39 results on '"Ahmad, T."'
Search Results
2. OC-001 anti-TNF Withdrawal in IBD: Initial Results from a Pan-UK Study
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Kennedy, NA, Warner, B, Johnston, E, Basquill, C, Harris, R, Lamb, CA, Singh, A, Fadra, AS, Cameron, F, Basavaraju, U, Mason, J, Lithgo, K, Penez, L, Stansfield, C, Lal, S, Cummings, F, Hart, A, Johnson, M, Russell, R, Wilson, D, Gooding, I, Thomson, J, Gaya, D, Lindsay, J, Ahmad, T, Mansfield, J, Gordon, J, Satsangi, J, Irving, P, and Lees, CW
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- 2014
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3. Fulminant Crohn's colitis after allogeneic stem cell transplantation
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Sonwalkar, SA, James, RM, Ahmad, T, Zhang, L, Verbeke, CS, Barnard, DL, Jewell, DP, and Hull, MA
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Inflammatory bowel diseases -- Physiological aspects -- Case studies ,Hodgkin's disease -- Case studies -- Physiological aspects ,Crohn's disease -- Case studies -- Physiological aspects ,Stem cells -- Transplantation ,Health ,Influence ,Physiological aspects ,Case studies - Abstract
We report a case of fulminant Crohn's colitis that occurred following non-myeloablative allogeneic stem cell transplantation for Hodgkin's lymphoma. Adoptive transfer of inflammatory bowel disease by haematopoietic cells is recognised [...]
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- 2003
4. Genotype-phenotype analysis of the Crohn's disease susceptibility haplotype on chromosome 5q31
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Armuzzi, A, Ahmad, T, Ling, K-L, de Silva, A, Cullen, S, van Heel, D, Orchard, TR, Welsh, KI, Marshall, SE, and Jewell, DP
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Molecular genetics -- Research -- Genetic aspects ,Genotype -- Evaluation -- Research -- Genetic aspects ,Statistics -- Research ,Phenotype -- Evaluation -- Research -- Genetic aspects ,Crohn's disease -- Genetic aspects -- Risk factors -- Research ,Health ,Evaluation ,Genetic aspects ,Research ,Risk factors - Abstract
Background and aims: Recent molecular data suggest that genetic factors may underlie the disease heterogeneity observed in both ulcerative colitis (UC) and Crohn's disease (CD). A locus on chromosome 5q [...]
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- 2003
5. New IBD genes?
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McGovern, D and Ahmad, T
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- 2005
6. NOD2 (CARD15), the first susceptibility gene for Crohnʼs disease
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McGOVERN, D P B, VAN HEEL, D A, AHMAD, T, and JEWELL, D P
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- 2001
7. IS THERE A ROLE FOR MICA AND MICB IN DETERMINING SUSCEPTIBILITY AND PHENOTYPE IN ULCERATIVE COLITIS?
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Ahmad, T., Bunce, M., Crawshaw, J., Mulcahy-Hawes, K., Large, O., Barnardo, M., Cook, J., Welsh, K., and Jewell, D.P.
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Gastrointestinal diseases -- Research ,Health ,Research - Abstract
T. Ahmad [1] M. Bunce [2] J. Crawshaw [1] K. Mulcahy-Hawes [1] O. Large [1] M. Barnardo [2] J. Cook [2] K. Welsh [3] D.P. Jewell [1] (1.) Depts of [...]
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- 2001
8. TNFα GENE POLYMORPHISMS AND EXTRAINTESTINAL MANIFESTATIONS OF IBD: FURTHER EVIDENCE FOR PHENOTYPE DETERMINING GENES IN THE MHC REGION
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Orchard, T.R., Ahmad, T., Welsh, K.I., and Jewell, D.P.
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Gastrointestinal diseases -- Research ,Health ,Research - Abstract
T.R. Orchard [1,2] T. Ahmad [1] K.I. Welsh [1] D.P. Jewell [1] (1.) Gastroenterology Unit & Transplant Immunology, University of Oxford; (2.) Dept of Gastroenterology, St Mary's Hospital, London, UK [...]
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- 2001
9. NOVEL CHEMOKINE RECEPTOR 9 POLYMORPHISMS: CANDIDATE GENES FOR CROHN'S DISEASE (CD)?
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McGovern, D.P.B., Heel, D.A. van, Dechairo, B., Ahmad, T., Lench, N.J., and Jewell, D.P.
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Gastrointestinal diseases -- Research ,Health ,Research - Abstract
D.P.B. McGovern [1] D.A. van Heel [1] B. Dechairo [2] T. Ahmad [1] N.J. Lench [2] D.P. Jewell [1] (1.) Wellcome Trust Centre for Human Genetics and Gastroenterology Unit, University [...]
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- 2001
10. PWE-017 Prospective Evaluation of The Safety and Efficacy of Switching Stable Patients with Inflammatory Bowel Disease from Remicade™ to Biosimilar Infliximab (IFX)
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Bennett, KJ, primary, Heap, GA, additional, Hawkins, S, additional, and Ahmad, T, additional
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- 2016
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11. PTU-055 Anti-TNF Patient Treatment Preferences: Data from the Pants Study
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Walker, G, primary, Heap, G, additional, Bewshea, C, additional, Ahmad, T, additional, Irving, P, additional, and Goodhand, J, additional
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- 2016
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12. PTH-080 Serious Infusion Reactions with Vedolizumab are Rare: A UK Multicenter Experience
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Irving, P, primary, Lees, C, additional, Hart, A, additional, Kemp, K, additional, Ahmad, T, additional, and Cummings, F, additional
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- 2016
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13. Association of epidermal growth factor module containing mucin like hormone receptor 3 (EMR 3) mutation with susceptibility and phenotype of Crohn's disease
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Yang, X., Ahmad, T., Low, J., Jewell, D.P., and Zhang, L.
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Hormone receptors -- Health aspects -- Research ,Chromosomes -- Health aspects -- Research ,Crohn's disease -- Care and treatment -- Research ,Health ,Care and treatment ,Research ,Health aspects - Abstract
Backgrounds: Linkage of Crohn's disease (CD) to chromosome 19p13 has been identified in a Canadian IBD population and confirmed in British Caucasians. EMR3 maps to this region, belongs to a [...]
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- 2004
14. Combining clinical risk factors and genotype to predict postoperative recurrence of Crohn's disease
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Johns, E, Ahmad, T, Hubbard, R, Jewell, D, and Travis, S
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- 2003
15. No association between Nod2 polymorphisms and susceptibility to, or progression of, primary sclerosing cholangitis
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Cullen, SN, Ahmad, T, Chapman, R, and Jewell, D
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- 2002
16. PTU-071 Cause of Death in the Exeter Inflammatory Bowel Disease (IBD) Population
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Wesley, E, primary, Beddoes, B, additional, Forbes, A, additional, Clarke, M, additional, Daneshmend, T K, additional, and Ahmad, T, additional
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- 2013
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17. PTH-192 Once Negative always Negative? – the Clinical Utility of Repeating TTG
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Merson, S, primary, So, K, additional, Brown, R, additional, and Ahmad, T, additional
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- 2013
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18. OC-050 5-Aminosalicylate (5-Asa) Induced Nephrotoxicity in Inflammatory Bowel Disease
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So, K, primary, Bewshea, C, additional, Heap, G A, additional, Muller, A F, additional, Daneshmend, T K, additional, Hart, A L, additional, Orchard, T R, additional, Irving, P M, additional, Russell, R K, additional, Wilson, D C, additional, Parkes, M, additional, Satsangi, J, additional, Lees, C W, additional, and Ahmad, T, additional
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- 2013
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19. PWE-233 Single centre comparison of mortality, hospital recorded serious adverse events (SAE) and primary care recorded opportunistic infections (OI) in IBD patients treated with anti-TNF compared to thiopurines alone: Abstract PWE-233 Figure 1
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Waters, O, primary, Saunders, M, additional, Bulsara, M, additional, and Ahmad, T, additional
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- 2012
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20. Barriers to transition care in inflammatory bowel disease: a survey of adult and paediatric gastroenterologists in the UK
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Sebastian, S., primary, Jenkins, H., additional, Arnott, I., additional, Croft, N., additional, Ahmad, T., additional, McCartney, S., additional, Russell, R. K., additional, and Lindsay, J. O., additional
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- 2011
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21. Infliximab rescue therapy for steroid refractory acute severe ulcerative colitis in the exeter ibd cohort
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Waters, O., primary, Saunders, M., additional, Clarke, M., additional, Daneshmend, T., additional, and Ahmad, T., additional
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- 2011
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22. Polymorphisms in the MEP1A gene are not associated with susceptibility to coeliac disease
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Yap, L.M., Lottaz, D., Ahmad, T., Zhang, L., Van Heel, D., McGovern, D., Negoro, K., Sterchi, E., Sanderson, I., Welsh, K., and Jewell, D.P.
