Publications by authors named "Polychronis Pavlidis"

35 Publications

Editorial: is tofacitinib another rescue option for acute severe ulcerative colitis?

Aliment Pharmacol Ther 2021 08;54(3):341-342

IBD Centre, Guy's and St Thomas' NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1111/apt.16482DOI Listing
August 2021

Near-focus narrow-band imaging classification of villous atrophy in suspected celiac disease: development and international validation.

Gastrointest Endosc 2021 Jul 3. Epub 2021 Jul 3.

King's Institute of Therapeutic Endoscopy, King's College Hospital, London, United Kingdom.

Background And Aims: There are no agreed-upon endoscopic signs for the diagnosis of villous atrophy (VA) in celiac disease (CD), necessitating biopsies for diagnosis. Here we evaluated the role of near-focus narrow-band imaging (NF-NBI) for the assessment of villous architecture in suspected CD with the development and further validation of a novel NF-NBI classification.

Methods: Patients with a clinical indication for duodenal biopsy were prospectively recruited. Six paired NF-white light (NF-WLE) and NF-NBI images with matched duodenal biopsy including the bulb, were obtained from each patient. Histopathology grading used Marsh-Oberhuber classification. A modified Delphi process was performed on images (n=498) and video recordings by 3 endoscopists to define NF-NBI classifiers, resulting in a 3-descriptor classification (villous shape, vascularity, crypt phenotype). Thirteen blinded endoscopists (5 expert, 8 nonexpert) then undertook a short training module on the proposed classification and evaluated paired NF-WLE/NF-NBI images.

Results: One hundred consecutive patients were enrolled (n=97 completed the study; 66 females:51.2+/-17.3 years). Thirteen endoscopists evaluated 50-paired NF-WLE/NF-NBI images each (24 biopsy-proven VA). Interobserver agreement among all validators for the diagnosis of villous morphology using the NF-NBI classification was substantial (κ0.71) and moderate (κ0.46) with NF-WLE. Substantial agreement was observed between all 3 NF-NBI Classification descriptors and histology (weighted κ 0.72-0.75) compared with NF-WLE to histology (κ0.34). A higher degree of confidence using NF-NBI was observed when assessing the duodenal bulb.

Conclusions: We have developed and validated a novel NF-NBI classification to reliably diagnose VA in suspected CD. There was utility for expert and nonexpert endoscopists alike, using readily available equipment and required minimal training.
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http://dx.doi.org/10.1016/j.gie.2021.06.031DOI Listing
July 2021

Results of the Seventh Scientific Workshop of ECCO: Precision Medicine in IBD-Disease Outcome and Response to Therapy.

J Crohns Colitis 2021 Sep;15(9):1431-1442

Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Inflammatory bowel diseases [IBD] are a heterogeneous spectrum with two extreme phenotypes, Crohn's disease [CD] and ulcerative colitis [UC], which both represent numerous phenotypical variations. Hence, we should no longer approach all IBD patients similarly, but rather aim to rethink clinical classifications and modify treatment algorithms to usher in a new era of precision medicine in IBD. This scientific ECCO workshop aims to provide a state-of-the-art overview on prognostic and predictive markers, shed light on key questions in biomarker development, propose best practices in IBD biomarker development [including trial design], and discuss the potential for multi-omic data integration to help drive further advances to make precision medicine a reality in IBD.
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http://dx.doi.org/10.1093/ecco-jcc/jjab050DOI Listing
September 2021

The effects of COVID-19 on IBD prescribing and service provision in a UK tertiary centre.

GastroHep 2020 Nov 5;2(6):318-326. Epub 2020 Dec 5.

Inflammatory Bowel Disease Unit Guy's and St Thomas' Hospital London UK.

Background: To quantify the effects of COVID-19 on our inflammatory bowel disease (IBD) unit, including service provision, prescribing practices and use of therapeutic drug monitoring (TDM).

Methods: We performed a single centre retrospective observational cohort study. Data was extracted from our IBD database, electronic patient records and radiology/endoscopy reporting systems between 16/3/20-17/4/20 and the corresponding period in 2019.

Results: A similar number of patients commenced biologic therapy before COVID-19 (n = 37) and during the pandemic (n = 36). Patients in the pre-COVID-19 cohort were older (median 36 vs 29 years,  = 0.009) with a longer median disease duration (9.3 vs 5.2 years,  = 0.02). During COVID-19 there was a nonsignificant increase in prescribing of vedolizumab (8/37, 22% vs 14/36, 39%,  = 0.13) and a higher proportion of patients were anti-TNF-naïve (3/17, 18% vs 18/24, 74%,  = 0.0004). There was a reduction in use of concomitant immunomodulators (22/29, 76% vs 4/34, 12%,  < 0.0001) and increased biologic use in thiopurine-naïve patients (3/37, 8% vs 15/36, 42%,  = 0.001). Use of TDM fell by 75% (240 vs 59 tests). Outpatient appointments fell by 68% and were conducted via telemedicine. MRI scanning, endoscopy, luminal surgery and inpatient numbers fell by 87%, 85%, 100% and 82% respectively. IBD Clinical Nurse Specialist and Pharmacist helpline contacts increased by 76% and 228% respectively.

Conclusions: We observed prescribing differences during COVID-19, bypassing the initiation of immunomodulators and/or anti-TNF therapy in favour of vedolizumab with a reduction in immunomodulator prescribing. We also observed a rapid reorganisation of service provision, including a shift towards telemedicine and online solutions.
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http://dx.doi.org/10.1002/ygh2.433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753474PMC
November 2020

Tofacitinib in Acute Severe Ulcerative Colitis-A Real-World Tertiary Center Experience.

