Person:

Cheifetz, Adam

OBJECTIVES: Poor adherence to mesalamine is common and driven by a combination of lifestyle and behavioral factors, as well as health beliefs. We sought to develop a valid tool to identify barriers to patient adherence and predict those at risk for future nonadherence. METHODS: A 10-item survey was developed from patient-reported barriers to adherence. The survey was administered to 106 patients with ulcerative colitis who were prescribed mesalamine, and correlated with prospectively collected 12-month pharmacy refills (medication possession ratio (MPR)), urine levels of salicylates, and self-reported adherence (Morisky Medication Adherence Scale (MMAS)-8). RESULTS: From the initial 10-item survey, 8 items correlated highly with the MMAS-8 score at enrollment. Computer-generated randomization produced a derivation cohort of 60 subjects and a validation cohort of 46 subjects to assess the survey items in their ability to predict future adherence. Two items from the patient survey correlated with objective measures of long-term adherence: their belief in the importance of maintenance mesalamine even when in remission and their concerns about side effects. The additive score based on these two items correlated with 12-month MPR in both the derivation and validation cohorts (P<0.05). Scores on these two items were associated with a higher risk of being nonadherent over the subsequent 12 months (relative risk (RR) =2.2, 95% confidence interval=1.5–3.5, P=0.04). The area under the curve for the performance of this 2-item tool was greater than that of the 10-item MMAS-8 score for predicting MPR scores over 12 months (area under the curve 0.7 vs. 0.5). CONCLUSIONS: Patients’ beliefs about the need for maintenance mesalamine and their concerns about side effects influence their adherence to mesalamine over time. These concerns could easily be raised in practice to identify patients at risk of nonadherence (Clinical Trial number NCT01349504).

Background: In patients with ulcerative colitis who fail corticosteroids and are treated with rescue therapy (e.g. infliximab or cyclosporine) but fail to respond, salvage therapy with infliximab or cyclosporine can be considered. We sought to assess the efficacy and safety of this third-line salvage therapy. Methods: We performed a meta-analysis of trials published in PubMed up to January 2015 relating to the use of third-line salvage therapy following failure of intravenous corticosteroids and infliximab or cyclosporine. Pooled outcome rates for each salvage strategy and pooled odds ratio comparing the two strategies were calculated using the random effects model. Heterogeneity was assessed by the Q and I2 statistics. Results: The search strategy yielded 40 articles of which 4 were eligible for inclusion. Four articles assessed patients who were treated with infliximab after failure of cyclosporine and 2 articles assessed the use of cyclosporine after failure of infliximab. There were 138 patients using infliximab as a third-line salvage therapy and 30 patients using cyclosporine. When comparing these two strategies, there was no significant difference in clinical response (RR 1.03, 95%CI 0.7-1.46 P=0.87), clinical remission (RR 0.69, 95%CI 0.30-1.57 P=0.37), or colectomy at 12 months (RR 1.14, 95%CI 0.79-1.67 P=0.48). Similarly, there was no significant difference in total (RR 1.91, 95% CI0.38-9.64 p=0.43) or serious adverse events (RR 1.18, 95%CI 0.34-4.07 P=0.80). Conclusion: While third-line salvage therapy may be efficacious in achieving short-term clinical response/remission, there remains a significant risk of colectomy and adverse events.

Induced regulatory T-cells (iT-reg) and T helper type 17 (Th17) in the mouse share common CD4 progenitor cells and exhibit overlapping phenotypic and functional features. Here, we show that human Th17 cells endowed with suppressor activity (supTh17) can be derived following exposure of iT-reg populations to Th17 polarizing conditions. In contrast to “pathogenic” Th17, supTh17 display immune suppressive function and express high levels of CD39, an ectonucleotidase that catalyzes the conversion of pro-inflammatory extracellular nucleotides ultimately generating nucleosides. Accordingly, supTh17 exhibit nucleoside triphosphate diphosphohydrolase activity, as demonstrated by the efficient generation of extracellular AMP, adenosine and other purine derivatives. In addition supTh17 cells are resistant to the effects of adenosine as result of the low expression of the A2A receptor and accelerated adenosine catalysis by adenosine deaminase (ADA). These supTh17 can be detected in the blood and in the lamina propria of healthy subjects. However, these supTh17 cells are diminished in patients with Crohn’s disease. In summary, we describe a human Th17 subpopulation with suppressor activity, which expresses high levels of CD39 and consequently produces extracellular adenosine. As these uniquely suppressive CD39+ Th17 cells are decreased in patients with inflammatory bowel disease, our findings might have implications for the development of novel anti-inflammatory therapeutic approaches in these and potentially other immune disorders.

Abstract: Anti-TNF medications have revolutionized the care of patients with inflammatory bowel disease. However, despite an initial robust effect, loss of response is common and long-term results are disappointing. Much of this lack of durability may be due to inadequate dose optimization, and recent studies suggest a correlation between serum drug concentrations and clinical outcomes. Currently, in clinical practice, measurement of drug concentrations and antibodies to drug are typically performed only when a patient presents with active inflammatory bowel disease symptoms or during a potential immune-mediated reaction to anti-TNF (“reactive” setting). However, proactive monitoring of anti-TNF concentrations with titration to a therapeutic window (i.e., therapeutic concentration monitoring) represents a new strategy with many potential clinical benefits including prevention of immunogenicity, less need for IFX rescue therapy, and greater durability of IFX treatment. This review will cover the salient features of anti-TNF pharmacokinetics and pharmacodynamics and provide a rational approach for the use of anti-TNF concentration testing in both the reactive and proactive settings.