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Celiac disease -- Care and treatment -- Research ,Genetic polymorphisms -- Research -- Health aspects ,Epithelial cells -- Research -- Health aspects ,Health ,Care and treatment ,Research ,Health aspects - Abstract
Background: Meprin α is an endopeptidase from intestinal epithelial cells that accumulates at the brush border membrane and is also secreted into the gut lumen. In the small intestine, meprin [...]
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- 2004
23. OC-046 Nudt15 variants contribute to thiopurine-induced myelosuppression in european populations
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Walker, GJ, Harrison, JW, Heap, GA, Heerasing, N, Hendy, PJ, Bewshea, C, Goodhand, JR, Weedon, MN, Kennedy, NA, and Ahmad, T
- Abstract
IntroductionThiopurines are commonly used in the maintenance treatment of inflammatory bowel disease (IBD) but this is limited by myelosuppression in 7% of patients.1Thiopurine S-methyltransferase (TPMT)variants only explain 20% of thiopurine-induced myelosuppression (TIM) in Europeans suggesting the presence of other genetic determinants.2We aimed to identify the clinical features of TIM and to identify novel variants associated with TIM through a genome wide association study and whole exome sequencing.MethodWe recruited 491 IBD patients with TIM from 82 hospitals. Inclusion criteria included drug exposure in the 7 days prior to TIM, white blood cell count ≤2.5 ×109/L, or neutrophil count ≤1.0 ×109/L and that TIM necessitated dose reduction/drug withdrawal. After expert adjudication, 329 cases assigned a high likelihood of causality were genotyped and exome sequenced with 635 thiopurine-tolerant IBD controls for use in the final analyses.ResultsWe first confirmed an association of TIM with TPMTin an initial GWAS. We then, using exome sequencing, discovered a novel 6 bp in-frame deletion (rs746071566; AGGAGTC/A,p.Gly17_Val18del) at position 48611918 of chromosome 13 in exon 1 of NUDT15(5.8% cases, 0.2% controls, OR=38.2,p=1.33×10-8). This deletion was replicated in an independent cohort (3/75 [4%] cases vs. 2/785 [0.3%] thiopurine-tolerant IBD controls; OR=16.2, p=0.006). All NUDT15coding variants were confirmed with complete concordance by Sanger sequencing. Multivariable logistic regression demonstrated that adjusted dose (OR 2.2,p=9.4×10-11), NUDT15genotype (OR 21.7,p=2.0×10-8) and TPMTgenotype (OR 2.2,p=2.6×10-4for MUT/WT and OR 51.2,p=1.8×10-4for MUT/MUT) were independently associated with TIM.ConclusionThese are the largest ever clinical and genetic analyses of thiopurine-induced myelosuppression. We identified NUDT15coding variants, including a novel 6 bp deletion; carriage of any coding variant confers a 22-fold increase in the odds of TIM, independent of TMPTgenotype and thiopurine dose. Although NUDT15variants are less common than TPMTvariants, their effect size for heterozygotes is greater. The number of patients needed to genotype to prevent TIM due to NUDT15coding variant heterozygosity is 100. The estimated absolute risk of TIM in NUDT15heterozygotes is 59%. A future clinical decision tool incorporating NUDT15and TPMTgenotypes will offer personalised thiopurine therapy and prevent the considerable morbidity and costs associated with severe bone marrow toxicity.Reference. Gisbert JP & Gomollón F.doi10.1111/j.1572-0241.2008.01848.x (2008). Yang SK et al. doi10.1038/ng.3060 (2014)Disclosure of InterestNone Declared
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- 2017
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24. OC-044 Profile trial: predicting outcomes for crohn’s disease using a molecular biomarker
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Lee, JC, Biasci, D, Noor, NM, McKinney, EF, Ahmad, T, Lewis, NR, Hart, AL, Lyons, PA, Parkes, M, and Smith, KG
- Abstract
IntroductionThe course of Crohn’s disease (CD) varies substantially between affected individuals, but reliable prognostic markers are not available in clinical practice. This hinders disease management because patients with aggressive disease will be undertreated by conventional “step-up” therapy, while those with indolent disease would be exposed to the risks of unnecessary immunosuppression of a “top-down” approach. Previously, we have described a transcriptional signature that is detectable within peripheral blood CD8 T cells at diagnosis and which correlates with subsequent disease course. To translate this work to the bedside and overcome the technical challenges of separating cell populations, we sought to develop a whole blood qPCR-based biomarker that can re-capitulate the CD8 subgroups without the need for cell separation. Here we describe the development and validation of this biomarker and the upcoming biomarker-stratified trial that will test whether it can deliver personalised medicine in CD.MethodFrom a training cohort of 69 newly diagnosed IBD patients, we simultaneously obtained a whole blood PAXgene RNA tube and peripheral blood CD8 T cell sample. Gene expression in both samples was measured by microarray. After confirming that the CD8 transcriptional signature was detectable and correlated with prognosis, we used machine learning to identify a transcriptional classifier in whole blood gene expression data that would re-capitulate the CD8 transcriptional subgroups. Model selection was performed using Bayesian Information Criterion and the genes identified were subsequently tested by qPCR and optimised to produce an 18 gene qPCR assay.ResultsIndependent validation of this biomarker was established using a second, independent cohort of 85 newly diagnosed patients with CD from 4 sites around the United Kingdom. This validated the biomarker and confirmed that the subgroups it identified had significantly different disease courses (analogous to those observed with the CD8 T cell subgroups). The hazard ratio for time to treatment escalation in this validation cohort was 3.52 (1.84–6.76, 95% confidence intervals, p=0.0002). We now propose to conduct the first ever biomarker-stratified trial in any inflammatory disease to determine whether this biomarker can deliver personalised medicine in CD.ConclusionWe have developed, optimised and validated a whole blood qPCR classifier that is able to predict disease course from diagnosis in IBD patients. This represents a major step towards personalised therapy in IBD, and we will soon investigate whether this could make personalised medicine a reality in CD.Disclosure of InterestNone Declared
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- 2017
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25. TUMOUR NECROSIS FACTOR ALPHA (TNF) GENE HAPLOTYPES AND PRIMARY SCLEROSING CHOLANGITIS.
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Cullen, S.N., Ahmad, T., Neville, M., Walton, R.W., Jewell, D.P., and Chapman, R.W.
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TUMOR necrosis factors , *PROMOTERS (Genetics) , *GENETIC polymorphisms - Abstract
Background: Previous studies have demonstrated an association between susceptibility to primary sclerosing cholangitis (PSC) and alleles on the classical autoimmune haplotype including the TNF promoter polymorphism TNF-308A. This study was designed to examine the association of PSC with 5 other polymorphic sites in the TNF promoter region. Methods: 100 patients with accurately characterised PSC, and 357 healthy controls were studied. Genotyping of 6 TNF promoter polymorphisms and high resolution class I and class Il HLA typing was carried out using PCR-SSP. SNPs within the TNF gene were constructed into gene haplotypes using the statistical computer software, PHASE. Analysis was carried out using a Chi-squared test with a Bonferroni correction factor of 7.Results: See Table. Conclusion: PSC is associated with TNF haplotype 2. This contains the variant allele -308A, which has previously been described in association with PSC. This allele is found on the highly conserved autoimmune haplotype A1 B8 DR3. An association between TNF -308A and PSC independent of other alleles on this haplotype was not found. Dissecting out the primary associated allele requires the study of a greater number of informative recombinant haplotypes which can only be achieved by much larger international collaborative studies. [ABSTRACT FROM AUTHOR]
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- 2003
26. NOD2/CARD15 MUTATIONS IN THE EXTRAINTESTINAL MANIFESTATIONS (EIMS) OF INFLAMMATORY BOWEL DISEASE.
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Orchard, T.R., Ahmad, T., and Jewell, D.P.
