Immune Aging and Advanced Therapy Outcomes in Older Adults With IBD

Older adults with inflammatory bowel disease (IBD) represent a clinically heterogeneous population. Chronological age alone may not adequately reflect physiological reserve, immune competence, frailty, or vulnerability to treatment-related adverse outcomes. Immunosenescence, characterized by age-related changes in immune cell composition and chronic low-grade inflammation, may contribute to differences in both treatment effectiveness and safety among older adults receiving advanced therapies. However, prospective evidence linking clinically accessible markers of immune aging to treatment outcomes in IBD remains limited.

This prospective, multicenter observational cohort study will evaluate older adults with IBD who initiate a new advanced therapy as part of routine clinical care. Treatment selection and subsequent treatment modifications will remain entirely at the discretion of the treating clinicians and participants. The study will characterize participants using complementary domains including immune-aging markers, frailty, nutritional status, comorbidity and polypharmacy, inflammatory disease activity, and treatment exposure. Candidate immune-aging measures include the CD4/CD8 ratio, lymphocyte measures, interleukin-6, neutrophil-to-lymphocyte ratio, and other routinely available inflammatory and nutritional biomarkers.

The primary analytical objective is to determine whether baseline immunosenescence and frailty phenotypes are associated with the overall balance of effectiveness and safety after initiation of advanced therapy. The study will also assess whether these measures provide prognostic information beyond conventional clinical factors such as age, disease activity, comorbidity burden, and treatment type. Additional analyses will explore heterogeneity across different mechanisms of advanced therapy, relationships between immune aging, frailty, and nutritional status, and differences between elderly-onset IBD and IBD diagnosed earlier in life but treated during older age.

The study is intended to establish a clinically applicable framework for risk stratification in older adults with IBD and to provide prospective data for future studies of individualized treatment strategies based on biological aging and vulnerability rather than chronological age alone.

Inclusion criteria

• Age 60 years or older, regardless of sex. Confirmed diagnosis of Crohn disease, ulcerative colitis, or inflammatory bowel disease-unclassified based on standard clinical, endoscopic, imaging, histologic, and laboratory criteria.

Planning to initiate, or having initiated within the previous 4 weeks, a new advanced therapy, including vedolizumab, ustekinumab, an anti-TNF agent, a JAK inhibitor, an S1P receptor modulator, or another approved or clinically available advanced therapy.

Active IBD or a clear indication for treatment escalation at the time of advanced therapy initiation.

Availability of core baseline clinical and laboratory assessments required for the study.

Expected ability to complete at least 52 weeks of follow-up. Ability of the participant or legally authorized representative to understand the study and provide written informed consent.

Exclusion criteria

• Uncertain diagnosis of IBD or another condition more likely to explain intestinal inflammation.

Active severe infection at enrollment, including sepsis, active tuberculosis, uncontrolled viral hepatitis, active cytomegalovirus colitis, or another serious opportunistic infection.

Clinically significant acute infection within 4 weeks before enrollment that may substantially affect baseline immune-aging measurements or short-term safety assessment.

Active malignancy or recent systemic treatment for malignancy, except for adequately treated low-risk cancers as judged by the investigator.

Severe immunodeficiency unrelated to IBD. Expected survival of less than 12 months or another severe end-stage condition likely to interfere with follow-up or interpretation of outcomes.

Inability to obtain core baseline variables within the predefined assessment window.

Continuous use of the same advanced therapy for more than 4 weeks before enrollment.

Participation in another interventional study that may substantially affect treatment effectiveness or safety assessment.

Any other condition that, in the investigator's judgment, would make participation inappropriate or compromise follow-up or data quality.