Biomarkers of Inflammation in Inflammatory Bowel Disease

Recent observations suggest that subjective measures of disease activity in inflammatory bowel disease (IBD) are often misleading. Objective measures of inflammation are more closely associated with important long-term outcomes, but often depend upon invasive and costly procedures such as ileocolonoscopy and cross-sectional imaging by computed tomography or magnetic resonance imaging. Noninvasive, accurate, and inexpensive measures of intestinal inflammation would allow clinicians to adopt widely the paradigm of adjusting therapies with a goal of controlling inflammation. Blood, stool, and urine markers have all been explored as indicators of intestinal inflammation in IBD, and although none has been universally adopted, some have been well-characterized, and others hold great promise. Serum C-reactive protein and fecal calprotectin are among the best-studied noninvasive biomarkers of inflammation in IBD, and their test characteristics have been described in the setting of differentiating IBD from irritable bowel syndrome, for grading inflammation, to describe the response to therapy, and in demonstrating recurrent inflammation after medical or surgically induced remission. High-throughput research platforms, including gene expression arrays, metabolomics and proteomics, are also being applied to the discovery of novel biomarkers of inflammation. It is certain that biomarkers of inflammation will attain growing importance in the clinic as we strive for more effective and cost-effective strategies to treat patients with IBD. Recent observations suggest that subjective measures of disease activity in inflammatory bowel disease (IBD) are often misleading. Objective measures of inflammation are more closely associated with important long-term outcomes, but often depend upon invasive and costly procedures such as ileocolonoscopy and cross-sectional imaging by computed tomography or magnetic resonance imaging. Noninvasive, accurate, and inexpensive measures of intestinal inflammation would allow clinicians to adopt widely the paradigm of adjusting therapies with a goal of controlling inflammation. Blood, stool, and urine markers have all been explored as indicators of intestinal inflammation in IBD, and although none has been universally adopted, some have been well-characterized, and others hold great promise. Serum C-reactive protein and fecal calprotectin are among the best-studied noninvasive biomarkers of inflammation in IBD, and their test characteristics have been described in the setting of differentiating IBD from irritable bowel syndrome, for grading inflammation, to describe the response to therapy, and in demonstrating recurrent inflammation after medical or surgically induced remission. High-throughput research platforms, including gene expression arrays, metabolomics and proteomics, are also being applied to the discovery of novel biomarkers of inflammation. It is certain that biomarkers of inflammation will attain growing importance in the clinic as we strive for more effective and cost-effective strategies to treat patients with IBD. The inflammatory bowel diseases (IBD), Crohn’s disease (CD) and ulcerative colitis (UC), are characterized by mucosal inflammation that may flare and remit over time. An important advance in recent years is the understanding that outcomes may be improved by directing treatment to the state of mucosal inflammation rather than to symptoms. It is now recognized that symptoms do not consistently reflect the presence or severity of mucosal inflammation, and evidence suggests that relying upon symptoms to guide therapy will lead to two important errors in management. First, symptoms may be present when mucosal inflammation is not substantially active. This may occur in as many as 20% of patients with CD1Peyrin-Biroulet L. Reinisch W. Colombel J.F. et al.Clinical disease activity, C-reactive protein normalisation and mucosal healing in Crohn's disease in the SONIC trial.Gut. 2014; 63: 88-95Crossref PubMed Scopus (332) Google Scholar or UC2Rutgeerts P. Sandborn W.J. Feagan B.G. et al.Infliximab for induction and maintenance therapy for ulcerative colitis.N Engl J Med. 2005; 353: 2462-2476Crossref PubMed