British Society of Gastroenterology guidance for management of inflammatory bowel disease during the COVID-19 pandemic

The COVID-19 pandemic is putting unprecedented pressures on healthcare systems globally. Early insights have been made possible by rapid sharing of data from China and Italy. In the UK, we have rapidly mobilised inflammatory bowel disease (IBD) centres in order that preparations can be made to protect our patients and the clinical services they rely on. This is a novel coronavirus; much is unknown as to how it will affect people with IBD. We also lack information about the impact of different immunosuppressive medications. To address this uncertainty, the British Society of Gastroenterology (BSG) COVID-19 IBD Working Group has used the best available data and expert opinion to generate a risk grid that groups patients into highest, moderate and lowest risk categories. This grid allows patients to be instructed to follow the UK government's advice for shielding, stringent and standard advice regarding social distancing, respectively. Further considerations are given to service provision, medical and surgical therapy, endoscopy, imaging and clinical trials.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.published version, accepted version, submitted versio

Adaptations to the British Society of Gastroenterology guidelines on the management of acute severe UC in the context of the COVID-19 pandemic: a RAND appropriateness panel

Objective: Management of acute severe UC (ASUC) during the novel COVID-19 pandemic presents significant dilemmas. We aimed to provide COVID-19-specific guidance using current British Society of Gastroenterology (BSG) guidelines as a reference point. Design: We convened a RAND appropriateness panel comprising 14 gastroenterologists and an IBD nurse consultant supplemented by surgical and COVID-19 experts. Panellists rated the appropriateness of interventions for ASUC in the context of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Median scores and disagreement index (DI) were calculated. Results were discussed at a moderated meeting prior to a second survey. Results: Panellists recommended that patients with ASUC should be isolated throughout their hospital stay and should have a SARS-CoV-2 swab performed on admission. Patients with a positive swab should be discussed with COVID-19 specialists. As per BSG guidance, intravenous hydrocortisone was considered appropriate as initial management; only in patients with COVID-19 pneumonia was its use deemed uncertain. In patients requiring rescue therapy, infliximab with continuing steroids was recommended. Delaying colectomy because of COVID-19 was deemed inappropriate. Steroid tapering as per BSG guidance was deemed appropriate for all patients apart from those with COVID-19 pneumonia in whom a 4-6 week taper was preferred. Post-ASUC maintenance therapy was dependent on SARS-CoV-2 status but, in general, biologics were more likely to be deemed appropriate than azathioprine or tofacitinib. Panellists deemed prophylactic anticoagulation postdischarge to be appropriate in patients with a positive SARS-CoV-2 swab.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.PMI is supported by a grant from the Medical Research Council [MR/T005564/1]published version, accepted version, submitted versio

