Use of biomarkers in inflammatory bowel disease | Medicina Clínica (English Edition)

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For its initial diagnosis and during follow-up, carrying out radiological and, especially, endoscopic studies is usually necessary. In this context, biomarkers of the disease are important as they are detected with a minimally invasive test that allows us to establish a clinical suspicion of IBD; this test is useful to select individuals who can benefit most from more invasive studies such as endoscopy, and they are surrogate markers of inflammatory activity: in the already diagnosed patient they can predict response to treatments, postoperative recurrence and are indicative of mucosal healing.This study is a review on the use of markers in IBD activity, with a focus on the most recent evidence.Serological markersSerological markers have been used in IBD to establish diagnosis, monitor activity, predict outbreaks or relapses and assess response to treatment. They have the advantage that they can be obtained in a minimally invasive manner and their cost is relatively low as they are widely used.<a class="elsevierStyleCrossRef" href="#bib0305">1</a> However, most are nonspecific and their concentration is modified in all types of inflammatory, digestive or extradigestive processes, so their correlation with clinical indexes and complementary IBD tests are sometimes weakened.<a class="elsevierStyleCrossRef" href="#bib0310">2</a>C-reactive proteinC-reactive protein (CRP) is produced by hepatocytes, whose secretion increases with inflammatory stimuli. It has a short half-life, so it rises rapidly after the inflammatory process is established and drops rapidly when it ceases: its blood concentration correlates directly with the severity of the inflammation.<a class="elsevierStyleCrossRef" href="#bib0315">3</a>CRP behaviour differs in CD and in UC. Most patients with active CD have elevated CRP, although there are studies with contradictory results when correlating clinical activity and their values; we also found that up to 10% of patients with CD and clinical criteria of activity may present persistently normal CRP values.<a class="elsevierStyleCrossRefs" href="#bib0320">4,5</a> Its role as marker is less reliable in cases of UC, and according to some studies approximately 50% of patients with an active UC flare will show normal CRP values. The explanation for this seems to be associated with CD's transmural inflammation compared to the mucosal involvement of UC.<a class="elsevierStyleCrossRef" href="#bib0330">6</a>Globular sedimentation rateThe erythrocyte sedimentation rate (ESR) measures the speed with which red blood cells settle in a capillary tube. It is an indirect measure of the degree of inflammation, since red blood cells generally fall slowly, and this speed increases in the presence of acute phase reactants. It is a nonspecific marker whose values vary in the presence of any inflammatory stimulus, including IBD activity.ESR values can be altered in patients with IBD but they do not differ between cases of CD and UC, a characteristic that CRP does have. On the other hand, evidence of a correlation between ESR with IBD clinical activity is scarce.<a class="elsevierStyleCrossRef" href="#bib0310">2</a>Certain factors can modify ESR, such as the number and size of red blood cells (anaemia affects their values), age or smoking. Medications that alter the corpuscular volume of red cells, such as thiopurine, are used in IBD, which should be remembered when interpreting ESR values in patients undergoing such treatment.<a class="elsevierStyleCrossRef" href="#bib0335">7</a>Their figures do not vary with the same speed as CRP because of the prolonged half-life of the proteins that contribute to their increase, so their value decreases slowly after the inflammatory process is resolved, limiting its usefulness in IBD, for example, to evaluate the response to treatment.ProcalcitoninPrecursor of calcitonin; under physiological conditions it is generated by the enzymatic processing of precalcitonin synthesised by thyroid cells; its serum value is practically undetectable. In bacterial infections, and especially in sepsis, an extrathyroidal synthesis of procalcitonin occurs in various organs (liver, lungs, kidneys and intestine), which increases its concentration. Some studies have evaluated the relationship between procalcitonin levels and IBD activity and found a slight elevation in patients with active CD, but never above normal levels.<a class="elsevierStyleCrossRef" href="#bib0340">8</a> It seems to be more useful in IBD for the prediction of infectious complications, whose symptoms are sometimes indistinguishable from the disease itself and include colitis by Clostridium difficile and other bacteria, intra-abdominal abscesses, postoperative infections and sepsis.<a class="elsevierStyleCrossRef" href="#bib0345">9</a>Pyruvate kinaseIs an enzyme that participates in glycolysis to produce ATP. Pyruvate kinase M2 (PKM2) is an isoenzyme that acts as an inflammatory mediator, situating itself at a midpoint between energy metabolism and the inflammatory process. Its exact role in inflammation is unknown, but it is known that their expression in intestinal cells can protect from apoptosis. It has been shown that the serum concentration of PKM2 is increased in patients with IBD, in the same way in both CD and UC, and without correlating with severity indices. On the other hand, PKM2 shows little interindividual variability and is not affected by other factors that do influence other markers, which makes it an attractive parameter for use in clinical practice, although it still needs further testing and to be studied with other biomarkers.<a class="elsevierStyleCrossRef" href="#bib0350">10</a>Serum antibodiesAntibodies against autoantigensAnti-neutrophil cytoplasmic antibodies (ANCA), and more specifically those with perinuclear pattern (p-ANCA), are associated with UC and appear as elevated in 55% of patients compared to 32% of the healthy population. Anti-Saccharomyces cerevisiae antibodies (ASCA) are associated with CD. These markers have good specificity (90%) and acceptable sensitivity (55%) when diagnosing CD or UC, but these values are worse when making a differential diagnosis between both if the involvement is exclusively colonic.<a class="elsevierStyleCrossRef" href="#bib0355">11</a>The positivity of these antibodies has been associated with a poor prognosis of the disease. Patients with negative UC and p-ANCA are predisposed to respond to infliximab, while those with positive p-ANCA have a higher risk of developing pouchitis after colectomy with an ileoanal reservoir.<a class="elsevierStyleCrossRefs" href="#bib0360">12,13</a> The positivity of ASCA in CD has been associate with more unfavourable behaviours, such as stenosing patterns, fistulizing, perianal disease and the need for surgery.Antimicrobial antibodies against intestinal microbiotaThere are several antibodies directed against microorganisms usually present in the intestinal flora. The main ones are the Outer-membrane-protein-C Antibody of Escherichia coli (anti-OmpC) and the anti-peptide antibody 12 associated with Pseudomonas fluorescens (anti-12). Both seem to be involved in immunotolerance phenomena and it has been suggested that, together with the previous, they comprise a panel of autoantibodies that can predict the development of the disease and the type of disease and its course, increasing the sensitivity and specificity of the disease and the individual determination of each.<a class="elsevierStyleCrossRef" href="#bib0370">14</a>Antidrug antibodiesAntidrugs are antibodies developed to work against the different biological therapies used in IBD. They antagonise the drug's molecule and can cause a loss of response to its effects, and even the appearance of adverse effects. The elevated titres of these antibodies correlate with the severity of the disease due to inactivation of the drug.<a class="elsevierStyleCrossRef" href="#bib0375">15</a> Its appearance, combined with the determination of the drug's trough levels, can serve as a guide for the best treatment strategy to be followed in patients who have lost response (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Faecal markersStudies into different faecal markers and their use in IBD and other disorders have shed increasing light on the subject in recent years. Its application in clinical practice heavily influences whether to carry out endoscopic studies, both in the initial diagnosis of the disease and during its follow-up.In the specific case of IBD, blood markers tend to be less sensitive than faecal markers. Because faeces are in direct contact with the intestinal walls, we can assume that the faecal concentration of these markers more faithfully reflect the extent and severity of the inflammatory process. Researches have observed that the presence of calprotectin – the main representative – in faeces is directly proportional to the activity of neutrophils in the enteral lumen.<a class="elsevierStyleCrossRefs" href="#bib0380">16,17</a>Many faecal markers of inflammatory activity have been studied, but the one that has most evidence in the literature and is the most commonly used in routine practice is faecal calprotectin (FCP).Faecal calprotectin and protein S100A12The S100 family includes 21 calcium and calcium-binding, low molecular weight proteins. It has multiple functions, such as regulating neutrophil activity, antimicrobial activity and the inflammatory response in general, with plasma levels rising between 5 and 40 times in the presence of infectious and/or inflammatory processes.