Article

D'Inca R, Dal Pont E, Di Leo V, et al. Can calprotectin predict relapse risk in inflammatory bowel disease

Department of Surgical and Gastroenterological Sciences, University of Padua, Padua, Italy.
The American Journal of Gastroenterology (Impact Factor: 9.21). 09/2008; 103(8):2007-14. DOI: 10.1111/j.1572-0241.2008.01870.x
Source: PubMed

ABSTRACT Assessing the clinical course of inflammatory bowel disease (IBD) patients consists of periodical clinical evaluations and laboratory tests. We aimed to assess the role of calprotectin tests in predicting clinical relapse in IBD patients.
Ninety-seven patients with ulcerative colitis (UC) and 65 with Crohn's disease (CD) in clinical remission were prospectively included in the study. A 10-g stool sample was collected for calprotectin assay. The cutoff level was set at 130 mg/kg of feces. Patients were followed up for 1 yr after the test or until relapse. The cumulative proportion of relapses was estimated by the Kaplan-Meier analysis. Statistics for equality of survival distribution were tested using the log-rank test.
The calprotectin test was positive in 44 UC patients and 26 of them relapsed within a year, while 11 of 53 UC patients with a negative calprotectin test relapsed within the same time frame. Thirty CD patients had a positive calprotectin test and 13 of them relapsed within a year, as did 7 of the 35 with a negative test result. A significant correlation emerged between a positive calprotectin test and the probability of relapse in UC patients (P= 0.000). In CD patients, only cases of colonic CD showed a significant correlation between a positive calprotectin test and the probability of relapse, i.e., 6 colonic CD patients were positive for the calprotectin test and 4 relapsed (P= 0.02).
Measuring calprotectin may help to identify UC and colonic CD patients at higher risk of clinical relapse.

