Extraintestinal manifestations at baseline, and the effect of tofacitinib, in patients with moderate to severe ulcerative colitis.

Introduction: Extraintestinal manifestations (EIMs) in patients with ulcerative colitis (UC) are common. Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of UC. We evaluated the efficacy of tofacitinib in patients with EIMs, and the impact of tofacitinib on EIMs in patients with UC in the OCTAVE clinical program.

Consensus Guidelines: Best Practices for Detection, Assessment and Management of Suspected Acute Drug-Induced Liver Injury During Clinical Trials in Adults with Chronic Viral Hepatitis and Adults with Cirrhosis Secondary to Hepatitis B, C and Nonalcoholic Steatohepatitis.

With the widespread development of new drugs to treat chronic liver diseases (CLDs), including viral hepatitis and nonalcoholic steatohepatitis (NASH), more patients are entering trials with abnormal baseline liver tests and with advanced liver injury, including cirrhosis. The current regulatory guidelines addressing the monitoring, diagnosis, and management of suspected drug-induced liver injury (DILI) during clinical trials primarily address individuals entering with normal baseline liver tests. Using the same laboratory criteria cited as signals of potential DILI in studies involving patients with no underlying liver disease and normal baseline liver tests may result in premature and unnecessary cessation of a study drug in a clinical trial population whose abnormal and fluctuating liver tests are actually due to their underlying CLD.

Tofacitinib in Patients with Ulcerative Colitis: Inflammatory Bowel Disease Questionnaire Items in Phase 3 Randomized Controlled Induction Studies.

Background: Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We examined the effect of tofacitinib induction treatment on Inflammatory Bowel Disease Questionnaire (IBDQ) items in adults with moderate to severe UC.

Methods: Data were pooled from the randomized, 8‑week, double-blind, phase 3 OCTAVE Induction 1 and 2 studies.

Efficacy and safety of tofacitinib dose de-escalation and dose escalation for patients with ulcerative colitis: results from OCTAVE Open.

Background: For patients with UC, flexible maintenance dosing therapy may confer advantages for safety, efficacy, costs and patient preference. Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of UC.

Aim: To assess the efficacy and safety of tofacitinib dose de-escalation and escalation in patients with UC.

The Impact of Raising the Bar for Clinical Trials in Ulcerative Colitis.

In order to identify the practical implications for both health care practitioners and patients in understanding differences between the results of trials assessing therapies for ulcerative colitis [UC], we reviewed clinical trials of therapies for moderate to severe UC, with a focus on trial design. Over time, patient populations in UC trials have become more refractory, reflecting that patients are failing treatment with additional and different classes of drug, including conventional therapies, immunosuppressant drugs, and anti-tumour necrosis factor therapies. Outcomes used to measure efficacy have become increasingly stringent in order to meet the expectations of patients and physicians, and the requirements of regulatory bodies.

Long-term safety and tolerability of oral tofacitinib in patients with Crohn's disease: results from a phase 2, open-label, 48-week extension study.

Background: Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for inflammatory bowel disease.

Aims: This 48-week open-label extension study primarily investigated long-term safety of tofacitinib 5 and 10 mg b.d.

Tofacitinib for induction and maintenance therapy of Crohn's disease: results of two phase IIb randomised placebo-controlled trials.

Objective: Tofacitinib is an oral, small-molecule Janus kinase inhibitor that is being investigated for IBD. We evaluated the efficacy and safety of tofacitinib for induction and maintenance treatment in patients with moderate-to-severe Crohn's disease (CD).

Design: We conducted two randomised, double-blind, placebo-controlled, multicentre phase IIb studies.

De novo sirolimus and reduced-dose tacrolimus versus standard-dose tacrolimus after liver transplantation: the 2000-2003 phase II prospective randomized trial.

We studied whether the use of sirolimus with reduced-dose tacrolimus, as compared to standard-dose tacrolimus, after liver transplantation is safe, tolerated and efficacious. In an international multicenter, open-label, active-controlled randomized trial (2000-2003), adult primary liver transplant recipients (n=222) were randomly assigned immediately after transplantation to conventional-dose tacrolimus (trough: 7-15 ng/mL) or sirolimus (loading dose: 15 mg, initial dose: 5 mg titrated to a trough of 4-11 ng/mL) and reduced-dose tacrolimus (trough: 3-7 ng/mL). The study was terminated after 21 months due to imbalance in adverse events.

Sirolimus conversion regimen versus continued calcineurin inhibitors in liver allograft recipients: a randomized trial.

A large prospective, open-label, randomized trial evaluated conversion from calcineurin inhibitor (CNI)- to sirolimus (SRL)-based immunosuppression for preservation of renal function in liver transplantation patients. Eligible patients received liver allografts 6-144 months previously and maintenance immunosuppression with CNI (cyclosporine or tacrolimus) since early posttransplantation. In total, 607 patients were randomized (2:1) to abrupt conversion (<24 h) from CNI to SRL (n = 393) or CNI continuation for up to 6 years (n = 214).

Repeat-dose sirolimus pharmacokinetics and pharmacodynamics in patients with hepatic allografts.