Inflamm Bowel Dis 2020 10;26(11):e147-e149

IBD Centre, Guy's and St Thomas' Hospitals NHS Foundation Trust, London,United Kingdom.

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http://dx.doi.org/10.1093/ibd/izaa157DOI Listing
October 2020

British Society of Gastroenterology endorsed guidance for the management of immune checkpoint inhibitor-induced enterocolitis.

Lancet Gastroenterol Hepatol 2020 07;5(7):679-697

The Royal Marsden Hospital, London, UK.

Immune checkpoint inhibitors are a novel class of cancer treatment that have improved outcomes for a subset of cancer patients. They work by antagonising inhibitory immune pathways, thereby augmenting immune-mediated antitumour responses. However, immune activation is not cancer-specific and often results in the activation of immune cells in non-cancer tissues, resulting in off-target immune-mediated injury and organ dysfunction. Diarrhoea and gastrointestinal tract inflammation are common and sometimes serious side-effects of this type of therapy. Prompt recognition of gastrointestinal toxicity and, in many cases, rapid institution of anti-inflammatory or biologic therapy (or both) is required to reverse these complications. Management of organ-specific complications benefits from multidisciplinary input, including engagement with gastroenterologists for optimal management of immune checkpoint inhibitor-induced enterocolitis. In this British Society of Gastroenterology endorsed guidance document, we have developed a consensus framework for the investigation and management of immune checkpoint inhibitor-induced enterocolitis.
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http://dx.doi.org/10.1016/S2468-1253(20)30014-5DOI Listing
July 2020

Therapeutic thresholds for golimumab serum concentrations during induction and maintenance therapy in ulcerative colitis: results from the GO-LEVEL study.

Aliment Pharmacol Ther 2020 07 7;52(2):292-302. Epub 2020 Jun 7.

Gastroenterology, Guy's & St Thomas' Hospital, London, UK.

Background: Significant associations between serum golimumab concentrations and favourable outcomes have been observed during both induction and maintenance therapy in ulcerative colitis (UC). However, data regarding optimal therapeutic serum golimumab concentration thresholds are limited.

Aims: To identify optimal serum golimumab concentration thresholds during induction and maintenance treatment with golimumab.

Methods: GO-LEVEL was an open label, phase IV study that included a prospective cohort of UC patients commencing golimumab, as well as a cross-sectional cohort receiving maintenance treatment. Patients commencing induction for active UC (defined as a simple clinical colitis activity index [SCCAI] >5 in addition to a raised faecal calprotectin [FC] >59μg/g or, raised C-reactive protein [CRP] [>5mg/L] or, Mayo endoscopic disease activity 2 or 3) were evaluated at weeks 6, 10 and 14. Patients receiving maintenance therapy were recruited either at the point of flare or during remission. Combined clinical-biochemical remission was defined as SCCAI ≤2 and FC <250μg/g. Serum golimumab concentrations were measured using a commercially available ELISA (LISATRACKER, Theradiag).

Results: Thirty-nine patients were included in the induction cohort, of whom 15 (38%) achieved combined clinical-biochemical remission at week 6. The median serum golimumab concentration of those in combined clinical-biochemical remission was significantly higher than those who were not (5.0 vs 3.1 μg/mL, respectively, P = 0.03). Receiver operating characteristic (ROC) curve analysis demonstrated 3.8 μg/mL as the optimal threshold (sensitivity 0.71, specificity 0.65, area under curve [AUC] 0.72, positive predictive value [PPV] 0.59 and negative predictive value [NPV] 0.79). Sixty-three patients were included in the maintenance cohort; 31 (49%) were in combined remission, 32 (51%) were not. The median serum golimumab concentration of those in combined remission was significantly higher (2.9 vs 2.1 μg/mL, respectively, P = 0.01). ROC curve analysis demonstrated 2.4 μg/mL as the optimal threshold (sensitivity 0.68, specificity 0.66, AUC 0.68, PPV 0.65 and NPV 0.66).

Conclusions: GO-LEVEL (NCT03124121) offers further evidence regarding golimumab's exposure-response relationship. Clinicians may consider using therapeutic drug monitoring to optimise golimumab dosing aiming to achieve our suggested therapeutic thresholds of 3.8 μg/mL at week 6 and 2.4 μg/mL during maintenance.
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http://dx.doi.org/10.1111/apt.15808DOI Listing
July 2020

ISX-9 manipulates endocrine progenitor fate revealing conserved intestinal lineages in mouse and human organoids.

Mol Metab 2020 04 17;34:157-173. Epub 2020 Feb 17.

Diabetes Research Group, School of Life Course Sciences, Faculty of Life Science and Medicine, King's College London, London, UK. Electronic address:

Objective: Enteroendocrine cells (EECs) survey the gut luminal environment and coordinate hormonal, immune and neuronal responses to it. They exhibit well-characterised physiological roles ranging from the control of local gut function to whole body metabolism, but little is known regarding the regulatory networks controlling their differentiation, especially in the human gut. The small molecule isoxazole-9 (ISX-9) has been shown to stimulate neuronal and pancreatic beta-cell differentiation, both closely related to EEC differentiation. Our aim was to use ISX-9 as a tool to explore EEC differentiation.

Methods: We investigated the effects of ISX-9 on EEC differentiation in mouse and human intestinal organoids, using real-time quantitative polymerase chain reaction (RT-qPCR), fluorescent-activated cell sorting, immunostaining and single-cell RNA sequencing.

