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- MATERIALS AND METHODS
Background: Fecal calprotectin and lactoferrin are promising noninvasive biomarkers for intestinal inflammation. In Crohn's disease (CD), during anti-TNF-alpha (TNF-α) treatment, the clinical significance of these markers has, however, been insufficiently explored.
Methods: Among CD patients receiving anti-TNF-α 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-α induction, 15 patients underwent ileocolonoscopy with scoring of the Crohn's Disease Index of Severity (CDEIS). Fecal samples for calprotectin and for lactoferrin measurements were collected and the Crohn's 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 μg/g to 130 μg/g (P = 0.001) and fecal lactoferrin from 105.0 μg/g to 2.7 μg/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 μg/g (range 813–2434) to 27 μg/g (13–130) and lactoferrin from 92.4 μg/g (35.5–235.6) to 1.9 μg/g (0.0–2.1).
Conclusions: Compared to pretreatment values, concentrations of fecal calprotectin and lactoferrin after the anti-TNF-α treatment were significantly lower. During anti-TNF-α therapy these fecal neutrophil-derived proteins may thus be useful surrogate markers for mucosal healing.
In Crohn's disease (CD), estimation of treatment response is widely based on changes in clinical disease activity and on nonspecific laboratory tests such as hemoglobin level and C-reactive protein (CRP). In clinical trials a change in the Crohn's Disease Activity Index (CDAI) is still almost the sole primary endpoint, although its correlation with endoscopic disease activity is weak.1 Recent studies and reviews suggest mucosal healing as becoming a therapeutic target for treatment of inflammatory bowel disease (IBD).2–5 During infliximab treatment, clinical improvement is accompanied by significant healing of endoscopic lesions and the disappearance of mucosal inflammatory infiltrate.6 Mucosal healing in CD is associated with a decreased number of disease-related procedures and hospital admissions.7 Detection of mucosal healing requires endoscopy, which is time-consuming, expensive, and unpleasant for patients. The neutrophil-derived proteins fecal calprotectin and lactoferrin correlate closely with endoscopic disease activity in ulcerative colitis (UC),8, 9 and as recently shown, also with the Crohn's Disease Index of Severity (CDEIS),10 appearing thus to be promising noninvasive surrogate markers for mucosal healing.
In IBD, fecal calprotectin concentration correlates strongly with the excretion of indium-111-labeled granulocytes, a sensitive marker of disease activity.11 In stool, both calprotectin and lactoferrin are stable12, 13 and easily measurable by commercial enzyme-linked immunosorbent assays (ELISA). These markers are sensitive for inflammation, but not disease-specific; in addition to IBD, fecal calprotectin may rise, for example in colon cancer, bacterial infections, and inflammation caused by nonsteroidal antiinflammatory drugs (NSAIDs).14–16 A normal fecal calprotectin level in clinical IBD remission seems to predict mucosal healing.17 Studies of fecal lactoferrin are fewer, but in clinically active IBD lactoferrin is significantly elevated.18, 19
Because the clinical significance of fecal markers in monitoring response to antitumor necrosis factor-alpha (TNF-α) therapy is insufficiently studied, we compared fecal calprotectin and lactoferrin to the CDEIS,20 to the CDAI, and to histologic activity before and after anti-TNF-α therapy.