The effect of induction therapy with infliximab or vedolizumab on hepcidin and iron status in patients with Inflammatory Bowel Disease

Background Differentiating absolute iron deficiency from functional iron restriction is challenging in active Inflammatory Bowel Disease (IBD). Hepcidin, the systemic iron regulator, could be the key in the diagnosis and management of absolute iron deficiency. In this study, we assessed hepcidin as a diagnostic iron deficiency marker and we explored the relationship between hepcidin, inflammation, hypoxia, and iron deficiency in patients receiving induction therapy with infliximab (IFX) or vedolizumab (VEDO). Methods 130 patients with IBD, who received induction therapy with IFX or VEDO for active disease, were included in this study. Clinical and biochemical data were extracted from medical records. Serum samples at baseline and week 6 of induction therapy were retrieved from the University Medical Center Groningen (UMCG) biobank and analysed for: hepcidin, inflammation (e.g., interleukins [IL] 6, 10, and Tumour Necrosis Factor-α [TNFα]), oxidative stress (free thiols), and hypoxia (e.g., erythropoietin [EPO], Macrophage Inflammatory Protein-3α [MIP3α]). For comparison, serum samples from 50 age- and gender-matched healthy controls were obtained from pre-donation biobank at the UMCG. Response to therapy was defined by either General Physician’s Assessment at week 14 of induction therapy, normalisation or at least a three-point decrease in clinical scores: Harvey-Bradshaw Index (HBI) for Crohn’s Disease, Simple Clinical Colitis Activity Index (SCCAI) for ulcerative colitis. Results Hepcidin correlated with ferritin and sTfR/log ferritin index [ρ = 0.74 and ρ = -0.79, respectively; P<0.001 for both markers], while inflammation- and hypoxia-associated markers showed only marginal correlations. Hepcidin accurately identified absolute iron deficiency: AUC(hepcidin) = 0.89 [95% CI: 0.82–0.95; P<0.001]. Induction with either IFX or VEDO decreased hepcidin [13.5 ng/mL vs. 9.5 ng/mL; P<0.001], ferritin [45.5 ug/L vs. 37.0 ug/L, P<0.05], and inflammatory markers at week 6, while transferrin increased [2.4 g/L vs. 2.5 g/L, P<0.001]. In total, 75.4% of patients responded to the induction therapy. Hepcidin and ferritin decreased, while transferrin increased (P<0.001 for all changes) in patients who responded to the therapy. In addition, hypoxia (EPO and MIP3α) and inflammatory markers such as faecal calprotectin, IL-6, IL-22, and TNFα improved significantly. In contrast, none of these improvements were observed in patients who did not respond to the therapy. Conclusion Hepcidin reflects iron deficiency in active IBD, but inflammation masks the severity of the deficiency. Induction therapy with either IFX or VEDO modulates hepcidin and iron indices, especially in patients who respond to the therapy

No Superiority of Tacrolimus Suppositories vs Beclomethasone Suppositories in a Randomized Trial of Patients With Refractory Ulcerative Proctitis

Background &amp; Aims: Ulcerative proctitis (UP) refractory to 5-aminosalicylic acid (5-ASA) suppositories is a challenge to treat, often requiring step up to immunomodulator or biological therapy. Topical tacrolimus is effective and safe in patients with refractory UP. However, it is not clear how tacrolimus suppositories fit into in the treatment algorithm of UP. Methods: We performed a randomized controlled, double-blind study at 8 hospitals in the Netherlands and Belgium from 2014 through 2017. Eighty-five patients with refractory UP (65% women) were randomly assigned to groups given once daily tacrolimus suppositories (2 mg; n = 43) or beclomethasone (3 mg; n = 42) for 4 weeks. The primary outcome was clinical response (decrease in Mayo score of 3 or more). Secondary outcomes included clinical remission, endoscopic response and remission, adverse events and quality of life. Outcomes were compared using Fisher's exact test and Mann-Whitney U test. Results: Proportions of patients with clinical responses were 63% in the tacrolimus group and 59% in the beclomethasone group (P =.812); proportions of patients in clinical remission were 46% and 38%, respectively (P =.638). Proportions of patients with an endoscopic response were 68% and 60% in the tacrolimus group and in the beclomethasone group (P =.636); proportions in endoscopic remission rates were 30% and 13%, respectively (P =.092) Median increases in the inflammatory bowel disease questionnaire score were 18.0 in the tacrolimus group and 20.5 in the beclomethasone group (P =.395). Adverse event rates did not differ significantly between groups. Conclusions: In a 4-week randomized controlled trial, tacrolimus and beclomethasone suppositories induce comparable clinical and endoscopic responses in patients with UP refractory to 5-ASA. There were no significant differences in adverse events rates. Tacrolimus and beclomethasone suppositories are therefore each safe and effective treatment options for 5-ASA refractory disease. EUDRACT 2013-001259-11; Netherlands Trial Register NL4205/NTR4416.</p

