The GETECCU clinical guideline for the treatment of ulcerative colitis: A guideline created using GRADE methodology

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Gisbert, Joaquín Hinojosa" "autores" => array:6 [ 0 => array:4 [ "nombre" => "Fernando" "apellidos" => "Gomollón" "email" => array:1 [ 0 => "fgomollon@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ …2] 1 => array:2 [ …2] ] ] 1 => array:3 [ "nombre" => "Santiago" "apellidos" => "García-López" "referencia" => array:1 [ 0 => array:2 [ …2] ] ] 2 => array:3 [ "nombre" => "Beatriz" "apellidos" => "Sicilia" "referencia" => array:1 [ 0 => array:2 [ …2] ] ] 3 => array:3 [ "nombre" => "Javier P." "apellidos" => "Gisbert" "referencia" => array:1 [ 0 => array:2 [ …2] ] ] 4 => array:3 [ "nombre" => "Joaquín" "apellidos" => "Hinojosa" "referencia" => array:1 [ 0 => array:2 [ …2] ] ] 5 => array:2 [ "colaborador" => "on behalf of GETECCU" "referencia" => array:1 [ 0 => array:2 [ …2] ] ] ] "afiliaciones" => array:5 [ 0 => array:3 [ "entidad" => "Department of Gastroenterology, Hospital Clínico Universitario Lozano Blesa, IIS, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Zaragoza, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Department of Gastroenterology, Hospital Universitario Miguel Servet, Zaragoza, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Department of Gastroenterology, Complejo Asistencial Universitario de Burgos, Burgos, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Department of Gastroenterology, Hospital Universitario de La Princesa, CIBEREHD, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Department of Gastroenterology, Hospital de Manises, Valencia, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Guía clínica GETECCU del tratamiento de la Colitis Ulcerosa elaborada con la metodología GRADE" ] ] "textoCompleto" => "1IntroductionUlcerative colitis (UC) is a chronic inflammatory bowel disease of multifactorial aetiology that mainly affects the colon. There is no single pathognomonic criterion to define it, the diagnosis being based on a series of clinical, endoscopic and histological criteria, as well as on the exclusion of infectious diseases with similar symptoms.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> Both its extension and severity vary in time for all patients; hence, the definition of a specific clinical scenario demands taking both the severity and the extension of the disease into account, in accordance with the definitions suggested by the World Gastroenterology Organization (WGO) in the “Montreal Classification”.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> Moreover, the disease can remain in a situation of clinical remission, requiring the application of different treatment strategies in situations of activity or remission. It has been established that certain maintenance treatments quite significantly reduce the probability of new flares of activity.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> Even though it was described at the end of the XIX century, its frequency over different populations has changed notably, especially during the second half of the XX century, together with other immune diseases and with a clear sustained tendency to increase with social and economic development. Because it frequently starts in youth or even in childhood, and its mortality is low, its prevalence is considerably higher (at last 20 or 30 times its incidence).<a class="elsevierStyleCrossRef" href="#bib0020">4</a> In Spain, epidemiological data suggest that up to the 1980s, it was an uncommon disease. However, over the past 30 years, it has reached incidence rates that are very similar to the ones described previously in north European countries and, in fact, in the most recent studies, data are completely similar.<a class="elsevierStyleCrossRef" href="#bib0025">5</a>This disease has been treated with drugs, surgery or both. In the first half of the XX century, treatment procedures, such as sulfasalazine, were introduced empirically; but already in 1955 the first clinical randomized controlled trial was published and showed that hydrocortisone was superior to placebo in the treatment of moderate or severe UC flares.<a class="elsevierStyleCrossRef" href="#bib0030">6</a> Up to 1980, observational studies of varying quality were predominant. Henceforth, numerous controlled clinical trials, epidemiological analyses, assessments of diagnostic measures and even complex genetic studies<a class="elsevierStyleCrossRef" href="#bib0035">7</a> have been carried out with an ever more solid scientific methodology. Currently, there are numerous nutritional, pharmacological, surgical and monitoring and follow-up alternatives available.<a class="elsevierStyleCrossRefs" href="#bib0040">8,9</a> Their application over the broad range of clinical scenarios with such diverse individual and social circumstances is not always easy and is one of the reasons that justify the creation of these guidelines.2Need for guidelinesAs this is a common, chronic disease that affects mostly young people and that has a increasing prevalence, the health, economic and social repercussions perfectly justify the need for tools to systematize the treatment of UC. However, we will point out other reasons for its creation in more detail.In the first place, the professionals involved in this entity are quite numerous. A partial list would include a gastroenterologist, a surgeon, a primary care physician, a nutritionist, a psychologist, a nurse, a stomatherapist, a rheumatologist, an ophthalmologist and a dermatologist. The need for coordination between these professionals and the patient also justifies the need for a Clinical Practice Guidelines (CPG).There is great evidence<a class="elsevierStyleCrossRef" href="#bib0050">10</a> that the usual variability of clinical practice affects patients with inflammatory bowel disease (IBD) quite significantly, with important clinical, economical, and social repercussions. In fact, a recent European collaborative study reflected enormous differences in the total cost of the management of the disease, regardless of the country's per capita income, and, what is clinically most significant, they reflected great differences in the distribution of this cost: the proportion of patients treated surgically was very variable (in UC between 10 and 40%).<a class="elsevierStyleCrossRef" href="#bib0055">11</a> This variability also justifies the need for a CPG.There are already several publications bearing the word “guidelines” in their title, being the most important among them for their rigour and diffusion the British guidelines (British Society of Gastroenterology),<a class="elsevierStyleCrossRef" href="#bib0060">12</a> the American guidelines<a class="elsevierStyleCrossRef" href="#bib0065">13</a> (American College of Gastroenterology), the guidelines of the World Gastroenterology Organization,<a class="elsevierStyleCrossRef" href="#bib0070">14</a> the guidelines of the “Asian Pacific” consensus group<a class="elsevierStyleCrossRef" href="#bib0075">15</a> and the European guidelines<a class="elsevierStyleCrossRefs" href="#bib0080">16,17</a> (European Crohn and Colitis Organization). Although these publications, especially the latter, are of great quality and are based on the clinical evidence available, they are actually consensus documents that are more or less elaborate. To our knowledge, there is no CPG in the world created based on a structured and systematic methodology.<a class="elsevierStyleCrossRef" href="#bib0090">18</a>One of the main objectives of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis (<a href="http://www.geteccu.org/">GETECCU</a>) is to improve the care of patients with inflammatory bowel disease, and strategically, it has established the creation of CPGs that serve as an aid for healthcare professionals, patients, researchers and payers. In the first phase of the project, we focus on the treatment of inflammatory bowel diseases.3Definitions<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">-Target population: Patients of any gender and age who are diagnosed with UC according to the internationally accepted criteria by Lennard-Jones<a class="elsevierStyleCrossRef" href="#bib0005">1</a> (<a class="elsevierStyleCrossRef" href="#tbl0660">Table 1</a>). These criteria are accepted by both the WGO<a class="elsevierStyleCrossRef" href="#bib0070">14</a> (World Gastroenterology Organization) and the ECCO<a class="elsevierStyleCrossRef" href="#bib0080">16</a> (European Crohn and Colitis Organization).<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0010">∘Complementary guidelines will be developed in the future to specify independent aspects that are relevant to the paediatric population, as well as special clinical scenarios.</li></ul><elsevierMultimedia ident="tbl0660"></elsevierMultimedia></li><li class="elsevierStyleListItem" id="lsti0015">-Ulcerative colitis (UC):<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0020">∘Severity criteria: The ones defined by the Montreal Classification,<a class="elsevierStyleCrossRef" href="#bib0010">2</a> whose validity has recently been ratified by a group of experts<a class="elsevierStyleCrossRef" href="#bib0095">19</a> (<a class="elsevierStyleCrossRef" href="#tbl0665">Table 2</a>):<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0025">▪Ulcerative colitis<ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0030">•Remission</li><li class="elsevierStyleListItem" id="lsti0035">•Mild</li><li class="elsevierStyleListItem" id="lsti0040">•Moderate</li><li class="elsevierStyleListItem" id="lsti0045">•Severe</li></ul></li><li class="elsevierStyleListItem" id="lsti0050">▪Confusing terms such as fulminant colitis or “very severe” will be avoided.</li><li class="elsevierStyleListItem" id="lsti0055">▪The differences between moderate-severe flare in the studies found in literature, especially pharmacological–biological studies, are not always well established (Box 1).</li><li class="elsevierStyleListItem" id="lsti0060">▪We will use the severity scale used in the Montreal Classification,<a class="elsevierStyleCrossRef" href="#bib0010">2</a> which has actually been extrapolated from the index that has been used longer, the Truelove–Witts index<a class="elsevierStyleCrossRef" href="#bib0030">6</a> (<a class="elsevierStyleCrossRef" href="#tbl0670">Table 3</a>) that in some publications, particularly Spanish publications, has been modified in a semi-quantitative manner (<a class="elsevierStyleCrossRef" href="#tbl0675">Table 4</a>). Actually, this index has not been validated formally in any study, and its use may be controversial<a class="elsevierStyleCrossRef" href="#bib0100">20</a> (Box 2). In fact, there is no reference clinical index of activity, that is why it is necessary to be familiar with many of them in order to interpret the results of the studies.