Joris Arts

Randomized, double-blind comparison of 4 mg/kg versus 2 mg/kg intravenous cyclosporine in severe ulcerative colitis.

BACKGROUND AND AIMS Cyclosporine A is highly effective in severe attacks of ulcerative colitis (UC) but is associated with important adverse effects that are mainly dose dependent. Our single center, randomized, double-blind, controlled trial aimed to evaluate the additional clinical benefit of 4 mg/kg over 2 mg/kg IV cyclosporine in the acute treatment of severe UC. METHODS Primary end point was the proportion of patients with a clinical response. Secondary end points included time to response, colectomy rate, and adverse effects. RESULTS Seventy-three patients were included. Day-8 response rates were 84.2% (32 of 38, 4 mg/kg) and 85.7% (32 of 35, 2 mg/kg) after a median of 4 days in both groups. Short-term colectomy rates were 13.1% (4 mg/kg) and 8.6% (2 mg/kg). Mean cyclosporine blood levels were 237 +/- 33 in the 2-mg/kg group and 332 +/- 43 ng/mL in the 4-mg/kg group. Active smoking was inversely correlated with clinical response (odds ratio, 0.06), but concomitant azathioprine or steroids were not predictive. A trend toward a higher incidence of hypertension was observed in the 4-mg/kg group (23.7% vs. 8.6%, 2 mg/kg, P < 0.08). CONCLUSIONS High-dose IV cyclosporine has no additional clinical benefit over low dose in the treatment of severe UC. Although we did not observe differences in adverse effects on the short term, the use of 2 mg/kg IV cyclosporine should provide an improved toxicity profile for medical treatment of severe UC.

Long-term outcome of treatment with intravenous cyclosporin in patients with severe ulcerative colitis

ObjectivesIV cyclosporin A (CSA) is an effective therapy in patients with severe ulcerative colitis (UC). It remains unclear if this treatment affects the course of the disease in the long run. We investigated the long-term efficacy and safety in 86 patients with ulcerative colitis treated with IV CSA at our center. MethodsThe records of all patients treated with IV CSA between 11/1992 and 11/2000 were reviewed. ResultsSeventy-two of 86 patients (83.7%) responded to IV CSA therapy, administered for a mean of 9 ± 2 days. Following the initial treatment, 69 patients (96%) were discharged on oral CSA with mean blood CSA concentrations of 192 ± 55 ng/mL. Azathioprine was added in 64 (89%) patients. A second treatment with CSA was necessary in 11 patients; 1 patient received three courses of IV treatment.The duration of follow-up averaged 773 ± 369 days. Patients who were responders but were still having certain symptoms at discharge had a higher incidence of colectomy during follow-up. Of all initial responders, 18 (25%) underwent colectomy after a mean interval of 178 ± 141 days. The life-table predicts that of all treated patients, 55% will avoid a colectomy during a period of 3 years.Complications of CSA treatment were mostly reversible, but 3 patients (3.5%) died of opportunistic infections (1 of Pneumocystis carinii pneumonia and 2 of Aspergillus fumigatus pneumoniae). One patient with anaphylactic shock caused by the CSA solvent was successfully resuscitated. ConclusionsCSA is an effective treatment of the majority of patients with severe attacks of UC, although the toxicity and even mortality associated with its use necessitates careful evaluation, selection, and follow-up.

Pathophysiology, diagnosis and management of postoperative dumping syndrome

Dumping syndrome is a frequent complication of esophageal, gastric or bariatric surgery. Rapid gastric emptying, with the delivery to the small intestine of a significant proportion of solid food as large particles that are difficult to digest, is a key event in the pathogenesis of this syndrome. This occurrence causes a shift of fluid from the intravascular component to the intestinal lumen, which results in cardiovascular symptoms, release of several gastrointestinal and pancreatic hormones and late postprandial hypoglycemia. Early dumping symptoms comprise both gastrointestinal and vasomotor symptoms. Late dumping symptoms are the result of reactive hypoglycemia. Besides the assessment of clinical alertness and endoscopic or radiological imaging, a modified oral glucose tolerance test might help to establish a diagnosis. The first step in treating dumping syndrome is the introduction of dietary measures. Acarbose can be added to these measures for patients with hypoglycemia, whereas several studies advocate guar gum or pectin to slow gastric emptying. Somatostatin analogs are the most effective medical therapy for dumping syndrome, and a slow-release preparation is the treatment of choice. In patients with treatment-refractory dumping syndrome, surgical reintervention or continuous enteral feeding can be considered, but the outcomes of such approaches are variable.

Clinical trial: a randomized-controlled crossover study of intrapyloric injection of botulinum toxin in gastroparesis

Background  Uncontrolled studies suggest benefit of intrapyloric injection of botulinum toxin (botox) for the treatment of gastroparesis, but controlled data are lacking.

