Clinicians’ guide to the use of fecal calprotectin to ...patients with inflammatory bowel disease (IBD) is an essential part of effective disease management. Specifically, it is

Can J Gastroenterol Hepatol Vol 29 No 7 October 2015 369

ORIgInal aRTIClE

©2015 Pulsus Group Inc. All rights reserved

Clinicians’ guide to the use of fecal calprotectin to identify and monitor disease activity in

inflammatory bowel diseaseBrian Bressler MD1, Remo Panaccione MD2, Richard N Fedorak MD3, Ernest G Seidman MD4

1Department of Medicine, Division of Gastroenterology, St Paul’s Hospital, Vancouver, British Columbia; 2Department of Medicine, University of Calgary, Calgary; 3Division of Gastroenterology, University of Alberta, Edmonton, Alberta; 4Division of Gastroenterology, McGill University Health Centre, Montreal, Quebec

Correspondence: Dr Brian Bressler, University of British Columbia, 1190 Hornby Street, Suite 770, Vancouver, British Columbia V6Z 2K5. Telephone 604-688-6332 ext 245, fax 604-689-2004, e-mail [email protected]

Received for publication March 8, 2015. Accepted May 9, 2015

Objective monitoring of the extent and severity of inflammation in patients with inflammatory bowel disease (IBD) is an essential part of effective disease management. Specifically, it is used to deter-mine whether new symptoms reflect a change in inflammatory activity and, thus, require an optimization of therapy. While direct endoscopic examination of mucosal inflammation is the gold standard, frequent endoscopy is not always practical or feasible. Therefore, the use of a surrogate biomarker, such as fecal calprotectin (FC), can provide sig-nificant advantages in the management of these patients.

In IBD, inflammation with infiltration of the intestinal mucosa by neutrophils and macrophages, leads to secretion of cytosolic proteins, which can be detected in stool (1). Calprotectin is a calcium and zinc-binding protein that constitutes 60% of neutrophil cytosolic protein (2).

It is stable in feces for up to one week at room temperature. Thus, FC may provide an accurate assessment of the inflammatory burden in the gut.

An ideal biomarker would effectively and accurately distinguish inflammatory from noninflammatory disease, correlate with endo-scopic inflammation, demonstrate response to therapy and predict relapse (1,3-7). In addition, the biomarker test would be readily avail-able, easy to use and affordable. FC meets many of these criteria, is available throughout Canada and has the potential to significantly enhance IBD care. However, although changes in FC demonstrate good sensitivity and specificity in IBD patients, clinicians should be aware that elevated FC levels may be found in several non-IBD condi-tions (Table 1) (1,3).

B Bressler, R Panaccione, RN Fedorak, EG Seidman. Clinicians’ guide to the use of fecal calprotectin to identify and monitor disease activity in inflammatory bowel disease. Can J Gastroenterol Hepatol 2015;29(7):369-372.

BACKGROUND: Objective monitoring of the severity of inflamma-tion in patients with inflammatory bowel disease (IBD) is an essential part of disease management. However, repeat endoscopy to define extent and severity of inflammation is not practical. Fecal calprotectin (FC) is a biomarker that can be used as a surrogate test to distinguish inflammatory from noninflammatory gastrointestinal disease.METHODS: A targeted search of the literature regarding FC, focusing primarily on the past three years, was conducted to develop practical clinical guidance on the current utility of FC in the routine manage-ment of IBD patients.RESULTS: It is recommended that samples for FC testing be obtained from the first bowel excretion of the day. FC testing should be used as standard of care to accurately confirm inflammation and ‘real-time’ dis-ease activity when a clinician suspects an IBD flare. Although FC is a reliable marker of inflammation, its role in routine monitoring in improving long-term outcomes has not yet been fully assessed. Based on available evidence, the authors suggest the following cut-off values and management strategies: when FC levels are 100 µg/g to 250 µg/g, inflammation is possible and further testing (eg, colonoscopy) is required to confirm inflammation; and when FC levels are >250 µg/g, active inflammation is likely and strategies to con-trol inflammation should be initiated (eg, optimizing current therapies or switching to an alternative therapy).DISCUSSION: FC is a useful biomarker to accurately assess the degree of inflammation and should be incorporated into the management of patients with IBD.