<a class="elsevierStyleCrossRefs" href="#bib0100">20,21</a> We provide the most important ones:<ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0065">-The Mayo Index (DAI)<a class="elsevierStyleCrossRef" href="#bib0110">22</a> (<a class="elsevierStyleCrossRef" href="#tbl0680">Table 5</a>)<elsevierMultimedia ident="tbl0680"></elsevierMultimedia></li><li class="elsevierStyleListItem" id="lsti0070">-SEO's Index<a class="elsevierStyleCrossRef" href="#bib0115">23</a> (<a class="elsevierStyleCrossRef" href="#tbl0685">Table 6</a>)<elsevierMultimedia ident="tbl0685"></elsevierMultimedia></li><li class="elsevierStyleListItem" id="lsti0075">-Lichtiger's Index<a class="elsevierStyleCrossRef" href="#bib0120">24</a> (<a class="elsevierStyleCrossRef" href="#tbl0690">Table 7</a>)<elsevierMultimedia ident="tbl0690"></elsevierMultimedia></li><li class="elsevierStyleListItem" id="lsti0080">-The Walmsley Index, known as the Simple Activity Index<a class="elsevierStyleCrossRef" href="#bib0125">25</a> (<a class="elsevierStyleCrossRef" href="#tbl0695">Table 8</a>)<elsevierMultimedia ident="tbl0695"></elsevierMultimedia></li><li class="elsevierStyleListItem" id="lsti0085">-PUCAI (Paediatric Ulcerative Colitis Activity Index)<a class="elsevierStyleCrossRef" href="#bib0130">26</a> (<a class="elsevierStyleCrossRef" href="#tbl0700">Table 9</a>). Actually, this is the only index with a correct methodological validation, but it has only been used in paediatric population.<elsevierMultimedia ident="tbl0700"></elsevierMultimedia></li></ul><elsevierMultimedia ident="tbl0670"></elsevierMultimedia><elsevierMultimedia ident="tbl0675"></elsevierMultimedia></li></ul><elsevierMultimedia ident="tbl0665"></elsevierMultimedia></li><li class="elsevierStyleListItem" id="lsti0090">∘Extension criteria: The ones defined in the Montreal Classification.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> We must admit the fundamental limit of this classification: the extension may change over time and, in fact, a variable part of proctitis cases will evolve to a more extensive colitis<a class="elsevierStyleCrossRef" href="#bib0095">19</a>; however, for the analysis of the therapeutic effect, this is of a minor importance, because the colitis is analyzed at the extension it has at the moment the study is carried out:<ul class="elsevierStyleList" id="lis0035"><li class="elsevierStyleListItem" id="lsti0095">▪Extensive UC: involving the rectum beyond the splenic angle.</li><li class="elsevierStyleListItem" id="lsti0100">▪Left-sided UC: up to the splenic angle.</li><li class="elsevierStyleListItem" id="lsti0105">▪Ulcerative proctitis: limited involvement of the rectum (the upper limit of the inflammation does not go beyond the recto-sigmoid junction).</li></ul></li><li class="elsevierStyleListItem" id="lsti0110">∘Aside from the fundamental definitions, it is necessary to know other terms of regular use in medical literature about UC. As the definition is arbitrary, it would probably be most adequate follow a consensus, and the most accepted international consensus is the one of the ECCO:<a class="elsevierStyleCrossRef" href="#bib0080">16</a><ul class="elsevierStyleList" id="lis0040"><li class="elsevierStyleListItem" id="lsti0115">▪Remission: full resolution of symptoms, accompanied by mucosal healing (this aspect is not evaluated in many studies). Not all the trials use exactly the same definition of remission, and when this is relevant, we will specifically point it out in the text (Box 1).</li><li class="elsevierStyleListItem" id="lsti0120">▪Response: a significant improvement of clinical and/or endoscopic situation (severe to moderate, severe to mild, moderate to mild) without reaching remission.</li><li class="elsevierStyleListItem" id="lsti0125">▪Relapse: a new flare in a patient with an established UC after a remission has been achieved, either spontaneously or after medical treatment.</li><li class="elsevierStyleListItem" id="lsti0130">▪Steroid dependence:<ul class="elsevierStyleList" id="lis0045"><li class="elsevierStyleListItem" id="lsti0135">-the impossibility of reducing the dose of steroids under 10mg/day of prednisone (or its equivalent) after 3 months of starting the steroid treatment or</li><li class="elsevierStyleListItem" id="lsti0140">-a relapse within the first 3 months after having discontinued the treatment with steroids.</li></ul></li><li class="elsevierStyleListItem" id="lsti0145">▪Steroid resistance: A situation of clinical activity in spite of a 4-week treatment at full doses (0.75mg/kg/day of prednisolone or 1mg/kg/day of prednisone, or its equivalent). This definition is very controversial and will most likely be modified in the future. In fact, in the context of a severe flare, the majority of clinicians will define steroid-resistance as the lack of clinical response after the intravenous administration of steroids at full doses for 7 days. Moreover, there is a growing tendency to place the definition in 5 or even 3 days. To the effects of this CPG, we will use the concept of a month for mild or moderate flares, and 7 days for severe flares.</li><li class="elsevierStyleListItem" id="lsti0150">▪Pouchitis: inflammation of the ileal pouch created to maintain the intestine-anus continuity after a total colectomy. In many patients it behaves as a chronic illness.</li><li class="elsevierStyleListItem" id="lsti0155">▪Cuffitis: inflammation of the rectal mucosa cuff that remains in the anal area in some ileo-anal anastomoses.</li></ul></li></ul></li><li class="elsevierStyleListItem" id="lsti0160">-Pharmacological index<ul class="elsevierStyleList" id="lis0050"><li class="elsevierStyleListItem" id="lsti0165">∘Systemic drugs:<ul class="elsevierStyleList" id="lis0055"><li class="elsevierStyleListItem" id="lsti0170">▪Salicylates: sulfasalazine, mesalazine</li><li class="elsevierStyleListItem" id="lsti0175">▪Oral steroids:<ul class="elsevierStyleList" id="lis0060"><li class="elsevierStyleListItem" id="lsti0180">-Systemic steroids: hydrocortisone, prednisone, methylprednisolone, deflazacort, betamethasone, dexamethasone.</li><li class="elsevierStyleListItem" id="lsti0185">-Topical action: beclomethasone dipropionate (BDP), budesonide</li></ul></li><li class="elsevierStyleListItem" id="lsti0190">▪Immunomodulating drugs (immunosuppressants):<ul class="elsevierStyleList" id="lis0065"><li class="elsevierStyleListItem" id="lsti0195">-Thiopurine agents: azathioprine, mercaptopurine, thioguanine</li><li class="elsevierStyleListItem" id="lsti0200">-Methotrexate</li><li class="elsevierStyleListItem" id="lsti0205">-Calcineurinics: cyclosporine, tacrolimus</li></ul></li><li class="elsevierStyleListItem" id="lsti0210">▪Biological agents: infliximab, adalimumab.</li><li class="elsevierStyleListItem" id="lsti0215">▪Heparin.</li></ul></li><li class="elsevierStyleListItem" id="lsti0220">∘Topical drugs<ul class="elsevierStyleList" id="lis0070"><li class="elsevierStyleListItem" id="lsti0225">▪Mesalazine</li><li class="elsevierStyleListItem" id="lsti0230">▪Steroids<ul class="elsevierStyleList" id="lis0075"><li class="elsevierStyleListItem" id="lsti0235">-Oral administration: beclomethasone, budesonide</li><li class="elsevierStyleListItem" id="lsti0240">-Rectal administration:<ul class="elsevierStyleList" id="lis0080"><li class="elsevierStyleListItem" id="lsti0245">•High systemic bioavailability: hydrocortisone, prednisolone, triamcinolone, methylprednisolone and betamethasone</li><li class="elsevierStyleListItem" id="lsti0250">•Low systemic bioavailability: budesonide, beclomethasone and prednisolone-metasulphobenzoate</li></ul></li></ul></li></ul></li><li class="elsevierStyleListItem" id="lsti0255">∘Other treatment techniques:<ul class="elsevierStyleList" id="lis0085"><li class="elsevierStyleListItem" id="lsti0260">▪Aphaeresis: leucocyte aphaeresis, granulocyte aphaeresis</li></ul></li></ul></li></ul>4ObjectivesThe objectives were defined by the Elaboration Committee (see <a class="elsevierStyleCrossRefs" href="#sec0175">Appendices</a>), following the GRADE working methodology.<a class="elsevierStyleCrossRef" href="#bib0135">27</a> In summary, after choosing the three clinical scenarios to which recommendations may be applied (induction of remission in severe colitis, induction of remission in mild-to-moderate colitis, and maintenance of remission); in each of the scenarios, the possible variables of result were explained and defined in a numeric scale from 1 to 9 (1–3: are not included; 4–6: important but not critical; and 7–9: critical for decision-making) by the nine members of the Elaboration Committee. After being classified in order of importance, variables with an average score above 4 were included as result variables. In all the critical variables, the degree of internal agreement of the Committee was excellent, with unanimity in the score or with a maximum variability of one point. After this previous process, the following were defined as CPG objectives:<ul class="elsevierStyleList" id="lis0090"><li class="elsevierStyleListItem" id="lsti0265">▪To establish recommendations based on available tests for the induction treatment in the severe UC flare prioritizing the following assessment variables:</li></ul><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><ul class="elsevierStyleList" id="lis0095"><li class="elsevierStyleListItem" id="lsti0270">▪To establish recommendations for the induction treatment in the mild–moderate UC flare prioritizing the following assessment variables:</li></ul><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><ul class="elsevierStyleList" id="lis0100"><li class="elsevierStyleListItem" id="lsti0275">▪To establish recommendations for the maintenance treatment of UC in remission prioritizing the following assessment variables:</li></ul><elsevierMultimedia ident="tbl0015"></elsevierMultimedia>5Methodology<ul class="elsevierStyleList" id="lis0105"><li class="elsevierStyleListItem" id="lsti0280">∘For the elaboration of the CPG, AGREE methodology was followed, which is described in detail on the web page: <a href="http://www.agreecollaboration.org/">www.agreecollaboration.org</a>. Briefly, an interdisciplinary working team was formed, structured in a Design Committee (general for the different CPG promoted by <a href="http://www.geteccu.org/">GETECCU</a>), an Elaboration Committee (for the three first CPG), a Working Committee (specific for this CPG), an Internal Review Committee (for the three first CPG) and an External Review Committee (specific for this CPG). The External Review Committee included gastroenterologists, surgeons, primary care physicians, nurses and patients. A more detailed composition of all these committees is presented in the guidelines’ <a class="elsevierStyleCrossRefs" href="#sec0175">Appendices</a>. Throughout the entire process, both in the formation of the team as well as in the areas in which it was necessary, the methodological support of the specialized Cochrane Collaboration staff was available. After the objectives were defined by the Elaboration Committee, the Working Committee carried out a Systematic Literature Review, specifically directed at answering the key questions posed previously. After the information was obtained, it underwent an evaluation process, following the GRADE methodology.