Vedolizumab: what is the benefit from increasing the dose frequency?

Vedolizumab was introduced in 2014 as a therapy for Inflammatory Bowel Disease (IBD). Although recommendations from the National Institute for Health and Care Excellence were based on a maintenance dose of 300 mg administered intravenously every 8 weeks, the Summary of Product Characteristics includes an option of increasing the frequency of dosing for patients who initially respond but later experience a decrease in response. In this literature review of the evidence for a shorter duration between doses we identified seven studies which report that dose interval shortening recaptures response in around 50% of cases with remission rates of 11% to 34% between 4 and 52 weeks. A sustained response was seen in the majority of patients for up to 1 year, however, patients continued to receive escalated dosing for up to 100 weeks, which does not reflect clinical practice where short-term escalation is usually prescribed. There is a lack of randomised controlled trials and a lack of trials reporting endoscopic remission, which is the goal of care in IBD. The use of therapeutic drug monitoring (TDM) to guide dose escalation is uncertain and further studies are required to help clarify the role of TDM.

Improved quantitation of short-chain carboxylic acids in human biofluids using 3-nitrophenylhydrazine derivatization and liquid chromatography with tandem mass spectrometry (LC-MS/MS).

Short-chain carboxylic acids (SCCAs) produced by gut microbial fermentation may reflect gastrointestinal health. Their concentrations in serum and urine are indicative of specific metabolic pathway activity; therefore, accurate quantitation of SCCAs in different biofluids is desirable. However, it is often challenging to quantitate SCCAs since matrix effects, induced by the presence of a vast variety of other compounds other than SCCAs in complex biofluids, can suppress or enhance signals. Materials used for sample preparation may introduce further analytical challenges. This study reports for the first time a LC-MS/MS-based method to quantitate ten SCCAs (lactate, acetate, 2-hydroxybutyrate, propionate, isobutyrate, butyrate, 2-methylbutyrate, isovalerate, valerate and hexanoate) and evaluates the matrix effects in five human biofluids: serum, urine, stool, and contents from the duodenum and intestinal stoma bags. The optimized method, using 3-Nitrophenylhydrazone as a derivatization agent and a Charge Surface Hybrid reverse phase column, showed clear separation for all SCCAs at a concentration range of 0.1-100 µM, in a 10.5 min run without carry-over effects. The validation of the method showed a good linearity (R2 > 0.99), repeatability (CV ≤ 15%) assessed by intra- and inter-day monitoring. The lowest limit of detection (LLOD) was 25 nM and lowest limit of quantitation (LLOQ) was 50 nM for nine SCCA except acetate at 0.5 and 1 µM, respectively. Quantitative accuracy in all biofluids for most compounds was < ±15%. In summary, this methodology has the advantages over other techniques for its simple and fast sample preparation and a high level of selectivity, repeatability and robustness for SCCA quantification. It also reduced interferences from the matrix or sample containers, making it ideal for use in high-throughput analyses of biofluid samples from large-scale studies.

Prognostic factors associated with unhealed perineal wounds post-proctectomy for perianal Crohn's disease: a two-centre study.

AIM: The aim of this work was to determine the factors associated with poor wound healing in patients with perianal Crohn's disease (pCD) who had undergone proctectomy in the era of biologic therapies. METHOD: Case record review was performed on 103 patients with pCD who underwent proctectomy at St Mark's Hospital, Harrow and the Western General Hospital, Edinburgh between 2005 and 2017. Healing rates at 6 and 12 months post-proctectomy were considered; univariate analysis was performed. RESULTS: Sixty out of 103 patients (58.3%) had failure of wound healing at 6 months and 41/103 (39.8%) at 12 months. In total, 63.1% (65/103) patients received biologic therapies prior to proctectomy; however, exposure to biologics was not a significant factor in predicting failure of wound healing at 12 months (infliximab p = 0.255; adalimumab p = 0.889; vedolizumab p = 0.153). Male gender was the only variable associated with poor wound healing at 12 months on univariate analysis (p = 0.017). A lower pre-operative C-reactive protein was associated with early wound healing at 6 months compared with at 12 months (p = 0.041) on univariate analysis. Other parameters not associated with rates of wound healing included smoking status, corticosteroid exposure, thiopurine exposure, number of previous biologics, perianal sepsis on MRI within the last 12 months, duration of CD prior to proctectomy and pre-operative albumin. CONCLUSION: More than a third of patients had unhealed wounds 12 months after proctectomy. We report that unhealed wounds are more common in male patients. Importantly, our results also suggest that exposure to biologics does not affect rates of wound healing.