<a class="elsevierStyleCrossRefs" href="#bib0390">18–20</a> Calprotectin (heterodimer of S100A8 and S100A9) and protein S100A12 are the most representative of this family in terms of their ability to detect inflammatory activity. Calprotectin is an abundant and widely distributed protein in the body and is found in the cytosol of cells such as neutrophils, macrophages and eosinophils, it comprises 60% of the protein content of cytosol of neutrophils. S100A12 is also found in inflammation-regulating cells, although to a lesser extent.<a class="elsevierStyleCrossRefs" href="#bib0380">16,21</a> Its levels can be measured in plasma and other biological fluids such as saliva, cerebrospinal fluid or synovial fluid, which is also present in faeces, and its faecal concentration is six times higher than plasma concentration.<a class="elsevierStyleCrossRef" href="#bib0410">22</a>The blood concentrations of calprotectin can be altered in digestive diseases as varied as alcoholic liver disease, cystic fibrosis, bacterial peritonitis or IBD. Calprotectin faecal levels increase in different colon and small intestine diseases, including enteropathy induced by taking non-steroidal anti-inflammatory drugs, colorectal cancer, exocrine pancreatic insufficiency, diverticular disease of the colon, caeliac disease, bacterial overgrowth syndrome and infections such as those caused by C. difficile or IBD.<a class="elsevierStyleCrossRefs" href="#bib0385">17,23–29</a>Patients with active IBD have high values of calprotectin and S100A12 in their faeces because of the significant presence of neutrophils in mucosal lesions that is typical of the disease. They have both been proposed as surrogate markers for inflammation and have been shown to be useful for differentiating IBD from functional types and, therefore, for selecting patients who can benefit most from an endoscopic study in the presence of symptoms such as chronic diarrhoea or abdominal pain.<a class="elsevierStyleCrossRefs" href="#bib0450">30–32</a> Several meta-analyses have shown that the use of PFC in these patients prevent up to two thirds of colonoscopies from being performed, which translates into significant cost savings.<a class="elsevierStyleCrossRefs" href="#bib0465">33–35</a>PFC has a better relationship with the IBD activity than S100A12, and also correlates better with the UC activity than CD (especially in CD with exclusive involvement of the small intestine). Some differences have also been observed between the paediatric and adult population: S100 proteins correlate better with adult than childhood activity.<a class="elsevierStyleCrossRefs" href="#bib0465">33,36</a>Faecal calprotectin in the initial diagnosis of inflammatory bowel diseaseA suspicion of IBD is based on the presence of its typical symptoms (abdominal pain, chronic diarrhoea, weight loss, etc.), extraintestinal manifestations and certain radiological and analytical alterations. One of the most relevant analytical parameters is FCP: multiple studies have shown it to have a greater sensitivity and specificity than blood markers, and it is the most studied and common of all the faecal parameter.<a class="elsevierStyleCrossRef" href="#bib0455">31</a>In this context, FCP has shown a sensitivity and specificity of 93% (95% CI: 85–97%) and 96% (95% CI: 79–99%),<a class="elsevierStyleCrossRef" href="#bib0465">33</a> and it has been put forward as an effective tool to predict pathological colonoscopy in symptomatic individuals.<a class="elsevierStyleCrossRefs" href="#bib0450">30–32</a> The excellent specificity figures are reached through a careful selection of patients and after a meticulous differential diagnosis, since PFC can be elevated according to different IBD profiles. When assessing the symptomatic patient, aspects such as taking non-steroidal anti-inflammatory drugs, the possibility of caeliac disease or infections of the digestive tract must be considered before carrying out calprotectin determinations or when indicating an endoscopic study after an altered determination.<a class="elsevierStyleCrossRefs" href="#bib0385">17,23–30</a>The normal limit for the PFC established in most laboratories is 50μg/g. However, although this cut-off point provides a very high sensitivity, it has been noted that it is not very specific and conditions a high number of unnecessary endoscopic examinations. Furthermore, when the cut-off rises to figures such as 200μg/g, it gains in specificity at the expense of losing sensitivity, which can lead to missing a significant number of diagnoses. Although taking several samples of PFC could improve specificity, there is still no agreement on which is the best strategy to take when determinations have intermediate values.<a class="elsevierStyleCrossRefs" href="#bib0475">35–37</a>The role of PFC in the initial diagnosis of small bowel CD deserves special mention. In cases of suspected IBD, after a normal ileocolonoscopy, different clinical practice guidelines recommend carrying out small bowel studies, with the capsule endoscope procedure being the technique of choice.<a class="elsevierStyleCrossRef" href="#bib0490">38</a> The presence of different altered analytical parameters in symptomatic patients has shown to increase the rate of endoscopic capsule studies with findings compatible to small bowel CD; PFC is one of the most studied and relevant issues in this context. Different studies have shown its ability to predict the presence of inflammatory lesions in the small bowel, and in this case it presents a sensitivity ranging between 68% and 78.3% and a specificity of between 60% and 76%.<a class="elsevierStyleCrossRefs" href="#bib0495">39–42</a>The optimal cut-off point of PFC to confirm an indication for small bowel explorations has also been discussed. As in cases of suspected inflammatory bowel disease, a level of 50μg/g is sensitive but not specific, and cut-off points above 200μg/g are specific but not very sensitive. In the case of small bowel inflammatory disease, it has been seen that the best results are obtained in terms of sensitivity, specificity, predictive values and area under the curve, when the cut-off is set at 100μg/g t.<a class="elsevierStyleCrossRefs" href="#bib0505">41–43</a>The correlation between PFC levels and inflammatory activity in the small bowel is not as good as with colonic activity. Various studies have found that sensitivity, specificity and predictive values of PFC in the initial diagnosis of small bowel CD improve significantly when it is associated with other altered laboratory parameters, especially CRP.<a class="elsevierStyleCrossRefs" href="#bib0510">42-44</a>Faecal calprotectin in the follow-up of inflammatory bowel diseaseIn addition to the initial diagnosis of IBD, PFC has also shown its usefulness in the follow-up of IBD, having been put forward as a surrogate marker for activity in the established disease. Its good correlation with activity and its ability to predict mucosal healing make calprotectin a useful tool when determining which patients will require a colonoscopy during follow-up and which will not.Several studies have shown that its correlation with endoscopic and clinical scales of activity in UC is very good, having been proposed as a non-invasive marker for mucosal healing.<a class="elsevierStyleCrossRef" href="#bib0525">45</a> Its usefulness in assessing the response to different treatments has also been of interest, although in this specific case the studies available are mostly short and results are heterogeneous and disparate, especially when assessing early response.<a class="elsevierStyleCrossRefs" href="#bib0525">45–47</a> Some studies have shown that the association of PFC with other inflammatory activity markers, such as CRP, and with clinical indexes based on symptoms may increase its capacity to predict mucosal healing and response to treatment.<a class="elsevierStyleCrossRefs" href="#bib0525">45,48</a>The evidence is scarcer for the usefulness of PFC for predicting mucosal healing in colonic CD and its relationship with clinical activity indexes in colonic CD. Its levels may predict inflammatory activity in the follow-up of CD, but it is not so accurate in UC. Its correlation with clinical indices also seems to be worse, with asymptomatic patients maintaining high levels of PFC, which has been associated with the persistence of inflammatory activity despite the absence of symptoms.<a class="elsevierStyleCrossRef" href="#bib0545">49</a>The cut-off point when monitoring colonic IBD is also under consideration, and again the available evidence seems to support 100μg/g as the most appropriate.<a class="elsevierStyleCrossRef" href="#bib0545">49</a>There is also evidence of the usefulness of PFC in the follow-up of small bowel CD, as it has been seen to correlate well with the inflammatory activity observed in both the endoscopic capsule procedure and assisted enteroscopy studies, and it is able to predict mucosal healing. However, its correlation with clinical indices, as well as with colonic CD, is not as good as with UC, and studies have confirmed that a certain number of asymptomatic or paucisymptomatic patients can maintain high values of this parameter and endoscopic activity data, which is why some authors have recommended a follow-up based on periodic PFC determinations and endoscopic capsule studies (because they are minimally invasive), regardless of the patient's symptoms.