REVIEW ARTICLE
Role of Biomarkers in the Study and Management of Inflammatory Bowel Disease: A “Nonsystematic” Review David B. Sachar, MD; for the Biomarkers Task Force of the IOIBD
(Inflamm Bowel Dis 2014;20:2511–2518) Key Words: biomarkers, C-reactive protein, fecal calprotectin
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tool cannot be evaluated unless its purpose is known. This axiom is as applicable to the study of biomarkers as to any other instrument. In the case of inflammatory bowel disease (IBD), biomarkers are typically used by clinicians to serve any of 3 principal functions: diagnosis, interval assessment, or prognosis. The intense interest in biomarkers has been prompted largely by the failure of purely “clinical” indices to fulfill these purposes consistently and reliably.1 In this IOIBD Task Force White Paper, I shall review the data concerning the relative utility of 3 of the oldest, simplest, and most widely used biomarkers, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and orosomucoid (alpha-1 acid glycoprotein), as well as newer fecal markers (primarily calprotectin and lactoferrin) to fulfill each of these functions in the management of patients with IBD. It is the intent of this review to focus on fluctuating biomarkers that are reflective of the ongoing state of inflammatory activity, rather than the familiar and emerging serologic antibodies like ASCA, ANCA, anti-cBir1, and the like, a whole subject in itself.2
assessment of their patients with known or suspected IBD, including stool analysis for lactoferrin, calprotectin, or leukocyte elastase4–7 and the serologic markers pANCA, ASCA, OmpC, and anti-CBir-1,8,9 and other biochemical assays.10 ESR and CRP, in particular, have provided physicians with readily obtainable and reliable objective data that they can use to further refine their clinical impressions at a point even before consideration of more advanced studies. As long ago as the 1980s, it was well established that ESR and CRP were useful in distinguishing patients with inflammatory and infectious bowel diseases from those with functional disorders.11–13 Likewise, fecal calprotectin has recently proved useful in the diagnosis of suspected adult and pediatric IBD as well as in predicting relapses of IBD14 (Fecal markers are discussed in more detail on the “Assessment” section below). Indeed, the combination of history, physical examination, ESR, CRP, and occult fecal blood seems to be so reliable in making the distinction between irritable bowel syndrome and IBD that some argue that more complex or invasive studies seem to have little if any incremental value in the differential diagnosis of functional from organic bowel disease.15
DIAGNOSIS Although there is a substantial literature regarding the role of biomarkers in differentiating IBD from functional bowel disorders, recently masterfully reviewed by Lewis,3 in practice, this distinction can most often be made by a careful history and physical examination. In certain instances, though, the differential diagnosis between IBD and irritable bowel syndrome may require more advanced diagnostic tools, such as endoscopy, radiology, histology, or stool tests. Several sophisticated laboratory assays have also been proposed to assist clinicians in the diagnosis and interval Received for publication June 4, 2014; Accepted June 5, 2014. From the Dr. Henry Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York. The author has no conflicts of interest to disclose. Reprints: David B. Sachar, MD, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, New York, NY 10029 (e-mail: [email protected]). Copyright © 2014 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/MIB.0000000000000135 Published online 12 September 2014.
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ASSESSMENT The role of various biomarkers is much murkier when it comes to assessing the “activity” of Crohn’s disease (CD) or ulcerative colitis (UC) in patients.16 Here, the confusion often arises from the lack of a consensus “gold standard” of disease activity against which to measure the utility of a specific biomarker. Studies evaluating particular biomarkers for assessing clinical or inflammatory activity have therefore revolved primarily around defining the statistical correlation(s) between the candidate marker and other yardsticks of clinical disease activity and mucosal inflammation, including previously validated disease activity metrics, such as the Crohn’s Disease and Harvey–Bradshaw activity indices (CDAI and HBAI, respectively), endoscopic appearance, radionuclide excretion, fecal markers, and other parallel serum reactants (Table 1). On the whole, ESR, CRP, and orosomucoid have performed remarkably well in many of these correlative studies. www.ibdjournal.org |
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TABLE 1. Reference Numbers for Articles Showing Positive Correlations Clinical Activity and Outcomes CRP Fecal calprotectin Clinical activity and outcomes
References 4,11–13,19–21,29,31–35,39–41,44,48–55,77,80– 87,89,108,113,115,117,118,121–123,127 References 4,5,7,13,14,60,72,77–79,87,109–111 NA
Clinical Activity Indices Most attention, understandably, has focused on defining the correlation between proposed IBD biomarkers and standard clinical disease activity indices.17,18 Clearly, a prime goal of introducing objective biomarkers into the equation of clinical assessment is to detect subclinical inflammation while at the same time avoiding confusion between inflammatory activity and symptoms superimposed irritable bowel syndrome. An early seminal study of this subject came from France over 30 years ago.19 In an assessment of 11 laboratory markers among 54 patients with CD, André et al noted that only 3 measures, orosomucoid, ESR, and CRP, had statistically significant associations with clinical indices (CDAI, Harvey–Bradshaw, and van Hees). Ironically, of all of the markers that were studied, the parameter with the least robust correlation with disease activity indices was the hematocrit, the only laboratory measurement that had been included in the CDAI! A 1992, a German study came to the same conclusion.20 Analysis of 6 serologic biomarkers obtained from 75 consecutive hospitalized patients with CD found that hematocrit displayed the poorest correlation with clinical (CDAI, van Hees) and endoscopic indices. Although these investigators noted that serum cholinesterase seemed to have the highest correlation with endoscopic findings, ESR and CRP also performed well. Indeed, as long as 25 years ago, French investigators reported that the serologic biomarkers displaying the best correlations with clinical disease activity in patients with CD were, in decreasing order, orosomucoid, ESR, and CRP.21 Confirmatory observations have been published for CRP in adults in Tunisia22 and for children in Australia,23 for orosomucoid in children in the United Kingdom24 and in patients in Croatia25 and England,26 and for ESR in children all across North America.27 A biochemically oriented article from the United Kingdom reported that orosomucoid had an overall predictive value of 82.5% for discerning IBD activity.28 A French study has also shown that CRP correlates well with CDAI, although not as well as urinary neopterin.29 More recently, there has been an increased interest in highsensitivity CRP.30 It is noteworthy that a recent Finnish study found no incremental benefit from the use of high-sensitivity CRP over that of standard CRP in children.31 It is important to note that the tightness and even the direction of these correlations may vary when a given marker is used to study patients with either UC or CD, when evaluating
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Endoscopy References 20,44,48–55,77 References 7,14,77,82,83,88,112 References 20,126
patients with mucosal inflammation in different anatomic locations and even when different types of treatment are used. For example, several studies have suggested a trend for closer correlation between clinical activity and CRP in patients with CD and with ESR in those with UC.24,32–35 Similarly, Sachar et al have reported that the correlation of ESR with clinical activity depended on the extent of colonic involvement in both UC and CD,36 and that the association was inverse in cases of CD confined to the small bowel.37 Both of these findings have been confirmed in more recent scintigraphy studies.38 Others have also suggested a difference between clinical correlations with CRP between UC and CD,39 although this difference has not been observed with the use of high-sensitivity CRP.40 It has also been reported that effective antimetabolite treatment in children may normalize the CRP, whereas the ESR remains elevated,41 perhaps because ESR can be elevated for reasons other than inflammation. Indeed, regarding different mechanisms underlying the expression of different acute phase reactants, it is of interest that recent studies from France are pointing to the role of adipose tissue both in the pathogenesis of inflammation and in the synthesis of CRP.42 These observations all underscore the importance of “clinical phenotyping” before broadly defining the relevance of a particular biomarker for use in assessing patients with IBD.43
