Introduction

The rising global burden of Inflammatory Bowel Disease (IBD), coupled with population aging, has led to an increase in the number of older patients living with IBD. Individuals over the age of 60 contribute to 25-35% of the IBD population, forming 2 distinct groups: those (around 20%) diagnosed with IBD at a younger age that transition into older age, and those (around 15%) diagnosed later in life (“older onset” IBD). ¹

Disease Presentation

The differential diagnosis of IBD in older persons is wide and often needs judicious exclusion of infectious and ischemic colitis, diverticular disease, non-steroid anti-inflammatory drug (NSAID) use, colitis associated with radiation therapy, malabsorption, microscopic colitis, and colorectal carcinoma. A thorough history supported by suitable imaging, and endoscopy with biopsies can diagnose IBD accurately and avoid a delayed diagnosis, which is known to occur in up to 60% patients with “older onset” IBD. ¹

Abdominal pain and constitutional symptoms are less frequently observed in older patients with Crohn’s Disease (CD), who often present with rectal bleeding. Although rectal bleeding can be less frequent in older-onset ulcerative colitis (UC), the clinical presentation of UC is generally similar across age groups.² 

Disease Extent and Natural History

In older-onset CD, isolated colonic involvement (L2) is more common than ileocolonic (L3) disease. Disease phenotype is mostly inflammatory (B1), followed by stricturing (B2) and penetrating (B3) disease. Upper GI and perianal involvement are relatively uncommon. In older-onset UC, disease extent at diagnosis is mostly left-sided, followed by pancolitis. Isolated proctitis occurs less commonly. Although the clinical course of IBD in older persons has been suggested to be less aggressive, the first presentation of UC may be more severe in elderly-onset UC, with some studies suggesting a 30% increased risk of colectomy.³ Therefore, consideration of an individual’s specific disease characteristics, rather than chronological age alone, is required to predict disease course. ^1,2 

Managing IBD in older patients

General Considerations

Therapeutic decision-making in older IBD patients requires a nuanced approach, factoring challenges posed by polypharmacy (with a greater potential for drug interactions) and specific physical, cognitive and locomotor comorbidities. Medication adherence may also be compromised in those with a high pill burden.⁴ 

Comorbidities may affect treatment efficacy with the potential for adverse events. Additionally, age-related physiological decline in renal and cardiovascular function may impact on the pharmacokinetics of IBD medication. Anti-tumour necrosis factor (TNF) therapy is contra-indicated in those with severe heart failure (New-York-Heart-Association [NYHA] class III/IV). Bone health is also of particular concern, with older IBD patients being 1.3 times more likely to develop a fracture than younger patients, mandating risk assessment with bone mineral density scanning, FRAX score assessment and provision of bone-protective therapy for high-risk patients (those with active inflammation, reduced mobility or receiving prolonged courses or high-dose corticosteroids). ^1,5 

Medical treatment

Aminosalicylates

Aminosalicylates (5-ASAs) represent the mainstay of induction and maintenance therapy for UC although, their role in CD is controversial. Anorectal and fine motor dysfunction may limit the use of topical aminosalicylate therapy.⁶ A foam-based preparation, or a preparation with a lower volume of delivery, may aid enema retention.⁷ Oral 5-ASAs are generally safe, but rare side effects include worsening diarrhoea, pancreatitis, and idiosyncratic glomerulonephritis.⁸ Caution is advised when initiating 5-ASAs in those with pre-existing chronic kidney disease, with regular biochemical monitoring, and consideration of therapy cessation in those with severe renal impairment (eGFR <20ml/min). ^5,8

Corticosteroids

Corticosteroids remain the cornerstone for decisive induction of remission in both UC and CD although long-term use is inappropriate and can have detrimental effects. Steroids can exacerbate heart failure, impair glycaemic and hypertensive control, and increase risks of osteoporosis, fragility fractures, cataracts, and glaucoma. Steroids may alter cognition and are associated with delirium, psychosis, and hallucinations, which is a particular concern in older patients. ⁵

Data from the TREAT registry reports a risk for serious infections (HR 1.6) related to steroid use within 6 months, and higher mortality. ⁹ Despite the risks pertaining to poor steroid stewardship, older IBD patients receive higher average prednisolone doses than young patients, with >30% of patients receiving steroids for over 6 months; reflective, possibly, of physician hesitancy in escalating to advanced therapy.¹⁰

Budesonide MMX (a new modified-release, multi-matrix system preparation) has a high first-pass metabolism and subsequently less systemic exposure and may represent a safer but effective induction agent in older patients with mild-moderate distal small bowel CD or mild to moderate UC.⁵ 

