BSGIE survey on COVID-19 and gastrointestinal endoscopy in Belgium : results and recommendations.

BACKGROUND AND AIMS: With the first wave of the COVID-19 pandemic declining, activities in the gastrointestinal clinic are being recommenced after a period of stringent measures. Since a second COVID-19 wave is not entirely ruled out health care professionals might remain faced with the need to perform endoscopic procedures in patients with a confirmed positive or unknown COVID-19 status. With this report we aim to provide a practical relevant overview of preparation and protective measures for gastroenterologists based on the currently available guidelines and our local experience and results of a national Belgian survey, to guarantee a fast recall of an adequate infection prevention if COVID-19 reoccurs. METHODS: From the 23rd of March 2020 and the 13th of May 2020 we performed a Pubmed, Embase and Medline search, resulting in 37 papers on COVID-19 and endoscopy. Additionally, we combined these data with data acquired from the national BSGIE survey amongst Belgian gastroenterologists. RESULTS: Based on 72 completed surveys in both university and non-university hospitals, the results show (1) a dramatic (<20%) or substantial (<50%) decrease of normal daily endoscopy in 74% and 22% of the units respectively, (2) a difference in screening and protective measures between university and non-university hospitals. These findings were subsequently compared with the current guidelines. CONCLUSION: Based on new data from the BSGIE survey and current guidelines we tried to realistically represent the current COVID-19 trends in protective measures, screening and indications for endoscopy and to provide a practical overview as preparation for a possible second wave.

Systematic review with meta-analysis: prevalence, risk factors and costs of aminosalicylate use in Crohn's disease.

BACKGROUND: Aminosalicylates are the most frequently prescribed drugs for patients with Crohn's disease (CD), yet evidence to support their efficacy as induction or maintenance therapy is controversial. AIMS: To quantify aminosalicylate use in CD clinical trials, identify factors associated with use and estimate direct annual treatment costs of therapy. METHODS: MEDLINE, Embase and CENTRAL were searched to April 2017 for placebo-controlled trials in adults with CD treated with corticosteroids, immunosuppressants or biologics. The proportion of patients co-prescribed aminosalicylates in placebo arms was pooled using a random-effects model. Meta-regression was used to identify factors associated with aminosalicylate use. Annual treatment costs were estimated using the 2016 Ontario Drug Benefit Program. RESULTS: Forty-two induction and 10 maintenance trials were included. The pooled proportion of patients co-prescribed aminosalicylates was 44% [95% CI: 39%-49%] in induction trials and 49% [95% CI: 35%-64%] in maintenance trials. There was substantial to considerable heterogeneity (I2  = 86.0%, 91.8% for induction and maintenance trials, respectively). In multivariable meta-regression, aminosalicylate use has decreased over time in induction trials (OR 0.50 [95% CI: 0.34-0.74] per 10-year increment). While a decline has been seen over time, 35% of CD patients were still using aminosalicylates in contemporary trials from the last 5 years. The estimated annual cost for the lowest price mesalazine (mesalamine) formulation is approximately $32 million for the Canadian CD population. CONCLUSIONS: Over one-third of CD patients entering clinical trials are still co-prescribed aminosalicylates. A definitive trial is needed to inform the conventional practice of using aminosalicylates as CD maintenance therapy.

Randomised non-inferiority trial: 1600 mg versus 400 mg tablets of mesalazine for the treatment of mild-to-moderate ulcerative colitis.