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INFLAMMATION , *IMMUNE response , *CROHN'S disease - Abstract
Introduction: There has been much interest in the role of the innate immune system in inflammatory rheumatological conditions. CARD15 plays an important role in triggering an immune response to bacterial LPS, and polymorphisms in this gene are associated with Crohn's disease (CD). We have previously shown a genetic predisposition to ElMs, and have demonstrated abnormalities in the humoral immune response to enterobacteria in patients with arthritis associated with IBD. This study was performed to investigate whether polymorphisms in the CARD15 gene are associated with the presence of ElMs in IBD. Methods: DNA was obtained from 104 patients who had suffered Type 1 or Type 2 peripheral arthritis, erythema nodosum (EN) or uveitis (60 Crohn's disease and 44 ulcerative colitis). Genotyping for the 3 common po ymorphisms of CARD15 (Arg702Trp, Gly908Arg, and Leu1007fsinsC) was undertaken by SSP PCR, and allele frequencies were compared with 354 healthy controls and 244 CD patients. Results: Allele frequencies (%) are shown in the table below: ElMs were significantly associated with CARD15 polymorphisms, when compared to controls, particularly type 1 arthritis and EN. Further analysis was undertaken by IBD diagnosis, and the association between CARD15 polymorphisms and ElMs was seen in both UC and Crohn's patients. Discussion: CARD15 polymorphisms may be important in determining the ElMs of IBD, suggesting that bacteria may trigger them. Further studies are required to confirm these associations, and to investigate the interaction with previously described HLA associations. [ABSTRACT FROM AUTHOR]
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- 2003
27. PWE-066 Clinical features of demyelination during anti-tnf therapy: preliminary outcomes of the pred4 study
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Hendy, P, Heerasing, N, Walker, G, Heap, G, Bewshea, C, Kennedy, N, Goodhand, J, Harrower, T, Hobart, J, Spiers, A, Coles, A, Martin, R, and Ahmad, T
- Abstract
IntroductionAnti-TNFα therapy has been associated with demyelination since early trials in Multiple Sclerosis (MS) demonstrated disease worsening.Subsequent small case series have reported plausible clinical associations although epidemiological studies have produced conflicting data.The specific clinical features of demyelination following anti-TNF therapy have not been described.This study uses a systematic independent assessment of causality to describe the clinical characteristics and outcomes of anti-TNFα associated demyelination.MethodPatients were recruited from 28 hospitals.Inclusion criteria included i)no history of neurological symptoms prior to anti-TNFα exposure,ii)MRI brain and/or spinal cord or electrophysiological tests consistent with PNS or CNS demyelination,iii)demyelination illness confirmed by neurologist and drug withdrawn.An adjudication panel comprising at least 3 neurologists and a neuro-radiologist identified definite and probable cases from case report forms.Probable cases required a consistent history and signs and objective radiological±electrophysiological evidence of demyelination.Definite cases had a recurrence of demyelination on drug rechallenge.Results54 cases were recruited, of whom 35 (24 female) were adjudicated as definite or probable cases. Adalimumab,Infliximab,Etanercept and Certolizumab were implicated in 17/35 (49%), 15/35 (43%), 5/35 (14%), and 1/35 (3%) of cases respectively.Average age of symptom onset was 40 (95%CI 37–44) years. The mean duration of anti-TNFα exposure was 27 (95%CI 18–36) months prior to symptom onset onset of demyelination. 22 cases (63%) presented with brain ± spinal lesions, 8 (23%) spine only demyelination, and 5 (14%) peripheral demyelination.On drug withdrawal patients were followed for a mean of 42 (95%CI 32–52) months.Of those with CNS lesions, 11/30 (37%) developed a relapsing demyelinating syndrome or MS and only 5/30 (17%) had complete resolution of their symptoms with a mean time to resolution of 419 days (95% CI 36–802).ConclusionThis large case series adds comprehensive clinical information to the existing reports of demyelinating events associated with anti-TNFα therapy for inflammatory disorders.Consistent with known risk factors for MS, young females appear to be over represented.Over one third of patients appear to develop a relapsing illness/MS and complete neurological recovery is uncommon.We aim to build this cohort further so that we might explore clinically useful genetic markers that identify at-risk patients.Disclosure of InterestNone Declared
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- 2017
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28. PWE-047 The impact of infliximab (ifx) therapeutic drug monitoring on decisions made in a virtual biologics clinic for ibd
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Selinger, C, Lenti, M, Clark, T, Rafferty, H, O’Connor, A, Ahmad, T, and Hamlin, J
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IntroductionVirtual biologics clinics (VBC) are used to review annually patients receiving biological therapy. Decisions on continuing, switching or stopping therapy are based on review of clinical symptoms, disease history and investigations. Therapeutic drug monitoring (TDM) of Infliximab trough levels (ITL) and anti-drug antibodies (ADA) has previously not been universally available in the UK. The aim of this study was to assess whether access to TDM influences decision making within VBC.MethodAll IBD patients receiving Infliximab maintenance therapy were reviewed and two treatment decisions were recorded. The first decision was based on assessment of all clinical details but clinicians remained blinded to ITL and ADA data (Biohit assay). An administrator revealed ITL and ADA data and clinicians formed a second decision incorporating TDM. Decisions were standardised to: A - continue without change B -shorten infusion interval/increase IFX dose C - lengthen infusion interval D - stop IFX E - other.N= blindN= unblindedA169 122B9 16C5 15D5 28E3 122ResultsOf 201 patients reviewed TDM data were available for 191 (mean 40y old, 57% male). Diagnoses were Crohn’s disease in 160, ulcerative colitis in 18 and IBD-U in 13 cases. Mean duration of IFX treatment was 4 years (minimum 6 months), 57% received co-therapy with immunomodulator and 38% had shortened infusion intervals. Disease activity was remission in 70%, mild in 19%, moderate in 10% and severe in 1%. ITL were sub-therapeutic in 25% (<1.8 mg/L), therapeutic in 61% and supra-therapeutic in 14% (>7 mg/L); mean ITL was 3.85 mg/L. ADA were detected in 30% and were >50 AU/ml in 14%. Blinded treatment decisions were changed on unblinded review in 56 cases (29%, table 1, chi-square test: p<0.0001). Knowledge of ITL and ADA led to 7 patients receiving higher dose IFX or more frequent infusions whereas 33 patients were able to dose de-escalate or stop IFX therapy.DecisionConclusionBasing decisions on TDM rather than clinical acumen alone led to change in 29%. An additional 23 patients discontinued therapy (undetectable ITL + high ADA). This represents a considerable cost saving and reduces the exposure to potentially toxic therapies. Routine TDM should be considered as an integral part of VBC.Disclosure of InterestNone Declared
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- 2017
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29. PTH-092 Clinical validity and utility of faecal calprotectin in primary care
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Walker, GJ, Moore, L, Heerasing, N, Hendy, PJ, Bewshea, C, Goodhand, JR, Kennedy, NA, Calvert, C, and Ahmad, T
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IntroductionFaecal Calprotectin (FC) is recommended in primary care (1°care) to help differentiate inflammatory bowel disease (IBD) from irritable bowel syndrome (IBS), although data to justify this practice are limited.1,2In 2014 we introduced FC to 1°care and in parallel conducted a large prospective observational study to assess the clinical validity and utility of FC in this setting, and develop an integrated decision tool.MethodGPs from 57 local practices were recommended to submit an FC test for patients with suspected or possible IBD. Criteria for testing included age <46 years and a low suspicion of colorectal cancer (CRC). A request form captured patient symptoms and referral intentions. We used the following cut-offs: negative <50 µg/g, indeterminate 50–99 µg/g, positive ≥100 µg/g. We advised referral of patients with elevated FC and GP management for negative tests. Indeterminate tests were repeated. All patients were followed-up for ≥12 months and clinical data captured from 1° and 2°care records. We assessed the impact of FC on referral practice, time to diagnosis and endoscopic activity.Results1143 FC tests were submitted (Jan’14-Mar’16), with 761 used in this interim analysis. 458 (59%) were female and median age was 30 years. 50 (7%) patients were diagnosed with IBD, one (0.2%) with an adenoma ≥1 cm and none with CRC. FC≥100 µg/g had a sensitivity=0.92, specificity=0.75, PPV=0.21, NPV=0.99 (AUROC=0.83 [95%CI 0.79–0.87]) for IBD. False negative FC tests occurred in 4 patients later diagnosed with IBD. Red-flag symptoms were reported in 411 (54%) of all patients, 194 (47%) of whom were not referred to 2°care. FC was negative in 520 (68%), and yet 169 (33%) of this group were sill referred to GI services. Multivariable logistic regression demonstrated FC (log10FC=OR 48.2, p<0.01), family history (FHx) of IBD (OR 2.8, p=0.05), and rectal bleeding (OR 3.0, p<0.01) as the best predictors of IBD (R20.50). Based on pre-test referral intentions FC saved 252 referrals. The median time from GP referral to IBD diagnosis was 45 days (IQR 25–98).ConclusionFC is a sensitive and specific test in the primary care setting to distinguish IBD from IBS. It reduces referrals and subsequent endoscopic investigations in patients<46 years including those with red-flag symptoms, but deemed at low risk of CRC. However, a third of patients with a normal FC are still referred. This may reflect lack of confidence in FC and the challenges of managing some IBS patients. We propose a future clinical decision tool integrating FC with rectal bleeding and FHx IBD to facilitate rapid patient identification for secondary care referral.References. Waugh N, et al. doi:10.3310/hta17550(2013). NICE DG11 (2013).Disclosure of InterestNone Declared
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- 2017
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30. ANALYSIS OF THE CC CHEMOKINE RECEPTOR CCR5 δ32 MUTATION IN BEHCET'S DISEASE.