Immunomodulators

The risk of adverse events to thiopurine therapy is increased in older patients.¹ Myelosuppression, secondary to Thiopurine methyltransferase (TPMT) or NUDT-15 enzyme deficiency, or other less well-defined mechanisms, can result in severe leucopenia, with potentially serious consequences in older patients, in whom the risk of opportunistic infection is greater. TPMT testing prior to initiation of therapy is mandated, along with regular on-treatment biochemical monitoring. ^1,5 Thiopurines are associated with an increased risk of non-melanoma skin cancer and urinary tract malignancy.¹¹ Of further concern is the increased risk of non-Hodgkin’s lymphoma, particularly in males with a longer disease duration and use of combination immunosuppressive therapy.¹²Taken together, the risks associated with thiopurine therapy may therefore outweigh intended benefits and use should be avoided, if possible, in older IBD patients.⁵

Methotrexate may be used in Crohn’s disease or as combination therapy in UC. Adverse events include cytopenia, transaminase elevation and gastrointestinal disturbance with nausea, stomatitis, and diarrhoea. A higher discontinuation rate, owing to more pronounced side effects, and drug interactions, limit its use in older patients. ^1,5

Ciclosporin can be indicated in the case of steroid-failure in acute-severe UC. However, it’s use in older IBD patients is limited by its narrow therapeutic window, significant drug interactions and adverse events such as nephrotoxicity and worsening of hypertension.^1,5  

Anti-TNF therapy

Data regarding anti-TNF efficacy in older patients is conflicting. Data from a large, Dutch multi-centre, retrospective cohort study demonstrates higher treatment failure rates in older patients.¹³

The risk of serious infection, malignancy and death is increased in older anti-TNF users.¹ Advanced age is an independent risk factor for serious adverse events and treatment discontinuation and a predictor of mortality in patients on anti-TNF therapy.^14,15 However, risks related to poor contingency planning, poorly controlled disease and long-term steroid use must be carefully considered and balanced against the risks of advanced therapy. When used, anti-TNF monotherapy is preferred over combination therapy with an immunomodulator, although a greater differential risk of immunogenicity with use of Infliximab monotherapy over other anti-TNF therapies, should be taken into consideration.^1,16

Non-TNF biologics

Non-TNF targeting biologics (e.g., vedolizumab and ustekinumab) have a lower degree of systemic immune suppression and appear to be associated with a lower risk of serious infection and malignancy than anti-TNF agents.⁵

The largest cohort of older patients with Crohn’s disease, treated with ustekinumab, demonstrated similar efficacy between young and older patients with comparable steroid-free remission rates at week 16 and 54 and no differences in treatment persistence.¹⁷

A post-hoc analysis of the phase-III GEMINI trials found no significant differences in terms of efficacy and safety of Vedolizumab across age groups, although patient numbers in the older age group were small.¹⁸ The IG-IBD LIVE study, however, noted lower Vedolizumab persistence and rates of steroid-free-clinical-remission in older patients, although no age-dependent effect on efficacy was observed in CD.¹⁹ 

Combination therapy, using a thiopurine or methotrexate alongside Vedolizumab or Ustekinumab, has not been shown to confer any additional benefit, with comparable short-term clinical response and remission rates, endoscopic outcomes, and treatment persistence at 1 year in patients treated with combination therapy vs monotherapy with either agent.²⁰ 

Although few data exist on comparative safety in older patients, the safety of a “treatment strategy” is more important than the safety of a therapeutic agent per se, and dynamic risk-stratification strategies for predicting risk of treatment related complications are needed to facilitate treatment decisions in older people with IBD.¹

Small molecules

Janus kinase (JAK) inhibitors are a family of small molecules that block one or more of the intracellular tyrosine kinases, including JAK-1, JAK-2, JAK-3 and TYK-2. 