Endoscopy Published studies of the correlation between serologic biomarkers and endoscopic findings are inconsistent, to say the least. A study from Spain reported an excellent correlation between ESR and CRP with both clinical and endoscopic indices in UC but not in CD.44 One British study noted only a modest association between CRP (but not orosomucoid) and endoscopic activity in UC and CD,45 while an earlier study from England found virtually no correlation between ESR or CRP and either colonoscopic or histologic activity in Crohn’s colitis.46 Similarly, a Swedish study of 60 patients with ulcerative and Crohn’s colitis found poor correlations between laboratory and endoscopic findings, except for elevated orosomucoid only in patients with UC with severe and extensive lesions.47 A more recent Belgian study has noted that if patients with clinically active CD have normal CRP, they are not likely to have severe endoscopic lesions irrespective of their ESR or orosomucoid levels.48 More encouraging data regarding the use of CRP in patients with IBD were published from the Mayo Clinic in 2005. These
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investigators reported significant associations of elevated CRP with clinical, colonoscopic, and histologic activity in 104 patients with CD and with clinical and endoscopic activity as well as with high ESR in 43 patients with UC.49 Several studies have reported that CRP was a good predictor of endoscopic inflammation in UC50–53 and CD,54 and this year, a subanalysis of the SONIC data has demonstrated the correlation of reduction in CRP with mucosal healing seen on endoscopy.55 However, other studies from Sweden,56 the Netherlands,57 France,58 Belgium,59 and Finland60 have found only weak or absent correlations of CRP, ESR, and orosomucoid with clinical or endoscopic indices. The French investigators concluded that the extent of clinical disease activity in patients with CD seems to be virtually independent of both the severity of the mucosal lesions observed at endoscopy and value of biological measures, including ESR and CRP.58 Likewise, in a Cleveland Clinic study, there was only limited clinical utility to a “snapshot” measurement of CRP in distinguishing normal from inflamed ileal pouches after total proctocolectomy for UC.61 The prospects would therefore seem dim for any of these serum biomarkers to gain general acceptance as reliable substitutes or surrogate markers for endoscopy or histology.
Radionuclide Excretion The inconsistencies between blood biomarkers and tissue damage seen at endoscopy have been mirrored in studies using radionuclide excretion. Two studies using technetium-99m HMPAO SPECT found poor correlations between certain blood indicators, like ESR and CRP, and radionuclide results, particularly in small bowel CD.62,63 However, another study reported good correlation between indium-111 and orosomucoid, ESR and CRP levels in 58 patients with CD,64 while planar imaging with technetium-99m white blood cells was said to show good correlation with ESR in children with CD but not UC.65 Overall, though, it would seem that existing serologic biomarkers cannot be relied on to consistently reflect radionuclide-measured mucosal disease activity.
Fecal Markers Interest in fecal levels of stable serum proteins as markers of inflammatory activity date back over 30 years, with studies of fecal a-1-antitrypsin concentrations66–68 and clearances.69 Much more recently, Japanese investigators have studied fecal immunochemical testing as an assay of mucosal healing in UC.70 Canadian researchers this year have also reviewed in considerable detail the clinical utility of a range of fecal biomarkers, including calprotectin, lactoferrin, S100A12, pyruvate kinase, and matrix metalloproteinases.71 By far the 2 most widely studied fecal markers of inflammation, however, are calprotectin and lactoferrin. A large number of studies have been published regarding their correlation with clinical disease activity indices in IBD,72,73 and some of these studies can be consulted for information on their association with laboratory, endoscopic, and histologic markers as well.74 For example, a 2007 study from Boston reported a significant
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correlation between fecal lactoferrin and ESR in 62 children with UC and 79 with CD.75 More recently, however, data from an Italian study of 58 children with IBD showed a significant correlation of ESR (but not CRP) with clinical score, histologic grading, and fecal calprotectin only in the 26 patients with CD.76 Most recently, Benitez et al77 in Belgium reported a close correlation of CRP and fecal calprotectin with endoscopic lesions, response to therapy, and the risk of relapse. However, a Swiss study of 122 patients with UC found that fecal calprotectin correlated more closely with the simplified endoscopic score for CD than did CRP or the CDAI.78 Similarly, a German report indicates the superiority of fecal markers over CRP in correlating with endoscopic activity.79 Therefore, if one were to accept fecal markers as a “gold standard” of mucosal inflammation in patients with IBD, one would have to conclude with the Italian investigators that “CRP and ESR could not be accurate predictors of active intestinal inflammation in children with IBD.”76 Studies evaluating the utility fecal biomarkers in the interval assessment of children and adults with IBD have clearly evolved. Preliminary studies were qualitative and demonstrated elevated absolute levels of these biomarkers in patients with either active CD or UC ongoing “Second-generation” studies, however, are currently addressing how these fecal biomarkers can provide clinicians with more detailed information to optimize pharmacologic therapy and to predict disease flares and complications.80–87 Indeed, the thrust of interest in markers of inflammatory activity in IBD in the past few years has focused increasingly on fecal calprotectin, especially as a surrogate for endoscopic evaluation of impending postoperative relapse of CD.7,14,88 A recent and particularly ambitious evaluation by investigators at the Mayo Clinic of a range of markers, called the EMBARK study, has once again given high grades to CRP in combination with 2 more novel serum indicators, matrix metalloproteinase 9 and IL-22, particularly as correlated with cross-sectional imaging.89
Miscellaneous Indicators The number of proposed blood, urine, fecal, and tissue markers for IBD activity is almost countless. I shall cite only a few of them in this section for the purpose of reviewing how well they correlate with orosomucoid, ESR, or CRP. One study reports a correlation of CRP elevation with NFkappaB p65 expression in colonic tissues.90 One study reports a good correlation between CRP and serum amyloid A, with a higher specificity (100%) for the former.91 One study reports a better correlation of disease activity with serum amyloid A and circulating IL-6 than with either CRP or ESR.92 One study reports favorably on the correlation of soluble IL-2 receptor with clinical activity of CD, but indicates that the correlation was not greater than that with ESR.93 One study reports a high correlation between the van Hees activity index in CD and Factor VIII coagulation proteins, but the correlation was also high with orosomucoid, ESR, and CRP.94 One study evaluated serum procalcitonin as a marker for IBD activity but found that CRP was superior,95 although a more recent study reported that the combination of www.ibdjournal.org |
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procalcitonin and CRP was superior to CRP alone for CD.96 One study favored soluble urokinase plasminogen activator receptor as an inflammatory marker in children with IBD.97 Also in children, serum matrix metalloproteinase levels have been proposed as markers of CD activity.98 An Italian report considered postheparin plasma diamine oxidase as a marker of small bowel inflammation in CD.99 One study found serum-soluble triggering receptor expressed on myeloid cells-1 to be more closely correlated with UC (but not CD) activity than either ESR or CRP, although the latter correlations were also highly significant.100 The point of this superficial and somewhat arbitrary review of a wide variety of markers proposed over the years as indicators of IBD activity is not to make a brief either for or against any of their merits, but rather to provide a sense of the panoply of candidates proposed for the “holy grail” of IBD, namely, a single measurable number to provide objective quantitation of the elusive entity of “disease activity.”
