Inge Nordgaard-Lassen

Prednisolone treatment affects the performance of the QuantiFERON gold in-tube test and the tuberculin skin test in patients with autoimmune disorders screened for latent tuberculosis infection†‡

Background: During screening for latent tuberculosis infection (LTBI), before anti‐tumor‐necrosis‐factor‐&agr; treatment, most patients are already receiving immunosuppressive therapy. The objective was to evaluate the performance of the QuantiFERON Gold In‐Tube (QFT‐IT) and the Tuberculin Skin Test (TST). Methods: A prospective multicenter study included 248 patients with ulcerative colitis (39), Crohns disease (54), rheumatoid arthritis (111), and spondylo‐arthropathy (44). Results: QFT‐IT was positive in 7/248 (3%), negative in 229 (92%), and indeterminate in 12 (5%). TST was positive in 54/238 (23%) patients. Chest x‐ray was suspect for tuberculosis in 5/236 (2%), and 35/167 (21%) had ≥1 risk‐factors for infection with Mycobacterium tuberculosis. The main finding was a pronounced negative effect on QFT‐IT and TST performance associated with prednisolone treatment. During prednisolone treatment interferon gamma (IFN‐&ggr;) response to mitogen stimulation was impaired (median IFN‐&ggr; response 4.9 IU/mL; interquartile range [IQR] 0.8 to ≥10.0) compared to patients 1) not receiving corticosteroids (median ≥10.0; IQR 5.0 to ≥10.0; P = 0.0015) or 2) receiving long‐acting corticosteroids (median >10.0; IQR 9.7 to >10.0; P = 0.0058). Prednisolone treatment was strongly associated with negative TST, adjusted odds ratio (AOR) 0.22 (0.1–0.8; P = 0.018), and with an increased risk of indeterminate QFT‐IT results AOR 16.1 (4.1–63.2; P < 0.001), whereas no negative effect was found for long‐acting corticosteroids. Doses of ≥10 mg prednisolone were associated with a 27% risk of indeterminate results. Single use of azathioprine, methotrexate, or 5‐aminosalicylate (5‐ASA) did not affect the test results. Conclusions: Oral prednisolone severely suppressed QFT‐IT and TST performance, whereas the long‐acting corticosteroids methotrexate, azathioprine, and 5‐ASA did not have a similar detrimental effect. Patients should be screened for LTBI with QFT‐IT or TST prior to initiation of prednisolone therapy and negative QFT‐IT or TST results interpreted with caution in patients treated with any corticosteroid until further data are available. (Inflamm Bowel Dis 2011;)

Probiotic treatment of collagenous colitis: A randomized, double-blind, placebo-controlled trial with lactobacillus acidophilus and bifidobacterium animalis subsp. lactis

Background Probiotic treatment may be effective in diseases involving gut microflora and intestinal inflammation. In collagenous colitis (CC), a potential pathogenic role of the gut microflora has been proposed. The effect of probiotic treatment in CC is unknown. Our aim was to investigate the clinical effect of treatment with Lactobacillus acidophilus LA‐5 and Bifidobacterium animalis subsp. lactis BB‐12 (AB‐Cap‐10) in patients with CC. Materials and Methods Patients with CC and diarrhea were in a double‐blind placebo‐controlled study randomized (2:1) to AB‐Cap‐10 or placebo for 12 weeks. The primary end point was reduction in bowel frequency per week of ≥50%. Secondary end points were changes in bowel frequencies, stool consistency, stool weight, histopathology, and abdominal bloating and pain. Results Twenty‐nine patients were randomized: 21 to probiotics and 8 to placebo. Reduction in bowel frequency per week of ≥50% occurred in 6 of 21 (29%) and in 1 of 8 (13%) patients receiving probiotic and placebo, respectively (P = 0.635). No differences between treatments were observed regarding the secondary end points. Post hoc analysis showed a median reduction in bowel frequency per week from 32 (range 18–84) to 23 (range 11–56; P < 0.005), a reduction in number of days with liquid stools per week from 6 days (range 0–7 days) to 1 day (range 0–7 days; P < 0.005), and an increase in number of days with solid stools per week (P < 0.05) in the AB‐Cap‐10 group. Conclusions AB‐Cap‐10 had no significant effect on the chosen end points. Post hoc analysis demonstrated amelioration of clinical symptoms in the AB‐Cap‐10 group, indicating that probiotic treatment may potentially influence the disease course of CC.

