Towards optimal care in inflammatory bowel disease Thiopurines, tofacitinib and impact on working life

In this thesis, we aimed for further optimization of IBD care by evaluating efficacy and safety of ‘old’ and ‘new’ oral immunomodulators (thiopurines and tofacitinib) and by focusing on the disease impact on working life.
Optimized mercaptopurine treatment based on therapeutic drug monitoring (TDM) is superior to placebo to achieve combined clinical remission and endoscopic improvement in ulcerative colitis (UC) patients after one year. TDM did not prevent drug-related adverse events or drug withdrawal. Thiopurine methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) gene polymorphisms and high levels of 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP) are associated with development of thiopurine-induced leukopenia.
In a ‘real-world’ cohort, tofacitinib leads to corticosteroid-free clinical remission and endoscopic improvement in 39% of UC patients after one year. The tofacitinib safety profile is acceptable given its efficacy in this refractory population. In the majority of UC patients, tofacitinib reduces histological inflammation and induces a substantial decline of total STAT1, STAT3 and STAT5 expression in colonic mucosa. Low STAT1 expression after treatment is associated with tofacitinib response and presumably reflects the degree of histological inflammation. High JAK2 baseline expression seem associated with tofacitinib non-response.
Over half of the IBD patients report work productivity loss, predominantly caused by ‘on-the-job’ productivity loss (presenteeism). Fatigue is the most frequently reported reason for work productivity loss by IBD patients. Reduced health-related quality of life (HRQL) and fatigue lead to increased work productivity loss and considerable indirect healthcare costs. IBD-related problems negatively influence quality of working life (QWL). Fatigue, reduced HRQL and work productivity loss are associated with declined QWL.