PROGNOSIS Prediction of clinical course and outcome is every bit as important as differential diagnosis and activity assessment.101 For the past 20 years, therefore, investigators have sought laboratory predictors for relapse, treatment response, or complications.102 Indeed, there is already a vast literature, too extensive to review here, seeking associations between serologic markers and phenotypes and outcomes of CD and UC.103
Relapse Most of these prognostic efforts have focused on predicting relapse. One of the first attempts to develop a laboratory index for predicting clinical relapse in asymptomatic patients with CD was reported by Brignola et al.104 The serum orosomucoid and ESR, as well as a2 globulin, proved remarkably accurate (88%) in predicting a relapse within 18 months, although it must be said that this index was developed from a retrospective cohort and not tested prospectively in this study. To their credit, however, these investigators did subsequently apply their index to a prospective cohort, in whom there was indeed a very high relapse rate that was delayed but not prevented by the prophylactic administration of prednisolone.105 In a similar effort to identify laboratory predictors of impending relapse, Wright et al determined that orosomucoid and a1-antitrypsin levels increased between 3 months and 1 month before a relapse.106 Again, the predictive index was developed only retrospectively and not validated prospectively. Louis et al conducted a similar study in 36 patients with inactive CD and found (retrospectively) that a high serum level of IL-6 was highly predictive of relapse within 1 year. Serum orosomucoid or soluble IL-2 receptor levels were similarly elevated in these patients.107 Likewise, another study using the same retrospective 12- to 18month design was performed in 71 patients with CD by GETAID, with strong predictive value being noted for both increased ESR and CRP.108
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In addition, the potential role of fecal biomarkers is being widely investigated as a predictor of clinical relapse of IBD,60,87,109–111 and more specifically as a surrogate for endoscopic assessment of postoperative recurrence of CD,82,83,112 as well as for assessment of response to therapy,113 as discussed immediately below.
Treatment Response or Outcome Surrogate markers are often sought as indicators of treatment-induced endoscopic healing.114 Almost 20 years ago, it was noted that high CRP and stool frequency were fairly reliable predictors of failure of medical therapy in severe UC.115 In severe attacks of UC, high CRP along with high stool frequency and lowserum albumin have been associated with higher likelihood of failure of medical therapy.113 The same predictive value of CRP seems to be true for CD as well.116 High CRP 1 year after diagnosis of either UC or CD has also been reported to be a predictive factor for surgery within the subsequent 4 years.117 An international multicenter study of 128 children with UC found that CRP was a better predictor of short-term outcome than either ESR or albumin; but it is somewhat sobering to note that various clinical indicators performed even better in this regard than any blood test.118 Indeed, it had already been determined in the early development of the pediatric UC activity index that laboratory components like CRP did not add much benefit to the clinical components.119 Regarding effect of treatment on serum biomarkers, it is noteworthy that in one study clinical improvement and a decrease in serum orosomucoid (and haptoglobin) levels were both noted 1 month after a single infusion of Infliximab. These laboratory markers were increased 5 months later. However, there was no subsequent follow-up report of clinical outcome reported.120 In any event, it is evident that CRP is becoming a standard measurement for both prediction and assessment of response to therapeutic agents.121–123 In fact, both CRP and fecal calprotectin are being increasingly used as predictors of long-term response to therapy in IBD.124 Moreover, the emerging concept of “treatmentto-target” (setting objective therapeutic goals shown to correlate with best long-term clinical outcomes) demands “new goals and indices to prevent disability and improve quality of life.”125 Indeed, the growing focus on mucosal healing and treatment to target has emerged largely in recognition of the often poor correlation between purely clinical “indices” and objective signs of inflammation in CD.126 The treat-to-target movement has gained further impetus from the mounting evidence that mucosal healing is an important endpoint (or “target”) in predicting favorable clinical outcomes in patients with IBD.126,127
Complications Almost 30 years ago, a British study noted that patients with CD with serologic profile that included an ESR .45 mm/h, a CRP .33 mg/L, an orosomucoid .1.8 gm/L, and an albumin ,2.7 gm/L turned out to have intra-abdominal abscesses at surgery with a specificity .95% and sensitivity .35%.128 Today, we would presumably have additional radiologic tools to further substantiate this diagnosis.
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CONCLUSIONS 1. Serum orosomucoid, ESR, and especially CRP seem to have earned a well-established niche as indicators of at least systemic inflammatory activity in IBD, with some variation depending on category, anatomic location, and complications of the disease. 2. Fecal markers, primarily calprotectin, have also achieved a prominent, and perhaps even predominant, position among indicators of intestinal inflammation in the study of IBD. 3. IBD serum biomarkers cannot yet be consistently relied on as substitutes for interval endoscopic or histologic assessments of disease activity, although fecal calprotectin is showing promise for this purpose. 4. Validated biomarkers should be measured along with other proposed new markers of clinical, endoscopic, or histologic disease activity in efforts to determine whether the new markers provide clinicians with incremental benefit over more traditional measures in their efforts to improve management of their patients with IBD. 5. Any future studies of biomarkers should have clearly stated goals as to the use(s) for which the biomarkers are intended (e.g., diagnosis, assessment, or prognosis).
ACKNOWLEDGMENTS This article has been read and approved by the Biomarkers Task Force of the IOIBD. The author gratefully acknowledges the many suggestions and references offered by them and other members of the IOIBD, as well as those provided by the 2 anonymous reviewers of the article. This publication is dedicated to the memory of Dr. Lloyd Mayer.