BACKGROUND: High concentration mesalazine formulations are more convenient than conventional low concentration formulations for the treatment of ulcerative colitis (UC). AIM: To compare the efficacy and safety of 1600 mg and 400 mg tablet mesalazine formulations. METHODS: Patients with mild-to-moderate active UC (Mayo Clinic Score >5; N=817) were randomised to 3.2 g of oral mesalazine, administered as two 1600 mg tablets once, or four 400 mg tablets twice daily. We hypothesised that treatment with the 1600 mg tablet was non-inferior (within a 10% margin) to the 400 mg tablet for induction of clinical and endoscopic remission at week 8. Open-label treatment with the 1600 mg tablet continued for 26-30 weeks based on induction response. Predictors of treatment response were also explored. RESULTS: At week 8, remission occurred in 22.4% and 24.6% of patients receiving the 1600 mg and 400 mg tablets, respectively (absolute difference -2.2%, 95% CI: -8.1% to 3.8%, non-inferiority P=.005). Endoscopic and histopathologic disease activity, leucocyte concentration and age were significantly associated with clinical remission (P=.022, .042, .014 and .023, respectively). At week 38, 43.9% (296/675) of patients who continued treatment with the 1600 mg formulation were in remission, including 70.3% (142/202) of patients who received a reduced dose of mesalazine (1.6 g/d). The overall incidence of serious adverse events was low. CONCLUSIONS: Induction therapy with 3.2 mg mesalazine using two 1600 mg tablets once-daily was statistically and clinically non-inferior to a twice-daily regimen using four 400 mg tablets (NCT01903252).

The development of a magnetic resonance imaging index for fistulising Crohn's disease.

BACKGROUND: Magnetic resonance imaging (MRI) is the gold standard for assessment of perianal fistulising Crohn's disease (CD). The Van Assche index is the most commonly used MRI fistula index. AIMS: To assess the reliability of the Van Assche index, and to modify the instrument to improve reliability and create a novel index for fistulising CD. METHODS: A consensus process developed scoring conventions for existing Van Assche index component items and new items. Four experienced radiologists evaluated 50 MRI images in random order on three occasions. Reliability was assessed by estimates of intraclass correlation coefficients (ICCs). Common sources of disagreement were identified and recommendations made to minimise disagreement. A mixed effects model used a 100 mm visual anologue scale (VAS) for global severity as outcome and component items as predictors to create a modified Van Assche index. RESULTS: Intraclass correlation coefficients (95% confidence intervals) for intra-rater reliability of the original and modified Van Assche indices and the VAS were 0.86 (0.81-0.90), 0.90 (0.86-0.93) and 0.86 (0.82-0.89). Corresponding ICCs for inter-rater reliability were 0.66 (0.52-0.76), 0.67 (0.55-0.75) and 0.58 (0.47-0.66). Sources of disagreement included number, location, and extension of fistula tracts, and rectal wall involvement. A modified Van Assche index (range 0-24) was created that included seven component items. CONCLUSIONS: Although "almost perfect" intra-rater reliability was observed for the assessment of MRI images for fistulising CD using the Van Assche index, inter-rater reliability was considerably lower. Our modification of this index should result in a more optimal instrument.

Review article: dose optimisation of infliximab for acute severe ulcerative colitis.

BACKGROUND: Although optimal medical management of acute severe ulcerative colitis (UC) is ill-defined, infliximab has become a standard of care. Accumulating evidence suggests an increased rate of infliximab clearance in patients with acute severe UC and a reduced colectomy rate with an intensified infliximab induction regimen. AIM: To assess the strength of the current evidence for the relationship between infliximab pharmacokinetics, dosing strategies and disease behaviour in patients with acute severe UC. METHODS: We systematically searched MEDLINE and conference proceedings from 2000 to 2016 for relevant articles describing the pharmacokinetics of infliximab in acute severe UC and/or infliximab dose intensification strategies in acute severe UC. Eligible articles described randomised controlled trials, and cohort, cross-sectional, and case-controlled studies. RESULTS: Of 400 citations identified, 76 studies were eligible. Increased infliximab clearance occurs in patients with acute severe UC, and is driven by the total inflammatory burden and leakage of drug into the colonic lumen. Several cohort studies suggest that infliximab dose intensification is beneficial to at least 50% of acute severe UC patients and the results of case-controlled studies indicate that an intensified infliximab dosing regimen with 1-2 additional infusions in the first 3 weeks of treatment could reduce the early (3-month) colectomy rate by up to 80%, although these data require prospective validation. CONCLUSIONS: Uncontrolled studies suggest a benefit for infliximab dose optimisation in patients with acute severe UC. A randomised controlled trial in acute severe UC patients comparing a personalised infliximab dose-optimisation strategy with conventional dosing is a research priority.

