Issue 02

Mentoring in IBD is an innovative and successful educational program for Canadian gastroenterologists that now includes an annual national meeting, regional satellites in both official languages, a website, an educational newsletter series, and regular electronic communications answering key clinical questions with new research. This issue is based on the presentation made by the issue editor, Dr Peter Lakatos, at the annual national meeting, Mentoring in IBD XV: The Master Class, held November 7, 2014 in Toronto, Ontario.

Introduction

Ongoing inflammation in Crohn’s disease (CD) results in cumulative tissue damage, but current evidence indicates that tailored therapy and objective patient monitoring can alter the course of the disease (Figure 1).(1) Many patients with ulcerative colitis (UC) also experience disease progression: up to 20% undergo colectomy within 10 years and 30% within 25 years (Figure 2).(2) Early and aggressive intervention in patients with severe disease may improve long-term outcomes.

Several patient and disease characteristics can help to identify patients who have an increased risk of an aggressive disease course.(3) It is important to identify these patients as early as possible to allow treatment optimization with the intent of altering the course of disease. Tight monitoring of clinical status can assist in this goal. In turn, implementation of tight monitoring requires a priori definition of the goals of treatment (Table 1). Objective assessment of disease activity is needed when setting these targets, as the presence or absence of symptoms is not a reliable indicator of inflammation and disease activity.

Levels of specific disease markers, such as C-reactive protein (CRP) and fecal calprotectin, parallel endoscopic or histologic disease activity, and elevated levels in patients with quiescent disease predict near-term relapses in both CD and UC. These disease markers may have clinical utility for prognosis at diagnosis, short-term prediction of disease activity, and long-term prediction of prognosis, disease complication risk, postoperative recurrence risk, and treatment optimization.

C-reactive protein

Several studies have linked CRP levels to short-term disease activity in inflammatory bowel disease (IBD). Solem et al examined the relation between CRP and clinical, endoscopic, histologic, and radiographic activity in 147 patients with IBD.(4) In CD, CRP elevation was significantly associated with moderate-to-severe clinical activity, active disease at colonoscopy, and histologically severe inflammation. In patients with UC, CRP elevation was significantly associated with severe clinical activity, elevation in erythrocyte sedimentation rate (ESR), anemia, hypoalbuminemia, and active disease at colonoscopy. Jones et al assessed the correlations among the Crohn’s Disease Activity Index (CDAI), the Simple Endoscopic Score for Crohn’s Disease (SES-CD), CRP, interleukin-6 (IL-6), fecal calprotectin, and lactoferrin in 164 patients with CD.(5) The study found CRP, IL-6, fecal calprotectin, and lactoferrin were all significantly higher in patients with SES-CD scores greater than 7.

CRP levels can also predict relapse among patients in remission. Consigny et al evaluated data from a previous therapeutic trial of 71 patients with CD, looking for biological markers of near-term relapse.(6) Multivariate analysis identified 2 markers predictive of relapse: CRP >20 mg/L and ESR >15 mm. This information was used to develop a binary biological predictive score. The score was negative when both markers were below the cut-off value and positive when they exceeded that value. The relative risk (RR) of short-term relapse associated with a positive score was 8.0 (95% confidence interval [CI] 2.8–22.9). The score predicted relapse within 6 weeks with a sensitivity of 89% and a specificity of 43%. Kiss et al classified 260 patients with CD according to CRP levels at diagnosis.(7) An elevated CRP level at diagnosis was an independent predictor of 3-month (P=0.007) and 12-month (P=0.001) clinical relapse among patients in remission.

CRP levels can also help to predict outcomes of treatment. Using data collected during the A Crohn’s Disease Clinical Trial Evaluating Infliximab in a New Long-term Treatment Regimen (ACCENT) I trial, Reinisch et al evaluated CRP at baseline and after infliximab induction therapy at 14 weeks as a predictor of maintaining response or remission through 54 weeks among patients with CD who responded to induction.(8) Higher baseline CRP levels (≥0.7 mg/dL) were significantly associated with maintained remission, and CRP levels that had normalized at week 14 were associated with an increased chance of maintaining response or remission over 1 year of infliximab therapy. Travis et al studied whether early changes in inflammatory markers or other variables could predict 1-year outcomes among 51 episodes of severe colitis.(9) His data indicated that 85% of patients with stool frequency >8 or stool frequency 3 to 8 plus CRP >45 mg/L at 3 days required colectomy during that admission.

