Advancing inflammatory bowel disease care: challenging long-held notions, addressing therapy barriers and exploring fibrotic pathways

Inflammatory bowel disease (IBD), comprising Crohn’s disease (CD) and ulcerative colitis (UC), is a group of chronic inflammatory disorders of the gastrointestinal tract characterized by alternating periods of remission and relapse. Active disease typically causes abdominal pain, diarrhea, rectal bleeding, fatigue, and weight loss. In Crohn’s disease, strictures, fistulas, and abscesses may also develop due to transmural inflammation. Although no curative therapy exists, the introduction of biological agents, particularly anti-tumor necrosis factor (anti-TNF) antibodies, has markedly improved disease management. Nevertheless, many patients experience primary non-response, secondary loss of response, or intolerance. This thesis explores factors influencing the effectiveness, durability, and safety of anti-TNF therapy, and investigates the role of the chemokine CXCL4 in intestinal fibrosis in Crohn’s disease.

The long-term course of anti-TNF treatment was evaluated in a large clinical cohort of IBD patients. Discontinuation rates were highest during the first treatment year but declined substantially thereafter. Patients who remained on therapy beyond four years had a considerably lower annual discontinuation rate, suggesting a subgroup with stable, long-term benefit. Combination therapy with immunomodulators such as thiopurines or methotrexate can reduce anti-drug antibody formation but also increases the risk of serious adverse events. In this thesis, discontinuation of immunomodulators in patients with sustained response to infliximab combination therapy led to higher antibody formation and lower drug trough levels, yet without increased treatment failure when disease control and drug exposure were adequate.

Following the expiration of the infliximab patent, many patients were transitioned from the originator product to a biosimilar. Most tolerated this switch well, but a minority experienced adverse effects or perceived loss of efficacy. For these patients, switching back to the originator was safe and effective. Female patients were more likely to discontinue anti-TNF therapy due to adverse events, highlighting possible biological and psychosocial sex-related differences in drug tolerance.

Medication adherence, another key determinant of therapeutic success, was assessed using an electronic injection device with reminder functionality for adalimumab. The intervention did not improve adherence, suggesting that non-adherence in IBD is rarely caused by forgetfulness. Psychological factors—such as negative beliefs about medication or discomfort with self-injection—likely play a greater role and require tailored behavioral approaches.

In the translational part of the thesis, the chemokine CXCL4 was investigated for its potential role in fibrosis formation in Crohn’s disease. CXCL4 gene expression was significantly elevated in patients with active inflammation and fibrotic changes, correlating with disease severity. Histological analyses revealed CXCL4 deposits in epithelial L-cells within fibrotic and inflamed intestinal tissue, identifying these cells as a potential CXCL4 source. These findings implicate CXCL4 in the pathogenesis of intestinal fibrosis and warrant further mechanistic research.

In summary, this thesis identifies opportunities to optimize anti-TNF therapy and improve individualized treatment strategies in IBD. The findings support the long-term continuation of effective anti-TNF therapy, careful withdrawal of immunomodulators, increased awareness of sex-related and psychological factors, and the recognition of CXCL4 as a novel mediator and potential therapeutic target in fibrostenotic Crohn’s disease.