Prevalence of acid reflux in functional dyspepsia and its association with symptom profile

Aim: A subset of functional dyspepsia patients respond to acid suppressive therapy, but the prevalence of non-erosive reflux disease in functional dyspepsia and its relevance to symptoms have never been established. The aim of the present study was to study 24 hour pH monitoring in consecutive functional dyspepsia patients. Methods: A total of 247 patients with dyspeptic symptoms (166 women, mean age 44 (SEM 1) year), with a negative upper gastrointestinal endoscopy and without dominant symptoms of heartburn participated in the study. In all patients, the severity of dyspeptic symptoms and the presence of heartburn was assessed by a questionnaire and a 24 hour oesophageal pH monitoring study was performed. All patients underwent a gastric emptying breath test and in 113 a gastric barostat study was performed. Results: Abnormal pH monitoring (acid exposure >5% of time) was found in 58 patients (23%). Of 21 patients with a positive heartburn questionnaire, 76% had pathological pH monitoring, while this was the case in only 18.5% of patients with a negative heartburn questionnaire. Demographic characteristics and the prevalence of other pathophysiological mechanisms did not differ between heartburn negative patients with normal or abnormal acid exposure. Pathological acid exposure in heartburn negative patients was associated with the presence of epigastric pain (65 v 84%, p<0.005) and of moderate or severe pain (48 v 69%, p = 0.005). Conclusion: Pathological oesophageal acid exposure is only present in a subset of heartburn negative functional dyspepsia patients, which are characterised by a higher prevalence of epigastric pain.

Influence of erythromycin on gastric emptying and meal related symptoms in functional dyspepsia with delayed gastric emptying

Background and aims: Although delayed gastric emptying is considered a major pathophysiological mechanism in functional dyspepsia, the efficacy of prokinetic drugs has not been established. Recent studies using macrolide prokinetics were negative but receptor desensitisation may have played a role. The aim of the present study was to evaluate the influence on meal induced symptoms of acutely administered erythromycin in patients with gastroparesis. Methods: In 20 patients with functional dyspepsia, gastric emptying was studied twice using the 14C octanoic acid and 13C glycin breath test to establish the reproducibility of the test. Breath samples were taken before the meal and at 15 minute intervals for a period of 240 minutes postprandially. At each breath sampling, the patient was asked to grade the intensity (0–3) of six dyspeptic symptoms. Twenty four patients (three men, mean age 43.5 (3) years) with dyspeptic symptoms and delayed gastric emptying were studied twice after pretreatment with saline or erythromycin intravenously. Results: Meal related symptom severity scores were reproducible. Treatment with erythromycin significantly enhanced solid and liquid gastric emptying (t1/2 146 (27) v 72 (7) minutes, respectively (p<0.01), and 87 (6) v 63 (5) minutes (p<0.001)). Only the severity of bloating was significantly improved by erythromycin (23 (3.9) v 14.5 (2.7); p<0.01); all other symptoms and the cumulative meal related symptom score were not altered by erythromycin. Conclusions: In a setting where desensitisation played no role, erythromycin enhanced gastric emptying was not associated with a beneficial effect on meal related symptom severity.

Relationship Between Symptoms And Ingestion Of A Meal In Functional Dyspepsia

Backgound and aims: A subset of functional dyspepsia (FD) patients report meal-related symptoms, possibly representing a pathophysiologically homogeneous subgroup. The aim of the present study was to establish the time-course of symptoms in relation to meal ingestion, and to assess the relationship between self-reported meal-related symptoms and pathophysiological mechanisms in FD. Methods: 218 FD patients (149 women, mean (SEM) age 39 (1) years) filled out a symptom questionnaire, including meal-induced aggravation. All patients underwent a gastric emptying breath test with severity (0–4) scoring of six symptoms (pain, fullness, bloating, nausea, burning and belching) at each sampling (15 min interval for 4 h). In 129 patients, gastric sensitivity and accommodation were assessed by barostat. Results: The intensity of each FD symptom was significantly increased 15 min after the meal, compared with the premeal score, and remained elevated until the end of the measurement period (all p<0.05). The time-course of individual symptoms varied, with early peaks for fullness and bloating, intermediate peaks for nausea and belching, and late peaks for pain and burning. Meal-induced aggravation was reported by 79% of patients, and in these patients postprandial fullness, which peaked early, was the most intense symptom. In patients without self-reported meal-induced aggravation, epigastric pain, which had a delayed peak, was the most intense symptom and they had a lower prevalence of gastric hypersensitivity (27.5% vs 7.7%). Conclusion: Meal ingestion aggravates FD symptoms in the vast majority of patients, with symptom-specific time-courses. Postprandial fullness is the most severe symptom in patients reporting aggravation by a meal, while it is pain in those not reporting meal-related symptoms.

Determinants of symptom pattern in idiopathic severely delayed gastric emptying: gastric emptying rate or proximal stomach dysfunction?