According to some data, CRP levels may also predict longer-term outcomes of severe disease. Henriksen et al evaluated the relation of CRP levels to disease extent in patients with UC and to phenotype in patients with CD, and the predictive value of CRP levels for disease outcomes.(10) Data on CRP at diagnosis and after 1 and 5 years were available for 454 patients with UC and 200 patients with CD. CRP levels at diagnosis of UC increased with greater extent of disease. Among patients with extensive colitis, CRP levels >23 mg/L were associated with an increased risk of surgery (odds ratio [OR] 4.8, 95% CI: 1.5–15.1, P=0.02). CRP levels >10 mg/L at 1 year in patients with UC were associated with an increased risk of surgery over the next 4 years (OR 3.0, 95% CI: 1.1–7.8, P=0.02). Among patients with CD and terminal ileitis, CRP >53 mg/L at diagnosis significantly increased the risk of surgery (OR 6.0, 95% CI: 1.1–31.9, P=0.03). These results were confirmed by Lindgren et al, who evaluated clinical and biochemical parameters as predictors of steroid failure in 97 patients with acute UC.(11) The study found that fever, bloody diarrhea and CRP elevation persisting to Day 3 of intravenous corticosteroid therapy predicted treatment failure and that CRP ≥25 mg/L plus >4 bowel movements/day on Day 3 independently predicted a high risk of colectomy within 30 days.

Fecal calprotectin

Fecal calprotectin levels can also be linked to disease activity in both CD and UC. Using data from 140 ileocolonoscopies in patients with CD compared with 43 controls, Schoepfer et al evaluated the correlation between the SES-CD and fecal calprotectin, CRP, the white blood cell count, and the CDAI.(12) Calprotectin correlated most closely with the SES-CD (Spearman’s rank correlation coefficient r=0.75). In addition, only calprotectin discriminated between inactive endoscopic disease and mild disease activity, between mild and moderate disease activity, and between moderate and high disease activity. Using a cut-off value of 70 μg/g, calprotectin had an overall accuracy for detecting endoscopically active disease of 87%.

D’Haens et al examined the relation between fecal calprotectin levels and endoscopic disease activity in 126 patients with IBD and 32 patients with IBS undergoing colonoscopy and found significant correlations with endoscopic disease scores in both CD and in UC.(13) In CD, calprotectin levels <250 μg/g predicted endoscopic remission (Crohn’s Disease Endoscopic Index of Severity [CDEIS] ≤3) with 94.1% sensitivity and 62.2% specificity. In UC, calprotectin levels >250 μg/g predicted active mucosal disease activity (Mayo score >0) with a sensitivity of 71.0% and a specificity of 100.0%, and levels significantly correlated with symptom scores (r=0.561, P<0.001).

Schoepfer et al also evaluated the correlation between endoscopic disease activity, fecal calprotectin, Clinical Activity Index, CRP, and white blood cell count in 134 patients with UC compared with 48 controls undergoing colonoscopy.(14) Endoscopic disease activity correlated most closely with calprotectin (Spearman’s rank correlation coefficient r=0.834), and this marker could also reliably discriminate inactive from mild, moderate, and highly active disease; the overall accuracy of calprotectin in detecting endoscopically active disease (score ≥4) was 89%.

In a subanalysis of the infliximab diSconTinuation in CrOhn’s disease patients in stable Remission on combined therapy with Immunosuppressors (STORI) trial that involved close monitoring of both CRP and fecal calprotectin, de Suray et al found that elevated levels of CRP and fecal calprotectin were associated with an increased risk of short-term relapse and the combination may increase specificity.(15)

Ho et al investigated the utility of fecal calprotectin in predicting colectomy and corticosteroid and infliximab nonresponse in 90 inpatients with acute severe UC.(16) Fecal calprotectin was dramatically elevated and significantly higher among patients who went on to colectomy.

After measuring fecal calprotectin, Tibble et al followed 43 patients with CD and 37 patients with UC in clinical remission for 12 months.(17) Using a cut-off value of 50 mg/L, fecal calprotectin predicted relapse with a sensitivity of 90% and a specificity of 83%.

