Bram Verstockt

A Matrix-based Model Predicts Primary Response to Infliximab in Crohn's Disease

BACKGROUND Prediction of primary non-response [PNR] to anti-tumour necrosis factors [TNFs] in inflammatory bowel disease [IBD] is direly needed to select the optimal therapeutic class for a given patient. We developed a matrix-based prediction tool to predict response to infliximab [IFX] in Crohns disease [CD] patients. METHODS This retrospective single-centre study included 201 anti-TNF naïve CD patients who started with IFX induction therapy. PNR occurred in 16 [8%] patients. Clinical, biological [including serum TNF and the IBD serology 6 panel and genetic [the 163 validated IBD risk loci] markers were collected before start. Based on the best fitted regression model, probabilities of primary response to IFX were calculated and arranged in a prediction matrix tool. RESULTS Multiple logistic regression withheld three final independent predictors [p < 0.05] for PNR: age at first IFX, {odds ratio (OR) (95% confidence interval [CI] of 1.1 (1.0-1.1)}, body mass index [BMI] (0.86 [0.7-1.0]), and previous surgery (4.4 [1.2-16.5]). The accuracy of this prediction model did not improve when the genetic markers were added (area under the curve [AUC] from 0.80 [0.67-0.93] to 0.78 [0.65-0.91]). The predicted probabilities for PNR to IFX increased from 1% to 53% depending on the combination of final predictors. CONCLUSIONS Readily available clinical factors [age at first IFX, BMI, and previous surgery] outperform serological and IBD risk loci in prediction of primary response to infliximab in this real-life cohort of CD patients. This matrix tool could be useful for guiding physicians and may avoid unnecessary or inappropriate exposure to IFX in IBD patients unlikely to benefit.

A safety assessment of biological therapies targeting the IL-23/IL-17 axis in inflammatory bowel diseases

ABSTRACT Introduction: Many different compounds targeting the interleukin 23/17 axis have been developed and successfully studied in several autoimmune diseases, including inflammatory bowel diseases. Nevertheless, interfering with key immunological pathways raises potential safety concerns. This review focuses on the safety profile of these novel biological therapies. Areas covered: A literature search until March 2017 was performed to collect safety data on different compounds targeting this pathway, with emphasis on ustekinumab and secukinumab. Firstly, the authors discuss briefly how genetics can inform about potential safety issues. Secondly, they extensively describe safety issues (common adverse events, infections, malignancies…), immunogenicity, exposure to ustekinumab in specific populations and provide advice for vaccination. Finally, they address safety profiles of secukinumab and other biological targeting the IL-23/17 axis in IBD. Expert opinion: Current evidence suggests that ustekinumab therapy overweigh the potential drug-related risks. Additional safety data beyond randomized-controlled trials, derived from statistically powered, large prospective studies with long-term follow-up are urgently needed to assess the real-life ustekinumab-related risks and to establish the correct position of these novel class of biologicals in IBD treatment. Combining immunomodulators with ustekinumab seems to be safe, though prospective data specifically addressing this topic are currently missing. Similarly, the combination of different biological therapies still has to be studied.

Postoperative Outcomes in Ustekinumab-Treated Patients Undergoing Abdominal Operations for Crohn’s Disease

Background Ustekinumab, a monoclonal antibody targeting interleukins-12 and -23 is used to treat adults with Crohns disease [CD]. We determined the 30-day postoperative infectious complication rate among CD patients who received ustekinumab within the 12 weeks prior to an abdominal operation as compared with patients who received anti-tumor necrosis factor [TNF] agents. Methods A retrospective chart review of adults with CD who underwent an abdominal operation between January 1, 2015 and May 1, 2017 was performed across six sites. Surgical site infection [SSI] was defined as superficial skin and soft tissue infection, intra-abdominal abscess, anastomotic leak, and mucocutaneous separation of the stoma. Results Forty-four patients received ustekinumab and 169 patients received anti-TNF therapy within the 12 weeks prior to surgery. The two groups were similar, except anti-TNF patients were more likely to have received combination therapy with an immunomodulator [P = 0.006]. There were no significant differences in postoperative SSI [13% in ustekinumab versus 20% in anti TNF-treated patients, p = 0.61] or hospital readmission rates [18% versus 10%, respectively, p = 0.14], but ustekinumab-treated patients had a higher rate of return to the operating room [16% versus 5%; P = 0.01]. There were no significant predictors identified on multivariable analysis. Conclusions Of the 44 patients with CD who received ustekinumab within the 12 weeks prior to a major abdominal operation, 13% experienced a 30-day postoperative SSI, not statistically different from the 20% found in the anti-TNF cohort. Ustekinumab treatment within 12 weeks of surgery does not appear to increase the risk of postoperative SSI above that of CD patients treated with anti-TNF medications.