Scopus (3119) Google Scholar who have no significant mucosal inflammation, potentially leading to abandonment of effective therapy or unnecessary escalation. Conversely, patients with active inflammation may fail to report symptoms, leading to under-treatment of the disease, with progression to complications in CD, and higher likelihood of symptomatic recurrence in both CD and UC. With this renewed focus on the state of bowel inflammation as a guide to therapy has come a resurgent interest in biomarkers of inflammation. Ileocolonoscopy and cross-sectional imaging are important tests that can inform the clinician about the current state of disease, such as anatomic extent and location, presence and severity of inflammation, and the occurrence of disease complications. However, while widely accepted as representing the state of bowel inflammation, endoscopy and imaging have notable limitations of cost, inconvenience, and invasiveness, making these modalities unsuitable for frequent monitoring of patients with IBD. Laboratory testing that is rapid, convenient, noninvasive, inexpensive, standardized, reproducible, and accurate in reflecting the state of bowel inflammation in IBD would greatly assist in the management of these patients (Table 1).Table 1Desirable Attributes of Biomarkers of Inflammation in IBDAttributeRationaleNoninvasiveIncreased patient acceptance; superior safety and cost compared to endoscopy or imagingConvenientIncreased patient acceptanceRapidRapid turnaround time from test to result accelerates clinical decision-makingInexpensiveTest helps to minimize cost of care. Cost of test should be balanced against benefit in ultimate patient outcomes (cost-effective)ReproducibleLow variation in the result with repetition of the test using the same process/instrumentation over timeSpecificity for the diseaseResult is specific to intestinal inflammation, and preferably to IBD, as opposed to other bowel condiitionsAccurateTest maintains good balance between test performance characteristics of sensitivity and specificity. Note that different thresholds for the same test may be desirable, depending upon the test scenarioPreciseRepeated testing of a sample clusters tightly around the same mean. Note that precision does not imply accuracy, which is the ability of a test to cluster around the true value for the analyteStandardizedTest results for an analyte are comparable across assays, or can be converted to a single standardAvailableWide availability increases adoption and utilizationStableAnalyte is stable for storage and transport after acquistion, without degradation that would interfere with accurate measurementDynamic rangeTests with wider dynamic range have the potential to more easily distinguish between different degrees of inflammationDefined thresholdsCutoff values that differentiate between states where inflammation is absent or present, or between different grades of inflammation (eg, mild, moderate, severe)ResponsiveTest result changes rapidly in concordance with change in the state of inflammationIBD, inflammatory bowel disease. Open table in a new tab IBD, inflammatory bowel disease. Although many noninvasive biomarkers of IBD disease activity have been described (Table 2), primarily blood and stool biomarkers, each has notable limitations with regard to the ideal characteristics described above. None have been fully validated for each of the clinical scenarios for which biomarkers of disease activity are needed. The validity and limitations of inflammation biomarkers used in IBD are summarized below. In addition, a description of investigational approaches to discovering biomarkers follows.Table 2Biomarkers of inflammation in IBDSourceIndicator typeMarkersBloodAcute phase reactantsC-reactive proteinErythrocyte sedimentation rateα-1-acid glycoprotein (orosomucoid)β2-microglobulinSialic acidSerum amyloid AFerritinTransferrinHaptoglobinCeruloplasminα-1-antitrypsinFibrinogenProthrombinPlasminoginFactor XIISerum albuminComplement (C1s, C2, C3, C4)CytokineInterleukin-6Interleukin-1βInterleukin-8Interleukin-10Tumor necrosis factor αCellularPlatelet countWhite-blood cell countOther inflammatory and cell regulationAdenosine deaminaseMicroRNA (miRNA) speciesCalprotectin (S100A8/S100A9)Soluble