scholarly journals Vitamin D-Related Genetics as Predictive Biomarker of Clinical Remission in Adalimumab-Treated Patients Affected by Crohn’s Disease: A Pilot Study

2021 ◽  
Vol 14 (12) ◽  
pp. 1230
Author(s):  
Jessica Cusato ◽  
Lorenzo Bertani ◽  
Miriam Antonucci ◽  
Cristina Tomasello ◽  
Gian Paolo Caviglia ◽  
...  
Keyword(s):  
Vitamin D ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Clinical Remission ◽  
Predictive Biomarker ◽  
Nucleotide Polymorphisms ◽  
Protein Levels ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Bowel Diseases

Adalimumab (ADA) is a human anti-tumor necrosis factor (TNF-α) monoclonal antibody used in inflammatory bowel diseases, such as Crohn’s disease (CD). Vitamin-D (VD) is important for biological functions, such as the modulation of expression of genes encoding enzymes and transporters involved in drug metabolism and transport. ADA trough levels were associated with VD concentrations in patients with IBD, but no data are present in the literature concerning VD pathway-related gene single-nucleotide polymorphisms (SNPs) in affecting clinical outcomes. For this reason, the aim of this study was to evaluate the ability of VD-related genetics to predict clinical remission at 3 and 12 months in patients affected by CD treated with ADA. Patients affected by CD were included in this study. SNPs in CYP27B1, CYP24A1, GC, and VDR genes were analyzed through real-time PCR. A total of 63 patients were enrolled. Calprotectin, hemoglobin, and C-reactive protein levels were influenced by SNPs in VDR, CYP27B1, and GC genes. After 3 months of therapy, clinical remission was predicted by smoke, systemic steroids, and VDR BsmI, whereas at 12 months by GC 1296AA/AC and VD supplementation. This study reports the association between VD pathway-related genetics and ADA treatment. Further studies are needed to confirm these promising data.

Vitamin D Status Is Associated with Intestinal Inflammation as Measured by Fecal Calprotectin in Crohn’s Disease in Clinical Remission

2015 ◽  
Vol 60 (8) ◽  
pp. 2427-2435 ◽  
Author(s):  
Tara Raftery ◽  
Megan Merrick ◽  
Martin Healy ◽  
Nasir Mahmud ◽  
Colm O’Morain ◽  
...  
Keyword(s):  
Vitamin D ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Clinical Remission ◽  
Intestinal Inflammation ◽  
Fecal Calprotectin ◽  
Vitamin D Status

scholarly journals DOP20 Genetic of vitamin D as predictor of response to adalimumab in Crohn’s Disease

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S058-S061
Author(s):  
J Cusato ◽  
D G Ribaldone ◽  
L Bertani ◽  
M Antonucci ◽  
C Tomasello ◽  
...  
Keyword(s):  
Vitamin D ◽  
Crohn’S Disease ◽  
Side Effects ◽  
Crohn's Disease ◽  
Clinical Outcome ◽  
Personalised Medicine ◽  
Perianal Disease ◽  
Nucleotide Polymorphisms ◽  
Biological Drugs ◽  
Adalimumab Therapy