When IBD is not IBD

Abstract Entamoeba histolytica colitis can mimic Crohn’s disease. However, a fulminant infection can be life-threatening, especially after exposure to systemic steroids. We present a case of the patient who was initially diagnosed with ileocolonic Crohn’s disease, but developed a hepatic E histolytica abscess while undergoing anti-TNF therapy. After revision of the initial diagnostic biopsies, the diagnosis was questioned and E histolytica was confirmed using PCR and histopathology. As intestinal amoebiasis is the most common form of amoebic infection, care should be taken in case of refractory IBD or at initial diagnosis in patients who travelled to endemic areas. We therefore discuss the epidemiology, clinical features, diagnostic tools and pathophysiology of E Histolytica in order to raise awareness among gastroenterologists treating patients with inflammatory bowel disease.

Genetic Influences on the Development of Fibrosis in Inflammatory Bowel Disease

Intestinal fibrosis is a common complication in inflammatory bowel disease. These fibrotic processes develop in genetically susceptible individuals, influenced by an interplay with environmental, immunological and disease-related factors. A deeper understanding of the genetic factors driving fibrogenesis might help to unravel the pathogenesis, and ultimately lead to development of new, anti-fibrotic therapies. Here we review the genetic factors that have been associated with the development of fibrosis in patients with both Crohn’s disease and ulcerative colitis, as well as their potential pathophysiological mechanism(s).

ECCO-ESGAR Guideline for Diagnostic Assessment in IBD Part 1: Initial diagnosis, monitoring of known IBD, detections of complications

Christian Maaser,a Andreas Sturm,b Stephan R. Vavricka,c Torsten Kucharzik,d Gionata Fiorino,e Vito Annese,f Emma Calabrese,g Daniel C. Baumgart,h Dominik Bettenworth,i Paula Borralho Nunes,j, Johan Burisch,k, Fabiana Castiglione,l Rami Eliakim,m Pierre Ellul,n Yago González-Lama,o Hannah Gordon,p Steve Halligan,q Konstantinos Katsanos,r Uri Kopylov,m Paulo G. Kotze,s Eduards Krustiņš,t Andrea Laghi,u Jimmy K. Limdi,v Florian Rieder,w Jordi Rimola,x Stuart A. Taylor,y Damian Tolan,z Patrick van Rheenen,aa Bram Verstockt,bb, Jaap Stokercc; on behalf of the European Crohn’s and Colitis Organisation [ECCO] and the European Society of Gastrointestinal and Abdominal Radiology [ESGAR]

GlycA, a nuclear magnetic resonance spectroscopy measure for protein glycosylation, is a viable biomarker for disease activity in IBD

Abstract Background and Aims Glycoprotein acetylation [GlycA] is a novel nuclear magnetic resonance [NMR] biomarker, measured in serum or plasma, that summarizes the signals originating from glycan groups of certain acute-phase glycoproteins. This biomarker has been shown to be robustly associated with cardiovascular and short-term all-cause mortality, and with disease severity in several inflammatory conditions. We investigated GlycA levels in a cohort of healthy individuals [HCs], patients with Crohn’s disease [CD] and patients with ulcerative colitis [UC] prior to and after therapeutic control of inflammation. Methods Serum samples of 10 HCs, 37 CD patients and 21 UC patients before and after biologic therapy were subjected to high-throughput NMR analysis by Nightingale Health Ltd. Paired C-reactive protein [CRP] and fecal calprotectin [fCal] measurements were used to characterize baseline differences, treatment effects and post-treatment association with endoscopic response [50% SES-CD decrease at Week 24] and mucosal healing [SES-CD ≤ 2 for CD, Mayo endoscopic score ≤ 1 for UC]. Results GlycA levels were significantly higher in patients with active inflammamtory bowel disease [IBD] compared with those in healthy controls, and accurately reflected the mucosal recovery to a ‘healthy’ state in both CD and UC patients achieving mucosal healing. In CD patients who experienced an endoscopic response without achieving full mucosal healing, GlycA levels also decreased but did not normalize to HC levels. Overall, GlycA correlated well with CRP and fCal, and accurately tracked disease activity in CRP-negative patients [<5 mg/dL]. Conclusion GlycA holds promise as a viable serological biomarker for disease activity in IBD, even in patients without elevated CRP, and should therefore be tested in large prospective cohorts.

