Thesis defense Hans-Paul Schultheiss

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Crohn’s disease (CD) and ulcerative colitis (UC), collectively referred to as inflammatory bowel diseases (IBD), are chronic, immune-mediated disorders characterised by relapsing and remitting inflammation of the gastrointestinal tract. With a rising global prevalence and considerable heterogeneity in disease course and therapeutic response, IBD continues to pose substantial challenges in long-term management. Although biologic therapies, particularly anti-tumour necrosis factor (anti-TNF) agents, have significantly improved treatment outcomes, issues such as primary non-response, secondary loss-of-response, and limited predictive biomarkers constrain their effectiveness.

This thesis investigates multiple facets of optimising anti-TNF therapy in IBD. It examines the long-term durability of anti-TNF treatment, identifying temporal trends in treatment discontinuation and the influence of clinical and demographic risk factors. The impact of withdrawing concomitant immunomodulators during anti-TNF maintenance is assessed, particularly in relation to immunogenicity, anti-drug antibody formation, and sustained clinical efficacy. In light of increasing economic pressure, the use of biosimilar anti-TNF agents is evaluated, including the clinical implications of switching back to originator compounds, with an emphasis on therapeutic equivalence and patient outcomes. Furthermore, the thesis explores sex-related differences in treatment persistence, highlighting the potential for sex to serve as a stratification variable in clinical decision-making.

Patient adherence to therapy is recognised as a critical yet often overlooked determinant of treatment success. The multifactorial nature of non-adherence is discussed, and a reminder-based digital intervention is evaluated for its capacity to improve adherence to subcutaneously administered anti-TNF agents, such as adalimumab.

The second part of the thesis addresses the fibrotic complications of CD, focusing on fibrostenotic disease phenotypes that are poorly responsive to medical therapy. CXCL4 (C-X-C motif chemokine ligand 4), a pro-inflammatory and pro-fibrotic mediator implicated in systemic sclerosis and other fibrotic disorders, is investigated for its potential role in intestinal fibrosis. Expression patterns of CXCL4 are analysed in patients with and without inflammation and/or fibrosis, positioning it as a potential mechanistic link between chronic inflammation and tissue remodelling, as well as a candidate biomarker or therapeutic target.

Collectively, these investigations contribute to a more refined understanding of anti-TNF therapy optimisation, sex- and behaviour-related treatment variation, and fibrogenesis in IBD, offering new insights to guide personalised therapeutic strategies and future research directions.