<a class="elsevierStyleCrossRef" href="#bib0550">50</a>LactoferrinLactoferrin is an iron-binding glycoprotein secreted by multiple glandular epithelia, whose levels can be measured in different secretions such as saliva, tears, faeces, etc. Lactoferrin is an important factor in inflammatory response, and like calprotectin is present in neutrophils and its levels are proportional to their activity.<a class="elsevierStyleCrossRef" href="#bib0555">51</a>It is the second most evidenced faecal marker, after calprotectin. Regarding its ability to differentiate inflammatory conditions from functional disorders, the results of different studies show contradictory data, and although it may be a useful parameter, its use is not recommended when calprotectin is available, since it is considered significantly superior.<a class="elsevierStyleCrossRefs" href="#bib0380">16,36,40</a>Immunological tests for faecal occult bloodImmunological tests for faecal occult blood measures the presence of human haemoglobin in faeces. They are cheap and widespread studies that have shown great sensitivity in the screening of colorectal cancer. Different studies have shown that they can also be useful in the follow-up of UC: normal levels of faecal occult blood can predict endoscopic mucosal and histological healing, and high levels are able to predict outbreaks of the disease; their accuracy in this specific scenario is equivalent to that of PFC.<a class="elsevierStyleCrossRefs" href="#bib0560">52,53</a>Although the tests are easily accessible and universally available, there is not much evidence supporting their use for more than the follow-up of UC, so they cannot be recommended for an initial diagnosis of the disease or for managing colonic or small bowel CD.Other faecal markersOther existing faecal markers have been studied much less despite the fact that they could be useful in the management of IBD. Most of them are parameters that have been studied and have promising results, but the samples have been small and the results not sufficient enough to establish a specific role in the management of IBD.<a class="elsevierStyleCrossRefs" href="#bib0490">38,54</a> Some of the more well-known markers, with greater and more recent evidence, are included in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>New markersThere are certain, recently discovered markers, but data on them and on their usefulness in IBD is limited. However, the results obtained in some published works are of interest and they may be implemented into usual clinical practice in the not too distant future.MicroRNAA microRNA is a single-stranded RNA of short length (18–25 nucleotides) whose function is not to encode proteins, but to regulate other biological processes such as cell proliferation or differentiation, apoptosis, immune response and expression of other genes at the post-transcriptional level. The dysregulation of micro-RNA may be involved in processes such as inflammation, cancer or autoimmune diseases.<a class="elsevierStyleCrossRef" href="#bib0575">55</a>These micro-RNAs have been studied in intestinal mucosa, blood and faeces, and described as useful in the: initial diagnosis of IBD, differentiation between UC and CD, monitoring of activity, response to treatment and risk prediction of colorectal cancer.<a class="elsevierStyleCrossRef" href="#bib0580">56</a>Metabolic analysisMetabolomics studies the chemical processes that involve metabolites, defining the metabolome as the total number of all metabolites present in cells, tissues, organs or organisms. Multiple metabolites (amino acids or lipids, among others) have been studied in different biological media (intestinal mucosa, faeces, urine or plasma), and many of them demonstrated their usefulness to differentiate between healthy patients or those with IBD, and CD and UC.<a class="elsevierStyleCrossRefs" href="#bib0540">48–59</a>Because of the tendency to perform increasingly less invasive tests in patients, a recent development within metabolomics is worth highlighting: a test that can use exhaled air to differentiate between patients with IBD and healthy patients, with special focus on the paediatric population.<a class="elsevierStyleCrossRefs" href="#bib0575">55,60</a>Proteomic analysisProteomics studies the function and structure of the proteome – the set of proteins encoded by the genome – including its isoforms, modifications, interactions and structure.<a class="elsevierStyleCrossRef" href="#bib0585">57</a>Proteins play a fundamental role in the biological processes of the human being, and their use as biomarkers for the diagnosis and/or follow-up of diseases such as IBD has been explored.<a class="elsevierStyleCrossRef" href="#bib0575">55</a>Since inflammation occurs in the digestive tract, samples of the intestinal mucosa were initially analysed, but studies later expanded to blood and faeces. They have been identified as useful biomarkers in the diagnosis of IBD, the differentiation between CD and UC, and the prediction of response to treatment.<a class="elsevierStyleCrossRef" href="#bib0590">58</a>Analysis of gene expressionThe evaluation of gene expression by quantifying the mRNA extracted from whole blood cells or from intestinal mucosal biopsies has allowed us to identify multiple genes involved in the inflammatory response to IBD. Identified genetic profiles could be used as molecular biomarkers to differentiate between healthy patients and those with IBD, between CD and UC, or to predict the inflammatory activity of the disease.<a class="elsevierStyleCrossRef" href="#bib0590">58</a>Gut microbiotaThe human intestine is colonised by microorganisms that form the microbiota, whose functions are to produce energy for the colonocytes, synthesise vitamins and amino acids, and eliminate antigens from the intestinal lumen, preventing their translocation to the bloodstream. The imbalance of intestinal microbiota and the reduction of its diversity (dysbiosis) are associated with IBD and its clinical course, which is why microbiota characteristics have been studied as a potential biomarker of the disease.<a class="elsevierStyleCrossRef" href="#bib0595">59</a>Stem cellsAlthough there are multiple studies on using stem cells to treat CD, their usefulness as biomarkers has been less researched. Recent studies show how pluripotential cells (haematopoietic, mesenchymal or endothelial stem cells) – which play an important role in the regeneration of the gastrointestinal mucosa when it is damaged – are mobilised to the peripheral blood in patients with IBD, so their measurement in blood samples could be used as a biomarker of the disease.<a class="elsevierStyleCrossRef" href="#bib0595">59</a>Extracellular microvesiclesThey are compounds secreted by cell types that act in intercellular communication, since they transport RNA and proteins from one cell to the other. Recent evidence suggests they have a role in chronic autoimmune diseases, and there are studies examining their use as biomarkers in IBD.<a class="elsevierStyleCrossRef" href="#bib0595">59</a>ConclusionsIBD is a complex profile in which a multitude of cells and molecules are involved in the body's inflammatory response to it. Some of them are easily measurable, both in blood and in faeces, and can be used as surrogate markers of disease activity. This, and their ability to differentiate between organic and functional, makes them useful when selecting patients for endoscopic studies, to predict mucous healing and response to treatments.Although the ‘perfect marker’ does not exist, faecal markers have taken centre stage, especially PFC. There is ample evidence regarding its usefulness during the different stages of the disease, for UC and CD, and for colonic and small bowel disease. It is important to note that its accuracy increases significantly when it is associated with other markers, such as CRP, and clinical activity scales.Finally, there is great interest in the study of many other markers, both serological and faecal, in an attempt to carry out an increasingly precise control of IBD. Although there are promising and very interesting results from some of these markers, a greater number of studies are needed until they can be applied in usual clinical practice.Conflict of interestThe authors declare no conflict of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres1178787" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1100242" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1178788" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1100243" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Serological markers" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "C-reactive protein" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Globular sedimentation rate" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Procalcitonin" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Pyruvate kinase" ] 4 => array:3 [ "identificador" => "sec0035" "titulo" => "Serum antibodies" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "Antibodies against autoantigens" ] 1 => array:2 [ "identificador" => "sec0045" "titulo" => "Antimicrobial antibodies against intestinal microbiota" ] 2 => array:2 [ "identificador" => "sec0050" "titulo" => "Antidrug antibodies" ] ] ] ] ] 6 => array:3 [ "identificador" => "sec0055" "titulo" => "Faecal markers" "secciones" => array:4 [ 0 => array:3 [ "identificador" => "sec0060" "titulo" => "Faecal calprotectin and protein S100A12" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0065" "titulo" => "Faecal calprotectin in the initial diagnosis of inflammatory bowel disease" ] 1 => array:2 [ "identificador" => "sec0070" "titulo" => "Faecal calprotectin in the follow-up of inflammatory bowel disease" ] ] ] 1 => array:2 [ "identificador" => "sec0075" "titulo" => "Lactoferrin" ] 2 => array:2 [ "identificador" => "sec0080" "titulo" => "Immunological tests for faecal occult blood" ] 3 => array:2 [ "identificador" => "sec0085" "titulo" => "Other faecal markers" ] ] ] 7 => array:3 [ "identificador" => "sec0090" "titulo" => "New markers" "secciones" => array:7 [ 0 => array:2 [ "identificador" => "sec0095" "titulo" => "MicroRNA" ] 1 => array:2 [ "identificador" => "sec0100" "titulo" => "Metabolic analysis" ] 2 => array:2 [ "identificador" => "sec0105" "titulo" => "Proteomic analysis" ] 3 => array:2 [ "identificador" => "sec0110" "titulo" => "Analysis of gene expression" ] 4 => array:2 [ "identificador" => "sec0115" "titulo" => "Gut microbiota" ] 5 => array:2 [ "identificador" => "sec0120" "titulo" => "Stem cells" ] 6 => array:2 [ "identificador" => "sec0125" "titulo" => "Extracellular microvesicles" ] ] ] 8 => array:2 [ "identificador" => "sec0130" "titulo" => "Conclusions" ] 9 => array:2 [ "identificador" => "sec0135" "titulo" => "Conflict of interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2018-07-21" "fechaAceptado" => "2018-10-02" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1100242" "palabras" => array:4 [ 0 => "Inflammatory bowel disease" 1 => "Crohn's disease" 2 => "Ulcerative colitis" 3 => "Biomarkers" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1100243" "palabras" => array:4 [ 0 => "Enfermedad inflamatoria intestinal" 1 => "Enfermedad de Crohn" 2 => "Colitis ulcerosa" 3 => "Marcadores" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "There are many useful biomarkers for initial diagnosis and the management of inflammatory bowel disease. Serologic biomarkers have been traditionally used because they are widely disposable, but recently faecal biomarkers, especially faecal calprotectin, have acquired great importance as they have shown to be more precise when establishing suspicion of the disease and also as predictors of mucosal healing or persistence of inflammatory activity. Faecal calprotectin is a good tool for predicting abnormal endoscopic studies, but has limited specificity because its levels can be altered in many digestive diseases presenting with similar symptoms. The precision of faecal calprotectin is higher when associated with other altered parameters, especially with C-reactive protein, or with clinical scores of inflammatory activity. Finally, there are many new generation serologic and faecal biomarkers. Despite there not being much evidence about these yet, some of them have shown promising results in different studies." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "Existe una gran variedad de marcadores útiles tanto en el diagnóstico como en el seguimiento de la enfermedad inflamatoria intestinal. Clásicamente se han utilizado los serológicos, ampliamente distribuidos y accesibles, pero en los últimos años han cobrado importancia los fecales, en especial la calprotectina fecal, por haber demostrado mayor precisión a la hora tanto de establecer la sospecha de la enfermedad como de predecir la curación mucosa o la persistencia de actividad inflamatoria. La calprotectina fecal muestra buena capacidad para predecir estudios endoscópicos patológicos, pero tiene una especificidad limitada ya que puede alterarse en otros cuadros digestivos con síntomas similares. La calprotectina fecal presenta mayor precisión cuando se asocia a otros parámetros, en especial a la proteína C reactiva, y a escalas clínicas de actividad inflamatoria. Finalmente, hay múltiples marcadores de nueva generación, serológicos y fecales, de los que hay escasa evidencia, aunque algunos han mostrado resultados prometedores en diferentes estudios." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Egea Valenzuela J, Antón Ródenas G, Sánchez Martínez A. Marcadores de actividad en la enfermedad inflamatoria intestinal. Med Clin (Barc). 2019;152:310–316." ] ] "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Appropriate drug levels \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Decreased drug levels \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Antidrug antibodies (+) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Repeat the determination (false positive?) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Change of medication within the same group \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Antidrug antibodies (−) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Change of therapeutic target \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Increase the drug dose or add an immunomodulator \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2008652.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Strategy to be followed in patients who have lost response according to drug levels and the presence or absence of antibodies against it." ] ] 1 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "UC: ulcerative colitis; CD: Crohn's disease; IBD: inflammatory bowel disease." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Type and origin \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Biological function \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Usefulness in IBD \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cathelicidins \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Peptides produced in neutrophils \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Antimicrobial activity; altered in cases of infection \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Their faecal levels are altered in IBD, to a greater extent in UC than in CD \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Beta-glucuronidases \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Enzymes present in colonocytes lysosomes, among others \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Metabolism of carbohydrates and deconjugation of drugs, toxins and hormones \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Faecal expression is decreased in individuals with IBD compared to the healthy population \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Lipocalin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Glycoprotein secreted by neutrophils \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">It is part of the antimicrobial barrier \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Their faecal levels are elevated in IBD and could be correlated with inflammatory activity \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">High mobility group 1 protein \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Nuclear nonhistone protein, DNA binding \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Maintains the cellular nuclear structure and is a mediator in inflammatory processes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Its expression is increased in the faeces of patients with IBD, and is able to detect microscopic inflammation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Neopterin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Metabolite of the guanosine cycle secreted by T lymphocytes and macrophages \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Inhibits the folate metabolism in pathogenic microorganisms \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Its faecal levels may be increased in patients with inflammatory activity \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Polymorphonuclear elastase \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Protease present in neutrophils \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">It is secreted by neutrophils before inflammatory stimuli \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Its faecal levels are increased in active IBD; it can predict mucous healing and can differentiate CD from UC \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pyruvate kinase M2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pyruvate kinase isoenzyme, present in leukocytes, among others \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Enzyme participates in the glycolysis processes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Its faecal levels are elevated in active IBD and it can predict clinical and endoscopic activity and responses to different treatments \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Matrix metalloprotease 9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Protease with the ability to degrade intercellular collagen and extracellular matrix \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">It is considered relevant in the pathogenesis of IBD and capable of recruiting neutrophils and activating angiogenesis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Its faecal levels are elevated in patients with IBD and also correlate with clinical and endoscopic activity indexes \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2008651.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Other faecal markers for which there is less evidence and in which a specific role has not yet been defined in inflammatory bowel disease." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:60 [ 0 => array:3 [ "identificador" => "bib0305" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Biomarkers in inflammatory bowel disease: current practices and recent advances" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "H.N. 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Use of biomarkers in inflammatory bowel disease

Marcadores de actividad en la enfermedad inflamatoria intestinal

Juan Egea Valenzuela

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jev1@um.es

Corresponding author.

