Randomized Trial of Ciprofloxacin Doxycycline and Hydroxychloroquine Versus Budesonide in Active Crohn’s Disease (2020)

Type of publication:
Randomised controlled trial

Author(s):
Rhodes J.M.; Subramanian S.; Martin K.; Probert C.; Flanagan P.K.; Horgan G.W.; Mansfield J.; Parkes M.; Hart A.; Dallal H.; Iqbal T.; *Butterworth J.; Culshaw K.

Citation:
Digestive Diseases and Sciences; 2020 [epub ahead of print]

Abstract:
Background: Increased mucosa-associated E. coli are present in Crohn’s disease, but their role in pathogenesis is uncertain. Aim(s): To assess efficacy and safety of an antibiotic/hydroxychloroquine combination effective against E. coli inside macrophages. Method(s): Adults with moderately active disease (CDAI > 220-450 plus C reactive protein >= 5 mg/l and/or fecal calprotectin > 250 mug/g) were randomized to receive (open-label) oral budesonide (Entocort CR 9 mg/day 8 weeks, 6 mg/day 2 weeks, 3 mg/day 2 weeks) or oral ciprofloxacin 500 mg bd, doxycycline 100 mg bd, hydroxychloroquine 200 mg tds for 4 weeks, followed by doxycycline 100 mg bd and hydroxychloroquine 200 mg tds for 20 weeks. Primary endpoints were remission (CDAI <= 150) at 10 weeks, remission maintained to 24 weeks, and remission maintained to 52 weeks. Patients not responding (CDAI fall by > 70) by 10 weeks were invited to crossover onto the alternative therapy. Result(s): Fifty-nine patients were recruited across 8 sites. Including crossover, 39 patients received antibiotics/hydroxychloroquine and 39 received budesonide. At 10 weeks, 24 weeks, and 52 weeks on initial therapy, only 2/27, 2/27, and 1/27 were in remission on antibiotics/hydroxychloroquine compared with 8/32, 1/32, and 1/32 on budesonide (P = 0.092 at 10 weeks). Withdrawals by 10 weeks due to adverse events were seen in 15 receiving antibiotics/hydroxychloroquine and 6 budesonide. Results including crossover were more promising with 9/24 patients receiving antibiotics/hydroxychloroquine per protocol in remission by 24 weeks. No correlation was seen between response to antibiotics/hydroxychloroquine and ASCA/OmpC antibody status or disease location. Conclusion(s): Overall results with this antibiotic/hydroxychloroquine combination were unimpressive, but long-term remission is seen in some patients and justifies further study.

Altmetrics:

Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial (2020)

Type of publication:
Randomised controlled trial

Author(s):
The HALT-IT Trial Collaborators (including *John Jones and *Charlotte Owen)

Citation:
Lancet, 2020; Vol. 395: pp. 1927–36

Abstract:
Background: Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding.
Methods: We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124.
Findings: Between July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid
(5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11952 (99·5%) received the first dose of the allocated
treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the
tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82–1·18).
Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and
placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein
thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of
5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98).
Interpretation: We found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our
results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a
randomised trial.

Link to full-text [Open access, no password required]

Altmetrics:

Practice pattern variability in the management of acute severe colitis: A UK provider survey (2019)

Type of publication:
Journal article

Author(s):
Sebastian S.; Lisle J.; Subramanian S.; Dhar A.; Shenoy A.; Limdi J.; *Butterworth J.; Allen P.B.; Samuel S.; Moran G.; Shenderey R.; Parkes G.; Raine T.; Lobo A.J.; Kennedy N.A.

Citation:
Frontline Gastroenterology; Jul 2020; vol. 11 (no. 4); p. 272-279

Abstract:
Introduction: Lack of comparative trial data on dosing regimens of infliximab in patients with acute severe ulcerative colitis (ASUC) failing intravenous corticosteroids has resulted in variability of rescue regimes in ASUC with potential impact on clinical outcomes. We aimed to evaluate practice variability and physician perspectives in decision-making with rescue therapy. Methodology: An internet-based survey of members of the inflammatory bowel disease (IBD) section of the British Society of Gastroenterology was conducted. The survey evaluated provider characteristics and general practice in the setting of ASUC, followed by a vignette with linked questions.
Result(s): The response rate of the survey was 31% (209/682 IBD section members). 134 (78%) reported they would use standard infliximab dose (5 mg/kg) while 37 (22%) favoured a higher front-loading dose of 10 mg/kg citing low albumin, high C-reactive protein as their reason for their preference. IBD specialists chose the higher front-loading dose more often compared with other gastroenterologists (p=0.01) In the specific case vignette, accelerated induction (AI) was favoured by 51% of the respondents while 25% used the standard induction regime and 19% favoured colectomy. IBD specialists more often favoured AI compared with other gastroenterologists (p=0.03) with the main reason being presence of predictors of low infliximab levels (74%). The reasons cited for favouring standard induction (n=57) included lack of evidence for AI (18), their usual practice (11), unlicensed regime (7), and safety concerns (4).
Conclusion(s): There are significant variations in practice in the use of infliximab rescue therapies with an urgent need for development of care pathways to standardise practice.