Lin et al performed a meta-analysis of 13 studies, which included 744 patients with UC and 727 patients with CD, assessing the diagnostic accuracy of fecal calprotectin in differentiating between active IBD and remission at several cut-off values (Table 2).(18)

Anemia

Anemia is an important and prevalent surrogate measure of disease activity in IBD and is usually due to iron deficiency, chronic diseases, vitamin deficiencies (e.g.B₁₂ or folate), or a combination.(19) Differentiating between these causes is critical for appropriate management. Ferritin, which is an acute-phase reactant, is useful in determining the type of anemia present, as it is decreased (<30 ng/L) in iron deficiency, increased in anemia of chronic disease (100 ng/mL), and possibly normal in anemia of mixed etiology.(20)

Using biomarkers in clinical practice

The accumulation of data on the clinical utility of CRP and fecal calprotectin in monitoring patient status and early results from hypothesis-driven randomized controlled trials (such as Randomized Evaluation of an Algorithm for Crohn’s Treatment [REACT]) confirm that optimized therapy using tight monitoring results in superior long-term outcomes, including reductions in hospitalization, surgery, and complications (Figure 3).(21)

Conclusion

Biomarkers are important in both short- and long-term follow-up of patients with IBD. It is vital to stratify patients by risk, and to establish relevant goals of therapy. A comprehensive evaluation, including clinical and endoscopic presentation and fecal, serologic, and routine laboratory tests is recommended. Patient-specific strategies for follow-up using individualized and objective measures of disease activity can help to optimize long-term outcomes.

Clinical case

Case presentation

A 35-year-old male has had endoscopically and histologically confirmed ulcerative pancolitis for 7 years. At the time of diagnosis in 2007, his CRP was 65 mg/L and he was initially treated with mesalamine 4.8 g/d plus 30 days of rectal mesalamine and prednisone 40 mg, tapered over 14 weeks. He rapidly went into a clinical remission and eventually reduced his mesalamine to 2.4 g/d maintenance therapy. He lives 7 hours from a major metropolitan centre and has had his mesalamine prescription renewed by his family physician over the years.

He is newly married and his wife arranges a follow-up appointment with your office. In your office, he states he is well and asymptomatic. He has one more bowel motion per day than normal with no blood, equating to a partial Mayo score of 1, indicating full remission. Laboratory testing reveals the following:

–  Normal hemoglobin, mean cell volume (MCV) and platelets

–  Ferritin 12 pmol/L (normal range 12-300 pmol/L)

–  Iron 9 μmol/L (normal range 10-30 μmol/L)

The rest of his laboratory investigations are normal.

Commentary

Clinical assessment is no longer adequate to follow patients with IBD, and objective monitoring is now an important part of monitoring clinical status. In this situation, CRP and fecal calprotectin are appropriate to identify the presence of subclinical disease activity.

Case evolution

His test results are the following:

–  CRP: 18 mg/L (normal range 1-8 mg/L)

–  Fecal calprotectin: 356 μg/g (normal range <200 μg/g)

Commentary

The biomarker results indicate the presence of inflammation, which has increased over the past few weeks, and the risk of relapse, so additional investigation is warranted. In addition, objective monitoring is now sufficient to optimize therapy.

Case evolution

You decide to have him drive 7 hours back to see you for a colonoscopy. The colonoscopy demonstrates loss of vascular pattern and granularity up to 35 cm, loss of vascular pattern only with no granularity from 35 to 65 cm, and a normal endoscopic picture from 65 cm to the cecum. The ileum is normal.

Commentary

As colonoscopy indicates the presence of active disease and the biomarker results indicate the likelihood of relapse, more intensive treatment is recommended to prevent the development of clinical relapse. Increasing the dose of oral mesalamine from 2.4 g/day and adding a rectal formulation are appropriate responses in this situation.