, Gonzalo Antón Ródenas, Ana Sánchez Martínez

Servicio de Medicina del Aparato Digestivo, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Inflammatory bowel disease &#40;IBD&#41; is a chronic disorder that fundamentally comprises two conditions&#58; Crohn&#39;s disease &#40;CD&#41; and ulcerative colitis &#40;UC&#41;&#46; For its initial diagnosis and during follow-up&#44; carrying out radiological and&#44; especially&#44; endoscopic studies is usually necessary&#46; In this context&#44; biomarkers of the disease are important as they are detected with a minimally invasive test that allows us to establish a clinical suspicion of IBD&#59; this test is useful to select individuals who can benefit most from more invasive studies such as endoscopy&#44; and they are surrogate markers of inflammatory activity&#58; in the already diagnosed patient they can predict response to treatments&#44; postoperative recurrence and are indicative of mucosal healing&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">This study is a review on the use of markers in IBD activity&#44; with a focus on the most recent evidence&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Serological markers</span><p id="par0015" class="elsevierStylePara elsevierViewall">Serological markers have been used in IBD to establish diagnosis&#44; monitor activity&#44; predict outbreaks or relapses and assess response to treatment&#46; They have the advantage that they can be obtained in a minimally invasive manner and their cost is relatively low as they are widely used&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">1</span></a> However&#44; most are nonspecific and their concentration is modified in all types of inflammatory&#44; digestive or extradigestive processes&#44; so their correlation with clinical indexes and complementary IBD tests are sometimes weakened&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">2</span></a></p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">C-reactive protein</span><p id="par0020" class="elsevierStylePara elsevierViewall">C-reactive protein &#40;CRP&#41; is produced by hepatocytes&#44; whose secretion increases with inflammatory stimuli&#46; It has a short half-life&#44; so it rises rapidly after the inflammatory process is established and drops rapidly when it ceases&#58; its blood concentration correlates directly with the severity of the inflammation&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">3</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">CRP behaviour differs in CD and in UC&#46; Most patients with active CD have elevated CRP&#44; although there are studies with contradictory results when correlating clinical activity and their values&#59; we also found that up to 10&#37; of patients with CD and clinical criteria of activity may present persistently normal CRP values&#46;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">4&#44;5</span></a> Its role as marker is less reliable in cases of UC&#44; and according to some studies approximately 50&#37; of patients with an active UC flare will show normal CRP values&#46; The explanation for this seems to be associated with CD&#39;s transmural inflammation compared to the mucosal involvement of UC&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">6</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Globular sedimentation rate</span><p id="par0030" class="elsevierStylePara elsevierViewall">The erythrocyte sedimentation rate &#40;ESR&#41; measures the speed with which red blood cells settle in a capillary tube&#46; It is an indirect measure of the degree of inflammation&#44; since red blood cells generally fall slowly&#44; and this speed increases in the presence of acute phase reactants&#46; It is a nonspecific marker whose values vary in the presence of any inflammatory stimulus&#44; including IBD activity&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">ESR values can be altered in patients with IBD but they do not differ between cases of CD and UC&#44; a characteristic that CRP does have&#46; On the other hand&#44; evidence of a correlation between ESR with IBD clinical activity is scarce&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">2</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Certain factors can modify ESR&#44; such as the number and size of red blood cells &#40;anaemia affects their values&#41;&#44; age or smoking&#46; Medications that alter the corpuscular volume of red cells&#44; such as thiopurine&#44; are used in IBD&#44; which should be remembered when interpreting ESR values in patients undergoing such treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">7</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Their figures do not vary with the same speed as CRP because of the prolonged half-life of the proteins that contribute to their increase&#44; so their value decreases slowly after the inflammatory process is resolved&#44; limiting its usefulness in IBD&#44; for example&#44; to evaluate the response to treatment&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Procalcitonin</span><p id="par0050" class="elsevierStylePara elsevierViewall">Precursor of calcitonin&#59; under physiological conditions it is generated by the enzymatic processing of precalcitonin synthesised by thyroid cells&#59; its serum value is practically undetectable&#46; In bacterial infections&#44; and especially in sepsis&#44; an extrathyroidal synthesis of procalcitonin occurs in various organs &#40;liver&#44; lungs&#44; kidneys and intestine&#41;&#44; which increases its concentration&#46; Some studies have evaluated the relationship between procalcitonin levels and IBD activity and found a slight elevation in patients with active CD&#44; but never above normal levels&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">8</span></a> It seems to be more useful in IBD for the prediction of infectious complications&#44; whose symptoms are sometimes indistinguishable from the disease itself and include colitis by <span class="elsevierStyleItalic">Clostridium difficile</span> and other bacteria&#44; intra-abdominal abscesses&#44; postoperative infections and sepsis&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">9</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Pyruvate kinase</span><p id="par0055" class="elsevierStylePara elsevierViewall">Is an enzyme that participates in glycolysis to produce ATP&#46; Pyruvate kinase M2 &#40;PKM2&#41; is an isoenzyme that acts as an inflammatory mediator&#44; situating itself at a midpoint between energy metabolism and the inflammatory process&#46; Its exact role in inflammation is unknown&#44; but it is known that their expression in intestinal cells can protect from apoptosis&#46; It has been shown that the serum concentration of PKM2 is increased in patients with IBD&#44; in the same way in both CD and UC&#44; and without correlating with severity indices&#46; On the other hand&#44; PKM2 shows little interindividual variability and is not affected by other factors that do influence other markers&#44; which makes it an attractive parameter for use in clinical practice&#44; although it still needs further testing and to be studied with other biomarkers&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">10</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Serum antibodies</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Antibodies against autoantigens</span><p id="par0060" class="elsevierStylePara elsevierViewall">Anti-neutrophil cytoplasmic antibodies &#40;ANCA&#41;&#44; and more specifically those with perinuclear pattern &#40;p-ANCA&#41;&#44; are associated with UC and appear as elevated in 55&#37; of patients compared to 32&#37; of the healthy population&#46; Anti-Saccharomyces cerevisiae antibodies &#40;ASCA&#41; are associated with CD&#46; These markers have good specificity &#40;90&#37;&#41; and acceptable sensitivity &#40;55&#37;&#41; when diagnosing CD or UC&#44; but these values are worse when making a differential diagnosis between both if the involvement is exclusively colonic&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">11</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">The positivity of these antibodies has been associated with a poor prognosis of the disease&#46; Patients with negative UC and p-ANCA are predisposed to respond to infliximab&#44; while those with positive p-ANCA have a higher risk of developing <span class="elsevierStyleItalic">pouchitis</span> after colectomy with an ileoanal reservoir&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">12&#44;13</span></a> The positivity of ASCA in CD has been associate with more unfavourable behaviours&#44; such as stenosing patterns&#44; fistulizing&#44; perianal disease and the need for surgery&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Antimicrobial antibodies against intestinal microbiota</span><p id="par0070" class="elsevierStylePara elsevierViewall">There are several antibodies directed against microorganisms usually present in the intestinal flora&#46; The main ones are the Outer-membrane-protein-C Antibody of <span class="elsevierStyleItalic">Escherichia coli</span> &#40;anti-OmpC&#41; and the anti-peptide antibody 12 associated with <span class="elsevierStyleItalic">Pseudomonas fluorescens</span> &#40;anti-12&#41;&#46; Both seem to be involved in immunotolerance phenomena and it has been suggested that&#44; together with the previous&#44; they comprise a panel of autoantibodies that can predict the development of the disease and the type of disease and its course&#44; increasing the sensitivity and specificity of the disease and the individual determination of each&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">14</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Antidrug antibodies</span><p id="par0075" class="elsevierStylePara elsevierViewall">Antidrugs are antibodies developed to work against the different biological therapies used in IBD&#46; They antagonise the drug&#39;s molecule and can cause a loss of response to its effects&#44; and even the appearance of adverse effects&#46; The elevated titres of these antibodies correlate with the severity of the disease due to inactivation of the drug&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">15</span></a> Its appearance&#44; combined with the determination of the drug&#39;s trough levels&#44; can serve as a guide for the best treatment strategy to be followed in patients who have lost response &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Faecal markers</span><p id="par0080" class="elsevierStylePara elsevierViewall">Studies into different faecal markers and their use in IBD and other disorders have shed increasing light on the subject in recent years&#46; Its application in clinical practice heavily influences whether to carry out endoscopic studies&#44; both in the initial diagnosis of the disease and during its follow-up&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">In the specific case of IBD&#44; blood markers tend to be less sensitive than faecal markers&#46; Because faeces are in direct contact with the intestinal walls&#44; we can assume that the faecal concentration of these markers more faithfully reflect the extent and severity of the inflammatory process&#46; Researches have observed that the presence of calprotectin &#8211; the main representative &#8211; in faeces is directly proportional to the activity of neutrophils in the enteral lumen&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">16&#44;17</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Many