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.

Metabolic and inflammatory faecal markers in collagenous colitis.

Objectives To evaluate the excretion of the inflammatory and metabolic faecal markers calprotectin, lactoferrin, and short-chain fatty acids in symptomatic and quiescent collagenous colitis. Methods Faecal samples from 21 patients with active collagenous colitis, 12 patients retested in remission, and 13 controls were analysed. Calprotectin was determined using an enzyme-linked immunosorbent assay. Lactoferrin was estimated by a latex agglutination test. Short-chain fatty acids were determined by steam distillation followed by gas–liquid chromatography. Results Calprotectin was increased in patients with active collagenous colitis [80 μg/g (6.25–1899)] (median and range) compared with patients with quiescent collagenous colitis [26 μg/g (6.25–340)], P=0.025 and controls [6.25 μg/g (6.25–99)], P=0.002. Eight patients (38%) with active collagenous colitis had normal levels of calprotectin. Lactoferrin was detected in one patient only. Concentrations of total short-chain fatty acids did not differ in patients with active collagenous colitis compared with quiescent collagenous colitis or controls (P=0.75), whereas concentrations of the branched-chain fatty acids were decreased in patients with active collagenous colitis versus controls (P<0.005). In-vitro incubations demonstrated increased ratios of acetate in patients with active and quiescent collagenous colitis compared with controls (P<0.05), with a corresponding decrease in branched-chain fatty acids ratios (P<0.05). Conclusion Faecal calprotectin was increased in collagenous colitis; however, increased excretion was not a universal finding limiting the use of calprotectin as an inflammatory marker in collagenous colitis. Faecal lactoferrin was almost undetectable. Luminal fermentative conditions are altered in collagenous colitis. Fermentative alterations could be secondary to changes in substrate availability and intestinal transit time.

Active ulcerative colitis associated with low prevalence of Blastocystis and Dientamoeba fragilis infection

Department of Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark, Department of Gastroenterology, Hvidovre University Hospital, Copenhagen, Denmark, Department of Clinical Microbiology, Slagelse Hospital, Slagelse, Denmark, Department of Clinical Microbiology, Hvidovre University Hospital, Copenhagen, Denmark, and National Food Institute, Technical University of Denmark, Copenhagen, Denmark

Ciprofloxacin and probiotic Escherichia coli Nissle add-on treatment in active ulcerative colitis: A double-blind randomized placebo controlled clinical trial

BACKGROUND AND AIM Ulcerative colitis (UC) is a chronic inflammatory bowel disease. The probiotic bacterium Escherichia coli Nissle 1917 (EcN) has been used to maintain and induce clinical remission in UC. Our aim was to test the effect of Ciprofloxacin and/or orally administered EcN as add-on to conventional therapies in patients with active UC. PATIENTS AND METHODS Our single center double-blinded randomized placebo controlled study included patients with a Colitis Activity Index (CAI) score of at least 6. Patients were randomized to Ciprofloxacin or placebo for 1week followed by EcN or placebo for 7weeks. All 4 treatments were given as add-on treatments. RESULTS One hundred subjects with active UC were recruited. In the per-protocol analysis we, surprisingly, found that in the group receiving placebo/EcN fewer patients, 54%, reached remission compared to the group receiving placebo/placebo, 89%, p<0.05. Among patients treated with Cipro/placebo and Cipro/EcN, 78% and 66% reached remission, respectively. Furthermore, the group receiving placebo/EcN had the largest number of withdrawals, 11 of 25 (44%), compared to 15 of 75 (20%) in any of the other groups, p<0.05. Indication of lack of mucosal healing was found in the group treated with placebo/Nissle, since only 4 (29%) of the 14 patients, who completed the study, reported no blood in stools at week 12 (p<0.02), compared to 63%, 67% and 65% in groups treated with Cipro/Nissle, Cipro/placebo and placebo/placebo, respectively. CONCLUSIONS Our data suggest that there is no benefit in the use of E. coli Nissle as an add-on treatment to conventional therapies for active ulcerative colitis. Furthermore, treatment with E. coli Nissle without a previous antibiotic cure resulted in fewer patients reaching clinical remission.

