Diagnostic accuracy of faecal calprotectin in patients with active perianal fistulas

Background: Faecal calprotectin (FC) is a marker of mucosal inflammation. Objective: The aim of this study was to determine the diagnostic accuracy of FC to (a) differentiate between perianal fistulizing Crohn's disease (pCD) and cryptoglandular perianal fistulas; and (b) detect mucosal inflammation in pCD. Methods: Patients with active perianal fistulas who had FC measured and a complete ileocolonoscopy within 10 weeks were retrospectively included. Results: Fifty-six patients were included (pCD, n = 37) of whom 19 pCD patients exhibited ulcers. FC was significantly higher in pCD compared to cryptoglandular fistulas (µg/g) (708.0 (207.0–1705.0) vs 32.0 (23.0–77.0), p < 0.001). Area-under-the-curve (AUC) value for FC receiver operating characteristic (ROC) statistics was 0.900. Optimal FC cut-off was ≥ 150 µg/g. To differentiate pCD from cryptoglandular fistulas in the absence of luminal inflammation, optimal cut-off remained ≥ 150 µg/g (AUC = 0.857, sensitivity = 0.81, specificity = 0.89, positive predictive value (PPV) = 93.8% and negative predictive value (NPV) = 70.8%). In pCD, FC was significantly increased in the presence of ulcers (1672.0 vs 238.0, p = 0.004). Optimal cut-off was ≥ 250 µg/g (AUC = 0.776; sensitivity = 0.89, specificity = 0.56, PPV - 68.0% and NPV = 83.0%). Conclusion: FC discriminates pCD from cryptoglandular fistulas, even in the absence of intestinal ulcers. In active pCD, an elevated FC does not accurately predict the presence of ulcers and should be interpreted with caution

Risk of malignancy in 22q11.2 deletion syndrome

22q11.2DS is a significant health problem because of its fairly high incidence. It is relevant to be vigilant regarding the diagnosis of cancer amongst 22q11.2 patients as there might be an increased risk, especially amongst patients with the 22q11.2 distal deletion syndrome

Systematic review: predictive biomarkers of therapeutic response in inflammatory bowel disease—Personalised medicine in its infancy

Background: Inflammatory bowel disease (IBD) is characterised by substantial heterogeneity in treatment response. With an expanding number of therapeutic agents, identifying optimal treatment at the patient level remains a major challenge. Aim: To systematically review the available literature on predictive biomarkers of therapeutic response in IBD. Methods: An electronic literature search was performed on 30 January 2018 using MEDLINE, EMBASE and the Cochrane Library. Retrospective, prospective, uncontrolled and controlled studies reporting on biomarkers predicting therapeutic response in paediatric and adult IBD populations were eligible for inclusion. The methodological quality of the included studies was assessed using the QUIPS tool. Due to anticipated heterogeneity and limited data, a qualitative, rather than quantitative, assessment was planned. Results: Of the 10 638 citations identified, 92 articles met the inclusion criteria. Several potential DNA, mRNA and protein markers were evaluated as predictive biomarkers. Most studies focused on predicting response to anti-TNF agents. Substantial between-study heterogeneity was identified with respect to both the biomarkers studied and the definition of response. None of the included studies received a low risk of bias rating for all six domains. Currently, none of the biomarkers is sufficiently predictive for clinical use. Conclusions: The search for predictive biomarkers is still in its infancy and current evidence is limited. Future research efforts should take into account the high patient heterogeneity within prospective trials with objective response assessment. Predictive models will most likely comprise a combination of several molecular markers from integrated omics-levels and clinical characteristics

Multi-omics of human plasma reveals molecular features of dysregulated inflammation and accelerated aging in schizophrenia.

Schizophrenia is a devastating psychiatric illness that detrimentally affects a significant portion of the worldwide population. Aging of schizophrenia patients is associated with reduced longevity, but the potential biological factors associated with aging in this population have not yet been investigated in a global manner. To address this gap in knowledge, the present study assesses proteomics and metabolomics profiles in the plasma of subjects afflicted with schizophrenia compared to non-psychiatric control patients over six decades of life. Global, unbiased analyses of circulating blood plasma can provide knowledge of prominently dysregulated molecular pathways and their association with schizophrenia, as well as features of aging and gender in this disease. The resulting data compiled in this study represent a compendium of molecular changes associated with schizophrenia over the human lifetime. Supporting the clinical finding of schizophrenia's association with more rapid aging, both schizophrenia diagnosis and age significantly influenced the plasma proteome in subjects assayed. Schizophrenia was broadly associated with prominent dysregulation of inflammatory and metabolic system components. Proteome changes demonstrated increased abundance of biomarkers for risk of physiologic comorbidities of schizophrenia, especially in younger individuals. These findings advance our understanding of the molecular etiology of schizophrenia and its associated comorbidities throughout the aging process

Laparoscopic ileocaecal resection versus infliximab for terminal ileitis in Crohn's disease:retrospective long-term follow-up of the LIR!C trial