Deficient Resident Memory T Cell and CD8 T Cell Response to Commensals in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: The intestinal microbiota is closely associated with resident memory lymphocytes in mucosal tissue. We sought to understand how acquired cellular and humoral immunity to the microbiota differ in health versus inflammatory bowel disease [IBD]. METHODS: Resident memory T cells [Trm] in colonic biopsies and local antibody responses to intraepithelial microbes were analysed. Systemic antigen-specific immune T and B cell memory to a panel of commensal microbes was assessed. RESULTS: Systemically, healthy blood showed CD4 and occasional CD8 memory T cell responses to selected intestinal bacteria, but few memory B cell responses. In IBD, CD8 memory T cell responses decreased although B cell responses and circulating plasmablasts increased. Possibly secondary to loss of systemic CD8 T cell responses in IBD, dramatically reduced numbers of mucosal CD8+ Trm and γδ T cells were observed. IgA responses to intraepithelial bacteria were increased. Colonic Trm expressed CD39 and CD73 ectonucleotidases, characteristic of regulatory T cells. Cytokines/factors required for Trm differentiation were identified, and in vitro-generated Trm expressed regulatory T cell function via CD39. Cognate interaction between T cells and dendritic cells induced T-bet expression in dendritic cells, a key mechanism in regulating cell-mediated mucosal responses. CONCLUSIONS: A previously unrecognised imbalance exists between cellular and humoral immunity to the microbiota in IBD, with loss of mucosal T cell-mediated barrier immunity and uncontrolled antibody responses. Regulatory function of Trm may explain their association with intestinal health. Promoting Trm and their interaction with dendritic cells, rather than immunosuppression, may reinforce tissue immunity, improve barrier function, and prevent B cell dysfunction in microbiota-associated disease and IBD aetiology.

Predictors of anti-TNF treatment failure in anti-TNF-naive patients with active luminal Crohn's disease: a prospective, multicentre, cohort study.

