R-Biopharm – for reliable diagnostics Calprotectin – scientific literature R-Biopharm – for reliable diagnostics Content 1. Highlights ............................................................................................................3 2. Benefits of calprotectin management ..................................................................4 3. Calprotectin as a marker for the diagnosis of IBD ................................................5 3.1. Adult patients ......................................................................................................5 3.2. Pediatric patients ................................................................................................5 3.3. Cost-effectiveness of calprotectin measurements for suspected inflammatory bowel disease ................................................................................6 3.4. Diagnostic algorithm for suspected inflammatory bowel disease .........................6 4. Calprotectin as a surrogate marker for disease activity in IBD ������������������������������7 5. Calprotectin as a surrogate marker for mucosal healing in IBD ...........................8 6. Calprotectin as a predictive marker for relapse in IBD �����������������������������������������9 7. Calprotectin as a predictive marker for post-operative relapse in Crohn’s disease .............................................................................................10 8. Calprotectin as an aid in the decision to stop an IBD drug ................................. 11 9. Calprotectin and treat-to-target ........................................................................12 10. Conclusion ......................................................................................................... 13 2 1. Highlights What is calprotectin? In children > 4 years old, calprotectin normalizes to adult values.1 Also in the elderly above 60 (normal Calprotectin is a calcium, zinc and manganese values < 112 µg/g) and patients being treated with binding protein that is present in the cytosol of non-steroidal anti-inflammatory drugs (NSAIDs), neutrophils, but can also found in monocytes increased concentrations can be observed.1,5 and macrophages. It is a heterodimer of 24 kDa consisting of two subunits, S100A8 and How is it measured? S100A9. Following neutrophil disintegration at an inflammatory site, calprotectin is released thereby Fecal calprotectin is most commonly measured in exerting its antimicrobial activities through the the stool using a variety of immunoassays, which sequestration of zinc and manganese. Depending show, in general, comparable assay performance on the site of inflammation, calprotectin can be characteristics. found in serum, cerebrospinal fluid, synovial fluid, urine and faeces.1 What is the usefulness of calprotectin for the diagnosis of IBD? Calprotectin in stool was shown to be highly In patients with gastro-intestinal symptoms such as representative of the amount of neutrophils in abdominal pain, diarrhea and rectal bleeding with a the gut lumen and intestinal inflammation.2 suspicion of inflammatory bowel disease (IBD), fecal Increased levels have been observed in patients calprotectin testing can help differentiate between with inflammatory bowel disease (IBD), colorectal IBD and IBS (or non-IBD in children) and reduce the cancers and non-steroidal anti-inflammatory drug- number of unnecessary colonoscopies. induced enteropathy. What is the usefulness of calprotectin for What is the normal range of the management of IBD? calprotectin? The normal range for fecal calprotectin in healthy In patients being treated for IBD, fecal calprotectin adults is considered to be < 50 µg/g.1 In children can be used as a surrogate marker for disease activity ≤ 4 years, intestinal permeability is higher resulting and mucosal healing, as a predictive marker of in higher normal calprotectin concentrations of future (post-operative) relapse and in the decision to < 538 µg/g for children < 6 months, < 214 µg/g for stop an IBD drug. children between 6 months and 3 years, and < 75 µg/g for children 3 - 4 years old.3,4,6 References: 1. D’Angelo et al. Calprotectin in Daily Practice: Where do we 4. Zhu et al. Fecal Calprotectin in Healthy Children Aged 1-4 stand in 2017? Digestion 2017;95:293-301 Years. PLoS ONE 2016;11: e0150725 2. Roseth et al. Assessment of disease activity in ulcerative colitis 5. Joshi et al. Age-related faecal calprotectin, lactoferrin and by faecal calprotectin, a novel granulocyte marker protein. tumour M2-PK concentrations in healthy volunteers. Ann Clin Digestion 1997;58:176-180 Biochem 2010;47:259-263 3. Oord et al. Fecal calprotectin in healthy children. Scand J Clin 6. Rodeck et al. Pädiatrische Gastroenterologie, Hepatologie und Lab