Fraser Cummings - Academia.edu (original) (raw)

Papers by Fraser Cummings

The Lancet Gastroenterology & Hepatology

Generics and Biosimilars Initiative Journal

Frontline Gastroenterology, 2022

IntroductionPatients with suspected inflammatory bowel disease (IBD) referred from primary care o... more IntroductionPatients with suspected inflammatory bowel disease (IBD) referred from primary care often face diagnostic and treatment delays. This study aimed to compare a novel direct-access IBD endoscopy pathway with the traditional care model.MethodSingle centre real-world study analysing primary care referrals with suspected IBD. Group A: patients triaged to direct-access IBD endoscopy. Group B: patients undergoing traditional outpatient appointments before the availability of direct-access IBD endoscopy. Demographics, fecal calprotectin (FCP), C-reactive protein (CRP), disease activity score, endoscopy findings, treatment and follow-up were collected and statistically analysed. Ranked semantic analysis of IBD symptoms contained within referral letters was performed.ResultsReferral letters did not differ significantly in Groups A and B. Demographic data, FCP and CRP values were similar. Referral to treatment time (RTT) at the time of IBD endoscopy was reduced from 177 days (Group ...

Posters, 2021

that were more abundant in IBD than controls (propan-1-ol and phenol) returned to levels similar ... more that were more abundant in IBD than controls (propan-1-ol and phenol) returned to levels similar to controls following treatment (figure 1). Within IBD, the subtype (CD versus colitis (UC and IBDunclassified)) described a small amount of variation (3%, p=0.006), with three faecal VOCs (6-methylhept-5-en-2-one; benzaldehyde; 4-methylphenol) significantly different in abundance between CD and colitis (t-test, p<0.05). Conclusion/Interpretation Characterisation of faecal VOCs may advance the understanding of the pathogenesis of IBD, disease sub-types and response to treatment.

Journal of Crohn's and Colitis, 2020

Background Anti-TNF exposure has been linked to demyelination events. We sought to describe the c... more Background Anti-TNF exposure has been linked to demyelination events. We sought to describe the clinical features of demyelination events following anti-TNF treatment and to test whether affected patients were genetically predisposed to multiple sclerosis [MS]. Methods We conducted a case-control study to describe the clinical features of demyelination events following anti-TNF exposure. We compared genetic risk scores [GRS], calculated using carriage of 43 susceptibility loci for MS, in 48 cases with 1219 patients exposed to anti-TNF who did not develop demyelination. Results Overall, 39 [74%] cases were female. The median age [range] of patients at time of demyelination was 41.5 years [20.7–63.2]. The median duration of anti-TNF treatment was 21.3 months [0.5-99.4] and 19 [36%] patients were receiving concomitant immunomodulators. Most patients had central demyelination affecting the brain, spinal cord, or both. Complete recovery was reported in 12 [23%] patients after a median ti...

Journal of Crohn's and Colitis, 2019

Background and Aims Mucosal healing is important in Crohn’s disease therapies. Epithelial homeost... more Background and Aims Mucosal healing is important in Crohn’s disease therapies. Epithelial homeostasis becomes dysregulated in Crohn’s, with increased permeability, inflammation, and diarrhoea. MicroRNAs are small non-coding RNAs that regulate gene expression and show changes in inflammatory bowel disease. Tumour necrosis factor alpha [TNFα] inhibitor protein 3 is raised in Crohn’s and regulates TNFα-mediated activation of NFκB. We investigated TNFα regulation by microRNA in Crohn’s disease [CD], and studied effects on epithelial permeability and inflammation. Methods Colonic epithelium from CD and healthy donor biopsies was isolated using laser capture microdissection, and microRNA was quantified. Tumour necrosis factor alpha inhibitor protein 3 was characterised immunohistochemically on serial sections. Expression effect of microRNA was confirmed with luciferase reporter assays. Functional barrier permeability studies and innate cytokine release were investigated with cell and expl...