Predicting outcome in Crohn’s disease

Crohn’s disease is a chronic immune-mediated disease which can cause inflammation in the gastrointestinal tract anywhere between mouth and anus. It is now understood to be the result of a complex interplay between genetic, microbial and environmental factors. The detail of these interactions remains an important focus of research. Clinicians and patients are faced with an increasing range of therapeutic options for Crohn’s. Key decision points include first presentation to gastrointestinal services, assessment of risk of disease progression, escalation to biologic therapy, and withdrawal of immunomodulator or biologic therapies. Biomarkers are needed that help stratify patients at these times to facilitate shared decision-making. In this thesis, I have brought together seven of the first-author papers published from the work conducted during my period of study. I first investigated the associations between NOD2, the strongest genetic association for Crohn’s disease, and the faecal microbiome. NOD2 encodes a bacterial pattern recognition receptor, and so disease-associated genetic variants might be expected to lead to an alteration in the microbiota. Although I demonstrated clear associations between the presence of inactive Crohn’s and changes in the faecal microbial composition, I was unable to show an impact of NOD2 genotype in either patients with Crohn’s or in volunteers without gastrointestinal disease. Calprotectin is the dominant protein in the cytosol of neutrophils. Its measurement in faecal samples has become well-established as a tool for non-invasive assessment of intestinal inflammation. I have investigated its use here for both diagnosis and prognosis in Crohn’s disease. In the diagnosis paper, I have assessed the diagnostic accuracy in of faecal calprotectin in a large cohort of patients referred to secondary care with lower gastrointestinal symptoms. I demonstrated a high negative predictive value, with very few false negatives even after three years of follow-up. In patients with established Crohn’s disease, I have then gone onto show that higher concentrations of faecal calprotectin, independent of symptoms, are associated with a greater risk of progressing to stricturing or penetrating disease, hospitalisation or resectional surgery. All of the therapies used in Crohn’s disease carry long-term risks including an elevated risk of infection and certain cancers. For this reason, among others, clinicians and patients must regularly assess the risk-benefit of continued therapy versus withdrawal of medication. I conducted two national, multicentre studies to better understand the outcomes of treatment withdrawal; one for thiopurines, and the other for anti-tumour necrosis factor alpha (anti-TNF), two of the most widely used classes of maintenance medication for Crohn’s disease. I demonstrated a relapse rate of 39% at two years following withdrawal of thiopurines for Crohn’s disease, and for 56% two years following anti-TNF withdrawal. I identified factors predictive of an increased risk of relapse, and for anti-TNF performed a systematic review and meta-analysis of all of the available published data. Anti-TNF therapies were the first targeted biologic therapy licensed for Crohn’s disease and they remain an important tool for the induction and maintenance of remission. Their introduction has been transformative for many patients, but secondary loss of response is common. In the final paper included in this thesis, I present the results from PANTS, a 120- site study of infliximab and adalimumab in 1,610 patients with Crohn’s disease. I have demonstrated the importance of good early drug concentrations for outcome, and explored the relationship between patient factors, drug and anti-drug antibody concentrations and longer term outcomes. As part of the PANTS study, we have collected longitudinal biological samples, and building on the clinical data presented in this thesis, I have described some of the early downstream analyses of genetic associations with anti-drug antibody formation, as well as plans for analyses of DNA methylation, transcription, serum protein concentrations, immunoglobulin G glycosylation and variation in the microbiome. This thesis brings together work spanning a breadth of translational and clinical research into Crohn’s disease. I have contributed to better understanding of pathogenesis, and to prediction of outcome at key decision points within the clinical disease course. These projects, particularly the PANTS study, provide a strong foundation for further research to better understand this important disease

DOP28 Understanding the molecular mechanisms of anti-TNF treatment failure in patients with Crohn’s disease: A pilot serum proteomic analysis of the PANTS cohort

Background Proteomic biomarkers have been linked to anti-TNF treatment failure, but previous studies have been insufficiently powered to stratify associations by drug level. The Personalised Anti-TNF Therapy in Crohn’s disease (PANTS) is a prospective UK-wide study investigating treatment failure in 1610 anti-TNF naïve patients. We aimed to identify proteomic markers of treatment failure. Methods We sampled patients with primary non-response (PNR) (n = 223) and remission (n = 219) who had a baseline CRP ≥4 mg/l and/or calprotectin >100 µg/g. PNR was defined at week 14 as ongoing steroids, or both of HBI failed to fall by ≥3 points or to ≤4 and CRP failed to fall by ≥50% or to ≤3 mg/l. Non-remission at week 54 was defined as HBI >4 and CRP >3 mg/l and no steroids. Targeted serum proteomic analysis of 180 proteins using Olink Inflammation and Immune Response panels were performed. Mann–Whitney U tests were used to identify baseline proteins that predicted PNR and non-remission. Sub-group analyses stratified by drug level were undertaken. Pharmacokinetic (PK) failure was defined as PNR with low drug level (infliximab level <2 mg/l, adalimumab level <6 mg/l) and pharmacodynamic (PD) failure as PNR despite adequate drug level. Significant proteins were entered into multivariable logistic regression models and Bayesian information criterion (BIC) with backward stepwise selection were used to build predictive models of treatment failure. We applied 10-fold cross-validation to test the models. P-values of < 0.05 were considered significant. Results Elevated fibroblast growth factor 21 (FGF21) (OR 1.3, CI 1.1–1.4, p = 3.4 × 10–5) and interleukin-10 receptor subunit α (IL10RA) (OR 1.6, CI 1.2–2.1, p = 6.3 × 10–4) predicted PNR (Figure 1). At week 14, FGF21 (OR 1.5, CI 1.3–1.9, p = 1.8 × 10–6) and IL10RA (OR 1.8, CI 1.3–2.3, p = 5.8 × 10–5) levels were also associated with PNR. graphic Sub-group analyses showed baseline FGF21 (OR 1.4, CI 1.2–1.7, p = 2.0 × 10–4) predicted PK failure and that IL10-RA (OR 1.6, CI 1.1–2.2, p = 6.7 × 10–3) predicted PD failure (Figure 2). graphic In separate models, non-remission at week 54 was predicted by baseline (FGF21; OR 1.3, CI 1.1–1.4, p = 1.4 × 10–4, IL10-RA; OR 1.5, CI 1.1–2.0, p = 3.6 × 10–3) and week 14 (FGF21; OR 1.4, CI 1.2–1.7, p = 3.6 × 10–4, IL10-RA; OR 1.7, CI 1.3–2.4, p = 1.7 × 10–4) FGF21 and IL10-RA levels. Model validation of baseline FGF21 and IL10-RA showed an area under the curve of 0.61 (CI 0.57–0.64) for PNR and 0.60 (CI 0.56–0.64) for non-remission at week 54. Conclusion Our study identified FGF-21 and IL10-RA as proteins of interest associated with PK and PD treatment failure, respectively. Functional studies to determine the molecular mechanism driving dysregulation of these proteins are required.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.published version, accepted version (12 month embargo), submitted versio