Abstract Background Personalised medicine is the direction towards are converging many efforts of experts in inflammatory bowel diseases (IBDs). The advent of biological drugs, with anti-TNF as first category, have revolutionized the managements of these patients. Unfortunately, several unmet needs are present, like an efficacy in about two third of the patients, onset of side effects like infections, paradoxical IMIDs. Being able to treat with these drugs only patients who will respond would avoid losing time without disease improvement and possible side effects. Vitamin D is important for several biological functions, such as regulation of the immune response and modulation of expression of genes encoding enzymes and transporters involved in drug metabolism and transport. Vitamin D is activated by cytochrome (CYP) 27B1, inactivated by CYP24A1, transported in kidney by Vitamin D binding protein (VDBP, encoded by GC gene) and carries out its activities through its receptor (VDR). No data are available concerning vitamin D genetics and response to anti-TNF drug adalimumab. The aim of this study was to describe the relationship between vitamin D pathway-related gene single nucleotide polymorphisms (SNPs) and adalimumab clinical outcome in a cohort of patients affected by Crohn’s disease. Methods We performed a multi-centre prospective study including patients affected by Crohn’s disease who started adalimumab therapy. SNPs in CYP27B1, CYP24A1, GC and VDR genes were analysed. Clinical outcome was considered as clinical response and remission at 3 months of therapy. Results We enrolled 69 patients. Median age was 40 (IQR 31–56) years, males were 40 (58%). Median basal calprotectin was 396 (IQR 188–851) mg/Kg, and 36 (53.7%) had a positive PCR value. We documented the following associations: CYP27B1 + 2838 CT/TT with perianal disease (p= 0.002), basal calprotectin (p= 0.018) and T3 calprotectin (p= 0.035), figure 1; CYP27B1-1260 GT/TT with perianal disease (p= 0.006), basal calprotectin (p= 0.036) and T3 calprotectin (p= 0.024); VDR ApaI CA/AA with basal calprotectin (p= 0.014) and T3 calprotectin (p= 0.036); VDR BsmI GA/AA with perianal disease (p= 0.036), and GC 1296 TG/GG with basal calprotectin (p= 0.014), figure 2. GC 1296 TG/GG genotype polymorphism (p= 0.044, figure 3) predicted clinical remission at multivariate analysis. Finally, median concentrations adalimumab trough levels at 3 months were 7.4 (IQR 5.5; 11.7) ug/mL. CYP24A1 3999 (p=0.025) and VDR TaqI (p=0.016) SNPs affected these levels. Conclusion This is the first study reporting the association between vitamin D pathway-related genetics and adalimumab treatment in a cohort of patients affected by IBD. Further studies in different and larger cohorts are needed to clarify these aspects.

Vitamin D status in children with inflammatory bowel disease

2021 ◽  
Vol 19 (1) ◽  
pp. 5-10
Author(s):  
I.Yu. Pronina ◽  
◽  
V.S. Tsvetkova ◽  
A.S. Potapov ◽  
E.L. Semikina ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Inflammatory Bowel Disease ◽  
Vitamin D ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Bowel Disease ◽  
Vitamin D Status ◽  
Vitamin D Levels ◽  
Bowel Diseases ◽  
Inflammatory Bowel

Objective. To study vitamin D status in children with inflammatory bowel diseases (IBD) depending on the diagnosis, gender, age and a season of examination. Patients and methods. The study included 244 children (130 boys and 114 girls) aged 3 to 18 years. The patients were divided into 2 groups depending on the nosological form of disease: Crohn’s disease (CD) – 130 children, ulcerative colitis (UC) – 114 children. Blood vitamin D levels were determined by the method of competitive electrochemiluminescence. Results. Normal levels of vitamin D (>30 ng/ml) were found only in 11.1% of children with IBD (in 11.5% with CD and 10.5% with UC). Vitamin D status corresponded to deficiency levels in 65.9% of cases, of them 15.2% had deep deficiency (<10 ng/ml). Vitamin D status decreased with increasing age of the patients (ρ = -0.2686). No statistically significant differences were found in vitamin D levels that would be dependent on the season of examination, neither were they found in groups of patients with CD and UC. Conclusion. The study showed an extremely low vitamin D status in patients with IBD. The problem of assessing vitamin D levels in children with IBD and its monitoring as well as development of individual algorithms for supplementation remains topical. Key words: vitamin D, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, children

scholarly journals The Role of Vitamin D Level and Related Single Nucleotide Polymorphisms in Crohn’s Disease

Nutrients ◽  
2013 ◽  
Vol 5 (10) ◽  
pp. 3898-3909 ◽  
Author(s):  
Andre Carvalho ◽  
Karen Bishop ◽  
Dug Han ◽  
Stephanie Ellett ◽  
Amalini Jesuthasan ◽  
...  
Keyword(s):  
Vitamin D ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Single Nucleotide Polymorphisms ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide

scholarly journals Gene Polymorphisms of NOD2, IL23R, PTPN2 and ATG16L1 in Patients with Crohn’s Disease: On the Way to Personalized Medicine?