Frontline Gastroenterology, 2019

ObjectiveSymptoms and clinical course during inflammatory bowel disease (IBD) vary among individu... more ObjectiveSymptoms and clinical course during inflammatory bowel disease (IBD) vary among individuals. Personalised care is therefore essential to effective management, delivered by a strong patient-centred multidisciplinary team, working within a well-designed service. This study aimed to fully rewrite the UK Standards for the healthcare of adults and children with IBD, and to develop an IBD Service Benchmarking Tool to support current and future personalised care models.DesignLed by IBD UK, a national multidisciplinary alliance of patients and nominated representatives from all major stakeholders in IBD care, Standards requirements were defined by survey data collated from 689 patients and 151 healthcare professionals. Standards were drafted and refined over three rounds of modified electronic-Delphi.ResultsConsensus was achieved for 59 Standards covering seven clinical domains; (1) design and delivery of the multidisciplinary IBD service; (2) prediagnostic referral pathways, proto...

Clinical Medicine, 2019

To improve detection and establish the frequency of steroidinduced hyperglycaemia among inpatient... more To improve detection and establish the frequency of steroidinduced hyperglycaemia among inpatients with a flare of inflammatory bowel disease (IBD) receiving intravenous hydrocortisone by improving capillary blood glucose (CBG) monitoring in line with locally adapted Joint British Diabetes Societies (JBDS) guidelines.

Gut, 2016

This study aimed to evaluate its impact, which is not well known to date, on the numbers of GP re... more This study aimed to evaluate its impact, which is not well known to date, on the numbers of GP referrals made to a high volume endoscopy unit in London and the numbers and prognosis of the cancers diagnosed. Methods This was a retrospective observational study, analysing departmental and patient records at the Barking, Havering and Redbridge Hospitals NHS Trust. Total numbers of GP 'urgent' priority and 'two-week wait' (2 WW) cancer pathway referrals for UGI endoscopies were collected from a six month period before the onset of the campaign and compared with a six month period after the campaign onset. The total numbers, demographics and outcomes of the oesophago-gastric cancers referred and diagnosed in the pre-and post-campaign period were recorded. Student paired t tests and c2 tests were used to assess for statistical significance. Results There were 1143 urgent/2 WW UGI endoscopy referrals made by GP's in the pre-campaign period and 1448 referrals in the post-campaign period. There was a statistically significant rise of mean monthly 2 WW referrals in the postcampaign period by 36.5% (p = 0.001). The extra demand was most noticeable in the 2 month post-campaign period with a mean weekly referral rate increase of 46.5% (p = 0.001), equating to 20 extra UGI endoscopies requested per week. However, there was no statistically significant change in the overall rates of oesophago-gastric cancers detected in any age group (47 cancers pre-campaign vs. 38 post-campaign), in their staging or the proportion that could be treated with curative intent. Most of the cancers diagnosed in both groups actually presented as dysphagia (35-37%) and/ or weight loss (22-27%) rather than dyspepsia (10-11%). Conclusion The national oesophago-gastric cancer awareness campaign significantly increased the demand placed on endoscopy services but did not meet its aim of detecting more cancers at an earlier curative stage. Most diagnosed were still in advanced stages 3 and 4. Perhaps future campaigns should place more emphasis on promoting awareness of dysphagia, which was more strongly associated with cancer detection, in addition to dyspepsia, in order to increase cancer detection rates.

