Martti Färkkilä

Crohn's Disease Activity Assessed by Fecal Calprotectin and Lactoferrin : Correlation with Crohn's Disease Activity Index and Endoscopic Findings

Background: Correlation of endoscopic Crohns disease activity with fecal calprotectin and lactoferrin is insufficiently studied. We evaluated the clinical significance of these neutrofil‐derived proteins in assessment of Crohns disease activity by comparing them with endoscopic disease activity and with Crohns disease activity index (CDAI) and serum CRP. Methods: A total of 77 CD patients underwent one or more ileocolonoscopies (n = 106) with scoring of Crohns disease index of severity (CDEIS). Patients provided stool samples for calprotectin and lactoferrin measurements and blood samples for CRP. Clinical activity was based on the CDAI. Results: Both fecal calprotectin and lactoferrin correlated significantly with CDEIS (Spearmans r 0.729 and 0.773, P < 0.001). With a cutoff level of 200 &mgr;g/g for a raised fecal calprotectin concentration, sensitivity was 70%, specificity 92%, positive predictive value (PPV) 94%, and negative predictive value (NPV) 61% in predicting endoscopically active disease (CDEIS ≥ 3). A fecal lactoferrin concentration of 10 &mgr;g/g as the cutoff value gave a sensitivity, specificity, PPV, and NPV of 66%, 92%, 94%, and 59%. Sensitivity of CDAI ≥ 150 to detect endoscopically active disease was only 27%, specificity 94%, PPV 91%, and NPV 40%. A raised serum CRP (> 5 mg/l) gave a sensitivity, specificity, PPV, and NPV of 48%, 91%, 91%, and 48%. Conclusions: For evaluation of Crohns disease activity, based on endoscopic findings, more sensitive surrogate markers than is CDAI or CRP are fecal calprotectin and lactoferrin. These prove to be useful tools for estimation of disease activity in Crohns disease.

A probiotic mixture alleviates symptoms in irritable bowel syndrome patients: a controlled 6-month intervention

Background : Irritable bowel syndrome is a gastrointestinal disorder of unknown aetiology. The effect of probiotics in this syndrome remains unclear.

Ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous steroids: a parallel, open-label randomised controlled trial

BACKGROUND Ciclosporin and infliximab are potential rescue treatments to avoid colectomy in patients with acute severe ulcerative colitis refractory to intravenous corticosteroids. We compared the efficacy and safety of these drugs for this indication. METHODS In this parallel, open-label, randomised controlled trial, patients were aged at least 18 years, had an acute severe flare of ulcerative colitis defined by a Lichtiger score greater than 10 points, and had been given an unsuccessful course of high-dose intravenous steroids. None of the patients had previously received ciclosporin or infliximab. Between June 1, 2007, and Aug 31, 2010, patients at 27 European centres were randomly assigned (via computer-derived permutation tables; 1:1) to receive either intravenous ciclosporin (2 mg/kg per day for 1 week, followed by oral drug until day 98) or infliximab (5 mg/kg on days 0, 14, and 42). In both groups, azathioprine was started at day 7 in patients with a clinical response. Neither patients nor investigators were masked to study treatment. The primary efficacy outcome was treatment failure defined by absence of a clinical response at day 7, a relapse between day 7 and day 98, absence of steroid-free remission at day 98, a severe adverse event leading to treatment interruption, colectomy, or death. Analysis was by intention to treat. This trial is registered with EudraCT (2006-005299-42) and ClinicalTrials.gov (NCT00542152). FINDINGS 115 patients were randomly assigned; 58 patients were allocated to receive ciclosporin and 57 to receive infliximab. Treatment failure occurred in 35 (60%) patients given ciclosporin and 31 (54%) given infliximab (absolute risk difference 6%; 95% CI -7 to 19; p=0·52). Nine (16%) patients in the ciclosporin group and 14 (25%) in the infliximab group had severe adverse events. INTERPRETATION Ciclosporin was not more effective than infliximab in patients with acute severe ulcerative colitis refractory to intravenous steroids. In clinical practice, treatment choice should be guided by physician and centre experience. FUNDING Association François Aupetit, Société Nationale Française de Gastroentérologie, and the International Organization for the study of Inflammatory Bowel Disease.