Background: Idiopathic gastroparesis is a syndrome characterised by severely delayed gastric emptying of solids without an obvious underlying organic cause. Although delayed gastric emptying is traditionally considered the mechanism underlying the symptoms in these patients, poor correlations with symptom severity have been reported. Aims: To investigate proximal stomach function and to study the correlation of delayed gastric emptying and proximal stomach dysfunction with symptom pattern and severity in idiopathic gastroparesis. Methods: 58 consecutive patients (19 men, mean (standard deviation) age 41 (2) years) with severely delayed solid gastric emptying (gastric half-emptying time (t1/2)>109 min) without an organic cause were recruited. They filled out a symptom-severity questionnaire and underwent a gastric barostat study for assessment of gastric sensitivity and accommodation. Correlation of these mechanisms with symptom pattern and overall symptom severity (sum of individual symptoms) was analysed. Results: At two different cut-off levels for gastric emptying (upper limit of normal t1/2 up to 1.5 and 2 times), no significant change in symptom pattern occurred. 25 (43%) patients had impaired accommodation, and this was associated with higher prevalence of early satiety (p<0.005) and weight loss (p = 0.009). 17 (29%) patients had hypersensitivity to gastric distension, and this was associated with higher prevalences of epigastric pain (p = 0.005), early satiety (p = 0.04) and weight loss (p<0.005). Overall symptom severity was not correlated with gastric emptying or accommodation, but only with sensitivity to gastric distension (R = −0.3898, p = 0.003) and body weight (R = −0.4233, p = 0.001). Conclusions: In patients with idiopathic gastroparesis, the symptom pattern is determined by proximal stomach dysfunction rather than by the severity of delayed emptying.

A randomised, double-blind trial comparing budesonide formulations and dosages for short-term treatment of eosinophilic oesophagitis

Objective To investigate the efficacy and safety of two different budesonide formulations (effervescent tablet for orodispersible use (BET) and viscous suspension (BVS)) with different daily dosages for short-term treatment of eosinophilic oesophagitis (EoE). Design Adults with active EoE (n=76) randomly received 14 days’ treatment with either BET 2×1 mg/day (BET1, n=19) or BET 2×2 mg/day (BET2, n=19), or BVS 2×5 mL (0.4 mg/mL)/day (BVS, n=19) or placebo (n=19) in a double-blind, double-dummy fashion, with a 2-week follow-up. Primary end point was histological remission (mean of <16 eosinophils/mm2 hpf). Secondary end points included endoscopy score, dysphagia score, drug safety and patients preference for drug formulation. Results Histological remission occurred in 100%, 94.7% and 94.7% of budesonide (BET1, BET2, BVS, respectively) and in 0% of placebo recipients (p<0.0001). The improvement in total endoscopic intensity score was significantly higher in the three budesonide groups compared with placebo. Dysphagia improved in all groups at the end of treatment; however, improvement of dysphagia persisted only in those treated with BET1 (p=0.0196 vs placebo). There were no serious adverse events. Local fungal infection (stained fungi) occurred in two patients of each budesonide group (10.5%). The effervescent tablet was preferred by 80% of patients. Conclusions BET or BVS was highly effective and safe for short-term treatment of EoE. The 1 mg (twice daily) dosage was equally effective as the 2 mg twice daily dosage. The majority of patients preferred the effervescent tablet formulation. ClinicalTrials.gov number NCT02280616; EudraCT number, 2009-016692-29.

Botulinum toxin reduces Dysphagia in patients with nonachalasia primary esophageal motility disorders.

BACKGROUND & AIMS Endoscopic injection of botulinum toxin (BTX) has shown benefits for patients with diffuse esophageal spasm (DES) and nutcracker esophagus (NE) in small uncontrolled trials. We investigated the effect of BTX on symptoms of patients with DES or NE and assessed manometry findings in a prospective, double-blind, randomized, controlled study. METHODS We assessed 22 patients with dysphagia-predominant, manometry-confirmed DES or NE (6 men; age, 63 ± 2 y) at a tertiary care medical center. Patients were given injections of BTX (8 × 12.5 U) or saline (8 × 0.5 mL) in 4 quadrants, at 2 and 7 cm above the esophagogastric junction. After 1 month, patients crossed over between groups and received endoscopic injections of BTX or saline. When the study began and 4 weeks after each injection, the patients were assessed by esophageal manometry and completed a symptom questionnaire (to determine solid and liquid dysphagia, chest pain, and regurgitation and heartburn; all scored 0-4). Responders were defined based on modified Vantrappen criteria for achalasia. RESULTS After BTX injections, patients had significant decreases in total symptom scores (sum of solid and liquid dysphagia and chest pain; from 7.6 ± 0.7 to 4.8 ± 0.8; P = .01); this decrease was not observed in patients who received saline injections. Moreover, BTX injection stabilized unintentional weight loss (weight gain of 0.3 ± 0.3 after BTX injection vs further weight loss of 1.6 ± 0.5 kg after saline injection; P = .01). Fifty percent of patients had a response 1 month after BTX injection, compared with 10% after saline injection (P = .04); 30% still had a response 1 year after BTX injection. BTX injection also caused a significant decrease in the mean esophagogastric junction pressure, compared with baseline (15.8 ± 1.7 vs 24.0 ± 2.8 mm Hg; P = .02). CONCLUSIONS In a prospective controlled study of patients with DES and NE, injections of BTX reduced symptoms and stabilized unintentional weight loss. TRIAL REGISTRY http://www.targid.eu, ML2669, ML6294.