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54. Yang L, Ge ZZ, Gao YJ, et al. Assessment of capsule endoscopy scoring index, clinical disease activity, and C-reactive protein in small bowel Crohn’s disease. J Gastroenterol Hepatol. 2013;28:829–833. 55. Peyrin-Biroulet L, Reinisch W, Colombel JF, et al. Clinical disease activity, C-reactive protein normalisation and mucosal healing in Crohn’s disease in the SONIC trial. Gut. 2014;63:88–95. 56. Stjernman H, Tysk C, Almer S, et al. Factors predicting the outcome of disease activity assessment in Crohn’s disease. Inflamm Bowel Dis. 2009;15:1859–1866. 57. Crama-Bohbouth G, Peña AS, Biemond I, et al. Are activity indices helpful in assessing active intestinal inflammation in Crohn’s disease? Gut. 1989;30:1236–1240. 58. Cellier C, Sahmoud T, Froguel E, et al. Correlations between clinical activity, endoscopic severity, and biological parameters in colonic or ileocolonic Crohn’s disease: a prospective multicentre study of 121 cases. Gut. 1994;35:231–235. 59. Denis MA, Reenaers C, Fontaine F, et al. Assessment of EAI and biological inflammatory markers in clinically active Crohn’s disease with normal C-reactive protein serum level. Inflamm Bowel Dis. 2007; 13:1100–1105. 60. af Bjorkesten CG, Nieminen U, Turunen U, et al. Surrogate markers and clinical indices, alone or combined, as indicators for endoscopic remission in anti-TNF treated luminal Crohn’s disease. Scand J Gastroenterol. 2012;47:528–537. 61. Lu H, Lian L, Navaneethan U, et al. Clinical utility of C-reactive protein in patients with ileal pouch anal anastomosis. Inflamm Bowel Dis. 2010; 16:1678–1684. 62. Weldon MJ, Masoomi AM, Britten AJ, et al. Quantification of inflammatory bowel disease activity using technetium-99m HMPAO labelled leucocyte single photon emission computerised tomogrpahy (SPECT). Gut. 1995;36:243–250. 63. Scholmerich J, Schmidt E, Schümichen C, et al. Scintigraphic assessment of bowel involvement and disease activity in Crohn’s disease using technetium 99m-hexamethyl propylene amine oxime as leukocyte label. Gastroenterology. 1988;95:1287–1293. 64. Fischbach W, Becker W. Clinical relevance of activity parameters in Crohn’s disease estimated by the faecal excretion of 111In-labeled granulocytes. Digestion. 1991;50:149–152. 65. Charron M. Temporal correlation of the erythrocytic sedimentation rate with Tc-99m WBC uptake on children with inflammatory bowel diseases. Clin Nucl Med. 2003;28:905–907. 66. Karbach U, Ewe K, Bodenstein H. Alpha-1-antitrypsin, a reliable endogenous marker for intestinal protein loss and its application in patients with Crohn’s disease. Gut. 1983;24:718–723. 67. Meyers S, Wolke A, Field SP, et al. Fecal alpha-1-antitrypsin measurement: an indicator of Crohn’s disease activity. Gastroenterology. 1985; 89:13–18. 68. Meyers S, Lichtiger S, Feuer EJ, et al. Fecal alpha-1-antitrypsin as a measure of Crohn’s disease activity: the effect of therapy and anatomical extent of disease. J Clin Gastroenterol. 1988;10:491–497. 69. Boirivant M, Pallone F, Ciaco A, et al. Usefulness of fecal alpha 1-antitrypsin clearance and fecal concentration as early indicator of postoperative asymptomatic recurrence in Crohn’s disease. Dig Dis Sci. 1991;36:347–352. 70. Nakarai A, Kato J, Hiraoka S, et al. Evaluation of mucosal healing of ulcerative colitis by a quantitative fecal immunochemical test. Am J Gastroenterol. 2013;108:83–89. 71. Kopylov U, Rosenfeld G, Bressler B, et al. Clinical utility of fecal biomarkers for the diagnosis and management of inflammatory bowel disease. Inflamm Bowel Dis. 2014;20:742–756. 72. Konikoff MR, Denson LA. Role of fecal calprotectin as a biomarker of intestinal inflammation in inflammatory bowel disease. Inflamm Bowel Dis. 2006;12:524–534. 73. Rogler G, Aldeguer X, Kruis W, et al. Concept for a rapid point-of-care calprotectin diagnostic test for diagnosis and disease activity monitoring in patients with inflammatory bowel disease: expert clinical opinion. J Crohns Colitis. 2013;7:670–677. 74. Vieira A, Fang CB, Rolim EG, et al. Inflammatory bowel disease activity assessed by fecal calprotectin and lactoferrin: correlation with laboratory parameters, clinical, endoscopic and histological indexes. BMC Res Notes. 2009;2:221–227.
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75. Walker TR, Land ML, Kartashov A, et al. Fecal lactoferrin is a sensitive and specific marker of disease activity in children and young adults with inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2007;44: 414–422. 76. Canani RB, Terrin G, Rapacciuolo L, et al. Faecal calprotectin as reliable non-invasive marker to assess the severity of mucosal inflammation in children with inflammatory bowel disease. Dig Liver Dis. 2008;40:547–553. 77. Benitez JM, Meuwis MA, Reenaers C, et al. Role of endoscopy, crosssectional imaging and biomarkers in Crohn’s disease monitoring. Gut. 2013;62:1806–1816. 78. Schoepfer AM, 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;105:162–169. 79. Langhorst J, Eisenbruch S, Koelzer J, et al. Noninvasive markers in the assessment of intestinal inflammation in inflammatory bowel diseases: performance of fecal lactoferrin, calprotectin, and PMN-elastase, CRP, and clinical indices. Am J Gastroenterol. 2008;103:162–169. 80. Laharie D, Mesli S, El Hajbi F, et al. Prediction of Crohn’s disease relapse with faecal calprotectin in infliximab responders: a prospective study. Aliment Pharmacol Ther. 2011;34:462–469. 81. Lamb CA, Mohiuddin MK, Gicquel J, et al. Faecal calprotectin or lactoferrin can identify postoperative recurrence in Crohn’s disease. Br J Surg. 2009;96:663–674. 82. Orlando A, Modesto I, Castiglione F, et al. The role of calprotectin in predicting endoscopic post-surgical recurrence in asymptomatic Crohn’s disease: a comparison with ultrasound. Eur Rev Med Pharmacol Sci. 2006;10:17–22. 83. Scarpa M, D’Incà R, Basso D, et al. Fecal lactoferrin and calprotectin after ileocolonic resection for Crohn’s disease. Dis Colon Rectum. 2007; 50:861–869. 84. Sipponen T, Savilahti E, Kolho KL, 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;14:40–46. 85. Sipponen T, Björkesten CG, Färkkilä M, et al. Faecal calprotectin and lactoferrin are reliable surrogate markers of endoscopic response during Crohn’s disease treatment. Scand J Gastroenterol. 2010;45:325–331. 86. D’Haens G, Ferrante M, Vermeire S. Fecal calprotectin is a surrogate marker for endoscopic lesions in inflammatory bowel disease. Inflamm Bowel Dis. 2012;18:2218–2224. 87. Wagner M, Peterson CG, Ridefelt P, et al. Fecal markers of inflammation used as surrogate markers for treatment outcome in relapsing inflammatory bowel disease. World J Gastroenterol. 2008;14:5584–5589. 88. Mao R, Xiao YL, Gao X, et al. Fecal calprotectin in predicting relapse of inflammatory bowel disease: a meta-analysis of prospective studies. Inflamm Bowel Dis. 2013;18:1894–1897. 89. Faubion WA Jr, Fletcher JG, O’Byrne S, et al. EMerging BiomARKers in Inflammatory Bowel Disease (EMBARK) study identifies fecal calprotectin, serum MMP9, and serum IL-22 as a novel combination of biomarkers for Crohn’s disease activity: role of cross-sectional imaging. Am J Gastroenterol. 2013;109:1891–1900. 90. Yang CH, Chen XY, Yang F, et al. Correlation of C-reactive protein with activity of Crohn’s disease. Zhonghua Yi Xue Za Zhi. 2006;16:1253–1255. 91. Chambers RE, Stross P, Barry RE, et al. Serum amyloid A protein compared with C-reactive protein, alpha 1-antichymotrypsin and alpha 1-acid glycoprotein as a monitor of inflammatory bowel disease. Eur J Clin Invest. 1987;17:460–467. 92. Niederau C, Backmerhoff F, Schumacher B, et al. Inflammatory mediators and acute phase proteins in patients with Crohn’s disease and ulcerative colitis. Hepatogastroenterology. 1997;44:90–107. 93. Louis E, Belaiche J, Van Kemseke C, et al. Soluble interleukin-2 receptor in Crohn’s disease: assessment of disease activity and prediction of relapse. Dig Dis Sci. 1995;40:1750–1756. 94. Zielen S, Bender SW, Kreuz W. Crohn’s disease activity: assessment by Factor VIII coagulation proteins. J Pediatr Gastroenterol Nutr. 1985;4: 730–734. 95. Oruc¸ N, Ozütemiz O, Osmanoglu N, et al. Diagnostic value of serum procalcitonin in determining the activity of inflammatory bowel disease. Turk J Gastroenterol. 2009;20:9–12.