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.

The Impact of Endoscopic Inflammation and Mucosal Healing on Health-related Quality of Life in Ulcerative Colitis Patients

BACKGROUND Health-related quality of life [HRQoL] is impaired in ulcerative colitis and is correlated to clinical disease activity. The recent shift towards more objective treatment goals like mucosal healing generates a need for evaluating the association between endoscopic disease activity, mucosal healing and HRQoL. METHODS In this cross-sectional study, patients with either active or inactive ulcerative colitis underwent sigmoidoscopy. Clinical disease activity was assessed by the Simple Clinical Colitis Activity Index [SCCAI], endoscopic inflammation by the Mayo Endoscopic Subscore [MES], and HRQoL by the Short Inflammatory Bowel Disease Questionnaire [SIBDQ] and Short Health Scale [SHS]. RESULTS A total of 110 patients, 71% with active disease, had a median SCCAI score of 3 and a median MES score of 1. Patients in clinical remission had a mean SIBDQ of 60 and SHS of 6. HRQoL decreased significantly with increasing clinical (SIBDQ [χ(2) = 61.8, p < 0.0001] and SHS [χ(2) = 63.4, p < 0.0001]) and endoscopic disease activity (SIBDQ [χ(2) = 33.1, p < 0.0001] and SHS [χ(2) = 40.3, p < 0.0001]). Mucosal healing was associated with a higher HRQoL than active inflammation (59/46, p < 0.0001 [SIBDQ] and 7/20, p < 0.0001 [SHS]). Decreased HRQoL was observed with more extensive disease. Linear regression revealed strong association between SIBDQ and SHS. CONCLUSIONS Not only clinical disease activity but also endoscopic inflammation and disease extent were associated with decreased HRQoL. Patients with mucosal healing had significant higher HRQoL, emphasising the importance of this treatment goal. Both SHS and SIBDQ are easy to use and to implement, and were strongly correlated.

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

Abstract 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 (rs = 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.

Extraintestinal pathogenic Escherichia coli are associated with intestinal inflammation in patients with ulcerative colitis.

E. coli of the phylogenetic group B2 harbouring Extra intestinal Pathogenic Escherichia coli (ExPEC) genes are frequently seen as colonizers of the intestine in patients with active ulcerative colitis (UC). In this study, we describe the influence of E. coli Nissle (EcN) B2 as add-on treatment to conventional therapies in patients with active UC. For this study one hundred active UC patients were randomized to ciprofloxacin or placebo for 1 week followed by EcN or placebo for 7 weeks. Stool samples were collected at weeks 0, 1, 8, 12, where E. coli were characterized and fecal calprotectin was measured. We showed that in the active UC patient group receiving Placebo/EcN, fewer patients reached remission, in comparison to the patient group receiving Placebo/placebo (p < 0.05). Active UC patients initially colonized with E. coli B2 had increased fecal calprotectin values and Colitis Activity Index scores in comparison to patients colonized with E. coli A and D (p < 0.05*). In conclusion, treatment of UC patients with E. coli Nissle (B2) does not promote clinical remission and active UC patients colonized with E. coli B2 have an increased intestinal inflammation.