Faculty Bibliography

The marijuana plant Cannabis sativa and its derivatives, cannabinoids, have grown increasingly popular as a potential therapy for inflammatory bowel disease (IBD). Studies have shown that modulation of the endocannabinoid system, which regulates various functions in the body and has been shown to play a key role in the pathogenesis of IBD, has a therapeutic effect in mouse colitis. Epidemiologic data and human therapy studies reveal a possible role for cannabinoids in the symptomatic treatment of IBD, although it has yet to be determined in human populations whether cannabinoids have therapeutic anti-inflammatory effects in IBD or are simply masking its many debilitating symptoms. Large, double-blind, randomized, placebo-controlled trials using serial inflammatory markers, biopsy findings, and endoscopic disease severity to demonstrate objective improvement in IBD are necessary before cannabis can be empirically accepted and recommended as an IBD treatment option. Questions concerning its safety profile and adverse effects prompt the need for further research, particularly in regard to dosing and route of administration to maximize benefits and limit potential harms. Cannabis use should be reserved for symptomatic control in patients with severe IBD refractory to the currently available standard-of-care and complementary and alternative medicines.

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.

One goal of human genetics is to understand the genetic basis of disease, a challenge for diseases of complex inheritance because risk alleles are few relative to the vast set of benign variants. Risk variants are often sought by association studies in which allele frequencies in case subjects are contrasted with those from population-based samples used as control subjects. In an ideal world we would know population-level allele frequencies, releasing researchers to focus on case subjects. We argue this ideal is possible, at least theoretically, and we outline a path to achieving it in reality. If such a resource were to exist, it would yield ample savings and would facilitate the effective use of data repositories by removing administrative and technical barriers. We call this concept the Universal Control Repository Network (UNICORN), a means to perform association analyses without necessitating direct access to individual-level control data. Our approach to UNICORN uses existing genetic resources and various statistical tools to analyze these data, including hierarchical clustering with spectral analysis of ancestry; and empirical Bayesian analysis along with Gaussian spatial processes to estimate ancestry-specific allele frequencies. We demonstrate our approach using tens of thousands of control subjects from studies of Crohn disease, showing how it controls false positives, provides power similar to that achieved when all control data are directly accessible, and enhances power when control data are limiting or even imperfectly matched ancestrally. These results highlight how UNICORN can enable reliable, powerful, and convenient genetic association analyses without access to the individual-level data.