Inflammatory bowel disease: towards a personalized medicine

The management of inflammatory bowel disease (IBD) has been transformed over the last two decades by the arrival of tumor necrosis factor (TNF) antagonist agents. Recently, alternative drugs have been approved, directed at leukocyte-trafficking molecules (vedolizumab) or other inflammatory cytokines (ustekinumab). New therapeutics are currently being developed in IBD and represent promising targets as they involve other mechanisms of action (JAK molecules, Smad 7 antisense oligonucleotide etc.). Beyond TNF antagonist agents, these alternative drugs are needed for early-stage treatment of patients with aggressive IBD or when the disease is resistant to conventional therapy. Personalized medicine involves the determination of patients with a high risk of progression and complications, and better characterization of patients who may respond preferentially to specific therapies. Indeed, more and more studies aim to identify factors predictive of drug response (corresponding to a specific signaling pathway) that could better manage treatment for patients with IBD. Once treatment has started, disease monitoring is essential and remote patient care could in some circumstances be an attractive option. Telemedicine improves medical adherence and quality of life, and has a positive impact on health outcomes of patients with IBD. This review discusses the current application of personalized medicine to the management of patients with IBD and the advantages and limits of telemedicine in IBD

The PERFUSE study: The experience of patients receiving Adalimumab biosimilar SB5

International audienceBackgroundSB5 is an EMA-approved adalimumab biosimilar, having demonstrated bioequivalence, equivalent efficacy, and similar safety and immunogenicity to the reference product.AimsDescribe patient training and satisfaction using patient-reported outcome measures (PROMs) and assess their impact on 12-month persistence on SB5.MethodsThe observational PERFUSE study included 318 Crohn's disease (CD) patients and 88 ulcerative colitis (UC) patients in 27 sites across France between October 2018 and December 2020. PROMs were collected at 1-month post-baseline using an online questionnaire (ePRO) designed with patient associations. Treatment persistence was collected during routine visits (up to 15 months post-initiation). Results are presented by prior experience with subcutaneous biologics and training in proper use of the injection device.Results57.1% (n = 145) and 44.1% (n = 67) of naïve and pre-treated patients, respectively, answered the ePRO. Naïve patients were offered training more often (86.9% vs 31.3% respectively, p < 0.05), with disparities between sites. All subgroups’ satisfaction scores were high. 12-month persistence on SB5 was significantly higher for respondents than for non-respondents (68.0% [60.9; 74.1] vs 52.3% [44.5; 59.6]; p < 0.05) and in patients with a better perception of their illness (OR=1.02, [1.0; 1.05]; p < 0.05).ConclusionsEarly patient questionnaires may be useful to identify patients at higher risk of treatment discontinuation

Efficacy of ustekinumab, vedolizumab, or a second anti-TNF agent after the failure of a first anti-TNF agent in patients with Crohn’s disease: a multicentre retrospective study

International audienceAbstract Background No study has performed a face-to-face comparison of biologics after the failure of the first anti-TNF agent in patients with Crohn’s disease (CD). The aim of the study was to compare the efficacy of biologics in this setting. Methods Patients with CD who were refractory to a first anti-TNF agent, and treated with ustekinumab (UST), vedolizumab (VDZ), or a second anti-TNF drug as a second-line biological agent at 10 French tertiary centres from 2013 to 2019 were retrospectively included in this study. Results Among the 203 patients included, 90 (44%) received UST, 42 (21%) received VDZ and 71 (35%) received a second anti-TNF agent. The first anti-TNF agent was discontinued due to a primary nonresponse in 42 (21%) patients. At weeks 14–24, the rates of steroid-free remission were similar between the UST, VDZ and second anti-TNF groups (29%, 38% and 44%, respectively, p = 0.15). With a mean follow-up of 118 weeks, drug survival was shorter for patients who received ustekinumab treatment ( p = 0.001). In the case of trough level less than 5 µg/ml, patients treated with a second anti-TNF agent had a higher postinduction remission rate ( p = 0.002), and drug survival ( p = 0.0005). No other relevant factors were associated with treatment efficacy, including trough levels greater than 5 µg/ml. Conclusions VDZ, UST and a second anti-TNF agent exhibit similar efficacy in the short term, as second-biological line treatment in patients with CD who are refractory to a first anti-TNF agent, but shorter drug maintenance is observed for patients treated with UST