An induction or flare of arthritis and/or sacroiliitis by vedolizumab in inflammatory bowel disease: a case series.

BACKGROUND: In inflammatory bowel disease (IBD), a new biological therapy has recently been approved. Vedolizumab is a humanised IgG1 monoclonal antibody to α4ß7 integrin that modulates gut lymphocyte trafficking. Although an exclusively local effect of vedolizumab could be expected based on the restricted presence of the α4ß7-mucosal vascular addressin cell adhesion molecule 1 complex in the gut, past combined success with anti-tumour necrosis factor, and previous demonstration of α4ß7 integrin in the joint, led to the expectation of a therapeutic efficacy in spondyloarthritis. Nonetheless, the effect of vedolizumab on extraintestinal manifestations-and especially the joint-has not been reported so far. CASE REPORT: A series of five patients with IBD who were treated with vedolizumab and promptly developed new onset or exacerbation of sacroiliitis or arthritis are reported. CONCLUSIONS: Vedolizumab therapy does not seem to show any efficacy in and might even induce arthritis and/or sacroiliitis. However, larger cohort studies are needed to provide information on the prevalence, the evolution and underlying mechanism.

The predictive value of negative capsule endoscopy for the indication of Obscure Gastrointestinal Bleeding: no reassurance in the long term.

BACKGROUND: Capsule Endoscopy (CE) has become the first-line tool to identify an underlying etiology for Obscure Gastrointestinal Bleeding (OGIB) in the small bowel (SB). This study aims to investigate the long-term outcome of patients with a negative CE. METHODS: Retrospective review of standardized application forms of all patients who underwent CE for OGIB at the Ghent University Hospital between 2002 and 2013. Follow-up data on patients with a negative CE result (n=263) were collected by contacting the referring physician. RESULTS: Follow-up was available for 211 patients (Male, n=107 ; Female, n=104 ; Overt bleeding, n=76 ; Occult bleeding, n=135). Median follow-up time was 51.7 months (range 1.4-139.6 months). Ninety-six patients underwent further diagnostics, showing a cause for OGIB in 57 (59.4%). Final outcome for the complete cohort of negative CEs was : 139 (65.9%) true negative (i.e. non-SB cause of bleeding/ resolved OGIB), 19 (9%) false negative (i.e. SB cause of OGIB) and 53 (25.1%) ongoing bleeding without cause. Missed SB lesions were : angiodysplasia (n=11), Meckel's diverticulum (n=3), SB malignancy (n=3), jejunal erosions (n=1) and NSAID-induced SB ulcerations (n=1). Bleeding resolved in 138/209 patients (66%) of which 79 underwent non-specific therapy. CONCLUSIONS: Negative CEs in patients with OGIB do not reassure the treating physician, but warrant close monitoring. In suspicious cases, alternative diagnostic modalities are recommended, showing a high diagnostic yield. (Acta gastroenterol. belg., 2016, 79, 405-413).

Belgian recommendations for the management of anemia in patients with inflammatory bowel disease.

Anemia is the most common extraintestinal manifestation of inflammatory bowel disease (IBD) which, in most cases, results from an absolute or functional iron deficiency. Although anemia and iron deficiency may have a dramatic impact on the quality of life of IBD patients, they are underdiagnosed and undertreated. This paper provides evidence-based consensus guidelines and practical treatment algorithms that are directly applicable to the Belgian situation. In this way, the Belgian IBD research and development Group (BIRD) aims to increase awareness and knowledge among gastroenterologists in order to improve the management of anemia and iron deficiency in their IBD patients.

Hand-held fractional exhaled nitric oxide measurements as a non-invasive indicator of systemic inflammation in Crohn's disease.