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96. Oussalah A, Laurent V, Bruout O, et al. Additional benefit of procalcitonin to C-reactive protein to assess disease activity and severity for patients with Crohn’s disease. Aliment Pharmacol Ther. 2010;32:1135–1144. 97. Kolho KL, Valtonen E, Rintamaki H, et al. Soluble urokinase plasminogen activator receptor suPAR as a marker for inflammation in pediatric inflammatory bowel disease. Scand J Gastroenterol. 2012; 47:951–955. 98. Kofla-Dlubacz A, Matusiewicz M, Krzystek-Korpacka M, et al. Correlation of MMP-3 and MMP-9 with Crohn’s disease activity in children. Dig Dis Sci. 2012;57:706–712. 99. D’Agostino L, Daniele B, Pallone F, et al. Postheparin plasma diamine oxidase in patients with small bowel Crohn’s disease. Gastroenterology. 1988;95;1503–1509. 100. Park JJ, Cheon JH, Kim BY, et al. Correlation of serum-soluble triggering receptor expressed on myeloid cells-1 with clinical disease activity in inflammatory bowel disease. Dig Dis Sci. 2009;54: 1525–1531. 101. Sachar DB. Predicting relapses of Crohn’s disease: clouds in the crystal ball (editorial). Dig Dis Sci. 1987;32:206–208. 102. Beaugerie L, Sokol H. Clinical, serological and genetic predictors of inflammatory bowel disease course. World J Gastroenterol. 2012;18: 3806–3813. 103. Solberg IC, Lygren I, Cvancarova M, et al. Predictive value of serologic markers in a population-based Norwegiam cohort with inflammatory bowel disease. Inflamm Bowel Dis. 2009;15:406–414. 104. Brignola C, Campieri M, Bazzocchi G, et al. A laboratory index for predicting relapse in asymptomatic patients with Crohn’s disease. Gastroenterology. 1986;91:1490–1494. 105. Brignola C, Campieri M, Farruggia P, et al. The possible utility of steroids in the prevention of relapses of Crohn’s disease in remission: a preliminary study. J Clin Gastroenterol. 1988;10:631–634. 106. Wright JP, Young GO, Tigler-Wybrandi N. Predictors of acute relapse of Crohn’s disease: a laboratory and clinical study. Dig Dis Sci. 1987;32: 164–170. 107. Louis E, Belaiche J, van Kemseke C, et al. A high serum concentration of interleukin-6 is predictive of relapse in quiescent Crohn’s disease. Eur J Gastroenterol Hepatol. 1997;9:939–944. 108. Consigny Y, Modigliani R, Colombel JF, et al. A simple biological score for predicting low risk of short-term relapse in Crohn’s disease. Inflamm Bowel Dis. 2006;12:551–557. 109. García-Sánchez V, Iglesias-Flores E, González R, et al. Does fecal calprotectin predict relapse in patients with Crohn’s disease and ulcerative colitis? J Crohns Colitis. 2010;4:144–152. 110. Kallel L, Ayadi I, Matri S, et al. Fecal calprotectin is a predictive marker of relapse in Crohn’s disease involving the colon: a prospective study. Eur J Gastroenterol Hepatol. 2010;22:340–345. 111. Gisbert JP, Bermejo F, Pérez-Calle JL, et al. Fecal calprotectin and lactoferrin for the prediction of inflammatory bowel disease relapse. Inflamm Bowel Dis. 2009;15:1190–1198. 112. Biancone L, Onali S, Calabrese E, et al. Non-invasive techniques for assessing postoperative recurrence in Crohn’s disease. Dig Liver Dis. 2008;40(suppl 2):S265–S270. 113. Gelbmann CM. Prediction of treatment refractoriness in ulcerative colitis and Crohn’s disease—do we have reliable markers? Inflamm Bowel Dis. 2006;6:123–131. 114. Daperno M, Castiglione F, de Ridder L, et al. Results of the 2nd part Scientific Workshop of the ECCO. II: measures and markers of prediction to achieve, detect, and monitor intestinal healing in inflammatory bowel disease. J Crohns Colitis. 2011;5:484–498. 115. Travis SP, Farrant JM, Ricketts C, et al. Predicting outcome in severe ulcerative colitis. Gut. 1996;38:905–910. 116. Magro F, Rodrigues-Pinto E, Santos-Antunes J, et al. High C-reactive protein in Crohn’s disease patients predicts nonresponse to infliximab treatment. J Crohns Colitis. 2014:8:129–136. 117. Henriksen M, Jahnsen J, Lygren I, et al. C-reactive protein: a predictive factor and marker of inflammation in inflammatory bowel disease. Results from a prospective population-based study. Gut. 2008;57: 1518–1523. 118. Turner D, Mack D, Leleiko N, et al. Severe paediatric ulcerative colitis: a prospective multicenter study of outcomes and predictors of response. Gastroenterology. 2010;138:2282–2291. www.ibdjournal.org |
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119. Turner D, Hyams J, Markowitz J, et al. Appraisal of the pediatric ulcerative colitis activity index (PUCAI). Inflamm Bowel Dis. 2009;15:1218–1223. 120. Kupcova V, Turecky L, Detkova Z, et al. Changes in acute phase proteins after anti-tumor necrosis factor antibody (infliximab) treatment in patients with Crohn’s disease. Physiol Res. 2003;52:89–93. 121. Toedter GP, Blank M, Lang Y, et al. Relationship of C-reactive protein with clinical response after therapy with ustekinumab in Crohn’s disease. Am J Gastroenterol. 2009;104:2768–2773. 122. Reinisch W, Wang Y, Oddens BJ, et al. C-reactive protein, an indicator for maintained response or remission to infliximab in patients with Crohn’s disease: a post-hoc analysis from ACCENT I. Aliment Pharmacol Ther. 2012;35:568–576. 123. Hibi T, Sakuraba A, Watanabe M, et al. C-reactive protein is an indicator of serum infliximab level in predicting loss of response in patients with Crohn’s disease. J Gastroenterol. 2014;49:254–262.