BACKGROUND: Anti-TNF drugs are effective treatments for the management of Crohn's disease but treatment failure is common. We aimed to identify clinical and pharmacokinetic factors that predict primary non-response at week 14 after starting treatment, non-remission at week 54, and adverse events leading to drug withdrawal. METHODS: The personalised anti-TNF therapy in Crohn's disease study (PANTS) is a prospective observational UK-wide study. We enrolled anti-TNF-naive patients (aged ≥6 years) with active luminal Crohn's disease at the time of first exposure to infliximab or adalimumab between March 7, 2013, and July 15, 2016. Patients were evaluated for 12 months or until drug withdrawal. Demographic data, smoking status, age at diagnosis, disease duration, location, and behaviour, previous medical and drug history, and previous Crohn's disease-related surgeries were recorded at baseline. At every visit, disease activity score, weight, therapy, and adverse events were recorded; drug and total anti-drug antibody concentrations were also measured. Treatment failure endpoints were primary non-response at week 14, non-remission at week 54, and adverse events leading to drug withdrawal. We used regression analyses to identify which factors were associated with treatment failure. FINDINGS: We enrolled 955 patients treated with infliximab (753 with originator; 202 with biosimilar) and 655 treated with adalimumab. Primary non-response occurred in 295 (23·8%, 95% CI 21·4-26·2) of 1241 patients who were assessable at week 14. Non-remission at week 54 occurred in 764 (63·1%, 60·3-65·8) of 1211 patients who were assessable, and adverse events curtailed treatment in 126 (7·8%, 6·6-9·2) of 1610 patients. In multivariable analysis, the only factor independently associated with primary non-response was low drug concentration at week 14 (infliximab: odds ratio 0·35 [95% CI 0·20-0·62], p=0·00038; adalimumab: 0·13 [0·06-0·28], p<0·0001); the optimal week 14 drug concentrations associated with remission at both week 14 and week 54 were 7 mg/L for infliximab and 12 mg/L for adalimumab. Continuing standard dosing regimens after primary non-response was rarely helpful; only 14 (12·4% [95% CI 6·9-19·9]) of 113 patients entered remission by week 54. Similarly, week 14 drug concentration was also independently associated with non-remission at week 54 (0·29 [0·16-0·52] for infliximab; 0·03 [0·01-0·12] for adalimumab; p<0·0001 for both). The proportion of patients who developed anti-drug antibodies (immunogenicity) was 62·8% (95% CI 59·0-66·3) for infliximab and 28·5% (24·0-32·7) for adalimumab. For both drugs, suboptimal week 14 drug concentrations predicted immunogenicity, and the development of anti-drug antibodies predicted subsequent low drug concentrations. Combination immunomodulator (thiopurine or methotrexate) therapy mitigated the risk of developing anti-drug antibodies (hazard ratio 0·39 [95% CI 0·32-0·46] for infliximab; 0·44 [0·31-0·64] for adalimumab; p<0·0001 for both). For infliximab, multivariable analysis of immunododulator use, and week 14 drug and anti-drug antibody concentrations showed an independent effect of immunomodulator use on week 54 non-remission (odds ratio 0·56 [95% CI 0·38-0·83], p=0·004). INTERPRETATION: Anti-TNF treatment failure is common and is predicted by low drug concentrations, mediated in part by immunogenicity. Clinical trials are required to investigate whether personalised induction regimens and treatment-to-target dose intensification improve outcomes. FUNDING: Guts UK, Crohn's and Colitis UK, Cure Crohn's Colitis, AbbVie, Merck Sharp and Dohme, Napp Pharmaceuticals, Pfizer, and Celltrion.

Challenges in screening for latent tuberculosis in inflammatory bowel disease prior to biologic treatment: a UK cohort study.

OBJECTIVE: The aim of this study was to determine the occurrence of latent tuberculosis infections (LTBI) and active TB in a cohort of patients with inflammatory bowel disease (IBD) treated with biologics. We also examined the effects of immunosuppressive drugs on indeterminate interferon-gamma release assays (IGRA) in LTBI screening. DESIGN: Retrospective study of patients treated with biologics between March 2007 and November 2015. SETTING: St Mark's Hospital, North West London, UK. PATIENTS: 732 patients with IBD who were screened for LTBI using either tuberculin skin test or IGRA before starting a biologic treatment. METHODS: Retrospective case note review of all patients with IBD who were screened for LTBI prior to initiating biologics. Patients who developed active TB were identified from the London TB register. RESULTS: Of 732 patients with IBD, 31 (4.2%) were diagnosed with and treated for LTBI with no significant side effects. Six of 596 patients (1.0%) who received biologic treatment developed active TB. There was a higher proportion of indeterminate IGRA in the immunosuppressive medication group compared with the non-immunosuppressive group (33% (59/181) compared with 9% (6/66), p<0.001). The combination of steroids and thiopurines had the highest proportion of indeterminate IGRA (64%, 16/25). High and low doses of steroids were equally likely to result in an indeterminate IGRA result (67% (8/12) and 57% (4/7), respectively). CONCLUSIONS: This study highlights the challenges of LTBI screening prior to commencing biologic therapy and demonstrates the risk of TB in patients who have been screened and who are receiving prolonged and continuing doses of antitumour necrosis factor.