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Yang, X., Ahmad, T., Gogus, F., Wallace, G., Madanat, W., Kanawati, C.A., Yazici, H., Marshall, S.E., and Jewell, D.P.
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BEHCET'S disease , *INFLAMMATION , *UVEITIS , *CHEMOKINES - Abstract
Background: Behcet's disease (BD) is a chronic multi-system inflammatory disorder characterized by recurrent oral and genital inflammation, uveitis and pathergy. Reports of an association between HIV-I infection and BD suggest that retroviruses may play a role in the pathogenesis of this disease. Chemokine receptor CCR5 acts as a co-receptor permitting entry of the HIV-1 virus into CD4-positive T cells. Here we investigate whether a 32bp deletion of this gene (CCR5 832), implicated in susceptibility to, and progression of, HIV disease, is associated with BD. Methods: We studied 350 BD patients and 559 healthy ethnically matched controls recruited from 3 ethnic groups (Turkish: 109 BD, 96 controls; Palestinian 100 BD, 98 controls; UK white Caucasian: 131 BD, 365 controls). Genotyping for the CCR5 δ32 deletion was perfomed using PCR-SSP. Data were stratified by the presence of HLAB[sup *]51, an allele previously shown to be associated with BD in the 3 ethnic groups. Results: The CCR5 832 allele was significantly more common in UK white Caucasians than in either the Turkish or Palestinian cohorts (control allele frequency 14.2%, 4.2% and 0.5% respectively: P<1×10[sup 8]). No association was found with the CCR5 832 allele and BD in any of the three cohorts, even when stratified by the BD associated allele HLA-B[sup *]51. Conclusions: The CCR5 δ32 allele is common in UK white Caucasians but rare in both Turkish and Palestinian populations. The CCR5 δ32 allele is not associated with Behcet's disease in white UK Caucasians, Turkish, or Palestinian populations. [ABSTRACT FROM AUTHOR]
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- 2003
31. INNATE IMMUNOGENETICS AND INFLAMMATORY BOWEL DISEASE (IBD).
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McGovern, D.P.B., van Heel, D.A., Negoro, K., Ahmad, T., and Jewell, D.P.
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CROHN'S disease ,DISEASE susceptibility ,NUCLEOTIDES - Abstract
Background: The identification of NOD2(CARD15) as a susceptibility gene for Crohn's disease (CD) confirms the role of innate immunity in IBD. More recently a haplotype at IBD5 (Ch 5) has shown association with CD. Aims: To identify and test innate immunity single nucleotide polymorphisms (SNPs) for association with IBD. Methods: Interesting (positional and functional) SNPs were identified from databases or by direct sequencing. A two-stage approach was adopted to overcome problems of multiple testing. Stage 1: Casecontrol analysis (191 CD, 247 ulcerative colitis (UC) and 240 controls (HC)). Stage 2: Positive results from stage 1 to be confirmed by the transmission-disequilibrium test (TDT) (556 IBD (294 CD and 252 UC) trios). AIl results were stratified by phenotype and NOD2/IBD5 geno. Results: Case-control analysis (all % allele frequency (p value)): Toll-like receptor (TLR) 2, 3 intronic SNPs and 1 microsatellite marker, no IBD association. TLR2 'bacterial hyporesponsive' SNP (R753Q), HC 4.0, IBD 2.5 (0.13), UC 2.4 (0.12) and CD 2.6 (0.25). Fulminant UC requiring surgery (130 cases) 4.3%, 'mild' UC not requiring surgery (135 cases) 0.4% (0.0032)(OR 0.08). TLR4 SNP (bronchial hypo-responsiveness) HC 4.4, CD 3.1 (0.34) and UC (4.9 (0.71). Two novel MAL (TIRAP) SNPs, 4 novel Triggering receptor expressed on myeloid cells -1 (TREM-1) SNPs, TLR9 SNP, 4 P2X7 SNPs, and lactoferrin SNP, all-no association seen with any IBD geno- or phenotype. TDT analysis (transmissions/non-transmissions): TLR4 SNP (A896G): IBD 64/44 (0.054), UC 11/11, CD 36/23 (0.098), CD NOD2 negative 28/18 (0.14). Conclusions: These innate immunity SNPs are not significantly associated with IBD. The colectomy, non-colectomy TLR2 association suggests that intact innate immunity is needed for the development of fulminant UC. Studies of other SNPs in the innate immune system and their role in IBD are warranted. [ABSTRACT FROM AUTHOR]
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- 2003
32. Considerations for peripheral blood transport and storage during large-scale multicentre metabolome research.
- Author
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Alexander JL, Wyatt NJ, Camuzeaux S, Chekmeneva E, Jimenez B, Sands CJ, Fuller H, Takis P, Ahmad T, Doyle JA, Hart A, Irving PM, Kennedy NA, Lees CW, Lindsay JO, McIntyre RE, Parkes M, Prescott NJ, Raine T, Satsangi J, Speight RA, Jostins-Dean L, Powell N, Marchesi JR, Stewart CJ, and Lamb CA
- Subjects
- Humans, Metabolome, Metabolomics
- Abstract
Competing Interests: Competing interests: None declared.
- Published
- 2024
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33. Withdrawal of the British Society of Gastroenterology IBD risk grid for COVID-19 severity.
- Author
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Lees CW, Ahmad T, Lamb CA, Powell N, Din S, Cooney R, Kennedy NA, Ainley R, Wakeman R, and Selinger CP
- Subjects
- Humans, COVID-19, Gastroenterology, Inflammatory Bowel Diseases diagnosis
- Abstract
Competing Interests: Competing interests: None declared.
- Published
- 2023
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34. Vaccine escape, increased breakthrough and reinfection in infliximab-treated patients with IBD during the Omicron wave of the SARS-CoV-2 pandemic.