References

1. Pariente B, Cosnes J, Danese S, et al. Development of the Crohn’s disease digestive damage score, the Lémann score. Inflamm Bowel Dis. 2011;17(6):1415–22.
2. Langholz E, Munkholm P, Davidsen M, Binder V. Course of ulcerative colitis: analysis of changes in disease activity over years. Gastroenterology. 1994;107(1):3–11.
3. Yarur AJ, Strobel SG, Deshpande AR, Abreu MT. Predictors of aggressive inflammatory bowel disease. Gastroenterol Hepatol. 2011;7(10):652–9.
4. Solem CA, Loftus EV Jr, Tremaine WJ, et al. Correlation of C-reactive protein with clinical, endoscopic, histologic, and radiographic activity in inflammatory bowel disease. Inflamm Bowel Dis. 2005;11(8):707–12.
5. Jones J, Loftus EV Jr, Panaccione R, et al. Relationships between disease activity and serum and fecal biomarkers in patients with Crohn’s disease. Clin Gastroenterol Hepatol. 2008;6(11):1218–24.
6. Consigny Y, Modigliani R, Colombel JF, et al; Groupe d’Etudes Thérapeutiques des Affections Inflammatoires Digestives (GETAID). A simple biological score for predicting low risk of short-term relapse in Crohn’s disease. Inflamm Bowel Dis. 2006;12(7):551–7.
7. Kiss LS, Papp M, Lovasz BD, et al. High-sensitivity C-reactive protein for identification of disease phenotype, active disease, and clinical relapses in Crohn’s disease: a marker for patient classification? Inflamm Bowel Dis. 2012;18(9):1647–54.
8. Reinisch W, Wang Y, Oddens BJ, Link R. 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(5):568–76.
9. Travis SP, Farrant JM, Ricketts C, et al. Predicting outcome in severe ulcerative colitis. Gut. 1996;38(6):905–10.
10. 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(11):1518–23.
11. Lindgren SC, Flood LM, Kilander AF, et al. Early predictors of glucocorticosteroid treatment failure in severe and moderately severe attacks of ulcerative colitis. Eur J Gastroenterol Hepatol. 1998;10(10):831–5.
12. 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(1):162–9.
13. 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(12):2218–24.
14. 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(12):1851–8.
15. de Suray N, Salleron J, Vernier-Massouille G, et al. Close monitoring of CRP and fecal calprotectin levels to predict relapse in Crohn’s disease patients. A sub-analysis of the STORI study. J Crohn Colitis 2012;6(1):P274.
16. Ho GT, Lee HM, Brydon G, et al. Fecal calprotectin predicts the clinical course of acute severe ulcerative colitis. Am J Gastroenterol. 2009;104(3):673–8.
17. Tibble JA, Sigthorsson G, Bridger S, et al. Surrogate markers of intestinal inflammation are predictive of relapse in patients with inflammatory bowel disease. Gastroenterology. 2000;119(1):15–22.
18. Lin JF, Chen JM, Zuo JH, et al. Meta-analysis: fecal calprotectin for assessment of inflammatory bowel disease Inflamm Bowel Dis. 2014;20(8):1407–15.
19. Oustamanolakis P, Koutroubakis IE, Kouroumalis EA. Diagnosing anemia in inflammatory bowel disease: beyond the established markers. J Crohns Colitis. 2011;5(5):381–91.
20. Bermejo F, García-López S. A guide to diagnosis of iron deficiency and iron deficiency anemia in digestive diseases. World J Gastroenterol. 2009;15(37):4638–43.
21. Khanna R, Levesque BG, Bressler B, et al. Early combined immunosuppression for the management of Crohn’s disease: A community-based cluster randomized trial. Presented at the 9^th Congress of the European Crohn’s and Colitis Organisation; February 20-22, 2014; Copenhagen, Denmark.

Editor-in-Chief

John K. Marshall, MD MSc FRCPC AGAF, Chief of Gastroenterology Clinical Service, Hamilton Health Sciences; Professor of Medicine, Division of Gastroenterology, McMaster University , Hamilton, ON

Co-Editor-in-Chief

Richard N. Fedorak, MD FRCPC FRCP (London) FRCS, Dean, Faculty of Medicine & Dentistry; Professor of Medicine, Division of Gastroenterology, University of Alberta, Edmonton, AB

Issue Editor

Peter Laszlo Lakatos, MD PhD, Associate Professor, Head, Gastroenterology Unit, First Department of Medicine, Semmelweis University, Budapest, Hungary

Mentoring in IBD Curriculum Steering Committee

 Alain Bitton, MD FRCPC, McGill University, Montreal, QC
Brian Bressler, MD MS FRCPC, University of British Columbia, Vancouver, BC
Anne M. Griffiths, MC FRCPC, University of Toronto, Toronto, ON
Steven E. Gruchy, MD MSc FRCPC, Dalhousie University, Halifax, ON
Remo Panaccione, MD FRCPC, University of Calgary, Calgary, AB
Craig Render, MD FRPCP, University of British Columbia, University of Alberta, Kelowna, BC
Hillary Steinhart, MD MSc FRCPC, University of Toronto, Toronto, ON
Jennifer Stretton, ACNP MN BScN, St. Joseph’s Healthcare, Hamilton, ON

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