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Abstract: The first ECCO pathogenesis workshop focused on anti-TNF therapy failures in inflammatory bowel diseases (IBDs). The overall objective was to better understand and explore primary non response and loss of response to anti-TNF agents in IBD. The outcome of this workshop is presented into two parts. This first section addresses definitions, frequency and pharmacological aspects of anti-TNF therapy failure, including pharmacokinetics of anti-TNF monoclonal antibodies and immune and non-immune mediated clearance of anti-TNF mAbs. The second section concerns the biological roles of TNF and TNF antagonists, including mechanisms of action of anti-TNF agents, and discuss hypothesis regarding their failures and phenomenon of paradoxical inflammation, including the potential role of TNF independent inflammatory pathways. [ABSTRACT FROM AUTHOR]

Summary: Background: The long‐term outcome of patients with acute severe ulcerative colitis (ASUC) responding to intravenous steroids (IVS) has been poorly reported. Aims: To assess relapse‐free survival in patients with ASUC responding to IVS. Methods: Between January 2006 and December 2017, 142 consecutive patients with ASUC (according to modified Truelove‐and‐Witts criteria) responding to IVS were included in this multicentre retrospective study. Relapse was defined by a partial Mayo Clinic score >4 and/or the need for another maintenance therapy. Results: Among the 142 included patients (100 naïve of immunomodulator and/or biological agent) hospitalised for ASUC, 59 (41.5%) were treated at discharge with 5‐aminosalicylic acid, 60 (42%) with immunomodulators, 18 (13%) with anti‐tumour necrosis factor (TNF) agents and 5 (3.5%) with vedolizumab. After a median follow‐up of 4.8 (2.6‐7.3) years, 90 (63.4%) had relapsed and 12 (8.5%) had required colectomy. The probabilities of relapse‐free survival were 58%, 48% and 40% at 1, 2 and 5 years respectively. The multivariate analysis demonstrated that patients with <6 liquid stools per day at day 3 (hazard ratio 0.56, 95%CI [0.34‐0.91]), a partial Mayo Clinic score <2 at day 5 (0.41 [0.21‐0.80]) and anti‐TNF maintenance therapy (0.37 [0.16‐0.87]) were less likely to relapse. The probabilities of colectomy‐free survival were 96%, 95% and 91% at 1, 2 and 5 years respectively. Conclusion: Despite a high relapse rate, patients with ASUC responding to IVS had a low rate of colectomy after 5 years of follow‐up. Early response to IVS and maintenance therapy with biological agents were associated with a lower rate of relapse. [ABSTRACT FROM AUTHOR]

The author discusses the impact of the tumour necrosis factor on immune cells with respect to inducing the T-cell apoptosis and the inhibition of the T-cell function. The treatment of the therapeutic arsenal of the inflammatory bowel diseases can be achieved from the reaction of the immunosuppressants with the monoclonal antibodies of the anti-tumour necrosis factor. Information on the improvement of treatment efficiency through the use of immunosuppressants is also presented.

INTRODUCTION: New therapeutic options for patients with Crohn's disease (CD) with perianal lesions failing anti-tumor necrosis factor (TNF) agents are needed. We aimed to assess the effectiveness of ustekinumab in perianal CD (pCD) and predictors of clinical success in a real-life multicenter cohort. METHODS: We conducted a national multicenter retrospective cohort study in patients with either active or inactive pCD who received ustekinumab. In patients with active pCD at treatment initiation, the success of ustekinumab was defined by clinical success at 6 months assessed by the physician's judgment without additional medical or surgical treatment for pCD. Univariate and multivariable logistic regression analyses were performed to identify predictors of success. In patients with inactive pCD at ustekinumab initiation, the pCD recurrencefree survival was calculated using the Kaplan-Meier method. RESULTS: Two hundred seven patients were included, the mean age was 37.7 years, the mean duration of CD was 14.3 years, andthemean number ofpriorperianal surgerieswas 2.8.Two hundred five (99%) patients had previously been exposed to at least 1 anti-TNF and 58 (28%) to vedolizumab. The median follow-up time was 48 weeks; 56/207 (27%) patients discontinued therapy after a median time of 43 weeks. In patients with active pCD, successwas reached in 57/148 (38.5%) patients. Among patientswith setons at initiation, 29/88 (33%) had a successful removal. The absence of optimizationwas associatedwith treatment success (P50.044, odds ratio 2.74; 95% confidence interval: 0.96-7.82). In multivariable analysis, the number of prior anti-TNF agents (3) was borderline significant (P 5 0.056, odds ratio 0.4; 95%confidence interval: 0.15-1.08). In patients with inactive pCD at initiation, the probability of recurrence-free survival was 86.2% and 75.1% at weeks 26 and 52, respectively. DISCUSSION: Ustekinumab appears as a potential effective therapeutic option in perianal refractory CD. Further prospective studies are warranted. [ABSTRACT FROM AUTHOR]

Objectives Vedolizumab (VDZ) blocks α4β7 integrin and is licenced for the treatment of IBD. It has been associated with mild SpA-related features, including sacroiliitis and synovitis. Herein we report a series of cases demonstrating the emergence of severe SpA-associated enthesitis/osteitis following successful IBD therapy with VDZ. Methods We evaluated 11 VDZ-treated patients with IBD across seven centres who developed severe active SpA and/or enthesopathy, with the aim of characterizing the VDZ-associated SpA or entheseal flares. Imaging features demonstrating particularly severe disease were recorded. Results De novo SpA developed in 9 of 11 patients and flare of known SpA in 2 patients, with 4 patients requiring hospitalization due to disease severity. Available data showed that one of seven cases were HLA-B27 positive. The median time from VDZ initiation to flare was 12 weeks, with IBD well controlled in 7 of 10 patients (no data for 1 patient) at flare. Severe SpA enthesitis/osteitis was evident on MRI or US, including acute sacroiliitis (n = 5), extensive vertebral osteitis (n = 1), peri-facetal oedema (n = 1) and isolated peripheral enthesitis (n = 3). Due to arthritis severity, VDZ was discontinued in 9 of 11 patients and a change in therapy, including alternative anti-TNF, was initiated. Conclusion Severe SpA, predominantly HLA-B27 negative, with osteitis/enthesitis may occur under successful VDZ treatment for IBD, including in subjects with prior anti-TNF therapy for intestinal disease. [ABSTRACT FROM AUTHOR]

Abstract: Reports of autoimmune diseases, including psoriasis- and dermatitis-like skin reactions with anti-tumor necrosis factor-α (TNF-α), are increasing, likely a reflection of the growing use of these agents. This paradoxical phenomenon can no longer be considered rare, with some studies providing incidence estimates of greater than 10%. This paradoxical inflammation has been reported in patients receiving treatment with anti-TNF-α agents for a variety of inflammatory conditions, including inflammatory bowel disease, psoriasis and rheumatoid arthritis and appears to be a class effect. Moreover, there have recently been reports of autoimmune arthralgia occurring in patients receiving anti-TNF-α agents. Further studies are necessary to determine the true incidence of this phenomenon and to identify those patients most likely to be at risk. [Copyright &y& Elsevier]

Abstract: This second section of the first ECCO pathogenesis workshop on anti-TNF therapy failures in inflammatory bowel diseases addresses the biological roles of TNFα and the effects and mechanisms of action of TNFα antagonists. Mechanisms underlying their failure, including induction of TNF-independent inflammatory pathways and phenomena of paradoxical inflammation are discussed. [ABSTRACT FROM AUTHOR]