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In 1997, the first consensus guidelines for haematopoietic SCT (HSCT) in autoimmune diseases (ADs) were published, while an international coordinated clinical programme was launched. These guidelines provided broad principles for the field over the following decade and were accompanied by comprehensive data collection in the European Group for Blood and Marrow Transplantation (EBMT) AD Registry. Subsequently, retrospective analyses and prospective phase I/II studies generated evidence to support the feasibility, safety and efficacy of HSCT in several types of severe, treatment-resistant ADs, which became the basis for larger-scale phase II and III studies. In parallel, there has also been an era of immense progress in biological therapy in ADs. The aim of this document is to provide revised and updated guidelines for both the current application and future development of HSCT in ADs in relation to the benefits, risks and health economic considerations of other modern treatments. Patient safety considerations are central to guidance on patient selection and HSCT procedural aspects within appropriately experienced and Joint Accreditation Committee of International Society for Cellular Therapy and EBMT accredited centres. A need for prospective interventional and non-interventional studies, where feasible, along with systematic data reporting, in accordance with EBMT policies and procedures, is emphasized.

The ileal mucosa of Crohn disease (CD) patients is abnormally colonized by adherent-invasive E. coli (AIEC) that are able to adhere to and invade intestinal epithelial cells. Here, we show that CD-associated AIEC strains adhere to the brush border of primary ileal enterocytes isolated from CD patients but not controls without inflammatory bowel disease. AIEC adhesion is dependent on type 1 pili expression on the bacterial surface and on carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) expression on the apical surface of ileal epithelial cells. We report also that CEACAM6 acts as a receptor for AIEC adhesion and is abnormally expressed by ileal epithelial cells in CD patients. In addition, our in vitro studies show that there is increased CEACAM6 expression in cultured intestinal epithelial cells after IFN-gamma or TNF-alpha stimulation and after infection with AIEC bacteria, indicating that AIEC can promote its own colonization in CD patients.

ObjectivesPreventing postoperative recurrence after ileocolonic resection (ICR) for Crohn's disease (CD) is challenging. Defining the disturbances of the microbial composition and community structure after ICR and their link with early disease recurrence is crucial.DesignMicrobiota composition (fingerprinting and 16S rDNA sequencing) and community structure (correlation networks of bacterial species) were assessed from ileal mucosa sampled in 20 patients undergoing ICR and 6 months later during endoscopy from above (neoterminal ileum) and below (subanastomotic colon) the surgical anastomosis.ResultsICR had a dramatic effect on gut microbial ecosystem. At surgery, CD mucosa harboured a dysbiotic microbiota with high proportions of α/β Proteobacteria and Bacilli. Six months later, half of the patients had recurrent lesions at ileocolonoscopy and presented higher numbers of Lachnospiraceae. Recurrence of endoscopic lesions was associated with enrichment in Enterococcus durans while patients in remission had increased proportions of Dorea longicatena and Bacteroides plebeius. Structural differences were striking between recurrence and remission microbiota; while the microbiota of patients with CD recurrence exhibited a loose community structure, the microbiota of patients in remission displayed communities that were robustly correlated to each other. Microbiota colonising the neoterminal ileum and subanastomotic colon 6 months after ICR only differed in patients with recurrence.ConclusionsICR modifies the gut microbiome. Remission after 6 months was associated with homogenous bacterial distribution around the anastomosis. Community structure and bacterial networks highlight target species, including Faecalibacterium prausnitzii and Ruminococcus gnavus, which may allow precise modulations of the overall microbial ecosystem towards remission pattern.

