P029 Expression of miR-21 in mucosal biopsies give clues to anti-TNF treatment non-response in IBD children and adults
Pallikkunnath James, J.(1);Schnack Nielsen, B.(2);Langholz, E.(3,4);Mikkel , M.(5,6,7);Estrid , H.(1);Buhl Riis, L.(8);
(1)Herlev University Hospital, Department of Pathology, 2730- Herlev, Denmark;(2)Bioneer A/S, Molecular histology and detection, 2970 Hørsholm, Denmark;(3)Herlev University Hospital, Gastroenheden D, 2730 Herlev, Denmark;(4)University of Copenhagen, Institute for Clinical Medicine, 2200 Copenhagen, Denmark;(5)Hvidovre Hospital- Universty of Copenhagen, The Pediatric Department, 2650 Hvidovre, Denmark;(6)Hvidovre Hospital- University of Copenhagen, Copenhagen Center for Inflammatory Bowel Disease in Children- Adolescents and Adults, 2650 Hvidovre, Denmark;(7)Holbæk Sygehus, The Pediatric Department, 4300 Holbæk, Denmark;(8)Herlev University Hospital, Department of Pathology-, 2730- Herlev, Denmark;
The use of anti-tumor necrosis factor (TNF) treatment has improved the treatment of IBD patients. However, approximately 30% of patients fail to respond to TNF inhibitors, and up to 50% of the patients who initially benefited from treatment with TNF inhibitors lose the response over time. Thus, identifying predictors of non-response and deciding on a treatment strategy according to biomarker profiles could enhance overall IBD disease management. MicroRNA-21 (miR-21) has been found to confer drug resistance to e.g. trastuzumab, 5-fluorouracil, and cisplatin. In this study, we hypothesized that miR-21 may play a role in anti-TNF drug resistance and therefore, miR-21 levels may be a predictive biomarker of anti TNF response in IBD.
Archived formalin-fixed, paraffin-embedded (FFPE) mucosal biopsies of IBD patients (30 adults and 27 children) were used in this study. All biopsies were collected at the time of initiation of biologics. Patients were stratified into three groups according to treatment response: Responders, Primary non-responders (PNR), and Secondary non-responders (SNR). Responders were treated with anti-TNF for a minimum of 3 years and did not experience loss of response thereafter. PNRs lost response during the first year of treatment. SNRs were treated for a minimum of 3 years with subsequent loss of response. MiR-21 expressions were quantified using Quantitative Real-Time PCR (miRCURY LNA RT Kit, Qiagen). Expression of miR-27a was used as the endogenous reference microRNA based on previous studies.
In adults, responders had less miR-21 expression compared to PNRs and SNRs (relative median of miR-21 expression in folds [IQR]: 3.45[3.36 - 4.2], 5.05 [3.61 - 6.88], and 7.58 [6.21 - 8.2] in responders, PNRs, and SNRs respectively, p=0.04 and p=<0.01). In children, however, responders had an increased miR-21 expression compared to PNRs and SNRs (relative median of miR-21 expression in folds [IQR]: 19.94[15.88–24.59], 9.79[7.69– 14.44], and 10.58[5.66–12.91] in responders, PNRs, and SNRs respectively, p=0.03 and p=0.01). Expression of MiR-21 was found to be higher in children than adults (relative median of miR-21 expression in folds [IQR]: 4.65[3.45-7.21], and 13.6[8.37–19.05], respectively, p=<0.01).
Higher miR-21 expression indicates a higher response rate in children, whereas higher miR-21 expression could predict resistance to anti-TNF treatment in adults. MiR-21 expression could potentially be used as a predictive biomarker for anti-TNF treatment response in IBD patients with varying measures for children and adults.