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 866
Author(s):  
Peter Hoffmann ◽  
David Lamerz ◽  
Petra Hill ◽  
Marietta Kirchner ◽  
Annika Gauss
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Risk Allele ◽  
University Hospital ◽  
Interleukin 12 ◽  
Nucleotide Polymorphisms ◽  
Bowel Diseases ◽  
History Of ◽  
Inflammatory Bowel ◽  
Genetic And Environmental Factors

Genetic and environmental factors are involved in the pathogenesis of inflammatory bowel diseases (IBD). The study aimed at investigating the potential influence of single nucleotide polymorphisms (SNPs) NOD2 rs2066844, NOD2 rs2066845, NOD2 rs2066847, IL23R rs11209026, PTPN2 rs2542151, PTPN2 rs7234029, and ATG16L1 rs2241880 on the response to immunomodulatory therapies and disease course in Crohn’s disease (CD). This is an uncontrolled retrospective monocentric study including patients from the IBD outpatient clinic of Heidelberg University Hospital. Therapy responses and disease courses were related to genetic findings. 379 patients with CD were included. The presence of at least one PTPN2 rs7234029 risk allele was associated with nonresponse to anti-interleukin-12/23 treatment (89.9% vs. 67.6%, p = 0.005). The NOD2 rs2066844 risk allele was associated with a first-degree family history of colon cancer (12.7% vs. 4.7%, p = 0.02), the ATG16L1 rs2241880 risk allele with ileal CD manifestation (p = 0.027), and the IL23R rs11209026 risk allele with a higher rate of CD-related surgeries per disease year (0.08 vs. 0.02, p = 0.025). The results of this study underline the relevance of genetic influences in CD. The association of the PTPN2 rs7234029 risk allele with nonresponse to anti-interleukin-12/23 treatment in CD patients is a novel finding and requires further investigation.

scholarly journals DOP66 The effect of exclusive enteral nutrition on circulating inflammatory protein levels in paediatric patients with Crohn’s Disease

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S100-S101
Author(s):  
M Pidoux ◽  
M Logan ◽  
S Milling ◽  
U Z Ijaz ◽  
R Hansen ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Enteral Nutrition ◽  
Clinical Response ◽  
Clinical Remission ◽  
Innate Immune ◽  
Plasma Samples ◽  
Exclusive Enteral Nutrition ◽  
Protein Levels ◽  
Inflammatory Proteins

Abstract Background Exclusive enteral nutrition (EEN) is the recommended first line treatment for active paediatric Crohn’s disease (CD). The mechanism of action and immunological effects of EEN remain unclear. This study compared circulating inflammatory proteins of patients with CD and ulcerative colitis (UC) with non-inflammatory bowel disease (non-IBD) controls and explored the effect of EEN in children with active CD. Methods Patients with CD were treated with EEN for 8 weeks, with plasma samples collected prior to EEN start and upon EEN completion. Levels of 92 inflammatory proteins were quantified using Olink Inflammation panel. Paired faecal samples were collected to measure faecal calprotectin (FC) levels by ELISA. Patients in which FC decreased &gt;50% during EEN were classed as FC responders; whereas patients who had a &lt;50% decrease in FC were classed as FC non-responders. Results 84 patients were recruited (CD:54, UC:11, non-IBD:19). Paired plasma samples were collected from 18 patients with CD receiving EEN. Of these 18 patients, 72% achieved clinical remission by the end of EEN (wPCDAI &lt;12.5 points). Prior to EEN start, 29 proteins were significantly different between patients with CD compared to non-IBD; and 25 proteins were significantly different between UC and non-IBD, Fig 1. EEN lead to the significant alteration of 23 proteins. This included 5 proteins, CCL23, CXCL10, IL6, IL24, and MMP-1 which were higher in patients with CD prior to EEN start compared to non-IBD, Fig 2. In patients who achieved clinical remission during EEN, 22 proteins significantly changed from their EEN start levels by the end of EEN, Fig 3. FC responders had a similar pattern of protein changes, in which 22 proteins changed significantly during EEN, Fig 4. 16/22 (72%) of the proteins that changed significantly in the FC responder group during EEN, also changed during EEN in patients who entered clinical remission including significant reductions in several innate immune proteins such as IL-6 and IL-18. Patients who did not achieve clinical remission did not have significant reductions in these proteins. Despite being higher in patients with CD prior to treatment compared to non-IBD, the level of 17 proteins, including IL17a and oncostatin M, did not change in FC responders during EEN. Conclusion EEN leads to alteration of multiple inflammatory proteins, in keeping with a reduction in innate immune pro-inflammatory activity and improvement in clinical response, although some inflammatory proteins remain elevated. Figure 1: Venn diagram of proteins significantly different Figure 2: Effect of EEN on protein levels Figure 3: Effect of EEN on protein levels, stratified based on clinical response during EEN Figure 4: Effect of EEN on protein levels, stratified based on FC response

scholarly journals Vedolizumab Efficacy, Safety, and Pharmacokinetics With Reduced Frequency of Dosing From Every 4 Weeks to Every 8 Weeks in Patients With Crohn’s Disease or Ulcerative Colitis