BackgroundMonoclonal antibodies targeting the interleukin (IL)-23p19 subunit are effective in the treatment of psoriatic disease but have different molecular attributes that may translate to differences in clinical efficacy. Within this class, guselkumab (GUS) is a fully human IgG1 monoclonal antibody with a native Fc region, while risankizumab (RIS) is a humanised IgG1 antibody with a mutated Fc region. Binding of these therapeutic antibodies to Fcγ receptor (FcγR) I, also known as CD64, is of interest, as CD64+ IL-23-producing myeloid cells are increased within inflamed tissue of patients with psoriatic disease [1]. Furthermore, the incidence and prevalence of psoriatic arthritis increases with the severity of psoriasis [2], and joint disease activity is positively correlated with frequency of peripheral CD64+ monocytes [3].ObjectivesFunctional characteristics of the antigen-binding and Fc regions of GUS and RIS were compared.MethodsIL-23 binding affinity was evaluated in vitro using a kinetic exclusion assay (KinExA) and surface plasmon resonance. In vitro cellular potency was measured by impact on IL-23-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation in human peripheral blood mononuclear cells. Binding of GUS and RIS to FcγRs was assessed in cells transfected with individual FcγRs. Primary human “inflammatory” monocytes differentiated with granulocyte-macrophage colony-stimulating factor and interferon-γ (IFN-γ) were induced to produce IL-23 via toll-like receptor stimulation and used to assess binding of GUS and RIS to CD64 and potential capture of endogenously secreted IL-23 by flow cytometry. The potential for GUS binding to CD64 on IFN-γ primed monocytes to trigger activation was assessed using a 41-plex cytokine bead assay.ResultsGUS and RIS displayed comparable picomolar binding affinity for IL-23 and equivalent high potency for inhibiting IL-23-induced STAT3 phosphorylation. GUS showed strongest binding to CD64 compared with other FcγRs, whereas RIS had negligible binding to any FcγR. GUS, but not RIS, showed dose-dependent Fc-mediated binding to CD64 on primary human “inflammatory” monocytes. Moreover, CD64-bound GUS was able to simultaneously capture IL-23 endogenously secreted from the same cells (Figure 1). GUS binding to CD64 on monocytes did not induce cytokine production.ConclusionGUS, but not RIS, simultaneously binds CD64+ myeloid cells via its Fc region and neutralises IL-23 with high affinity and potency. Our in vitro data suggest a mechanistic benefit through enrichment of GUS within inflamed tissue of patients with psoriatic disease, where CD64+ IL-23-producing myeloid cells are increased, such that GUS potently neutralises IL-23 at its source of production. These findings may contribute to differences in clinical-therapeutic profiles between antibodies.References[1]Mehta, H. et al. J Invest Dermatol. 2021;141:1707-1718.[2]Merola, J. et al. J Am Acad Dermatol. 2022;86:748-757.[3]Matt, P. et al. Scand J Rheumatol. 2015;44:464-73.Acknowledgements:NIL.Disclosure of InterestsDennis McGonagle Consultant of: AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, and UCB, Raja Atreya Consultant of: AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Dr. Falk Pharma, Ferring, Fresenius Kabi, Galapagos, Gilead, GlaxoSmithKline, InDex Pharmaceuticals, Janssen, Kliniksa Pharmaceuticals, Merk Sharp & Dohme, Novartis, Pfizer, Roche, Samsung Bioepsis, Stelic, Sterna Biologicals, Takeda, and Tillotts, Maria Abreu Consultant of: Prometheus Bioscience, Takeda, Pfizer, Janssen, Focus Medical Communications, Boehringer Ingelheim, Gilead, Imedex, Cornerstone Health, Landos Biophama, UCB, Eli Lilly, Bristol Myers Squibb, Arena Pharmaceuticals, and Cosmo Pharmaceuticals, Grant/research support from: Prometheus Bioscience, Takeda, Pfizer, Janssen, Focus Medical Communications, Boehringer Ingelheim, Gilead, Imedex, Cornerstone Health, Landos Biophama, UCB, Eli Lilly, Bristol Myers Squibb, Arena Pharmaceuticals, and Cosmo Pharmaceuticals, James Krueger Consultant of: AbbVie, Aclaris, Allergan, Almirall, Amgen, Arena, Aristea, Asana, Aurigene, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Escalier, Galapagos, Janssen, Eli Lilly, MoonLake Immunotherapeutics, Nimbus Lackshmi, Novartis, Pfizer, Sanofi, Sienna Biopharmaceuticals, Sun Pharma, Target-Derm, UCB, Valeant, and Ventyx, Grant/research support from: AbbVie, Akros, Allergan, Amgen, Avillion, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Exicure Incyte, Innovaderm, Janssen, Kyowa Kirin, Eli Lilly, Nimbus Lackshmi, Novan, Novartis, Parexel, Pfizer, Regeneron, UCB, and Vitae Pharmaceuticals, Kilian Eyerich Consultant of: AbbVie, Almirall, Boehringer Ingelheim, Bristol Myers Squibb, Hexal, LEO Pharma, Eli Lilly, Janssen, Pfizer, Novartis, Sanofi, and UCB, Kacey Sachen Shareholder of: Johnson & Johnson, Employee of: Janssen, Carrie Greving Shareholder of: Johnson & Johnson, Employee of: Janssen, Deepa Hammaker Shareholder of: Johnson & Johnson, Employee of: Janssen, Phuc Bao Shareholder of: Johnson & Johnson, Employee of: Janssen, Eilyn Lacy Shareholder of: Johnson & Johnson, Employee of: Janssen, Indra Sarabia Shareholder of: Johnson & Johnson, Employee of: Janssen, Janise Deming Shareholder of: Johnson & Johnson, Employee of: Janssen, Merle Elloso Shareholder of: Johnson & Johnson, Employee of: Janssen, Christopher T. Ritchlin Consultant of: UCB, AbbVie, Amgen, Lilly, Pfizer, Novartis, Gilead, and Janssen, Grant/research support from: UCB, AbbVie, Amgen, Lilly, Pfizer, Novartis, Gilead, and Janssen, Iain McInnes Shareholder of: Compugen, Evelo, and Causeway Therapeutics, Consultant of: Compugen, AstraZeneca, Bristol Myers Squibb, Amgen, Eli Lilly, GlaxoSmithKline, Janssen, Novartis, Roche, UCB, AbbVie, Cabaletta, Gilead, Pfizer, and Sanofi; Board member for: National Health Service Greater Glasgow and Clyde; Trustee of: Versus Arthritis, Grant/research support from: Compugen, AstraZeneca, Bristol Myers Squibb, Amgen, Eli Lilly, GlaxoSmithKline, Janssen, Novartis, Roche, UCB, AbbVie, Cabaletta, Gilead, Pfizer, and Sanofi, Matthieu Allez Speakers bureau: AbbVie, Amgen, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Janssen, Eli Lilly, Ferring, Galapagos, Gilead, IQVIA, Novartis, Pfizer, Genentech/Roche, Takeda, and Tillotts, Consultant of: AbbVie, Amgen, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Janssen, Eli Lilly, Ferring, Galapagos, Gilead, IQVIA, Novartis, Pfizer, Genentech/Roche, Takeda, and Tillotts, Grant/research support from: Janssen, Genentech/Roche, and Takeda, Anne Fourie Shareholder of: Johnson & Johnson, Employee of: Janssen.