Post-marketing studies have shown that Tofacitinib, a non-selective JAK inhibitor, particularly in its use in Rheumatoid Arthritis patients, may increase the risk of thromboembolic events and major-adverse-cardiovascular-events. The greatest risk has been observed in those aged > 50 years and with ≥ 1 cardiovascular risk factor. ²¹ The OCTAVE trials, assessing Tofacitinib in Ulcerative Colitis, have also demonstrated a clear dose-dependent signal towards the development of Herpes Zoster infection, with age ≥ 60, low body weight and previous anti-TNF use identified as risk factors. ²² Interestingly, manifestations of Herpes Zoster tend to be limited to cutaneous presentations, with visceral disease much less likely. Nonetheless, treatment discontinuation for the duration of anti-viral therapy and consideration of treatment cessation may be warranted.²² Whether such risk can be extrapolated to the more selective, potentially safer, JAK-1 inhibitors remains an important question. The incidence of Herpes Zoster in patients exposed to Filgotinib and Upadacitinib may be lower, although long-term follow up and real-world data are needed.²³ Presently, JAK-inhibitors should be avoided or used with caution in those aged 65 years or above, those at increased risk of major cardiovascular problems (such as heart attack or stroke), those who smoke or have done so for a long time in the past and those at increased risk of cancer[A1] .²⁴

Sphingosine-1-phosphate receptor (S1PR) modulators are a newer class of small molecules. Ozanimod, a highly selective S1PR, binds with high affinity to S1P1 and S1P5, causing sequestration of peripheral lymphocytes, and received NICE recommendation for use in moderate-to-severely active UC in 2022. A post-hoc analysis of the TRUE NORTH study examined the efficacy and safety of Ozanimod in patients < 60 and ≥ 60 years, and reported similar adjusted treatment differences, favouring Ozanimod over placebo, across all efficacy endpoints, between age groups at week 10 and 52. No obvious safety signals were noted in older patients in this analysis. ²⁵

Surgery

Approximately a quarter of IBD surgeries are performed in older patients, with similar indications, morbidity, and mortality across age groups.³ Surgery with stoma formation is an acceptable option to older patients, although these patients have longer hospital stays, higher rates of post-operative complications and mortality. Although restorative ileal-pouch-anal-anastomosis (IPAA) can be offered to older patients, postoperative complication rates and length of stay in this patient group are higher than in adult patients. This necessitates careful patient selection, consideration of cognitive function, pre-procedure anal-sphincter function and locomotor function, to improve outcomes for such patients.^1,5 Older IBD patients are at higher risk of venous thrombo-embolism (VTE) and prophylaxis is advocated, particularly in hospitalised patients. Treatment of VTE in IBD should follow established guidelines with mindfulness for a potential increased bleeding risk.^1,5

IBD related Cancers

The older population with IBD has a higher risk of cancer, of any type, than younger patients. The risks are highest for colorectal cancer, but also for non-Hodgkin’s lymphoma, urinary tract malignancies and non-melanoma skin cancer, with multifactorial aetiology including duration of immunosuppressive therapy, but also an increasing duration of IBD^{. 11,12,26} Patients with IBD, particularly patients with UC and concomitant PSC, have a higher risk of cholangiocarcinoma than the general population. Patients with refractory, long-standing stricturing small bowel Crohn’s disease have an increased risk of small-bowel cancers, particularly small-bowel adenocarcinoma.²⁷ When evaluating the appropriateness of ongoing colorectal cancer surveillance in older IBD patients, consideration should be given to an individual patients’ risk profile according to age of IBD diagnosis, their fitness to undergo colectomy in the event of a cancer diagnosis, and quality of life and life expectancy beyond colectomy.^1,5 

Prescribing for Patients with a Prior History of Malignancy

Therapeutic decision-making in patients with a prior history of malignancy requires a multi-disciplinary approach, which must involve the patient, gastroenterologist, and oncologist. Factors influencing treatment decision include IBD-specific details (disease activity, phenotype and previous treatment requirements), cancer-specific details (type and stage, time since diagnosis, risk of recurrence, current anti-cancer therapy and IBD-therapy specific cancer risk) and patient specifics (co-morbidities, perception of risk and preference.)²⁸ In those patients with low recurrence risk (lymphoma or cervical) cancers, a 2-year post-cancer therapy drug holiday is recommended prior to starting immunosuppressive IBD treatment. In intermediate or high recurrence risk (breast, colon, skin, lung, and urinary tract) cancers, 5 years is suggested.²⁷ In patients with moderate-severe IBD disease activity requiring consideration of advanced therapy, and in whom cancer-recurrence risk is deemed acceptable, biologic therapy should be considered. Here, agents with lower rates of systemic immunosuppression, associated with lower rates of immunogenicity negating the need for combination therapy, and associated with lower rates of malignancy, such as Vedolizumab or Ustekinumab may be selected preferentially.^{1,5,20,27,28.}