Link to full-text [NHS OpenAthens account required]

Infliximab induction regimes in steroid refractory acute severe colitis: A multi-centre retrospective cohort study with propensity score analysis (2019)

Type of publication:
Conference abstract

Author(s):
Sebastian S.; Myers S.; Syed N.; Argyriou K.; Samuel S.; Moran G.; Martin G.; Allen P.B.; *Los L.; *Butterworth J.; Fiske J.; Limdy J.; Ranjan R.; Dhar A.; Cooper B.; Shenoy A.H.; Patel N.; Subramanian S.; Goodoory V.; Shaikh F.; Shenderey R.; Ching H.L.; Lobo A.; Jayasooriya N.; Parkes G.; Brooks J.; Raine T.

Citation:
Journal of Crohn’s and Colitis; Mar 2019; vol. 13

Abstract:
Background: While infliximab is used as rescue therapy for steroid refractory acute severe colitis (ASUC),
between 30 and 40% of patients do not respond and undergo colectomy. Accelerated induction regimes of
infliximab have been proposed to improve response rates. We aimed to evaluate colectomy rates in steroid
refractory ASUC patients receiving standard induction (SI) vs. accelerated induction (AI) of infliximab.
Method(s): Data collected on hospitalised patients receiving rescue therapy for steroid refractory ASUC. The choice of rescue therapy was at the discretion of the treating clinician. Accelerated induction (AI) was defined as receiving second dose of infliximab within 8 days of first rescue therapy or receiving front loading dose of 10 mg/kg. Our primary outcome was the short-term (in-patient, 30 days and 90 days) colectomy rate. Secondary outcomes were 12-month colectomy rates, length of hospital stay (LOS), and complication rates. We used a propensity score analysis with optimal calliper matching using a priori defined high-risk covariates at the start of rescue therapy (albumin, CRP, CRP-albumin ratio, haemoglobin nadir and pancolitis) to reduce potential provider selection bias.
Result(s): A total of 131 patients receiving infliximab rescue therapy were included, of whom 102 patients
received SI and 29 received AI. There was no difference in age, duration of diagnosis, age at rescue therapy,
Montreal class or use of steroids, 5ASAs or thiopurines prior to index admission. In the unmatched overall
cohort, there was no difference in colectomy during index admission (13% vs. 20%, p = 0.26), 30-day colectomy (18% vs. 20%, p = 0.45), 90-day colectomy (20% vs. 24%, p = 0.38) or 6 month colectomy (25% vs. 27%, p = 0.49). The LOS was shorter in the SI group (14.87 +/- 8.1 days vs. 19.31 +/- 5.8 days, p = 0.007). In patients who underwent colectomy, there were no differences in complications or serious infection rates. In the propensity score-matched cohort of 52 patients, there was no difference in overall colectomy rates between SI and AI groups (57% vs. 31%, p = 0.09), but the index admission colectomy (53% vs. 23%, p = 0.045) and 30-day colectomy (57% vs. 27%, p = 0.048) rates were higher in those receiving SI. There was no significant difference in LOS between SI and AI groups (23.6 +/- 4.3 vs. 18.2 +/- 7.1 days, p = 0.09) or in overall complication and infection rates but there was a mortality in AI group.
Conclusion(s): In this retrospective cohort study, there was no difference in overall colectomy rates in ASUC patients receiving different induction dosing regimens of infliximab. However, using propensity score matching, the short-term colectomy rates appear to be better in those receiving accelerated induction regime. A prospective study to confirm findings is planned.

Link to full-text [No password required]

A randomised, multi-centre, double-blind, placebo-controlled study of a targeted release oral cyclosporine formulation in the treatment of mild-to-moderate ulcerative colitis: Efficacy results (2019)

Type of publication:
Conference abstract

Author(s):
Bloom S.; Iqbal T.; Nwokolo C.; *Smith M.; O’Donoghue D.; Hall J.; Dzyngel B.