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124. Robin X, Cavaille A, Clavel L, et al. Intérêt des biomarqueurs dans la prise en charge des MICI. Presse Med. 2014;43:66–73. 125. Hommes D, Colombel JF, Emery P, et al. Changing Crohn’s disease management: need for new goals and indices to prevent disability and improve quality of life. J Crohns Colitis. 2012;6(suppl 2): S224–S234. 126. Pineton de Chambrun G, Peyrin-Biroulet L, Lémann M, et al. Clinical implications of mucosal healing for the outcome of IBD. Nat Rev Gastroenterol Hepatol. 2010;7:15–29. 127. Froslie KF, Jahnsen J, Moum BA, et al. Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology. 2007;133:412–422. 128. Pettit SH, Holbrook IB, Irving MH. Comparison of clinical scores and acute phase proteins in the assessment of acute Crohn’s disease. Br J Surg. 1985;72:1013–1016.
Role of Biomarkers in the Study and Management of Inflammatory Bowel Disease: A “Nonsystematic” Review David B. Sachar, MD; for the Biomarkers Task Force of the IOIBD
(Inflamm Bowel Dis 2014;20:2511–2518) Key Words: biomarkers, C-reactive protein, fecal calprotectin
A
tool cannot be evaluated unless its purpose is known. This axiom is as applicable to the study of biomarkers as to any other instrument. In the case of inflammatory bowel disease (IBD), biomarkers are typically used by clinicians to serve any of 3 principal functions: diagnosis, interval assessment, or prognosis. The intense interest in biomarkers has been prompted largely by the failure of purely “clinical” indices to fulfill these purposes consistently and reliably.1 In this IOIBD Task Force White Paper, I shall review the data concerning the relative utility of 3 of the oldest, simplest, and most widely used biomarkers, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and orosomucoid (alpha-1 acid glycoprotein), as well as newer fecal markers (primarily calprotectin and lactoferrin) to fulfill each of these functions in the management of patients with IBD. It is the intent of this review to focus on fluctuating biomarkers that are reflective of the ongoing state of inflammatory activity, rather than the familiar and emerging serologic antibodies like ASCA, ANCA, anti-cBir1, and the like, a whole subject in itself.2
assessment of their patients with known or suspected IBD, including stool analysis for lactoferrin, calprotectin, or leukocyte elastase4–7 and the serologic markers pANCA, ASCA, OmpC, and anti-CBir-1,8,9 and other biochemical assays.10 ESR and CRP, in particular, have provided physicians with readily obtainable and reliable objective data that they can use to further refine their clinical impressions at a point even before consideration of more advanced studies. As long ago as the 1980s, it was well established that ESR and CRP were useful in distinguishing patients with inflammatory and infectious bowel diseases from those with functional disorders.11–13 Likewise, fecal calprotectin has recently proved useful in the diagnosis of suspected adult and pediatric IBD as well as in predicting relapses of IBD14 (Fecal markers are discussed in more detail on the “Assessment” section below). Indeed, the combination of history, physical examination, ESR, CRP, and occult fecal blood seems to be so reliable in making the distinction between irritable bowel syndrome and IBD that some argue that more complex or invasive studies seem to have little if any incremental value in the differential diagnosis of functional from organic bowel disease.15
DIAGNOSIS Although there is a substantial literature regarding the role of biomarkers in differentiating IBD from functional bowel disorders, recently masterfully reviewed by Lewis,3 in practice, this distinction can most often be made by a careful history and physical examination. In certain instances, though, the differential diagnosis between IBD and irritable bowel syndrome may require more advanced diagnostic tools, such as endoscopy, radiology, histology, or stool tests. Several sophisticated laboratory assays have also been proposed to assist clinicians in the diagnosis and interval Received for publication June 4, 2014; Accepted June 5, 2014. From the Dr. Henry Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York. The author has no conflicts of interest to disclose. Reprints: David B. Sachar, MD, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, New York, NY 10029 (e-mail: [email protected]). Copyright © 2014 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/MIB.0000000000000135 Published online 12 September 2014.
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ASSESSMENT The role of various biomarkers is much murkier when it comes to assessing the “activity” of Crohn’s disease (CD) or ulcerative colitis (UC) in patients.16 Here, the confusion often arises from the lack of a consensus “gold standard” of disease activity against which to measure the utility of a specific biomarker. Studies evaluating particular biomarkers for assessing clinical or inflammatory activity have therefore revolved primarily around defining the statistical correlation(s) between the candidate marker and other yardsticks of clinical disease activity and mucosal inflammation, including previously validated disease activity metrics, such as the Crohn’s Disease and Harvey–Bradshaw activity indices (CDAI and HBAI, respectively), endoscopic appearance, radionuclide excretion, fecal markers, and other parallel serum reactants (Table 1). On the whole, ESR, CRP, and orosomucoid have performed remarkably well in many of these correlative studies. www.ibdjournal.org |
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TABLE 1. Reference Numbers for Articles Showing Positive Correlations Clinical Activity and Outcomes CRP Fecal calprotectin Clinical activity and outcomes
References 4,11–13,19–21,29,31–35,39–41,44,48–55,77,80– 87,89,108,113,115,117,118,121–123,127 References 4,5,7,13,14,60,72,77–79,87,109–111 NA
Clinical Activity Indices Most attention, understandably, has focused on defining the correlation between proposed IBD biomarkers and standard clinical disease activity indices.17,18 Clearly, a prime goal of introducing objective biomarkers into the equation of clinical assessment is to detect subclinical inflammation while at the same time avoiding confusion between inflammatory activity and symptoms superimposed irritable bowel syndrome. An early seminal study of this subject came from France over 30 years ago.19 In an assessment of 11 laboratory markers among 54 patients with CD, André et al noted that only 3 measures, orosomucoid, ESR, and CRP, had statistically significant associations with clinical indices (CDAI, Harvey–Bradshaw, and van Hees). Ironically, of all of the markers that were studied, the parameter with the least robust correlation with disease activity indices was the hematocrit, the only laboratory measurement that had been included in the CDAI! A 1992, a German study came to the same conclusion.20 Analysis of 6 serologic biomarkers obtained from 75 consecutive hospitalized patients with CD found that hematocrit displayed the poorest correlation with clinical (CDAI, van Hees) and endoscopic indices. Although these investigators noted that serum cholinesterase seemed to have the highest correlation with endoscopic findings, ESR and CRP also performed well. Indeed, as long as 25 years ago, French investigators reported that the serologic biomarkers displaying the best correlations with clinical disease activity in patients with CD were, in decreasing order, orosomucoid, ESR, and CRP.21 Confirmatory observations have been published for CRP in adults in Tunisia22 and for children in Australia,23 for orosomucoid in children in the United Kingdom24 and in patients in Croatia25 and England,26 and for ESR in children all across North America.27 A biochemically oriented article from the United Kingdom reported that orosomucoid had an overall predictive value of 82.5% for discerning IBD activity.28 A French study has also shown that CRP correlates well with CDAI, although not as well as urinary neopterin.29 More recently, there has been an increased interest in highsensitivity CRP.30 It is noteworthy that a recent Finnish study found no incremental benefit from the use of high-sensitivity CRP over that of standard CRP in children.31 It is important to note that the tightness and even the direction of these correlations may vary when a given marker is used to study patients with either UC or CD, when evaluating
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Endoscopy References 20,44,48–55,77 References 7,14,77,82,83,88,112 References 20,126
patients with mucosal inflammation in different anatomic locations and even when different types of treatment are used. For example, several studies have suggested a trend for closer correlation between clinical activity and CRP in patients with CD and with ESR in those with UC.24,32–35 Similarly, Sachar et al have reported that the correlation of ESR with clinical activity depended on the extent of colonic involvement in both UC and CD,36 and that the association was inverse in cases of CD confined to the small bowel.37 Both of these findings have been confirmed in more recent scintigraphy studies.38 Others have also suggested a difference between clinical correlations with CRP between UC and CD,39 although this difference has not been observed with the use of high-sensitivity CRP.40 It has also been reported that effective antimetabolite treatment in children may normalize the CRP, whereas the ESR remains elevated,41 perhaps because ESR can be elevated for reasons other than inflammation. Indeed, regarding different mechanisms underlying the expression of different acute phase reactants, it is of interest that recent studies from France are pointing to the role of adipose tissue both in the pathogenesis of inflammation and in the synthesis of CRP.42 These observations all underscore the importance of “clinical phenotyping” before broadly defining the relevance of a particular biomarker for use in assessing patients with IBD.43