Results: ISX-9 increased the number of neurogenin3-RFP (Ngn3)-positive endocrine progenitor cells and upregulated NeuroD1 and Pax4, transcription factors that play roles in mouse EEC specification. Single-cell analysis showed induction of Pax4 expression in a developmentally late Ngn3+ population of cells and potentiation of genes associated with progenitors biased toward serotonin-producing enterochromaffin (EC) cells. Further, we observed enrichment of organoids with functional EC cells that was partly dependent on stimulation of calcium signalling in a population of cells residing outside the crypt base. Inducible Pax4 overexpression, in ileal organoids, uncovered its importance as a component of early human endocrine specification and highlighted the potential existence of two major endocrine lineages, the early appearing enterochromaffin lineage and the later developing peptidergic lineage which contains classical gut hormone cell types.

Conclusion: Our data provide proof-of-concept for the controlled manipulation of specific endocrine lineages with small molecules, whilst also shedding new light on human EEC differentiation and its similarity to the mouse. Given their diverse roles, understanding endocrine lineage plasticity and its control could have multiple therapeutic implications.
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http://dx.doi.org/10.1016/j.molmet.2020.01.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036449PMC
April 2020

Interleukin-22 orchestrates a pathological endoplasmic reticulum stress response transcriptional programme in colonic epithelial cells.

Gut 2020 03 2;69(3):578-590. Epub 2019 Dec 2.

School of Immunology and Microbial Sciences, King's College London, London, UK

Objective: The functional role of interleukin-22 (IL22) in chronic inflammation is controversial, and mechanistic insights into how it regulates target tissue are lacking. In this study, we evaluated the functional role of IL22 in chronic colitis and probed mechanisms of IL22-mediated regulation of colonic epithelial cells.

Design: To investigate the functional role of IL22 in chronic colitis and how it regulates colonic epithelial cells, we employed a three-dimentional mini-gut epithelial organoid system, in vivo disease models and transcriptomic datasets in human IBD.

Results: As well as inducing transcriptional modules implicated in antimicrobial responses, IL22 also coordinated an endoplasmic reticulum (ER) stress response transcriptional programme in colonic epithelial cells. In the colon of patients with active colonic Crohn's disease (CD), there was enrichment of IL22-responsive transcriptional modules and ER stress response modules. Strikingly, in an IL22-dependent model of chronic colitis, targeting IL22 alleviated colonic epithelial ER stress and attenuated colitis. Pharmacological modulation of the ER stress response similarly impacted the severity of colitis. In patients with colonic CD, antibody blockade of IL12p40, which simultaneously blocks IL12 and IL23, the key upstream regulator of IL22 production, alleviated the colonic epithelial ER stress response.

Conclusions: Our data challenge perceptions of IL22 as a predominantly beneficial cytokine in IBD and provide novel insights into the molecular mechanisms of IL22-mediated pathogenicity in chronic colitis. Targeting IL22-regulated pathways and alleviating colonic epithelial ER stress may represent promising therapeutic strategies in patients with colitis.

Trial Registration Number: NCT02749630.
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http://dx.doi.org/10.1136/gutjnl-2019-318483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034350PMC
March 2020

Human retinoic acid-regulated CD161 regulatory T cells support wound repair in intestinal mucosa.

Nat Immunol 2018 12 5;19(12):1403-1414. Epub 2018 Nov 5.

MRC, Centre for Transplantation, King's College London, London, UK.

Repair of tissue damaged during inflammatory processes is key to the return of local homeostasis and restoration of epithelial integrity. Here we describe CD161 regulatory T (T) cells as a distinct, highly suppressive population of T cells that mediate wound healing. These T cells were enriched in intestinal lamina propria, particularly in Crohn's disease. CD161 T cells had an all-trans retinoic acid (ATRA)-regulated gene signature, and CD161 expression on T cells was induced by ATRA, which directly regulated the CD161 gene. CD161 was co-stimulatory, and ligation with the T cell antigen receptor induced cytokines that accelerated the wound healing of intestinal epithelial cells. We identified a transcription-factor network, including BACH2, RORγt, FOSL2, AP-1 and RUNX1, that controlled expression of the wound-healing program, and found a CD161 T cell signature in Crohn's disease mucosa associated with reduced inflammation. These findings identify CD161 T cells as a population involved in controlling the balance between inflammation and epithelial barrier healing in the gut.
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http://dx.doi.org/10.1038/s41590-018-0230-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474659PMC
December 2018

Complement receptor CD46 co-stimulates optimal human CD8 T cell effector function via fatty acid metabolism.

Nat Commun 2018 10 10;9(1):4186. Epub 2018 Oct 10.

School of Immunology and Microbial Sciences, King's College London, London, UK.

The induction of human CD4 Th1 cells requires autocrine stimulation of the complement receptor CD46 in direct crosstalk with a CD4 T cell-intrinsic NLRP3 inflammasome. However, it is unclear whether human cytotoxic CD8 T cell (CTL) responses also rely on an intrinsic complement-inflammasome axis. Here we show, using CTLs from patients with CD46 deficiency or with constitutively-active NLRP3, that CD46 delivers co-stimulatory signals for optimal CTL activity by augmenting nutrient-influx and fatty acid synthesis. Surprisingly, although CTLs express NLRP3, a canonical NLRP3 inflammasome is not required for normal human CTL activity, as CTLs from patients with hyperactive NLRP3 activity function normally. These findings establish autocrine complement and CD46 activity as integral components of normal human CTL biology, and, since CD46 is only present in humans, emphasize the divergent roles of innate immune sensors between mice and men.
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http://dx.doi.org/10.1038/s41467-018-06706-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180132PMC
October 2018

Golimumab: early experience and medium-term outcomes from two UK tertiary IBD centres.