CARD15/NOD2 gene variants are associated with familially occurring and complicated forms of Crohn’s disease

Background: Variants of the caspase activating recruitment domain 15/nucleotide oligomerisation domain 2 (CARD15/NOD2) gene have been associated with susceptibility to Crohn’s disease (CD). Aim: Our aim was to evaluate the allele frequencies of the CARD15 variants R702W, G908R, and 1007fs in Finnish inflammatory bowel disease (IBD) patients and to search for possible associations between CARD15 variants and occurrence of familial forms of IBD or complicated forms of CD. Patients and methods: We investigated 198 sporadic CD patients, 46 probands with familial CD, 27 CD probands from mixed IBD families, 99 unrelated patients with ulcerative colitis (UC), and 300 control individuals for the occurrence of the CARD15 gene variants R702W, G908R, and 1007fs. Results: In CD patients, the allele frequencies for the rare variants of these polymorphisms were 3.3%, 0.6%, and 4.8% (total 8.7%), and the corresponding frequencies in healthy controls were 1.8%, 0%, and 1.7% (total 3.5%) (8.7% v 3.5%; p<0.01). In UC patients allele frequencies were comparable with those in controls. The frequency of the 1007fs polymorphism variant allele was significantly higher among all CD patients than in controls (4.8% v 1.7%; p<0.01) but there was no significant difference in allele frequencies between the CD and UC groups. The 1007fs allele frequency was higher in familial CD than in non-familial cases with CD (10.9% v 3.5%; p<0.01). There were no significant differences in the allele frequencies of the R702W and G908R polymorphisms between CD patients, UC patients, and controls. We found that 15.5% of CD patients, 9.1% of UC patients, and 6.7% of controls carried at least one of the CARD15 variants. In CD patients carrying at least one of the three NOD2 variants, the ileum was affected more often than in non-carrier CD patients (90% v 73%; p<0.05), they had stricturing or penetrating disease more often than non-carriers (88% v 56%; p<0.01), and they had an increased need for bowel surgery. Conclusions: The frequency of NOD2 gene variants was lower in genetically homogenous Finns than in other populations. The 1007fs variant was associated with CD. The occurrence of CARD15 variants predicted ileal location as well as stricturing and penetrating forms of CD.

Effect of Lactobacillus rhamnosus GG on ileal pouch inflammation and microbial flora

Background : Preliminary trials of probiotics in preventing recurrent chronic pouchitis have been encouraging.

Budesonide Induces Remission More Effectively Than Prednisone in a Controlled Trial of Patients With Autoimmune Hepatitis

BACKGROUND & AIMS Autoimmune hepatitis (AIH) is a chronic liver disease associated with cirrhosis and liver failure. Corticosteroid therapy induces long-term remission but has many side effects. We compared the effects of budesonide (a steroid that is rapidly metabolized, with low systemic exposure) and prednisone, both in combination with azathioprine. METHODS We performed a 6-month, prospective, double-blind, randomized, active-controlled, multicenter, phase IIb trial of patients with AIH without evidence of cirrhosis who were given budesonide (3 mg, three times daily or twice daily) or prednisone (40 mg/d, tapered to 10 mg/d); patients also received azathioprine (1-2 mg/kg/d). Treatment was followed by a 6-month, open-label phase during which all patients received budesonide in addition to azathioprine. The primary end point was complete biochemical remission, defined as normal serum levels of aspartate aminotransferase and alanine aminotransferase, without predefined steroid-specific side effects, at 6 months. RESULTS The primary end point was achieved in 47/100 patients given budesonide (47.0%) and in 19/103 patients given prednisone (18.4%) (P < .001; 97.5% 1-side confidence interval [CI] = 16.2). At 6 months, complete biochemical remission occurred in 60% of the patients given budesonide versus 38.8% of those given prednisone (P = .001; CI: 7.7); 72.0% of those in the budesonide group did not develop steroid-specific side effects versus 46.6% in the prednisone group (P < .001; CI = 12.3). Among 87 patients who were initially given prednisone and then received budesonide after 6 months, steroid-specific side effects decreased from 44.8% to 26.4% at month 12 (P < .002). CONCLUSIONS Oral budesonide, in combination with azathioprine, induces and maintains remission in patients with noncirrhotic AIH, with a low rate of steroid-specific side effects.

Correlation of faecal calprotectin and lactoferrin with an endoscopic score for Crohn's disease and histological findings

Background  Faecal calprotectin and lactoferrin increasingly serve as surrogate markers of disease activity in IBD. Data on the correlation of these markers with simple endoscopic score for Crohn’s disease (SES‐CD) and with histological findings are as yet limited.