Investigation of iron deficiency anaemia .

Iron deficiency anaemia (IDA) is an important, common clinical condition and 8-15% of these patients will be diagnosed with a gastrointestinal cancer. IDA is defined as haemoglobin below the lower limit of normal, in the presence of characteristic iron studies. This article will discuss the causes and clinical diagnosis of iron deficiency, including interpretation of common laboratory tests that differentiate this from other causes of anaemia. We suggest an initial approach for investigating the cause of iron deficiency in these patients and also consider the subsequent treatment and indications for further investigation.

Fecal microbial transplantation: an update.

PURPOSE OF REVIEW: The purpose of this article is to provide an update on recent developments in fecal microbiota transplantation (FMT) in the last year. RECENT FINDINGS: Although FMT is an accepted treatment for recurrent Clostridium difficile infection (CDI), recently it is also gaining acceptance for the treatment of refractory CDI. FMT is showing promise in ulcerative colitis and is experimental in many other conditions. The optimal practical aspects to enhance the success of FMT are still being established. SUMMARY: The implication of current research is that the indications of FMT may be extended to other conditions in the future.

Improving the management of spontaneous bacterial peritonitis in cirrhotic patients: assessment of an intervention in trainee doctors.

Spontaneous bacterial peritonitis (SBP) in cirrhotic patients is a serious complication associated with a high mortality rate. A baseline audit of the acute medical take (AMT) at Northwick Park suggested a lack of awareness regarding management. A questionnaire based on contemporary SBP guidelines was circulated to all trainee doctors (FY1 to SpR). Ascitic fluid testing requests were analysed over a six-month period. The electronic requesting system was updated to include prompts and direct links to Trust SBP guidelines, and a one-hour lecture to all members of the AMT, supported by an educational booklet on SBP, was performed. Re-audit was carried out six months post-intervention, the AMT completed a second questionnaire and ascitic fluid testing requests were re-audited. In comparable pre- and post-intervention AMT cohorts, a clinical and educational intervention led to a significant improvement in understanding of when to investigate (p≤0.001), samples (p = 0.002) and containers (p≤0.001) required, urgency of obtaining results (p≤0.001), and initiation of treatment for suspected SBP (p = 0.007). Significantly more ascitic samples were sent, with specific suspicion of SBP more readily documented, crucial to expediting laboratory processing. Targeted education and production of a clinical algorithm has significantly improved the management of patients with SBP.

The endoscopy safety checklist: A longitudinal study of factors affecting compliance in a tertiary referral centre within the United Kingdom.

Gastrointestinal endoscopy is a widely used diagnostic and therapeutic procedure both within the United Kingdom and worldwide. With an increasingly older population the potential for complications is increased. The Wolfson Unit for Endoscopy at St. Mark's Hospital in London is a tertiary referral centre, which conducts over 14,000 endoscopic procedures annually. However, despite this high throughput, our baseline observations were that the procedure for safety checks was highly variable. Over a seven-day period we conducted a questionnaire-based survey to all staff members involved with endoscopy within our unit. We found that there was little consensus between team members, both in terms of essential safety checks and designating responsibility for the checks. A panel of experts was convened in order to devise a safety checklist and a strategy for increasing compliance with the checklist among all staff members. Using a combination of electronic and physical reminders and incentives, we found that there was a significant increase in completed checklist (53% to 66%, p = 0.021) and decrease in the number of checklists left blank post intervention (10% to 2%, p=0.03). We believe that post implementation validation of safety checklists is an important method to ensure their proper use.

Meta-analysis of secure randomised controlled trials of ß-blockade to prevent perioperative death in non-cardiac surgery.