ST2Serum tryptophanStoolBarrier/epithelial disruptionFecal occult bloodFecal immunochemical testα-1-antitrypsinM2-pyruvate kinaseCytokineTumor necrosis factor αInterleukin-1βInterleukin-4Interleukin-10InflammatoryCalprotectin (S100A8/S100A9)Lactoferrin (S100A12)LysozymePolymorphonuclear elastaseMyeloperoxidaseMetalloproteinase-9NeopterinChitinase 3-Like-1UrineInflammationNeopterinNeutrophil gelatinase-associated lipocalinα-1-acid-glycoproteinZn-α-2-glycoproteinF-2-isoprostanesProstaglandin E metabolite (PGE-M)Leukotriene E-4BreathInflammationVolatile organic compounds (“breath print”)IBD, inflammatory bowel disease. Open table in a new tab IBD, inflammatory bowel disease. The intense bowel inflammation of IBD is accompanied by an acute phase response detectable in the serum and blood. The acute phase response is characterized by increased elaboration of proteins involved in coagulation and fibrinolysis, such as fibrinogen, plasminogen, Factor VIII, and prothrombin; complement system components such as C1 inhibitor, C1s, C2, C3, C4, C5 and C9; proteinase inhibitors, including α-1-antitrypsin, α1 anti-chymotrypsin; transport proteins such as haptoglobin and ceruloplasmin; and a variety of other proteins such as C-reactive protein (CRP), serum amyloid A (SAA), ferritin, fibronectin and orosomucoid.3Vermeire S. Van Assche G. Rutgeerts P. Laboratory markers in IBD: useful, magic, or unnecessary toys?.Gut. 2006; 55: 426-431Crossref PubMed Scopus (704) Google Scholar Other serum proteins, such as albumin, transferrin, α2 macroglobulin and Factor XII, are depressed in the acute phase response.3Vermeire S. Van Assche G. Rutgeerts P. Laboratory markers in IBD: useful, magic, or unnecessary toys?.Gut. 2006; 55: 426-431Crossref PubMed Scopus (704) Google Scholar Serum levels of proinflammatory cytokines, many of which stimulate the acute phase response, may also be elevated. These may include TNF-α, interferon-β, transforming growth factor-β, and interleukin (IL)-1β, IL-6, IL-8, IL-12, IL-17, and IL-23.4Cioffi M. Rosa A.D. Serao R. et al.Laboratory markers in ulcerative colitis: current insights and future advances.World J Gastrointest Pathophysiol. 2015; 6: 13-22Crossref PubMed Google Scholar Other potential serum markers include adenosine deaminase,5Maor I. Rainis T. Lanir A. et al.Adenosine deaminase activity in patients with Crohn's disease: distinction between active and nonactive disease.Eur J Gastroenterol Hepatol. 2011; 23: 598-602Crossref PubMed Scopus (20) Google Scholar soluble ST2,6Diaz-Jimenez D. Nunez L.E. Beltran C.J. et al.Soluble ST2: a new and promising activity marker in ulcerative colitis.World J Gastroenterol. 2011; 17: 2181-2190Crossref PubMed Scopus (47) Google Scholar and tryptophan.7Gupta N.K. Thaker A.I. Kanuri N. et al.Serum analysis of tryptophan catabolism pathway: correlation with Crohn's disease activity.Inflamm Bowel Dis. 2012; 18: 1214-1220Crossref PubMed Scopus (99) Google Scholar Cellular components of blood may also indicate inflammation, as is reflected in elevations of white blood cell and platelet counts.4Cioffi M. Rosa A.D. Serao R. et al.Laboratory markers in ulcerative colitis: current insights and future advances.World J Gastrointest Pathophysiol. 2015; 6: 13-22Crossref PubMed Google Scholar The erythrocyte sedimentation rate (ESR) is an indirect measure of inflammation, largely through an increase in plasma viscosity due to elaboration of acute phase response proteins. However, ESR is also affected by the hematocrit both in anemia and polycythemia, as well as in other diseases and physiologic states such as aging and pregnancy, reducing its accuracy and specificity in IBD.8Mendoza J.L. Abreu M.T. Biological markers in inflammatory bowel disease: Practical consideration for clinicians.Gastroenterologie Clinique Et Biologique. 2009; 33: S158-S173Crossref PubMed Google Scholar Few blood or serum markers of inflammation have been extensively validated in IBD, and fewer still are in routine use in the clinic. CRP and ESR are the most widely available and used. CRP has a relatively short half-life of ∼19 hours, making it a more responsive indicator of acute inflammation than most other acute phase reactants.8Mendoza J.L. Abreu M.T. Biological markers in inflammatory bowel disease: Practical consideration for clinicians.Gastroenterologie Clinique Et Biologique. 