Frontline Gastroenterol 2018 Jul 11;9(3):221-231. Epub 2017 Oct 11.

IBD Centre, Guy's and St Thomas' NHS Foundation Trust, London, UK.

Objective: To gain an understanding of the effectiveness of golimumab in a 'real-world' setting.

Design: Retrospective cohort study using prospectively maintained clinical records.

Setting: Two UK tertiary IBD centres.

Patients: Patients with ulcerative colitis (UC) were given golimumab at Guy's & St Thomas and King's College Hospitals between September 2014 and December 2016.

Intervention: Golimumab, a subcutaneously administered antitumour necrosis factor agent.

Main Outcome Measures: Clinical disease activity was assessed at baseline and at the first clinical review following induction therapy using the Simple Clinical Colitis Activity Index (SCCAI). Response was defined as an SCCAI reduction of 3 points or more. Remission was defined as an SCCAI of less than 3.

Results: Fifty-seven patients with UC completed golimumab induction therapy. Paired preinduction and postinduction SCCAI values were available for 31 patients and fell significantly from 7 (2-19) to 3 (0-11) (p<0.001). To these 31, an additional 13 patients who did not have paired SCCAI data but stopped treatment due to documented 'non-response' in the opinion of their supervising clinician, were added. Among this combined cohort, 23/44 (52%) had a clinical response, 15/44 (34%) achieved remission and 13/44 (30%) achieved corticosteroid-free remission.Faecal calprotectin and CRP fell (FC: pre-induction: 1096 (15-4800) μg/g, post-induction: 114 (11-4800) μg/g, p = 0.011; n = 20; CRP: pre-induction: 4 (1-59) mg/L, post-induction: 2 (1-34) mg/L, p = 0.01 for n = 43). Post-induction endoscopy was carried out in 23 patients and a mucosal healing (Mayo 0 or 1) rate of 35% was observed.

Conclusions: Our experience mirrors previously reported real-world cohorts and demonstrates similar outcomes to those observed in randomised controlled trials. These data demonstrate a meaningful reduction in clinical, biochemical and endoscopic disease activity as well as a steroid-sparing effect in patients with previously refractory disease.
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http://dx.doi.org/10.1136/flgastro-2017-100895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056089PMC
July 2018

Gastrointestinal toxicity of immune checkpoint inhibitors: from mechanisms to management.

Nat Rev Gastroenterol Hepatol 2018 04 7;15(4):222-234. Epub 2018 Mar 7.

Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, First Floor College House, North Wing, St Thomas' Hospital, Westminster Bridge Road, London, UK.

Immune checkpoint inhibitor therapies are a novel group of monoclonal antibodies with proven effectiveness in a wide range of malignancies, including melanoma, renal cell carcinoma, non-small-cell lung cancer, urothelial carcinoma and Hodgkin lymphoma. Their use in a range of other indications, such as gastrointestinal and head and neck cancer, is currently under investigation. The number of agents included in this drug group is increasing, as is their use. Although they have the potential to improve the treatment of advanced malignancies, they are also associated with a substantial risk of immune-related adverse events. The incidence of gastrointestinal toxicity associated with their use is second only in frequency to dermatological toxicity. Thus, gastroenterologists can expect to be increasingly frequently consulted by oncologists as part of a multidisciplinary approach to managing toxicity. Here, we describe this novel group of agents and their mechanisms of action. We review the manifestations of gastrointestinal toxicity associated with their use so that it can be recognized early and diagnosed accurately. We also discuss the proposed mechanisms underlying this toxicity and describe an algorithmic and, wherever possible, evidence-based approach to its management.
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http://dx.doi.org/10.1038/nrgastro.2018.14DOI Listing
April 2018

Vedolizumab: early experience and medium-term outcomes from two UK tertiary IBD centres.

Frontline Gastroenterol 2017 Jul 10;8(3):196-202. Epub 2016 Aug 10.

IBD Centre, Guy's & St Thomas' NHS Foundation Trust, IBD Centre, London, UK.

Objective: To gain an understanding of the efficacy of vedolizumab in a 'real-world' setting.

Design: Retrospective cohort study using prospectively maintained clinical records.

Setting: Two UK tertiary inflammatory bowel disease (IBD) centres.

Patients: Patients with IBD commenced on vedolizumab at Guy's & St Thomas' and King's College Hospitals during November 2014-November 2015.

Intervention: Vedolizumab, a monoclonal antibody to α-4 β-7 integrins that selectively inhibit leucocyte migration into the gut.

Main Outcome Measures: Clinical disease activity was assessed at baseline, weeks 14 and 30 using Harvey-Bradshaw Index (HBI) for Crohn's disease (CD) and Simple Clinical Colitis Activity Index (SCCAI) for ulcerative colitis (UC). Response was defined as HBI or SCCAI reduction ≥3. Remission was defined as HBI <5 or SCCAI <3. Continuous data are summarised as medians, followed by range.

