Faculty Bibliography

BACKGROUND & AIMS: Crohn's disease (CD) has the highest prevalence in Ashkenazi Jewish populations. We sought to identify rare, CD-associated frameshift variants of high functional and statistical effects. METHODS: We performed exome-sequencing and array-based genotype analyses of 1477 Ashkenazi Jewish individuals with CD and 2614 Ashkenazi Jewish individuals without CD (controls). To validate our findings, we performed genotype analyses of an additional 1515 CD cases and 7052 controls for frameshift mutations in the colony stimulating factor 2 receptor beta common subunit gene (CSF2RB). Intestinal tissues and blood samples were collected from patients with CD; lamina propria leukocytes were isolated and expression of CSF2RB and GMCSF-responsive cells were defined by mass cytometry (CyTOF analysis). Variants of CSF2RB were transfected into HEK293 cells and expression and functions of gene products were compared. RESULTS: In the discovery cohort, we associated CD with a frameshift mutation in CSF2RB (P=8.52x10-4); the finding was validated in the replication cohort (combined P=3.42x10-6). Incubation of intestinal lamina propria leukocytes with GMCSF resulted in high levels of phosphorylation of STAT5 and lesser increases in phosphorylation of ERK and AKT. Cells co-transfected with full-length and mutant forms of CSF2RB had reduced pSTAT5 following stimulation with GMCSF, compared to cells transfected with control CSF2RB, indicating a dominant negative effect of the mutant gene. Monocytes from patients with CD who were heterozygous for the frameshift mutation (6% of CD cases analyzed) had reduced responses to GMCSF and markedly decreased activity of aldehyde dehydrogenase; activity of this enzyme has been associated with immune tolerance. CONCLUSIONS: In a genetic analysis of Ashkenazi Jewish individuals, we associated CD with a frameshift mutation in CSF2RB. Intestinal monocytes from carriers of this mutation had reduced responses to GMCSF, providing an additional mechanism for alterations to the innate immune response in individuals with CD.

OPINION STATEMENT: A substantial and growing proportion of patients with inflammatory bowel disease (IBD) are elderly, and these patients require tailored treatment strategies. However, significant challenges exist in the management of this population due to the paucity of data. Establishing the initial diagnosis and assessing the etiology of future symptoms and flares can be challenging as several other prevalent diseases can masquerade as IBD, such as ischemic colitis, diverticular disease, and infectious colitis. Important pharmacologic considerations include reduced glomerular filtration rate and drug-drug interactions in the elderly. No drug therapy is absolutely contraindicated in this population; however, special risk and benefit assessments should be made. Older patients are more susceptible to side effects of steroids such as delirium, fractures, and cataracts. Budesonide can be an appropriate alternative for mild to moderate ulcerative colitis (UC) or Crohn's disease (CD) as it has limited systemic absorption. Pill size and quantity, nephrotoxicity, and difficulty of administration of rectal preparations should be considered with 5-aminosalicylic (5-ASA) therapy. Biologics are very effective, but modestly increase the risk of infection in a susceptible group. Based on their mechanisms, integrin receptor antagonists (e.g., vedolizumab) may reduce these risks. Use of antibiotics for anorectal or fistulizing CD or pouchitis in UC increases the risk of Clostridium difficile infection. Pre-existing comorbidities, functional status, and nutrition are important indicators of surgical outcomes. Morbidity and mortality are increased among IBD patients undergoing surgery, often due to postoperative complications or sepsis. Elderly adults with IBD, particularly UC, have very high rates of venous thromboembolism (VTE). Colonoscopy appears safe, but the optimal surveillance interval has not been well defined. Should the octogenarian, nonagenarian, and centurion undergo colonoscopy? The length of surveillance should likely account for the individual's overall life expectancy. Specific health maintenance should emphasize administering non-live vaccines to patients on thiopurines or biologics and regular skin exams for those on thiopurines. Smoking cessation is crucial to overall health and response to medical therapy, even among UC patients. This article will review management of IBD in the elderly.

BACKGROUND: Ozanimod (RPC1063) is an oral agonist of the sphingosine-1-phosphate receptor subtypes 1 and 5 that induces peripheral lymphocyte sequestration, potentially decreasing the number of activated lymphocytes circulating to the gastrointestinal tract. METHODS: We conducted a double-blind, placebo-controlled phase 2 trial of ozanimod in 197 adults with moderate-to-severe ulcerative colitis. Patients were randomly assigned, in a 1:1:1 ratio, to receive ozanimod at a dose of 0.5 mg or 1 mg or placebo daily for up to 32 weeks. The Mayo Clinic score was used to measure disease activity on a scale from 0 to 12, with higher scores indicating more severe disease; subscores range from 0 to 3, with higher scores indicating more severe disease. The primary outcome was clinical remission (Mayo Clinic score 1) at 8 weeks. RESULTS: The primary outcome occurred in 16% of the patients who received 1 mg of ozanimod and in 14% of those who received 0.5 mg of ozanimod, as compared with 6% of those who received placebo (P=0.048 and P=0.14, respectively, for the comparison of the two doses of ozanimod with placebo). Differences in the primary outcome between the group that received 0.5 mg of ozanimod and the placebo group were not significant; therefore, the hierarchical testing plan deemed the analyses of secondary outcomes exploratory. Clinical response (decrease in Mayo Clinic score of >/=3 points and >/=30% and decrease in rectal-bleeding subscore of >/=1 point or a subscore