comorbidities was the most important factor influencing gastroenterologists’ decision on recommending colectomy in UC patients. However, comorbidities also significantly impact the postoperative outcomes of IBD patients, being associated with an important increase in mortality rate [
      • Kaplan G.G.
      • Hubbard J.
      • Panaccione R.
      • et al.
      Risk of comorbidities on postoperative outcomes in patients with inflammatory bowel disease.
      ]. There are conflicting data on the risk of postoperative complications in elderly IBD patients, but many studies demonstrate a higher risk of complications and mortality [
      • Cheng D.
      • Cushing K.C.
      • Cai T.
      • Ananthakrishnan A.N.
      Safety and efficacy of tumor necrosis factor antagonists in older patients with ulcerative colitis: patient-level pooled analysis of data from randomized trials.
      ,
      • Bautista M.C.
      • Otterson M.F.
      • Zadvornova Y.
      • et al.
      Surgical outcomes in the elderly with inflammatory bowel disease are similar to those in the younger population.
      ,
      • Hruz P.
      • Juillerat P.
      • Kullak-Ublick G.A.
      • Schoepfer A.M.
      • Mantzaris G.J.
      • Rogler G.
      Management of the elderly inflammatory bowel disease patient.
      ,
      • Fazio V.W.
      • Tekkis P.P.
      • Remzi F.
      • et al.
      Quantification of risk for pouch failure after ileal pouch anal anastomosis surgery.
      ,
      • Delaney C.P.
      • Fazio V.W.
      • Remzi F.H.
      • et al.
      Prospective, age-related analysis of surgical results, functional outcome, and quality of life after ileal pouch-anal anastomosis.
      ,
      • Sacleux S.C.
      • Sarter H.
      • Fumery M.
      • et al.
      Post-operative complications in elderly onset inflammatory bowel disease: a population-based study.
      ,
      • Bollegala N.
      • Jackson T.D.
      • Nguyen G.C.
      Increased postoperative mortality and complications among elderly patients with inflammatory bowel diseases: an analysis of the national surgical quality improvement program cohort.
      ]. In a recent systematic review, elderly-onset UC patients had high rates of serious post-operative complications (10%) with a 4% mortality [
      • Rozich J.J.
      • Dulai P.S.
      • Fumery M.
      • Sandborn W.J.
      • Singh S.
      Progression of elderly onset inflammatory bowel diseases: a systematic review and meta-analysis of population-based cohort studies.
      ].
      ECCO recommends that age should not be used as a sole predictor of surgical risk in IBD patients and surgery must not be delayed when clearly indicated [
      • Sturm A.
      • Maaser C.
      • Mendall M.
      • et al.
      European Crohn's and colitis organisation topical review on IBD in the elderly.
      ]. Some groups advocate a timely proctocolectomy rather than combination treatment in elderly-onset UC, particularly due to the potential curative nature of the procedure [
      • Mañosa M.
      • Calafat M.
      • de Francisco R.
      • et al.
      Phenotype and natural history of elderly onset inflammatory bowel disease: a multicentre, case-control study.
      ]. Ileal J pouch anal anastomosis is a preferential surgical technique in UC if the patient has good anal sphincter function and no history of faecal incontinence, with a high rate of satisfaction in this group [
      • Delaney C.P.
      • Fazio V.W.
      • Remzi F.H.
      • et al.
      Prospective, age-related analysis of surgical results, functional outcome, and quality of life after ileal pouch-anal anastomosis.
      ]. Patients with diminished anal sphincter function may have superior quality of life with colectomy and ileorectal anastomosis or end-ileostomy surgery [
      • Longo W.E.
      • Virgo K.S.
      • Bahadursingh A.N.
      • Johnson F.E.
      Patterns of disease and surgical treatment among United States veterans more than 50 years of age with ulcerative colitis.
      ,
      • Taleban S.
      • Colombel J.F.
      • Mohler M.J.
      • Fain M.J.
      Inflammatory bowel disease and the elderly: a review.
      ].
      The decision of surgery should be balanced against medical treatment, considering patient and disease-associated factors. Since emergency surgery is the main factor accounting for post-operative complications, surgery should preferably be performed in an elective rather than emergent setting [
      • Sacleux S.C.
      • Sarter H.
      • Fumery M.
      • et al.
      Post-operative complications in elderly onset inflammatory bowel disease: a population-based study.
      ,
      • Myrelid P.
      Editorial: post-operative complications in elderly onset inflammatory bowel disease—What is surgery, what is disease, and what is delay of surgery?.
      ] As such, gastroenterologists and surgeons should work in a multidisciplinary team aiming at avoidance of emergency surgical procedures by adequately controlling disease activity, whether by an appropriate medical treatment, an elective surgical procedure or a combination of both.

      3.5 Health maintenance

      Concerning preventive medicine in elderly IBD patients, we refer to the published ECCO guidelines on the prevention and management of infections in IBD [
      • Kucharzik T.
      • Ellul P.
      • Greuter T.
      • et al.
      ECCO guidelines on the prevention, diagnosis, and management of infections in inflammatory bowel disease.
      ], and the soon to be updated ECCO guidelines on malignancies [
      • Annese V.
      • Beaugerie L.
      • Egan L.
      • et al.
      European evidence-based consensus: inflammatory bowel disease and malignancies.
      ], as many of the same principles apply to this age group.
      Advanced age is an independent risk factor for opportunistic infections [
      • Cottone M.
      • Kohn A.
      • Daperno M.