Results: Fifty patients were included: 27 CD, 20 UC and 3 IBD-U (included in the UC group for analysis). At baseline visit, the median HBI was 8 (1-16) and SCCAI was 6 (0-15). At week 14, these values had fallen to 5 (0-15) (p=0.117) and 4 (0-10) (p=0.005), respectively. Additionally, week 30 data were available for 19 patients (9 CD, 10 UC). The clinical disease activity scores at that point were HBI 2 (0-7) (p=0.039) and SCCAI 2 (0-10) (p=0.023). At baseline, 37 (74%) of the 50 patients had clinically active disease. Of the patients with active disease, 22 (59%) responded and 14 (38%) achieved remission at week 14.

Conclusions: Our early experience with vedolizumab demonstrates a clear benefit in terms of disease control as well as a steroid-sparing effect in a cohort, which included patients with complex and previously refractory disease.
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http://dx.doi.org/10.1136/flgastro-2016-100720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5558276PMC
July 2017

An Atlas of Human Regulatory T Helper-like Cells Reveals Features of Th2-like Tregs that Support a Tumorigenic Environment.

Cell Rep 2017 07;20(3):757-770

MRC Centre for Transplantation, King's College London, Guy's Hospital, SE1 9RT London, UK. Electronic address:

Regulatory T cells (Tregs) play a pivotal role in maintaining immunological tolerance, but they can also play a detrimental role by preventing antitumor responses. Here, we characterized T helper (Th)-like Treg subsets to further delineate their biological function and tissue distribution, focusing on their possible contribution to disease states. RNA sequencing and functional assays revealed that Th2-like Tregs displayed higher viability and autocrine interleukin-2 (IL-2)-mediated activation than other subsets. Th2-like Tregs were preferentially found in tissues rather than circulation and exhibited the highest migratory capacity toward chemokines enriched at tumor sites. These cellular responses led us to hypothesize that this subset could play a role in maintaining a tumorigenic environment. Concurrently, Th2-like Tregs were enriched specifically in malignant tissues from patients with melanoma and colorectal cancer compared to healthy tissue. Overall, our results suggest that Th2-like Tregs may contribute to a tumorigenic environment due to their increased cell survival, higher migratory capacity, and selective T-effector suppressive ability.
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http://dx.doi.org/10.1016/j.celrep.2017.06.079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5529316PMC
July 2017

Gastric Lesion in a Patient With Lynch Syndrome.

Gastroenterology 2017 Aug 29;153(2):e5-e6. Epub 2017 Jun 29.

Department of Gastroenterology, King's College Hospital London, United Kingdom.

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http://dx.doi.org/10.1053/j.gastro.2016.12.045DOI Listing
August 2017

Vedolizumab in Inflammatory Bowel Disease Associated with Autoimmune Liver Disease Pre- and Postliver Transplantation: A Case Series.

Inflamm Bowel Dis 2016 10;22(10):E39-40

*Gastroenterology Department, King's College Hospital, London, United Kingdom †Gastroenterology Department, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom ‡Institute of Liver Studies, King's College Hospital, London, United Kingdom.

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http://dx.doi.org/10.1097/MIB.0000000000000906DOI Listing
October 2016

Early change in faecal calprotectin predicts primary non-response to anti-TNFα therapy in Crohn's disease.

Scand J Gastroenterol 2016 Dec 12;51(12):1447-1452. Epub 2016 Jul 12.

a Department of Gastroenterology , King's College Hospital , Hill, London , Denmark, UK.

Objective: The early identification of primary non-response to anti-TNFα therapy facilitates the timely management of patients with Crohn's disease (CD). A recent, pilot study to detect prognostic markers of early response to anti-TNFα therapy identified the two genes coding for the calprotectin subunits (S100A8, S100A9) to be among the most highly expressed gene transcripts in non-responders. This study tests the hypothesis that measurements of faecal calprotectin (FCAL) pre- and post-anti-TNFα induction can predict primary non-response.

Methods: Retrospective study of 32 CD patients treated over a two-year period. Outcomes were assessed at 6 months based on clinical activity scores and the use of corticosteroids: (a) remission: Harvey-Bradshaw index (HBI) < 5, off corticosteroids >2 months; (b) response: drop in HBI >3, off corticosteroids; (c) non-response: ΔFCAL (and ΔCRP, respectively) was calculated as (FCAL post-induction - FCAL pre-induction) × 100/FCAL pre induction.

Results: At 6 months, 23 (72%) patients had responded (median (interquartile range) HBI: 4 (3-5), FCAL: 55 (27-146)), 17 (73%) of whom were in remission [HBI: 3 (2.5-4) and FCAL: 42 (16-115)]. There was a significant difference in the ΔFCAL from baseline to post-induction in the three groups (p < 0.0001). Comparing non-responders to combined response and remission groups, the AUC of ΔFCAL to predict outcome at 6 months was 0.97. Using ROC analysis, a Δ70% returned a sensitivity and specificity of 99% and 96%, respectively (likelihood ratio, LR= 23). ΔCRP did not predict 6 months outcomes.

Conclusions: A drop in FCAL <70% after induction predicts primary non-response to anti-TNFα in CD.
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http://dx.doi.org/10.1080/00365521.2016.1205128DOI Listing
December 2016

Long-term Safety and Efficacy of Low-dose Azathioprine and Allopurinol Cotherapy in Inflammatory Bowel Disease: A Large Observational Study.

Inflamm Bowel Dis 2016 07;22(7):1639-46

*Surrey and Sussex Healthcare NHS Trust, East Surrey Hospital, Redhill, United Kingdom; †Department of Gastroenterology, King's College Hospital NHS Foundation Trust, King's Health Partners; ‡East Surrey Clinical Commissioning Group Assistant Chair; and §School of Pharmacy and Mater Research Institute, The University of Queensland, Brisbane, Australia.