Endoscopy Published studies of the correlation between serologic biomarkers and endoscopic findings are inconsistent, to say the least. A study from Spain reported an excellent correlation between ESR and CRP with both clinical and endoscopic indices in UC but not in CD.44 One British study noted only a modest association between CRP (but not orosomucoid) and endoscopic activity in UC and CD,45 while an earlier study from England found virtually no correlation between ESR or CRP and either colonoscopic or histologic activity in Crohn’s colitis.46 Similarly, a Swedish study of 60 patients with ulcerative and Crohn’s colitis found poor correlations between laboratory and endoscopic findings, except for elevated orosomucoid only in patients with UC with severe and extensive lesions.47 A more recent Belgian study has noted that if patients with clinically active CD have normal CRP, they are not likely to have severe endoscopic lesions irrespective of their ESR or orosomucoid levels.48 More encouraging data regarding the use of CRP in patients with IBD were published from the Mayo Clinic in 2005. These
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investigators reported significant associations of elevated CRP with clinical, colonoscopic, and histologic activity in 104 patients with CD and with clinical and endoscopic activity as well as with high ESR in 43 patients with UC.49 Several studies have reported that CRP was a good predictor of endoscopic inflammation in UC50–53 and CD,54 and this year, a subanalysis of the SONIC data has demonstrated the correlation of reduction in CRP with mucosal healing seen on endoscopy.55 However, other studies from Sweden,56 the Netherlands,57 France,58 Belgium,59 and Finland60 have found only weak or absent correlations of CRP, ESR, and orosomucoid with clinical or endoscopic indices. The French investigators concluded that the extent of clinical disease activity in patients with CD seems to be virtually independent of both the severity of the mucosal lesions observed at endoscopy and value of biological measures, including ESR and CRP.58 Likewise, in a Cleveland Clinic study, there was only limited clinical utility to a “snapshot” measurement of CRP in distinguishing normal from inflamed ileal pouches after total proctocolectomy for UC.61 The prospects would therefore seem dim for any of these serum biomarkers to gain general acceptance as reliable substitutes or surrogate markers for endoscopy or histology.
Radionuclide Excretion The inconsistencies between blood biomarkers and tissue damage seen at endoscopy have been mirrored in studies using radionuclide excretion. Two studies using technetium-99m HMPAO SPECT found poor correlations between certain blood indicators, like ESR and CRP, and radionuclide results, particularly in small bowel CD.62,63 However, another study reported good correlation between indium-111 and orosomucoid, ESR and CRP levels in 58 patients with CD,64 while planar imaging with technetium-99m white blood cells was said to show good correlation with ESR in children with CD but not UC.65 Overall, though, it would seem that existing serologic biomarkers cannot be relied on to consistently reflect radionuclide-measured mucosal disease activity.
Fecal Markers Interest in fecal levels of stable serum proteins as markers of inflammatory activity date back over 30 years, with studies of fecal a-1-antitrypsin concentrations66–68 and clearances.69 Much more recently, Japanese investigators have studied fecal immunochemical testing as an assay of mucosal healing in UC.70 Canadian researchers this year have also reviewed in considerable detail the clinical utility of a range of fecal biomarkers, including calprotectin, lactoferrin, S100A12, pyruvate kinase, and matrix metalloproteinases.71 By far the 2 most widely studied fecal markers of inflammation, however, are calprotectin and lactoferrin. A large number of studies have been published regarding their correlation with clinical disease activity indices in IBD,72,73 and some of these studies can be consulted for information on their association with laboratory, endoscopic, and histologic markers as well.74 For example, a 2007 study from Boston reported a significant
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correlation between fecal lactoferrin and ESR in 62 children with UC and 79 with CD.75 More recently, however, data from an Italian study of 58 children with IBD showed a significant correlation of ESR (but not CRP) with clinical score, histologic grading, and fecal calprotectin only in the 26 patients with CD.76 Most recently, Benitez et al77 in Belgium reported a close correlation of CRP and fecal calprotectin with endoscopic lesions, response to therapy, and the risk of relapse. However, a Swiss study of 122 patients with UC found that fecal calprotectin correlated more closely with the simplified endoscopic score for CD than did CRP or the CDAI.78 Similarly, a German report indicates the superiority of fecal markers over CRP in correlating with endoscopic activity.79 Therefore, if one were to accept fecal markers as a “gold standard” of mucosal inflammation in patients with IBD, one would have to conclude with the Italian investigators that “CRP and ESR could not be accurate predictors of active intestinal inflammation in children with IBD.”76 Studies evaluating the utility fecal biomarkers in the interval assessment of children and adults with IBD have clearly evolved. Preliminary studies were qualitative and demonstrated elevated absolute levels of these biomarkers in patients with either active CD or UC ongoing “Second-generation” studies, however, are currently addressing how these fecal biomarkers can provide clinicians with more detailed information to optimize pharmacologic therapy and to predict disease flares and complications.80–87 Indeed, the thrust of interest in markers of inflammatory activity in IBD in the past few years has focused increasingly on fecal calprotectin, especially as a surrogate for endoscopic evaluation of impending postoperative relapse of CD.7,14,88 A recent and particularly ambitious evaluation by investigators at the Mayo Clinic of a range of markers, called the EMBARK study, has once again given high grades to CRP in combination with 2 more novel serum indicators, matrix metalloproteinase 9 and IL-22, particularly as correlated with cross-sectional imaging.89
Miscellaneous Indicators The number of proposed blood, urine, fecal, and tissue markers for IBD activity is almost countless. I shall cite only a few of them in this section for the purpose of reviewing how well they correlate with orosomucoid, ESR, or CRP. One study reports a correlation of CRP elevation with NFkappaB p65 expression in colonic tissues.90 One study reports a good correlation between CRP and serum amyloid A, with a higher specificity (100%) for the former.91 One study reports a better correlation of disease activity with serum amyloid A and circulating IL-6 than with either CRP or ESR.92 One study reports favorably on the correlation of soluble IL-2 receptor with clinical activity of CD, but indicates that the correlation was not greater than that with ESR.93 One study reports a high correlation between the van Hees activity index in CD and Factor VIII coagulation proteins, but the correlation was also high with orosomucoid, ESR, and CRP.94 One study evaluated serum procalcitonin as a marker for IBD activity but found that CRP was superior,95 although a more recent study reported that the combination of www.ibdjournal.org |
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procalcitonin and CRP was superior to CRP alone for CD.96 One study favored soluble urokinase plasminogen activator receptor as an inflammatory marker in children with IBD.97 Also in children, serum matrix metalloproteinase levels have been proposed as markers of CD activity.98 An Italian report considered postheparin plasma diamine oxidase as a marker of small bowel inflammation in CD.99 One study found serum-soluble triggering receptor expressed on myeloid cells-1 to be more closely correlated with UC (but not CD) activity than either ESR or CRP, although the latter correlations were also highly significant.100 The point of this superficial and somewhat arbitrary review of a wide variety of markers proposed over the years as indicators of IBD activity is not to make a brief either for or against any of their merits, but rather to provide a sense of the panoply of candidates proposed for the “holy grail” of IBD, namely, a single measurable number to provide objective quantitation of the elusive entity of “disease activity.”