      • et al.
      Advanced age is an independent risk factor for severe infections and mortality in patients given anti-tumor necrosis factor therapy for inflammatory bowel disease.
      ]. To counteract the increased risk of infections, vaccinations are strongly recommended before starting a biological or immune-suppressive therapy in all IBD patients, and particularly in elderly age [
      • Beaugerie L.
      • Rahier J.F.
      • Kirchgesner J.
      Predicting, preventing, and managing treatment-related complications in patients with inflammatory bowel diseases.
      ]. This is particularly important for anti-JAK therapies, which are associated with a significant increased risk of severe herpes zoster infection [
      • Winthrop K.L.
      • Melmed G.Y.
      • Vermeire S.
      • et al.
      Herpes zoster infection in patients with ulcerative colitis receiving tofacitinib.
      ].
      Regarding colorectal cancer (CRC) screening, there is some evidence suggesting an increased risk of CRC in elderly-onset IBD, with a recommendation of an earlier start of surveillance in this group. However, other studies have not found an increased risk of CRC in this particular cohort [
      • Sturm A.
      • Maaser C.
      • Mendall M.
      • et al.
      European Crohn's and colitis organisation topical review on IBD in the elderly.
      ,
      • Hruz P.
      • Juillerat P.
      • Kullak-Ublick G.A.
      • Schoepfer A.M.
      • Mantzaris G.J.
      • Rogler G.
      Management of the elderly inflammatory bowel disease patient.
      ,
      • Cheddani H.
      • Dauchet L.
      • Fumery M.
      • et al.
      Cancer in elderly onset inflammatory bowel disease: a population-based study.
      ,
      • Baars J.E.
      • Kuipers E.J.
      • van Haastert M.
      • Nicolaï J.J.
      • Poen A.C.
      • van der Woude C.J.
      Age at diagnosis of inflammatory bowel disease influences early development of colorectal cancer in inflammatory bowel disease patients: a nationwide, long-term survey.
      ,
      • Annese V.
      • Daperno M.
      • Rutter M.D.
      • et al.
      European evidence based consensus for endoscopy in inflammatory bowel disease.
      ]. The continuation of CRC screening in older patients should consider the general health status/frailty of the patient and impact of comorbidities against the potential increasing risks of colonoscopy with age [
      • Sturm A.
      • Maaser C.
      • Mendall M.
      • et al.
      European Crohn's and colitis organisation topical review on IBD in the elderly.
      ,
      • Gisbert J.P.
      • Chaparro M.
      Systematic review with meta-analysis: inflammatory bowel disease in the elderly.
      ].
      Malnutrition is more frequent in IBD patients >65 years than in younger ones [
      • Ananthakrishnan A.N.
      • McGinley E.L.
      • Binion D.G.
      Inflammatory bowel disease in the elderly is associated with worse outcomes: a national study of hospitalizations.
      ]. Malabsorption, increased intestinal loss and decreased food intake play a role in protein-calorie malnutrition with subsequent associated infectious risk [
      • Hruz P.
      • Juillerat P.
      • Kullak-Ublick G.A.
      • Schoepfer A.M.
      • Mantzaris G.J.
      • Rogler G.
      Management of the elderly inflammatory bowel disease patient.
      ]. It is recommended an annual review of diet, body weight assessment, and regular evaluation of ferritin, albumin and vitamins D and B12 levels [
      • Butter M.
      • Weiler S.
      • Biedermann L.
      • et al.
      Clinical manifestations, pathophysiology, treatment and outcome of inflammatory bowel diseases in older people.
      ].
      Osteoporosis and osteoporotic fractures are increased by 40–60% in IBD patients and older IBD patients have a further increased risk due to malnutrition, vitamin D deficiency and reduced physical activity besides age-related bone loss [
      • Butter M.
      • Weiler S.
      • Biedermann L.
      • et al.
      Clinical manifestations, pathophysiology, treatment and outcome of inflammatory bowel diseases in older people.
      ]. For this reason, dual energy X-ray absorptiometry screening is recommended amongst older IBD patients with corticosteroid use and/or other risk factors [
      • Harbord M.
      • Annese V.
      • Vavricka S.R.
      • et al.
      The first european evidence-based consensus on extra-intestinal manifestations in inflammatory bowel disease.
      ] and vitamin D/calcium supplementation and treatment of the underlying disease are mandatory [
      • Hruz P.
      • Juillerat P.
      • Kullak-Ublick G.A.
      • Schoepfer A.M.
      • Mantzaris G.J.
      • Rogler G.
      Management of the elderly inflammatory bowel disease patient.
      ].

      4. Conclusion

      With the ageing of the population, IBD clinics must prepare for the expected increased number of elderly IBD patients. In this review we point out the specific challenges physicians face in the management of this group of patients, such as comorbidities, increased risk of treatment complications, and lack of high-quality evidence to inform clinical practice. Biological age may be more relevant than chronological age, and it is of upmost importance that specific risk stratification tools are developed to help guide treatment options.
      The previous notion of a milder course of disease in the elderly was likely a misconception, often defined by a decreased use of immunomodulators and biologics in this age group. Awareness must be raised for the similarity of the disease course of elderly patients with that of adult-onset IBD. The same principles of management must be followed, with the same available treatments – whether medical or surgical – available to be used and obtain an adequate disease control. Newer biologics with maybe better safety profiles may be preferred. Desired outcomes must be individualized and discussed with each specific patient, considering a relatively shorter life expectancy and, consequently, a lower risk of developing long-term complications of both treatments and disease. A personalized management would maximise the benefit/risk ratio, obtaining the best results for patients’ quality of life, even in the long-term.

