Person:

Cheifetz, Adam

Background: Vitamin D deficiency is common in patients with Crohn’s disease (CD), although whether this impairs immune responsiveness, and is related to disease activity per se, remains unclear. We sought to investigate vitamin D pathways in patients with CD according to measures of inflammation and immune response. Methods: Prospectively collected samples of a well-characterized cohort of patients with CD were used to measure serum 25(OH)-vitamin D levels by enzyme-linked immunoassay. Related gene expression was determined by polymerase chain reaction in T cells. The effect of vitamin D on the proliferation of isolated CD4+ cells was determined. Results: Patients with active CD had lower serum vitamin D levels than those in clinical remission; this measurement was independent of season or reported use of vitamin D supplements. Harvey–Bradshaw Index scores, but not C-reactive protein, correlated with serum vitamin D levels. Gene expression of the vitamin D receptor was higher in peripheral blood T cells from patients with active disease than in those in remission. The proportion of CD25hi CD4+ cells from patients with CD increased in the presence of vitamin D. After treatment with infliximab, significant increases in serum vitamin D levels were noted in patients. Conclusions: Low vitamin D levels are associated with disease activity in CD and increase after infliximab treatment.

Background A number of treatments have been shown to reduce the risk of postoperative recurrence of Crohn's disease (CD). The optimal strategy is unknown. The aim was to evaluate the comparative cost-effectiveness of postoperative strategies to prevent clinical recurrence of CD.

Methods Three prophylactic strategies were compared to “no prophylaxis”; mesalamine, azathioprine (AZA) / 6-mercaptopurine (6-MP), and infliximab. The probability of clinical recurrence, endoscopic recurrence, and therapy discontinuation due to adverse drug reactions (ADRs) were extracted from randomized controlled trials (RCTs). Quality-of-life scores and treatment costs were derived from published data. The primary model evaluated quality-adjusted life years (QALYs) and cost-effectiveness at 1 year after surgery. Sensitivity analysis assessed the impact of a range of recurrence rates on cost-effectiveness. An exploratory analysis evaluated cost-effectiveness outcomes 5 years after surgery.

Results A strategy of “no prophylaxis” was the least expensive one at 1 and 5 years after surgery. Compared to this approach, AZA/6-MP had the most favorable incremental cost-effectiveness ratio (ICER) (USD 299,188/QALY gained), and yielded the highest net health benefits of the medication strategies at 1 year. Sensitivity analysis determined that the ICER of AZA/6-MP was preferable to mesalamine up to a recurrence rate of 52%, but mesalamine dominated at higher rates. In the 5-year exploratory analysis, mesalamine had the most favorable ICER over 5 years (USD 244,177/QALY gained).

Conclusions Compared to no prophylactic treatment, AZA/6-MP has the most favorable ICER in the prevention of clinical recurrence of postoperative CD up to 1 year. At 5 years, mesalamine had the most favorable ICER in this model.

Objectives Patients with ulcerative colitis (UC) who are in clinical remission may still have underlying endoscopic inflammation, which is associated with inferior clinical outcomes. The goal of this study was to determine the prevalence of, and factors associated with, active endoscopic disease in patients with UC who are in clinical remission.

Design Prospective observational study in a single center. Patients with UC in clinical remission (by SCCAI) were enrolled prospectively at time of surveillance colonoscopy. Disease phenotype, endoscopic activity (Mayo sub-score) and histological score (Geboes) were recorded, and blood was drawn for peripheral blood biomarkers.

Results 149 patients in clinical remission were prospectively enrolled in this cohort; 81% had been in clinical remission for > 6 months, and 86% were currently prescribed maintenance medications. At endoscopy 45% of patients in clinical remission had any endoscopic inflammation (Mayo endoscopy sub-score >0) and 13% had scores >1. In a multivariate model, variables independently associated with a Mayo endoscopic score >1 were remission for < 6 months (p=.001), WBC (p=0.01) and CRP (p=0.009). A model combining these three variables had a sensitivity of 94% and a specificity of 73% for predicting moderate-severe endoscopic activity in patients in clinical remission (AUC 0.86). In an unselected sub-group of patients who had peripheral blood mononuclear cell mRNA profiling, GATA3 mRNA levels were significantly higher in patients with endoscopic activity.

Conclusions Duration of clinical remission, WCC and CRP can predict the probability of on-going endoscopic activity despite clinical remission in patients with UC. These parameters could be used to identify patients who require intensification of treatment to achieve mucosal healing.

Background Patients with inflammatory bowel disease have higher proportions of immunoglobulin G (IgG) antibodies lacking N-galactose, also called agalactosyl IgG, in their serum. Such agalactosyl IgGs have been associated with disease activity and the immunogenicity of biologics. The aim was to describe the relationship between circulating levels of a subset of agalactosyl IgGs (anti-α-Gal) and Crohn’s disease (CD) phenotypes.

Methods Prospectively collected serum samples of a well-characterized cohort of patients with inflammatory bowel disease and controls were used. Serum anti-α-Gal levels were measured by a high-affinity enzyme-linked immunosorbent assay and referenced to a standard control.

Results Serum samples from 167 subjects were tested; 62 with CD, 76 with ulcerative colitis, and 29 controls. Agalactosyl anti-α-Gal levels were significantly higher in active CD than in active ulcerative colitis (P = 0.0043) or healthy controls (P < 0.0001). Among patients with CD, agalactosyl anti-α-Gal levels were significantly higher in those with a history of arthritis, than those without (P = 0.0002), but lower in those taking immunomodulators (P = 0.03). There was no correlation between agalactosyl anti-α-Gal levels and indices of Crohn’s severity, including C-reactive protein levels or Harvey– Bradshaw index. Patients who were primary or secondary nonresponders to infliximab had similar agalactosyl anti-α-Gal levels to clinical responders.

Conclusions Patients with CD have greater amounts of agalactosylated anti-α-Gal antibodies in their serum, particularly in those with associated joint disease. This increase seems to be independent of indices of disease activity, but is influenced by immunomodulator use.

CD39 (ENTPD1) is expressed by subsets of pathogenic human CD4+ T cells, such as T helper type 17 (Th17) cells. These Th17 cells are considered important in intestinal inflammation, such as seen in Crohn’s disease. Recently, CD161 (NKR-P1A) has been shown to be a phenotypic marker of human Th17 cells. In this study, we report that co-expression of CD161 and CD39 not only identifies these cells but also promotes Th17 generation. We note that human CD4+CD39+CD161+ T cells can be induced under stimulatory conditions that promote Th17 in vitro. Furthermore, CD4+CD39+CD161+ cells purified from blood and intestinal tissues, from both healthy controls and patients with Crohn’s disease, are of the Th17 phenotype and exhibit pro-inflammatory functions. CD39 is co-expressed with CD161, and this association augments acid sphingomyelinase (ASM) activity upon stimulation of CD4+ T cells. These pathways regulate mTOR and STAT3 signaling to drive the Th17 phenotype. Inhibition of ASM activity by pharmacological blockers or knockdown of ASM abrogates STAT3 signaling, thereby limiting IL-17 production in CD4+ T cells obtained from both controls and patients with active Crohn’s disease. Increased levels of CD39+CD161+ CD4+ T cells in blood or lamina propria are noted in patients with Crohn’s disease; and levels directly correlate with clinical disease activity. Hence, co-expression of CD39 and CD161 by CD4+ T cells might serve as a biomarker to monitor Th17 responsiveness. Collectively, CD39 and CD161 modulate human Th17 responses in Crohn's disease through alterations in purinergic nucleotide-mediated responses and ASM catalytic bioactivity, respectively.