Faecal Microbiota Transplantation Engraftment After Budesonide or Placebo in Patients With Active Ulcerative Colitis Using Pre-selected Donors:A Randomized Pilot Study

Background: Faecal microbiota transplantation [FMT] shows some efficacy in treating patients with ulcerative colitis [UC], although variability has been observed among donors and treatment regimens. We investigated the effect of FMT using rationally selected donors after pretreatment with budesonide or placebo in active UC. Methods: Patients ≥18 years old with mild to moderate active UC were randomly assigned to 3 weeks of budesonide [9 mg] or placebo followed by 4-weekly infusions of a donor faeces suspension. Two donors were selected based on microbiota composition, regulatory T cell induction and short-chain fatty acid production in mice. The primary endpoint was engraftment of donor microbiota after FMT. In addition, clinical efficacy was assessed. Results: In total, 24 patients were enrolled. Pretreatment with budesonide did not increase donor microbiota engraftment [p = 0.56] nor clinical response, and engraftment was not associated with clinical response. At week 14, 10/24 [42%] patients achieved [partial] remission. Remarkably, patients treated with FMT suspensions from one donor were associated with clinical response [80% of responders, p &lt; 0.05] but had lower overall engraftment of donor microbiota. Furthermore, differences in the taxonomic composition of the donors and the engraftment of certain taxa were associated with clinical response. Conclusion: In this small study, pretreatment with budesonide did not significantly influence engraftment or clinical response after FMT. However, clinical response appeared to be donor-dependent. Response to FMT may be related to transfer of specific strains instead of overall engraftment, demonstrating the need to characterize mechanisms of actions of strains that maximize therapeutic benefit in UC.</p

Vedolizumab for Inflammatory Bowel Disease:Two-Year Results of the Initiative on Crohn and Colitis (ICC) Registry, A Nationwide Prospective Observational Cohort Study: ICC Registry - Vedolizumab

Contains fulltext : 220028.pdf (Publisher’s version ) (Open Access)Prospective data of vedolizumab treatment for patients with inflammatory bowel disease (IBD) beyond 1 year of treatment is scarce but needed for clinical decision making. We prospectively enrolled 310 patients with IBD (191 with Crohn's disease (CD) and 119 patients with ulcerative colitis (UC)) with a follow-up period of 104 weeks (interquartile range: 103-104) in a nationwide registry. The corticosteroid-free clinical remission rate (Harvey Bradshaw Index ≤ 4, Short Clinical Colitis Activity index ≤ 2) at weeks 52 and 104 were 28% and 19% for CD and 27% and 28% for UC, respectively. Fifty-nine percent maintained corticosteroid-free clinical remission between weeks 52 and 104. Vedolizumab with concomitant immunosuppression showed comparable effectiveness outcomes compared with vedolizumab monotherapy (week 104: 21% vs. 23%; P = 0.77), whereas 8 of 13 severe infections occurred in patients treated with concomitant immunosuppression. To conclude, the clinical effect was 19% for CD and 28% for UC after 2 years of follow-up regardless of concomitant immunosuppression

Prognostic Value of the Modified Rutgeerts Score for Long-Term Outcomes After Primary Ileocecal Resection in Crohn’s Disease