Key Words: Disease activity; Fecal calprotectin; Inflammatory bowel disease; Monitoring

Le guide du clinicien sur l’utilisation de la calprotectine fécale afin de déterminer et de surveiller l’activité des maladies inflammatoires de l’intestin

HISTORIQUE : Il est essentiel de surveiller objectivement la gravité des maladies inflammatoires de l’intestin (MII) dans le cadre de leur prise en charge. Cependant, il n’est pas pratique de faire une nouvelle endoscopie pour définir l’étendue et la gravité de l’inflammation. La calprotectine fécale (CF) est un biomarqueur qui peut remplacer l’endoscopie pour distinguer les maladies gastro-intestinales inflam-matoires de celles qui ne le sont pas.MÉTHODOLOGIE : Les chercheurs ont réalisé une analyse bib-liographique sur la CF axée sur les trois années précédentes afin de rédiger des orientations cliniques sur l’utilité de la CF dans la prise en charge habituelle des patients atteints d’une MII.RÉSULTATS : Pour effectuer les tests de CF, il est recommandé de prélever la première excrétion intestinale de la journée. Lorsqu’un clinicien craint une récidive de MII, les tests de CF doivent servir de norme de soins pour confirmer avec précision l’inflammation et l’activité de la maladie « en temps réel ». Même si la CF est un mar-queur fiable d’inflammation, son rôle dans la surveillance systématique en vue d’améliorer les résultats cliniques à long terme n’a pas encore été pleinement évalué. D’après les données disponibles, les auteurs pro-posent les valeurs seuils et les stratégies de prise en charge suivantes : lorsque les taux de CF sont sous les 50 µg/g à 100 µg/g, la maladie est probablement en rémission et le traitement doit être maintenu. Lorsque les taux de CF se situent entre plus de 100 µg/g et 250 µg/g, l’inflammation est possible et d’autres tests (p. ex., coloscopie) s’imposent pour confirmer l’inflammation. Enfin, lorsque les taux de CF sont supérieurs à 250 µg/g, l’inflammation active est probable, et il faut adopter des stratégies pour contrôler l’inflammation (p. ex., opti-misation des traitements en place ou transition vers un autre traite-ment).ExPOSÉ : La CF est un biomarqueur utile pour évaluer le degré d’inflammation avec précision. Elle devrait faire partie de la prise en charge des patients atteints d’une MII.

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Blood-based biomarkers, such as C-reactive protein (CRP) are often more acceptable, but they have limited sensitivity, with at least 50% of patients with active ulcerative colitis (UC) having normal CRP levels (8). CRP also has limited specificity, particularly in patients with infections, or rheumatoid or other autoimmune disorders (1). While CRP may be useful in some IBD patients, elevated FC levels demonstrate a significantly superior correlation with active dis-ease compared with CRP measurements (8-13).

The present user’s guide will outline the pragmatic elements a clin-ician should be aware of relating to the use of FC in practice.

When should samples be collected for FC testing?FC levels decrease with increasing time between bowel movements; therefore, it is recommended that samples be obtained from the first bowel movement of the day (14). Because of the day-to-day variability in FC levels (14), retrieving samples at similar times over two consecu-tive days is preferable.

What test should be used? The standard test to assess FC levels in IBD patients is the ELISA. This method has been used for >20 years, but is time consuming, labour intensive and requires specialized laboratory equipment (7,15). The Bühlmann Quantum Blue Reader (Alpco Immunoassays, USA) device offers an alternative method to the standard ELISA technique. It demonstrates an excellent correlation with standard ELISA assays and provides accurate results within 30 min (7). The ELISA method is cost-efficient for high throughput when running multiple samples simultaneously.