2020 ◽  
Vol 14 (8) ◽  
pp. 1066-1073 ◽  
Author(s):  
Séverine Vermeire ◽  
Milan Lukáš ◽  
Fernando Magro ◽  
Shashi Adsul ◽  
Dirk Lindner ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Adverse Events ◽  
Clinical Remission ◽  
Serious Adverse Events ◽  
Protein Levels ◽  
Reactive Protein ◽  
Reduced Frequency ◽  
Extended Access

Abstract Background and Aims Vedolizumab was shown to be safe and effective for the treatment of Crohn’s disease [CD] and ulcerative colitis [UC] in the GEMINI Long-Term Safety [LTS] study. The vedolizumab Extended Access Program [XAP] provides patients with continued treatment. This XAP pharmacokinetics [PK] sub-study investigated vedolizumab efficacy, safety, and PK. Methods Vedolizumab dosing frequency was reduced from every 4 weeks [Q4W] to every 8 weeks [Q8W] at XAP enrolment, and patients were followed for 56 weeks. Outcomes included: efficacy, loss of clinical benefit, and re-escalation to Q4W dosing; and vedolizumab PK, immunogenicity, and adverse events. Results Among 167 enrolled patients [CD = 88, UC = 79], 80 [91%] with CD and 73 [92%] with UC completed 56 weeks; 76 [86%] and 71 [90%] with CD and UC, respectively, remained on Q8W dosing for 56 weeks. Clinical remission, corticosteroid-free clinical remission, and C-reactive protein levels were stable among patients remaining on Q8W through Week 56. Four patients with CD and two with UC resumed Q4W dosing [three with CD regained clinical response]. Patients with CD who completed Week 56 on Q8W dosing had median trough vedolizumab concentrations of 43.6 µg/mL at enrolment and 10.4 µg/mL at Week 56; concentrations were 42.4 µg/mL and 13.3 µg/mL, respectively, in patients with UC. Treatment-related adverse events were infrequent; no new or serious adverse events related to vedolizumab were reported. Conclusions In the XAP-PK sub-study, adherence to Q8W dosing was high, with no loss of efficacy; very few patients required re-escalation to Q4W. There were no new safety signals.

scholarly journals Diminished Vitamin D Receptor Protein Levels in Crohn’s Disease Fibroblasts: Effects of Vitamin D

Nutrients ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 973
Author(s):  
Laura Gisbert-Ferrándiz ◽  
Jesús Cosín-Roger ◽  
Carlos Hernández ◽  
Dulce C. Macias-Ceja ◽  
Dolores Ortiz-Masiá ◽  
...  
Keyword(s):  
Vitamin D ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Epithelial Cells ◽  
Vitamin D Receptor ◽  
Receptor Protein ◽  
Intestinal Fibrosis ◽  
Protein Levels ◽  
Therapeutic Value ◽  
Mechanistic Basis

Vitamin D (VD) deficiency has been associated to Crohn’s disease (CD) pathogenesis, and the exogenous administration of VD improves the course of the disease, but the mechanistic basis of these observations remains unknown. Vitamin D receptor (VDR) mediates most of the biological functions of this hormone, and we aim to analyze here the expression of VDR in intestinal tissue, epithelial cells, and fibroblasts from CD patients. The effects of VD on a fibroblast wound healing assay and murine intestinal fibrosis are also analyzed. Our data show diminished VDR protein levels in surgical resections and epithelial cells from CD patients. In intestinal fibroblasts isolated from damaged tissue of CD patients, we detected enhanced migration and decreased VDR expression compared with both fibroblasts from non-damaged tissue of the same CD patient or control fibroblasts. Treatment with VD increased VDR protein levels, avoided the accelerated migration in CD fibroblasts, and prevented murine intestinal fibrosis induced by the heterotopic transplant model. In conclusion, our study demonstrates diminished VDR protein levels associated with enhanced migration in intestinal fibroblasts from damaged tissue of CD patients. In these cells, VD accumulates VDR and normalizes migration, which supports that CD patients would benefit from the VD anti-fibrotic therapeutic value that we demonstrate in a murine experimental model.