2009; 33: S158-S173Crossref PubMed Google Scholar Assays vary in their sensitivity and definitions of normal cutoff values, from 0.8 mg/L for highly sensitive assays to 5 mg/L for standard sensitivity assays. However, results in the clinic span from 0.8 to 200 mg/L, providing a wide dynamic range for this test. In the typical acute phase response, hepatocytes produce CRP in response to proinflammatory cytokines, chiefly IL-6, tumor necrosis factor α and IL-1β.8Mendoza J.L. Abreu M.T. Biological markers in inflammatory bowel disease: Practical consideration for clinicians.Gastroenterologie Clinique Et Biologique. 2009; 33: S158-S173Crossref PubMed Google Scholar More recently it has been recognized that CRP is also expressed in mesenteric adipocytes in patients with CD9Peyrin-Biroulet L. Gonzalez F. Dubuquoy L. et al.Mesenteric fat as a source of C reactive protein and as a target for bacterial translocation in Crohn's disease.Gut. 2012; 61: 78-85Crossref PubMed Scopus (188) Google Scholar, accounting for the typically higher levels of CRP seen in CD than in UC. Nevertheless, in patients with acute severe UC, elevated CRP is associated with higher likelihood of colectomy10Travis S.P. Farrant J.M. Ricketts C. et al.Predicting outcome in severe ulcerative colitis.Gut. 1996; 38: 905-910Crossref PubMed Scopus (601) Google Scholar, perhaps reflecting transmural extension of inflammation normally confined to the mucosa among those with the highest severity of UC. Genetic determinants of CRP expression are also complex11Danik J.S. Ridker P.M. Genetic determinants of C-reactive protein.Curr Atheroscler Rep. 2007; 9: 195-203Crossref PubMed Scopus (27) Google Scholar, and as many as 25% of patients with demonstrable activity of CD on endoscopy do not express levels of CRP above the normal threshold.12Vermeire S. Van Assche G. Rutgeerts P. C-reactive protein as a marker for inflammatory bowel disease.Inflamm Bowel Dis. 2004; 10: 661-665Crossref PubMed Scopus (373) Google Scholar As compared to blood or serum biomarkers, stool markers have the advantage of increased specificity for inflammatory processes localized to the bowel. While some fecal markers, such as α-1-antitrypsin and occult blood, reflect disruption of the mucosal barrier, such markers are not as accurate as others that are associated with the pathogenic inflammatory processes underlying IBD.13Foell D. Wittkowski H. Roth J. Monitoring disease activity by stool analyses: from occult blood to molecular markers of intestinal inflammation and damage.Gut. 2009; 58: 859-868Crossref PubMed Scopus (172) Google Scholar Products of leukocyte degranulation, such as lysozyme, myeloperoxidase, eosinophilic cationic protein, eosinophilic protein X, lactoferrin, matrix metalloproteinase (MMP)-9, neopterin, and polymorphonuclear elastase, are relatively stable proteins found in the stools of patients with active IBD in higher concentrations than in the stool of healthy normal individuals.13Foell D. Wittkowski H. Roth J. Monitoring disease activity by stool analyses: from occult blood to molecular markers of intestinal inflammation and damage.Gut. 2009; 58: 859-868Crossref PubMed Scopus (172) Google Scholar In addition, the damage-associated molecular pattern (DAMP) proteins S100A8/S100A9, collectively called calprotectin, and S100A12, are also stable in stool, and are increased in active IBD.13Foell D. Wittkowski H. Roth J. Monitoring disease activity by stool analyses: from occult blood to molecular markers of intestinal inflammation and damage.Gut. 2009; 58: 859-868Crossref PubMed Scopus (172) Google Scholar Fecal M2-pyruvate kinase14Chung-Faye G. Hayee B. Maestranzi S. et al.Fecal M2-pyruvate kinase (M2-PK): a novel marker of intestinal inflammation.Inflamm Bowel Dis. 2007; 13: 1374-1378Crossref PubMed Scopus (73) Google Scholar and chitinase 3-like-115Aomatsu T. Imaeda H. Matsumoto K. et al.Faecal chitinase 3-like-1: a novel biomarker of disease activity in paediatric inflammatory bowel disease.Aliment Pharmacol Ther. 2011; 34: 941-948Crossref PubMed Scopus (34) Google Scholar levels have also been found to increase in relation to disease activity in IBD. Some limitations of fecal biomarkers include patients’ disinclination to collect stool, and the lack of specificity of fecal biomarkers for IBD, as opposed to other infectious or inflammatory processes.16Lehmann F.S. Burri E. Beglinger C. The role and utility of faecal markers in inflammatory bowel disease.Therap Adv Gastroenterol. 