<a class="elsevierStyleCrossRef" href="#bib0140">28</a> Thus, the quality of the studies was evaluated considering the study's design, their consistency and the direct and indirect evidence. Considering a combination of the four components, quality was defined as High (very unlikely that new studies change the estimation), Moderate (it is likely that new studies change the reliability of the result), Low (it is very likely that new studies will have an impact on the result's reliability and that they might modify it) and Very low (any estimated results are very doubtful). Aside from the essential factors mentioned, for the overall estimation of quality of the evidence, other factors such as the number of patients studied, the strength of the associations that were found, the presence of dose–response gradients (in pharmacological studies) and the acknowledgement or not of possible confounding factors identified by the evaluators were taken into account. In any case, all of these factors are considered cumulatively and with a specific methodology that may be consulted in the references. In order to establish recommendations, we considered not only the quality of the evidence, but we also carried out a weighing between the potential benefits of the intervention, its risks, and its applicability in the population that will be treated and, finally, its costs. Even without having analyzed formal cost-effectiveness analyses, costs are always considered from a global standpoint and are compared, not only considering direct costs, but also the indirect costs and the context (regarding the costs of alternatives). The recommendations issued are classified into four degrees: recommendation or we recommend, which implies strongly advising the clinician: Do it; suggestion or we suggest which means to advise the clinical probably do it; suggestion against or we do no suggest which implies the same as probably don’t do it; and we recommend avoiding or we do not recommend which strongly and clearly indicates don’t do it. This type of classification is both easily understandable and flexible, because it can be adapted to the very different clinical scenarios possible.</li><li class="elsevierStyleListItem" id="lsti0285">∘The Systematic Literature Review was carried out with free and conditioned searches in the following databases: PUBMED, EMBASE, TRIPDATABASE, and COCHRANE COLLABORATION, as well as in textbooks and by cross-referencing several studies. A review was carried out for each one of the questions asked. Furthermore, cross references were carried out in specialty texts and in all the recent reviews. In all the cases in which a systematic review was already published, it was used if its methodology was deemed adequate by the Working Committee, following the criteria of the Cochrane Foundation. If there were doubts about the methodology, the source data were reviewed, and if there were several systematic reviews, the choice was made firstly based on methodological criteria, and secondly, on time criteria (the most recent cases were preferred in case of methodological equivalence). Only documents published completely were evaluated. Nonetheless, at the moment of the final writing of the Guidelines, the Writing Committee considered some results reported formally during the last national and international congresses on some specific points that will be specified in the text. The limit for the inclusion of studies is February 2011. In the reference list, we only include key studies, systematic reviews and quotes after these.</li><li class="elsevierStyleListItem" id="lsti0290">∘This CPG will be of free and universal access. It will be published in several formats (hard and soft copy) and will be available freely on the Internet to be accessed accessible by any professional and/or patient.</li><li class="elsevierStyleListItem" id="lsti0295">∘The information will be presented answering general questions posed in three formats: review of the evidence, summarized explanatory text and decision algorithms. In sum, the evidence is presented answering each one of the questions asked, whereas the explanatory texts are articulated around the six specific algorithms that have been elaborated.</li><li class="elsevierStyleListItem" id="lsti0300">∘The strategic decisions about the CPG will be taken by GETECCU, represented by its Board of Directors, and by the Guidelines Elaboration Committee named to this effect.</li><li class="elsevierStyleListItem" id="lsti0305">∘The costs are covered by GETECCU, who has obtained a GRANT (with no restrictions) from MSD.</li><li class="elsevierStyleListItem" id="lsti0310">∘The conflicts of interest of the authors are explained in Appendix.</li></ul>6Induction of remission in patients with active ulcerative colitisAny situation in which the patient has symptoms and/or signs indicating disease activity is considered an active colitis. In case of doubt, endoscopy and histology are reference techniques for defining the symptoms. For severity and extension we used the Montreal Classification<a class="elsevierStyleCrossRef" href="#bib0010">2</a> (<a class="elsevierStyleCrossRef" href="#tbl0665">Table 2</a>). The key information necessary for the clinician is summarized in algorithms 1, 2 and their corresponding explanatory text. The review of the evidence is presented by answering the questions elaborated by the working group.6.1Severe UC flare (of any anatomical extension) (<a class="elsevierStyleCrossRef" href="#enun0005">Algorithm 1</a>)6.1.1Steroids<ul class="elsevierStyleList" id="lis0110"><li class="elsevierStyleListItem" id="lsti0315">-Are steroids effective in induction of remission in patients with a severe UC flare?</li></ul>Text of the guidelines:<elsevierMultimedia ident="tbl0020"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0025"></elsevierMultimedia>Formulation of the recommendation<elsevierMultimedia ident="tbl0030"></elsevierMultimedia>Comment by the elaborating group:<elsevierMultimedia ident="tbl0035"></elsevierMultimedia>6.1.2Immunomodulators<ul class="elsevierStyleList" id="lis0115"><li class="elsevierStyleListItem" id="lsti0320">-Is cyclosporine effective in induction of remission in patients with a severe UC flare? and in a situation of steroid resistance?</li></ul>Text of the guidelines:<elsevierMultimedia ident="tbl0040"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0045"></elsevierMultimedia>Formulation of the recommendation<elsevierMultimedia ident="tbl0050"></elsevierMultimedia>Comment by the elaborating group<elsevierMultimedia ident="tbl0055"></elsevierMultimedia><ul class="elsevierStyleList" id="lis0120"><li class="elsevierStyleListItem" id="lsti0325">-Is tacrolimus effective in induction of remission in patients with a severe UC flare? and in a situation of steroid resistance?</li></ul>Text of the guidelines:<elsevierMultimedia ident="tbl0060"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0065"></elsevierMultimedia>Formulation of the recommendation<elsevierMultimedia ident="tbl0070"></elsevierMultimedia>Comment by the elaborating group<elsevierMultimedia ident="tbl0075"></elsevierMultimedia>6.1.3Biological treatments<ul class="elsevierStyleList" id="lis0125"><li class="elsevierStyleListItem" id="lsti0330">-Is infliximab effective in induction of remission in patients with a severe UC flare? and in a situation of steroid resistance?</li></ul>Text of the guidelines:<elsevierMultimedia ident="tbl0080"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0085"></elsevierMultimedia>Formulation of the recommendation<elsevierMultimedia ident="tbl0090"></elsevierMultimedia>Comment by the elaborating group<elsevierMultimedia ident="tbl0095"></elsevierMultimedia>6.1.4Heparin<ul class="elsevierStyleList" id="lis0130"><li class="elsevierStyleListItem" id="lsti0335">-Is heparin (at anti-coagulant doses) effective in induction of remission in patients with a severe UC flare?</li></ul>Text of the guidelines:<elsevierMultimedia ident="tbl0100"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0105"></elsevierMultimedia>Formulation of the recommendation<elsevierMultimedia ident="tbl0110"></elsevierMultimedia>Comment by the elaborating group<elsevierMultimedia ident="tbl0115"></elsevierMultimedia>6.1.5Antibiotics<ul class="elsevierStyleList" id="lis0135"><li class="elsevierStyleListItem" id="lsti0340">-Are antibiotics effective in induction of remission in patients with a severe UC flare?</li></ul>Text of the guidelines:<elsevierMultimedia ident="tbl0120"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0125"></elsevierMultimedia>Formulation of the recommendation<elsevierMultimedia ident="tbl0130"></elsevierMultimedia>Comment by the elaborating group<elsevierMultimedia ident="tbl0135"></elsevierMultimedia>6.1.6Surgery<ul class="elsevierStyleList" id="lis0140"><li class="elsevierStyleListItem" id="lsti0345">-Is surgery effective in induction of remission in patients with a severe UC flare?</li></ul>Colectomy was established as treatment for UC when there were no medical alternatives. Gradually, with technical advances in anaesthesia and in postoperative control, colectomy reached mortality rates that are clearly below the spontaneous course of the flare. The absence of controlled studies in this field is one of the clearest examples of situations that are self-evident, but impossible to demonstrate. There is no reasonable doubt that colectomy is a very effective treatment in severe UC flares, a scenario for which, in the absence of medical treatment, mortality rates of 22–77% were described. Even if we do not have controlled studies either, the results of the Oxford series in the 1960s and 1970s in studies conducted by Sidney Truelove in the steroid era<a class="elsevierStyleCrossRef" href="#bib0275">55</a> are very convincing. The best results were obtained when a fixed day was set a priori in which the patient with no response to steroids was intervened (in the Oxford series, this was decided to be on the fifth day of treatment; in the Scandinavian series, it was decided to be a little later, but it yielded very similar results<a class="elsevierStyleCrossRef" href="#bib0280">56</a>). It is curious to see how, after introducing new medical alternatives such as cyclosporine or infliximab, most experts emphasize on making an early decision (third, fifth, seventh or tenth day, according to the authors). On some occasions, surgery is the best choice: perforation, severe haemorrhage that is not controlled with endoscopic treatment, toxic megacolon of more than 72h duration. In others, it is probably the preferred choice: e.g., severe colitis with a very prolonged clinical history and/or a previous diagnosis of dysplasia. In most cases, however, it is just a back-up option and it is only indicated if the previous medical treatment has failed. In any case, uncontrolled but extensive experience suggests that in the severe UC flare treatment, the collaboration of a surgical team from the moment the patient is admitted helps make more coherent decisions every time, taking into consideration several treatment options.Summary of the evidence<elsevierMultimedia ident="tbl0140"></elsevierMultimedia>Formulation of the recommendation:<elsevierMultimedia ident="tbl0145"></elsevierMultimedia>Comment by the elaborating group:<elsevierMultimedia ident="tbl0150"></elsevierMultimedia>6.1.7Parenteral nutrition<ul class="elsevierStyleList" id="lis0145"><li class="elsevierStyleListItem" id="lsti0350">-Is parenteral nutrition effective in induction of remission in patients with a severe UC flare?