BACKGROUND: Current European and American guidelines recommend the perioperative initiation of a course of ß-blockers in those at risk of cardiac events undergoing high- or intermediate-risk surgery or vascular surgery. The Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography (DECREASE) family of trials, the bedrock of evidence for this, are no longer secure. We therefore conducted a meta-analysis of randomised controlled trials of ß-blockade on perioperative mortality, non-fatal myocardial infarction, stroke and hypotension in non-cardiac surgery using the secure data. METHODS: The randomised controlled trials of initiation of ß-blockers before non-cardiac surgery were examined. Primary outcome was all-cause mortality at 30 days or at discharge. The DECREASE trials were separately analysed. RESULTS: Nine secure trials totalling 10 529 patients, 291 of whom died, met the criteria. Initiation of a course of ß-blockers before surgery caused a 27% risk increase in 30-day all-cause mortality (p=0.04). The DECREASE family of studies substantially contradict the meta-analysis of the secure trials on the effect of mortality (p=0.05 for divergence). In the secure trials, ß-blockade reduced non-fatal myocardial infarction (RR 0.73, p=0.001) but increased stroke (RR 1.73, p=0.05) and hypotension (RR 1.51, p<0.00001). These results were dominated by one large trial. CONCLUSIONS: Guideline bodies should retract their recommendations based on fictitious data without further delay. This should not be blocked by dispute over allocation of blame. The well-conducted trials indicate a statistically significant 27% increase in mortality from the initiation of perioperative ß-blockade that guidelines currently recommend. Any remaining enthusiasts might best channel their energy into a further randomised trial which should be designed carefully and conducted honestly.

Meta-analysis of symptomatic response attributable to the pacing component of cardiac resynchronization therapy.

AIMS: Prognostic benefit from CRT compared with controls is well established. Symptomatic response rates, however, are controversial and have never been systematically evaluated with standard subtraction of control rates to establish the incremental symptomatic response effect of CRT pacing. METHODS AND RESULTS: First, we identified 150 consecutive CRT papers and assessed researchers' perceptions of the symptomatic response to CRT. The mean quoted response rate was 66%. Only 26 studies acknowledged the existence of response without the device. Secondly, we examined actual symptomatic response rates in the randomized trials (CARE-HF, COMPANION, CONTAK-CD, MIRACLE, MIRACLE-ICD, MIRACLE-ICD II, MUSTIC, and REVERSE) totalling 3904 patients. The NYHA status improved in 51% of those randomized to CRT vs. 35% of controls (incremental effect 16%). This incremental improvement was significantly greater in open studies (with no device for controls) than in blinded studies (control arm receiving a device but no CRT, such as a defibrillator or a CRT programmed off), 20% vs. 13%, P < 0.001. CONCLUSIONS: Quoting CRT responder rates in isolation without recognizing spontaneous 'response' is common but unwise. The incremental symptomatic response rate from CRT pacing is ∼16%, much lower than widely reported. This value is similar to that for drugs in heart failure and should not be considered disappointing: they both exert powerful prognostic benefits. For scientific purposes, e.g. to explore potential improvements, symptomatic benefit from CRT should be quantified, like all other effects, by comparison with a control.

Protective effects of heat shock protein 27 in a model of ALS occur in the early stages of disease progression.

Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disorder, characterised by progressive motor neuron degeneration and muscle paralysis. Heat shock proteins (HSPs) have significant cytoprotective properties in several models of neurodegeneration. To investigate the therapeutic potential of heat shock protein 27 (HSP27) in a mouse model of ALS, we conducted an extensive characterisation of transgenic mice generated from a cross between HSP27 overexpressing mice and mice expressing mutant superoxide dismutase (SOD1(G93A)). We report that SOD1(G93A)/HSP27 double transgenic mice showed delayed decline in motor strength, a significant improvement in the number of functional motor units and increased survival of spinal motor neurons compared to SOD1(G93A) single transgenics during the early phase of disease. However, there was no evidence of sustained neuroprotection affecting long-term survival. Marked down-regulation of HSP27 protein occurred during disease progression that was not associated with a reduction in HSP27 mRNA, indicating a translational dysfunction due to the presence of mutant SOD1 protein. This study provides further support for the therapeutic potential of HSPs in ALS and other motor neuron disorders.