The mucosa‐associated lymphoid tissue (MALT) has the task of protecting the host from pathogens while maintaining the integrity of the gut. Immune responses are tightly regulated such that there is tolerance of nonpathogenic bacteria as well as dietary antigens present in the intestinal lumen. The failure to control these responses leads to a disruption in tolerance, which has been proposed as one mechanism involved in the development of inflammatory bowel disease (IBD). Different mechanisms are involved in the control of immune responses in the intestinal tract, including active suppression by regulatory T cells. Distinct subsets of regulatory T cells coexist in the intestinal mucosa, which is a fertile environment for their growth. Most of these are defined by their phenotype and/or their ability to produce regulatory cytokines such as interleukin‐10 and transforming growth factor‐β A lack of activation and/or expansion of regulatory cells could play a role in the uncontrolled inflammation seen in IBD. Regulatory T cells may be activated by cytokines, and their inductive phase may be antigen‐driven. There are limited data relating to the true surface interactions regulating the activation of these cells. Most of the CD4+ regulatory T cells (Tr1, Th3, and CD4+ CD25+) are thought to interact with dendritic cells. Subsets of regulatory T cells (such as CD8+ TrE cells) may recognize antigens presented by intestinal epithelial cells. A better understanding of the mechanisms by which these regulatory T cells are expanded and/or activated in the intestinal mucosa may provide clues as how to use them as a novel therapeutic tool in the treatment of patients with IBD.