</li></ul>There are not enough studies to create a GRADE table in the case of parenteral nutrition either. However, we can state several basic principles, either due to the existence of controlled studies, or the existence of direct and/or experimental data.<a class="elsevierStyleCrossRef" href="#bib0285">57</a><ul class="elsevierStyleList" id="lis0150"><li class="elsevierStyleListItem" id="lsti0355">•In contrast with what was suggested in the first half of the XX century, absolute diet does not have any primary therapeutic effectiveness and hence, except in cases of absolute oral intolerance, intestinal obstruction or extreme severity, oral nutrition must not be discontinued.</li><li class="elsevierStyleListItem" id="lsti0360">•Parenteral nutrition has no primary efficacy in the treatment of UC, and generally, enteral nutrition must be preferred.<a class="elsevierStyleCrossRef" href="#bib0290">58</a> Moreover, it is more expensive and it entails a higher risk of infection and thromboembolic phenomena when compared to enteral nutrition.</li><li class="elsevierStyleListItem" id="lsti0365">•In case a complete caloric and nutritional supply cannot be assured, enteral nutrition must be used, either as a supplement or even as the sole source of nutrition.</li><li class="elsevierStyleListItem" id="lsti0370">•In case of severe flares, a relatively extensive hospital stay should be foreseen. There are studies from the 1980s,<a class="elsevierStyleCrossRef" href="#bib0295">59</a> corroborated in years as recent as 2008<a class="elsevierStyleCrossRef" href="#bib0300">60</a>; showing that hospitalized patients are discharged (on average) in a worse nutritional condition than the one they had on admission. Moreover, numerous experimental and clinical tests confirm that an adequate nutrition is necessary for the correct functioning of the immune system. In patients with severe UC, the risk of nosocomial infections, either opportunistic or not, is very high due to several factors: hospitalization, use of tubes and catheters, an increased intestinal permeability (rupture of the mucous barrier), malnourishment and the use of immunomodulating drugs being the most important. The measures for the control of infections will help reduce the risk, but we can ensure a greater medical impact by assuring a proper nutrition. Also, we can decrease the negative effects of some drugs, keeping a good nutritional status (calcium and vitamin D to prevent osteoporosis; prevention of hypercholesterolemia and hypomagnesaemia in case cyclosporine is used).</li></ul>Summary of the evidence:<elsevierMultimedia ident="tbl0155"></elsevierMultimedia>Formulation of the recommendation:<elsevierMultimedia ident="tbl0160"></elsevierMultimedia>Comment by the elaborating group:<elsevierMultimedia ident="tbl0165"></elsevierMultimedia>Algorithm 1Severe flare: algorithm and explanatory text<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Treatment of severe UC flare is summarized in <a class="elsevierStyleCrossRef" href="#enun0005">Algorithm 1</a>. When the diagnosis of severe UC flare is established, in most cases hospitalization is a prudent strategy.<a class="elsevierStyleCrossRefs" href="#bib0040">8,13,17,61</a> From the first moment, a strategy must be proposed that includes immediate measures, the options in case these fail and also the possible treatment in the mid and long term. Therefore, all the diagnostic information must be reviewed (<a class="elsevierStyleCrossRef" href="#tbl0705">Table 10</a>) by re-evaluating all the data that may be of interest when it comes to making decisions in each specific case.<a class="elsevierStyleCrossRef" href="#bib0305">61</a><elsevierMultimedia ident="tbl0705"></elsevierMultimedia>In most cases, the initial treatment (except if there is an absolute contraindication due to previous severe toxicity (for instance, steroid-associated psychosis) or a situation of surgical urgency) will be based on the administration of intravenous steroids, with a dose equivalent to 1mg/kg of prednisone per day. It can be administered in a single or fragmented dose, or even in continuous infusion. Furthermore, the treatment with other measures must be completed in order to prevent thromboembolism, obtain an adequate nutrition and, in selected cases, administer antibiotics (<a class="elsevierStyleCrossRef" href="#tbl0710">Table 11</a>). The clinical follow-up must be, at minimum, daily, and preferably jointly managed with the surgeon. It is practical to include in the diagnostic evaluation those tests that inform us about the risks of the side effects of infliximab, cyclosporine or azathioprine, as they may allow to start the treatments with a greater safety, and if found to be necessary, instituting the necessary preventive measures.<elsevierMultimedia ident="tbl0710"></elsevierMultimedia>It is advisable to set, from the first day, a time point for evaluating the response, and it is most adequate to do it between the third and fifth day after starting the treatment. In fact, currently most authors tend to recommend an initial evaluation at 72h.<a class="elsevierStyleCrossRef" href="#bib0305">61</a> At that moment, the patient may have reached remission (in which case, he/she will progressively move from the treatment phase to the maintenance phase) or not. If remission has not been obtained, there are several indices (for example, Ho's index,<a class="elsevierStyleCrossRef" href="#bib0310">62</a><a class="elsevierStyleCrossRef" href="#tbl0715">Table 12</a>) that allow us to predict the probability of response if the steroid treatment were to be extended. A recent simple model, evaluated prospectively in a hospital, suggests that with four parameters (rectal bleeding, CRP, platelet count and the number of bowel movements) evaluated by the third day, it may be decided with great precision if it is necessary to switch to another treatment or not. If this were to be confirmed in other sites, this model may allow us to make decisions with data available at any other site with great ease.<a class="elsevierStyleCrossRef" href="#bib0315">63</a> On occasions, the situation is very clear, and a new medical treatment (infliximab or cyclosporine) is initiated between the third and fifth days. In other patients, the situation is not that clear, and it is preferred to carry out a re-evaluation between the fifth and seventh days after starting on steroids. If remission has not been reached by the seventh day it is best to start the alternative treatment.<elsevierMultimedia ident="tbl0715"></elsevierMultimedia>When steroids fail, there are mainly three options: cyclosporine, infliximab and surgery. The lack of comparative studies hinders us from being specific. In this decision node, the opinion of the well-informed patient is very important, with the collaboration of relatives and associated people, and it is absolutely necessary to rule out other causes of refractoriness, especially a colon infection by CMV<a class="elsevierStyleCrossRef" href="#bib0320">64</a> and by Clostridium difficile (by means of the study of signs of infection by CMV in a rectal biopsy, and by looking for specific toxins in faeces, respectively). The following favour surgery: a prolonged history of the disease and/or the presence of dysplasia in previous controls, as well as two clinical situations: toxic megacolon and massive haemorrhage. However, in almost all cases, a medical option can be tried. If the patient has suffered a severe flare while already on treatment with thiopurines (drugs that would be necessary in the post-cyclosporine maintenance treatment), it would, probably, be most indicated to use infliximab. In the rest of the cases, the choice may be between cyclosporine<a class="elsevierStyleCrossRef" href="#bib0185">37</a> or infliximab,<a class="elsevierStyleCrossRef" href="#bib0215">43</a> a decision in which the team's experience and other local factors (the possibility of determining blood levels of cyclosporine, for example) are determinant. The general recommendations for the use of infliximab<a class="elsevierStyleCrossRef" href="#bib0325">65</a> (<a class="elsevierStyleCrossRef" href="#tbl0720">Table 13</a>) or cyclosporine<a class="elsevierStyleCrossRef" href="#bib0185">37</a> must be followed (<a class="elsevierStyleCrossRefs" href="#tbl0725">Tables 14–16</a>).<elsevierMultimedia ident="tbl0720"></elsevierMultimedia><elsevierMultimedia ident="tbl0725"></elsevierMultimedia><elsevierMultimedia ident="tbl0730"></elsevierMultimedia><elsevierMultimedia ident="tbl0735"></elsevierMultimedia>In any of the medical options chosen, a new moment of evaluation must be planned, and probably, it would be most reasonable to carry out an evaluation after seven days of having started the new treatment. At this point, there are no set norms. If there is a worsening or an absolute lack of improvement, in most cases, the most reasonable course of action is surgery; if there is remission, we may move on to the maintenance regimen. Nonetheless, it is very common for intermediate situations to take place, in which all the possibilities must be evaluated. Thus, it has been described that in spite of the failure with cyclosporine, some patients may avoid surgery by using infliximab,<a class="elsevierStyleCrossRef" href="#bib0330">66</a> and also, less frequently, the opposite path has been taken.In all the decision nodes, the opinion of the patient, or that of his/her relatives and/or friends, the opinion of the surgeon and the opinion of the gastroenterologist must be considered carefully. We cannot emphasize enough on how relevant it is to share all the information with the patient from the start.6.2Mild and moderate UC flare (<a class="elsevierStyleCrossRef" href="#enun0010">Algorithm 2</a>)6.2.1Salicylates<ul class="elsevierStyleList" id="lis0155"><li class="elsevierStyleListItem" id="lsti0375">-Is the treatment with oral salicylates effective in induction of remission in patients with a mild–moderate UC flare?</li></ul>Text of the guidelines:<elsevierMultimedia ident="tbl0170"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0175"></elsevierMultimedia>Formulation of the recommendation<elsevierMultimedia ident="tbl0180"></elsevierMultimedia>Comment by the elaborating group:<elsevierMultimedia ident="tbl0185"></elsevierMultimedia><ul class="elsevierStyleList" id="lis0160"><li class="elsevierStyleListItem" id="lsti0380">-Is the combined treatment with oral and topical salicylates more effective than oral treatment alone in induction of remission in patients with a mild–moderate UC flare?</li></ul>Text of the guidelines:<elsevierMultimedia ident="tbl0190"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0195"></elsevierMultimedia>Formulation of the recommendation<elsevierMultimedia ident="tbl0200"></elsevierMultimedia>Comment by the elaborating group<elsevierMultimedia ident="tbl0205"></elsevierMultimedia><ul class="elsevierStyleList" id="lis0165"><li class="elsevierStyleListItem" id="lsti0385">-Is the treatment with topical salicylates alone effective in induction of remission in patients with a mild–moderate flare of left-sided UC?