2015; 8: 23-36Crossref PubMed Scopus (97) Google Scholar In addition, it appears that intra-individual variability of some fecal markers, including calprotectin, may be large, even when comparing different stool specimens collected over the course of a day.17Lasson A. Stotzer P.O. Ohman L. et al.The intra-individual variability of faecal calprotectin: a prospective study in patients with active ulcerative colitis.J Crohns Colitis. 2015; 9: 26-32PubMed Google Scholar Calprotectin and lactoferrin have been studied more extensively than other proposed fecal biomarkers, and are readily available in clinical laboratories. A small number of substances excreted in urine have been investigated as biomarkers of inflammation in IBD. These include a variety of prostaglandin and leukotriene pathway products,18Cracowski J.L. Bonaz B. Bessard G. et al.Increased urinary F-2-isoprostanes in patients with Crohn's disease.American Journal of Gastroenterology. 2002; 97: 99-103Crossref PubMed Google Scholar, 19Johnson J.C. Schmidt C.R. Shrubsole M.J. et al.Urine PGE-M: A metabolite of prostaglandin E-2 as a potential biomarker of advanced colorectal neoplasia.Clin Gastroenterol Hepatol. 2006; 4: 1358-1365Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar, 20Stanke-Labesque F. Pofelski J. Moreau-Gaudry A. et al.Urinary leukotriene E-4 excretion: A biomarker of inflammatory bowel disease activity.Inflam Bowel Dis. 2008; 14: 769-774Crossref PubMed Scopus (33) Google Scholar, 21Arai Y. Arihiro S. Matsuura T. et al.Prostaglandin E-major urinary metabolite as a reliable surrogate marker for mucosal inflammation in ulcerative colitis.Inflam Bowel Dis. 2014; 20: 1208-1216Crossref PubMed Scopus (40) Google Scholar neutrophil gelatinase-associated lipocalin,22Bolignano D. Della Torre A. Lacquaniti A. et al.Neutrophil gelatinase-associated lipocalin levels in patients with Crohn disease undergoing treatment with infliximab.J Invest Med. 2010; 58: 569-571Crossref PubMed Scopus (35) Google Scholar alpha 1-acid-glycoprotein and Zn-alpha 2-glycoprotein,23Marko L. Szigeti N. Szabo Z. et al.Potential urinary biomarkers of disease activity in Crohn's disease.Scand J Gastroenterol. 2010; 45: 1440-1448Crossref PubMed Scopus (10) Google Scholar and neopterin.24Nancey S. Perret-Liaudet A. Moussata D. et al.Urinary neopterin is a valuable tool in monitoring Crohn's disease activity.Inflam Bowel Dis. 2008; 14: 1548-1554Crossref PubMed Scopus (21) Google Scholar None is extensively validated, and none is in common use in the clinic. Inflammation biomarkers may be useful in a variety of important clinical scenarios (see Figure 1 for applications of biomarkers of inflammation in CD). In the broadest sense, inflammation biomarkers have been used in IBD for 2 main purposes: (1) identifying patients with symptoms of IBD who should be further investigated for a possible IBD diagnosis; and (2) measuring or monitoring disease activity in response to induction or maintenance therapy. The latter purpose includes diverse settings, such as identifying patients who have successfully responded after introducing new therapy, detecting patients who are relapsing while receiving stable therapy, screening for relapse after surgical resection in Crohn’s disease, and increasingly for predicting patients likely to experience clinical relapse upon withdrawal of therapy. It is important to recognize that different cutoff thresholds may optimize performance of the same biomarker assay, depending upon the clinical scenario. For the majority of patients with chronic abdominal pain or diarrhea, a clinically useful biomarker should balance sensitivity and negative predictive value to screen patients who would benefit from more invasive testing, such as endoscopy and histopathology or imaging, to confirm a diagnosis of IBD, while avoiding these more expensive, intrusive and riskier diagnostics for those who are very unlikely to have IBD. A recent meta-analysis explored the utility of CRP, ESR, fecal calprotectin (FC) and fecal lactoferrin to exclude IBD in adult patients with irritable bowel syndrome (IBS). Patients with CRP ≤0.5 mg/dL or FC ≤40 μg/g were found to have a ≤1% probability of having IBD. ESR and fecal lactoferrin, in isolation, did not have adequate clinical utility in excluding IBD.25Menees S.B. Powell C. Kurlander J. et al.A meta-analysis of the utility of c-reactive protein, erythrocyte sedimentation rate, fecal calprotectin, and fecal lactoferrin to exclude inflammatory bowel disease in adults with IBS.Am J Gastroenterol. 