Manuscript DoiAdvance : 10.1093/ecco-jcc/jjv100 Journal of Crohn's and Colitis Access published June 12, 2015 Page 1 Editorial for JOURNAL OF CROHN’S AND COLITIS, vs 20150518-v1 The “Red Flag Instrument” for early Detection of Crohn’s Disease: is it ready for rip t Clinical Practice? Alain Schoepfer, MD1, Stephan Vavricka, MD2 Alain Schoepfer, MD, PD+MER1 Division of Gastroenterology and Hepatology us c 1 Centre Hospitalier Universitaire Vaudois / CHUV Tel: + 41 21 314 71 58 Fax: + 41 21 314 47 18 2 ed [email protected] M 1011 Lausanne, Switzerland an Rue de Bugnon 44, 07/2409 Stephan R. Vavricka, MD pt Professor of Medicine, Divison of Gastroenterology and Hepatology Triemlispital and University Hopsital Zurich ce Birmensdorferstrasse 497 CH-8063 Zurich, Switzerland +41 44 466 13 17 Fax: +41 44 466 29 05 Ac Tel: Email: [email protected] Disclosures Alain Schoepfer: none related to this article Stephan Vavricka: none related to this article. Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected] Manuscript Doi : 10.1093/ecco-jcc/jjv100 Page 2 Writing assistance: none Word count: 1201 words rip t Editorial The term “diagnostic delay” describes the time interval between the first appearance of disease-related symptoms and the diagnosis of a particular disease. Diagnostic delay can be us c separated into an interval from first appearance of disease-related symptoms until first medical attention is sought (“patient-related interval”) and the interval from first contact with the physician until diagnosis of the underlying disease is established (“physician-related an interval”) (Figure 1). Several factors such as auto-medication of the patient or access to the primary care physician or a specialist can influence the length of diagnostic delay. M Figure 1: Diagnostic delay, the time from first appearance of Crohn’s disease-related symptoms until diagnosis, can be separated into an interval that is patient-related and an Ac ce pt ed interval that is physician-related. Manuscript Doi : 10.1093/ecco-jcc/jjv100 Page 3 Several recently published studies have revealed that length of diagnostic delay can indeed represent an issue for at least a proportion of patients with Crohn’s disease (CD). Data from the Swiss IBD Cohort Study in 932 CD patients found a median diagnostic delay of 12 months.1 Twenty-five percent of all CD patients needed >24 months after symptom onset to rip t establish the diagnosis. Age <40 years at CD diagnosis and ileal disease location were identified as risk factors for a diagnostic delay >24 months (above the 75th percentile). The length of diagnostic delay may not only represent a period of suffering and poor quality of life us c for the patients, but it is also related to the occurrence of bowel damage and consecutive CD-related surgery.2 Several studies have shown that immunomodulatory treatment provides better results in case of short disease duration.3 As such, it is relevant to diagnose an CD early before relevant bowel damage has occurred.4,5 Several factors may influence the length of diagnostic delay on physician’s side: first, M abdominal complaints expressed by CD patients can be unspecific and may also be observed in patients with irritable bowel syndrome. The diagnostic accuracy of the Rome criteria is moderate to discriminate patients with irritable bowel syndrome (IBS) from organic ed bowel disease.6 Physicians may therefore treat CD patients with IBS medication for a considerable time before CD is finally diagnosed. Third, limitations of the access to primary pt care physicians and/or gastroenterologists or waiting lists for endoscopies may also prolong diagnostic delay. ce In this issue, Danese et al. present data on the development and field-testing of a “red flags” symptom instruments that should allow discrimination of CD patients from healthy Ac controls and IBS patients. Item generation was based on a literature review and IBD expert input. Out of 21 items, the authors identified 8 key items with a good discriminative value between CD and the non-CD population. The “red flag” index ranges from 0 to 24 points and an index of ≥8 was highly predictive for underlying CD with sensitivity and specificity bootstrap estimates of 0.94 (95%-confidence interval 0.88-0.99) and 0.94 (95%-CI 0.900.97), respectively. The “red flags” instrument is supposed to be used primarily by primary care physicians. The instrument is completed during an interview with the patient who recalls his/her symptoms over the last 12 months. Manuscript Doi : 10.1093/ecco-jcc/jjv100 Page 4 The results of this study are of interest for several reasons. First, the “red flags” instrument is easy to complete and does not take much time. Second, the completion is based on patient