Citation:
Journal of Crohn’s and Colitis; Mar 2019; vol. 13

Abstract:
Background: Cyclosporine (CsA) is an effective treatment for patients with acute severe ulcerative colitis (UC), and studies have shown that it has an impact on disease activity comparable to the anti-TNF agent,
infliximab.1,2 Concerns regarding systemic toxicities have limited its role to short-term induction therapy and as a bridge to other therapies. ST-0529 is a novel low dose, controlled release formulation of CsA. A Phase 1 dose-ranging study demonstrated that tissue concentrations improved when it is given twice daily (BID).3
Methods: A total of 118 subjects with mild (baseline DAI < 6) or moderate (baseline DAI >= 6) UC were
randomised 1:1 to receive 75 mg ST-0529 once daily or placebo (53 and 65 patients, respectively) for 4 weeks in a multi-centre, randomised, double-blind, placebo-controlled, Phase IIa study. Patients using UC medications (eg low-dose steroids, 5-aminosalicylates, and immunomodulatory agents) on screening could continue them if agreed to maintain a stable dosing regimen during the study. The primary objective was to evaluate the efficacy of ST-0529 in inducing clinical remission (DAI score <=2, with no individual score >1 and rectal bleeding subscore of 0 or 1). The secondary objectives included clinical response, mucosal and histological healing, safety, and tolerability.
Result(s): A numerical although not statistically significant advantage of ST-0529 over placebo was found for rates of clinical remission (ST-0529: 13.2%; placebo: 6.3%, p = 0.2211) and clinical response (ST-0529: 30.2%; placebo: 18.8%, p = 0.1923). There were no differences between the treatment groups for mucosal and histological healing. ST-0529 was safe and well-tolerated. A post hoc subgroup analysis was performed to evaluate effects by disease severity. Clinical remission and clinical response rates in subjects with moderate (baseline DAI >=6) and mild (baseline DAI <6) disease (ITT, N = 118)
Conclusion(s): In this pilot study, ST-0529 given once daily, was safe, well tolerated, and showed a numerically higher, but not statistically significant difference in remission rate in patients with mild-to-moderate UC compared with placebo after 4 weeks of treatment. In the post hoc analysis, differences in the clinical response between treatment subgroups achieved statistical significance in some subgroups, the largest clinical response rate in moderate UC patients taking 5-aminosalicylates and/or steroids. These preliminary data, added to the data from a Phase 1 study, support further development of ST-0529 as a treatment for the induction and maintenance of remission in UC patients with moderate to severe disease. (Table Presented).

Link to full-text [NHS OpenAthens account required]

Coeliac disease (2019)

Type of publication:
Journal article

Author(s):
*Butterworth J.; *Los L.

Citation:
Medicine (United Kingdom); 2019; vol. 47, no. 5, p. 314-319

Abstract:
Coeliac disease (CD) is a common, chronic, immune-mediated small bowel enteropathy resulting from gluten exposure in genetically susceptible individuals. Considerable clinical and immunopathological heterogeneity is seen in newly diagnosed patients, and the diagnosis is not always straightforward even for experienced physicians. Population screening using tissue transglutaminase 2 has revealed a higher prevalence of seropositivity than previously appreciated. There is a wide differential diagnosis for mucosal villous atrophy, crypt hyperplasia and increased intraepithelial lymphocyte concentrations. Life-long adherence to a gluten-free diet is currently the only recommended treatment for CD, although many newer approaches are being explored. CD is rightly described as a multisystem disorder and is associated with other gastrointestinal and non-gastrointestinal related disorders, numerous complications and possibly reduced survival. The landscape has recently expanded with the identification that some patients with symptoms suggestive of CD but without the mucosal changes seem to respond to a gluten-free diet. This group of patients are currently labelled as having non-coeliac gluten sensitivity. Controversy exists over whether this is a separate disease entity. This review briefly discusses the important clinical, immunological and therapeutic aspects of CD.

Diagnostic yield of biliary brushing cytology: A single centre study (2016)

Type of publication:
Conference abstract

Author(s):
*Wasimi M., Azam A.S., Abdullah P., Muzaffar S.

Citation:
Journal of Pathology, March 2016, vol. 238, Supplement 1, p.S19

Abstract:
Introduction: Biliary brushing cytology is a commonly used technique for the diagnosis of extra hepatic biliary and pancreatic malignancy. Despite a high specificity, the sensitivity remains low and variable. British Society of Gastroenterology guidelines recommend cytological analysis of brushing taken from the biliary structure to support diagnosis of malignancy in suspected individuals. We report here a single center experience of diagnostic yield of cytological specimens of biliary brushings. Objectives: (a) To determine the percentage of biliary brushing cytology cases with positive, negative, false positive and false negative results. (b) To determine the positive and negative predictive value of this test in our centre. (c) To see the correlation between cytological, radiological and clinical findings. Methodology: This is a retrospective data analysis of all biliary brushing cytology cases reported over three years from Jan 2012 to Jan 2014. The data was obtained from cytology reports and findings were correlated with the radiological diagnosis, outcome from the MDT meetings and subsequent follow up from the clinic letters. Results: A total of 34 biliary brushing cytology cases were reported between 2012 to 2014. Among them 22 were men and 12 were women. Average age was 69 years (Range 24-92 years). Out of 34, 15 cases (44%) showed presence of malignant cells and all these were true positives with underlying pancreatic and biliary malignancy. Among the remaining 19 cases, 10 cases were true negatives and 9 cases were false negatives. In our cohort, the specificity of biliary brushing cytology was 100% and sensitivity was 63%. The positive predictive value 100% and negative predictive value 53%. Conclusion: Biliary brushing cytology in conjunction with radiological investigation and serology is a useful technique in patients with suspected pancreato-biliary malignancy. Our results are comparable to studies done in other centres. To be re-audited.