      Declaration of Competing Interest

      The authors have no conflicts of interest to declare.

      References

        • Kaplan G.G.
        • Windsor J.W.
        The four epidemiological stages in the global evolution of inflammatory bowel disease.
        Nat Rev Gastroenterol Hepatol. 2021; 18: 56-66
        • Ng S.C.
        • Shi H.Y.
        • Hamidi N.
        • et al.
        Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies.
        Lancet North Am Ed. 2017; 390: 2769-2778
        • Bitton A.
        • Vutcovici M.
        • Sewitch M.
        • Suissa S.
        • Brassard P.
        Mortality trends in Crohn's disease and ulcerative colitis: a population-based study in Québec, Canada.
        Inflamm Bowel Dis. 2016; 22: 416-423
        • Sturm A.
        • Maaser C.
        • Mendall M.
        • et al.
        European Crohn's and colitis organisation topical review on IBD in the elderly.
        J Crohns Colitis. 2017; 11: 263-273
        • Coward S.
        • Clement F.
        • Benchimol E.I.
        • et al.
        Past and future burden of inflammatory bowel diseases based on modeling of population-based data.
        Gastroenterology. 2019; 156 (1345-53.e4)
        • Gisbert J.P.
        • Chaparro M.
        Systematic review with meta-analysis: inflammatory bowel disease in the elderly.
        Aliment Pharmacol Ther. 2014; 39: 459-477
        • Amano T.
        • Shinzaki S.
        • Asakura A.
        • et al.
        Elderly onset age is associated with low efficacy of first anti-tumor necrosis factor treatment in patients with inflammatory bowel disease.
        Sci Rep. 2022; 12: 5324
        • Higashiyama M.
        • Komoto S.
        • Suzuki Y.
        • et al.
        Relation of geriatric nutritional risk index with clinical risks in elderly-onset ulcerative colitis.
        J Gastroenterol Hepatol. 2021; 36: 163-170
        • Rozich J.J.
        • Dulai P.S.
        • Fumery M.
        • Sandborn W.J.
        • Singh S.
        Progression of elderly onset inflammatory bowel diseases: a systematic review and meta-analysis of population-based cohort studies.
        Clin Gastroenterol Hepatol. 2020; 18 (2437-47.e6)
        • Mañosa M.
        • Calafat M.
        • de Francisco R.
        • et al.
        Phenotype and natural history of elderly onset inflammatory bowel disease: a multicentre, case-control study.
        Aliment Pharmacol Ther. 2018; 47: 605-614
        • Everhov Å.H.
        • Halfvarson J.
        • Myrelid P.
        • et al.
        Incidence and treatment of patients diagnosed with inflammatory bowel diseases at 60 years or older in Sweden.
        Gastroenterology. 2018; 154 (518-28.e15)
        • Mak J.W.Y.
        • Lok Tung Ho C.
        • Wong K.
        • et al.
        Epidemiology and natural history of elderly-onset inflammatory bowel disease: results from a territory-wide Hong Kong IBD registry.
        J Crohns Colitis. 2021; 15: 401-408
        • Singh S.
        • Underwood F.E.
        • Loftus E.V.
        • et al.
        Sa1769: worldwide incidence of older-onset inflammatory bowel diseases in the 21STCentury: a systematic review of population-based studies.
        Gastroenterology. 2019; 156 (S-394-S-5)
        • Quezada S.M.
        • Steinberger E.K.
        • Cross R.K.
        Association of age at diagnosis and Crohn's disease phenotype.
        Age Ageing. 2013; 42: 102-106
        • Charpentier C.
        • Salleron J.
        • Savoye G.
        • et al.
        Natural history of elderly-onset inflammatory bowel disease: a population-based cohort study.
        Gut. 2014; 63: 423-432
        • Moon J.M.
        • Kang E.A.
        • Han K.
        • et al.
        Trends and risk factors of elderly-onset Crohn's disease: a nationwide cohort study.
        World J Gastroenterol. 2020; 26: 404-415
        • Silverberg M.S.
        • Satsangi J.
        • Ahmad T.
        • et al.
        Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a working party of the 2005 montreal world congress of gastroenterology.
        Can J Gastroenterol. 2005; 19: 5a-36a
        • Wagtmans M.J.
        • Verspaget H.W.
        • Lamers C.B.
        • van Hogezand R.A.
        Crohn's disease in the elderly: a comparison with young adults.
        J Clin Gastroenterol. 1998; 27: 129-133
        • Foxworthy D.M.
        • Wilson J.A.
        Crohn's disease in the elderly. Prolonged delay in diagnosis.
        J Am Geriatr Soc. 1985; 33: 492-495
        • Keyashian K.
        • Dehghan M.
        • Sceats L.
        • Kin C.
        • Limketkai B.N.
        • Park K.T.
        Comparative incidence of inflammatory bowel disease in different age groups in the United States.
        Inflamm Bowel Dis. 2019; 25: 1983-1989
        • Ananthakrishnan A.N.
        • Shi H.Y.
        • Tang W.
        • et al.
        Systematic review and meta-analysis: phenotype and clinical outcomes of older-onset inflammatory bowel disease.
        J Crohns Colitis. 2016; 10: 1224-1236
        • Hwang S.W.
        • Kim J.H.
        • Im J.P.
        • et al.