Background: Low-dose azathioprine with allopurinol (LDAA) has been proposed as a potent therapy in inflammatory bowel disease (IBD) with the benefit of overcoming side effects regularly associated with thiopurine monotherapy and poor responses. Concerns regarding safety remain, while a layer of complexity has been added by the trend toward treatment directed by red cell thioguanine nucleotide (TGN) profiling. We report on the clinical efficacy and safety of LDAA use in IBD undirected by metabolite profiling.

Methods: Observational study of clinical practice from a single IBD center. Patient outcomes were defined clinically based on established activity scores and corticosteroid withdrawal. Red cell TGN was monitored only for suspected nonadherence.

Results: Overall, 113/164 (69%) patients with Crohn's disease and 83/136 (61%) patients with ulcerative/unclassified colitis had a clinical response by the end of follow-up (median 19 months), while 85 (52%) patients with Crohn's disease and 74 (54%) patients with ulcerative/unclassified colitis were in clinical remission. Clinical response was seen in 45/57 (79%) patients with Crohn's disease and 34/53 (64%) patients with ulcerative/unclassified colitis who were thiopurine naive, had active IBD, and received LDAA as the first line immunomodulator, while in 35 (61%) and 28 (53%), respectively, remission was achieved. LDAA was stopped in 20/300 (7%) patients because of side effects, all of which resolved on drug cessation.

Conclusions: This is the largest cohort supporting the favorable safety profile and high efficacy of LDAA in IBD. It presents 2 advances in therapy: prescribing LDAA for thiopurine-naive patients, and bypassing TGN monitoring in favor of clinical monitoring (blood counts, etc.), which will make it more accessible for clinics without access to TGN assays.
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http://dx.doi.org/10.1097/MIB.0000000000000827DOI Listing
July 2016

A new form of chronic inflammatory bowel disease associated with chronic liver disease.

Scand J Gastroenterol 2016 5;51(6):644-5. Epub 2016 Jan 5.

b Department of Colorectal Surgery and Gastroenterology , King's College Hospital , London , UK.

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http://dx.doi.org/10.3109/00365521.2015.1128141DOI Listing
August 2016

Contrasting Pattern of Chronic Inflammatory Bowel Disease in Primary and Autoimmune Sclerosing Cholangitis.

EBioMedicine 2015 Oct 2;2(10):1523-7. Epub 2015 Sep 2.

Institute of Liver Studies, King's College Hospital, Denmark Hill, London, UK.

Background: Primary sclerosing cholangitis (PSC) and autoimmune sclerosing cholangitis (AISC) are related, but distinct chronic liver diseases. PSC is associated with a high prevalence of ulcerative colitis while the intestinal inflammation associated with AISC is less well characterised.

Aims: To assess and contrast aspects of intestinal inflammation in patients with AISC and PSC and compare the clinical features with those of patients with ulcerative colitis and Crohn's disease.

Methods: 23 and 22 patients with AISC and PSC, respectively, underwent review of colonoscopy and biopsy findings, capsule enteroscopy and assessment of clinical and inflammatory (faecal calprotectin) disease activity, which was compared with that of patients with ulcerative colitis and Crohn's disease (n = 55 each).

Findings: Five and 6 patients with AISC and PSC, respectively, had normal colonoscopy and faecal calprotectin levels of 34.4 ± 8.3 and 39.7 ± 8.4 μg/g, respectively (normal < 50 μg/g), whereas 18 and 16, respectively, had identical variably severe, right sided colitis with frequent rectal sparing, consistent with ulcerative colitis. Mean (± SD) faecal calprotectin levels did not differ significantly (p > 0.05) between patients with intestinal inflammation in AISC (588 ± 549 μg/g), PSC (421 ± 351 μg/g), ulcerative colitis (501 ± 656 μg/g) or Crohn's disease (476 ± 571 μg/g). Capsule enteroscopy showed that 7 of 18 (39%) (p < 0.03) of those with AISC had small bowel mucosal breaks whereas no patient with PSC had these findings.

Interpretation: Collectively these findings lend support to the suggestion that the chronic inflammatory bowel disease associated with PSC and in particular AISC may represent a distinct nosologic entity different from classic ulcerative colitis and Crohn's disease.
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http://dx.doi.org/10.1016/j.ebiom.2015.08.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4634318PMC
October 2015

Aspirin Induced Adverse Effects on the Small and Large Intestine.

Curr Pharm Des 2015 ;21(35):5089-93

Department of Colorectal Surgery, King's College Hospital, London, SE5 9RS, UK.

Aspirin is in many ways a non- steroidal anti-inflammatory drug (NSAID) prototype. Similar to conventional NSAIDs the gastric side effects of aspirin are well studied. However its potential adverse effects on the small and large intestine are less well known and under- researched. Experimental studies support a pathogenic pathway leading to NSAID enteropathy involving the topical effects on the intestinal barrier (mucous layer, enterocytes) that lead to dysfunction and increased intestinal permeability followed by increased exposure to luminal triggers and acute inflammation. Although aspirin has a toxic effect in vitro, enteral or parenteral administration in vivo, in animal models, did not result to intestinal injury. In man, experimental studies have revealed changes in intestinal permeability similar to conventional NSAIDs but of lesser magnitude. The clinical implication of these changes though is not known. Population studies have associated aspirin use with occult gastrointestinal bleeding from the small or large bowel although the magnitude of this risk is difficult to estimate but certainly small. Associations to colitis flare-ups have been made in case reports and retrospective cohort studies but low dose aspirin appears safe. Complications of diverticular disease may also be more frequent with aspirin use.
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http://dx.doi.org/10.2174/1381612821666150915110058DOI Listing
August 2016

Diagnostic and clinical significance of Crohn's disease-specific pancreatic anti-GP2 and anti-CUZD1 antibodies.

