Studies of experimental biomarkers during glucocorticoid and anti-tumor necrosis factor-alpha therapy in inflammatory bowel disease and juvenile idiopathic arthritis
Year: 2012
Type: dissertation
Abstract: Glucocorticoids (GCs) and anti-tumor necrosis factor-α (anti-TNF-α) agents are used for treatment of inflammatory bowel diseases (IBD) and juvenile idiopathic arthritis (JIA). Here, the attenuation of inflammation during GC and anti-TNF-α therapies was evaluated by using experimental biomarkers in aim to find new tools to optimize GC and anti-TNF-α therapy. The serum samples were prospectively collected from IBD patients before the start of oral GC or anti-TNF-α therapy. The second sample was collected from pediatric IBD patients two to four weeks after the start of GC therapy or after the first IFX infusion. Twenty-eight children had oral GCs. Sixteen pediatric IBD patients received IFX. Fifteen adult CD patients had therapy induction with TNF-α agent. Thirty-two pediatric controls were included. Twenty-one JIA patients had intra-articular glucocorticoid therapy (IACS). The JIA patients provided serum samples on the morning before the IACS, seven and 24 hours thereafter, and at two months. A new biological assay based on analysis of the effect of patient serum on donor derived peripheral blood mononuclear cells (target cells) was developed. As read-outs, the target-cell IFNγ, IL-5, FOXP3 and GITR expressions were analyzed with ELISA or PCR. Additionally, serum glucocorticoid bioactivity (GBA) or matrix metalloproteinases (MMP-7-9), their tissue inhibitors (TIMP-1-2), alpha-2-macroglobulin (α2M), human neutrophil elastase (HNE) and myeloperoxidase (MPO) were measured. In the first study with in pediatric IBD patients at the start of oral GC therapy, in comparison with pre-treatment serum, patient serum after GC therapy reduced target cell IFNγ secretion (p=0.017 for naїve cells and p=0.006 for activated cells) and GITR expression (p=0.033 and p=0.005 respectively). The decrease on serum induced FOXP3 expression was seen on naїve target cells (p=0.05). These changes did not correlate with weight-related GC dose, but the observed changes represented the sum effect of individual inflammatory activity in patients. In the second study, IACS increased serum GBA (p=0.001) and decreased cortisol (p=0.002) within 24 hours of the injection. The patient serum induced IL-5 secretion showed a trend of decrease (p=0.085). These findings indicate a leakage of biologically active GC from the joint. In the third study, with adult Crohn`s disease patients at the start of anti-TNF-α therapy, before therapy the high serum induced FOXP3 and GITR expression on activated target cells were associated with low endoscopic activity, CDEIS (r=-0.621, p=0.013 for FOXP3 and r=-0.625, p=0.013 for GITR) and to low ESR (r=-0.548, p=0.034 for FOXP3). Interestingly, the low pre-treatment FOXP3 and GITR expression on target cells were associated with a pronounced decrease of CDEIS during the therapy (r=0.600, p=0.018 for FOXP3 and r=0.589, p=0.021 for GITR). It is possible that there is a group of IBD patients who do not benefit from additional enhancement of regulatory T-cells induced by anti-TNF-α agents. In the final study, serum MMPs, TIMPs, α2M, HNE and MPO were measured from pediatric IBD patients during GC and anti-TNF-α therapies. The serum level of MMP-7, MMP-8, MMP-9, α2M, HNE, MPO in all IBD patients and TIMP-1 in the GC treatment group was higher than in the controls (all p≤0.022). During the GC therapy, the attenuation of inflammation was seen as a decrease of MMP-7 and TIMP-1 (both p≤0.001). During the anti-TNF-α therapy, α2M and HNE increased (both p≤0.026). The increase of α2M was suggested as an additional mechanism mediating anti-TNF-α agent s therapeutic effect.
Source: Työväentutkimus Vuosikirja
Author: Hanne Rintamäki
Language: English
Topic: Inflammatory Bowel Disease
Subfield: Gastroenterology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W1602464466