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Kennedy NA, Janjua M, Chanchlani N, Lin S, Bewshea C, Nice R, McDonald TJ, Auckland C, Harries LW, Davies M, Michell S, Kok KB, Lamb CA, Smith PJ, Hart AL, Pollok RC, Lees CW, Boyton RJ, Altmann DM, Sebastian S, Powell N, Goodhand JR, and Ahmad T
- Subjects
- Humans, SARS-CoV-2, COVID-19 Vaccines, Infliximab therapeutic use, Pandemics, Reinfection epidemiology, Reinfection prevention & control, BNT162 Vaccine, ChAdOx1 nCoV-19, Antibodies, Viral, COVID-19 epidemiology, COVID-19 prevention & control, Vaccines, Inflammatory Bowel Diseases drug therapy
- Abstract
Objective: Antitumour necrosis factor (TNF) drugs impair serological responses following SARS-CoV-2 vaccination. We sought to assess if a third dose of a messenger RNA (mRNA)-based vaccine substantially boosted anti-SARS-CoV-2 antibody responses and protective immunity in infliximab-treated patients with IBD., Design: Third dose vaccine induced anti-SARS-CoV-2 spike (anti-S) receptor-binding domain (RBD) antibody responses, breakthrough SARS-CoV-2 infection, reinfection and persistent oropharyngeal carriage in patients with IBD treated with infliximab were compared with a reference cohort treated with vedolizumab from the impaCt of bioLogic therApy on saRs-cov-2 Infection and immuniTY (CLARITY) IBD study., Results: Geometric mean (SD) anti-S RBD antibody concentrations increased in both groups following a third dose of an mRNA-based vaccine. However, concentrations were lower in patients treated with infliximab than vedolizumab, irrespective of whether their first two primary vaccine doses were ChAdOx1 nCoV-19 (1856 U/mL (5.2) vs 10 728 U/mL (3.1), p<0.0001) or BNT162b2 vaccines (2164 U/mL (4.1) vs 15 116 U/mL (3.4), p<0.0001). However, no differences in anti-S RBD antibody concentrations were seen following third and fourth doses of an mRNA-based vaccine, irrespective of the combination of primary vaccinations received. Post-third dose, anti-S RBD antibody half-life estimates were shorter in infliximab-treated than vedolizumab-treated patients (37.0 days (95% CI 35.6 to 38.6) vs 52.0 days (95% CI 49.0 to 55.4), p<0.0001).Compared with vedolizumab-treated, infliximab-treated patients were more likely to experience SARS-CoV-2 breakthrough infection (HR 2.23 (95% CI 1.46 to 3.38), p=0.00018) and reinfection (HR 2.10 (95% CI 1.31 to 3.35), p=0.0019), but this effect was uncoupled from third vaccine dose anti-S RBD antibody concentrations. Reinfection occurred predominantly during the Omicron wave and was predicted by SARS-CoV-2 antinucleocapsid concentrations after the initial infection. We did not observe persistent oropharyngeal carriage of SARS-CoV-2. Hospitalisations and deaths were uncommon in both groups., Conclusions: Following a third dose of an mRNA-based vaccine, infliximab was associated with attenuated serological responses and more SARS-CoV-2 breakthrough infection and reinfection which were not predicted by the magnitude of anti-S RBD responses, indicative of vaccine escape by the Omicron variant., Trial Registration Number: ISRCTN45176516., Competing Interests: Competing interests: NAK reports grants from F. Hoffmann-La Roche, grants from Biogen, grants from Celltrion Healthcare, grants from Galapagos, non-financial support from Immundiagnostik, during the conduct of the study; grants and non-financial support from AbbVie, grants and personal fees from Celltrion, personal fees and non-financial support from Janssen, personal fees from Takeda, personal fees and non-financial support from Dr Falk Pharma, outside the submitted work. SL reports non-financial support from Pfizer, non-financial support from Ferring, outside the submitted work. LWH declares an interest in SENISCA as founder and Chief Scientific Officer. KBK reports personal fees from Janssen, personal fees from Takeda, personal fees from PredictImmune, personal fees from Amgen, outside the submitted work. CAL reports grants from Genentech, grants and personal fees from Janssen, grants and personal fees from Takeda, grants from AbbVie, personal fees from Ferring, grants from Eli Lilly, grants from Pfizer, grants from Roche, grants from UCB Biopharma, grants from Sanofi Aventis, grants from Biogen IDEC, grants from Orion OYJ, personal fees from Dr Falk Pharma, grants from AstraZeneca, outside the submitted work. PJS reports speaker fees and advisory board sponsorship from Janssen, Celltrion, AbbVie, Tillotts Pharma, Galapagos, Amgen, Dr Falk Pharma and Takeda outside the submitted work. AH reports personal fees from AbbVie, personal fees from Allergan, personal fees from BMS, personal fees from Celltrion, personal fees from Dr Falk Pharma, personal fees from GSK, personal fees from Takeda, personal fees from Pfizer, personal fees from Janssen, personal fees from Galapogos, personal fees from AstraZeneca, outside the submitted work. RCP reports acting as consultant, advisory board member, speaker or recipient of educational grant from Dr Falk Pharma, Ferring, Janssen, Pharmacosmos and Takeda, outside the submitted work. CWL reports personal fees from AbbVie, personal fees from Janssen, personal fees from Pfizer, personal fees from Takeda, grants from Gilead, personal fees from Gilead, personal fees from Galapagos, personal fees from Iterative Scopes, personal fees from Trellus Health, personal fees from Celltion, personal fees from Ferring, personal fees from BMS, during the conduct of the study. RB and DA are members of the Global T cell Expert Consortium and have consulted for Oxford Immunotec outside the submitted work. SS reports grants from Takeda, AbbVie, Amgen, Tillots Pharma, personal fees from Jaansen, Takeda, Galapagos, Celltrion, Dr Falk Pharma, Tillots Pharma, Cellgene, Pfizer, Pharmacocosmos, outside the submitted work. NP reports personal fees from Takeda, personal fees from Janssen, personal fees from Pfizer, personal fees from Bristol-Myers Squibb, personal fees from AbbVie, personal fees from Roche, personal fees from Lilly, personal fees from Allergan, personal fees from Celgene, outside the submitted work; and NP has served as a speaker/advisory board member for AbbVie, Allergan, Bristol-Myers Squibb, Celgene, Dr Falk Pharma, Ferring, Janssen, Pfizer, Tillotts Pharma, Takeda and Vifor Pharma. JRG reports grants from F. Hoffmann-La Roche, grants from Biogen, grants from Celltrion Healthcare, grants from Galapagos, non-financial support from Immundiagnostik, during the conduct of the study. TA reports grants and non-financial support from F. Hoffmann-La Roche, grants from Biogen, grants from Celltrion Healthcare, grants from Galapagos, non-financial support from Immundiagnostik, during the conduct of the study; personal fees from Biogen, grants and personal fees from Celltrion Healthcare, personal fees and non-financial support from Immundiagnostik, personal fees from Takeda, personal fees from ARENA, personal fees from Gilead, personal fees from Adcock Ingram Healthcare, personal fees from Pfizer, personal fees from Genentech, non-financial support from Tillotts Pharma, outside the submitted work., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2023
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35. Infliximab is associated with attenuated immunogenicity to BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines in patients with IBD.