</li></ul>Text of the guidelines:<elsevierMultimedia ident="tbl0210"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0215"></elsevierMultimedia>Formulation of the recommendation<elsevierMultimedia ident="tbl0220"></elsevierMultimedia>Comment by the elaborating group:<elsevierMultimedia ident="tbl0225"></elsevierMultimedia><ul class="elsevierStyleList" id="lis0170"><li class="elsevierStyleListItem" id="lsti0390">-Is treatment with topical salicylates more effective than oral treatment in induction of remission in patients with left-sided UC flare?</li></ul>Text of the guidelines:<elsevierMultimedia ident="tbl0230"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0235"></elsevierMultimedia>Formulation of the recommendation<elsevierMultimedia ident="tbl0240"></elsevierMultimedia>Comment by the elaborating group<elsevierMultimedia ident="tbl0245"></elsevierMultimedia>6.2.2Steroids<ul class="elsevierStyleList" id="lis0175"><li class="elsevierStyleListItem" id="lsti0395">-Are systemic oral steroids effective in induction of remission in patients with mild–moderate UC flares?</li></ul>Text of the guidelines:<elsevierMultimedia ident="tbl0250"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0255"></elsevierMultimedia>Formulation of the recommendation:<elsevierMultimedia ident="tbl0260"></elsevierMultimedia>Comment by the elaborating group:<elsevierMultimedia ident="tbl0265"></elsevierMultimedia><ul class="elsevierStyleList" id="lis0180"><li class="elsevierStyleListItem" id="lsti0400">-Are the new oral steroids of low bioavailability effective in induction of remission in patients with mild–moderate UC flares?</li></ul>Text of the guidelines:<elsevierMultimedia ident="tbl0270"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0275"></elsevierMultimedia>Formulation of the recommendation<elsevierMultimedia ident="tbl0280"></elsevierMultimedia>Comment by the elaborating group<elsevierMultimedia ident="tbl0285"></elsevierMultimedia><ul class="elsevierStyleList" id="lis0185"><li class="elsevierStyleListItem" id="lsti0405">-Is the treatment with rectal steroids effective in induction of remission in patients with a mild–moderate flare of left-sided UC?</li></ul>Text of the guidelines:<elsevierMultimedia ident="tbl0290"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0295"></elsevierMultimedia>Formulation of the recommendation<elsevierMultimedia ident="tbl0300"></elsevierMultimedia>Comment by the elaborating group<elsevierMultimedia ident="tbl0305"></elsevierMultimedia><ul class="elsevierStyleList" id="lis0190"><li class="elsevierStyleListItem" id="lsti0410">-Are low bioavailability rectal steroids more effective than those of high bioavailability in the induction of remission in patients with mild–moderate UC flares?</li></ul>Text of the guidelines:<elsevierMultimedia ident="tbl0310"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0315"></elsevierMultimedia>Formulation of the recommendation:<elsevierMultimedia ident="tbl0320"></elsevierMultimedia>Comment by the elaborating group:<elsevierMultimedia ident="tbl0325"></elsevierMultimedia><ul class="elsevierStyleList" id="lis0195"><li class="elsevierStyleListItem" id="lsti0415">-Are topical salicylates more effective than rectal steroids in the induction of remission in patients with a mild–moderate UC flare?</li></ul>Text of the guidelines:<elsevierMultimedia ident="tbl0330"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0335"></elsevierMultimedia>Formulation of the recommendation<elsevierMultimedia ident="tbl0340"></elsevierMultimedia>Comment by the elaborating group:<elsevierMultimedia ident="tbl0345"></elsevierMultimedia>6.2.3Immunomodulators<ul class="elsevierStyleList" id="lis0200"><li class="elsevierStyleListItem" id="lsti0420">-Are thiopurine immunomodulators effective in induction of remission in patients with a moderate flare of steroid-dependent and/or steroid-resistant UC?</li></ul>Text of the guidelines:<elsevierMultimedia ident="tbl0350"></elsevierMultimedia>Summary of the evidence:<elsevierMultimedia ident="tbl0355"></elsevierMultimedia>Formulation of the recommendation:<elsevierMultimedia ident="tbl0360"></elsevierMultimedia>Comment by the elaborating group:<elsevierMultimedia ident="tbl0365"></elsevierMultimedia><ul class="elsevierStyleList" id="lis0205"><li class="elsevierStyleListItem" id="lsti0425">-Is methotrexate effective in induction of remission in patients with a moderate flare of steroid-dependent UC?</li></ul>Text of the guidelines:<elsevierMultimedia ident="tbl0370"></elsevierMultimedia>Summary of the evidence:<elsevierMultimedia ident="tbl0375"></elsevierMultimedia>Formulation of the recommendation:<elsevierMultimedia ident="tbl0380"></elsevierMultimedia>Comment by the elaborating group:<elsevierMultimedia ident="tbl0385"></elsevierMultimedia>6.2.4Biological therapies<ul class="elsevierStyleList" id="lis0210"><li class="elsevierStyleListItem" id="lsti0430">-Is infliximab effective in induction of remission in patients with a moderate flare of steroid-dependent and/or steroid-resistant UC?</li></ul>Text of the guidelines:<elsevierMultimedia ident="tbl0390"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0395"></elsevierMultimedia>Formulation of the recommendation:<elsevierMultimedia ident="tbl0400"></elsevierMultimedia>Comment by the elaborating group:<elsevierMultimedia ident="tbl0405"></elsevierMultimedia><ul class="elsevierStyleList" id="lis0215"><li class="elsevierStyleListItem" id="lsti0435">-Is adalimumab effective in induction of remission in patients with a moderate flare of steroid-dependent and/or steroid-resistant UC?</li></ul>Text of the guidelines:<elsevierMultimedia ident="tbl0410"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0415"></elsevierMultimedia>Formulation of the recommendation:<elsevierMultimedia ident="tbl0420"></elsevierMultimedia>Comment by the elaborating group:<elsevierMultimedia ident="tbl0425"></elsevierMultimedia>6.2.5Aphaeresis<ul class="elsevierStyleList" id="lis0220"><li class="elsevierStyleListItem" id="lsti0440">-Is the treatment with aphaeresis effective in induction of remission in patients with a moderate flare of steroid-dependent UC?</li></ul>Text of the guidelines:<elsevierMultimedia ident="tbl0430"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0435"></elsevierMultimedia>Formulation of the recommendation<elsevierMultimedia ident="tbl0440"></elsevierMultimedia>Comment by the elaborating group:<elsevierMultimedia ident="tbl0445"></elsevierMultimedia>Algorithm 2Mild to moderate flare: algorithm and explanatory text<elsevierMultimedia ident="fig0010"></elsevierMultimedia>We had to group patients this way, as clinical trials use this classification system. Of course, within the same global definition, an almost infinite number of possible clinical scenarios are included (Box 1). The clinician will recommend very different actions with very mild or almost severe situations: all of them fit the definition. Aside from severity, the clinician needs information about the extension of the disease and (fundamentally) about the response and tolerance to treatments of the specific patient in previous flares. Hence, there are patients who tolerate topical therapy very poorly, or patients in whom mesalazine causes a paradoxical reaction with increased diarrhoea. Once more, we are forced to emphasize on the extraordinary practical importance of a complete medical history. Being the flare mild or moderate, the attitude will be completely different in proctitis, in which the local treatment will be basic, and the rest of colitis in which a combined local and oral treatment will be the norm. Of course, just as between the mildest flare and the most intense moderate flare there is a whole continuum; the limits of the treatment in terms of extension are not absolutely rigid: it may be acceptable to treat a case of proctosigmoiditis exclusively with topical treatment, and it may also be acceptable to treat an extensive colitis exclusively with oral medication.Just as we have reviewed in detail, the clinician has a variety of treatment measures that, generally, he/she uses in an escalated manner: more simple measures and with less risks in the milder flares that broadens if no response is obtained. A strategy of using the less aggressive<a class="elsevierStyleCrossRef" href="#fn0005">a</a> options first is only acceptable if a strategy in the mid and long term that involves knowing the patient's response to the treatment in a reasonable time frame has been planned from the beginning. Actually, it is impossible to define a uniform timeframe exactly, due to the enormous inter-individual variability. Generally speaking, the milder the clinical case, the greater the interval may be before knowing the patient's response, but in no case must it be over one month, in order to be able to choose other treatment systems if the one we have recommended fails. Nowadays we have to bear in mind some factors that may make follow-up easier. First, the communication with the patient does not always have to be in person, as the telephone and the Internet can perfectly work for maintaining a contact that is much more fluent, rapid and simple. Second, within the Units of Inflammatory Disease, the nursing staff has an increasingly more important role, and among their missions it may be included to more closely monitor the patients’ situation. In fact, software tools have been developed that have proven to be helpful in gaining more control in controlled trials. In the entire process, the patient's participation is fundamental, and therefore, all efforts must be made to transmit the information and to listen to the patient's point of view.The therapeutic tools that are managed in most of the mild to moderate active flares are salicylates, low bioavailability steroids and systemic steroids. Furthermore, one can choose between rectal and oral routes, and a combination of both. The algorithm suggests a reasonable path, especially if we start from a mild flare, by progressively adopting more aggressive measures, sequentially. However, depending on the patient's medical history and the severity of the flare, the clinician may recommend to directly starting the treatment regimen in a much more advanced point. Thus, for example, if a patient who is receiving 3g daily of maintenance oral mesalazine, with an extensive colitis, and that presents with a UC flare since a week ago with five bloody bowel movements daily, fever and asthenia, after ruling out infection, it is reasonable to directly begin the treatment with oral steroids, completing the treatment with topical salicylates in the case of intense rectal symptoms being present. Moreover, of course, in this case, follow-up will be carried out in only one week's time, aside from leaving open communication channels with the patient in case there was a previous worsening. That is, depending on the clinical scenario, the history and the specific experiences of the patient, both the patient and the healthcare professionals must come to an agreement that modulates the recommendations of the general algorithm.7Maintenance treatment of patients with ulcerative colitis in remissionColitis in remission is defined as the one in which the patient have a complete resolution of the symptoms accompanied by mucosal healing defined with clinical and endoscopic indices. In routine daily clinical practice, endoscopic assessment is usually not considered necessary, as the clinical assessment of the patients has a sensitivity of 86% and a specificity of 76% and would be defined as the presence of at least 3 bowel movements/day or maybe even better, the recovery of the patient's prior normal bowel rhythm, without rectal bleeding or defecation urgency.7.1Maintenance of remission obtained after a mild–moderate flare7.1.1UC not treated with steroids (<a class="elsevierStyleCrossRef" href="#enun0015">Algorithm 3</a>)<ul class="elsevierStyleList" id="lis0225"><li class="elsevierStyleListItem" id="lsti0445">-Is treatment with oral salicylates effective in maintenance of remission in patients after a mild–moderate UC flare treated with salicylates?