PROGNOSIS Prediction of clinical course and outcome is every bit as important as differential diagnosis and activity assessment.101 For the past 20 years, therefore, investigators have sought laboratory predictors for relapse, treatment response, or complications.102 Indeed, there is already a vast literature, too extensive to review here, seeking associations between serologic markers and phenotypes and outcomes of CD and UC.103
Relapse Most of these prognostic efforts have focused on predicting relapse. One of the first attempts to develop a laboratory index for predicting clinical relapse in asymptomatic patients with CD was reported by Brignola et al.104 The serum orosomucoid and ESR, as well as a2 globulin, proved remarkably accurate (88%) in predicting a relapse within 18 months, although it must be said that this index was developed from a retrospective cohort and not tested prospectively in this study. To their credit, however, these investigators did subsequently apply their index to a prospective cohort, in whom there was indeed a very high relapse rate that was delayed but not prevented by the prophylactic administration of prednisolone.105 In a similar effort to identify laboratory predictors of impending relapse, Wright et al determined that orosomucoid and a1-antitrypsin levels increased between 3 months and 1 month before a relapse.106 Again, the predictive index was developed only retrospectively and not validated prospectively. Louis et al conducted a similar study in 36 patients with inactive CD and found (retrospectively) that a high serum level of IL-6 was highly predictive of relapse within 1 year. Serum orosomucoid or soluble IL-2 receptor levels were similarly elevated in these patients.107 Likewise, another study using the same retrospective 12- to 18month design was performed in 71 patients with CD by GETAID, with strong predictive value being noted for both increased ESR and CRP.108
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In addition, the potential role of fecal biomarkers is being widely investigated as a predictor of clinical relapse of IBD,60,87,109–111 and more specifically as a surrogate for endoscopic assessment of postoperative recurrence of CD,82,83,112 as well as for assessment of response to therapy,113 as discussed immediately below.
Treatment Response or Outcome Surrogate markers are often sought as indicators of treatment-induced endoscopic healing.114 Almost 20 years ago, it was noted that high CRP and stool frequency were fairly reliable predictors of failure of medical therapy in severe UC.115 In severe attacks of UC, high CRP along with high stool frequency and lowserum albumin have been associated with higher likelihood of failure of medical therapy.113 The same predictive value of CRP seems to be true for CD as well.116 High CRP 1 year after diagnosis of either UC or CD has also been reported to be a predictive factor for surgery within the subsequent 4 years.117 An international multicenter study of 128 children with UC found that CRP was a better predictor of short-term outcome than either ESR or albumin; but it is somewhat sobering to note that various clinical indicators performed even better in this regard than any blood test.118 Indeed, it had already been determined in the early development of the pediatric UC activity index that laboratory components like CRP did not add much benefit to the clinical components.119 Regarding effect of treatment on serum biomarkers, it is noteworthy that in one study clinical improvement and a decrease in serum orosomucoid (and haptoglobin) levels were both noted 1 month after a single infusion of Infliximab. These laboratory markers were increased 5 months later. However, there was no subsequent follow-up report of clinical outcome reported.120 In any event, it is evident that CRP is becoming a standard measurement for both prediction and assessment of response to therapeutic agents.121–123 In fact, both CRP and fecal calprotectin are being increasingly used as predictors of long-term response to therapy in IBD.124 Moreover, the emerging concept of “treatmentto-target” (setting objective therapeutic goals shown to correlate with best long-term clinical outcomes) demands “new goals and indices to prevent disability and improve quality of life.”125 Indeed, the growing focus on mucosal healing and treatment to target has emerged largely in recognition of the often poor correlation between purely clinical “indices” and objective signs of inflammation in CD.126 The treat-to-target movement has gained further impetus from the mounting evidence that mucosal healing is an important endpoint (or “target”) in predicting favorable clinical outcomes in patients with IBD.126,127
Complications Almost 30 years ago, a British study noted that patients with CD with serologic profile that included an ESR .45 mm/h, a CRP .33 mg/L, an orosomucoid .1.8 gm/L, and an albumin ,2.7 gm/L turned out to have intra-abdominal abscesses at surgery with a specificity .95% and sensitivity .35%.128 Today, we would presumably have additional radiologic tools to further substantiate this diagnosis.
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CONCLUSIONS 1. Serum orosomucoid, ESR, and especially CRP seem to have earned a well-established niche as indicators of at least systemic inflammatory activity in IBD, with some variation depending on category, anatomic location, and complications of the disease. 2. Fecal markers, primarily calprotectin, have also achieved a prominent, and perhaps even predominant, position among indicators of intestinal inflammation in the study of IBD. 3. IBD serum biomarkers cannot yet be consistently relied on as substitutes for interval endoscopic or histologic assessments of disease activity, although fecal calprotectin is showing promise for this purpose. 4. Validated biomarkers should be measured along with other proposed new markers of clinical, endoscopic, or histologic disease activity in efforts to determine whether the new markers provide clinicians with incremental benefit over more traditional measures in their efforts to improve management of their patients with IBD. 5. Any future studies of biomarkers should have clearly stated goals as to the use(s) for which the biomarkers are intended (e.g., diagnosis, assessment, or prognosis).
ACKNOWLEDGMENTS This article has been read and approved by the Biomarkers Task Force of the IOIBD. The author gratefully acknowledges the many suggestions and references offered by them and other members of the IOIBD, as well as those provided by the 2 anonymous reviewers of the article. This publication is dedicated to the memory of Dr. Lloyd Mayer.
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