DOP69 Tofacitinib in ulcerative colitis: Early ‘real-world’ experience from four UK tertiary centres

Background Tofacitinib is a partially selective Janus kinase inhibitor that was approved for the treatment of refractory moderate to severe ulcerative colitis (UC) in 2018. We report the real-world clinical effectiveness and adverse effects of tofacitinib in UC. Methods We conducted a retrospective observational cohort study of tofacitinib-treated patients with UC between October 2018 to October 2019 from 4 UK centres. Disease activity was assessed using the Simple Clinical Colitis Activity Index (SCCAI) or Partial Mayo Score (PMS) depending on the study site. Response and remission were defined at week 8 and 26 as a reduction in SCCAI or PMS of ≥3, and SCCAI <3 or PMS <2, respectively. Corticosteroid-free remission was defined as remission with no corticosteroid use at the time of assessment irrespective of baseline corticosteroid status. Results We included 140 patients (65% M; median age 37y [range 16–81]) with a median disease duration of 5.5y (IQR 2.2–11.8). Forty-six per cent (65/140) were receiving corticosteroids at baseline and 83% (116/140) had previously received at least one biologic (62 anti-TNF, 4 vedolizumab, 50 both). Median (IQR) serum CRP and faecal calprotectin levels at baseline were 4 mg/l (1.6–15) and 540 µg/g (316–1175). Response and remission rates were 73% (81/111) and 56% (62/111) respectively at week 8 (median ΔSCCAI of −3 [IQR -6 to -1], median ΔPMS −4 [−6 to −1]) and 48% (39/82) and 39% (32/82) respectively at week 26 (median ΔSCCAI −3 [IQR −7 to –1], median ΔPMS −4 [−6 to –1]). Steroid-free remission was seen in 47% (52/111) and 37% (30/82) patients at week 8 and 26. Patients with response or remission had a significantly lower CRP (p = 0.02) but not calprotectin (p = 0.38) levels at baseline. Response and remission rates were no different stratified by prior biologic use (p = 0.56). Treatment was discontinued after a median of 3 months (IQR 2–4) in 43 patients: 32 with primary non-response, 9 loss of response and in 1 each because of an adverse drug reaction (headache) and patient choice. 7/17 patients had a clinical response to dose re-escalation following a loss of response on dose reduction. The median time to dose de-escalation was 67 (IQR 25–240) days. Seven patients were hospitalised and 5 underwent colectomy. Six serious infections were noted including 2 herpes zoster infections but there were no venous thromboembolic events. Median total cholesterol, low-density lipoprotein and high-density lipoprotein increased from 4.4 mmol/l (IQR 3.7–5.2), 2.47 (1.9–2.9) and 1.5 (1.1–1.9) to 4.8 mmol/l (4.1–6.0), 2.8 (2.13.5) and 1.7 (1.4–1.9) respectively after 8 weeks of tofacitinib. graphic Conclusion Clinical effectiveness and side-effect profile of tofacitinib in UC in this multi-centre real-world cohort were similar to that reported in the pivotal OCTAVE clinical trials.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.published version, accepted version (12 month embargo), submitted versio

Drug-like antagonists of P2Y receptors — from lead identification to drug development

P2Y receptors are expressed in virtually all cells and tissue types and mediate an astonishing array of biological functions, including platelet aggregation, smooth muscle cell proliferation, and immune regulation. The P2Y receptors belong to the G protein-coupled receptor superfamily and are composed of eight members encoded by distinct genes that can be subdivided into two groups on the basis of their coupling to specific G-proteins. Extensive research has been undertaken to find modulators of P2Y receptors, although to date only a limited number of small-molecule P2Y receptor antagonists have been approved by drug/medicines agencies. This Perspective reviews the known P2Y receptor antagonists, highlighting oral drug-like receptor antagonists, and considers future opportunities for the development of small molecules for clinical evaluation