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Kennedy NA, Lin S, Goodhand JR, Chanchlani N, Hamilton B, Bewshea C, Nice R, Chee D, Cummings JF, Fraser A, Irving PM, Kamperidis N, Kok KB, Lamb CA, Macdonald J, Mehta S, Pollok RC, Raine T, Smith PJ, Verma AM, Jochum S, McDonald TJ, Sebastian S, Lees CW, Powell N, and Ahmad T
- Subjects
- Adult, Antibodies, Monoclonal, Humanized therapeutic use, Antibodies, Viral immunology, Antibody Formation immunology, BNT162 Vaccine, COVID-19 immunology, COVID-19 Vaccines administration & dosage, ChAdOx1 nCoV-19, Female, Humans, Male, Middle Aged, SARS-CoV-2, Serologic Tests, COVID-19 prevention & control, COVID-19 Vaccines immunology, Gastrointestinal Agents adverse effects, Inflammatory Bowel Diseases drug therapy, Infliximab therapeutic use
- Abstract
Objective: Delayed second dose SARS-CoV-2 vaccination trades maximal effectiveness for a lower level of immunity across more of the population. We investigated whether patients with inflammatory bowel disease treated with infliximab have attenuated serological responses to a single dose of a SARS-CoV-2 vaccine., Design: Antibody responses and seroconversion rates in infliximab-treated patients (n=865) were compared with a cohort treated with vedolizumab (n=428), a gut-selective anti-integrin α4β7 monoclonal antibody. Our primary outcome was anti-SARS-CoV-2 spike (S) antibody concentrations, measured using the Elecsys anti-SARS-CoV-2 spike (S) antibody assay 3-10 weeks after vaccination, in patients without evidence of prior infection. Secondary outcomes were seroconversion rates (defined by a cut-off of 15 U/mL), and antibody responses following past infection or a second dose of the BNT162b2 vaccine., Results: Geometric mean (SD) anti-SARS-CoV-2 antibody concentrations were lower in patients treated with infliximab than vedolizumab, following BNT162b2 (6.0 U/mL (5.9) vs 28.8 U/mL (5.4) p<0.0001) and ChAdOx1 nCoV-19 (4.7 U/mL (4.9)) vs 13.8 U/mL (5.9) p<0.0001) vaccines. In our multivariable models, antibody concentrations were lower in infliximab-treated compared with vedolizumab-treated patients who received the BNT162b2 (fold change (FC) 0.29 (95% CI 0.21 to 0.40), p<0.0001) and ChAdOx1 nCoV-19 (FC 0.39 (95% CI 0.30 to 0.51), p<0.0001) vaccines. In both models, age ≥60 years, immunomodulator use, Crohn's disease and smoking were associated with lower, while non-white ethnicity was associated with higher, anti-SARS-CoV-2 antibody concentrations. Seroconversion rates after a single dose of either vaccine were higher in patients with prior SARS-CoV-2 infection and after two doses of BNT162b2 vaccine., Conclusion: Infliximab is associated with attenuated immunogenicity to a single dose of the BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines. Vaccination after SARS-CoV-2 infection, or a second dose of vaccine, led to seroconversion in most patients. Delayed second dosing should be avoided in patients treated with infliximab., Trial Registration Number: ISRCTN45176516., Competing Interests: Competing interests: NAK reports grants from F. Hoffmann-La Roche AG, grants from Biogen Inc, grants from Celltrion Healthcare, grants from Galapagos NV, non-financial support from Immundiagnostik, during the conduct of the study; grants and non-financial support from AbbVie, grants and personal fees from Celltrion, personal fees and non-financial support from Janssen, personal fees from Takeda, personal fees and non-financial support from Dr Falk, outside the submitted work. SL reports non-financial support from Pfizer, non-financial support from Ferring, outside the submitted work. JRG reports grants from F. Hoffmann-La Roche AG, grants from Biogen, grants from Celltrion Healthcare, grants from Galapagos NV, non-financial support from Immundiagnostik, during the conduct of the study. DC reports non-financial support from Ferring, personal fees and non-financial support from Pfizer, outside the submitted work. JRFC reports grants and personal fees from Samsung, Pfizer & Biogen; personal fees and non-financial support from Janssen & Abbvie; grants, personal fees and non-financial support from Takeda; personal fees from MSD, Sandoz, Celltrion & NAPP, outside the submitted work. AF reports personal fees from Takeda UK Ltd, personal fees from Dr Falk Pharma, personal fees from Tillotts, personal fees from Abbvie Ltd, personal fees from Sheild, personal fees from Ferring, from Pharmacosmos, personal fees from Allergan, personal fees from Janssen, outside the submitted work. PMI reports grants and personal fees from Takeda, grants from MSD, grants and personal fees from Pfizer, personal fees from Galapagos, personal fees from Gilead, personal fees from Abbvie, personal fees from Janssen, personal fees from Boehringer Ingelheim, personal fees from Topivert, personal fees from VH2, personal fees from Celgene, personal fees from Arena, personal fees from Samsung Bioepis, personal fees from Sandoz, personal fees from Procise, personal fees from Prometheus, outside the submitted work. NK reports personal fees from Janssen, outside the submitted work. KBK reports personal fees from Janssen, personal fees from Takeda, personal fees from PredictImmune, personal fees from Amgen, outside the submitted work. CAL reports grants from Genentech, grants and personal fees from Janssen, grants and personal fees from Takeda, grants from AbbVie, personal fees from Ferring, grants from Eli Lilly, grants from Pfizer, grants from Roche, grants from UCB Biopharma, grants from Sanofi Aventis, grants from Biogen IDEC, grants from Orion OYJ, personal fees from Dr Falk Pharma, grants from AstraZeneca, outside the submitted work. JM reports grants and personal fees from Takeda Pharmaceuticals, grants and personal fees from Biogen, personal fees and non-financial support from AbbVie, personal fees from Grifols, personal fees from Sandoz, personal fees from Celltrion, personal fees and non-financial support from Janssen, personal fees from Vifor Pharmaceuticals, personal fees from Predictimmune, personal fees from Bristol Myers Squibb, non-financial support from Ferring Pharmaceuticals, outside the submitted work. RCGP reports acting as consultant, advisory board member, speaker or recipient of educational grant from Dr Falk, Ferring, Janssen, Pharmacosmos and Takeda. TR reports grants and personal fees from Abbvie, personal fees from BMS, personal fees from Celgene, personal fees from Ferring, personal fees from Gilead, personal fees from GSK, personal fees from LabGenius, personal fees from Janssen, personal fees from Mylan, personal fees from MSD, personal fees from Novartis, personal fees from Pfizer, personal fees from Sandoz, personal fees from Takeda, personal fees from Galapagos, personal fees from Arena, outside the submitted work. PJS reports speaker fees and advisory board sponsorship from Janssen, Celltrion and Takeda outside the submitted work. AMV reports personal fees and non-financial support from Takeda, personal fees and non-financial support from Celltrion, personal fees and non-financial support from Merck Sharp & Dohme, outside the submitted work. SJ is an employee of Roche Diagnostics and holds Roche shares. SS reports grants from Takeda, Abbvie, AMGEN, Tillots Pharma, personal fees from Jaansen, Takeda, Galapagos, Celltrion, Falk Pharma, Tillots pharma, Cellgene, Pfizer, Pharmacocosmos, outside the submitted work. CWL reports personal fees from Abbvie, personal fees from Janssen, personal fees from Pfizer, personal fees from Takeda, grants from Gilead, personal fees from Gilead, personal fees from Galapagos, personal fees from Iterative Scopes, personal fees from Trellus Health, personal fees from Celltion, personal fees from Ferring, personal fees from BMS, during the conduct of the study. NP reports personal fees from Takeda, personal fees from Janssen, personal fees from Pfizer, personal fees from Bristol-Myers Squibb, personal fees from Abbvie, personal fees from Roche, personal fees from Lilly, personal fees from Allergan, personal fees from Celgene, outside the submitted work; and NP has served as a speaker/advisory board member for Abbvie, Allergan, Bristol Myers Squibb, Celgene, Falk, Ferring, Janssen, Pfizer, Tillotts, Takeda and Vifor Pharma. TA reports grants and non-financial support from F. Hoffmann-La Roche AG, grants from Biogen Inc, grants from Celltrion Healthcare, grants from Galapagos NV, non-financial support from Immundiagnostik, during the conduct of the study; personal fees from Biogen, grants and personal fees from Celltrion Healthcare, personal fees and non-financial support from Immundiagnostik, personal fees from Takeda, personal fees from ARENA, personal fees from Gilead, personal fees from Adcock Ingram Healthcare, personal fees from Pfizer, personal fees from Genentech, non-financial support from Tillotts, outside the submitted work., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2021
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36. Anti-SARS-CoV-2 antibody responses are attenuated in patients with IBD treated with infliximab.