IntroductionThe prognostic value of the modified Rutgeerts score (mRS) in patients with Crohn's disease (CD) needs to be further elucidated. This study assessed the prognostic value of the mRS for long-term outcomes after primary ileocecal resection in patients with CD.METHODS: Patients with CD after primary ileocecal resection with an available mRS at first postoperative ileocolonoscopy (index mRS) were retrospectively included. The primary outcome was surgical recurrence. Secondary outcomes were clinical recurrence and progression to severe endoscopic recurrence (‡i3). Cox proportional hazard models were used to assess the association between index mRS and outcomes. RESULTS: Six hundred fifty-two patients were included (mean follow-up: 6.4 years, SD: 4.6). Surgical recurrence rates were 7.7%, 5.3%, 12.9%, 19.1%, 28.8%, 47.8% for index mRS i0, i1, i2a, i2b, i3, and i4, respectively. Clinical recurrence occurred in 42.2% (i0), 53.7% (i1), 58.5% (i2a), 80.2% (i2b), 79.4% (i3), and 95.3% (i4) of patients. Progression to severe endoscopic recurrence occurred in 21.1% (i0), 33.9% (i1), 26.8% (i2a), and 33.3% (i2b) of patients. An index mRS of i2b (adjusted hazard ratio [aHR] 3.0; 1.5–5.6), i3 (aHR 4.0; 2.0–7.9) and i4 (aHR 8.0; 4.0–16.0) were associated with surgical recurrence. An index mRS of i1 (aHR 1.7; 1.2–2.4), i2a (aHR 1.7; 1.2–2.4), i2b (aHR 4.4; 3.2–6.0), i3 (aHR 3.6; 2.5–5.2), and i4 (aHR 7.3; 4.8–10.9) were associated with clinical recurrence. An index mRS of i1 (aHR 2.0; 1.1–3.7) or i2b (aHR 2.5; 1.4–4.6) was associated with progression to severe endoscopic recurrence.DISCUSSION: The increasing mRS corresponds closely with the risk of surgical and clinical recurrence. An index mRS ‡ i2b is associated with surgical recurrence, an index mRS ‡ i1 is associated with clinical recurrence, and i1 or i2b with progression to severe endoscopic recurrence. These results support tight monitoring of disease activity and treatment optimization in patients with ileal lesions and a more conservative management in patients with anastomotic lesions.</p

Prognostic Value of the Modified Rutgeerts Score for Long-Term Outcomes After Primary Ileocecal Resection in Crohn’s Disease

IntroductionThe prognostic value of the modified Rutgeerts score (mRS) in patients with Crohn's disease (CD) needs to be further elucidated. This study assessed the prognostic value of the mRS for long-term outcomes after primary ileocecal resection in patients with CD.METHODS: Patients with CD after primary ileocecal resection with an available mRS at first postoperative ileocolonoscopy (index mRS) were retrospectively included. The primary outcome was surgical recurrence. Secondary outcomes were clinical recurrence and progression to severe endoscopic recurrence (‡i3). Cox proportional hazard models were used to assess the association between index mRS and outcomes. RESULTS: Six hundred fifty-two patients were included (mean follow-up: 6.4 years, SD: 4.6). Surgical recurrence rates were 7.7%, 5.3%, 12.9%, 19.1%, 28.8%, 47.8% for index mRS i0, i1, i2a, i2b, i3, and i4, respectively. Clinical recurrence occurred in 42.2% (i0), 53.7% (i1), 58.5% (i2a), 80.2% (i2b), 79.4% (i3), and 95.3% (i4) of patients. Progression to severe endoscopic recurrence occurred in 21.1% (i0), 33.9% (i1), 26.8% (i2a), and 33.3% (i2b) of patients. An index mRS of i2b (adjusted hazard ratio [aHR] 3.0; 1.5–5.6), i3 (aHR 4.0; 2.0–7.9) and i4 (aHR 8.0; 4.0–16.0) were associated with surgical recurrence. An index mRS of i1 (aHR 1.7; 1.2–2.4), i2a (aHR 1.7; 1.2–2.4), i2b (aHR 4.4; 3.2–6.0), i3 (aHR 3.6; 2.5–5.2), and i4 (aHR 7.3; 4.8–10.9) were associated with clinical recurrence. An index mRS of i1 (aHR 2.0; 1.1–3.7) or i2b (aHR 2.5; 1.4–4.6) was associated with progression to severe endoscopic recurrence.DISCUSSION: The increasing mRS corresponds closely with the risk of surgical and clinical recurrence. An index mRS ‡ i2b is associated with surgical recurrence, an index mRS ‡ i1 is associated with clinical recurrence, and i1 or i2b with progression to severe endoscopic recurrence. These results support tight monitoring of disease activity and treatment optimization in patients with ileal lesions and a more conservative management in patients with anastomotic lesions.</p

