▸ Zeuzem S, Dusheiko G, Salupere R, et al . Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N Engl J Med 2014;370:21.
▸ Jacobson IM, Gordon SC, Kowdley KV, et al . Sofosbuvir for hepatitis C genotype 2 or 3 in Patients without Treatment Options. N Engl J Med 2013;368:1867–77.
This paper reviews the outcomes of the VALENCE study which evaluated an interferon-free treatment regime for patients with genotypes 2 and 3 hepatitis C virus (HCV).1 While demonstrating promising efficacy in the treatment of genotype 2 infected patients and certain subtypes of patients with genotype 3 infection, it also provides a timely reminder that careful patient selection is required.
Sofosbuvir (trade name Sovaldi) is an oral direct acting antiviral agent (NS5B polymerase inhibitor) licensed in the UK for the treatment of hepatitis C. It is currently under review at the National Institute for Health and Care Excellence. The study was designed as a phase III blinded placebo controlled trial of treatment of genotype 2 and 3 …
This prospective study, 1 by some margin the largest of its kind, demonstrates emphatically the safety and efficacy of endoscopic therapy for Barrett's oesophageal mucosal adenocarcinoma (OmAC).
The association between Barrett's oesophagus (BO) and oesophageal cancer has been recognised since the 1970s. Treatment options for Barrett's neoplastic lesions include surgical oesophageal resection, endoscopic resection (ER) alone and ER combined with ablative therapy. Society guidelines exhibit variance with regard to management of OmAC. Furthermore, data are limited to small studies, with short follow-up, with high grade dysplasia (HGD) and OmAC included as one entity. This study aimed to clarify the safety and efficacy of endoscopic therapy for OmAC and to investigate the associations of treatment failure.
Data were collected prospectively from all patients referred to a single tertiary …
Abstract Background Acute severe ulcerative colitis (ASUC) is a severe manifestation of ulcerative colitis (UC) that requires hospitalisation. Despite significant advances in therapeutic options for UC and in the medical management of steroid-refractory ASUC, the initial treatment paradigm for ASUC has not changed since the 1950s and is based on the use of intravenous (IV) corticosteroids. Approximately 50% of patients do not respond and require further medical or surgical therapy. Interleukin 1 (IL-1) has been identified as a key mediator of colonic inflammation and plays a pivotal role in local activation of neutrophils and a number of downstream inflammatory mediators. The IL-1 axis has been repeatedly identified as a therapeutic target in UC. The Interleukin 1 (IL-1) blockade in Acute Severe Colitis (IASO) trial investigated whether antagonism of IL-1 signalling could improve outcomes in patients with ASUC. Methods We performed a phase II, multicentre randomised (1:1), placebo-controlled, double-blinded trial of IL-1 blockade with short-duration anakinra, given alongside IV corticosteroids to adult patients hospitalised with suspected or confirmed ASUC. The primary outcome was the incidence of medical (ie infliximab/ciclosporin) or surgical rescue therapy (colectomy) within 10 days following the commencement of IV corticosteroid therapy. Secondary outcomes included disease activity, time to clinical response, time to rescue therapy, colectomy incidence by day 98 post IV corticosteroids and safety. The trial aimed to recruit 214 patients across 20 sites in the UK. Prespecified analyses were performed for feasibility and for futility. Results At the time of the prespecified interim futility analysis, 113 patients had been randomised, 55 to placebo, and 58 to anakinra (figure 1). The incidence of medical or surgical rescue therapy by day 10 was higher in the anakinra group than in the placebo group (43% vs 26%). The incidence of colectomy by day 98 was higher in the anakinra group (11% vs 4%). These differences were not statistically significant. Logistic models containing a mixture of baseline stratification factors did not suggest that the need for rescue therapy would be reduced with anakinra treatment and on the advice of the independent data monitoring committee, the trial was terminated for futility. There was a higher incidence of adverse event in the placebo group, the most common was worsening of ulcerative colitis. Conclusion This trial shows that adding anakinra to current standard care with IV corticosteroids in patients with ASUC did not reduce the need for rescue therapy or colectomy. This suggests that IL-1 blockade is not a therapeutic target in ASUC. There were no safety concerns with anakinra treatment.
ABSTRACT The peak incidence of inflammatory bowel diseases (IBD) occurs during the child-bearing years, and so questions about fertility, pregnancy and breast feeding are often asked by patients. It is known that patients with IBD receive twice as much information about pregnancy-related issues from gastroenterologists as from any other source (including the internet). Therefore, the role of the gastroenterologist in correctly educating patients to avoid misconceptions is paramount, and this should be done proactively prior to planning pregnancy so that the patient's health and medications can be optimised. A clear understanding of medication safety during pregnancy and lactation will improve clinical management.
Inflammatory bowel disease (IBD) is increasing in incidence in both the developed and the developing world. Genetic, immunological and environmental factors are known to be involved. Genome-wide studies have examined the contribution played by host genetics in the development of IBD and have estimated that genetic factors are responsible for about 25 % of the disease risk. Having an IBD-associated genotype does not always lead to development of the disease phenotype, and hence it seems likely that environmental factors are key to triggering development of the disease in genetically susceptible individuals. The gut microbiota contains more cells than its human host, and mounting evidence attests to the importance of the microbiota in the development of several diseases, including IBD, metabolic syndrome and CVD. The present paper reviews the interplay between the microbiota and the mucosal immune system in health and in IBD; and discusses the evidence base for the use of therapeutic modulation of the microbiota to prevent and treat IBD.
Anti-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.
Method
Patients 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.
Results
54 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).
Conclusion
This 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.
Anti tumour necrosis factor (anti-TNF) drugs increase the risk of serious respiratory infection and impair protective immunity following pneumococcal and influenza vaccination. Here we report SARS-CoV-2 vaccine-induced immune responses and breakthrough infections in patients with inflammatory bowel disease, who are treated either with the anti-TNF antibody, infliximab, or with vedolizumab targeting a gut-specific anti-integrin that does not impair systemic immunity. Geometric mean [SD] anti-S RBD antibody concentrations are lower and half-lives shorter in patients treated with infliximab than vedolizumab, following two doses of BNT162b2 (566.7 U/mL [6.2] vs 4555.3 U/mL [5.4], p <0.0001; 26.8 days [95% CI 26.2 - 27.5] vs 47.6 days [45.5 - 49.8], p <0.0001); similar results are also observed with ChAdOx1 nCoV-19 vaccination (184.7 U/mL [5.0] vs 784.0 U/mL [3.5], p <0.0001; 35.9 days [34.9 - 36.8] vs 58.0 days [55.0 - 61.3], p value < 0.0001). One fifth of patients fail to mount a T cell response in both treatment groups. Breakthrough SARS-CoV-2 infections are more frequent (5.8% (201/3441) vs 3.9% (66/1682), p = 0.0039) in patients treated with infliximab than vedolizumab, and the risk of breakthrough SARS-CoV-2 infection is predicted by peak anti-S RBD antibody concentration after two vaccine doses. Irrespective of the treatments, higher, more sustained antibody levels are observed in patients with a history of SARS-CoV-2 infection prior to vaccination. Our results thus suggest that adapted vaccination schedules may be required to induce immunity in at-risk, anti-TNF-treated patients.
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