        Influence of age at diagnosis on the clinical characteristics of Crohn's disease in Korea: results from the CONNECT study.
        J Gastroenterol Hepatol. 2017; 32: 1716-1722
        • Jeuring S.F.
        • van den Heuvel T.R.
        • Zeegers M.P.
        • et al.
        Epidemiology and long-term outcome of inflammatory bowel disease diagnosed at elderly age-an increasing distinct entity?.
        Inflamm Bowel Dis. 2016; 22: 1425-1434
        • Fries W.
        • Viola A.
        • Manetti N.
        • et al.
        Disease patterns in late-onset ulcerative colitis: results from the IG-IBD “AGED study”.
        Dig Liver Dis. 2017; 49: 17-23
        • Viola A.
        • Monterubbianesi R.
        • Scalisi G.
        • et al.
        Late-onset Crohn's disease: a comparison of disease behaviour and therapy with younger adult patients: the Italian Group for the Study of Inflammatory Bowel Disease ‘AGED’ study.
        Eur J Gastroenterol Hepatol. 2019; : 31
        • Barnes E.L.
        • Hanson J.S.
        • Regueiro M.D.
        • et al.
        Older adult patients use more aminosalicylate monotherapy compared with younger patients with inflammatory bowel disease: TARGET-IBD.
        J Clin Gastroenterol. 2022; 56: 529-535
        • Nguyen G.C.
        • Bernstein C.N.
        • Benchimol E.I.
        Risk of surgery and mortality in elderly-onset inflammatory bowel disease: a population-based cohort study.
        Inflamm Bowel Dis. 2017; 23: 218-223
        • Rozich J.J.
        • Luo J.
        • Dulai P.S.
        • et al.
        Disease- and treatment-related complications in older patients with inflammatory bowel diseases: comparison of adult-onset vs elderly-onset disease.
        Inflamm Bowel Dis. 2021; 27: 1215-1223
        • Solberg I.C.
        • Lygren I.
        • Jahnsen J.
        • et al.
        Clinical course during the first 10 years of ulcerative colitis: results from a population-based inception cohort (IBSEN Study).
        Scand J Gastroenterol. 2009; 44: 431-440
        • Nyboe Andersen N.
        • Pasternak B.
        • Friis-Møller N.
        • Andersson M.
        • Jess T.
        Association between tumour necrosis factor-α inhibitors and risk of serious infections in people with inflammatory bowel disease: nationwide Danish cohort study.
        BMJ: Br Med J. 2015; 350: h2809
        • Asscher V.E.R.
        • Waars S.N.
        • van der Meulen-de Jong A.E.
        • et al.
        Deficits in geriatric assessment associate with disease activity and burden in older patients with inflammatory bowel disease.
        Clin Gastroenterol Hepatol. 2022; 20: e1006-e1e21
        • Klotz U.
        Pharmacokinetics and drug metabolism in the elderly.
        Drug Metab Rev. 2009; 41: 67-76
        • Calafat M.
        • Mañosa M.
        • Cañete F.
        • et al.
        Increased risk of thiopurine-related adverse events in elderly patients with IBD.
        Aliment Pharmacol Ther. 2019; 50: 780-788
        • Mesonero F.
        • Fernández C.
        • Sánchez-Rodríguez E.
        • et al.
        Polypharmacy in patients with inflammatory bowel disease: prevalence and outcomes in a single-center series.
        J Clin Gastroenterol. 2022; 56: e189-ee95
        • Juneja M.
        • Baidoo L.
        • Schwartz M.B.
        • et al.
        Geriatric inflammatory bowel disease: phenotypic presentation, treatment patterns, nutritional status, outcomes, and comorbidity.
        Dig Dis Sci. 2012; 57: 2408-2415
        • Argollo M.
        • Gilardi D.
        • Peyrin-Biroulet C.
        • Chabot J.F.
        • Peyrin-Biroulet L.
        • Danese S.
        Comorbidities in inflammatory bowel disease: a call for action.
        Lancet Gastroenterol Hepatol. 2019; 4: 643-654
        • Kariyawasam V.C.
        • Kim S.
        • Mourad F.H.
        • et al.
        Comorbidities rather than age are associated with the use of immunomodulators in elderly-onset inflammatory bowel disease.
        Inflamm Bowel Dis. 2019; 25: 1390-1398
        • Lakatos P.L.
        Prevalence, predictors, and clinical consequences of medical adherence in IBD: how to improve it?.
        World J Gastroenterol. 2009; 15: 4234-4239
        • Hong S.J.
        • Galati J.
        • Katz S.
        Crohn's disease of the elderly: unique biology and therapeutic efficacy and safety.
        Gastroenterol Clin North Am. 2022; 51: 425-440
        • Nguyen N.H.
        • Ohno-Machado L.
        • Sandborn W.J.
        • Singh S.
        Infections and cardiovascular complications are common causes for hospitalization in older patients with inflammatory bowel diseases.
        Inflamm Bowel Dis. 2018; 24: 916-923
        • Schwartz J.
        • Stein D.J.
        • Lipcsey M.
        • Li B.
        • Feuerstein J.D.
        High rates of mortality in geriatric patients admitted for inflammatory bowel disease management.
        J Clin Gastroenterol. 2022; 56: e20-ee6
        • Ananthakrishnan A.N.
        • McGinley E.L.
        • Binion D.G.
        Inflammatory bowel disease in the elderly is associated with worse outcomes: a national study of hospitalizations.
