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 immuno-modulator (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 ...

BACKGROUND & AIMS: Anti-tumor necrosis factor (anti-TNF) therapies are the most widely used biologic drugs for treating immune-mediated diseases, but repeated administration can induce the formation of anti-drug antibodies. The ability to identify patients at increased risk for development of anti-drug antibodies would facilitate selection of therapy and use of preventative strategies. METHODS: We performed a genomewide association study to identify variants associated with time to development of anti-drug antibodies in a discovery cohort of 1240 biologic-naïve patients with Crohn's disease starting infliximab or adalimumab therapy. Immunogenicity was defined as an anti-drug antibody titer !10 AU/mL using a drug-tolerant enzyme-linked immunosorbent assay. Significant association signals were confirmed in a replication cohort of 178 patients with inflammatory bowel disease. RESULTS: The HLA-DQA1*05 allele, carried by approximately 40% of Europeans, significantly increased the rate of immunogenicity (hazard ratio [HR], 1.90; 95% confidence interval [CI], 1.60-2.25; P ¼ 5.88 Â 10-13). The highest rates of immunogenicity, 92% at 1 year, were observed in patients treated with infliximab monotherapy who carried HLA-DQA1*05; conversely the lowest rates of immunogenicity, 10% at 1 year, were observed in patients treated with adalimumab combination therapy who did not carry HLA-DQA1*05. We confirmed this finding in the replication cohort (HR, 2.00; 95% CI, 1.35-2.98; P ¼ 6.60 Â 10-4). This association was consistent for patients treated with adalimumab (HR, 1.89; 95% CI, 1.32-2.70) or infliximab (HR, 1.92; 95% CI, 1.57-2.33), and for patients treated with anti-TNF therapy alone

Gastric acid suppression could improve heartburn by healing oesophagitis or by reduction of oesophageal sensitivity to acid. To independently assess changes in oesophageal sensitivity, it would be necessary to study patients with reflux disease but no oesophagitis. The aim ofthis study was to investigate the effect of acid suppression on oesophageal sensitivity and to assess the time course of any measured effect. Twenty seven patients were recruited, of whom 25 completed the study (14 men and 11 women, mean (SD) age 50 (15) (23), and 144 (25) seconds for weeks 4, 5, and 8). Heartburn symptom score decreased significantly with famotidine (mean scores 3*6, 1-9, 2*1, and 2-6 at weeks 0, 4, 5, and 8 (p=0 001)) and showed a significant negative correlation with time to heartburn (rs=-0*60; p<0)0001).It is concluded that oesophageal sensitivity to acid is reduced by famotidine independent of an effect on oesophagitis; the effect wanes one to four weeks after the end of treatment and correlates with change in heartburn score. (Gut 1994; 35: 447-450) Numerous treatment studies of patients with gastro-oesophageal reflux have shown that suppression of gastric acid has a beneficial effect on symptoms'; two early controlled studies with cimetidine showed in addition that active treatment resulted in an increase in the time to heartburn during oesophageal acid perfusion.23 Because most studies have recruited patients with endoscopic oesophagitis, however, it is difficult to know whether symptomatic improvement is a result of improvement in the oesophagitis or some other factor. It has been shown that healing of oesophagitis is accompanied by histological improvement, including reduction in dermal papillary elongation.4 This is difficult to assess, as such changes, being patchy, are liable to sampling error and also occur in the distal two centimetres of the normal oesophagus.56 Nevertheless, it has been suggested that symptoms improve as a result of the increased thickness of epithelium (acting as a mechanical barrier to acid) above sensory nerve endings in the dermal papillae.7 Alternatively, oesophageal afferent nerves may in fact be sensitised by repeated exposure to acid. A similar phenomenon has been described in cutaneous pain receptors89 and nociceptors in other viscera. '°I It is unresolved whether symptom improvement is a result of healing of the oesophagitis or desensitisation of oesophageal sensory receptors sensitised by exposure to refluxed gastric acid. The well recorded lack of correlation between endoscopic oesophagitis" and symptoms together with the tendency of symptoms to recur rapidly after anti-secretory treatment has finished would favour the second. The aims of this study were therefore to examine the effects ofa four week course ofacid inhibition treatment with a potent H2 receptor blocker (famotidine)" on oesophageal acid sensitivity and symptoms in subjects with symptomatic gastro-oesophageal reflux but no oesophagitis and to explore the time course of any effect after treatment has fini...

Ten healthy volunteers and 13 patients with oesophageal motility disorders whose primary presenting complaint was chest pain were studied by distending an intraoesophageal balloon in 1 ml steps to the point of a sensation of discomfort. The net balloon pressure (intraballoon pressure when inflated within the oesophagus minus the pressure recorded at the same volume outside the patient) was measured at each volume increment and the distension volume at the perception of discomfort was noted. The measurements were repeated after intravenous injection of edrophonium (80 Ftg/kg) and again after 1.2 mg intravenous atropine. Oesophageal wall compliance was similar in patients and controls, and the two groups showed a similar effect of decreased compliance with edrophonium and increased compliance after atropine. There were no significant differences between patients and controls of distending volume at perception of discomfort. Edrophonium, however, resulted in a significant reduction in distension threshold for pain (p<0.03) in patients. A similar though non-significant trend was seen in controls. In both controls and patients, distension volume for pain production after atropine was significantly (p<0.01) higher than after edrophonium. From these results and other published data, we suggest that the pain receptor for noxious stretch and after edrophonium challenge is likely to be an 'in series' mechanoreceptor located in oesophageal longitudinal muscle.

Nineteen diabetic patients with autonomic neuropathy were enrolled in a double-blind crossover study of cisapride, metoclopramide and placebo. Symptoms were evaluated from diary cards and from assessments undertaken at the end of each eight week treatment period.Measurements of oesophageal transit, gastric emptying and whole gut transit were made before treatment began and at the end of each treatment period. Three patients dropped out early in the study, and the results from 16 patients were analysed.The severity of autonomic neuropathy, judged from cardiovascular reflex tests, correlated with delayed oesophageal transit and prolonged gastric emptying, but abnormal oesophageal transit and gastric emptying were often unrelated to the presence of upper gastrointestinal symptoms. Neither cisapride nor metoclopramide had a statistically significant effect on oesophageal transit, gastric emptying or whole-gut transit, nor was any significant effect on symptoms identified, although a trend towards reduced nausea and vomiting with metoclopramide and reduced epigastric fullness and diarrhoea with cisapride was suggested.