Link to more details or full-text: http://onlinelibrary.wiley.com/doi/10.1002/path.4705/epdf

Validation of the English translation of the low anterior resection syndrome score (2015)

Type of publication:
Journal article

Author(s):
Juul T., Christensen P., Janjua A.Z., Laurberg S., Emmertsen K.J., Moran B., Khan R.B., Kurasz C., Waldron E., Battersby N.J., Janjau Z., Moran B.J., Shahir T., Chan K., Glynne-Jones R., Kelly S., Evans K., Hughes R., Smith F., Heath B., Leinhardt D., Norton A., Jayne D., Moriarty C., Laing E., Mawdsley S., Bourner L., Narula N., Ward J., *Lacy-Colson J., *Moore H., *Potts S., Branagan G., Bell L., Chave H., Carter V., Mirza N., Pereira G., Williams J.G., Last K., Todd J., Woodcock N.

Citation:
Colorectal Disease, October 2015, vol./is. 17/10(908-916)

Abstract:
Aim: Many patients having anterior resection for rectal cancer suffer from severe long-term bowel dysfunction, known as low anterior resection syndrome (LARS). The LARS score was developed in Denmark, and Swedish, Spanish and German versions have been validated. The aim of this study was to validate the English translation of the LARS score in British rectal cancer patients. Method: Rectal cancer patients who underwent an anterior resection in 12 UK centres received the LARS score questionnaire, the EORTC QLQ-C30 and a single ad hoc quality of life question. A subgroup of patients received the LARS score questionnaire twice. Results: The response rate was 80% and 451 patients were included in the analyses. A strong association between LARS score and quality of life (convergent validity) was found (P < 0.01), discriminative validity was good (P < 0.02) and the test-retest reliability was high (intraclass correlation coefficient 0.83). Conclusion: The English translation of the LARS score has shown good psychometric properties comparable with recently published results from an international multicentre study. Thus, the English translation of the LARS score can be considered a valid and reliable tool for measuring LARS.

Laparoscopic anti-reflux surgery (LARS): Determine the hiatal defect repair using the intra-operatively calculated surface area (SA) cm2 (2014)

Type of publication:
Conference abstract

Author(s):
*Sukha A., *Adjepong S., *Pattar J., *Sigurdsson A.

Citation:
International Journal of Surgery, November 2014, vol./is. 12/(S100)

Abstract:
Introduction: The aim of this study was to evaluate laparoscopic antireflux surgery (LARS) techniques when repairing hiatal defects using the intra operatively calculated surface area (SA) at single-centre Upper Gastrointestinal Laparoscopic Unit. Methods: 100 patients (mean age = 59, average BMI 31) with symptoms of GORD underwent LARS. The SA (cm2) was calculated using an endoscopic ruler and the formula;(1/2 x base x height) x2. The method of closure; Surgisis +/-simple tension free sutures, was recorded for each hiatal closure. Results: The mean calculated SA repaired was 9.0cm2 and there was a 2%(2) recurrence rate. There were 3 modalities of repair; 1) Surgisis, posterior and anterior sutures (mean SA=10.0cm2, average BMI = 28); 2) Surgisis and posterior sutures (mean SA=9.5cm2, average BMI=29); 3) posterior sutures only (mean SA =6.1cm2, average BMI=32, mean number of sutures 3). Conclusions: It was found that the greater the average SA cm2 of the hiatus hernia the greater the number of modalities of repair used. There was no correlation found between BMI and the surface area of the hiatus hernia. Currently there are no set standard for method of repair based on the SA of the defect; however guidelines have been derived from this study.

Link to more details or full-text:
http://www.journal-surgery.net/article/S1743-9191(14)00735-3/pdf

Abdominal cocoon (2014)

Type of publication:
Journal article

Author(s):
*Christian B S Katz, *Robert T Diggory, Abdus Samee

Citation:
BMJ Case Reports 2014; doi:10.1136/bcr-2013-203102

Abstract:
Intestinal obstruction secondary to cocoon formation is not common. We report a case of a patient who had presented with abdominal pain and distension accompanied by vomiting. Investigations, laparotomy and histology together revealed primary peritoneal carcinoma as the cause of the patient’s symptoms.

Link to more details or full-text: http://casereports.bmj.com/content/2014/bcr-2013-203102.full.pdf+html