BACKGROUND AND AIMS: Active inflammatory bowel disease (IBD) is associated with increased activity of inducible nitric oxide synthase (iNOS), which increases both mucosal and plasma nitric oxide (NO) levels. Increased fractional exhaled nitric oxide (FeNO) levels have been described in patients with IBD. Currently, hand-held FeNO measurement devices are available, enabling a fast in-office analysis of this non-invasive disease activity marker. In this pilot study, we investigated the utility of in-office FENO measurements in patients with Crohn's disease (CD). METHODS: Fifty CD patients and 25 healthy controls (HC) were included, all of whom were free of atopic or pulmonary disorders and respiratory symptoms at the time of inclusion. The Crohn's disease activity index (CDAI) was calculated, and the inflammatory parameters and fecal calprotectin levels were assessed. FeNO was measured with a hand-held device. RESULTS: A significant increase in FeNO (median, [interquartile range]) was observed in steroid-free CD patients with clinically active disease (CDAI>150; 22 [8] ppb) compared with CD patients in clinical remission (CDAI<150; 11 [6] ppb; P<0.001) and HC's (17 [9] ppb; P<0.05). Active CD patients treated with corticosteroids had significantly lower FeNO compared with active CD patients without steroids (12 [10] ppb vs 25 [19] ppb; P<0.05). FeNO displayed a strong correlation with the CDAI (R=0.68; P<0.001). Fair correlations were found between FeNO and several systemic inflammatory markers, but no significant correlation was found with fecal calprotectin. CONCLUSION: This pilot study suggests that hand-held FeNO measurements could be an attractive non-invasive indicator of systemic inflammation in Crohn's disease.

Longitudinal quantification of inflammation in the murine dextran sodium sulfate-induced colitis model using µPET/CT.

BACKGROUND: This study investigates whether deoxy-2-[18F]fluoro-d-glucose (FDG) micro-positron emission tomography (µPET)/computed tomography (CT) can serve as a tool for monitoring of the commonly used dextran sodium sulfate (DSS)-induced murine model of inflammatory bowel disease (IBD). METHODS: DSS-colitis was induced in Sv129 mice. In a first experiment, four animals were serially scanned with CT and FDG-µPET on days 0, 3, 7, 11, and 14. The ratio of the mean voxel count of the PET images in the colon and the brain was compared with the histological inflammation score and the colonic myeloperoxidase levels. A second experiment was performed to investigate whether FDG-µPET was able to detect differences in inflammation between two DSS-treated groups, one receiving placebo (n = 4) and one receiving dimethyloxalylglycine (DMOG) (n = 4), a compound that protects against DSS-induced colitis. RESULTS: The progression of the colonic/brain FDG-signal ratio (over days 0-14) agreed with the predicted histological inflammation score, obtained from a parallel DSS-experiment. Moreover, the quantification of normalized colonic FDG-activity at the final timepoint (day 14) showed an excellent correlation with both the MPO levels (Spearman's rho = 1) and the histological inflammation score (Spearman's rho = 0.949) of the scanned mice. The protective action of DMOG in DSS colitis was clearly demonstrated with FDG-µPET/CT (normalized colonic FDG-activity DMOG versus placebo: P < 0.05). CONCLUSIONS: FDG-µPET-CT is a feasible and reliable noninvasive method to monitor murine DSS-induced colitis. The implementation of this technique in this widely used IBD model opens a new window for pathophysiological research and high-throughput screening of potential therapeutic compounds in preclinical IBD research.

Subclinical gut inflammation in spondyloarthritis is associated with a pro-angiogenic intestinal mucosal phenotype.

