Outcome of concomitant treatment with thiopurines and allopurinol in patients with inflammatory bowel disease: A nationwide Danish cohort study.

BACKGROUND: Thiopurine and allopurinol in combination are associated with clinical remission in inflammatory bowel diseases but their influence on subsequent outcomes is unclear. We compared outcomes during exposure to both thiopurines and allopurinol versus thiopurines alone. METHODS: We established a nationwide cohort of patients with inflammatory bowel diseases exposed to thiopurines ± allopurinol during 1999-2014, using registry data. Patients were followed until hospitalization, surgery, anti-TNFα, or death (as a primary composite outcome). We used Poisson regression analyses to calculate incidence rate ratios overall and stratified by calendar period (assuming the combined exposure was unintended before 2009). RESULTS: A total of 10,367 patients with inflammatory bowel diseases (Crohn's disease, n = 5484; ulcerative colitis, n = 4883) received thiopurines. Of these, 217 (2.1%) also received allopurinol. During 24,714 person years of follow-up, we observed 40 outcomes among thiopurine-allopurinol-exposed patients, and 4745 outcomes among those who were thiopurine exposed; incidence rate ratio, 1.26 (95% confidence interval, 0.92-1.73). The incidence rate ratios decreased over time: 4.88 (95% confidence interval 2.53-9.45) for 1999-2003, 2.19 (95% confidence interval, 1.17-4.09) for 2004-2008 and 0.80 (95% confidence interval, 0.52-1.23) for 2009-2014. CONCLUSION: Our nationwide inflammatory bowel disease cohort study shows that concomitant thiopurine-allopurinol is as safe to use as thiopurines alone, with a tendency towards a positive effect on clinical outcomes in recent calendar periods when combined use was intended.

Fecal Calprotectin Predicts Relapse and Histological Mucosal Healing in Ulcerative Colitis.

BACKGROUND: Mucosal healing in ulcerative colitis leads to a decreased need for medication and decreased risk of disease relapse and colectomy. Histological healing seems to improve the disease prognosis even further. An assessment of both endoscopic and histological mucosal healing requires endoscopy, and the need for a reliable noninvasive biomarker to predict disease relapse is obvious. METHODS: Seventy patients were included and followed up for 12 months. Inclusion criteria were a total Mayo score ≤1 and a Mayo endoscopic score = 0. The patients underwent sigmoidoscopy with rectal biopsies. Fecal calprotectin (FC) was measured 2 to 3 days before the sigmoidoscopy. The tissue samples were evaluated for neutrophilic inflammation. We aimed at testing the predictive performance of FC and histological inflammatory activity on disease relapse. RESULTS: A baseline FC level of more than 321 mg/kg predicted disease relapse at both the 6- and 12-month follow-ups. Histological inflammatory activity, C-reactive protein, or length of remission was not predictive of relapse. Of note, 11.8% of all patients had histological inflammatory activity despite endoscopic remission and were found to have a higher level of FC (236.5 versus 56 mg/kg, P = 0.02). A receiver operating characteristic analysis estimated a cutoff level of ≤40.5 mg/kg for FC (area under the curve, 0.755 and confidence interval 95%, 0.5895-0.9208) for predicting a histological inflammatory activity score of 0. CONCLUSIONS: FC measurements can be used to identify patients with increased risk of relapse after 6 and 12 months and to predict histological mucosal healing. Regular measurement of FC may alter disease monitoring and improve prognosis, and may decrease the need for endoscopy.

[Optimized thiopurine treatment in chronic inflammatory bowel disease]. / Optimering af thiopurinbehandling ved kronisk inflammatorisk tarmsygdom.

Thiopurines are effective in maintaining remission in chronic inflammatory bowel diseases, but incomplete response or side effects are common during standard-dose treatment. In this article thiopurine metabolism and pharmacogenetic aspects are summarized showing their benefits in improving therapy in chronic inflammatory bowel disease. An increasing body of evidence suggests that a large part of the observed non-pancreatic side effects and poor responses can be solved by tailoring thiopurine therapy using measurement of thiopurine methyltransferase and metabolites and by using a combination therapy with low-dose thiopurines and allopurinol.

Level of Fecal Calprotectin Correlates With Endoscopic and Histologic Inflammation and Identifies Patients With Mucosal Healing in Ulcerative Colitis.

BACKGROUND & AIMS: In patients with ulcerative colitis (UC), mucosal healing is an important goal of treatment. However, mucosal healing is difficult to determine on the basis of clinical evaluation alone, and endoscopy is uncomfortable and can cause complications. Fecal calprotectin (FC) is a marker of inflammation, and its levels have been associated with disease activity. We investigated the association between level of FC and mucosal healing and clinical disease activity in patients with UC. METHODS: We performed an observational cross-sectional study of 120 patients with active or inactive UC who underwent sigmoidoscopy at Copenhagen University Hospital Hvidovre from September 2012 through 2014. Endoscopic inflammation was evaluated by using the Mayo Endoscopic Score (MES) and Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and histologic inflammatory activity by a slightly modified Harpaz Index, which measures acute inflammation. The Partial Mayo Score was used to measure the clinical disease activity. RESULTS: A cutoff level of FC of 192 mg/kg identified patients with endoscopic evidence of mucosal healing, which was based on the MES and UCEIS, with positive predictive values of 0.71 and 0.65, respectively; negative predictive values were 0.90 and 0.93, respectively. A cutoff level of 171 mg/kg identified patients with histologic evidence of mucosal healing, with positive predictive value of 0.75 and negative predictive value of 0.90. Levels of FC increased significantly with increases in endoscopic and histologic disease activity. There was high concordance between MES and UCEIS as well as between MES or UCEIS and histologic inflammatory activity. The histologic activity index had an interobserver variation of 4.35%. CONCLUSIONS: Level of FC identifies patients with UC who have endoscopic and histologic features of mucosal healing and correlates with endoscopic and histologic inflammatory activity. The UCEIS seems to be as accurate as the MES in identifying patients with mucosal healing and as easy to use. The histologic activity index had a high concordance with recognized endoscopic score systems.