Interleukin-15 and Its Soluble Receptor Mediate the Response to Infliximab in Patients With Crohn's Disease

International audienceBACKGROUND & AIMS: Infliximab is a monoclonal antibody against tumor necrosis factor that is used to treat patients with inflammatory bowel disease. We investigated serum levels and cellular expression of inter-leukin (IL)-15 and its receptor (sIL-15Ra) in patients with Crohn's disease (CD) treated with infliximab; and the effect on sIL-15Ra secretion by epithelial cells. METHODS: CD patients were given infliximab (n = 40; 3 infusions); 37 healthy controls were studied. Serum levels of IL-15, sIL-15Ra, and complex were determined by radioimmunoassay and cytokine levels by enzyme-linked immunosorbent assay. IL-15Ra and A Desintegrin and Metalloproteinase 17 levels were assessed by immunohis-tochemistry. Epithelial cell lines (HT-29 and Caco-2) were cultured with infliximab, adalimumab, or etanercept. Patients were classified as responders and nonresponders according to their Crohn's Disease Activity Index and clinical observations. RESULTS: Before infliximab, IL-15 was higher in responders than in controls and nonre-sponders. After infliximab, IL-15 decreased in responders while remaining stable in nonresponders. sIL-15Ra and IL-15/sIL-15Ra complex levels were higher in CD than in controls and increased only in responders after inflix-imab. IL-15Ra and A Desintegrin and Metalloproteinase 17 colocalized in epithelial cells and were higher in CD patients. In vitro, infliximab but not adalimumab and etanercept induced sIL-15Ra secretion by epithelial cells. CONCLUSIONS: Serum level of sIL-15Ra and the IL-15/sIL-15Ra complex increased in responder patients and the response was associated with a decrease of IL-15. Infliximab induced the release of the IL-15 receptor alpha, suggesting a specific modulation of IL-15 and its soluble receptor by reverse signaling through transmembrane tumor necrosis factor alpha

Correction: Efficacy of ustekinumab, vedolizumab, or a second anti-TNF agent after the failure of a first anti-TNF agent in patients with Crohn’s disease: a multicentre retrospective study

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Characterisation of early mucosal and neuronal lesions following Shigella flexneri infection in human colon.

BACKGROUND: Shigella, an enteroinvasive bacteria induces a major inflammatory response responsible for acute rectocolitis in humans. However, early effect of Shigella flexneri (S. flexneri) infection upon the human mucosa and its microenvironement, in particular the enteric nervous system, remains currently unknown. Therefore, in this study, we sought to characterize ex vivo the early events of shigellosis in a model of human colonic explants. In particular, we aimed at identifying factors produced by S. flexneri and responsible for the lesions of the barrier. We also aimed at determining the putative lesions of the enteric nervous system induced by S. flexneri. METHODOLOGY/PRINCIPAL FINDINGS: We first showed that, following 3 h of infection, the invasive but not the non-invasive strain of S. flexneri induced significant desquamation of the intestinal epithelial barrier and a reduction of epithelial height. These changes were significantly reduced following infection with SepA deficient S. flexneri strains. Secondly, S. flexneri induced rapid neuronal morphological alterations suggestive of cell death in enteric submucosal neurones. These alterations were associated with a significant increase in the proportion of vasoactive intestinal peptide (VIP) immunoreactive (IR) neurons but not in total VIP levels. The NMDA receptor antagonist MK-801 blocked neuronal morphological changes induced by S. flexneri, but not the increase in the proportion of VIP-IR. CONCLUSIONS/SIGNIFICANCE: This human explant model can be used to gain better insight into the early pathogenic events following S. flexneri infection and the mechanisms involved