BACKGROUND: Vascular endothelial growth factor (VEGF-A) and placental growth factor (PlGF) are major regulators of pathological angiogenesis, which is a prominent feature of both Crohn's disease (CD) and peripheral synovitis in spondyloarthritis. OBJECTIVE: To investigate the presence of VEGF-A and PlGF in the gut of spondyloarthritis patients and to link this finding with subclinical gut inflammation in these patients. METHODS: Intestinal biopsies from healthy controls, CD patients, spondyloarthritis patients with or without subclinical gut inflammation and rheumatoid arthritis (RA) patients were stained for VEGF-A, PlGF, CD31 and vascular cell adhesion molecule 1 (VCAM-1) and digitally analysed. RESULTS: Spondyloarthritis patients with subclinical gut inflammation had markedly increased intestinal VEGF-A expression (p<0.001), mucosal vascularisation (p<0.001) and VCAM-1 expression (p<0.01) compared with healthy controls and RA patients, which, unlike in CD patients, was also seen when the gut inflammation was in a quiescent state. PlGF expression was highly increased in the subclinically inflamed gut of spondyloarthritis (p<0.01 compared with healthy controls), but not at all in CD. CONCLUSION: A pro-angiogenic intestinal phenotype is observed in spondyloarthritis patients with quiescent chronic gut inflammation. This favours an environment for enhanced trafficking of immune cells in this subpopulation.

Novel development in extraintestinal manifestations and spondylarthropathy.

The important co-existence of spondylarthritis (SpA) and inflammatory bowel disease (IBD) within the same individual suggests common etiopathogenic mechanisms. This is supported by intriguing similarities between both diseases at the subclinical and molecular level. The recent advances in IBD genetics have led to the identification of common pathways involved in both IBD and SpA, including bacterial recognition and ER stress. This offers the opportunity to develop potential new therapeutic strategies for both diseases. Transgenic animals which develop both joint and gut inflammation (like the TNF(ΔARE) mice and the HLA-B27 transgenic rats) are a very useful tool to test such novel therapeutics and to get further mechanistic insight into the pathogenetic link between SpA and IBD. This review will focus on the recent scientific progress in our understanding of the link between SpA and IBD. Based on this, potential novel therapeutic strategies are discussed.

Impact of reimbursement policy in Belgium on the referral pattern and diagnostic yield of capsule endoscopy. A single-centre study.

INTRODUCTION: Since the first of July 2008, capsule endoscopy (CE) is partially reimbursed for patients with obscure gastrointestinal bleeding (OGIB). OBJECTIVE: To evaluate the impact of reimbursement of CE on the referral pattern and the diagnostic yield of CE. METHODS: We retrospectively selected data from patients who underwent a CE in the University Hospital of Ghent between July 2002 and June 2009. Following data were analysed: number of CEs, indication, number of transfusion-dependent patients, haemoglobin level and relevance of the CE findings. RESULTS: There was an increase in the number of patients referred for CE after the first of July 2008. Simultaneously, the number of relevant findings was decreasing. Between July 2002 and June 2003, 66.7% of the capsule endoscopies showed relevant bowel lesions. Over the last 2 years, the diagnostic yield has been decreasing to 40.5% in the period July 2007-June 2008 and only 30.2% in the period July 2008-June 2009. Transfusion need and haemoglobin level at the moment of CE had a significant influence on the diagnostic yield (P < 0.001 for both parameters). CONCLUSIONS: The number of patients referred for CE has risen since the reimbursement of CE. However, there is a trend towards referral of less severe bleeders, with less transfusion need and a higher haemoglobin level. This significantly lowers the diagnostic yield of CE.

Prevalence of high risk human papillomavirus types among Nicaraguan women with histological proved pre-neoplastic and neoplastic lesions of the cervix.

OBJECTIVES: To determine the prevalence of high risk human papillomavirus (HPV) types in Nicaraguan women with histological proved pre-neoplastic and neoplastic cervical lesions, and to assess its potential impact on preventive strategies. METHODS: 206 women with histopathological confirmed cervical lesions (CIN I or worse) were screened for HPV DNA on a liquid based cytology sample, using an HPV short fragment polymerase chain reaction based assay. HPV positive samples were genotyped with a reverse hybridisation line probe assay (Lipa). HPV negative samples were re-analysed using type specific real time polymerase chain reaction. RESULTS: Of all lesions CIN II or worse, 12% tested negative. Prevalence of high risk HPV increased from 48.1% in cervical intraepithelial neoplasia I (CIN I) to 94.7% in invasive squamous cervical carcinoma (SCC). The most prevalent high risk HPV types were, in order of prevalence rate, HPV 16, 58, 31 and 52. HPV 16 and/or HPV 31 were present in 63.2% of SCC cases. CONCLUSION: Targeting HPV 16 and 31 with prophylactic vaccines could possibly have an important impact on the incidence of invasive cervical carcinoma in Nicaragua. Further research is needed to define the oncogenic potential of other high prevalent HPV genotypes. Meanwhile, primary prevention and cervical cancer screening programmes should be optimised.