Purpose: To determine sirolimus steady-state pharmacokinetics, and to assess the relationship between time-normalized trough sirolimus concentration (C(min,TN)) and evidence of efficacy (rejection and death) and adverse reactions (stomatitis and pneumonia) in liver allograft patients.

Methods: Dense sampling of sirolimus was performed over a single daily-dosing interval in 11 hepatic allograft recipients on day 28 and at 3 months after start of treatment. Serial trough concentration sampling was performed in 380 hepatic allograft recipients on days 1, 7, 14, 28, 42, 60, 90, 180, 270 and 360 after start of treatment.

Lower malignancy rates in renal allograft recipients converted to sirolimus-based, calcineurin inhibitor-free immunotherapy: 24-month results from the CONVERT trial.

Background: Long-term immunosuppression imposes increased malignancy risk in renal allograft recipients, significantly contributing to overall morbidity and mortality. This study examined malignancy rates in renal allograft recipients at 2 years after conversion to a sirolimus (SRL)-based, calcineurin inhibitor (CNI)-free regimen.

Methods: This open-label, randomized, multicenter study (the CONVERT Trial) randomly assigned 830 patients to SRL conversion (n=555) or CNI continuation (n=275).

Ulcer formation with low-dose enteric-coated aspirin and the effect of COX-2 selective inhibition: a double-blind trial.

Background & Aims: We assessed the risk of ulcers with low-dose aspirin and the interaction of low-dose aspirin with a COX-2 selective inhibitor in a double-blind trial that compared placebo, low-dose aspirin, rofecoxib + low-dose aspirin, and ibuprofen.

Methods: Osteoarthritis patients > or =50 years of age without ulcers or erosive esophagitis at baseline endoscopy were assigned randomly to placebo, enteric-coated aspirin 81 mg/day, rofecoxib 25 mg combined with aspirin 81 mg/day, or ibuprofen 800 mg 3 times a day. Repeat endoscopies were performed at 6 and 12 weeks.

The utility of ultrasound site selection for pediatric percutaneous liver biopsy.

Background: The site for percutaneous liver biopsy is determined by physical examination and anatomic landmarks. The authors compared physical examination with ultrasound examination to determine liver location, size, and an optimal biopsy site.

Methods: A pediatric gastroenterology fellow or attending gastroenterologist initially selected a biopsy site by physical examination.

Terminal ileum intubation in pediatric colonoscopy and diagnostic value of conventional small bowel contrast radiography in pediatric inflammatory bowel disease.

Background: Small bowel contrast radiography is often suggested as the first diagnostic tool in evaluating pediatric inflammatory bowel disease. The purpose of this study was to determine the sensitivity and specificity of small bowel radiography compared with terminal ileal biopsies in diagnosing pediatric inflammatory bowel disease, and to determine the success rate and safety of terminal ileum intubation during pediatric colonoscopy.

Methods: We retrospectively reviewed the records of 164 subjects who had colonoscopies with terminal ileal biopsies between 1994 and 1996.

Liver transplantation at the University of Pennsylvania and the Children's Hospital of Philadelphia.

The liver transplant program at the University of Pennsylvania and the Children's Hospital of Philadelphia experienced healthy growth in its clinical activity in the past 5 years. Patterns of referral and patient evaluation were established, care of patients while waiting on the list or being followed after transplantation was streamlined. We are now achieving excellent outcomes while transplanting relatively sicker patients.

Normal thiopurine methyltransferase levels do not eliminate 6-mercaptopurine or azathioprine toxicity in children with inflammatory bowel disease.

6-mercaptopurine (6-MP) and azathioprine (AZA) are used to treat inflammatory bowel disease (IBD). Side effects include infection, leukopenia, hepatitis, and pancreatitis. The level of thiopurine methyltransferase (TPMT), which metabolizes 6-MP to 6-methylmercaptopurine, may reflect the risk of side effects.

Azathioprine and 6-mercaptopurine for the treatment of perianal Crohn's disease in children.

Numerous adult studies show a 30-65% response rate to azathioprine (AZA) or 6-mercaptopurine (6-MP) for significant perianal Crohn's disease. The aim of this study was to evaluate whether these drugs healed pediatric perianal Crohn's disease. Records of pediatric Crohn's patients were retrospectively reviewed for significant perianal disease treated with AZA or 6-MP for > or =6 months.

Supraceliac aortic pseudoaneurysms after liver transplantation in infants.

Background: Reconstruction of the hepatic artery in infants undergoing liver transplantation presents challenging vascular situations. Microvascular techniques ensure arterial blood flow via small caliber vessels but are insufficient when inflow is poor. In these situations, the use of allogeneic grafts to the supraceliac aorta have been advocated.

Single toxin detection is inadequate to diagnose Clostridium difficile diarrhea in pediatric patients.

Background & Aims: Clostridium difficile is an important cause of symptomatic diarrhea in pediatric patients. The bacterium produces two toxins, although many laboratories assay for only one. We questioned this diagnostic approach when patients had positive results for C.