- Author
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Kennedy NA, Goodhand JR, Bewshea C, Nice R, Chee D, Lin S, Chanchlani N, Butterworth J, Cooney R, Croft NM, Hart AL, Irving PM, Kok KB, Lamb CA, Limdi JK, Macdonald J, McGovern DP, Mehta SJ, Murray CD, Patel KV, Pollok RC, Raine T, Russell RK, Selinger CP, Smith PJ, Bowden J, McDonald TJ, Lees CW, Sebastian S, Powell N, and Ahmad T
- Subjects
- Adult, Antibodies, Monoclonal, Humanized therapeutic use, COVID-19 epidemiology, Female, Humans, Male, Middle Aged, Prospective Studies, Serologic Tests, United Kingdom epidemiology, Antibodies, Viral immunology, Antibody Formation immunology, Gastrointestinal Agents therapeutic use, Inflammatory Bowel Diseases drug therapy, Infliximab therapeutic use, SARS-CoV-2 immunology
- Abstract
Objective: Antitumour necrosis factor (anti-TNF) drugs impair protective immunity following pneumococcal, influenza and viral hepatitis vaccination and increase the risk of serious respiratory infections. We sought to determine whether infliximab-treated patients with IBD have attenuated serological responses to SARS-CoV-2 infections., Design: Antibody responses in participants treated with infliximab were compared with a reference cohort treated with vedolizumab, a gut-selective anti-integrin α4β7 monoclonal antibody that is not associated with impaired vaccine responses or increased susceptibility to systemic infections. 6935 patients were recruited from 92 UK hospitals between 22 September and 23 December 2020., Results: Rates of symptomatic and proven SARS-CoV-2 infection were similar between groups. Seroprevalence was lower in infliximab-treated than vedolizumab-treated patients (3.4% (161/4685) vs 6.0% (134/2250), p<0.0001). Multivariable logistic regression analyses confirmed that infliximab (vs vedolizumab; OR 0.66 (95% CI 0.51 to 0.87), p=0.0027) and immunomodulator use (OR 0.70 (95% CI 0.53 to 0.92), p=0.012) were independently associated with lower seropositivity. In patients with confirmed SARS-CoV-2 infection, seroconversion was observed in fewer infliximab-treated than vedolizumab-treated patients (48% (39/81) vs 83% (30/36), p=0.00044) and the magnitude of anti-SARS-CoV-2 reactivity was lower (median 0.8 cut-off index (0.2-5.6) vs 37.0 (15.2-76.1), p<0.0001)., Conclusions: Infliximab is associated with attenuated serological responses to SARS-CoV-2 that were further blunted by immunomodulators used as concomitant therapy. Impaired serological responses to SARS-CoV-2 infection might have important implications for global public health policy and individual anti-TNF-treated patients. Serological testing and virus surveillance should be considered to detect suboptimal vaccine responses, persistent infection and viral evolution to inform public health policy., Trial Registration Number: ISRCTN45176516., Competing Interests: Competing interests: NAK reports grants from F. Hoffmann-La Roche AG, grants from Biogen Inc, grants from Celltrion Healthcare, grants from Galapagos NV, non-financial support from Immundiagnostik, during the conduct of the study; grants and non-financial support from AbbVie, grants and personal fees from Celltrion, personal fees and non-financial support from Janssen, personal fees from Takeda, personal fees and non-financial support from Dr Falk, outside the submitted work. JRG reports grants from F. Hoffmann-La Roche AG, grants from Biogen Inc, grants from Celltrion Healthcare, grants from Galapagos NV, non-financial support from Immundiagnostik, during the conduct of the study. DC reports non-financial support from Ferring, personal fees and non-financial support from Pfizer, outside the submitted work. SL reports non-financial support from Pfizer, non-financial support from Ferring, outside the submitted work. RC reports personal fees from Takeda, outside the submitted work. NMC reports trial funding, advisory board and speaker fees paid to his institution from AbbVie, Eli Lilly, Takeda, Shire, Pfizer and Janssen. ALH reports personal fees from Abbvie, personal fees from Allergan, personal fees from BMS, personal fees from Celltrion, personal fees from Falk, personal fees from GSK, personal fees from Takeda, personal fees from Pfizer, personal fees from Janssen, personal fees from Galapogos, personal fees from Astra Zeneca, outside the submitted work. PMI reports grants and personal fees from Takeda, grants from MSD, grants and personal fees from Pfizer, personal fees from Galapagos, personal fees from Gilead, personal fees from Abbvie, personal fees from Janssen, personal fees from Boehringer Ingelheim, personal fees from Topivert, personal fees from VH2, personal fees from Celgene, personal fees from Arena, personal fees from Samsung Bioepis, personal fees from Sandoz, personal fees from Procise, personal fees from Prometheus, outside the submitted work. KBK reports personal fees from Janssen, personal fees from Takeda, personal fees from PredictImmune, personal fees from Amgen, outside the submitted work. CAL reports grants from Genentech, grants and personal fees from Janssen, grants and personal fees from Takeda, grants from AbbVie, personal fees from Ferring, grants from Eli Lilly, grants from Pfizer, grants from Roche, grants from UCB Biopharma, grants from Sanofi Aventis, grants from Biogen IDEC, grants from Orion OYJ, personal fees from Dr Falk Pharma, grants from AstraZeneca, outside the submitted work. JKL reports personal fees from MSD, personal fees from Janssen, grants and personal fees from Takeda, grants and personal fees from Galapagos, personal fees from Tillotts, outside the submitted work. JM reports grants and personal fees from Takeda Pharmaceuticals, grants and personal fees from Biogen, personal fees and non-financial support from AbbVie, personal fees from Grifols, personal fees from Sandoz, personal fees from Celltrion, personal fees and non-financial support from Janssen, personal fees from Vifor Pharmaceuticals, personal fees from Predictimmune, personal fees from Bristol Myers Squibb, non-financial support from Ferring Pharmaceuticals, outside the submitted work. DPBM reports grants from the Leona M. and Harry B. Helmsley Charitable Trust, during the conduct of the study; personal fees from Takeda Pharmaceuticals, personal fees from Pfizer, personal fees from Bridge Biotherapeutics, personal fees from Palatin Technologies, personal fees from Boehringer-Ingelheim, personal fees and other from Prometheus Biosciences, personal fees from Gilead, outside the submitted work. KVP reports personal fees and non-financial support from Takeda, personal fees and non-financial support from Janssen, personal fees and non-financial support from Abbvie, personal fees from DrFalk, non-financial support from Ferring, outside the submitted work. RCGP reports acting as consultant, advisory board member, speaker or recipient of educational grant from Dr Falk, Ferring, Janssen, Pharmacosmos and Takeda. TR reports grants and personal fees from Abbvie, personal fees from BMS, personal fees from Celgene, personal fees from Ferring, personal fees from Gilead, personal fees from GSK, personal fees from LabGenius, personal fees from Janssen, personal fees from Mylan, personal fees from MSD, personal fees from Novartis, personal fees from Pfizer, personal fees from Sandoz, personal fees from Takeda, personal fees from Galapagos, personal fees from Arena, outside the submitted work. RKR reports grants from NHS Research Scotland Senior Research Fellowship, personal fees from Nestlé, personal fees from AbbVie, personal fees from Dr Falk, personal fees from Takeda, personal fees from Napp, personal fees from Mead Johnson, personal fees from Nutricia, personal fees from 4D Pharma, outside the submitted work. CPS reports grants and personal fees from AbbVie, grants and personal fees from Janssen, grants and personal fees from Takeda, personal fees from Dr Falk, personal fees from Pfizer, personal fees from Galapagos, personal fees from Arena, personal fees from Fresenius Kabi, outside the submitted work. PJS reports speaker fees and advisory board sponsorship from Janssen, Celltrion and Takeda outside the submitted work. CWL reports personal fees from Abbvie, personal fees from Janssen, personal fees from Pfizer, personal fees from Takeda, grants from Gilead, personal fees from Gilead, personal fees from Galapagos, personal fees from Iterative Scopes, personal fees from Trellus Health, personal fees from Celltion, personal fees from Ferring, personal fees from BMS, during the conduct of the study. SS reports grants from Takeda, Abbvie, AMGEN, Tillots Pharma, personal fees from Jaansen, Takeda, Galapagos, Celltrion, Falk Pharma, Tillots pharma, Cellgene, Pfizer, Phamrmacocosmos, outside the submitted work. NP reports personal fees from Takeda, personal fees from Janssen, personal fees from Pfizer, personal fees from Bristol-Myers Squibb, personal fees from Abbvie, personal fees from Roche, personal fees from Lilly, personal fees from Allergan, personal fees from Celgene, outside the submitted work; and NP has served as a speaker/advisory board member for Abbvie, Allergan, Bristol Myers Squibb, Celgene, Falk, Ferring, Janssen, Pfizer, Tillotts, Takeda and Vifor Pharma. TA reports grants and non-financial support from F. Hoffmann-La Roche AG, grants from Biogen Inc, grants from Celltrion Healthcare, grants from Galapagos NV, non-financial support from Immundiagnostik, during the conduct of the study; personal fees from Biogen Inc, grants and personal fees from Celltrion Healthcare, personal fees and non-financial support from Immundiagnostik, personal fees from Takeda, personal fees from ARENA, personal fees from Gilead, personal fees from Adcock Ingram Healthcare, personal fees from Pfizer, personal fees from Genentech, non-financial support from Tillotts, outside the submitted work., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2021
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37. A blood-based prognostic biomarker in IBD.