[Optimized thiopurine treatment in chronic inflammatory bowel disease].

Thiopurines are effective in maintaining remission in chronic inflammatory bowel diseases, but incomplete response or side effects are common during standard-dose treatment. In this article thiopurine metabolism and pharmacogenetic aspects are summarized showing their benefits in improving therapy in chronic inflammatory bowel disease. An increasing body of evidence suggests that a large part of the observed non-pancreatic side effects and poor responses can be solved by tailoring thiopurine therapy using measurement of thiopurine methyltransferase and metabolites and by using a combination therapy with low-dose thiopurines and allopurinol.

[Faecal calprotectin is a useful biomarker for intestinal inflammation].

Faecal calprotectin is a biomarker for inflammation in the intestinal mucosa. Faecal calprotectin has the ability to detect inflammatory causes of gastrointestinal symptoms and to distinguish these from irritable bowel syndrome. The test is very sensitive but not specific to any particular gastrointestinal disease. In inflammatory bowel disease, faecal calprotectin correlates with symptoms, biochemical markers and the endoscopic findings. It can be used to monitor disease activity, treatment response and mucosal healing as well as predict relapse. We propose an algorithm for the use of faecal calprotectin in patients with unspecific abdominal complaints.

The correlation between fecal calprotectin, simple clinical colitis activity index and biochemical markers in ulcerative colitis during high-dose steroid treatment.

OBJECTIVE: Monitoring active ulcerative colitis (UC) is essential for making correct and timely treatment decisions. The current monitoring is based on symptom scores and biochemical markers, among which the role of fecal calprotectin (FC) is debated. The aims were to assess the development in FC during steroid treatment and to compare FC with symptom scores and biochemical markers. MATERIAL AND METHODS: A prospective observational study, including 16 patients with active UC requiring high-dose steroid treatment. FC, C-reactive protein (CRP), leukocytes, hemoglobin, albumin, and simple clinical colitis activity index (SCCAI) were assessed before the initiation of treatment, as well as on days 2, 6, 13, and 27. The one-year follow-up data were retrospectively obtained. RESULTS: All patients had significant decreasing levels of FC (-1014 mg/kg, p = 0.0061), CRP (-10 mmol/l, p = 0.0313), and SCCAI (-3, p = 0.0002) during the first 4 days. After 27 days, the FC had decreased to 216 mg/kg (p = 0.002). A significant correlation between the changes in CRP and SCCAI was found (r(s) = 0.65, p = 0.03) but not between FC and CRP or SCCAI. Overall, significant correlations between absolute levels of FC, CRP, and SCCAI were found. Levels of FC on day 0 and day 4 were not predictive of sustained clinical remission at 1-year follow up. CONCLUSIONS: FC, CRP, and SCCAI seem to be reliable markers of treatment response during steroid treatment. High initial levels of FC and a subsequent rapid reduction during steroid treatment were identified. FC levels were not found to be predictive of disease prognosis after one year.

[The use of adalimumab in severe fistulising Crohn's disease]. / Behandling af svaer aktiv morbus Crohn med adalimumab.

So far infliximab is the only approved anti-TNF-alpha antibody for patients with Crohn's disease. Development of antibodies to infliximab may result in allergic reactions or reduced effect. We report three patients who received adalimumab, which induced longstanding remission in all three patients.

Development and evaluation of an ELISA for human trefoil factor 3.

BACKGROUND: The three trefoil factors (TFF1, TFF2, and TFF3) are small peptides believed to cross-link mucous glycoproteins and to play a role in the maintenance and repair of the gastrointestinal mucosa. To define the physiologic and potential diagnostic values of TFF3, assays able to measure TFF3 are warranted. METHODS: An ELISA was developed that uses two antibodies from rabbits immunized with recombinant human TFF3 and a calibrator (3-100 pmol/L) prepared from recombinant human TFF3. RESULTS: The ELISA had a detection limit of 3.0 pmol/L. The imprecision (CV) was 5-9% for mean concentrations of 13-65 pmol/L, corresponding to serum concentrations of 65-330 pmol/L. There was no cross-reaction toward human TFF1 and TFF2 (40 nmol/L). Neither food intake nor the menstrual cycle influenced the values of TFF3 significantly. The central 95% reference interval for TFF3 in serum from healthy blood donors (n = 300) was 91-250 pmol/L and showed no variation with age and limited variation with sex. TFF3 was increased in serum from patients (n = 12) with inflammation and/or ulceration of the upper gastrointestinal tract (P <0.05), whereas in serial measurements of serum from three patients with severe exacerbation of chronic inflammatory bowel disease restricted to the colon, normal concentrations and only minor variations during treatment and tapering were observed. CONCLUSIONS: The ELISA measures TFF3 in human serum and represents a specific and precise method for measurement of TFF3, which will be of value for further studies of TFF3 in health and disease.