</li></ul>Text of the guidelines:<elsevierMultimedia ident="tbl0450"></elsevierMultimedia>Summary of the evidence:<elsevierMultimedia ident="tbl0455"></elsevierMultimedia>Formulation of the recommendation:<elsevierMultimedia ident="tbl0460"></elsevierMultimedia>Comment by the elaborating group:<elsevierMultimedia ident="tbl0465"></elsevierMultimedia><ul class="elsevierStyleList" id="lis0230"><li class="elsevierStyleListItem" id="lsti0450">-Is the treatment with topical salicylates effective in the maintenance of remission in patients after a mild–moderate flare of left sided UC treated with salicylates?</li></ul>Text of the guidelines:<elsevierMultimedia ident="tbl0470"></elsevierMultimedia>Summary of the evidence:<elsevierMultimedia ident="tbl0475"></elsevierMultimedia>Formulation of the recommendation:<elsevierMultimedia ident="tbl0480"></elsevierMultimedia>Comment by the elaborating group:<elsevierMultimedia ident="tbl0485"></elsevierMultimedia>Algorithm 3Maintenance treatment after induction of remission with mesalazine and/or topical steroids: algorithm and explanatory text<elsevierMultimedia ident="fig0015"></elsevierMultimedia>In patients in whom it has not been necessary to use systemic steroids to control the disease, the maintenance treatment with salicylates must always be tried as the first option. There are many years of experience with sulfasalazine and it is a perfectly useful drug, as long as the patient is not a male who is trying to conceive. However, due to safety and convenience, most patients receive treatment with mesalazine. As it is a long-term treatment, the essential point is to achieve good compliance, and for this, it is probably very useful to use a single daily dose, regardless of the pharmaceutical formulation chosen. Fortunately, there are several formulations available nowadays in Spain: 400mg tablets, 500mg tablets, 1g sachets of microgranules, 1.2g tablets and 1.5g sachets of microgranules. The patient's preferences are very important in the selection of one or another form, in order to facilitate compliance. There are also differences in the cost that may be substantial and that could prompt the clinician to recommend one form or another.In the distal forms, the proofs about the efficacy of the maintenance treatment are somewhat weaker, and it is not always easy to achieve good compliance. In fact, given the scarce evidence available in the long term, most authors recommend to maintain treatment only for 6 months if it is the first episode of proctitis, and if it has been mild; and to extend its duration in cases of refractoriness or frequent relapses. It should be assessed how hard it is for patients to permanently adhere to a topical treatment, which is always, at the very least, inconvenient. Adaptation to each circumstance is key in this case, and the information that is well transmitted to the patient is essential to come to an agreement on a treatment in each case.7.1.2Steroid-dependent/steroid-resistant UC (<a class="elsevierStyleCrossRef" href="#enun0020">Algorithm 4</a>)<ul class="elsevierStyleList" id="lis0235"><li class="elsevierStyleListItem" id="lsti0455">-Is the treatment with thiopurine immunomodulators effective in the maintenance of remission in patients after a mild–moderate flare of steroid-dependent UC?</li></ul>Text of the guidelines:<elsevierMultimedia ident="tbl0490"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0495"></elsevierMultimedia>Formulation of the recommendation:<elsevierMultimedia ident="tbl0500"></elsevierMultimedia>Comment by the elaborating group:<elsevierMultimedia ident="tbl0505"></elsevierMultimedia><ul class="elsevierStyleList" id="lis0240"><li class="elsevierStyleListItem" id="lsti0460">-Is methotrexate effective in the maintenance of remission in patients after a mild–moderate flare of steroid-dependent/resistant UC?</li></ul>Text of the guidelines:<elsevierMultimedia ident="tbl0510"></elsevierMultimedia>Summary of the evidence:<elsevierMultimedia ident="tbl0515"></elsevierMultimedia>Formulation of the recommendation:<elsevierMultimedia ident="tbl0520"></elsevierMultimedia>Comment by the elaborating group:<elsevierMultimedia ident="tbl0525"></elsevierMultimedia><ul class="elsevierStyleList" id="lis0245"><li class="elsevierStyleListItem" id="lsti0465">-Is the treatment with infliximab effective in the maintenance of remission in patients after a mild–moderate flare of steroid-dependent/resistant UC?</li></ul>Text of the guidelines:<elsevierMultimedia ident="tbl0530"></elsevierMultimedia>Summary of the evidence:<elsevierMultimedia ident="tbl0535"></elsevierMultimedia>Formulation of the recommendation:<elsevierMultimedia ident="tbl0540"></elsevierMultimedia>Comment by the elaborating group:<elsevierMultimedia ident="tbl0545"></elsevierMultimedia>Algorithm 4Maintenance treatment after induction of remission with systemic steroids: algorithm and explanatory text<elsevierMultimedia ident="fig0020"></elsevierMultimedia>If it is a first flare, and control has been obtained without an excessive difficulty (hospitalization has not been necessary, the response to steroids has been obtained quickly), it is worth to try a maintenance treatment based on the use of mesalazine (oral, and in some cases oral and rectal). However, if the flare has required hospitalization or if the control has been slow and laborious, or if the patient already meets criteria for steroid-dependence, the most reasonable option is to use thiopurines (azathioprine or mercaptopurine). Once again, it is necessary to create awareness for the patient about the importance of compliance. Moreover, regular controls must be instituted to monitor the appearance of a possible toxicity. In case thiopurines failing, either due to toxicity or to lack of efficacy, there are mainly two options. Up until relatively recently, the trend was to recommend the patient elective surgery. However, infliximab has been available for several years, and it obtains a significant response rate in this subgroup of patients. Choosing between both alternatives requires knowing each patient's circumstances, as the clinical scenarios are rather variable. Nowadays, in most cases, the treatment with infliximab is tried first, and only in some circumstances (for example, a long medical history with low-grade dysplasia in the last colonoscopy) is surgery preferred as the first line of treatment. The use of biological agents has represented a very clear advance in these patients, but there are still numerous uncertainties that the clinician must solve in each case: Should we administer immunomodulators simultaneously? If so, for how long? Is there any moment in which we must suppress the biological agent? Only over the next years will useful information be collected to respond to these questions.In some of these patients, there is no response to immunomodulators or to biological agents, and both the clinician and the patient him/herself are reluctant to proceed with surgery because the presentation is not very severe. With the data currently available, this is probably the niche in which aphaeresis has a place. If used, it is recommended to do so within clinical trials, or at least in observational studies, so as to contribute to gathering information that will clarify the exact role that aphaeresis has in these patients. It would also be an option, in patients who respond initially to infliximab but who later lose the response, to try to use adalimumab. Observational studies suggest this.7.2Maintenance of the remission obtained after a severe flare (<a class="elsevierStyleCrossRefs" href="#enun0025">Algorithms 5 and 6</a>)<ul class="elsevierStyleList" id="lis0250"><li class="elsevierStyleListItem" id="lsti0470">-Is the maintenance treatment with thiopurine immunomodulators effective in patients with severe UC who have obtained remission with infliximab? (<a class="elsevierStyleCrossRef" href="#enun0025">Algorithm 5</a>)</li></ul>Text of the guidelines:<elsevierMultimedia ident="tbl0550"></elsevierMultimedia>Summary of the evidence:<elsevierMultimedia ident="tbl0555"></elsevierMultimedia>Formulation of the recommendation:<elsevierMultimedia ident="tbl0560"></elsevierMultimedia>Comment by the elaborating group:<elsevierMultimedia ident="tbl0565"></elsevierMultimedia><ul class="elsevierStyleList" id="lis0255"><li class="elsevierStyleListItem" id="lsti0475">-Is the maintenance treatment with infliximab effective in patients with severe UC who have obtained remission with infliximab? (<a class="elsevierStyleCrossRef" href="#enun0025">Algorithm 5</a>).</li></ul>Text of the guidelines:<elsevierMultimedia ident="tbl0570"></elsevierMultimedia>Summary of the evidence:<elsevierMultimedia ident="tbl0575"></elsevierMultimedia>Recommendation:<elsevierMultimedia ident="tbl0580"></elsevierMultimedia>Comment by the elaborating group:<elsevierMultimedia ident="tbl0585"></elsevierMultimedia>Algorithm 5Maintenance treatment after induction of remission with infliximab: algorithm and explanatory text<elsevierMultimedia ident="fig0025"></elsevierMultimedia>When remission with infliximab has been obtained, we find ourselves with 2 different scenarios, according to whether the patient has taken thiopurines before or not. If the patient had not received them, the rational course of action would be to use the combination of infliximab and thiopurines for a period of time (perhaps six months to a year) and then try to withdraw infliximab. Not enough studies have been published, but some experts warn against this possibility, because when relapses appear, when trying to control them again by reintroducing infliximab, failure could be frequent. If the patient had already been treated with thiopurines, he/she must continue the treatment with infliximab as maintenance. Although it is not reflected in the algorithm, we may also distinguish two different situations in this scenario. The first would be when thiopurines had been withdrawn due to a prior severe toxicity. In this case, it is clear that maintenance should be made with infliximab as monotherapy. It could be discussed whether to combine mesalazine as, although there are no specific inconveniences for the association, no advantages have been shown either. The second situation would be those patients in whom thiopurines had failed. In this case, they also require maintenance with infliximab, but it seems reasonable to maintain the association with thiopurines at least for six months in order to reduce the immunogenicity of the anti-TNF agent. In the long term, in every case, the real (cost) or possible (risks) disadvantages of biological agents must be weighed against their advantages (perhaps a greater response rate). There are no data that allow us to establish a uniform recommendation in these patients. In any case, all the changes must be made with the patient in remission, and very likely at the moment of making decisions, in a subgroup of patients who require these complex medications for the control, remission must be defined clinically, through laboratory tests, endoscopically, and maybe even histologically.If, in the course of the disease of these patients, there is failure with infliximab in spite of its “intensification” (either due to toxicity, or due to a loss of response), surgery must be proposed. The treatment with adalimumab is worth trying as compassionate use, because a series of observational studies suggest that this alternative may be effective in up to 2/3 of the patients.