The Lancet Gastroenterology & Hepatology, 2016

Background Up to 60% of patients with Crohn's disease need intestinal resection within the fi rst... more Background Up to 60% of patients with Crohn's disease need intestinal resection within the fi rst 10 years of diagnosis, and postoperative recurrence is common. We investigated whether mercaptopurine can prevent or delay postoperative clinical recurrence of Crohn's disease. Methods We did a randomised, placebo-controlled, double-blind trial at 29 UK secondary and tertiary hospitals of patients (aged >16 years in Scotland or >18 years in England and Wales) who had a confi rmed diagnosis of Crohn's disease and had undergone intestinal resection. Patients were randomly assigned (1:1) by a computer-generated web-based randomisation system to oral daily mercaptopurine at a dose of 1 mg/kg bodyweight rounded to the nearest 25 mg or placebo; patients with low thiopurine methyltransferase activity received half the normal dose. Patients and their carers and physicians were masked to the treatment allocation. Patients were followed up for 3 years. The primary endpoint was clinical recurrence of Crohn's disease (Crohn's Disease Activity Index >150 plus 100-point increase in score) and the need for anti-infl ammatory rescue treatment or primary surgical intervention. Primary and safety analyses were by intention to treat. Subgroup analyses by smoking status, previous thiopurines, previous infl iximab or methotrexate, previous surgery, duration of disease, or age at diagnosis were also done. This trial is registered with the International Standard Randomised Controlled Trial Register (ISRCTN89489788) and the European Clinical Trials Database (EudraCT number 2006-005800-15).

Gastroenterology, 2015

Introduction UC is thought to be characterised by a TH-2 predominant immune response. MicroRNAs (... more Introduction UC is thought to be characterised by a TH-2 predominant immune response. MicroRNAs (miRNA) are short 19–23 nucleotide long strands of single-stranded RNA which modify post transcriptional gene expression by degrading or inhibiting translation of mRNA. miR31 and miR155 are miRNA that directly and indirectly target genes in the IL-13 dependant pathway. Confounding factors in current IBD miRNA studies include disease activity and medication. The specific function of miRNAs in UC, how they might be influenced by medications, and potential clinical utility is yet to be investigated. In this study we aim to investigate how the expression of a number of miRNA and mRNA is influenced by medications and then explore these findings further using a human ex-vivo culture system. Method Sigmoid biopsies from 40 patients with untreated active and inactive UC, normal controls, and patients treated with 5-ASA, Azathioprine, Infliximab and Adalimumab were frozen in liquid nitrogen. RT-qPCR was performed to analyse the relative expression of miRNA and mRNA. An ex vivo model was designed. 6 biopsies were taken from 8 patients with active untreated UC, with a Mayo score of 6 or greater. Biopsies were placed in tissue culture media in 6 separate wells with either no treatment, 5-ASA, 6-TG, Infliximab, or Adalimumab, were incubated for 24hrs at 37 o C. RT-qPCR was performed to assess expression of miR31 and miR155 and mRNA of CCL18 and SOCS1 that are important in the TH-2 pathway. Results miR31 and miR155 expression was increased in patients with untreated active and inactive UC compared to normal mucosa. CCL18 expression was also increased in untreated active disease compared to inactive and normal mucosa. Azathioprine reduced miR31, miR155 and CCL18 expression to levels seen in quiescent disease. Infliximab treatment reduced miR155, and CCL18 expression to that of inactive disease, which was not seen in Adalimumab. Anti-TNFs did not reduce miR31 expression to the level of untreated inactive disease. 5ASAs had no impact on expression of the miRNA nor mRNA studied. Ex vivo treated samples confirmed down regulation of miR31 was confined to 6-TG and not seen in anti-TNF treatment, and that CCL18 expression is also reduced by 6-TG and Infliximab, but not Adalimumab. Conclusion Our data confirmed that miR31 miR155 and CCL18 are increased in active UC compared to normal mucosa and inactive disease. We demonstrate that thiopurine therapy reduces expression of miR31 and CCl18 in contrast to anti-TNF agents. This model may have utility in increasing understanding of the mechanisms of action of IBD medications. It highlights the importance of controlling for medication when analysing miRNA expression in whole tissue biopsies. Disclosure of interest None Declared.