        Inflamm Bowel Dis. 2009; 15: 182-189
        • Khan N.
        • Vallarino C.
        • Lissoos T.
        • Darr U.
        • Luo M.
        Risk of malignancy in a nationwide cohort of elderly inflammatory bowel disease patients.
        Drugs Aging. 2017; 34: 859-868
        • Kochar B.D.
        • Cai W.
        • Ananthakrishnan A.N.
        Inflammatory bowel disease patients who respond to treatment with anti-tumor necrosis factor agents demonstrate improvement in pre-treatment frailty.
        Dig Dis Sci. 2022; 67: 622-628
        • Kochar B.
        • Cai W.
        • Cagan A.
        • Ananthakrishnan A.N.
        Frailty is independently associated with mortality in 11 001 patients with inflammatory bowel diseases.
        Aliment Pharmacol Ther. 2020; 52: 311-318
        • Faye A.S.
        • Wen T.
        • Soroush A.
        • et al.
        Increasing prevalence of frailty and its association with readmission and mortality among hospitalized patients with IBD.
        Dig Dis Sci. 2021; 66: 4178-4190
        • Clegg A.
        • Young J.
        • Iliffe S.
        • Rikkert M.O.
        • Rockwood K.
        Frailty in elderly people.
        Lancet. 2013; 381: 752-762
        • Fried L.P.
        • Tangen C.M.
        • Walston J.
        • et al.
        Frailty in older adults: evidence for a phenotype.
        J Gerontol Ser A. 2001; 56: M146-MM57
        • Thompson C.
        • Taleban S.
        Incorporating frailty in the treatment program of elderly patients with gastrointestinal disease.
        Curr Treat Options Gastroenterol. 2020; 18: 635-656
        • Mitnitski A.B.
        • Mogilner A.J.
        • Rockwood K.
        Accumulation of deficits as a proxy measure of aging.
        ScientificWorldJournal. 2001; 1321027
        • Kochar B.
        • Cai W.
        • Cagan A.
        • Ananthakrishnan A.N.
        Pretreatment frailty is independently associated with increased risk of infections after immunosuppression in patients with inflammatory bowel diseases.
        Gastroenterology. 2020; 158 (2104-11.e2)
        • Qian A.S.
        • Nguyen N.H.
        • Elia J.
        • Ohno-Machado L.
        • Sandborn W.J.
        • Singh S.
        Frailty is independently associated with mortality and readmission in hospitalized patients with inflammatory bowel diseases.
        Clin Gastroenterol Hepatol. 2021; 19 (2054-63.e14)
        • Pedersen M.
        • Cromwell J.
        • Nau P.
        Sarcopenia is a predictor of surgical morbidity in inflammatory bowel disease.
        Inflamm Bowel Dis. 2017; 23: 1867-1872
        • Rasiah J.
        • Gruneir A.
        • Oelke N.D.
        • Estabrooks C.
        • Holroyd-Leduc J.
        • Cummings G.G.
        Instruments to assess frailty in community dwelling older adults: a systematic review.
        Int J Nurs Stud. 2022; 134104316
        • Peyrin-Biroulet L.
        • Sandborn W.
        • Sands B.E.
        • et al.
        Selecting therapeutic targets in inflammatory bowel disease (STRIDE): determining therapeutic goals for treat-to-target.
        Am J Gastroenterol. 2015; 110: 1324-1338
        • Turner D.
        • Ricciuto A.
        • Lewis A.
        • et al.
        STRIDE-II: an update on the selecting therapeutic targets in inflammatory bowel disease (STRIDE) initiative of the international organization for the study of IBD (IOIBD): determining therapeutic goals for treat-to-target strategies in IBD.
        Gastroenterology. 2021; 160: 1570-1583
        • LeBlanc J.F.
        • Wiseman D.
        • Lakatos P.L.
        • Bessissow T.
        Elderly patients with inflammatory bowel disease: updated review of the therapeutic landscape.
        World J Gastroenterol. 2019; 25: 4158-4171
        • Butter M.
        • Weiler S.
        • Biedermann L.
        • et al.
        Clinical manifestations, pathophysiology, treatment and outcome of inflammatory bowel diseases in older people.
        Maturitas. 2018; 110: 71-78
        • Arnott I.
        • Rogler G.
        • Halfvarson J.
        The management of inflammatory bowel disease in elderly: current evidence and future perspectives.
        Inflamm Intest Dis. 2018; 2: 189-199
        • Singh S.
        • Stitt L.W.
        • Zou G.
        • et al.
        Early combined immunosuppression may be effective and safe in older patients with Crohn's disease: post hoc analysis of REACT.
        Aliment Pharmacol Ther. 2019; 49: 1188-1194
        • Beaugerie L.
        • Rahier J.F.
        • Kirchgesner J.
        Predicting, preventing, and managing treatment-related complications in patients with inflammatory bowel diseases.
        Clin Gastroenterol Hepatol. 2020; 18 (1324-35 e2)
        • Lin E.
        • Lin K.
        • Katz S.
        Serious and opportunistic infections in elderly patients with inflammatory bowel disease.
        Gastroenterol Hepatol. 2019; 15 (N Y): 593-605
        • Chan W.
        • Kariyawasam V.C.
        • Kim S.
        • et al.
        Gastroenterologists' preference and risk perception on the use of immunomodulators and biological therapies in elderly patients with ulcerative colitis: an international survey.
        Eur J Gastroenterol Hepatol. 2020; 32: 976-983
        • Kochar B.
