Ulcerative colitis immune cell landscapes and differentially expressed gene signatures determine novel regulators and predict clinical response to biologic therapy.

The heterogeneous pathobiology underlying Ulcerative Colitis (UC) is not fully understood. Using publicly available transcriptomes from adult UC patients, we identified the immune cell landscape, molecular pathways, and differentially expressed genes (DEGs) across patient cohorts and their association with treatment outcomes. The global immune cell landscape of UC tissue included increased neutrophils, T CD4 memory activated cells, active dendritic cells (DC), and M0 macrophages, as well as reduced trends in T CD8, Tregs, B memory, resting DC, and M2 macrophages. Pathway analysis of DEGs across UC cohorts demonstrated activated bacterial, inflammatory, growth, and cellular signaling. We identified a specific transcriptional signature of one hundred DEGs (UC100) that distinctly separated UC inflamed from uninflamed transcriptomes. Several UC100 DEGs, with unidentified roles in UC, were validated in primary tissue. Additionally, non-responders to anti-TNFα and anti-α4ß7 therapy displayed distinct profiles of immune cells and pathways pertaining to inflammation, growth, and metabolism. We identified twenty resistant DEGs in UC non-responders to both therapies of which four had significant predictive power to treatment outcome. We demonstrated the global immune landscape and pathways in UC tissue, highlighting a unique UC signature across cohorts and a UC resistant signature with predictive performance to biologic therapy outcome.

Open-label prospective therapeutic clinical trials: oral vancomycin in children and adults with primary sclerosing cholangitis.

BACKGROUND: Oral vancomycin (OV) in primary sclerosing cholangitis (PSC) has been evaluated as a potential therapeutic agent. We report the long-term biochemical course and outcomes of patients with PSC treated with OV. METHODS: Patients were enrolled in 2 open-label clinical trials (ClinicalTrials.gov Identifier: NCT01802073 and NCT01322386) and offered OV at 50 mg/kg/day in 3 divided doses if weight <30kg, and 500 mg 3 times/day if weight ≥30kg. Patients with biliary strictures requiring stenting or awaiting liver transplant were excluded. Liver biochemistry, MRCP and histology were documented at baseline and while on OV. The primary outcome was a decrease in elevated gamma glutamyl transferase (GGT), alkaline phosphatase (ALP), and/or alanine aminotransferase (ALT) from baseline. RESULTS: 30 subjects were enrolled, and 29 additional subjects who learned of the clinical trial requested OV (total n = 59; median age was 13.5 years [range, 1.5-44 years]; 64.4% were male; and 94.9% had inflammatory bowel disease [IBD]). The median treatment duration was 2.7 years (range, 0.2-14 years). Ninety-six percent (57/59), 81.3% (48/59), and 94.9% (56/59) experienced reduction of GGT, ALP, and ALT, respectively. Furthermore, 39% (23/59), 22% (13/59), and 55.9% (33/59) experienced normalization of GGT, ALP, and ALT, respectively, within the first 6 months of OV treatment. One patient underwent liver transplantation 8 years after beginning OV treatment, and one developed biliary strictures requiring endoscopic intervention. OV was well-tolerated by patients, and no patient developed treatment-related adverse events. CONCLUSION: In PSC, OV was well-tolerated and was associated with improvement in liver chemistry. A randomized placebo-controlled clinical trial is warranted.

Prevalence of Anal Dysplasia in Patients With Inflammatory Bowel Disease.

BACKGROUND & AIMS: Although the prevalence of anal dysplasia is higher in some immunosuppressed populations, the prevalence in patients with inflammatory bowel disease (IBD) is unknown. We examined the prevalence of abnormal anal cytology among IBD patients, and its relation to the human papilloma virus (HPV). METHODS: Adults with IBD and age-matched healthy controls (HC) were recruited. IBD patients were categorized as nonimmunosuppressed (IBD-N) or immunosuppressed (IBD-I). Anal Papanicolaou tests were performed for HPV testing and classification by a cytopathologist as follows: negative, atypical squamous cells of undetermined significance (ASC-US), low-grade squamous intraepithelial lesion, high-grade squamous intraepithelial lesion, cancer, or unsatisfactory. RESULTS: A total of 270 subjects (100 IBD-I, 94 IBD-N, and 76 HC) were recruited. ASC-US were detected in 19 subjects, with a trend toward a higher prevalence among IBD subjects compared with HC (8.8% vs 2.6%; P = .10). The prevalence did not differ with respect to immunosuppression. Crohn's disease (CD) subjects had a higher prevalence of ASC-US compared with others with IBD (P = .02). Among those with CD, female sex and disease duration longer than 10 years were risk factors. There were no cases of low-grade squamous intraepithelial lesion, high-grade squamous intraepithelial lesion, or anal cancer in the cohort. HPV was present in 5.3% and 1.5% of subjects with and without ASC-US, respectively (P = .26). CONCLUSIONS: Although there was a trend toward abnormal anal Papanicolaou tests in IBD subjects compared with HC, there was no difference based on immunosuppression. The presence of HPV did not correlate with abnormal anal cytology. Risk factors associated with this increased trend include female CD subjects and those with a longer duration of CD. ClinicalTrials.gov number: NCT01860963; https://clinicaltrials.gov/ct2/show/NCT01860963.