FC testing is available in all provinces in Canada, with the majority of tests being performed using ELISA. However, provincial funding is currently available only in Alberta and Quebec, while in other prov-inces, the cost must be covered by the patient or a third party.

Should FC levels be measured in asymptomatic IBD patients?Although FC is a reliable marker of inflammation, the role of routine monitoring of FC levels in clinically asymptomatic patients has not been fully assessed. It is not yet known whether a strategy of routine monitoring coupled with early optimization of therapy on detection of relapse would improve health outcomes (16,17). Nevertheless, this may be a clinically useful approach and warrants further investigation.

When should FC levels be measured, as the standard of care, to monitor IBD patients?In the context of a suspected flare, assessing FC levels enables accurate and expedient confirmation of inflammation and ‘real-time’ disease

activity. Several recent trials and meta-analyses have established that FC is an accurate surrogate marker of active endoscopic disease in IBD patients, with high sensitivity (70% to 100%) and specificity (44% to 100%) (8,13,18-21). In general, FC levels are highest among patients with active disease, less so in patients with quiescent disease and low-est in non-IBD control subjects (21).

What are the potential future applications of FC in IBD care?Routine use of FC levels to monitor risk for flare in quiescent IBD, response to treatment or postoperative recurrence is not currently recommended, although these indications do warrant further investigation.

Studies suggest that in patients with quiescent disease, serial FC measurements showing increasing levels may be useful to actively monitor the risk for flare (8,17,22,23). In one study involving 53 con-secutive IBD patients who were followed for 12 months (9), elevated FC levels (>340 µg/g) indicated an 18-fold higher risk for relapse (Figure 1). Conversely, reductions in FC levels have been associated with better response to treatment in IBD patients (24-27).

As a biomarker of inflammation, FC has been shown to be respon-sive to treatment intensification. A randomized trial involving patients with quiescent UC found that FC levels were lowered by increasing the dose of mesalamine (28). Moreover, relapse occurred sooner in patients with FC levels >200 µg/g compared with those with lower FC levels (P=0.01). This suggests that FC has a role in the mon-itoring of UC patients, one that enables the clinician to respond to elevated levels to prevent a clinical flare.

Using FC levels to monitor patients for postoperative recurrence could decrease the need for follow-up colonoscopy at six to 12 months and help optimize IBD outcomes. The predictive value of FC for pos-toperative recurrence has been established in patients who have undergone ileocolonic resection for Crohn disease (29-32). However, FC levels in the postoperative patient may not be as consistent as they are in other clinical situations (32).

How are test results interpreted?Suggested potential cut-off values and courses of action are provided in Figure 2; however, individual patient variability exists. Therefore, in a particular patient, rising FC levels over time are the best indicator of

TAble 1Factors and conditions associated with elevated fecal calprotectin levels (1,3)Infectious Inflammatory conditions•Bacterialdysentery •Inflammatoryboweldisease•Giardia lamblia •Autoimmuneenteropathy•Helicobacter pylori gastritis •Cirrhosis•Infectiousdiarrhea •Cysticfibrosis•Viralgastroenteritis •DiverticulitisNeoplasms •Eosinophiliccolitis/enteritis•Colonicandgastricpolyps •Gastroesophagealrefluxdisease•Colorectalcancer •Juvenilepolyp•Gastriccarcinoma •Microscopiccolitis•Intestinallymphoma •Pepticulcer

•UntreatedceliacdiseaseDrugs Other•NSAIDs •Age

Use of FC to identify and monitor disease activity in IbD

Can J Gastroenterol Hepatol Vol 29 No 7 October 2015 371

increased disease activity for that individual. Another approach to improve the reliability of FC testing would be to obtain a baseline FC level during a period of known active inflammation. An elevated FC level in this context will help clinicians determine whether this is a reli-able biomarker for monitoring inflammation in an individual patient.