BACKGROUND: The LIR!C trial showed that laparoscopic ileocaecal resection is a cost-effective treatment that has similar quality-of-life outcomes to treatment with infliximab, an anti-tumour necrosis factor (TNF) drug. We aimed to compare long-term outcomes of both interventions and identify baseline factors associated with the duration of treatment effect in each group. METHODS: In this retrospective follow-up study, we collected data from patients who participated in the LIR!C trial, a multicentre randomised controlled trial that compared quality of life after surgical resection versus infliximab in adult patients with non-stricturing and immunomodulator-refractory ileocaecal Crohn's disease. From Jan 1 to May 1, 2018, we collected follow-up data from the time from enrolment in the LIR!C trial until the last visit at either the gastrointestinal surgeon or gastroenterologist. In this study, outcomes of interest were need for surgery or repeat surgery or anti-TNF therapy, duration of treatment effect, and identification of factors associated with the duration of treatment effect. Duration of treatment effect was defined as the time without need for additional Crohn's disease-related treatment (corticosteroids, immunomodulators, biologics, or surgery). FINDINGS: We collected long-term follow-up data for 134 (94%) of 143 patients included in the LIR!C trial, of whom 69 were in the resection group and 65 were in the infliximab group. Median follow-up was 63·5 months (IQR 39·0-94·5). In the resection group, 18 (26%) of 69 patients started anti-TNF therapy and none required a second resection. 29 (42%) patients in the resection group did not require additional Crohn's disease-related medication, although 14 (48%) of these patients were given prophylactic immunomodulator therapy. In the infliximab group, 31 (48%) of 65 patients had a Crohn's disease-related resection, and the remaining 34 patients maintained, switched, or escalated their anti-TNF therapy. Duration of treatment effect was similar in both groups, with a median time without additional Crohn's disease-related treatment of 33·0 months (95% CI 15·1-50·9) in the resection group and 34·0 months (0·0-69·3) in the infliximab group (log-rank p=0·52). In both groups, therapy with an immunomodulator, in addition to the allocated treatment, was associated with duration of treatment effect (hazard ratio for resection group 0·34 [95% CI 0·16-0·69] and for infliximab group 0·49 [0·26-0·93]). INTERPRETATION: These findings further support laparoscopic ileocaecal resection as a treatment option in patients with Crohn's disease with limited (affected segment ≤40 cm) and predominantly inflammatory terminal ileitis for whom conventional treatment is not successful. FUNDING: None

Evaluation of optimal biopsy location for assessment of histological activity, transcriptomic and immunohistochemical analyses in patients with active Crohn’s disease

Background: The appropriate location for biopsy procurement relative to an ulcer in active Crohn's disease is unknown. Aim: To explore the relationship between biopsy location, histological disease activity, proinflammatory gene expression and the presence of inflammatory cells. Methods: Fifty-one patients with Crohn's disease and ulcers >0.5 cm diameter in the colon and/or ileum were prospectively enrolled at three centres. Biopsies were obtained from 0 mm, 7 to 8 mm and 21 to 24 mm from the edge of the largest ulcer. Histological activity was blindly assessed with the Global Histological Disease Activity Score, the Robarts Histopathology and Nancy Histological indices. Messenger ribonucleic acid (mRNA) levels for interleukins-6, -8 and -23 (p19 and p40 subunits), CD31 and S100A9 were measured using quantitative polymerase chain reaction. The number of CD3+, CD68+ and myeloperoxidase-positive cells was quantified by immunohistochemistry. Data were analysed using mixed models with location and segment as fixed effects and patients as random effect to account for correlation among segments within a patient. Results: Histological disease activity scores (P < 0.0001), proinflammatory gene expression levels (P < 0.005) and numbers of myeloperoxidase-positive cells (P < 0.0001) were highest in biopsies from the ulcer edge in the colon and ileum, with decreasing gradients observed with distance from the edge (P < 0.05). No differences between colonic and ileal samples were detected for the parameters measured at any location. Conclusions: Biopsies from the ulcer edge in patients with Crohn's disease yielded the greatest histological disease activity and mRNA levels and had similar readouts in the colon and ileum. Research is needed to confirm this conclusion for other measures

Cost-effectiveness of laparoscopic ileocaecal resection versus infliximab treatment of terminal ileitis in Crohn's disease: The LIR!C Trial

Objective Evaluate the cost-effectiveness of laparoscopic ileocaecal resection compared with infliximab in patients with ileocaecal Crohn's disease failing conventional therapy. Design A multicentre randomised controlled trial was performed in 29 centres in The Netherlands and the UK. Adult patients with Crohn's disease of the terminal ileum who failed >3 months of conventional immunomodulators or steroids without signs of critical strictures were randomised to laparoscopic ileocaecal resection or infliximab. Outcome measures included quality-adjusted life-years (QALYs) based on the EuroQol (EQ) 5D-3L Questionnaire and the Inflammatory Bowel Disease Questionnaire (IBDQ). Costs were measured from a societal perspective. Analyses were performed according to the intention-to-treat principle. Missing cost and effect data were imputed using multiple imputation. Cost-effectiveness planes and cost-effectiveness acceptability curves were estimated to show uncertainty. Results In total, 143 patients were randomised. Mean Crohn's disease total direct healthcare costs per patient at 1 year were lower in the resection group compared with the infliximab group (mean difference €-8931; 95% CI €-12 087 to €-5097). Total societal costs in the resection group were lower than in the infliximab group, however not statistically significant (mean difference €-5729, 95% CI €-10 606 to €172). The probability of resection being cost-effective compared with infliximab was 0.96 at a willingness to pay (WTP) of €0 per QALY gained and per point improvement in IBDQ Score. This probability increased to 0.98 at a WTP of €20 000/QALY gained and 0.99 at a WTP of €500/point of improvement in IBDQ Score. Conclusion Laparoscopic ileocaecal resection is a cost-effective treatment option compared with infliximab. Clinical trial registration number Dutch Trial Registry NTR1150; EudraCT number 2007-005042-20 (closed on 14 October 2015)