Incidence and risk of intestinal and extra-intestinal complications in Medicaid patients with inflammatory bowel disease: a 5-year population-based study.

BACKGROUND AND AIM: Intestinal and extra-intestinal complications are associated with inflammatory bowel disease (IBD) but their exact incidence is not well known. In order to improve our understanding of their incidence and impact, we assessed the complications associated with ulcerative colitis (UC) and Crohn's disease (CD) in a population-based study in Medicaid patients. METHODS: We utilized a retrospective cohort design and identified cases of UC and CD using Medi-Cal, the Medicaid program for the State of California. The disease cohort was age- and gender-matched to four controls each and the intestinal and extra-intestinal complications of CD and UC (analyzed separately) were studied over a period of 5 years following the initial diagnosis. RESULTS: For UC, the total number of intestinal complications, per 100 cases, was 92 observed compared to 21 expected; the total number of extra-intestinal complications was 42 observed compared to 30 expected. For CD, the number of intestinal complications was 81 observed compared to 20 expected and for extra-intestinal complications, 37 observed compared to 26 expected (all p < 0.001). For both UC and CD, bleeding was the most frequently seen intestinal complication, while the most common extra-intestinal complication was osteoporosis. CONCLUSIONS: IBD is associated with several intestinal and extra-intestinal complications of variable incidence and risk. Success of therapeutic regimens should be measured by decreases in incidence, risks, and costs of these complications, in addition to the usual impact on disease activity.

Risks and benefits of the use of concomitant immunosuppressives and biologics in inflammatory bowel disease.

With the introduction of biologic therapies for inflammatory bowel disease, significant questions have arisen regarding their best optimization. Although initial recommendations were to combine immunosuppressives with biologics to reduce immunogenicity, trials with 3 different anti-tumor necrosis factor agents (infliximab, adalimumab, and certolizumab) and a humanized monoclonal antibody that targets alpha-4 integrins (natalizumab) have failed to demonstrate the clinical superiority of combination therapy when high-dose induction and scheduled maintenance therapy was prescribed for up to 1 year. However, immunosuppressive agents should be considered with episodic biologic therapy to decrease immunogenicity and secondary loss of response. The issue of whether induction with biologics and maintenance therapy with immunosuppressives as monotherapy is as safe and effective as induction and maintenance with biologics alone still remains to be addressed. Further, with the use of concomitant immunosuppressives and biologics, evolving data raise concerns for an increase in adverse events, including opportunistic infections, neurological disorders, and cancer. Specific therapeutic decisions need to be individualized and the clinician must help the patient weigh quality-of-life issues with readiness to assume possible risks.

Treatment of diarrhea in patients with inflammatory bowel disease: concepts and cautions.

Diarrhea continues to be a prevalent symptom in patients with inflammatory bowel disease (IBD), requiring a wide differential diagnosis to define the pathophysiologic mechanisms in individual patients. It is essential that physicians properly evaluate complaints of diarrhea by assessing both patient symptoms and potential physiologic impacts on fluid and electrolyte status. Underlying mechanisms of diarrhea with IBD are the location, extent, and severity of inflammation; malabsorption; altered motility; and iatrogenic causes such as medications, diet, and antibiotic-associated colitis (eg, Clostridium difficile). When treating diarrhea, physicians need to control inflammatory activity using appropriate treatment algorithms. Therapies include aminosalicylates, corticosteroids, immune modifiers, and, most recently, biologic treatment. Other medications, including loperamide, diphenoxylate, codeine sulfate, and tinctures of opium, slow motility and increase the absorption of fluids and nutrients. For iatrogenic issues, medications that cause diarrhea should be withdrawn and individual diets modified. Not all diarrheas in the IBD patient are the same; therefore, it is essential to tailor therapies according to presumed etiologies. Antidiarrheal agents are not recommended in extremely ill patients and those with known hypersensitivity or evidence of obstruction or colonic dilation, fever, or abdominal tenderness. Concomitant use of loperamide with diphenoxylate and atropine should be avoided in early pregnancy.