Clin Chem Lab Med 2016 Feb;54(2):249-56

Background: Pancreatic autoantibodies (PAB) targeting GP2 and CUZD1 are Crohn's disease (CrD)-markers. The clinical significance of anti-GP2 antibodies has been assessed, but that of anti-CUZD1 remains elusive. The aim of the study was to assess the clinical utility of anti-CUZD1/anti-GP2 by novel cell-based indirect immunofluorescence (IIF) assays in CrD.

Methods: A total of 212 CrD and 249 UC patients followed up at a London IBD centre were investigated to simultaneously detect PABs, anti-GP2 and anti-CUZD1 by IIF using primate pancreatic tissue, and HEK293 over-expressing CUZD1 or GP2.

Results: Overall, 88 (41.5%) CrDs compared to 26 (10.4%) UCs (p<0.001) tested positive for IgA and/or IgG anti-GP2 and/or anti-CUZD1 antibodies, while ASCA were found in 67.5% CrDs versus 19.2% UCs (p<0.0001); ASCA and/or PAB (anti-GP2 or anti-CUZD1) were detected in 76% CrD versus 34% UC patients. IgG anti-GP2 antibodies were less prevalent in L2 phenotype (p=0.002) and more prevalent in patients with stricturing disease (p=0.0418), even when a higher cut-off (≥1000 RU) was used (p=0.0396). Also, anti-GP2 IgG positive CrD patients had younger age of disease onset. IgA and/or IgG ASCA and anti-GP2 IgG antibody positive CrDs had younger onset of disease (p<0.0001), were more likely to have both ileal and colonic disease (p<0.0001) and had more stricturing (p<0.0001) than seronegative patients. Clinical correlates were not found for anti-CUZD1 positivity.

Conclusions: PAB testing increases ASCA's serological sensitivity for CrD. Anti-GP2 detection, in isolation or in combination with ASCA, stratify CrD patients who phenotypically are characterised by a much younger onset of disease, extensive and stricturing behaviour.
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http://dx.doi.org/10.1515/cclm-2015-0376DOI Listing
February 2016

Cholestyramine treats primary sclerosing cholangitis-associated inflammatory bowel disease.

J Crohns Colitis 2015 Feb 5;9(2):210. Epub 2014 Dec 5.

Gastroenterology Department, King's College Hospital, London, UK.

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http://dx.doi.org/10.1093/ecco-jcc/jju020DOI Listing
February 2015

Diagnostic and clinical significance of Crohn's disease-specific anti-MZGP2 pancreatic antibodies by a novel ELISA.

Clin Chim Acta 2015 Feb 12;441:176-81. Epub 2014 Dec 12.

Inova Diagnostics, Inc., San Diego, CA 92131, USA. Electronic address:

Background: We developed a new IgA and IgG anti-MZGP2 antibody ELISAs based on recombinant isoform-4 of human zymogen granule protein-2 (GP2), which is the major autoantigen of Crohn's disease (CrD)-specific pancreatic autoantibodies and assessed their clinical relevance in the largest inflammatory bowel disease (IBD) cohort tested to date.

Methods: 832 sera were studied, including 617 consecutive IBD patients from 323 CrD and 294 ulcerative colitis (UC) follow-up in a tertiary centre, and 112 pathological and 103 normal controls.

Results: Sensitivity of IgA anti-MZGP2 for CrD in the IBD population was 15% and specificity was 98% (95, 99), while the sensitivity and specificity of IgG anti-MZGP2 were 27% and 97%. IgA and IgG anti-MZGP2 combined testing led to a sensitivity of 31% and a specificity of 96%. Positivity for either ASCA (IgA or IgG) or anti-MZGP2 (IgA or IgG) showed a sensitivity of 75% (70, 80) and a specificity of 84% (79, 89). IgA anti-MZGP2 antibodies were more prevalent in CrD patients with early disease onset (p=0.011). Also, anti-MZGP2 positive patients more frequently had extensive disease with ileal involvement. Patients with longer disease duration were more likely to have IgG anti-MZGP2 antibodies.

Conclusions: Our novel ELISA confirms the high specificity of anti-MZGP2 antibodies for CrD and their association with disease severity phenotypes.
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http://dx.doi.org/10.1016/j.cca.2014.12.010DOI Listing
February 2015

Splitting a therapeutic dose of thioguanine may avoid liver toxicity and be an efficacious treatment for severe inflammatory bowel disease: a 2-center observational cohort study.

Inflamm Bowel Dis 2014 Dec;20(12):2239-46

*Department for Digestive Diseases, Surrey and Sussex Healthcare NHS Trust, East Surrey Hospital, Redhill, United Kingdom; †Mater Research Institute, University of Queensland, Woolloongabba, Australia; ‡Mater Pathology Service, South Brisbane, Australia; and §Department of Gastroenterology, Mater Health Services, South Brisbane, Australia.

Background: Thioguanine (TG) is a treatment for inflammatory bowel disease, but association with nodular regenerative hyperplasia has restricted its use. We conjectured that splitting a therapeutic daily dose of TG would be efficacious and should avoid liver toxicity.

