Voskuil, M.D. (2015) Predicting response to anti-TNF therapy in inflammatory bowel disease. thesis, Medicine.
Full text available on request.Abstract
Abstract Introduction Inflammatory bowel disease (IBD) is a chronic gastrointestinal inflammatory disease consisting of Crohn’s disease (CD) and ulcerative colitis (UC). Anti-TNF therapy is currently the most effective treatment for IBD, but large proportions of patients do not respond to these agents. Because of the high costs and the risk for severe side effects, predicting primary nonresponse and secondary loss of response is direly needed. The aim of this study was to replicate known, and to identify novel genetic, environmental, serological and clinical factors that are associated with primary non-response and loss of response to anti-TNF therapy. Methods Detailed clinical data regarding naïve anti-TNF IBD patients treated in a large IBD specialised centre between from 2000 to 2014 were obtained from a prospectively maintained clinical database. For all patients biochemical inflammatory parameters (CRP, WBC, Hb, thrombocytes, albumin in blood and faecal calprotectin) were collected prior to anti-TNF treatment and at eight, sixteen and 24 weeks after initiation and at discontinuation/follow-up. Patients were genotyped using the ImmunoChip array. Response was defined based on clinical evaluation and supported by biochemical inflammatory parameters. Results We identified 316 naïve anti-TNF IBD patients. 64 (20.3%) patients had primary nonresponse, 56 (17.7%) had loss of response and 196 (62.0%) had maintained remission. Patients with loss of response had significantly higher baseline CRP levels (p=0.021). CD (p<0.001, OR = 3.5) significantly predicted maintained remission and patients in this group had significantly lower CRP (p=0.028) and higher albumin (p=0.014) levels after induction. Minor allele carriage of FAS, rs1800682 (p=0.007, OR 2.5) and FCGR2A, rs12142756 (p=0.01, OR 2.5) was significantly associated with less favourable clinical response. Furthermore, the carriage of the minor alleles of TNFRS1A, rs984337 (p=0.016), FAS, rs7898005 (p=0.04 and FASLG, rs10458360 (p=0.009) was associated with less favourable biochemical response (measured by change in CRP). We performed a genome-wide association study with 711,382 SNPs for both clinical response and biochemical response. No significant associations were found for clinical response. We identified several significant associations for biochemical response (rs6936820, p=1.7 x 10-17; rs116553443, p=1.9 x 10-14; rs2044264, p=6.9 x 10-8 and rs144604054, p=2.0 x 10-7). Conclusion CD and prompt normalisation of CRP and albumin levels upon treatment were associated with maintained remission on anti-TNF treatment in IBD patients. Polymorphisms in the TNFRS1A, FAS, FASLG and FCGR2A genes may contribute to predict efficacy of anti-TNF therapy. Our promising GWAS associations with biochemical response to anti-TNF need replication in independent cohorts. These findings could aid clinical decision-making regarding individualised treatment options for IBD patients, but confirmation in larger studies is necessary.
| Item Type: | Thesis (Thesis) |
|---|---|
| Supervisor name: | Spekhorst, L.M. MD ‐PhD student and Festen, E.A.M. MD PhD Gastroenterologist and in training. and Department of Gastroenterology and and Hepatolgy and department and of Genetics, University and of Groningen University and Medical Centre and Goningen and The Netherlands and Weersma, R.K. and MD and PhD and Professor and of and Gastroenterology and Netherlands |
| Faculty: | Medical Sciences |
| Date Deposited: | 25 Jun 2020 10:39 |
| Last Modified: | 25 Jun 2020 10:39 |
| URI: | https://umcg.studenttheses.ub.rug.nl/id/eprint/72 |
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