        • Kalasapudi L.
        • Ufere N.N.
        • Nipp R.D.
        • Ananthakrishnan A.N.
        • Ritchie C.S.
        Systematic review of inclusion and analysis of older adults in randomized controlled trials of medications used to treat inflammatory bowel diseases.
        Inflamm Bowel Dis. 2021; 27: 1541-1543
        • Gisbert J.P.
        • Marin A.C.
        • Chaparro M.
        Systematic review: factors associated with relapse of inflammatory bowel disease after discontinuation of anti-TNF therapy.
        Aliment Pharmacol Ther. 2015; 42: 391-405
        • Chaparro M.
        • Ordas I.
        • Cabre E.
        • et al.
        Safety of thiopurine therapy in inflammatory bowel disease: long-term follow-up study of 3931 patients.
        Inflamm Bowel Dis. 2013; 19: 1404-1410
        • Gonzalez-Lama Y.
        • Taxonera C.
        • Lopez-Sanroman A.
        • et al.
        Methotrexate in inflammatory bowel disease: a multicenter retrospective study focused on long-term efficacy and safety. The Madrid experience.
        Eur J Gastroenterol Hepatol. 2012; 24: 1086-1091
        • Kim M.
        • Katz S.
        • Green J.
        Drug management in the elderly IBD patient.
        Curr Treat Options Gastroenterol. 2015; 13: 90-104
        • Manosa M.
        • Calafat M.
        • de Francisco R.
        • et al.
        Phenotype and natural history of elderly onset inflammatory bowel disease: a multicentre, case-control study.
        Aliment Pharmacol Ther. 2018; 47: 605-614
        • Cheng D.
        • Cushing K.C.
        • Cai T.
        • Ananthakrishnan A.N.
        Safety and efficacy of tumor necrosis factor antagonists in older patients with ulcerative colitis: patient-level pooled analysis of data from randomized trials.
        Clin Gastroenterol Hepatol. 2021; 19 (939-46.e4)
        • Adar T.
        • Faleck D.
        • Sasidharan S.
        • et al.
        Comparative safety and effectiveness of tumor necrosis factor alpha antagonists and vedolizumab in elderly IBD patients: a multicentre study.
        Aliment Pharmacol Ther. 2019; 49: 873-879
        • Amano T.
        • Shinzaki S.
        • Asakura A.
        • et al.
        Elderly onset age is associated with low efficacy of first anti-tumor necrosis factor treatment in patients with inflammatory bowel disease.
        Sci Rep. 2021; 12: 5324
        • Desai A.
        • Zator Z.A.
        • de Silva P.
        • et al.
        Older age is associated with higher rate of discontinuation of anti-TNF therapy in patients with inflammatory bowel disease.
        Inflamm Bowel Dis. 2013; 19: 309-315
        • Lobaton T.
        • Ferrante M.
        • Rutgeerts P.
        • Ballet V.
        • Van Assche G.
        • Vermeire S.
        Efficacy and safety of anti-TNF therapy in elderly patients with inflammatory bowel disease.
        Aliment Pharmacol Ther. 2015; 42: 441-451
        • Paul S.
        • Roblin X.
        Letter: immunogenicity of anti-TNF in elderly IBD patients.
        Aliment Pharmacol Ther. 2019; 50: 336
        • Yajnik V.
        • Khan N.
        • Dubinsky M.
        • et al.
        Efficacy and safety of vedolizumab in ulcerative colitis and crohn's disease patients stratified by age.
        Adv Ther. 2017; 34: 542-559
        • Khan N.
        • Pernes T.
        • Weiss A.
        • et al.
        Efficacy of vedolizumab in a nationwide cohort of elderly inflammatory bowel disease patients.
        Inflamm Bowel Dis. 2022; 28: 734-744
        • Pugliese D.
        • Privitera G.
        • Crispino F.
        • et al.
        Effectiveness and safety of vedolizumab in a matched cohort of elderly and nonelderly patients with inflammatory bowel disease: the IG-IBD LIVE study.
        Aliment Pharmacol Ther. 2022; 56: 95-109
        • Garg R.
        • Aggarwal M.
        • Butler R.
        • et al.
        Real-world effectiveness and safety of ustekinumab in elderly Crohn's disease patients.
        Dig Dis Sci. 2022; 67: 3138-3147
        • Bertani L.
        • Mumolo M.G.
        • Tapete G.
        • et al.
        Fecal calprotectin: current and future perspectives for inflammatory bowel disease treatment.
        Eur J Gastroenterol Hepatol. 2020;
        • Alsoud D.
        • Vermeire S.
        • Verstockt B.
        Biomarker discovery for personalized therapy selection in inflammatory bowel diseases: challenges and promises.
        Curr Res Pharmacol Drug Discov. 2022; 3100089
        • Bertani L.
        • Tricò D.
        • Pugliese D.
        • et al.
        Serum triiodothyronine-to-thyroxine (T3/T4) ratio predicts therapeutic outcome to biological therapies in elderly IBD patients.
        Aliment Pharmacol Ther. 2021; 53: 273-280
        • Pasqualetti G.
        • Calsolaro V.
        • Bernardini S.
        • et al.
        Degree of peripheral thyroxin deiodination, frailty, and long-term survival in hospitalized older patients.
        J Clin Endocrinol Metab. 2018; 103: 1867-1876
        • Gisbert J.P.
        • Gonzalez-Lama Y.
        • Mate J.
        5-Aminosalicylates and renal function in inflammatory bowel disease: a systematic review.