Some controversy remains as to optimal cut-off values. Results vary depending on the specific test used (33). The sensitivity and specifi-city of FC as a marker for active disease was found to differ at various cut-off values. A meta-analysis of 13 studies (n=1471) compared cut-off FC levels of 50 µg/g, 100 µg/g and 250 µg/g, and found that with higher levels the sensitivity decreased, while the specificity increased (19). In patients with a pretest probability of active disease of 66%

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11. 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;105:162-9.

12. Schoepfer AM, Beglinger C, Straumann A, et al. Ulcerative colitis: Correlation of the Rachmilewitz endoscopic activity index with fecal calprotectin, clinical activity, C-reactive protein, and blood leukocytes. Inflamm Bowel Dis 2009;15:1851-8.

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17. Tibble JA, Sigthorsson G, Bridger S, Fagerhol MK, Bjarnason I. Surrogate markers of intestinal inflammation are predictive of relapse in patients with inflammatory bowel disease. Gastroenterology 2000;119:15-22.

18. D’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;18:2218-24.

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Figure 2) Interpreting fecal calprotectin (FC) test results

(endoscopy-positive cases), an elevated FC level increased the prob-ability to 90%, whereas a negative FC test decreased the probability to 26% (19). Cut-off values and management strategies based on the currently available evidence are shown in Figure 2.

ACKNOWLEDGEMENTS: The authors thank AbbVie Canada for their generous support of the development of the manuscript, as well as Pauline Lavigne and Steven Portelance for editorial assistance.

DISCLOSURES: Dr Bressler has received research grants and/or served as a consultant and/or speaker for: AbbVie, Alba Therapeutics, Alpco, Amgen, BMS, Celltrion, Ferring, Genentech, GSK, Hospira, Janssen, Pendopharm, Shire, Takeda and Warner Chilcott. Dr Panaccione has received research grants and/or served as a consultant and/or speaker for: Abbott, AbbVie Amgen, Aptalis, AstraZeneca, Baxter, Eisai, Ferring, Janssen, Merck, Schering-Plough, Shire, Centocor, Elan, Glaxo-Smith Kline, UCB, Pfizer, Bristol-Myers Squibb, Warner Chilcott, Takeda, Prometheus, Proctor and Gamble, and Millenium. Dr Seidman has received research funding or served as a consultant and/or speaker for: AbbVie, Alpco, Aptavis, Covidien, Janssen, Prometheus, Shire, Takeda and Vertex. Dr Fedorak has received research grants and/or served as a consultant and/or speaker for: AbbVie/Abbott, Alba, Bristol-Myers Squibb, Celltrion, Centoco, Ferring Pharma, GSK, Genentec, Janssen, Merck, Milllennium, Novartis, Pfizer, Proctor & Gamble, Roche, Shire, VSL#3, and is an owner/shareholder with Metabolomic Technologies Inc.

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28. Osterman MT, Aberra FN, Cross R, et al. Mesalamine dose escalation reduces fecal calprotectin in patients with quiescent ulcerative colitis. Clin Gastroenterol Hepatol 2014;12:1887-93,e3.

29. 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.

30. Lamb CA, Mohiuddin MK, Gicquel J, et al. Faecal calprotectin or lactoferrin can identify postoperative recurrence in Crohn’s disease. Br J Surg 2009;96:663-74.

31. Lobaton 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:e641-51.

32. Scarpa M, D’Inca R, Basso D, et al. Fecal lactoferrin and calprotectin after ileocolonic resection for Crohn’s disease. Dis Colon Rectum 2007;50:861-9.

33. Gisbert JP, McNicholl AG. Questions and answers on the role of faecal calprotectin as a biological marker in inflammatory bowel disease. Dig Liver Dis 2009;41:56-66.

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Clinicians’ guide to the use of fecal calprotectin to ...patients with inflammatory bowel disease (IBD) is an essential part of effective disease management. Specifically, it is