2015; 110: 444-454Crossref PubMed Scopus (215) Google Scholar An earlier meta-analysis in adults found a pooled sensitivity of 93% and pooled specificity of 96% for FC to diagnose IBD.26van Rheenen P.F. Van de Vijver E. Fidler V. Faecal calprotectin for screening of patients with suspected inflammatory bowel disease: diagnostic meta-analysis.BMJ. 2010; 341: c3369Crossref PubMed Scopus (493) Google Scholar It should be noted that cutoff values in these studies ranged from 24 to 150 μg/g of stool. However, threshold values may be affected by differences among the commercially available assays used in the studies and in the clinic.27Kristensen V. Moum B. Correspondence: fecal calprotectin and cut-off levels in inflammatory bowel disease.Scand J Gastroenterol. 2015; : 1-2Google Scholar Studies point to a lower specificity of FC for IBD in children. The most recent and largest meta-analysis of FC in children found a sensitivity of 98% and specificity of 68% in diagnosing IBD, with positive and negative likelihood ratios of 3.07 and 0.03.28Henderson P. Anderson N.H. Wilson D.C. The diagnostic accuracy of fecal calprotectin during the investigation of suspected pediatric inflammatory bowel disease: a systematic review and meta-analysis.Am J Gastroenterol. 2014; 109: 637-645Crossref PubMed Scopus (151) Google Scholar Notably, some studies indicate that disease type (CD vs UC) and disease location (colitis vs enteritis)29Jones J. Loftus E.V. Panaccione R. et al.Relationships between disease activity and serum and fecal biomarkers in patients with Crohn's disease.Clin Gastroenterol Hepatol. 2008; 6: 1218-1224Abstract Full Text Full Text PDF PubMed Scopus (330) Google Scholar may be associated with distinct levels of FC, of potential relevance to the pediatric cohorts included in the meta-analysis. Once a diagnosis of IBD has been confirmed, biomarkers of inflammation may be useful in clinical situations that require objective assessment of the burden or severity of inflammation. Such scenarios include correctly categorizing disease severity, identifying those patients who have had improvement or resolution of their inflammation, and identifying patients who have had recrudescence of inflammation after medically or surgically induced remission, even in advance of the recurrence of clinical symptoms. Nearly all studies have found biomarkers of inflammation to have higher correlation with endoscopic disease activity than with clinical disease activity indices focusing on symptoms. This discrepancy is most notable in CD, where the correlation of stool biomarkers of inflammation to endoscopic disease activity, as measured by the Crohn’s Disease Endoscopic Index of Severity (CDEIS) or the Simple Endoscopic Severity Index (SES-CD), is considerably higher than its correlation to the Crohn’s Disease Activity Index (CDAI).30D'Haens G. Ferrante M. Vermeire S. et al.Fecal calprotectin is a surrogate marker for endoscopic lesions in inflammatory bowel disease.Inflamm Bowel Dis. 2012; 18: 2218-2224Crossref PubMed Scopus (585) Google Scholar, 31Sipponen T. Savilahti E. Kolho K.L. et al.Crohn's disease activity assessed by fecal calprotectin and lactoferrin: correlation with Crohn's disease activity index and endoscopic findings.Inflamm Bowel Dis. 2008; 14: 40-46Crossref PubMed Scopus (394) Google Scholar Patients with quiescent CD (CDAI <150) are observed to have wide variability in FC concentrations, underscoring the mismatch of symptoms and inflammation.32Lasson A. Simren M. Stotzer P.O. et al.Fecal calprotectin levels predict the clinical course in patients with new onset of ulcerative colitis.Inflamm