faecal markers of inflammatory activity have been studied&#44; but the one that has most evidence in the literature and is the most commonly used in routine practice is faecal calprotectin &#40;FCP&#41;&#46;</p><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Faecal calprotectin and protein S100A12</span><p id="par0095" class="elsevierStylePara elsevierViewall">The S100 family includes 21 calcium and calcium-binding&#44; low molecular weight proteins&#46; It has multiple functions&#44; such as regulating neutrophil activity&#44; antimicrobial activity and the inflammatory response in general&#44; with plasma levels rising between 5 and 40 times in the presence of infectious and&#47;or inflammatory processes&#46;<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">18&#8211;20</span></a> Calprotectin &#40;heterodimer of S100A8 and S100A9&#41; and protein S100A12 are the most representative of this family in terms of their ability to detect inflammatory activity&#46; Calprotectin is an abundant and widely distributed protein in the body and is found in the cytosol of cells such as neutrophils&#44; macrophages and eosinophils&#44; it comprises 60&#37; of the protein content of cytosol of neutrophils&#46; S100A12 is also found in inflammation-regulating cells&#44; although to a lesser extent&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">16&#44;21</span></a> Its levels can be measured in plasma and other biological fluids such as saliva&#44; cerebrospinal fluid or synovial fluid&#44; which is also present in faeces&#44; and its faecal concentration is six times higher than plasma concentration&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">22</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">The blood concentrations of calprotectin can be altered in digestive diseases as varied as alcoholic liver disease&#44; cystic fibrosis&#44; bacterial peritonitis or IBD&#46; Calprotectin faecal levels increase in different colon and small intestine diseases&#44; including enteropathy induced by taking non-steroidal anti-inflammatory drugs&#44; colorectal cancer&#44; exocrine pancreatic insufficiency&#44; diverticular disease of the colon&#44; caeliac disease&#44; bacterial overgrowth syndrome and infections such as those caused by <span class="elsevierStyleItalic">C&#46; difficile</span> or IBD&#46;<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">17&#44;23&#8211;29</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Patients with active IBD have high values of calprotectin and S100A12 in their faeces because of the significant presence of neutrophils in mucosal lesions that is typical of the disease&#46; They have both been proposed as surrogate markers for inflammation and have been shown to be useful for differentiating IBD from functional types and&#44; therefore&#44; for selecting patients who can benefit most from an endoscopic study in the presence of symptoms such as chronic diarrhoea or abdominal pain&#46;<a class="elsevierStyleCrossRefs" href="#bib0450"><span class="elsevierStyleSup">30&#8211;32</span></a> Several meta-analyses have shown that the use of PFC in these patients prevent up to two thirds of colonoscopies from being performed&#44; which translates into significant cost savings&#46;<a class="elsevierStyleCrossRefs" href="#bib0465"><span class="elsevierStyleSup">33&#8211;35</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">PFC has a better relationship with the IBD activity than S100A12&#44; and also correlates better with the UC activity than CD &#40;especially in CD with exclusive involvement of the small intestine&#41;&#46; Some differences have also been observed between the paediatric and adult population&#58; S100 proteins correlate better with adult than childhood activity&#46;<a class="elsevierStyleCrossRefs" href="#bib0465"><span class="elsevierStyleSup">33&#44;36</span></a></p><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Faecal calprotectin in the initial diagnosis of inflammatory bowel disease</span><p id="par0115" class="elsevierStylePara elsevierViewall">A suspicion of IBD is based on the presence of its typical symptoms &#40;abdominal pain&#44; chronic diarrhoea&#44; weight loss&#44; etc&#46;&#41;&#44; extraintestinal manifestations and certain radiological and analytical alterations&#46; One of the most relevant analytical parameters is FCP&#58; multiple studies have shown it to have a greater sensitivity and specificity than blood markers&#44; and it is the most studied and common of all the faecal parameter&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">31</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">In this context&#44; FCP has shown a sensitivity and specificity of 93&#37; &#40;95&#37; CI&#58; 85&#8211;97&#37;&#41; and 96&#37; &#40;95&#37; CI&#58; 79&#8211;99&#37;&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">33</span></a> and it has been put forward as an effective tool to predict pathological colonoscopy in symptomatic individuals&#46;<a class="elsevierStyleCrossRefs" href="#bib0450"><span class="elsevierStyleSup">30&#8211;32</span></a> The excellent specificity figures are reached through a careful selection of patients and after a meticulous differential diagnosis&#44; since PFC can be elevated according to different IBD profiles&#46; When assessing the symptomatic patient&#44; aspects such as taking non-steroidal anti-inflammatory drugs&#44; the possibility of caeliac disease or infections of the digestive tract must be considered before carrying out calprotectin determinations or when indicating an endoscopic study after an altered determination&#46;<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">17&#44;23&#8211;30</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">The normal limit for the PFC established in most laboratories is 50<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;g&#46; However&#44; although this cut-off point provides a very high sensitivity&#44; it has been noted that it is not very specific and conditions a high number of unnecessary endoscopic examinations&#46; Furthermore&#44; when the cut-off rises to figures such as 200<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;g&#44; it gains in specificity at the expense of losing sensitivity&#44; which can lead to missing a significant number of diagnoses&#46; Although taking several samples of PFC could improve specificity&#44; there is still no agreement on which is the best strategy to take when determinations have intermediate values&#46;<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">35&#8211;37</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">The role of PFC in the initial diagnosis of small bowel CD deserves special mention&#46; In cases of suspected IBD&#44; after a normal ileocolonoscopy&#44; different clinical practice guidelines recommend carrying out small bowel studies&#44; with the capsule endoscope procedure being the technique of choice&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">38</span></a> The presence of different altered analytical parameters in symptomatic patients has shown to increase the rate of endoscopic capsule studies with findings compatible to small bowel CD&#59; PFC is one of the most studied and relevant issues in this context&#46; Different studies have shown its ability to predict the presence of inflammatory lesions in the small bowel&#44; and in this case it presents a sensitivity ranging between 68&#37; and 78&#46;3&#37; and a specificity of between 60&#37; and 76&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">39&#8211;42</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">The optimal cut-off point of PFC to confirm an indication for small bowel explorations has also been discussed&#46; As in cases of suspected inflammatory bowel disease&#44; a level of 50<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;g is sensitive but not specific&#44; and cut-off points above 200<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;g are specific but not very sensitive&#46; In the case of small bowel inflammatory disease&#44; it has been seen that the best results are obtained in terms of sensitivity&#44; specificity&#44; predictive values and area under the curve&#44; when the cut-off is set at 100<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;g t&#46;<a class="elsevierStyleCrossRefs" href="#bib0505"><span class="elsevierStyleSup">41&#8211;43</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">The correlation between PFC levels and inflammatory activity in the small bowel is not as good as with colonic activity&#46; Various studies have found that sensitivity&#44; specificity and predictive values of PFC in the initial diagnosis of small bowel CD improve significantly when it is associated with other altered laboratory parameters&#44; especially CRP&#46;<a class="elsevierStyleCrossRefs" href="#bib0510"><span class="elsevierStyleSup">42-44</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Faecal calprotectin in the follow-up of inflammatory bowel disease</span><p id="par0145" class="elsevierStylePara elsevierViewall">In addition to the initial diagnosis of IBD&#44; PFC has also shown its usefulness in the follow-up of IBD&#44; having been put forward as a surrogate marker for activity in the established disease&#46; Its good correlation with activity and its ability to predict mucosal healing make calprotectin a useful tool when determining which patients will require a colonoscopy during follow-up and which will not&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">Several studies have shown that its correlation with endoscopic and clinical scales of activity in UC is very good&#44; having been proposed as a non-invasive marker for mucosal healing&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">45</span></a> Its usefulness in assessing the response to different treatments has also been of interest&#44; although in this specific case the studies available are mostly short and results are heterogeneous and disparate&#44; especially when assessing early response&#46;<a class="elsevierStyleCrossRefs" href="#bib0525"><span class="elsevierStyleSup">45&#8211;47</span></a> Some studies have shown that the association of PFC with other inflammatory activity markers&#44; such as CRP&#44; and with clinical indexes based on symptoms may increase its capacity to predict mucosal healing and response to treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0525"><span class="elsevierStyleSup">45&#44;48</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">The evidence is scarcer for the usefulness of PFC for predicting mucosal healing in colonic CD and its relationship with clinical activity indexes in colonic CD&#46; Its levels may predict inflammatory activity in the follow-up of CD&#44; but it is not so accurate in UC&#46; Its correlation with clinical indices also seems to be worse&#44; with asymptomatic patients maintaining high levels of PFC&#44; which has been associated with the persistence of inflammatory activity despite the absence of symptoms&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">49</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">The cut-off point when monitoring colonic IBD is also under consideration&#44; and again the available evidence seems to support 100<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;g as the most appropriate&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">49</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">There is also evidence of