        Inflamm Bowel Dis. 2007; 13: 629-638
        • Lichtenstein G.R.
        • Feagan B.G.
        • Cohen R.D.
        • et al.
        Serious infections and mortality in association with therapies for Crohn's disease: TREAT registry.
        Clin Gastroenterol Hepatol. 2006; 4: 621-630
        • Brassard P.
        • Bitton A.
        • Suissa A.
        • Sinyavskaya L.
        • Patenaude V.
        • Suissa S.
        Oral corticosteroids and the risk of serious infections in patients with elderly-onset inflammatory bowel diseases.
        Am J Gastroenterol. 2014; 109 (quiz 803): 1795-1802
        • Stuck A.E.
        • Minder C.E.
        • Frey F.J.
        Risk of infectious complications in patients taking glucocorticosteroids.
        Rev Infect Dis. 1989; 11: 954-963
        • Akerkar G.A.
        • Peppercorn M.A.
        • Hamel M.B.
        • Parker R.A.
        Corticosteroid-associated complications in elderly Crohn's disease patients.
        Am J Gastroenterol. 1997; 92: 461-464
        • Hong S.J.
        • Katz S.
        The elderly IBD patient in the modern era: changing paradigms in risk stratification and therapeutic management.
        Therap Adv Gastroenterol. 2021; 1417562848211023399
        • Kandiel A.
        • Fraser A.G.
        • Korelitz B.I.
        • Brensinger C.
        • Lewis J.D.
        Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine.
        Gut. 2005; 54: 1121-1125
        • Beaugerie L.
        • Brousse N.
        • Bouvier A.M.
        • et al.
        Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study.
        Lancet. 2009; 374: 1617-1625
        • Siegel C.A.
        • Marden S.M.
        • Persing S.M.
        • Larson R.J.
        • Sands B.E.
        Risk of lymphoma associated with combination anti-tumor necrosis factor and immunomodulator therapy for the treatment of Crohn's disease: a meta-analysis.
        Clin Gastroenterol Hepatol. 2009; 7: 874-881
        • Lemaitre M.
        • Kirchgesner J.
        • Rudnichi A.
        • et al.
        Association between use of thiopurines or tumor necrosis factor antagonists alone or in combination and risk of lymphoma in patients with inflammatory bowel disease.
        JAMA. 2017; 318: 1679-1686
        • Peyrin-Biroulet L.
        • Khosrotehrani K.
        • Carrat F.
        • et al.
        Increased risk for nonmelanoma skin cancers in patients who receive thiopurines for inflammatory bowel disease.
        Gastroenterology. 2011; 141 (1621-28.e1-5)
        • Lewis J.D.
        • Schwartz J.S.
        • Lichtenstein G.R.
        Azathioprine for maintenance of remission in Crohn's disease: benefits outweigh the risk of lymphoma.
        Gastroenterology. 2000; 118: 1018-1024
        • Jorissen C.
        • Verstockt B.
        • Schils N.
        • Sabino J.
        • Ferrante M.
        • Vermeire S.
        Long-term clinical outcome after thiopurine discontinuation in elderly IBD patients.
        Scand J Gastroenterol. 2021; 56: 1323-1327
        • Calafat M.
        • Manosa M.
        • Canete F.
        • et al.
        Increased risk of thiopurine-related adverse events in elderly patients with IBD.
        Aliment Pharmacol Ther. 2019; 50: 780-788
        • Beaugerie L.
        • Kirchgesner J.
        Balancing benefit vs risk of immunosuppressive therapy for individual patients with inflammatory bowel diseases. Clinical gastroenterology and hepatology: the official clinical practice journal of the American.
        Gastroenterol Assoc. 2019; 17: 370-379
        • Calafat M.
        • Manosa M.
        • Ricart E.
        • et al.
        Risk of immunomediated adverse events and loss of response to infliximab in elderly patients with inflammatory bowel disease: a cohort study of the ENEIDA registry.
        J Crohns Colitis. 2022; 16: 946-953
        • Cottone M.
        • Kohn A.
        • Daperno M.
        • et al.
        Advanced age is an independent risk factor for severe infections and mortality in patients given anti-tumor necrosis factor therapy for inflammatory bowel disease.
        Clin Gastroenterol Hepatol. 2011; 9: 30-35
        • de Jong M.E.
        • Smits L.J.T.
        • van Ruijven B.
        • et al.
        Increased discontinuation rates of anti-TNF therapy in elderly inflammatory bowel disease patients.
        J Crohns Colitis. 2020; 14: 888-895
        • Kochar B.
        • Pate V.
        • Kappelman M.D.
        • et al.
        Vedolizumab is associated with a lower risk of serious infections than anti-tumor necrosis factor agents in older adults.
        Clin Gastroenterol Hepatol. 2022; 20 (1299-305.e5)
        • Kirchgesner J.
        • Desai R.J.
        • Beaugerie L.
        • Schneeweiss S.
        • Kim S.C.
        Risk of serious infections with vedolizumab versus tumor necrosis factor antagonists in patients with inflammatory bowel disease.
        Clin Gastroenterol Hepatol. 2022; 20 (314-24 e16)
        • Feagan B.G.
        • Sandborn W.J.
        • Gasink C.
        • et al.
        Ustekinumab as induction and maintenance therapy for Crohn's disease.
        N Engl J Med. 2016; 375: 1946-1960
        • Sands B.E.
        • Sandborn W.J.
        • Panaccione R.
        • et al.
