Faculty Bibliography

BACKGROUND & AIMS: Tofacitinib, an orally administered Janus kinase inhibitor, blocks signaling through gamma-chain-containing cytokines (interleukins 2, 4, 7, 9, 15, and 21). We performed a phase 2 trial to measure its efficacy in patients with moderate-to-severe active Crohn's disease. METHODS: Patients (N = 139; age, >/=18 y) with moderate-to-severe active Crohn's disease were assigned randomly to groups given 1 mg (n = 36), 5 mg (n = 34), or 15 mg (n = 35) tofacitinib or placebo (n = 34), twice daily for 4 weeks, at 48 centers in 12 countries. The primary end point was the proportion of clinical responders at week 4 (decrease from baseline in the Crohn's Disease Activity Index score of >/=70 points [Response-70]). Secondary end points included clinical remission (Crohn's Disease Activity Index score of <150 points) at week 4. RESULTS: A clinical response was observed in 36% (P = .467), 58% (P = .466), and 46% (P >/= .999) of patients given the 1-, 5-, and 15-mg doses of tofacitinib, compared with 47% of patients given placebo. Clinical remission was observed in 31% (P = .417), 24% (P = .776), and 14% (P = .540) of patients given the 1-, 5-, and 15-mg doses of tofacitinib, compared with 21% of patients given placebo. The 15-mg dose of tofacitinib reduced levels of C-reactive protein and fecal calprotectin from baseline. Adverse and serious adverse events were similar among groups. Dose-dependent increases in low- and high-density lipoprotein cholesterol were observed in patients given the 5- or 15-mg doses of tofacitinib. CONCLUSIONS: There were no significant differences in the percentage of patients with moderate-to-severe active Crohn's disease who achieved clinical responses (Response-70) or clinical remission after 4 weeks' administration of tofacitinib (1, 5, or 15 mg) or placebo twice daily. However, a large percentage of patients given placebo achieved Response-70 or remission. Reductions in C-reactive protein and fecal calprotectin levels among patients given the 15-mg dose of tofacitinib indicate its biologic activity. ClinicalTrials.gov number: NCT00615199.

OBJECTIVE: To evaluate the efficacy and safety of oral lubiprostone for relieving symptoms of opioid-induced constipation (OIC) in patients with chronic noncancer pain. DESIGN: Prospective, randomized, double-blind, placebo-controlled trial. SETTING: Seventy-nine US and Canadian centers. SUBJECTS: Patients aged >/= 18 years with OIC, defined as <3 spontaneous bowel movements (SBMs) per week. METHODS: Patients received lubiprostone 24 mcg or placebo twice daily for 12 weeks. The primary endpoint was change from baseline in SBM frequency at week 8. RESULTS: Among randomized patients (N=418; lubiprostone, N=210; placebo, N=208), most completed the study (lubiprostone, 67.1%; placebo, 69.7%). The safety and efficacy (intent-to-treat) populations included 414 (lubiprostone, N=208; placebo, N=206) and 413 (lubiprostone, N=209; placebo, N=204) patients, respectively. The mean (standard deviation) age was 50.4 (10.9) years; most patients were female (64.4%) and white (77.7%). Changes from baseline in SBM frequency rates were significantly higher at week 8 (P=0.005) and overall (P=0.004) in patients treated with lubiprostone compared with placebo. Pairwise comparisons showed significantly greater overall improvement for abdominal discomfort (P=0.047), straining (P<0.001), constipation severity (P=0.007), and stool consistency (P<0.001) with lubiprostone compared with placebo. Moreover, patients rated the effectiveness of lubiprostone as significantly (P<0.05) better than placebo for 11 of 12 weeks. The most common treatment-related adverse events (AEs) with lubiprostone and placebo were nausea (16.8% vs 5.8%, respectively), diarrhea (9.6% vs 2.9%), and abdominal distention (8.2% vs 2.4%). No lubiprostone-related serious AEs occurred. CONCLUSION: Lubiprostone effectively relieved OIC and associated signs and symptoms and was well tolerated in patients with chronic noncancer pain (http://clinicaltrials.gov/ct2/show/NCT00595946).

As the global population ages, the number of older people (>/=65 years) living with IBD is expected to increase. IBD therapeutics have advanced considerably over the past few decades with the introduction of multiple steroid-sparing agents as well as numerous clinical trials that have tested new therapeutic targets. However, the current paradigms for IBD management might not be directly translatable to older patients with IBD. Age-related factors such as immunodeficiency relative to younger patients, comorbidity, polypharmacy and diminished physical reserve directly or indirectly affect the natural history of their disease. This Review highlights how these age-associated variables can affect older patients with IBD and also illustrates the multiple gaps in our current knowledge of IBD in the elderly.

There has been limited research examining the risks, benefits, and use of common endoscopic procedures in the elderly. Furthermore, gastroenterology training programs do not routinely incorporate elderly concerns when dealing with common gastrointestinal issues. There exists a broad array of endoscopic procedures with varying inherent risks that must be weighed with each elderly patient in mind. This article discusses the benefits and drawbacks of the most common procedures and indications for endoscopy including upper endoscopy, colonoscopy, endoscopic retrograde cholangiopancreatography, endoscopic ultrasound, percutaneous endoscopic gastrostomy, and deep enteroscopy.

BACKGROUND AND AIMS: To evaluate the impact of preoperative radiation on pouch outcomes in patients with colitis-associated cancer (CAC). METHODS: CAC patients who underwent restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) from 1984 to 2009 were identified from our registry. The impact of preoperative pelvic radiation for CAC or other pelvic cancer on pouch related outcomes was evaluated. RESULTS: Sixty-three pouch patients with confirmed CAC were included (37 male, 58.7%). The mean age at pouch construction was 46.9+/-10.6 years. Seven patients were excluded due to the presence of persistent diverting ileostomy (n=2) or no follow-up (n=5). The remaining 56 patients were analyzed, including 9 who received pelvic radiation prior to IPAA creation for CRC or other cancers. Preoperative pelvic radiation was significantly associated with chronic pouchitis (P=0.024). There was, however, no correlation between pelvic radiation and pouch/anal transitional zone neoplasia, pouch stricture, pelvic abscess and pouch fistula/sinus. Pouch failure occurred in 13 patients after a median follow-up of 66.4 (range: 2.7-322.2) months. Although a simple statistical analysis based on the number of patients with pouch failure did not achieve significance (4/9 vs. 9/47, P=0.19), Kaplan-Meier analysis showed a strong association between preoperative pelvic radiation and the risk for pouch failure (P<0.001). A subgroup analysis of rectal cancer patients revealed that 3/7 patients (42.9%) with radiation and 3/17 (17.6%) without had pouch failure (P=0.31). Again, the association between pelvic radiation and pouch failure was confirmed using Kaplan-Meier analysis (P=0.02). CONCLUSIONS: Pelvic radiation administered prior to IPAA creation appears to be associated with poor pouch outcomes. Oncological benefits and pouch functional outcomes should be carefully balanced before pelvic radiation is considered prior to restorative proctocolectomy.