Vaccinations

There are no significant differences in vaccination guidelines for elderly and younger IBD patients, although older patients have a higher risk of infection and sub-optimal serological vaccine responses. Recommended vaccinations among immunosuppressed IBD patients across all age-groups include annual inactivated influenza vaccine, 5-yearly pneumococcal vaccine, hepatitis-B series, meningococcus (particularly for those with splenectomy) and 3 primary doses of the SARS-CoV-2 vaccines at any point in the treatment cycle; with a further booster dose as soon as possible.²⁹ Live vaccines (such as intranasal influenza, BCG, yellow fever, varicella, oral typhoid, anthrax, and MMR) must be avoided in immunosuppressed patients (those taking 20mg or more of prednisolone or equivalent steroid, are on treatment with effective doses of thiopurine, methotrexate or advanced therapies (biologic/small molecules) or have had these medications in the last 3 months). If required, live vaccines should be given at least 3 months after stopping, or at least 3 weeks prior to starting immunosuppressive therapy.²⁹ The inactivated varicella zoster vaccine is recommended for those above the age of 50 and immunosuppressed, and therefore should be offered to immunosuppressed elderly IBD patients, and particularly to patients receiving JAK inhibitor therapy.  

Conclusions and Learning Points

• Given the broad differential diagnosis, delays in diagnosis, a relative paucity of data in older patients from key clinical trials and lack of consensus guidelines; the management of these patients somewhat challenging
• The holistic management of older patients with IBD requires an appreciation of the possible disconnect between ‘chronological’ and ‘biological’ age
• ‘Undertreatment’ should be avoided. Treatment decisions should therefore be personalized, pragmatic and as evidence based as possible

Author Biographies

Dr Karishma Sethi-Arora, MBBS BSc MRCP (UK) ESEGH, Post-CCT Advanced IBD Fellow, Northern Care Alliance NHS Foundation Trust, Manchester

Dr Karishma Sethi-Arora is a Post CCT Fellow in Advanced IBD at the Northern Care Alliance. She completed an MBBS, with BSc in Gastroenterology, from Imperial College London, with a distinction in clinical sciences, in 2010. She undertook speciality training in Gastroenterology in London’s North-East Thames deanery before moving to the North-West. 

Clinically, her interests lie in the management of Inflammatory Bowel Disorders, with particular interests in women’s health and IBD management in older persons. She is currently undertaking a sub-speciality fellowship in Advanced Inflammatory Bowel disease, in which she is sub-investigator on a number of commercial studies and investigator-led, portfolio studies in IBD. 

She has a keen interest in Strategic Leadership and Organisational Culture and has a post-graduate certificate with distinction in Leadership in Healthcare. 

She is a passionate clinical educator and, in 2022, won the BSG’s Alistair McIntyre Prize for Improving Training in Gastroenterology, for her work in developing an e-learning package for the national dissemination of human factors training in endoscopy.

Professor J. K. Limdi, FRCP FRCPE FEBG DNM AGAF FACG, Consultant Gastroenterologist, Northern Care Alliance NHS Foundation Trust, Manchester, Hon. Clinical Professor of Gastroenterology, University of Manchester, Visiting Professor-Manchester Metropolitan University

Jimmy Limdi is a Consultant Gastroenterologist and Head of the Inflammatory Bowel Disease Section at Northern Care Alliance NHS Foundation Trust (NE Sector) and Professor of Clinical Gastroenterology at the Manchester Academic Health Sciences Centre, University of Manchester. He is also Hon. Professor at the Manchester Metropolitan University and Deputy Director of Research &Innovation at the Northern Care Alliance NHS Foundation Trust, Manchester.

Jimmy qualified in 1993 and completed postgraduate training in Internal Medicine and Gastroenterology in Yorkshire and Manchester, followed by a period of research at the ICMS, Barts and The London, and University College Hospitals, London and a Visiting Fellowship at Boston University and Harvard, Boston, USA. His clinical research interests in IBD include diet, gut permeability and nutriceuticals, early diagnosis and outcomes, IBD therapeutics, IBD in older persons, neuromotility in IBD exercise and IBD, dysplasia in IBD and women’s health related issues in IBD. 

He is a Principal and Chief Investigator to several IBD studies, is Associate editor of the Inflammatory Bowel Diseases journal and Therapeutic Advances in Gastroenterology, holds Editorial board and peer review appointments with leading gastroenterology journals and has published and lectured widely in the field. He has participated in several national and international peer review processes, Delphi panels and co-authored national and international IBD guidelines. He is currently a member of the BSG IBD Committee, BSG IBD section representative to the BSG Education Committee, BSG Education representative to the International Committee and previously BSG representative to the Association of Colo-Proctologists of GB&I and the BSG Food and Function CRG. He was the UK National Representative at the American College of Gastroenterology (ACG) between 2012 and 2021.