Person:

Moss, Alan

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon that typically manifests as diarrhea, abdominal pain, and bloody stool. Complications, such as colorectal cancer and extraintestinal manifestations, may also develop. The goals of management are to induce and maintain clinical remission and to screen for complications of this disease. Mesalamine is a 5-aminosalicylic acid compound that is the first-line therapy to induce and maintain clinical remission in patients with mild-to-moderate UC. For patients who are refractory to mesalamine or have more severe disease, steroids, azathioprine/mercaptopurine, cyclosporine, or infliximab may be used, induce and/or maintain remission. The various formulations of mesalamine available are primarily differentiated by the methods of delivery of the active compound of the drug to the colon. Mesalamine with Multi-Matrix System® (MMX) technology (Cosmo SpA, Milan, Italy) is an oral (1.2 g), once-daily tablet formulation of mesalamine used for the treatment of UC (Lialda® or Mezavant®, Shire Pharmaceuticals Inc, Wayne, PA). In clinical studies, MMX mesalamine (taken as a once-daily dose of 2.4 or 4.8 g) effectively induced and maintained clinical remission in patients with active mild-to-moderate UC. The overall safety profile of MMX mesalamine is similar to other oral mesalamine formulations. The use of such once-daily formulations has led to intense interest in whether simplified pill regimens can improve patient adherence to mesalamine therapy.

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: Inflammatory bowel disease (IBD) has been associated with renal stone formation. The objective of this study was to determine prospectively the prevalence of nephrolithiasis in a community-based population of patients with IBD and to analyze factors associated with renal calculus formation. Methods: Screening renal ultrasound was performed in a well characterized cohort of patients seen between 2009 and 2012 at an IBD clinic. We enrolled 168 patients, including 93 with Crohn’s disease and 75 with ulcerative colitis. Clinical and phenotypic variables associated with asymptomatic nephrolithiasis were determined. Results: Nephrolithiasis was detected in 36 patients with Crohn’s disease and in 28 patients with ulcerative colitis (38% for both). Although none of the patients had been previously hospitalized for symptomatic nephrolithiasis, nine with Crohn’s disease and five with ulcerative colitis had recurrent urinary tract infections or hydronephrosis. In patients with Crohn’s disease, ileocolonic (L3) disease was associated with a greater risk of nephrolithiasis than was ileal (L1) or colonic (L2) disease (odds ratio [OR] 2.3, 95% confidence interval [CI] 1.8–7). Active ulcerative colitis (regardless of severity) represented a significant risk factor for formation of renal calculi (OR 4.2, 95% CI 1.1–15, P = 0.02). Conclusion: In surgery-naïve patients with IBD in the community, asymptomatic nephrolithiasis is common and should be considered when renal dysfunction or infection is detected.

Interferon gamma (IFNγ)-producing CD8+ T cells (Tc1) play important roles in immunological disease. We now report that CD3/CD28-mediated stimulation of CD8+ T cells to generate Tc1 cells, not only increases IFNγ production but also boosts the generation of reactive oxygen species (ROS) and augments expression of CD39. Inhibition of NADPH oxidases or knockdown of gp91phox in CD8+ T cells abrogates ROS generation, which in turn modulates JNK and NFκB signalling with decreases in both IFNγ levels and CD39 expression. CD39+CD8+ T cells substantially inhibit IFNγ production by CD39−CD8+ T cells via the paracrine generation of adenosine, which is operational via adenosine type 2A receptors. Increases in numbers of CD39+CD8+ T cells and associated enhancements in ROS signal transduction are noted in cells from patients with Crohn's disease. Our findings provide insights into Tc1-mediated IFNγ responses and ROS generation and link these pathways to CD39/adenosine-mediated effects in immunological disease.

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.

Biological therapy revolutionized the treatment of inflammatory bowel disease (IBD) during the last decade. These monoclonal antibodies, which target tumor necrosis factor (TNF), integrins or IL12/23, have been approved—or are in development for—both Crohn’s disease (CD) and ulcerative colitis (UC). Early use of these agents taught clinicians that induction and maintenance therapy, coupled with immunomodulator agents, reduced the immunogenicity of these agents, and led to sustained remission in many patients. More recent data has demonstrated that, through dose adjustments, optimizing serum drug levels may also provide more durable maintenance of remission, and improved mucosal healing. This review examines clinical practices that may enhance clinical outcomes from biological therapy in IBD.