<ul class="elsevierStyleList" id="lis0260"><li class="elsevierStyleListItem" id="lsti0480">-Is the maintenance treatment with azathioprine effective in patients with severe UC who have obtained remission with cyclosporine? (<a class="elsevierStyleCrossRef" href="#enun0030">Algorithm 6</a>)</li></ul>Text of the guidelines:<elsevierMultimedia ident="tbl0590"></elsevierMultimedia>Summary of the evidence:<elsevierMultimedia ident="tbl0595"></elsevierMultimedia>Formulation of the recommendation:<elsevierMultimedia ident="tbl0600"></elsevierMultimedia>Comment by the elaborating group:<elsevierMultimedia ident="tbl0605"></elsevierMultimedia><ul class="elsevierStyleList" id="lis0265"><li class="elsevierStyleListItem" id="lsti0485">-Is the maintenance treatment with cyclosporine effective in patients with severe UC who have obtained remission with cyclosporine? (<a class="elsevierStyleCrossRef" href="#enun0030">Algorithm 6</a>).</li></ul>Text of the guidelines:<elsevierMultimedia ident="tbl0610"></elsevierMultimedia>Summary of the evidence:<elsevierMultimedia ident="tbl0615"></elsevierMultimedia>Formulation of the recommendation:<elsevierMultimedia ident="tbl0620"></elsevierMultimedia>Comment by the elaborating group:<elsevierMultimedia ident="tbl0625"></elsevierMultimedia><ul class="elsevierStyleList" id="lis0270"><li class="elsevierStyleListItem" id="lsti0490">-Is the maintenance treatment with tacrolimus effective in patients with severe UC who have obtained remission with tacrolimus? (<a class="elsevierStyleCrossRef" href="#enun0030">Algorithm 6</a>).</li></ul>Text of the guidelines:<elsevierMultimedia ident="tbl0630"></elsevierMultimedia>Summary of the evidence:<elsevierMultimedia ident="tbl0635"></elsevierMultimedia>Formulation of the recommendation:<elsevierMultimedia ident="tbl0640"></elsevierMultimedia>Comment by the elaborating group:<elsevierMultimedia ident="tbl0645"></elsevierMultimedia>Algorithm 6Maintenance treatment after induction of remission with cyclosporine (or tacrolimus): algorithm and explanatory text<elsevierMultimedia ident="fig0030"></elsevierMultimedia>Even though they have been used occasionally in other circumstances, in most cases, the use of cyclosporine or tacrolimus (from this moment onwards we will refer only to cyclosporine) is limited to severe flares that are refractory to steroids, and in some exceptional cases in which steroids are contraindicated. If remission is achieved, cyclosporine cannot be maintained indefinitely, as there is the risk of inducing irreversible renal toxicity. The alternative that is most used has been to maintain cyclosporine during a limited time (most groups recommend three months, although in Spain, several sites maintain it only for four weeks), associated to down-titrated steroids and to thiopurines. Together, the data available suggest that thiopurines reduce the need for colectomy in the mid and long term in this subgroup of patients with a reasonable toxicity. However, occasionally, the severe flare has been produced in a patient that was already being treated with thiopurines. In this specific case, clinicians are left with three options: to directly recommend elective surgery (an alternative that may have been assessed before, in the control of the severe refractory flare controlled with cyclosporine), start the maintenance treatment with infliximab, or try thiopurines once again. Of course, maintaining only thiopurines does not seem the most logical course of action, although it may be possible that in some specific circumstances, changing the patter of inflammation may recover its efficacy. In most cases, the patients and the healthcare professionals will have to choose between infliximab and surgery, and the decision will be made depending on the individual circumstances (duration of the disease, prior toxicity to drugs), of each patient's expectations (fear of surgery, accessibility to medical control) and of the local experience of the working group. When infliximab is chosen, which is a very reasonable decision in many cases, it is very reasonable to maintain thiopurines, at least during a minimum period of time that could be of 6–12 months.8Other treatments8.1Possible treatments8.1.1ProbioticsThe literature about probiotics and UC is very difficult to interpret, as: (a) the type and formulation of the different probiotics used in the different studies vary greatly; (b) comparisons to placebo are scarce, and in many of the studies, the arm with probiotics also receives treatment with other drugs (particularly amino-salicylates) and (c) the published results are incredibly heterogeneous. Therefore, currently there is no solid evidence in favour or against the use of probiotics in UC, except for the case of pouchitis (an entity that is not the subject of these CPG). Some recent data suggest that VSL3 may be of use in UC<a class="elsevierStyleCrossRef" href="#bib0690">138</a> in situations of a mild-moderate flare, both as isolated treatment and as complementary treatment to mesalazine, but these must be confirmed in spite of being a part of the basic treatment regimen.8.2Complementary treatments8.2.1AnaemiaThe treatment of anaemia and iron deficiency without anaemia is an essential part in the management of UC. There is a Guideline of International Consensus,<a class="elsevierStyleCrossRef" href="#bib0695">139</a> to which the reader is referred. It is never normal for patients to have anaemia or iron deficiency, and one of our goals must be to normalize haematological parameters by sensibly using transfusions, intravenous iron or oral iron according to the circumstances.8.2.2OtherIn the treatment of UC, there may be some special circumstances that are not outlined in these CPG. In the vast majority of these scenarios, the evidence available is scarce or of low quality, although on occasions, there are more than enough data for establishing a recommendation. As it is not a subject of these Guidelines, we recommend the readers to refer to the ECCO Consensus, to their chapter about special situations in UC.<a class="elsevierStyleCrossRef" href="#bib0700">140</a> It may also be useful to consult the ECCO consensus for the prevention of infectious complications.<a class="elsevierStyleCrossRef" href="#bib0705">141</a> The use of biological therapies is considered when there are other recent reference documents.<a class="elsevierStyleCrossRef" href="#bib0710">142</a> Moreover, the information about fertility, pregnancy and birth in patients with IBD has been critically examined in another very recent consensus document.<a class="elsevierStyleCrossRef" href="#bib0715">143</a>9Future perspectivesCurrently, it seems unlikely that in a reasonable time frame (perhaps until 2013, at least) the practical clinician will have more pharmacological options available for the treatment of UC. This does not mean that improvements that are directly applicable to the patients cannot be produced. Our opinion is that they may be produced, prompted by:<ul class="elsevierStyleList" id="lis0275"><li class="elsevierStyleListItem" id="lsti0495">•The application, in the daily practice, of the recommendations contained in Clinical Practice Guidelines, such as these ones.</li><li class="elsevierStyleListItem" id="lsti0500">•Acknowledging the importance of the maintenance treatment as a form of avoiding the appearance of flares and of substantially improving the patients’ quality of life.</li><li class="elsevierStyleListItem" id="lsti0505">•The study of barriers for a good treatment compliance, which is a problem that is at the root of many treatment failures, in order to be able to face this problem directly. This point is very important in the group of patients with UC, but it is even more so when topical treatments are necessary.</li><li class="elsevierStyleListItem" id="lsti0510">•The permanent education of patients to progressively acquire a shared responsibility in the long-term management of their disease. As this is a chronic entity, patients are better placed to control the problem, and only with knowledge of the disease and of the treatment possibilities will they be able to do so.</li><li class="elsevierStyleListItem" id="lsti0515">•New controlled and observational studies will provide critical information about the use of the therapeutic means that are already available. Specifically, at this moment at least 3 key studies are already advanced: a study about cyclosporine versus infliximab in severe UC flares, of which only its publication is pending (although it has already been reported in congresses, as we pointed out previously), another study about the efficacy of the combination of infliximab and thiopurines in the induction and maintenance of remission of UC, of which also only the publication is pending; and a study about the efficacy of granulocyte aphaeresis in the situation of steroid-dependence; this last one is still in the patient recruitment phase. Moreover, we expect the publication of a yet undetermined number of observational studies, especially regarding the cumulative experience with infliximab that would provide information about the duration of the response, possibilities of intensification and long-term toxicity. Jointly, all these data will make it necessary to review these guidelines in a maximum time frame of three years. Above all, we believe that these data will allow us to advance in the individualization of the treatment, by allowing to stratify patients, not just by the global clinical scenario, but also by other circumstances.</li><li class="elsevierStyleListItem" id="lsti0520">•Of course, the basic and clinical research will allow for an ever better definition of the different subgroups of patients, which would also make the individualized application of the treatments easier.</li></ul>10Help boxesBox 1: Severity and extension, problematic definitionsFew of us would have difficulties in distinguishing a living being from a non living being, yet stating an exact definition of life is not at all an easy task.