Bowel Dis. 2013; 19: 576-581Crossref PubMed Scopus (46) Google Scholar FC was highly correlated with both severity and extent of CD as measured by radiolabelled white cell scans, whereas disease activity as measured by the CDAI was not.33Gaya D.R. Lyon T.D. Duncan A. et al.Faecal calprotectin in the assessment of Crohn's disease activity.QJM. 2005; 98: 435-441Crossref PubMed Scopus (67) Google Scholar Some studies note a correlation between CRP and endoscopic severity in CD, although the association has not been as robust as with fecal markers.29Jones J. Loftus E.V. Panaccione R. et al.Relationships between disease activity and serum and fecal biomarkers in patients with Crohn's disease.Clin Gastroenterol Hepatol. 2008; 6: 1218-1224Abstract Full Text Full Text PDF PubMed Scopus (330) Google Scholar In one study, FC levels measured by a point-of-care assay device had better correlation with the endoscopic activity measured by the CDEIS than with the leukocyte count, platelet count or CRP.34Lobaton T. Lopez-Garcia A. Rodriguez-Moranta F. et al.A new rapid test for fecal calprotectin predicts endoscopic remission and postoperative recurrence in Crohn's disease.J Crohns Colitis. 2013; 7: e641-651Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar A threshold value of 272 μg/g was optimal for endoscopic remission (CDEIS <3), with area under the curve (AUC) 0.933, and with performance similar to ELISA-based FC assay with cutoff of 274 μg/g and AUC 0.925.34Lobaton T. Lopez-Garcia A. Rodriguez-Moranta F. et al.A new rapid test for fecal calprotectin predicts endoscopic remission and postoperative recurrence in Crohn's disease.J Crohns Colitis. 2013; 7: e641-651Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar However, FC levels correlated best with endoscopic activity when disease was found in colon and ileum (Pearson’s correlation r = 0.88) or colon alone (r = 0.73), as opposed to ileum alone (r = 0.44).34Lobaton T. Lopez-Garcia A. Rodriguez-Moranta F. et al.A new rapid test for fecal calprotectin predicts endoscopic remission and postoperative recurrence in Crohn's disease.J Crohns Colitis. 2013; 7: e641-651Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar Still, fecal markers hold promise for the detection of ileal recurrence after small bowel resection, as detailed below. Two cross-sectional studies by Schoepfer et al. compared CRP, FC and symptom-based indices to endoscopic scores of severity in UC and CD.35Schoepfer A.M. Beglinger C. Straumann A. et al.Fecal calprotectin more accurately reflects endoscopic activity of ulcerative colitis than the Lichtiger index, C-reactive protein, platelets, hemoglobin, and blood leukocytes.Inflam Bowel Dis. 2013; 19: 332-341Crossref PubMed Scopus (201) Google Scholar, 36Schoepfer A.M. Beglinger C. Straumann A. et al.Fecal calprotectin correlates more closely with the Simple Endoscopic Score for Crohn's disease (SES-CD) than CRP, blood leukocytes, and the CDAI.Am J Gastroenterol. 2010; 105: 162-169Crossref PubMed Scopus (437) Google Scholar In ulcerative colitis, FC could accurately discriminate between patients with mild, moderate and severe endoscopic appearance.35Schoepfer A.M. Beglinger C. Straumann A. et al.Fecal calprotectin more accurately reflects endoscopic activity of ulcerative colitis than the Lichtiger index, C-reactive protein, platelets, hemoglobin, and blood leukocytes.Inflam Bowel Dis. 2013; 19: 332-341Crossref PubMed Scopus (201) Google Scholar Ranges for FC were identified in association with the modified Baron score of endoscopic severity for UC, with grade 0 associated with median [interquartile range] of 16 [10-30] μg/g, grade 1 with 35 [25-48] μg/g, grade 2 with 102 [44-159] μg/g, grade 3 with 235 [176-319] μg/g, and grade 4 with 611 [406-868] μg/g (P < .001 for discriminating the different grades).35Schoepfer A.M. Beglinger C. Straumann A. et al.Fecal calprotectin more accurately reflects endoscopic activity of ulcerative colitis than the Lichtiger index, C-reactive protein, platelets, hemoglobin, and blood leukocytes.Inflam Bowel Dis. 2013; 19: 332-341Crossref PubMed Scopus (201) Google Scholar In the same study, a cutoff of ≥57 μg/g of stool optimized the sensitivity and specificity at 91% and 90%, respectively to ide