Effectiveness and Safety of Vedolizumab in Anti-TNF-Naïve Patients With Inflammatory Bowel Disease—A Multicenter Retrospective European Study

Background Vedolizumab (VDZ) is effective for treatment of ulcerative colitis (UC) and Crohns disease (CD). In GEMINI trials, anti-tumor necrosis factor (anti-TNF)-naïve patients had a superior response compared with anti-TNF-exposed patients. In real-world experience (RWE), the number of included anti-TNF-naïve patients was low. We aimed to evaluate the effectiveness and safety of VDZ in anti-TNF-naïve patients in an RWE setting. Methods This retrospective multicenter European pooled cohort study included consecutive active anti-TNF-naïve IBD patients treated with VDZ. The primary end point was clinical response at week 14. Patients with follow-up beyond week 14 and those discontinuing VDZ at any time were included for maintenance outcomes analysis. Results Since January 2015, 184 anti-TNF-naïve patients from 23 centers initiated VDZ treatment (Crohns disease [CD], 50; ulcerative colitis [UC], 134). In CD, 42/50 (82%) patients responded by week 14 and 32 (64%) were in clinical remission; 26/50 (52%) achieved corticosteroid-free remission (CSFR). At last follow-up (44 weeks; interquartile range [IQR], 30-52 weeks), 27/35 (77.1%) patients with available data responded to treatment; 24/35 (68.6%) were in clinical remission, 21/35 (60%) were in CSFR. For UC, 116/134 (79.1%) responded to treatment by week 14, including 53 (39.5%) in clinical remission; 49/134 (36.6%) achieved CSFR. At last follow-up (42.5 weeks; IQR, 30-52 weeks), 79/103 (76.7%) patients responded to treatment, 69/103 (67.0%) were in remission, and 61/103 (59.2%) were in CSFR. Adverse effects were reported in 20 (11%) of the patients, leading to treatment discontinuation in 6 (3.3%). Conclusions VDZ is similarly effective in ant-TNF-naïve CD and UC patients. The efficacy is higher than reported in anti-TNF-experienced patients and is comparable to that of anti-TNF biologics in this population.

TREM-1, the ideal predictive biomarker for endoscopic healing in anti-TNF-treated Crohn’s disease patients?

We read with great interest the study by Gaujoux et al , who described a whole blood marker for anti-tumour necrosis factor (TNF) responsiveness in patients with Crohn’s disease (CD). The availability of anti-TNF agents dramatically changed therapeutic strategies for patients with CD. However, an overall non-response rate of 30% has been observed, and, together with the approval of new classes of biological agents with a different mode of action, clearly indicates the need for predictive biomarkers. Gaujoux et al identified triggering receptor expressed on myeloid cells 1 ( TREM1) expression in whole blood as a biomarker for anti-TNF (non)response (higher expression in responders).1 In inflamed colonic tissue, TREM1 expression is also decreased in future infliximab responders.1 2 TREM-1 is known to amplify inflammation, whereas TREM-1 inhibition in vivo attenuates colitis by modulating autophagy and endoplasmic reticulum (ER) stress.3 We first measured serum TREM-1 (sTREM-1) (Human sTREM-1 ELISA (HK348), Hycult Biotech, Uden, the Netherlands) in 85 patients with CD with active disease prior to anti-TNF therapy (table 1). To reduce the risk of including treatment failures secondary to immunogenicity (and not drug mechanistic failure) or non-drug-related healers, all included patients had to have a good drug exposure, defined as a maintenance trough level >3.0 µg/mL for infliximab or >5.0 µg/mL for adalimumab. Interestingly, patients who achieved mucosal healing (complete absence of ulcerations and erosions4) after 6 months of anti-TNF therapy (adalimumab and infliximab) had significantly lower baseline sTREM-1 levels compared with non-responders (50.8 pg/mL …

Influence of early adalimumab serum levels on immunogenicity and long-term outcome of anti-TNF naive Crohn's disease patients: the usefulness of rapid testing

Proactive testing of adalimumab serum levels is debated.