        Ustekinumab as induction and maintenance therapy for ulcerative colitis.
        N Engl J Med. 2019; 381: 1201-1214
        • Rolston V.S.
        • Kimmel J.
        • Popov V.
        • et al.
        Ustekinumab does not increase risk of adverse events: a meta-analysis of randomized controlled trials.
        Dig Dis Sci. 2021; 66: 1631-1638
        • Hahn G.D.
        • Golovics P.A.
        • Wetwittayakhlang P.
        • et al.
        Safety of biological therapies in elderly inflammatory bowel diseases: a systematic review and meta-analysis.
        J Clin Med. 2022; 11
        • Deepak P.
        • Alayo Q.A.
        • Khatiwada A.
        • et al.
        Safety of tofacitinib in a real-world cohort of patients with ulcerative colitis.
        Clin Gastroenterol Hepatol. 2021; 19 (1592-601.e3)
        • Komoto S.
        • Higashiyama M.
        • Watanabe C.
        • et al.
        Clinical differences between elderly-onset ulcerative colitis and non-elderly-onset ulcerative colitis: a nationwide survey data in Japan.
        J Gastroenterol Hepatol. 2018; 33: 1839-1843
        • Kaplan G.G.
        • Hubbard J.
        • Panaccione R.
        • et al.
        Risk of comorbidities on postoperative outcomes in patients with inflammatory bowel disease.
        Arch Surg. 2011; 146: 959-964
        • Bautista M.C.
        • Otterson M.F.
        • Zadvornova Y.
        • et al.
        Surgical outcomes in the elderly with inflammatory bowel disease are similar to those in the younger population.
        Dig Dis Sci. 2013; 58: 2955-2962
        • Hruz P.
        • Juillerat P.
        • Kullak-Ublick G.A.
        • Schoepfer A.M.
        • Mantzaris G.J.
        • Rogler G.
        Management of the elderly inflammatory bowel disease patient.
        Digestion. 2020; 101: 105-119
        • Fazio V.W.
        • Tekkis P.P.
        • Remzi F.
        • et al.
        Quantification of risk for pouch failure after ileal pouch anal anastomosis surgery.
        Ann Surg. 2003; 238 (discussion 14-7): 605-614
        • Delaney C.P.
        • Fazio V.W.
        • Remzi F.H.
        • et al.
        Prospective, age-related analysis of surgical results, functional outcome, and quality of life after ileal pouch-anal anastomosis.
        Ann Surg. 2003; 238: 221-228
        • Sacleux S.C.
        • Sarter H.
        • Fumery M.
        • et al.
        Post-operative complications in elderly onset inflammatory bowel disease: a population-based study.
        Aliment Pharmacol Ther. 2018; 47: 1652-1660
        • Bollegala N.
        • Jackson T.D.
        • Nguyen G.C.
        Increased postoperative mortality and complications among elderly patients with inflammatory bowel diseases: an analysis of the national surgical quality improvement program cohort.
        Clin Gastroenterol Hepatol. 2016; 14: 1274-1281
        • Longo W.E.
        • Virgo K.S.
        • Bahadursingh A.N.
        • Johnson F.E.
        Patterns of disease and surgical treatment among United States veterans more than 50 years of age with ulcerative colitis.
        Am J Surg. 2003; 186: 514-518
        • Taleban S.
        • Colombel J.F.
        • Mohler M.J.
        • Fain M.J.
        Inflammatory bowel disease and the elderly: a review.
        J Crohns Colitis. 2015; 9: 507-515
        • Myrelid P.
        Editorial: post-operative complications in elderly onset inflammatory bowel disease—What is surgery, what is disease, and what is delay of surgery?.
        Aliment Pharmacol Ther. 2018; 48: 383-384
        • Kucharzik T.
        • Ellul P.
        • Greuter T.
        • et al.
        ECCO guidelines on the prevention, diagnosis, and management of infections in inflammatory bowel disease.
        J Crohns Colitis. 2021; 15: 879-913
        • Annese V.
        • Beaugerie L.
        • Egan L.
        • et al.
        European evidence-based consensus: inflammatory bowel disease and malignancies.
        J Crohn's Colitis. 2015; 9: 945-965
        • Winthrop K.L.
        • Melmed G.Y.
        • Vermeire S.
        • et al.
        Herpes zoster infection in patients with ulcerative colitis receiving tofacitinib.
        Inflamm Bowel Dis. 2018; 24: 2258-2265
        • Cheddani H.
        • Dauchet L.
        • Fumery M.
        • et al.
        Cancer in elderly onset inflammatory bowel disease: a population-based study.
        Am J Gastroenterol. 2016; 111: 1428-1436
        • Baars J.E.
        • Kuipers E.J.
        • van Haastert M.
        • Nicolaï J.J.
        • Poen A.C.
        • van der Woude C.J.
        Age at diagnosis of inflammatory bowel disease influences early development of colorectal cancer in inflammatory bowel disease patients: a nationwide, long-term survey.
        J Gastroenterol. 2012; 47: 1308-1322
        • Annese V.
        • Daperno M.
        • Rutter M.D.
        • et al.
        European evidence based consensus for endoscopy in inflammatory bowel disease.
        J Crohns Colitis. 2013; 7: 982-1018
        • Harbord M.
        • Annese V.
        • Vavricka S.R.
        • et al.
        The first european evidence-based consensus on extra-intestinal manifestations in inflammatory bowel disease.
        J Crohns Colitis. 2016; 10: 239-254