Immune-mediated pathology following hepatitis B vaccination. Two cases of polyarteritis nodosa and one case of pityriasis rosea-like drug eruption.

The association of hepatitis B virus infection and vasculitis or other immune-mediated manifestations is well documented. Reports on such manifestations in relation to hepatitis B vaccination are scarce, however. We report 2 patients who developed polyarteritis nodosa following vaccination against hepatitis B. In one patient this resulted in an ischemic and necrotic digital ulcus, necessitating surgical amputation. The other patient presented with typical cutaneous polyarteritis nodosa which responded well to corticosteroid treatment. A third patient developed a severe pityrias rosea-like eruption. He was treated with topical steroids with healing of the lesions, leaving only post-inflammatory hyperpigmentation. The literature on these associations is reviewed.

Long-term outcomes in the treatment of toenail onychomycosis.

Most clinical studies in subjects with toenail onychomycosis end with a final assessment at 48-52 weeks. This fails to take full account of the physiology of toenail growth, as toenails can take up to 12-18 months to grow out fully. Accurate assessment of long-term outcomes therefore requires follow-up of at least 2 years after completion of the study. We have evaluated long-term outcomes of treatment in the patients whom we contributed to two multicentre studies of oral therapy for toenail onychomycosis caused by dermatophyte infection. In the first, a dose-finding study for terbinafine (Lamisil), the high rates of mycological and clinical cure achieved by terbinafine at week 48 were maintained more than 2 years after completion of the study. In the second, a comparative study between terbinafine and itraconazole (Sporanox), the excellent mycological and clinical cure rates achieved by terbinafine at week 48 were again maintained more than 2 years after completion of the study. By contrast, the failure and relapse rates seen with itraconazole were much higher. Other studies undertaken in recent years have confirmed these positive findings with respect to terbinafine, and have demonstrated its superiority over itraconazole in maintaining mycological and clinical cure over long periods. These long-term benefits of terbinafine probably relate to its primarily fungicidal action against dermatophytes, compared to the fungistatic action of itraconazole and other triazole agents. Future clinical studies should therefore incorporate at least 2 years' follow-up.

Carbamazepine hypersensitivity syndrome: report of 4 cases and review of the literature.

We report 4 patients who developed a severe systemic hypersensitivity reaction when taking carbamazepine, To prove hypersensitivity to carbamazepine, we performed patch tests and in vitro lymphocyte transformation tests. Patch tests were uniformly and strongly positive in patients and negative in controls. Lymphocyte transformation tests were positive in 3 of 4 patients. We reviewed the literature on reports of carbamazepine-induced pseudolymphoma and other severe systemic hypersensitivity reactions. Considering the many common clinical, biochemical, and pathologic characteristics, we propose to group these reactions under the term "carbamazepine hypersensitivity syndrome." The syndrome is characterized by the development of fever, rash, and lymphadenopathy between 1 week and 3 months after the introduction of carbamazepine. A variety of other target organs may be involved, including the liver, kidneys, and lungs. The carbamazepine hypersensitivity syndrome is a clinical diagnosis. Patch tests and lymphocyte transformation tests are valuable tools to confirm the diagnosis, but are reliable only after all signs subside. Similar syndromes have been described with the other aromatic anticonvulsants (phenytoin, the other hydantoins, and phenobarbital), and there is evidence of a cross-reaction between carbamazepine and phenytoin. It is unknown whether the carbamazepine hypersensitivity syndrome should be considered a premalignant state, with an increased risk for the development of malignant lymphoma.