Invest 2014;74:254-258 Ernähung. Springer-Verlag 2008;1:684p 3 R-Biopharm – for reliable diagnostics 2. Benefits of calprotectin measurement Inflammatory bowel disease (IBD) intestinal inflammation that highly specifically differentiates between IBD and non-IBD causes IBD is a chronic relapsing-remitting disease of the of gastrointestinal symptoms, such as irritable gastrointestinal tract causing irreversible damage bowel syndrome (IBS), reducing the number of to the bowel if disease is not under control. Typical unnecessary and costly endoscopies. symptoms are abdominal pain, diarrhea, rectal bleeding, urgency and fatigue. There are two Calprotectin as a marker for the subtypes of IBD, Crohn’s disease and ulcerative management of IBD colitis. Whereas the inflammation in ulcerative colitis affects the rectum and/or colon only, inflammation Patients with IBD require lifelong treatment to in Crohn’s disease can occur from mouth to anus. control symptoms and prevent irreversible bowel Approximately 0.5 % of the Western population is damage and surgery. Today, gastroenterologists can burdened with IBD and its incidence is rising.1 Time make use of a broad spectrum of drugs, from small of first diagnosis is < 18 years for approximately molecules to biological drugs, to achieve ever more 25 % of patients.2 stringent treatment targets, including endoscopic and histological remission. Not all patients respond Calprotectin as a marker for the equally well to these treatments, however, and it diagnosis of IBD is a continuous struggle to find the right treatment for the right patient at the right time. In this The final diagnosis of IBD in patients representing setting, fecal calprotectin has been introduced with gastrointestinal symptoms and suspicion of IBD as a biomarker of disease activity reflecting is endoscopy, an invasive procedure that is highly intestinal inflammation. It is nowadays used in a accurate but not without risks. A lot of patients comprehensive treat-to-target approach, comprising without IBD, however, also undergo endoscopy, patient symptoms, disease activity scores (e.g. delaying appropriate treatment of these patients Crohn’s disease activity index), therapeutic drug and exposing them to an unpleasant and invasive monitoring and serological biomarkers like CRP and procedure. In this setting, fecal calprotectin albumin. has been introduced as a biomarker for References: 1. Ng et al. Worldwide incidence and prevalence of inflammatory 2. Kugathasan et al. Epidemiologic and clinical characteristics of bowel disease in the 21st century: a systematic review of children with newly diagnosed inflammatory bowel disease population-based studies. Lancet 2017;390:2769-2778 in Wisconsin: a statewide population-based study. J Pediatr 2003;143:525-531 4 3. Calprotectin as a marker for the diagnosis of IBD 3.1. Adult patients 3.2. Pediatric patients In adult patients with gastro-intestinal symptoms In pediatric patients with gastro-intestinal symptoms such as abdominal pain, diarrhea and rectal such as abdominal pain, diarrhea and rectal bleeding bleeding with a suspicion of IBD, fecal calprotectin with a suspicion of IBD, fecal calprotectin testing testing can help differentiate between IBD and IBS can help differentiate between IBD and non-IBD and and thereby reduce the number of unnecessary reduce the number of unnecessary colonoscopies. endoscopies. Why do we measure? Why do we measure? Pediatric patients with IBD have significantly Adult patients with IBD have significantly higher higher fecal calprotectin concentrations than fecal calprotectin concentrations than healthy healthy children or children with non-IBD related patients or patients with irritable bowel syndrome gastrointestinal symptoms. Testing for calprotectin (IBS). Testing for calprotectin may reduce the may reduce the number of costly and invasive number of costly and invasive endoscopies. endoscopies. Interpretation Interpretation Following meta-analysis of clinical studies using Following meta-analysis of clinical studies using ELISA, a cut-off of 50 µg/g yielded a sensitivity of ELISA, a cut-off of 50 µg/g yielded a sensitivity of 93 % and specificity of 94 % for the differentiation 99 % but moderate specificity of 74 %, while a of IBD from IBS (at a prevalence rate of 6.3 %). This cut-off of 100 µg/g had a sensitivity of 94 % but cut-off dominated the judgment of the general specificity of 82 % for differentiation of IBD from practitioner in primary care reducing the number of non-IBD (at a prevalence rate of 47.8 %). Both cut- unnecessary colonoscopies in patients without IBD.1 offs dominated direct referral for colonoscopy in the secondary care setting in a cost-effectiveness analysis.1 References: 1. Waugh et al. Faecal calprotectin testing