Infliximab is a monoclonal antibody against tumor necrosis factor (TNF) which has become an established therapy for Crohn’s disease over the last 10 years. Given the similarities between Crohn’s disease and ulcerative colitis (UC), it is no surprise that gastroenterologists have used infliximab in patients with UC who have failed other therapies. Although the initial controlled trials with infliximab in steroid-refractory disease were unimpressive, subsequent controlled trials have demonstrated the efficacy of infliximab in both moderate to severe disease, and as rescue-therapy to avoid colectomy. The long-term remission rates, colectomy-sparing effects, and the impact of concomitant immunomodulator therapy, remain to be determined in these patients. Whether infliximab is a superior strategy to cyclosporine in patients with steroid-refractory disease is controversial. This review examines the data on the efficacy and safety of infliximab as an induction and maintenance agent for UC.

Background

Infliximab (IFX) therapy escalation during maintenance treatment occurs frequently in clinical practice in patients with ulcerative colitis (UC). Outcomes for these patients have not been described.

Aim

To describe the prevalence of, and outcomes after, IFX escalation during maintenance therapy in patients with moderate-severe UC.

Methods

Retrospective observational study of clinical outcomes in ambulatory patients with moderate-severe UC treated with maintenance IFX.

Results

Fifty-six ambulatory patients received IFX for moderate-severe UC; fifty (89%) responded and proceeded to maintenance therapy. Mean duration of maintenance therapy was 14 months, with mean follow-up of 38 months. Twenty-seven patients (54%) required IFX therapy escalation after a mean of 6 maintenance infusions. Clinical remission was noted in 36% of the entire cohort (18/50) at 12 months; 19% in the escalation group, and 56% in the non-escalation group. Patients who required IFX escalation were less likely to be in clinical remission at 12 months (OR 0.2, 95% CI 0.1-0.6, p=0.01) when compared to those who did not. During the follow-up period, 27% of patients required a colectomy, and the mean time to colectomy was 17 months. Patients in the escalation group required a colectomy in 33% of cases, compared with 21% of non-escalation patients.

Conclusions

A significant proportion of ambulatory patients with UC treated with maintenance IFX required therapy escalation over time. This was associated with lower remission, and higher colectomy, rates.

Background

The rate of IBD exacerbation during pregnancy varies in the published literature.

Aim

We sought to perform a systematic review and meta-analysis of the effects of disease activity at conception on disease course during pregnancy in women with IBD.

Methods

Published studies and abstracts from standard sources were screened for appropriate studies. Data was pooled and analyzed using funnel and forest plots. Quality assessment scores were given using GRADE criteria.

Results

Fourteen studies were eligible for inclusion; ten studies contained patients with UC (N=1130), and six studies contained patients with CD (N=590). In patients with UC there was a significantly higher risk ratio of active disease during pregnancy in patients who commenced pregnancy with active disease (55%), when compared with those in remission at conception (36%) (RR 2.0, 95% CI: 1.5–3, p<0.001). This risk was also higher in patients with CD, (RR 2.0, 95% CI: 1.2–3.4, p=0.006). Thirteen of the studies rated “low” in all domains of a quality assessment, and there was significant statistical heterogeneity.

Conclusions

Patients with IBD who conceive when their disease is active are more likely to have active disease during pregnancy than those who conceive when in remission. All studies used in this analysis had a high risk of bias therefore further studies are required.

Background

A number of controlled trials and prospective studies have compared intravenous (IV) to oral (PO) iron for the treatment of IDA, with mixed results.

Methods

We conducted a systematic review of trials published to 2014 that compared IV to PO iron to treat iron deficiency in patients with IBD. Meta-analysis was performed to generate effect estimates. Quality assessment was also performed according to GRADE criteria.

Results

Five studies met our inclusion criteria, enrolling 694 patients. For the primary outcome of ‘response’ (Hb rise >2g/dl), there was no significant difference between IV or PO iron; risk ratio (RR) for response with IV was 1.08 (95% CI 0.9, 1.2, p=0.2). For the secondary outcome of mean change in Hb (g/dl), the mean difference between PO and IV iron was not statistically significant (mean difference 0.6g/dL, 96% CI −0.1, 1.3, p=0.08). IV iron was associated with a significantly greater initial rise in serum ferritin compared to PO iron (mean difference 89ng/ml, 95% CI 29, 148, p=0.003). There was a lower risk of withdrawal due to adverse events in these trials in the IV iron cohorts when compared to PO iron (RR 0.4, 95% CI 0.1, 1.0, p=0.05).

Conclusions

We found no significant difference between IV and PO iron in correcting iron-deficiency anemia in patients with IBD in this meta-analysis. Patients who received IV iron had a greater rise in serum ferritin, and were less likely to stop treatment due to adverse events, when compared to those who received PO iron.