reported outcomes and does not involve laboratory analyses with associated costs. The discriminative accuracy between CD and the non-CD population is rip t remarkably high. Overall, the results look very promising. The instrument may prove very useful for guidance of the decision which patients should be referred for colonoscopic workup. Is the “red flags” instrument ready for use in daily practice? Several points need to us c be discussed to answer this question. First, the instrument has been field-tested in 85 patients with early CD, 36 healthy controls, and 80 IBS patients. A validation in a second independent cohort of CD patients, an IBS patients, and healthy controls is awaiting. In the current article the authors report on the test accuracy of the “red flags” instrument for discriminating CD versus the “non-CD” M population which is composed of IBS patients and healthy controls. It would be interesting to know how accurately the instrument can discriminate early CD patients from IBS patients that show a predominance of diarrhea (IBS-D), or constipation (IBS-C), or a mixed type (IBS- ed M).7 Second, in a validation study also the test-retest reliability should be assessed. Third, the “red flags” instrument has been evaluated by gastroenterologists, but not yet by primary pt care physicians who represent the “target population”. The validation study should be performed involving also primary care physicians. Fourth, trials have been performed using ce fecal calprotectin and fecal lactoferrin to discriminate patients suffering from CD from IBS patients and have documented an excellent accuracy for both fecal calprotectin and fecal Ac lactoferrin in discriminating these two entities.8,9 It would be interesting to evaluate if the “redflags” index is complementary to fecal markers and if a combination of both would even increase the already high test accuracy for discriminating CD from IBS patients. In summary, the “red flags” index has a potential role to early diagnose CD patients at basically no associated costs. The index could guide decisions which patients need to undergo endoscopic workup. A future validation study should clarify the accuracy to discriminate CD from different IBS subtypes and involve the primary care physicians. Manuscript Doi : 10.1093/ecco-jcc/jjv100 Page 5 REFERENCES Vavricka SR, Spigaglia S, Rogler G, Pittet V, Michetti P, Felley C, Mottet C, Braegger C, rip t 1 Rogler D, Straumann A, Bauerfeind P, Fried M, Schoepfer AM. Systematic evaluation of risk us c factors for diagnostic delay in inflammatory bowel disease. Inflamm Bowel Dis 2012;18:496505. 2 Schoepfer AM, Dehlavi MA, Fournier N, Safroneeva E, Straumann A, Pittet V, Peyrin- Biroulet L, Michetti P, Rogler G, Vavricka SR. Diagnostic delay in Crohn’s disease is Gastroenterol 2013;108:1744-53. Schreiber S, Colombel JF, Bloomfield R, Nikolaus S, Scholmerich J, Panes J, Sandborn M 3 an associated with a complicated disease course and increased operation rate. Am J WJ. Increased response and remission rates in short-duration Crohn’s disease with ed subcutaneous certolizumab pegol: an analysis of PRECISE 2 randomized trial data. Am J Gastroenterol 2010;105:1574-82. Allen PB, Peyrin-Biroulet L. Moving towards disease modification in inflammatory bowel pt 4 disease therapy. Curr Opin Gastroenterol 2013;29:397-404. Peyrin-Biroulet L. Billioud V, D’Haens G, Panaccione R, Feagan B, Panes J, Danese S, ce 5 Schreiber S, Ogata H, Hibi T, Higgins PD, Beaugerie L, Chowers Y, Louis E, Steinwurz F, Ac Reinisch W, Rutgeerts P, Colombel JF, Travis S, Sandborn WJ. Development of the Paris definition of early Crohn’s disease for disease-modification trials: results of an international expert opinion process. Am J Gastroenterol 2012;107:1770-6. 6 Ford AC, Bercik P, Morgan DG, Bolino C, Pintos-Sanchez MI, Moayyedi P. Validation of the Rome III criteria for the diagnosis of irritable bowel syndrome in secondary care. Gastroenterology 2013;45:1262-70. 7 Spiller R, Aziz Q, Creed F, Emmanuel A, Houghton L, Hungin P, Jones R, Kumar D, Rubin G, Trudgill N, Whorwell P; Clinical Services Committee of The British Society of Manuscript Doi : 10.1093/ecco-jcc/jjv100 Page 6 Gastroenterology. Guidelines on the irritable bowel syndrome: mechanisms and practical management. Gut 2007;56:1770-98. 8 Schoepfer AM, Trummler M, Seeholzer P, Seibold-Schmid B, Seibold F. Discriminating IBD IBD antibodies. Inflamm Bowel Dis 2008 Jan;14:32-9. 9 rip t from IBS: comparison of the test performance of fecal markers, blood leukocytes, CRP, and van Rheenen PF, Van de Vijver E, Fidler V. Faecal calprotectin for screening of patients with suspected inflammatory bowel disease: diagnostic meta-analysis. BMJ 2010; Ac ce pt ed M an us c 15;341:c3369.