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    • "They did not find CRP or ESR to be useful in predicting relapse of IBD (Tibble et al., 2000b). Other studies have confirmed the results of Tibbel et al (Costa et al., 2005; D'Inca et al., 2008). "
    Ulcerative Colitis - Treatments, Special Populations and the Future, 11/2011; , ISBN: 978-953-307-739-0
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    ABSTRACT: Background: The fecal neutrophil-derived proteins calprotectin and lactoferrin have proven useful surrogate markers of intestinal inflammation. The aim of this study was to compare fecal calprotectin and lactoferrin concentrations to clinically, endoscopically, and histologically assessed Crohn’s disease (CD) activity, and to explore the suitability of these proteins as surrogate markers of mucosal healing during anti-TNFα therapy. Furthermore, we studied changes in the number and expression of effector and regulatory T cells in bowel biopsy specimens during anti-TNFα therapy. Patients and methods: Adult CD patients referred for ileocolonoscopy (n=106 for 77 patients) for various reasons were recruited (Study I). Clinical disease activity was assessed with the Crohn’s disease activity index (CDAI) and endoscopic activity with both the Crohn’s disease index of severity (CDEIS) and the simple endoscopic score for Crohn’s disease (SES-CD). Stool samples for measurements of calprotectin and lactoferrin, and blood samples for CRP were collected. For Study II, biopsy specimens were obtained from the ileum and the colon for histologic activity scoring. In prospective Study III, after baseline ileocolonoscopy, 15 patients received induction with anti-TNFα blocking agents and endoscopic, histologic, and fecal-marker responses to therapy were evaluated at 12 weeks. For detecting changes in the number and expression of effector and regulatory T cells, biopsy specimens were taken from the most severely diseased lesions in the ileum and the colon (Study IV). Results: Endoscopic scores correlated significantly with fecal calprotectin and lactoferrin (p<0.001). Both fecal markers were significantly lower in patients with endoscopically inactive than with active disease (p<0.001). In detecting endoscopically active disease, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for calprotectin ≥200 μg/g were 70%, 92%, 94%, and 61%; for lactoferrin ≥10 μg/g they were 66%, 92%, 94%, and 59%. Accordingly, the sensitivity, specificity, PPV, and NPV for CRP >5 mg/l were 48%, 91%, 91%, and 48%. Fecal markers were significantly higher in active colonic (both p<0.001) or ileocolonic (calprotectin p=0.028, lactoferrin p=0.004) than in ileal disease. In ileocolonic or colonic disease, colon histology score correlated significantly with fecal calprotectin (r=0.563) and lactoferrin (r=0.543). In patients receiving anti-TNFα therapy, median fecal calprotectin decreased from 1173 μg/g (range 88-15326) to 130 μg/g (13-1419) and lactoferrin from 105.0 μg/g (4.2-1258.9) to 2.7 μg/g (0.0-228.5), both p=0.001. The relation of ileal IL-17+ cells to CD4+ cells decreased significantly during anti-TNF treatment (p=0.047). The relation of IL-17+ cells to Foxp3+ cells was higher in the patients’ baseline specimens than in their post-treatment specimens (p=0.038). Conclusions: For evaluation of CD activity, based on endoscopic findings, more sensitive surrogate markers than CDAI and CRP were fecal calprotectin and lactoferrin. Fecal calprotectin and lactoferrin were significantly higher in endoscopically active disease than in endoscopic remission. In both ileocolonic and colonic disease, fecal markers correlated closely with histologic disease activity. In CD, these neutrophil-derived proteins thus seem to be useful surrogate markers of endoscopic activity. During anti-TNFα therapy, fecal calprotectin and lactoferrin decreased significantly. The anti-TNFα treatment was also reflected in a decreased IL-17/Foxp3 cell ratio, which may indicate improved balance between effector and regulatory T cells with treatment. Crohnin tauti on krooninen, tulehduksellinen suolistosairaus, jolle on tyypillistä jaksottainen ja usein suolen seinämän syvempiin osiin ulottuva tulehdus. Tavanomaiset, verestä määritettävät tulehduksen merkkiaineet CRP ja lasko eivät ole riittävän herkkiä suolen limakalvon tulehduksen arvioinnissa. Ulosteesta mitattavat, tulehduksen yhteydessä valkosoluista vapautuvat merkkiaineet kalprotektiini ja laktoferriini ovat osoittautuneet luotettaviksi suolen tulehduksellisten ja ei-tulehduksellisen tilojen erotusdiagnostiikassa. Näiden ulosteen merkkiaineiden käyttökelpoisuudesta Crohnin taudin aktiivisuuden monitoroinnissa on niukasti tietoa. Tämän väitöskirjatutkimuksen tavoitteena oli selvittää, miten ulosteen kalprotektiini ja laktoferriini korreloivat Crohnin taudin kliiniseen, endoskooppiseen ja histologiseen aktiivisuuteen ja miten ne toimivat Crohnin taudin hoidon monitoroinnissa. Lisäksi tarkastelimme suolen limakalvon effektori- ja regulatoristen T-solujen suhteen muutoksia TNF-alfa-salpaajahoidon aikana. Tutkimuksen ensimmäisessä osatyössä havaittiin, että ulosteen merkkiaineet kalprotektiini ja laktoferriini korreloivat hyvin Crohnin taudin endoskooppiseen aktiivisuuteen. Tämä korrelaatio oli parempi kuin tähystyslöydöksen korrelaatio taudin kliiniseen aktiivisuuteen tai seerumin CRP-arvoon. Kumpikin merkkiaine oli merkitsevästi korkeampi endoskooppisesti aktiivisessa kuin ei-aktiivisessa Crohnin taudissa. Ulosteen kalprotektiini ja laktoferriini olivat selvemmin koholla niillä potilailla, joilla tähystyksessä todettiin aktiivinen paksusuolen tai paksusuolen ja ohutsuolen loppuosan Crohnin tauti kuin niillä potilailla, joilla oli ohutsuolen loppuosaan rajoittuva tauti. Toisessa osatyössä osoitettiin Crohnin taudin histologisen aktiivisuuden korreloivan hyvin ulosteen merkkiaineisiin paksusuolen sekä paksusuolen ja ohutsuolen loppuosan Crohnin taudissa. Kolmannessa osatyössä havaittiin ulosteen kalprotektiinin ja laktoferriinin laskevan TNF-alfa-salpaajahoidon aikana merkitsevästi: ulosteen kalprotektiinin mediaaniarvo laski tasolta 1173 μg/g (normaali < 100 μg/g) tasolle 130 μg/g ja ulosteen laktoferriini laski tasolta 105,0 μg/g tasolle 2,7 μg/g (normaali < 7,25 μg/g). Neljännessä osatyössä osoitettiin ohutsuolen loppuosasta otetuissa koepaloissa effektori- ja regulatoristen T-solujen solujen suhteen pienentyvän TNF-alfa-salpaajahoidon aikana kuvastaen todennäköisesti hoidon myötä parantunutta effektori- ja regulatoristen T-solujen tasapainoa. Ulosteen kalprotektiini ja laktoferriini näyttävät soveltuvan hyvin Crohnin taudin aktiivisuuden arviointiin ja ovat herkempiä aktiivisuuden mittareita kuin laajalti käytössä oleva seerumin CRP-arvo. Nämä valkosoluproteiinit ovat käyttökelpoisia Crohnin taudin hoitovasteen monitoroinnissa.
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