scholarly journals P046 Vitamin D decreases PDIA3 and prevents the enhanced migration of fibroblasts from stricturing Crohn’s disease

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S156-S156
Author(s):  
L Gisbert-Ferrandiz ◽  
J Cosín-Roger ◽  
S Coll ◽  
C Bauset ◽  
D Ortiz-Masiá ◽  
...  
Keyword(s):  
Vitamin D ◽  
Wound Healing ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Protein Disulfide Isomerase ◽  
Statistical Significance ◽  
Protein Levels ◽  
And Migration ◽  
Protein Disulfide ◽  
Wounded Area

Abstract Background Fibrosis is a common complication in Crohn’s disease (CD) patients and fibroblasts play an important role in the fibrogenic process. Low vitamin D (VD) levels and a defective VD-signalling pathway have been reported in CD. VD signals through both vitamin D receptor (VDR) and protein disulfide-isomerase A3 (PDIA3) and we have previously demonstrated that VDR protein levels are reduced in fibroblasts isolated from CD patients and that VD increased VDR expression in these cells (A-2080; ECCO 2019). We aim to analyse here the effect of VD on both PDIA3 protein levels and migration in CD fibroblasts. Methods We used intestinal fibroblasts isolated from surgical resections of the damaged mucosa of CD patients with stricturing behaviour (B2). Control fibroblasts were obtained from the non-damaged intestine of patients with colorectal cancer. Fibroblasts were treated with VD (100 nM) or its vehicle for 24 h and PDIA3 protein levels were measured by Western Blot. In the wound healing analysis, a single scraping was done in the centre of the fibroblasts monolayer and FBS-free medium was added to the cells, which allows us to determine the ability of fibroblasts to migrate and close the wound. Photos were taken at 0, 24 and 48 h. Results of wound healing were expressed as the percentage of the wound at each time point for the maximal wounded area (time 0, 100%). Statistical significance was measured by ANOVA or t-test. Results No significant differences in PDIA3 protein levels were detected between control and CD fibroblasts but VD significantly decreased PDIA3 expression in CD fibroblasts (Figure 1A). In the wound healing assay, we detected that CD-B2 fibroblasts migrate faster than control cells, resulting in a reduced wounding area, 48 h later (Figure 1B). Treatment of these CD-B2 cells with VD decreased their migration rate, and 48 h later cells exhibited a higher and significant wounding area than vehicle-treated cells (Figure 1C). Conclusion Vitamin D decreased PDIA3 expression and prevented the accelerated migration detected in intestinal fibroblasts from B2-CD patients which suggest an anti-fibrotic effect of VD mediated by a direct effect of this hormone on intestinal fibroblasts.

scholarly journals Screening and Treatment of Vitamin D Deficiency in UK Patients with Crohn’s Disease: Self-Reported Practice among Gastroenterologists

Nutrients ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1064
Author(s):  
Jane Fletcher ◽  
Amelia Swift ◽  
Martin Hewison ◽  
Sheldon C Cooper
Keyword(s):  
Vitamin D ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Vitamin D Deficiency ◽  
British Society ◽  
Dietary Advice ◽  
Mean Frequency ◽  
Screening Practice ◽  
Vitamin D Levels ◽  
Bowel Diseases

Currently, there is no UK national recommendation to measure vitamin D levels in patients with inflammatory bowel diseases (IBD). Patients with IBD are at risk of developing vitamin D deficiency with the highest prevalence frequently reported in those with Crohn’s disease (CD). Treating vitamin D deficiency as part of CD management continues to be of interest. Our aim was to identify influences on practice and self-reported practice among British Society of Gastroenterology (BSG)-IBD section members in the screening and the treatment of vitamin D deficiency in patients with CD. A web-based survey was distributed via email to members of the BSG-IBD section. Reported screening practice was generally annual in those with a history of previous surgery related to CD or small bowel CD. A total of 83% of respondents (n = 64) thought that vitamin D levels should be routinely monitored in patients with CD. Treatments for mild/moderate deficiency included increased sunlight exposure (mean frequency = 21, SD = 15) and dietary advice (mean frequency = 22, SD = 14); in moderate/severe deficiency, oral supplementation was recommended (mean frequency = 14, SD = 13). Respondents reported factors most likely to influence practice, including clearer evidence and guidance. Well conducted studies in CD patients with identified vitamin D deficiency are needed to inform national guidance and clinical practice.

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