Journal of Crohn's and Colitis Supplements, 2008

Aim: To assess the role of C-reactive protein (CRP) as a predictor in longterm response of inflix... more Aim: To assess the role of C-reactive protein (CRP) as a predictor in longterm response of infliximab (IFX) therapy in patients with Crohn' s disease (CD). Patients and methods: 91 CD patients from the DCCD treated with IFX from 1999 till 2006 were included: 38 males, median age 34 years (16-66), median disease duration 6 years (0-33), in total treated with 559 IFX infusions, median 4 (1-28). The indication of IFX therapy was luminal and fistulazing disease in 60 and 31 patients respectively. The CRP level before the 1st IFX infusion was measured, level < 10mg/l was considered normal. The clinical outcome was evaluated according to Copenhagen phenotype model of IFX dependency (1,2): 1. Immediate response (IR) was evaluated 30 days after the 1st infusion: Complete response (CR); Partial response (PR); No response (NR) 2. Long-term response (LTR) ≤ 90 days after the last intended IFX: Prolonged (PRO): Maintenance of CR/PR; IFX dependency (ID): Relapse of symptoms after ending IFX requiring repeated IFX to regain CR/PR or repetitive IFX therapy > 1 year to sustain CR/PR; No response (NR) Mann-Whitney and Cruscal-Wallis tests were used to compare the differences in CRP levels. P<0.05 was considered statistically significant. Results: 77 (85%) patients obtained immediate response (45 CR, 32 PR). In LTR 32 (35%) patients became PRO, 41 (45%) became ID and 18 (20%) NR. There was no significant difference in mean CRP (mg/l) level before the 1st IFX infusion between immediate responders and non-responders (23, 8 vs. 18.1, p=0.43). Similarly, we did not find any association between CRP level at baseline and long-term response to IFX (PRO 21.2, ID 26.8 and NR 17.0, p= 0.21). Conclusion: Our results show that CRP is not a predictive factor neither in immediate outcome nor in long-term infliximab response. No association was revealed in infliximab dependent patients.

Nature Genetics, 2008

We report results of a nonsynonymous SNP scan for ulcerative colitis and identify a previously un... more We report results of a nonsynonymous SNP scan for ulcerative colitis and identify a previously unknown susceptibility locus at ECM1. We also show that several risk loci are common to ulcerative colitis and Crohn's disease (IL23R, IL12B, HLA, NKX2-3 and MST1), whereas autophagy genes ATG16L1 and IRGM, along with NOD2 (also known as CARD15), are specific for Crohn's disease. These data provide the first detailed illustration of the genetic relationship between these common inflammatory bowel diseases.

Zeitschrift für Gastroenterologie, 2005

Methotrexate (MTX) is an effective immunosuppressive treatment in inflammatory bowel disease (IBD... more Methotrexate (MTX) is an effective immunosuppressive treatment in inflammatory bowel disease (IBD) but its use is limited by unpredictable toxicity and efficacy. MTX metabolism is complex involving a number of enzymes. An individual&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s response to MTX may in part be genetically determined by functional genetic variation in genes encoding these enzymes. We report a pharmacogenetic evaluation of MTX therapy in IBD. We studied 102 IBD patients treated with MTX, and 202 patients with Crohn&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (CD), 205 patients with ulcerative colitis (UC) and 189 healthy volunteers served as controls to assess allele frequencies in the disease and healthy populations. All subjects were genotyped for four polymorphisms: G80A in the reduced folate carrier (RFC1) gene, G452T in the gamma-glutamyl hydrolase (GGH) gene and C677T and A1298C in the methylenetetrahydrofolate reductase (MTHFR) gene. Three non-conservative SNPs in the RFC1 and the MTHFR gene could not be detected in our patient cohort. Genotype-phenotype associations were evaluated with respect to efficacy and toxicity of MTX therapy. No significant differences in the allele frequencies between CD, UC and healthy controls were detected. Overall 21% of patients experienced MTX side effects. Patients homozygous for the MTHFR 1298C allele were more likely to experience one or more side effects compared to patients with the wild-type 1298AA genotype (21.0 vs. 6.3%, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). None of the genotyped SNPs or haplotypes, either alone or in combination, was associated with short-term efficacy or sustained response. Side effects of MTX in IBD are associated with a SNP in the MTHFR gene but response cannot be predicted by any of the investigated SNPs.