Rescue therapy with either cyclosporine (CYS) or infliximab (IFX) is an effective option in patients with intravenous steroid-refractory attacks of ulcerative colitis (UC). In patients who fail, colectomy is usually recommended, but a second-line rescue therapy with IFX or CYS is an alternative. The aims of this study were to investigate the efficacy and tolerance of IFX and CYS as a second-line rescue therapy in steroid-refractory UC or indeterminate colitis (IC) unsuccessfully treated with CYS or IFX. This was a retrospective survey of patients seen during the period 2000-2008 in the GETAID centers. Inclusion criteria included a delay of <1 month between CYS withdrawal (when used first) and IFX, or a delay of <2 months between IFX (when used first) and CYS, and a follow-up of at least 3 months after inclusion. Time-to-colectomy, clinical response, and occurrence of serious adverse events were analyzed. A total of 86 patients (median age 34 years; 49 males; 71 UC and 15 IC) were successively treated with CYS and IFX. The median (± s.e.) follow-up time was 22.6 (7.0) months. During the study period, 49 patients failed to respond to the second-line rescue therapy and underwent a colectomy. The probability of colectomy-free survival (± s.e.) was 61.3 ± 5.3% at 3 months and 41.3 ± 5.6 % at 12 months. A case of fatal pulmonary embolism occurred at 1 day after surgery in a 45-year-old man. Also, nine infectious complications were observed during the second-line rescue therapy. In patients with intravenous steroid-refractory UC and who fail to respond to CYS or IFX, a second-line rescue therapy may be effective in carefully selected patients, avoiding colectomy within 2 months in two-thirds of them. The risk/benefit ratio should still be considered individually.

BackgroundThe Spondyloarthritides (SpA) and inflammatory bowel disease (IBD) share common aetiopathogenetic and clinical manifestations. Vedolizumab, a humanised IgG1 monoclonal antibody to α4β7 integrin, has been approved for the treatment of inflammatory bowel disease (IBD) and inhibits α4β7 integrin at the gut level. Vedolizumab therapy for IBD has been associated with mild SpA related features including sacroiliitis and synovitis. Herein, we report the emergence of severe SpA under therapy with Vedolizumab.ObjectivesWe conducted a clinical evaluation of 7 vedolizumab treated patients with IBD that developed severe active SpA and/or enthesopathy with the aim of characterising the vedolizumab associated SpA/entheseal flares.MethodsVedolizumab treated IBD patients with SpA/enthesopathy were identified across four hospitals. We identified clinical, biochemical and imaging characteristics within routine case records as part of a clinical evaluation.ResultsWe identified 6/7 subjects that developed de novo SpA/enthesopathy and 1/7 (subject 1) with a severe flare of pre-existing SpA. There were 3/7 patients hospitalised due to the severity of skeletal disease. The median time from vedolizumab initiation to flare was 10 weeks (table 1 below). Subject 4 developed new-onset SpA with severe spinal vertebral end-plate oedema (T6–12) and inflammatory Romanus lesions (L3–4) (image below). Acute sacroiliitis was identified on MRI in 3 subjects, one of which showed evidence of radiographic bilateral grade 2 sacroiliitis. In at least 4 cases the IBD disease activity was considered to be low or well controlled. Following vedolizumab discontinuation, so far 3 patients have switched to alternative biologic therapies including certolizumab pegol, golimumab, and 1 subject to sulphasalazine. cpd=cigarettes per day, MTX=methotrexate, AZA=azathioprine, OC=oral corticosteroid, Pred=prednisolone, nr=non radiographic, MRI+ve= MRI positive, XR +ve = radiograph positive, NA=not available.ConclusionsThis case series demonstrates severe vedolizumab associated SpA/enthesopathy that resulted in hospitalised cases. The severity of vedolizumab related SpA flares is relatively severe disease in comparison to the literature. We recognise that vedolizumab is efficacious in IBD, however our observations highlight the need to monitor symptoms to identify patients that develop axial or peripheral SpA several weeks from commencing vedolizumab.Disclosure of InterestNone declared

Crohn's disease (CD) is an inflammatory pathology of the mucosal intestine that results from uncontrolled immune response towards commensal microbes. Clonal expansions of T cells have been found in patients with CD suggesting an antigen-specific stimulation of pathogenic T cells. Here we show, using T-cell receptor repertoire analysis by real-time PCR, that oligoclonal expansions are found in both CD8+ and CD4+ T cells in the blood and intestinal mucosa of CD patients. The majority of CD4+ T-cell-expanded clones are CD4+NKG2D+ T cells. These clonal expansions were found in both inflamed and neighboring healthy tissue and were persisting during the course of the disease. The presence of these CD4+NKG2D+ T-cell clones at the macroscopically normal edge of the surgical resection might be predictive of inflammation relapse post surgery.

