Ustekinumab versus adalimumab for induction and maintenance therapy in biologic-naive patients with moderately to severely active Crohn's disease: a multicentre, randomised, double-blind, parallel-group, phase 3b trial.

BACKGROUND: Active-comparator trials are important to inform patient and physician choice. We aimed to evaluate the efficacy and safety of monotherapy with either ustekinumab or adalimumab in biologic-naive patients with moderately to severely active Crohn's disease. METHODS: We conducted a randomised, double-blind, parallel-group, active-comparator, phase 3b trial (SEAVUE) at 121 hospitals or private practices in 18 countries. We included biologic-naive patients aged 18 years or older with moderately to severely active Crohn's disease and a Crohn's Disease Activity Index (CDAI) score of 220-450, who had not responded to or were intolerant to conventional therapy (or were corticosteroid dependent) and had at least one ulcer of any size at baseline endoscopic evaluation. Eligible patients were randomly assigned (1:1; via an interactive web response system) to receive ustekinumab (approximately 6 mg/kg intravenously on day 0, then 90 mg subcutaneously once every 8 weeks) or adalimumab (160 mg on day 0, 80 mg at 2 weeks, then 40 mg once every 2 weeks, subcutaneously) through week 56. Study treatments were administered as monotherapy and without dose modifications. Patients, investigators, and study site personnel were masked to treatment group assignment. The primary endpoint was the proportion of patients who were in clinical remission (CDAI score <150) at week 52 in the intention-to-treat population (ie, all patients who were randomly assigned to a treatment group). This trial is registered with ClinicalTrials.gov, NCT03464136, and EudraCT, 2017-004209-41. FINDINGS: Between June 28, 2018, and Dec 12, 2019, 633 patients were assessed for eligibility and 386 were enrolled and randomly assigned to receive ustekinumab (n=191) or adalimumab (n=195). 29 (15%) of 191 patients in the ustekinumab group and 46 (24%) of 195 in the adalimumab group discontinued study treatment before week 52. There was no significant difference between the ustekinumab and adalimumab groups in the occurrence of the primary endpoint; at week 52, 124 (65%) of 191 patients in the ustekinumab group versus 119 (61%) of 195 in the adalimumab group were in clinical remission (between-group difference 4%, 95% CI -6 to 14; p=0·42). Safety for both groups was consistent with previous reports. Serious infections were reported in four (2%) of 191 patients in the ustekinumab group and five (3%) of 195 in the adalimumab group. No deaths occurred through week 52 of the study. INTERPRETATION: Both ustekinumab and adalimumab monotherapies were highly effective in this population of biologic-naive patients, with no difference in the primary outcome between the drugs. FUNDING: Janssen Scientific Affairs.

Achalasia presenting after operative and nonoperative trauma.

Achalasia has been described following fundoplication and is attributed to vagal nerve damage during surgery. Similarly, other traumatic events to the distal esophagus may be linked to the development of achalasia. Operative and nonoperative trauma as a possible factor in the development of achalasia was studied. A retrospective analysis of patients with achalasia (n = 64) at our institution was performed. Collected data included age, gender, symptoms, and history of operative and nonoperative traumatic events. Comparisons were made to a group of patients with similar symptoms but normal esophageal manometry (n = 73). Achalasia was diagnosed by manometry in 125 patients over a 6-year period. All patients with complete medical records (n = 64) were studied. A history of operative or nonoperative trauma to the upper gastrointestinal tract prior to the development of symptomatic achalasia was present in 16 of 64 (25%). Significantly fewer patients (9.5%) with symptoms of dysphagia, but normal manometry and upper endoscopy, had precedent trauma to the upper gastrointestinal tract (P < 0.05). All cases of nonoperative trauma occurred in motor vehicle accidents. Cases of operative trauma included coronary artery bypass surgery (n = 4), bariatric surgery (n = 2), fundoplication (n = 3), heart/lung transplantation (n = 1), and others (n = 5). Patients with proven achalasia and a history of trauma were more likely to have chest pain (RR, 4.5; P = 0.012) but less likely to have regurgitation (RR, 0.51; P = 0.01) or nausea/vomiting (RR, 0.0; P = 0.27) than those without a history of antecedent trauma. In this series, significantly more patients with achalasia had a history of preceding trauma than did patients with similar symptoms and normal esophageal manometry. Following trauma, patients may be at increased risk for developing achalasia, possibly from neuropathic dysfunction due to vagal nerve damage. Patients with posttraumatic achalasia may have symptoms which differ from those of other achalasia patients.