the usefulness of PFC in the follow-up of small bowel CD&#44; as it has been seen to correlate well with the inflammatory activity observed in both the endoscopic capsule procedure and assisted enteroscopy studies&#44; and it is able to predict mucosal healing&#46; However&#44; its correlation with clinical indices&#44; as well as with colonic CD&#44; is not as good as with UC&#44; and studies have confirmed that a certain number of asymptomatic or paucisymptomatic patients can maintain high values of this parameter and endoscopic activity data&#44; which is why some authors have recommended a follow-up based on periodic PFC determinations and endoscopic capsule studies &#40;because they are minimally invasive&#41;&#44; regardless of the patient&#39;s symptoms&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">50</span></a></p></span></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Lactoferrin</span><p id="par0170" class="elsevierStylePara elsevierViewall">Lactoferrin is an iron-binding glycoprotein secreted by multiple glandular epithelia&#44; whose levels can be measured in different secretions such as saliva&#44; tears&#44; faeces&#44; etc&#46; Lactoferrin is an important factor in inflammatory response&#44; and like calprotectin is present in neutrophils and its levels are proportional to their activity&#46;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">51</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">It is the second most evidenced faecal marker&#44; after calprotectin&#46; Regarding its ability to differentiate inflammatory conditions from functional disorders&#44; the results of different studies show contradictory data&#44; and although it may be a useful parameter&#44; its use is not recommended when calprotectin is available&#44; since it is considered significantly superior&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">16&#44;36&#44;40</span></a></p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Immunological tests for faecal occult blood</span><p id="par0180" class="elsevierStylePara elsevierViewall">Immunological tests for faecal occult blood measures the presence of human haemoglobin in faeces&#46; They are cheap and widespread studies that have shown great sensitivity in the screening of colorectal cancer&#46; Different studies have shown that they can also be useful in the follow-up of UC&#58; normal levels of faecal occult blood can predict endoscopic mucosal and histological healing&#44; and high levels are able to predict outbreaks of the disease&#59; their accuracy in this specific scenario is equivalent to that of PFC&#46;<a class="elsevierStyleCrossRefs" href="#bib0560"><span class="elsevierStyleSup">52&#44;53</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">Although the tests are easily accessible and universally available&#44; there is not much evidence supporting their use for more than the follow-up of UC&#44; so they cannot be recommended for an initial diagnosis of the disease or for managing colonic or small bowel CD&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Other faecal markers</span><p id="par0190" class="elsevierStylePara elsevierViewall">Other existing faecal markers have been studied much less despite the fact that they could be useful in the management of IBD&#46; Most of them are parameters that have been studied and have promising results&#44; but the samples have been small and the results not sufficient enough to establish a specific role in the management of IBD&#46;<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">38&#44;54</span></a> Some of the more well-known markers&#44; with greater and more recent evidence&#44; are included in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">New markers</span><p id="par0195" class="elsevierStylePara elsevierViewall">There are certain&#44; recently discovered markers&#44; but data on them and on their usefulness in IBD is limited&#46; However&#44; the results obtained in some published works are of interest and they may be implemented into usual clinical practice in the not too distant future&#46;</p><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">MicroRNA</span><p id="par0200" class="elsevierStylePara elsevierViewall">A microRNA is a single-stranded RNA of short length &#40;18&#8211;25 nucleotides&#41; whose function is not to encode proteins&#44; but to regulate other biological processes such as cell proliferation or differentiation&#44; apoptosis&#44; immune response and expression of other genes at the post-transcriptional level&#46; The dysregulation of micro-RNA may be involved in processes such as inflammation&#44; cancer or autoimmune diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">55</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">These micro-RNAs have been studied in intestinal mucosa&#44; blood and faeces&#44; and described as useful in the&#58; initial diagnosis of IBD&#44; differentiation between UC and CD&#44; monitoring of activity&#44; response to treatment and risk prediction of colorectal cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">56</span></a></p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Metabolic analysis</span><p id="par0210" class="elsevierStylePara elsevierViewall">Metabolomics studies the chemical processes that involve metabolites&#44; defining the metabolome as the total number of all metabolites present in cells&#44; tissues&#44; organs or organisms&#46; Multiple metabolites &#40;amino acids or lipids&#44; among others&#41; have been studied in different biological media &#40;intestinal mucosa&#44; faeces&#44; urine or plasma&#41;&#44; and many of them demonstrated their usefulness to differentiate between healthy patients or those with IBD&#44; and CD and UC&#46;<a class="elsevierStyleCrossRefs" href="#bib0540"><span class="elsevierStyleSup">48&#8211;59</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">Because of the tendency to perform increasingly less invasive tests in patients&#44; a recent development within metabolomics is worth highlighting&#58; a test that can use exhaled air to differentiate between patients with IBD and healthy patients&#44; with special focus on the paediatric population&#46;<a class="elsevierStyleCrossRefs" href="#bib0575"><span class="elsevierStyleSup">55&#44;60</span></a></p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Proteomic analysis</span><p id="par0220" class="elsevierStylePara elsevierViewall">Proteomics studies the function and structure of the proteome &#8211; the set of proteins encoded by the genome &#8211; including its isoforms&#44; modifications&#44; interactions and structure&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">57</span></a></p><p id="par0225" class="elsevierStylePara elsevierViewall">Proteins play a fundamental role in the biological processes of the human being&#44; and their use as biomarkers for the diagnosis and&#47;or follow-up of diseases such as IBD has been explored&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">55</span></a></p><p id="par0230" class="elsevierStylePara elsevierViewall">Since inflammation occurs in the digestive tract&#44; samples of the intestinal mucosa were initially analysed&#44; but studies later expanded to blood and faeces&#46; They have been identified as useful biomarkers in the diagnosis of IBD&#44; the differentiation between CD and UC&#44; and the prediction of response to treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">58</span></a></p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Analysis of gene expression</span><p id="par0235" class="elsevierStylePara elsevierViewall">The evaluation of gene expression by quantifying the mRNA extracted from whole blood cells or from intestinal mucosal biopsies has allowed us to identify multiple genes involved in the inflammatory response to IBD&#46; Identified genetic profiles could be used as molecular biomarkers to differentiate between healthy patients and those with IBD&#44; between CD and UC&#44; or to predict the inflammatory activity of the disease&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">58</span></a></p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Gut microbiota</span><p id="par0240" class="elsevierStylePara elsevierViewall">The human intestine is colonised by microorganisms that form the microbiota&#44; whose functions are to produce energy for the colonocytes&#44; synthesise vitamins and amino acids&#44; and eliminate antigens from the intestinal lumen&#44; preventing their translocation to the bloodstream&#46; The imbalance of intestinal microbiota and the reduction of its diversity &#40;dysbiosis&#41; are associated with IBD and its clinical course&#44; which is why microbiota characteristics have been studied as a potential biomarker of the disease&#46;<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">59</span></a></p></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Stem cells</span><p id="par0245" class="elsevierStylePara elsevierViewall">Although there are multiple studies on using stem cells to treat CD&#44; their usefulness as biomarkers has been less researched&#46; Recent studies show how pluripotential cells &#40;haematopoietic&#44; mesenchymal or endothelial stem cells&#41; &#8211; which play an important role in the regeneration of the gastrointestinal mucosa when it is damaged &#8211; are mobilised to the peripheral blood in patients with IBD&#44; so their measurement in blood samples could be used as a biomarker of the disease&#46;<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">59</span></a></p></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Extracellular microvesicles</span><p id="par0250" class="elsevierStylePara elsevierViewall">They are compounds secreted by cell types that act in intercellular communication&#44; since they transport RNA and proteins from one cell to the other&#46; Recent evidence suggests they have a role in chronic autoimmune diseases&#44; and there are studies examining their use as biomarkers in IBD&#46;<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">59</span></a></p></span></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Conclusions</span><p id="par0255" class="elsevierStylePara elsevierViewall">IBD is a complex profile in which a multitude of cells and molecules are involved in the body&#39;s inflammatory response to it&#46; Some of them are easily measurable&#44; both in blood and in faeces&#44; and can be used as surrogate markers of disease activity&#46; This&#44; and their ability to differentiate between organic and functional&#44; makes them useful when selecting patients for endoscopic studies&#44; to predict mucous healing and response to treatments&#46;</p><p id="par0260" class="elsevierStylePara elsevierViewall">Although the &#8216;perfect marker&#8217; does not exist&#44; faecal markers have taken centre stage&#44; especially PFC&#46; There is ample evidence regarding its usefulness during the different stages of the disease&#44; for UC and CD&#44; and for colonic and small bowel disease&#46; It is important to note that its accuracy increases significantly when it is associated with other markers&#44; such as CRP&#44; and clinical activity scales&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">Finally&#44; there is great interest in the study of many other markers&#44; both serological and faecal&#44; in an attempt to carry out an increasingly precise control of IBD&#46; Although there are promising and very interesting results from some of these markers&#44; a greater number of studies are needed until they can be applied in usual clinical practice&#46;</p></span><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Conflict of interest</span><p id="par0270" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest&#46;</p></span></span>"