Nature Genetics, 2007

A genome-wide association scan in Crohn disease by the Wellcome Trust Case Control Consortium1 de... more A genome-wide association scan in Crohn disease by the Wellcome Trust Case Control Consortium1 detected strong association at 6 novel loci. We tested 37 SNPs from these and other loci for association in an independent case control sample. Replication was obtained for the IRGM gene on chromosome 5q33.1 which induces autophagy (replication P = 6.6 × 10 −4 , combined P = 2.1 × 10 −10), and for 9 other loci including NKX2-3 and gene deserts on chromosomes 1q and 5p13.

The Journal of Immunology, 2011

CD4 Th cells producing the proinflammatory cytokine IL-17 (Th17) have been implicated in a number... more CD4 Th cells producing the proinflammatory cytokine IL-17 (Th17) have been implicated in a number of inflammatory arthritides including the spondyloarthritides. Th17 development is promoted by IL-23. Ankylosing spondylitis, the most common spondyloarthritis (SpA), is genetically associated with both HLA-B27 (B27) and IL-23R polymorphisms; however, the link remains unexplained. We have previously shown that B27 can form H chain dimers (termed B272), which, unlike classical HLA-B27, bind the killer-cell Ig-like receptor KIR3DL2. In this article, we show that B272-expressing APCs stimulate the survival, proliferation, and IL-17 production of KIR3DL2+ CD4 T cells. KIR3DL2+ CD4 T cells are expanded and enriched for IL-17 production in the blood and synovial fluid of patients with SpA. Despite KIR3DL2+ cells comprising a mean of just 15% of CD4 T in the peripheral blood of SpA patients, this subset accounted for 70% of the observed increase in Th17 numbers in SpA patients compared with co...

Journal of Crohn's and Colitis, 2009

Poster Presentations agents. Therapeutic action of anti-TNF turns to blockade proinflammatory cyt... more Poster Presentations agents. Therapeutic action of anti-TNF turns to blockade proinflammatory cytokines cascade. Under pressure of microbial antigens antigen-presenting cells activates and secretes IFN-G and IL-2. IL-2 promotes clonal expansion of T-cells with Th-1 and Th-2 differentiation. Th-2 cells produce cytokines (IL-4, 5, 6, 10, 13) one of them IL-10 suppress activity of Th-1 and inhibits cellular immune response. Besides bacterial lipopolisacharides activate monocytes and lead to the induction of cytokines TNF, IL-1, 10, 12. These cytokines are also produced by transmembrane TNF-bearing macrophages in inflammatory sites. Infliximab administration inhibit production TNF IL-1 but not IL-10 in these cells. IL-10 concentration relatively increase after infliximab course. During and after anti-TNF therapy not only anti-TNF antibodies has been found but also autoantibodies, antinuclear, anticardiolipine antibodies and other. We evaluated level of IL-10 in patients with TNF therapy. 47 IBD patients (28 UC, 19 CD) who have received infliximab 5 mg/kg in moderate stage of disease were studied. Before treatment all of them had CRP levels more than 5 mg/l and TNF levels more than 2 norms. Retrospectively before the treatment two new biomarkers were analyzed: level of IL-10 less than norm and ratio of TNF to IL-10 more than 3 norms. In 7 (14.9%) IBD patients lost response to anti-TNF therapy were observed. Among them 6 (85.6%) had IL-10 level more or equal to norm before treatment and all of patients who lost response to infliximab had ratio TNF/IL-10 less than 3 norms. Clinical occurrences where cross-over and auto-antibody have important pathogenic role are extra intestinal manifestations (EIM). We analyzed EIM presents in 332 patients with IBD. Among them were 220 patients with UC and 112 CD patients. EIM in 89 (40.4%) UC patients and 55 (49.1%) patients with CD were found. Monorganic EIM in 63 (18.9%) patients and polyorganic in 86 (25.9%) were observed. Privilege cytokines profile changes in IBD patients with EIM were analyzed. Maximal increasing of IL-1 and TNF with decreasing IL-10 in plasma in patients with joints and cardiac EIM were observed. Conclusions: IL-10 is a perspective biomarker for identification response to anti-TNF-a agent. Joints extra-intestinal manifestations in IBD is one of clinical criteria to anti-TNF-a therapy.