Instructions for Authors

Nonadherence to medical therapy is frequently encountered in patients with inflammatory bowel disease (IBD). We aimed to identify predictors for future (non)adherence in IBD

Hereditary cancer registries improve the care of patients with a genetic predisposition to cancer:contributions from the Dutch Lynch syndrome registry

The Dutch Hereditary Cancer Registry was established in 1985 with the support of the Ministry of Health (VWS). The aims of the registry are: (1) to promote the identification of families with hereditary cancer, (2) to encourage the participation in surveillance programs of individuals at high risk, (3) to ensure the continuity of lifelong surveillance examinations, and (4) to promote research, in particular the improvement of surveillance protocols. During its early days the registry provided assistance with family investigations and the collection of medical data, and recommended surveillance when a family fulfilled specific diagnostic criteria. Since 2000 the registry has focused on family follow-up, and ensuring the quality of surveillance programs and appropriate clinical management. Since its founding, the registry has identified over 10,000 high-risk individuals with a diverse array of hereditary cancer syndromes. All were encouraged to participate in prevention programmes. The registry has published a number of studies that evaluated the outcome of surveillance protocols for colorectal cancer (CRC) in Lynch syndrome, as well as in familial colorectal cancer. In 2006, evaluation of the effect of registration and colonoscopic surveillance on the mortality rate associated with colorectal cancer (CRC) showed that the policy led to a substantial decrease in the mortality rate associated with CRC. Following discovery of MMR gene defects, the first predictive model that could select families for genetic testing was published by the Leiden group. In addition, over the years the registry has produced many cancer risk studies that have helped to develop appropriate surveillance protocols. Hereditary cancer registries in general, and the Lynch syndrome registry in particular, play an important role in improving the clinical management of affected families.</p

Lymphoproliferative disease in the rectum 4 years after local mesenchymal stromal cell therapy for refractory perianal Crohn's fistulas:a case report

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Pooled Resequencing of 122 Ulcerative Colitis Genes in a Large Dutch Cohort Suggests Population-Specific Associations of Rare Variants in MUC2

Genome-wide association studies have revealed several common genetic risk variants for ulcerative colitis (UC). However, little is known about the contribution of rare, large effect genetic variants to UC susceptibility. In this study, we performed a deep targeted re-sequencing of 122 genes in Dutch UC patients in order to investigate the contribution of rare variants to the genetic susceptibility to UC. The selection of genes consists of 111 established human UC susceptibility genes and 11 genes that lead to spontaneous colitis when knocked-out in mice. In addition, we sequenced the promoter regions of 45 genes where known variants exert cis-eQTL-effects. Targeted pooled re-sequencing was performed on DNA of 790 Dutch UC cases. The Genome of the Netherlands project provided sequence data of 500 healthy controls. After quality control and prioritization based on allele frequency and pathogenicity probability, follow-up genotyping of 171 rare variants was performed on 1021 Dutch UC cases and 1166 Dutch controls. Single-variant association and gene-based analyses identified an association of rare variants in the MUC2 gene with UC. The associated variants in the Dutch population could not be replicated in a German replication cohort (1026 UC cases, 3532 controls). In conclusion, this study has identified a putative role for MUC2 on UC susceptibility in the Dutch population and suggests a population-specific contribution of rare variants to UC