- Author
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Biasci D, Lee JC, Noor NM, Pombal DR, Hou M, Lewis N, Ahmad T, Hart A, Parkes M, McKinney EF, Lyons PA, and Smith KGC
- Subjects
- Adult, Biomarkers blood, Diagnosis, Differential, Female, Gene Expression, Gene Expression Profiling methods, Humans, Machine Learning, Male, Middle Aged, Phenotype, Predictive Value of Tests, Prognosis, Reproducibility of Results, Sensitivity and Specificity, Severity of Illness Index, CD8-Positive T-Lymphocytes metabolism, Colitis, Ulcerative blood, Colitis, Ulcerative diagnosis, Crohn Disease blood, Crohn Disease diagnosis
- Abstract
Objective: We have previously described a prognostic transcriptional signature in CD8 T cells that separates patients with IBD into two phenotypically distinct subgroups, termed IBD1 and IBD2. Here we sought to develop a blood-based test that could identify these subgroups without cell separation, and thus be suitable for clinical use in Crohn's disease (CD) and ulcerative colitis (UC)., Design: Patients with active IBD were recruited before treatment. Transcriptomic analyses were performed on purified CD8 T cells and/or whole blood. Phenotype data were collected prospectively. IBD1/IBD2 patient subgroups were identified by consensus clustering of CD8 T cell transcriptomes. In a training cohort, machine learning was used to identify groups of genes ('classifiers') whose differential expression in whole blood recreated the IBD1/IBD2 subgroups. Genes from the best classifiers were quantitative (q)PCR optimised, and further machine learning was used to identify the optimal qPCR classifier, which was locked down for further testing. Independent validation was sought in separate cohorts of patients with CD (n=66) and UC (n=57)., Results: In both validation cohorts, a 17-gene qPCR-based classifier stratified patients into two distinct subgroups. Irrespective of the underlying diagnosis, IBDhi patients (analogous to the poor prognosis IBD1 subgroup) experienced significantly more aggressive disease than IBDlo patients (analogous to IBD2), with earlier need for treatment escalation (hazard ratio=2.65 (CD), 3.12 (UC)) and more escalations over time (for multiple escalations within 18 months: sensitivity=72.7% (CD), 100% (UC); negative predictive value=90.9% (CD), 100% (UC))., Conclusion: This is the first validated prognostic biomarker that can predict prognosis in newly diagnosed patients with IBD and represents a step towards personalised therapy., Competing Interests: Competing interests: DB, JCL, EM, PAL and KGCS are coinventors on a patent covering the method of assessing prognosis in IBD. EM, PAL and KGCS are cofounders and consultants for PredictImmune. JCL is a consultant for PredictImmune., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)
- Published
- 2019
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38. Genetic and microbial factors modulating the ubiquitin proteasome system in inflammatory bowel disease.
- Author
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Cleynen I, Vazeille E, Artieda M, Verspaget HW, Szczypiorska M, Bringer MA, Lakatos PL, Seibold F, Parnell K, Weersma RK, Mahachie John JM, Morgan-Walsh R, Staelens D, Arijs I, De Hertogh G, Müller S, Tordai A, Hommes DW, Ahmad T, Wijmenga C, Pender S, Rutgeerts P, Van Steen K, Lottaz D, Vermeire S, and Darfeuille-Michaud A
- Subjects
- Bacterial Adhesion, Case-Control Studies, Cell Survival, Cells, Cultured, Colitis, Ulcerative enzymology, Colitis, Ulcerative microbiology, Crohn Disease enzymology, Crohn Disease microbiology, Deubiquitinating Enzyme CYLD, Dystroglycans genetics, Epithelial Cells microbiology, Escherichia coli pathogenicity, Genetic Association Studies, Humans, I-kappa B Proteins metabolism, Intestinal Mucosa microbiology, NF-kappa B metabolism, Peptide Hydrolases genetics, Polymorphism, Single Nucleotide, Proteasome Endopeptidase Complex metabolism, Tumor Suppressor Proteins genetics, Ubiquitin Thiolesterase genetics, Ubiquitin-Specific Proteases genetics, Colitis, Ulcerative genetics, Crohn Disease genetics, Epithelial Cells enzymology, Tumor Suppressor Proteins metabolism
- Abstract
Objective: Altered microbiota composition, changes in immune responses and impaired intestinal barrier functions are observed in IBD. Most of these features are controlled by proteases and their inhibitors to maintain gut homeostasis. Unrestrained or excessive proteolysis can lead to pathological gastrointestinal conditions. The aim was to validate the identified protease IBD candidates from a previously performed systematic review through a genetic association study and functional follow-up., Design: We performed a genetic association study in a large multicentre cohort of patients with Crohn's disease (CD) and UC from five European IBD referral centres in a total of 2320 CD patients, 2112 UC patients and 1796 healthy controls. Subsequently, we did an extensive functional assessment of the candidate genes to explore their causality in IBD pathogenesis., Results: Ten single nucleotide polymorphisms (SNPs) in four genes were significantly associated with CD: CYLD, USP40, APEH and USP3. CYLD was the most significant gene with the intronically located rs12324931 the strongest associated SNP (p(FDR)=1.74e-17, OR=2.24 (1.83 to 2.74)). Five SNPs in four genes were significantly associated with UC: USP40, APEH, DAG1 and USP3. CYLD, as well as some of the other associated genes, is part of the ubiquitin proteasome system (UPS). We therefore determined if the IBD-associated adherent-invasive Escherichia coli (AIEC) can modulate the UPS functioning. Infection of intestinal epithelial cells with the AIEC LF82 reference strain modulated the UPS turnover by reducing poly-ubiquitin conjugate accumulation, increasing 26S proteasome activities and decreasing protein levels of the NF-κB regulator CYLD. This resulted in IκB-α degradation and NF-κB activation. This activity was very important for the pathogenicity of AIEC since decreased CYLD resulted in increased ability of AIEC LF82 to replicate intracellularly., Conclusions: Our results reveal the UPS, and CYLD specifically, as an important contributor to IBD pathogenesis, which is favoured by both genetic and microbial factors., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)
- Published
- 2014
- Full Text
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39. Guidelines for the management of inflammatory bowel disease in adults.
- Author
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Mowat C, Cole A, Windsor A, Ahmad T, Arnott I, Driscoll R, Mitton S, Orchard T, Rutter M, Younge L, Lees C, Ho GT, Satsangi J, and Bloom S
- Subjects
- Adult, Anti-Bacterial Agents therapeutic use, Anti-Inflammatory Agents, Non-Steroidal therapeutic use, Delivery of Health Care organization & administration, Diagnostic Techniques, Digestive System, Evidence-Based Medicine methods, Evidence-Based Medicine standards, Gastrointestinal Agents therapeutic use, Glucocorticoids therapeutic use, Humans, Immunosuppressive Agents therapeutic use, Inflammatory Bowel Diseases diagnosis, Nutritional Support methods, Smoking Cessation, United Kingdom, Inflammatory Bowel Diseases therapy
- Abstract
The management of inflammatory bowel disease represents a key component of clinical practice for members of the British Society of Gastroenterology (BSG). There has been considerable progress in management strategies affecting all aspects of clinical care since the publication of previous BSG guidelines in 2004, necessitating the present revision. Key components of the present document worthy of attention as having been subject to re-assessment, and revision, and having direct impact on practice include: The data generated by the nationwide audits of inflammatory bowel disease (IBD) management in the UK in 2006, and 2008. The publication of 'Quality Care: service standards for the healthcare of people with IBD' in 2009. The introduction of the Montreal classification for Crohn's disease and ulcerative colitis. The revision of recommendations for the use of immunosuppressive therapy. The detailed analysis, guidelines and recommendations for the safe and appropriate use of biological therapies in Crohn's disease and ulcerative colitis. The reassessment of the role of surgery in disease management, with emphasis on the importance of multi-disciplinary decision-making in complex cases. The availablity of new data on the role of reconstructive surgery in ulcerative colitis. The cross-referencing to revised guidelines for colonoscopic surveillance, for the management of metabolic bone disease, and for the care of children with inflammatory bowel disease. Use of the BSG discussion forum available on the BSG website to enable ongoing feedback on the published document http://www.bsg.org.uk/forum (accessed Oct 2010). The present document is intended primarily for the use of clinicians in the United Kingdom, and serves to replace the previous BSG guidelines in IBD, while complementing recent consensus statements published by the European Crohn's and Colitis Organisation (ECCO) https://www.ecco-ibd.eu/index.php (accessed Oct 2010).
- Published
- 2011
- Full Text
- View/download PDF
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