Genes & Immunity, 2006

Killer immunoglobulin-like receptors (KIRs) are expressed on natural killer cells and some T-cell... more Killer immunoglobulin-like receptors (KIRs) are expressed on natural killer cells and some T-cell subsets and produce either activation or inhibitory signals upon binding with the appropriate human leucocyte antigen (HLA) ligand on target cells. Recent genetic association studies have implicated KIR genotype in the development of several inflammatory conditions. Ulcerative colitis (UC) is an inflammatory disorder of the colonic mucosa that results from an inappropriate activation of the immune system driven by host bacterial flora. We developed a polymerase chain reaction-sequence specific primer (SSP)-based assay to genotype 194 UC patients and 216 control individuals for 14 KIR genes, the HLA-Cw ligand epitopes of the KIR2D receptors and a polymorphism of the lectin-like-activating receptor NKG2D. Initial analysis found the phenotype frequency of KIR2DL2 and-2DS2 to be significantly increased in the UC cohort (P ¼ 0.030 and 0.038, respectively). Logistic regression analysis revealed a protective effect conferred by KIR2DL3 in the presence of its ligand HLA-Cw group 1 (P ¼ 0.019). These results suggest that KIR genotype and HLA ligand interaction may contribute to the genetic susceptibility of UC.

Gastroenterology, 2008

Methods: Retrospective, observational study of CD pts who received maintenance INFLIX for ≥1 year... more Methods: Retrospective, observational study of CD pts who received maintenance INFLIX for ≥1 year with intention for ongoing maintenance. Pts were categorized into those who either DISCONTINUED or CONTINUED INFLIX maintenance therapy. Duration of INFLIX therapy was recorded. Maintenance INFLIX infusions were categorized as either SCHEDULED (loading and maintenance q≤8 weeks) or PRIOR EPISODIC (history of episodic infusions prior to maintenance dosing). Maintenance INFLIX intensification was defined as infusions q<7 weeks or doses >5mg/kg. Demographics, reason for drug discontinuation and use of concomitant immunosuppression (i.e. azathioprine, 6MP, methotrexate) were reviewed. Reasons for INFLIX discontinuation were categorized as: loss of efficacy; allergy/immunogenicity; non-compliance; loss of insurance; other. Results: 153 CD pts received maintenance INFLIX treatment beyond 1 year and 42 (27%) ultimately discontinued treatment. Mean duration of maintenance INFLIX at the time of discontinuation was 42.4 ± 19.1 months (S.D.), while ongoing maintenance pts received 49.4 ± 19.8 months at the time of the study (p=NS). Main reasons for INFLIX discontinuation were allergy/adverse reaction (44.2%) and decreased efficacy (38.2%). A majority of DISCONTINUED pts (61.9%) were started on the anti-TNFα agent adalimumab. Use of concomitant immunosuppression between the DISCONTINUED and CONTINUED groups was similar (78.6% vs 83.8%, p=NS). The DISCONTINUED group had a higher rate of prior episodic dosing compared to CD pts who CONTINUED maintenance (28.8% vs 11.7%, p=0.025), while there was no difference in the rate of intensified dosing (57.2% vs 50.5%, p=NS). There was no difference in gender, smoking status, disease duration between CD pts who DISCONTINUED and CONTINUED INFLIX maintenance. Conclusions: One quarter of CD pts on long-term INFLIX maintenance discontinue treatment. Allergy/immunogenicity and loss of efficacy was associated with INFLIX discontinuation in 3/4 of these pts. A history of prior episodic dosing was significantly associated with INFLIX discontinuation, despite concomitant immunosuppression. These data emphasize need for optimization of INFLIX for successful long-term management.