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          "titulo" => "Introduction"
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          "titulo" => "Serological markers"
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              "identificador" => "sec0015"
              "titulo" => "C-reactive protein"
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              "titulo" => "Globular sedimentation rate"
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              "titulo" => "Procalcitonin"
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              "titulo" => "Pyruvate kinase"
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              "identificador" => "sec0035"
              "titulo" => "Serum antibodies"
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                  "identificador" => "sec0040"
                  "titulo" => "Antibodies against autoantigens"
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                  "titulo" => "Antimicrobial antibodies against intestinal microbiota"
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                  "titulo" => "Antidrug antibodies"
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          "titulo" => "Faecal markers"
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              "titulo" => "Faecal calprotectin and protein S100A12"
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                  "titulo" => "Faecal calprotectin in the initial diagnosis of inflammatory bowel disease"
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                  "titulo" => "Faecal calprotectin in the follow-up of inflammatory bowel disease"
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              "titulo" => "Lactoferrin"
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              "titulo" => "Immunological tests for faecal occult blood"
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              "identificador" => "sec0085"
              "titulo" => "Other faecal markers"
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          "titulo" => "New markers"
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              "titulo" => "MicroRNA"
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              "titulo" => "Metabolic analysis"
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              "identificador" => "sec0105"
              "titulo" => "Proteomic analysis"
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              "identificador" => "sec0110"
              "titulo" => "Analysis of gene expression"
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              "identificador" => "sec0115"
              "titulo" => "Gut microbiota"
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              "titulo" => "Stem cells"
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          "palabras" => array:4 [
            0 => "Inflammatory bowel disease"
            1 => "Crohn&#39;s disease"
            2 => "Ulcerative colitis"
            3 => "Biomarkers"
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            0 => "Enfermedad inflamatoria intestinal"
            1 => "Enfermedad de Crohn"
            2 => "Colitis ulcerosa"
            3 => "Marcadores"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">There are many useful biomarkers for initial diagnosis and the management of inflammatory bowel disease&#46; Serologic biomarkers have been traditionally used because they are widely disposable&#44; but recently faecal biomarkers&#44; especially faecal calprotectin&#44; have acquired great importance as they have shown to be more precise when establishing suspicion of the disease and also as predictors of mucosal healing or persistence of inflammatory activity&#46; Faecal calprotectin is a good tool for predicting abnormal endoscopic studies&#44; but has limited specificity because its levels can be altered in many digestive diseases presenting with similar symptoms&#46; The precision of faecal calprotectin is higher when associated with other altered parameters&#44; especially with C-reactive protein&#44; or with clinical scores of inflammatory activity&#46; Finally&#44; there are many new generation serologic and faecal biomarkers&#46; Despite there not being much evidence about these yet&#44; some of them have shown promising results in different studies&#46;</p></span>"
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        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Existe una gran variedad de marcadores &#250;tiles tanto en el diagn&#243;stico como en el seguimiento de la enfermedad inflamatoria intestinal&#46; Cl&#225;sicamente se han utilizado los serol&#243;gicos&#44; ampliamente distribuidos y accesibles&#44; pero en los &#250;ltimos a&#241;os han cobrado importancia los fecales&#44; en especial la calprotectina fecal&#44; por haber demostrado mayor precisi&#243;n a la hora tanto de establecer la sospecha de la enfermedad como de predecir la curaci&#243;n mucosa o la persistencia de actividad inflamatoria&#46; La calprotectina fecal muestra buena capacidad para predecir estudios endosc&#243;picos patol&#243;gicos&#44; pero tiene una especificidad limitada ya que puede alterarse en otros cuadros digestivos con s&#237;ntomas similares&#46; La calprotectina fecal presenta mayor precisi&#243;n cuando se asocia a otros par&#225;metros&#44; en especial a la prote&#237;na C reactiva&#44; y a escalas cl&#237;nicas de actividad inflamatoria&#46; Finalmente&#44; hay m&#250;ltiples marcadores de nueva generaci&#243;n&#44; serol&#243;gicos y fecales&#44; de los que hay escasa evidencia&#44; aunque algunos han mostrado resultados prometedores en diferentes estudios&#46;</p></span>"
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        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Egea Valenzuela J&#44; Ant&#243;n R&#243;denas G&#44; S&#225;nchez Mart&#237;nez A&#46; Marcadores de actividad en la enfermedad inflamatoria intestinal&#46; Med Clin &#40;Barc&#41;&#46; 2019&#59;152&#58;310&#8211;316&#46;</p>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Appropriate drug levels&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Decreased drug levels&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Antidrug antibodies &#40;&#43;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Repeat the determination &#40;false positive&#63;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Change of medication within the same group&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Antidrug antibodies &#40;&#8722;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Change of therapeutic target&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Increase the drug dose or add an immunomodulator&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Strategy to be followed in patients who have lost response according to drug levels and the presence or absence of antibodies against it&#46;</p>"
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          "leyenda" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">UC&#58; ulcerative colitis&#59; CD&#58; Crohn&#39;s disease&#59; IBD&#58; inflammatory bowel disease&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Type and origin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Biological function&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Usefulness in IBD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cathelicidins&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Peptides produced in neutrophils&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Antimicrobial activity&#59; altered in cases of infection&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Their faecal levels are altered in IBD&#44; to a greater extent in UC than in CD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Beta-glucuronidases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Enzymes present in colonocytes lysosomes&#44; among others&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Metabolism of carbohydrates and deconjugation of drugs&#44; toxins and hormones&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Faecal expression is decreased in individuals with IBD compared to the healthy population&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Lipocalin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Glycoprotein secreted by neutrophils&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">It is part of the antimicrobial barrier&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Their faecal levels are elevated in IBD and could be correlated with inflammatory activity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">High mobility group 1 protein&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nuclear nonhistone protein&#44; DNA binding&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Maintains the cellular nuclear structure and is a mediator in inflammatory processes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Its expression is increased in the faeces of patients with IBD&#44; and is able to detect microscopic inflammation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Neopterin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Metabolite of the guanosine cycle secreted by T lymphocytes and macrophages&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Inhibits the folate metabolism in pathogenic microorganisms&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Its faecal levels may be increased in patients with inflammatory activity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Polymorphonuclear elastase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Protease present in neutrophils&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">It is secreted by neutrophils before inflammatory stimuli&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Its faecal levels are increased in active IBD&#59; it can predict mucous healing and can differentiate CD from UC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pyruvate kinase M2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pyruvate kinase isoenzyme&#44; present in leukocytes&#44; among others&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Enzyme participates in the glycolysis processes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Its faecal levels are elevated in active IBD and it can predict clinical and endoscopic activity and responses to different treatments&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Matrix metalloprotease 9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Protease with the ability to degrade intercellular collagen and extracellular matrix&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">It is considered relevant in the pathogenesis of IBD and capable of recruiting neutrophils and activating angiogenesis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Its faecal levels are elevated in patients with IBD and also correlate with clinical and endoscopic activity indexes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Other faecal markers for which there is less evidence and in which a specific role has not yet been defined in inflammatory bowel disease&#46;</p>"
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