OBJECTIVES Antibodies to infliximab (ATIs) have been associated with loss of clinical response and lower serum infliximab (IFX) levels in some studies of patients with inflammatory bowel disease (IBD). This has important implications for patient management and development of novel biologic therapies. The objective of this study was to perform a systematic review and meta-analysis of studies that reported clinical outcomes and IFX levels according to patients’ ATI status.

METHODS MEDLINE, Web of Science, CINAHL, Scopus, and EMBASE were searched for eligible studies. Quality assessment was undertaken using GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria. Raw data from studies meeting inclusion criteria was pooled for meta-analysis of effect estimates. Sensitivity analysis was performed for all outcomes. Funnel plot was performed to assess for publication bias.

RESULTS Thirteen studies met the inclusion criteria, and reported results in 1,378 patients with IBD. All included studies had a high risk of bias in at least one quality domain. The pooled risk ratio (RR) of loss of clinical response to IFX in patients with IBD who had ATIs was 3.2 (95 % confidence interval (CI): 2.0–4.9, P < 0.0001), when compared with patients without ATIs. This effect estimate was predominantly based on data from patients (N = 494) with Crohn’s disease (RR: 3.2, 95 % CI: 1.9–5.5, P < 0.0001). Data only from patients with ulcerative colitis (n = 86) exhibited a non-significant RR of loss of response of 2.2 (95 % CI: 0.5–9.0, P = 0.3) in those with ATIs. Heterogeneity existed between studies, in both methods of ATI detection, and clinical outcomes reported. Three studies (n = 243) reported trough serum IFX levels according to ATI status; the standardized mean difference in trough serum IFX levels between groups was −0.8 (95 % CI −1.2, −0.4, P < 0.0001). A funnel plot suggested the presence of publication bias.

CONCLUSIONS The presence of ATIs is associated with a significantly higher risk of loss of clinical response to IFX and lower serum IFX levels in patients with IBD. Published studies on this topic lack uniform reporting of outcomes. High risk of bias was present in all the included studies.

Background Hospitalised patients with inflammatory bowel disease are 1.5- to 3.5-fold more likely to develop venous thromboembolism compared to controls. Clinical guidelines recommend pharmacological prophylaxis.

Aim To determine the rate of pharmacological venous thromboembolism prophylaxis prescription and administration in a cohort of hospitalised patients with severe active ulcerative colitis and to assess predictors of failure to order pharmacological prophylaxis at 24 h.

Methods This is a retrospective review of hospitalised patients with severe active ulcerative colitis, identified by ICD-9-CM discharge code 556.x, admitted to a single tertiary care hospital from 1 January 2005 to 31 August 2012. Adequate thromboembolism prophylaxis was defined as an order for low-dose unfractionated heparin two to three times daily, low-molecular weight heparin 40 mg daily or fondaparinux 2.5 mg daily ordered and administered for >80% of the admission. Patient related factors associated with failure to order prophylaxis at 24 h were accessed as secondary outcomes.

Results Three hundred and thirty-six patients were hospitalised with severe active ulcerative colitis. Hospitalists had prescribed appropriate pharmacological prophylaxis by 48 h in only 37% of cases. Of these, nurses administered all prescribed doses in 18% of cases. Only 7% of patients (22/304, 95% CI: 5–11%) received adequate pharmacological prophylaxis for >80% of their hospitalisation. Hematochezia (P = 0.002), elevated platelets (P = 0.008), male gender coupled with younger age (P = 0.005) and admission on a biologic (P = 0.03) were associated with failure to order prophylaxis.

Conclusion Hospitalised patients admitted with severe active ulcerative colitis are not receiving appropriate pharmacological venous thromboembolism prophylaxis.

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.

Purinergic signaling and associated ectonucleotidases, such as CD39 and CD73, have been implicated in the pathogenesis of inflammatory bowel disease (IBD). CD39 is known to be a Treg memory cell marker, and here we determine the phenotype and function of CD73+CD4+ T lymphocytes in patients with IBD. We describe elevated levels of CD73+CD4+ T cells in the peripheral blood and intestinal lamina propria of patients with active IBD. The functional phenotype of these CD73+CD4+ T cells was further determined by gene expression, ecto-enzymatic activity, and suppressive assays. Increased numbers of CD73+CD4+ T cells in the periphery and lamina propria were noted during active inflammation, which returned to baseline levels following anti-TNF treatment. Peripheral CD73+CD4+ T cells predominantly expressed CD45RO, and were enriched with IL-17A+ cells. The CD73+CD4+ cell population expressed higher levels of RORC, IL-17A, and TNF, and lower levels of FOXP3 and/or CD25, than CD73−CD4+ T cells. Expression of CD73 by peripheral CD4+ T cells was increased by TNF, and decreased by an anti-TNF monoclonal antibody (infliximab). In vitro, these peripheral CD73+CD4+ T cells did not suppress proliferation of CD25− effector cells, and expressed higher levels of pro-inflammatory markers. We conclude that the CD73+CD4+ T-cell population in patients with active IBD are enriched with cells with a T-helper type 17 phenotype, and could be used to monitor disease activity during 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.