Long-term treatment of ulcerative colitis with ciprofloxacin: A prospective, double-blind, placebo-controlled study

BACKGROUND & AIMS Although bacterial bowel flora may be one of the contributing factors in the pathogenesis of chronic mucosal inflammation, antibiotic treatment has no established role in ulcerative colitis. The aim of the study was to evaluate the role of ciprofloxacin in the induction and maintenance of remission in ulcerative colitis in patients responding poorly to conventional therapy with steroids and mesalamine. METHODS Ciprofloxacin (n = 38; 500-750 mg twice a day) or placebo (n = 45) was administered for 6 months in a double-blind, randomized study with a high but decreasing dose of prednisone and maintenance treatment with mesalamine including follow-up for the next 6 months. Clinical assessment and colonoscopic evaluation were performed at 0, 3, 6, and 12 months. Treatment failure, the primary end point, was defined as both symptomatic and endoscopic failure to respond. RESULTS During the first 6 months, the treatment-failure rate was 21% in the ciprofloxacin-treated group and 44% in the placebo group (P = 0.02). Endoscopic and histological findings were used as secondary end points and showed better results in the ciprofloxacin group at 3 months but not at 6 months. CONCLUSIONS Addition of a 6-month ciprofloxacin treatment for ulcerative colitis improved the results of conventional therapy with mesalamine and prednisone.

Fecal calprotectin, lactoferrin, and endoscopic disease activity in monitoring anti‐TNF‐alpha therapy for Crohn's disease

Background: Fecal calprotectin and lactoferrin are promising noninvasive biomarkers for intestinal inflammation. In Crohns disease (CD), during anti‐TNF‐alpha (TNF‐&agr;) treatment, the clinical significance of these markers has, however, been insufficiently explored. Methods: Among CD patients receiving anti‐TNF‐&agr; therapy we assessed the role of fecal calprotectin and lactoferrin as surrogate markers for mucosal healing. Before and 3 months after the beginning of anti‐TNF‐&agr; induction, 15 patients underwent ileocolonoscopy with scoring of the Crohns Disease Index of Severity (CDEIS). Fecal samples for calprotectin and for lactoferrin measurements were collected and the Crohns Disease Activity Index (CDAI) was calculated at the time of the endoscopies and 2 and 8 weeks after the first treatment. Results: The median CDEIS fell from 13.0 to 4.8 (P = 0.002) and CDAI from 158 to 68 (P = 0.005). Accordingly, the median fecal calprotectin concentration fell from 1173 &mgr;g/g to 130 &mgr;g/g (P = 0.001) and fecal lactoferrin from 105.0 &mgr;g/g to 2.7 &mgr;g/g (P = 0.001). Of the 15 patients, 11 (73%) showed an endoscopic response to treatment and 5 of these achieved endoscopic remission (CDEIS < 3). In those 5 patients the fecal calprotectin concentration declined from 1891 &mgr;g/g (range 813–2434) to 27 &mgr;g/g (13–130) and lactoferrin from 92.4 &mgr;g/g (35.5–235.6) to 1.9 &mgr;g/g (0.0–2.1). Conclusions: Compared to pretreatment values, concentrations of fecal calprotectin and lactoferrin after the anti‐TNF‐&agr; treatment were significantly lower. During anti‐TNF‐&agr; therapy these fecal neutrophil‐derived proteins may thus be useful surrogate markers for mucosal healing.

Budesonide combined with UDCA to improve liver histology in primary biliary cirrhosis: A three‐year randomized trial

Ursodeoxycholic acid (UDCA) is a safe medical therapy for primary biliary cirrhosis (PBC), but its effect on liver histology remains uncertain. Budesonide is a glucocorticoid with high receptor activity and high first‐pass metabolism in liver. We evaluated the combination of budesonide and UDCA on liver histology and compared this with UDCA alone in a 3‐year prospective, randomized, open multicenter study. Patients with PBC (n = 77), at stages I to III, were randomized into 2 treatment arms, A (n = 41): budesonide 6 mg/d and UDCA 15 mg/kg/d and B (n = 36): UDCA 15mg/kg/d. Liver histology was assessed at the beginning and at the end of the study. Liver function tests and glucose and cortisol values were determined every 4 months. Paired liver biopsy specimens were available from 69 patients (A = 37 and B = 32). Stage improved 22% in group A but deteriorated 20% in group B (P = .009). Fibrosis decreased 25% in group A but increased 70% in group B (P = .0009). S‐PIIINP decreased significantly in group A. Inflammation decreased in both groups, 34% in group A (P = .02), but only 10% in group B (P = NS). Serum liver enzymes decreased significantly in both treatment arms. Bilirubin values rose in group B but stayed stable in group A (A/B P = .002). A mild systemic glucocorticoid effect from budesonide was evident after 2 years. In conclusion, budesonide combined with UDCA improved liver histology, whereas the effect of UDCA alone was mainly on laboratory values. Studies with longer follow‐up using a combination of budesonide and UDCA are warranted to confirm safety and effects. (HEPATOLOGY 2005.)