Influence of Ageing on the Pharmacology, Efficacy and Safety of Oral Targeted Therapies for Inflammatory Bowel Disease: Focus on Janus Kinase (JAK) Inhibitors and Sphingosine-1-Phosphate (S1P) Receptor Modulators

Older adults represent a rapidly expanding subgroup of patients with inflammatory bowel disease, yet they remain markedly under-represented in pivotal clinical trials, limiting age-specific estimates of drug benefit and harm. This review synthesises the available evidence on the influence of ageing on the pharmacology, efficacy and safety of orally administered targeted inflammatory bowel disease therapies, focusing on registered Janus kinase inhibitors (tofacitinib, upadacitinib, filgotinib) and sphingosine-1-phosphate receptor modulators (ozanimod, etrasimod). Because the available age-stratified evidence is sparse and heterogeneous, a narrative review methodology was chosen to map the literature and identify knowledge gaps. We pragmatically report age-related findings using the age cut-offs applied in original studies and map outcomes including clinical and endoscopic response/remission, corticosteroid sparing and adverse drug events of special interest (serious/opportunistic infections, cardiovascular and thromboembolic events, malignancies and treatment discontinuation). Across the limited age-stratified datasets, efficacy appears largely maintained in older patients, but the evidence base is heterogeneous and frequently lacks dedicated analyses. Ageing-related physiological changes, comorbidity, frailty and polypharmacy are expected to modulate pharmacokinetic and pharmacodynamic variability and to amplify the clinical relevance of class-specific safety concerns, particularly infections, major adverse cardiovascular events and malignancy signals with Janus kinase inhibition and initiation-related cardiovascular/conduction considerations with sphingosine-1-phosphate modulation. There is, however, no clear consensus on how ageing-related vulnerability, including frailty and comorbidity burden, should be defined, measured, and reported across studies, which complicates the interpretation and comparison of outcomes. In the absence of robust outcome data for older adults with inflammatory bowel disease, treatment selection should be guided by biological vulnerability (frailty, organ function, comorbidity burden) and structured risk-mitigation strategies, while future research should prioritise age- and frailty-enriched prospective studies with geriatric-relevant outcomes and long-term pharmacovigilance.