Active-comparator trials are important to inform patient and physician choice. We aimed to evaluate the efficacy and safety of monotherapy with either ustekinumab or adalimumab in biologic-naive patients with moderately to severely active Crohn's disease. We conducted a randomised, double-blind, parallel-group, active-comparator, phase 3b trial (SEAVUE) at 121 hospitals or private practices in 18 countries. We included biologic-naive patients aged 18 years or older with moderately to severely active Crohn's disease and a Crohn's Disease Activity Index (CDAI) score of 220–450, who had not responded to or were intolerant to conventional therapy (or were corticosteroid dependent) and had at least one ulcer of any size at baseline endoscopic evaluation. Eligible patients were randomly assigned (1:1; via an interactive web response system) to receive ustekinumab (approximately 6 mg/kg intravenously on day 0, then 90 mg subcutaneously once every 8 weeks) or adalimumab (160 mg on day 0, 80 mg at 2 weeks, then 40 mg once every 2 weeks, subcutaneously) through week 56. Study treatments were administered as monotherapy and without dose modifications. Patients, investigators, and study site personnel were masked to treatment group assignment. The primary endpoint was the proportion of patients who were in clinical remission (CDAI score <150) at week 52 in the intention-to-treat population (ie, all patients who were randomly assigned to a treatment group). This trial is registered with ClinicalTrials.gov, NCT03464136, and EudraCT, 2017-004209-41. Between June 28, 2018, and Dec 12, 2019, 633 patients were assessed for eligibility and 386 were enrolled and randomly assigned to receive ustekinumab (n=191) or adalimumab (n=195). 29 (15%) of 191 patients in the ustekinumab group and 46 (24%) of 195 in the adalimumab group discontinued study treatment before week 52. There was no significant difference between the ustekinumab and adalimumab groups in the occurrence of the primary endpoint; at week 52, 124 (65%) of 191 patients in the ustekinumab group versus 119 (61%) of 195 in the adalimumab group were in clinical remission (between-group difference 4%, 95% CI –6 to 14; p=0·42). Safety for both groups was consistent with previous reports. Serious infections were reported in four (2%) of 191 patients in the ustekinumab group and five (3%) of 195 in the adalimumab group. No deaths occurred through week 52 of the study. Both ustekinumab and adalimumab monotherapies were highly effective in this population of biologic-naive patients, with no difference in the primary outcome between the drugs. Janssen Scientific Affairs.

Ciclosporin and infliximab are potential rescue treatments to avoid colectomy in patients with acute severe ulcerative colitis refractory to intravenous corticosteroids. We compared the efficacy and safety of these drugs for this indication. In this parallel, open-label, randomised controlled trial, patients were aged at least 18 years, had an acute severe flare of ulcerative colitis defined by a Lichtiger score greater than 10 points, and had been given an unsuccessful course of high-dose intravenous steroids. None of the patients had previously received ciclosporin or infliximab. Between June 1, 2007, and Aug 31, 2010, patients at 27 European centres were randomly assigned (via computer-derived permutation tables; 1:1) to receive either intravenous ciclosporin (2 mg/kg per day for 1 week, followed by oral drug until day 98) or infliximab (5 mg/kg on days 0, 14, and 42). In both groups, azathioprine was started at day 7 in patients with a clinical response. Neither patients nor investigators were masked to study treatment. The primary efficacy outcome was treatment failure defined by absence of a clinical response at day 7, a relapse between day 7 and day 98, absence of steroid-free remission at day 98, a severe adverse event leading to treatment interruption, colectomy, or death. Analysis was by intention to treat. This trial is registered with EudraCT (2006-005299-42) and ClinicalTrials.gov (NCT00542152). 115 patients were randomly assigned; 58 patients were allocated to receive ciclosporin and 57 to receive infliximab. Treatment failure occurred in 35 (60%) patients given ciclosporin and 31 (54%) given infliximab (absolute risk difference 6%; 95% CI −7 to 19; p=0·52). Nine (16%) patients in the ciclosporin group and 14 (25%) in the infliximab group had severe adverse events. Ciclosporin was not more effective than infliximab in patients with acute severe ulcerative colitis refractory to intravenous steroids. In clinical practice, treatment choice should be guided by physician and centre experience. Association François Aupetit, Société Nationale Française de Gastroentérologie, and the International Organization for the study of Inflammatory Bowel Disease.