Therapeutic drug monitoring of inflammatory bowel disease: established drugs revisited

This thesis focuses on therapeutic drug monitoring (TDM) for optimizing mesalazine in patients with ulcerative colitis (UC) and methotrexate in patients with Crohn’s disease (CD).

TDM OF MESALAZINE
In the first two chapters, we study drug (5-aminosalicylate; 5-ASA) and metabolite (Nacetyl-5-ASA) concentrations in UC patients treated with oral mesalazine in order to investigate their potential for TDM. In Chapter 2 we summarize previously published studies (n=39) on mucosal and fecal 5-ASA concentrations, and their correlation with patients’ disease activity. We show that higher doses of mesalazine seem to correlate with increased fecal concentrations but not with increased mucosal concentrations, and mucosal 5-ASA concentrations and disease activity are inversely related.
In Chapter 3, we measure fecal, mucosal and urinary 5-ASA and N-acetyl-5-ASA concentrations in UC patients with active disease (n=13) and compare those with concentrations in quiescent disease (n=15), in order to investigate the fecal excretion-effect relationship. Contrary to previous studies, we observe no relationship between fecal or mucosal (N-acetyl-)5-ASA concentration and disease activity. These findings render fecal 5-ASA excretion an unsuitable tool for TDM in UC.

TDM OF METHOTREXATE
Erythrocyte methotrexate-polyglutamates (MTX-PGs) have been proposed as a tool for TDM in patients with immune mediated diseases (IMIDs) treated with methotrexate. Chapter 4 presents a meta-analysis that synthesizes current evidence regarding the relationship of erythrocyte MTX-PGs and methotrexate’ efficacy and toxicity in patients with IMIDs using low-dose methotrexate without biologics. We observe a clear concentration-effect relationship in patients with RA, JIA, and psoriasis. Robust IBD-specific data was lacking, which emphasizes the need of the following chapters. Chapter 5, 6, and 7 focus on the potential of intracellular MTX-PGs, measured by mass spectrometry, for TDM in CD patients. We confirm the first two prerequisites of TDM: easy measurable drug concentration and the presence of significant between-individual variability. Concerning the influence of various biochemical and clinical factors on the drug level, we identify that subcutaneous MTX administration lead to higher MTX-PGs as compared to oral administration, as well as a higher age and lower glomerular filtration rate of the patient. Chapter 6:. In a prospective multicenter cohort we initiate subcutaneous methotrexate treatment without concomitant biological therapy in 80 adults with CD. After the 12 months’ visit, only 21 patients (26%) continue subcutaneous methotrexate monotherapy. Twenty-nine (36%) patients discontinue methotrexate because of toxicity, 21 (26%) patients because of disease activity, and four (5%) patients because of a combination of active disease and toxicity. We identify a significant concentration-effect relationship for MTX-PG3: for every 10nmol/L increase in MTX-PG3 the rate of discontinuation of methotrexate subcutaneous monotherapy decreases with 14-16% within the first 12 months and fecal calprotectin levels decreases by 37 μg/g at 6 months. Surprisingly, a higher MTX-PG3 concentration are associated with a lower incidence of methotrexate-related gastrointestinal side effects. In chapter 7, we measure MTX-PG accumulation in peripheral blood mononuclear cells, (n=9) and in intestinal mucosa (n=27). The accumulation of MTX-PG in PBMCs is approximately 10-fold higher compared to erythrocytes. Interestingly, intestinal mucosa contains relatively large amounts of MTX-PG4,5 and even MTX-PG6 in all biopsies, in contrast to PBMCs.

MEASURING METHOTREXATE-RELATED GASTROINTESTINAL INTOLERANCE
Gastrointestinal complaints, such as nausea, are the most common side effects (42.5%) of methotrexate and the main reason for discontinuation of therapy (22.5%, Chapter 6). In order to measure methotrexate-related gastrointestinal intolerance, the methotrexate intolerance severity score (MISS) has been developed, originally in Dutch patients with JIA. We validate this patient questionnaire in CD adults (Chapter 8) participating in our prospective cohort. Finally, in Chapter 9, we evaluate the potential benefit of orally administered methotrexate compared to subcutaneous administered methotrexatein patients with various IMIDs. Evidence is inconclusive.