Methods: We report on 62 patients with severe inflammatory bowel disease not responding to prednisolone, conventional thiopurines, biologics, or calcineurin inhibitors. Patients were prescribed oral split-daily TG to avoid individual doses >0.3 mg/kg. Data on concomitant medication, clinical efficacy measured by Harvey-Bradshaw Index for Crohn's, or Simple Clinical Colitis Score for ulcerative/indeterminate colitis (UC), and some paired endoscopies were available. Safety was followed clinically and with bloods at 2 centers. All patients at the U.K. center had a liver biopsy or magnetic resonance imaging after 6 months. Twenty-one patients had serial ultrasounds at the Australian center.

Results: At 6 months, 19/21 of patients with Crohn's disease and 27/38 with ulcerative colitis had improved clinical activity. At study end, 53% of patients maintained improved clinical activity of steroids. Median duration of TG was 8 (0.3-45) months, median dose was 0.6 (0.3-1) mg/kg per day. Previous thiopurine-related adverse reactions were not encountered. Twenty-nine patients withdrew because of loss to follow-up, medical adverse events, or surgery. Possible early nodular regenerative hyperplasia was found on liver biopsy in 1 patient who was heterozygote deficient for thiopurine methyltransferase; the TG dose was lowered. TG was discontinued in a patient with nodular regenerative hyperplasia and concomitant antiphospholipid syndrome. There was 1 successful term pregnancy; cord blood and breast milk TG were low.

Conclusions: Split-dose TG seemed well tolerated and efficacious in this retrospective study of patients with difficult inflammatory bowel disease.
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http://dx.doi.org/10.1097/MIB.0000000000000206DOI Listing
December 2014

Diagnostic accuracy and clinical application of faecal calprotectin in adult patients presenting with gastrointestinal symptoms in primary care.

Scand J Gastroenterol 2013 Sep 24;48(9):1048-54. Epub 2013 Jul 24.

Brighton and Sussex University Hospitals, Digestive Diseases Centre, Brighton, UK.

Objective: Assessment of faecal calprotectin (fCal) test performance in primary care within an irritable bowel syndrome (IBS) diagnostic pathway.

Methods: Study based on consecutively collected fCal data from 962 patients, aged 18-45, presenting to their general practitioner (GP) with persistent gastrointestinal symptoms.

Results: Six hundred and eighty six (71%) patients had a negative (<50 μg/g) and 276 (29%) had a positive fCal. 28% (77/276) of the patients testing positive and 3% (17/686) of those testing negative had an organic diagnosis. At 50 μg/g the sensitivity of the test for organic disease was 82%, (95% confidence interval [CI] 73-89) and the specificity was 77% (95% CI 74-80), with negative predictive value (NPV) and positive predictive value (PPV) of 98% and 28%, respectively. A cut-off increase to 150 μg/g reduces the NPV by 1% whilst increasing the PPV to 71%. This would reduce colonoscopy and flexible sigmoidoscopy bookings by 10% at the cost of four missed cases of inflammatory bowel disease.

Conclusions: This study provides the first evidence on the use of fCal testing in primary care. The low prevalence of organic disease in this setting has a significant impact on test performance. This suggests a need for change in cut-off value, to improve PPV whilst accepting a reduction in test sensitivity, if it is to be used as part of the pathway for management of patients with suspected IBS.
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http://dx.doi.org/10.3109/00365521.2013.816771DOI Listing
September 2013

Anti-GP2 antibodies in inflammatory bowel disease patients with ileal pouch.

J Crohns Colitis 2013 Dec 9;7(11):e602-3. Epub 2013 Jul 9.

Division of Transplantation Immunology and Mucosal Biology, King's College London School of Medicine at King's College Hospital, London SE5 9RJ, UK.

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http://dx.doi.org/10.1016/j.crohns.2013.06.010DOI Listing
December 2013

PR3-ANCA: a promising biomarker for ulcerative colitis with extensive disease.

Clin Chim Acta 2013 Sep 24;424:267-73. Epub 2013 Jun 24.

INOVA Diagnostics, Inc., San Diego, CA, United States. Electronic address:

Background: We determined if PR3-ANCA is a biomarker that differentiates ulcerative colitis (UC) from Crohn's disease (CrD).

Methods: A total of 946 sera were tested, including 86 granulomatosis with polyangiitis (GPA) and 491 inflammatory bowel disease (IBD) patients (283 UC and 208 CrD), 264 pathological controls (various diseases) and 105 healthy individuals. All samples were tested for PR3-ANCA by ELISA (QUANTA Flash Lite®, INOVA Diagnostics) and chemiluminescent immunoassays (CIA QUANTA Flash PR3). Conventional anti-neutrophil cytoplasmic antibody (ANCA) indirect immunofluorescence assays (IIF) was performed with NOVA Lite™ (INOVA Diagnostics).

Results: PR3-ANCA by CIA were detected in 31.1% UC vs. 1.9% CrD sera (p=2.2E-16), and by ELISA in 6% UC and 0% CrD (p=0.0003). In GPA patients, PR3-ANCA were detected in 75.6% by CIA and 61.6% by ELISA (p<0.05). PR3-ANCA by CIA were more prevalent in E3-UC compared to E1/2-UC (p<0.05), and in patients with shorter disease duration (p<0.0001). PR3-ANCA showed similar sensitivity, but significantly higher specificity (p<0.05), compared to atypical pANCA by IIF.

Conclusion: The novel PR3 CIA may prove helpful in the differentiation of CrD from UC, as well as in the identification of UC patients with more extensive disease.
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http://dx.doi.org/10.1016/j.cca.2013.06.005DOI Listing
September 2013
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