<a class="elsevierStyleCrossRef" href="#bib0720">144</a> A similar paradox is produced practically every time we face a patient with ulcerative colitis (UC). For the patients, it is easy to know if they are doing well, not so well, poorly or very badly; and for the expert clinician it would not be very difficult to know – at least in appearance – if the patient is doing well, not so well, poorly or very badly. However, the problem arises when, in order to be able to compare two patients or two moments in the same patient, we have to use some sort of objective index. UC is a complex disease, with very variable intestinal and extraintestinal symptoms; and with repercussions in laboratory findings and/or endoscopically that are also very diverse and changing. Furthermore, it is frequent to find severe discrepancies between clinical data, data from laboratory tests, and/or endoscopic data. The first technical approximation to this issue was done by Sidney Truelove and Lloyd Witts in the classic clinical trial about hydrocortisone in colitis.<a class="elsevierStyleCrossRef" href="#bib0725">145</a> From that moment on, numerous clinical, biological, endoscopic and histological indices have been used. Curiously, few have been validated formally, and the vast majority lack sufficient reproducibility. There is also an important limitation for the daily use of these classifications: the human brain is not fond of complex classifications.<a class="elsevierStyleCrossRef" href="#bib0730">146</a> In order to create these CPG, we were forced to classify patients into two great situations of severity: mild to moderate versus severe. This is the only way of systematizing the information currently available in literature. The broadness of the mild-moderate concept is especially troublesome, as it spans from a patient who has 3 bowel movements per day and mild abdominal discomfort (if his/her normal situation is one bowel movement per day without any discomfort) to a patient who has 5 bowel movements with blood, that force him/her to get up at night, and who has an important asthenia linked to an anaemia with a haemoglobin of 11.2g/dL. In fact, it is possible that the former has mild symptoms and is not taking any treatment, while the latter has intense symptoms in spite of already receiving a combination of oral mesalazine, rectal mesalazine and oral steroids. For their inclusion in the clinical trial, both patients are in the same group; for the clinician it is obvious that the first patient would receive oral mesalazine, which would soothe him/her and the clinician would then follow-up one month later; however, for the second patient, the clinician may seriously consider using infliximab. It is not feasible to collect all of these possibilities into a few simple algorithms, nor do all circumstances fit in the GRADE tables, as complex as these may be. These GUIDELINES intend to make the work easier, but of course, they cannot replace the clinician.Box 2: Activity indicesThe variable clinical course of inflammatory bowel diseases makes the concept of activity of the disease essential. However, there is no single definition of activity, as there are several different viewpoints (for example, the patient versus clinician versus investigator) and different consequences of the disease that are to be measured: biochemical changes, histological lesion, radiological lesion, endoscopic lesion, clinical symptoms, quality of life, financial repercussion, morbidity, mortality and others. The need to have a practical definition arose in the clinical trial of hydrocortisone compared to placebo, carried out by Sidney Truelove and Lloyd Witts between 1952 and 1955.<a class="elsevierStyleCrossRef" href="#bib0030">6</a> To be able to evaluating the result of the treatment, they created a very simple classification that distinguished the extremes (mild versus severe), with an intermediate category, with parameters that were all clinical or in terms of laboratory tests. The simplicity of the classification, and the fact that it was the first, led it to be imposed both in clinical practice and in many studies. However, it has never been validated with a formal methodology (its internal reliability, reproducibility and external reliability are unknown). During the 56 years that have elapsed since then, numerous indices have appeared that are clinical, clinical–biological, endoscopic, histological, of quality of life, of work repercussion and of other types that have been used in very different studies. In fact, it is often very difficult to compare the results of several studies, because they use different measuring systems, and because even when they use the same, the cut-off points chosen for the definitions are not always the same. When the different options are analyzed with a methodological rigour, the results are discouraging: there is no correlation between laboratory values and endoscopy, between endoscopy and clinical presentation, between histology and laboratory tests, between the patient's and doctor's viewpoint, etc. Curiously, the last ones in arriving at the problem, the paediatric gastroenterologists expert in inflammatory bowel disease, have applied a more rigourous methodology from the beginning, and have developed the PUCAI (Paediatric Ulcerative Colitis Activity Index),<a class="elsevierStyleCrossRef" href="#bib0735">147</a> probably the first index that has been validated correctly. For the purposes of these guidelines there is one more issue: even if we wanted to be rigourous with the indices, we could not, because the studies were made before the indices in many cases. Therefore, we decided to use the Montreal classification, which divides the possible situations of activity into four: remission, mild, moderate and severe. Data from most studies can be extrapolated to this type of classification. Of course, some confusion may arise, especially at the limits (Box 1). Many studies analyze not only clinical indices, but also endoscopic and at times, histological indices. Also, in this case, we have been forced to simplify sometimes, assuming a possible loss of quality of the data, compensated on many occasions by the great number of patients included. Although we admit that in the future, the concepts of remission (for example, recently it has been proposed to define remission as the absolute absence of clinical symptoms and mucosal healing demonstrated in colonoscopy<a class="elsevierStyleCrossRef" href="#bib0740">148</a>) will always include objective parameters (endoscopic, histological or biological), the definitions of response and remission are almost always clinical, because the studies analyzed, in many cases, do not allow for another approach. Finally, we have to point out that in the case of a severe flare, the variables chosen by the Committee are clearly definable: mortality or the need for colectomy; which makes the studies more easily comparable.Box 3: Practical considerations about the doses of immunomodulating drugsSteroids: Systemic steroids have been used by several routes (oral, intravenous, rectal) and in many different formulations and products. If we consider prednisone as the reference steroid (it is the one most commonly used), the standard dose for treatment start is 1mg/kg/day, orally. In order to adjust the doses of other steroids, we have to take into account the potency equivalences between them (<a class="elsevierStyleCrossRef" href="#tbl0740">Table 17</a>), the route of administration that may vary the bioavailability significantly, and that there may be differences in the toxicity and individual effects of the different products. The IV steroid that is most used is methylprednisolone, which is more potent than prednisone (4mg of methylprednisolone are equal to 5mg of prednisone; not considering the obvious difference in bioavailability). The initial dose is usually maintained for two weeks, although depending on the response, it may be acceptable from one week up to four. When the dose is reduced, there are several guidelines for down-titrating the dose. The most usual practice is to remove 10mg from the daily dose of prednisone weekly until reaching 20mg/day, and from that point, remove 5mg from the daily dose weekly until discontinuing it. It is usually not justified to maintain the treatment for more than three months without having considered and tried an alternative treatment.<elsevierMultimedia ident="tbl0740"></elsevierMultimedia>Cyclosporine: Cyclosporine is used exclusively in the severe or moderate flare that is refractory to steroids, and its administration must not be extended for more than three to six months due to the risk of irreversible toxicity, particularly renal toxicity. Although defenders of the oral route are not lacking, the studies justifying its use have almost all been carried out initially using the intravenous route. Initially, a dose of 4mg/kg/day was chosen, although later an individual adjustment may be needed depending on the blood levels obtained and of toxicity. In a randomized study, it was shown that 2mg/kg/day were as effective as 4; although actually, in both groups, the mean final dose that was administered was very similar because adjustments by levels and toxicity were allowed. With the data available, it seems prudent to begin with 2mg/kg/day and up-titration if no toxicity is produced, and the levels considered therapeutic are not reached.Tacrolimus: The doses used are of 0.01–0.02mg/kg when it is used intravenously, and of 0.1–0.2mg/kg when it is used orally; adjusting individually according to the blood levels, the toxicity and the response.Azathioprine and mercaptopurine: The mean dose of azathioprine is of 2.5mg/kg/day and the mean dose of mercaptopurine is of 1–1.5mg/kg/day. However, there is great individual variability in the response and toxicity, which is why the doses may be adjusted in terms of the effectiveness and toxicity. If they are available, metabolite levels may be used as a guide, at least in selected patients. However, in most sites, adjustments have to be carried out considering the clinical presentation, the total leukocytes, transaminases and other analytical parameters. Their usefulness cannot be ruled out completely if they have been maintained for a period of less than 6 months.11Conflicts of interest of the authors of the guidelineThis guide has been possible to some extent by an unrestricted grant of MSD. MSD was not involved in any part of the development or scientific aspects of the guide.F. Gomollón has received grants for assistance to scientific meetings from Abbott and MSD. He has also received consultancy fees from FAES-FARMA, Abbott and MSD. He has also received research support from MSD.S. García-López has received grants for assistance to scientific meetings from Abbott, MSD, FAES-FARMA, Ferring and Shire. He has also received consultancy fees from Abbott and MSD.B. Sicilia has received grants for assistance to scientific meetings from Abbott and MSD.Javier P. Gisbert has received grants for assistance to scientific meetings from Abbott and MSD. He has also received consultancy fees from FAES-FARMA, Abbott and MSD.Joaquin Hinojosa has received grants for assistance to scientific meetings from Abbott and MSD. He has also received consultancy fees from FAES-FARMA, Abbott and MSD.The rest of the authors of the guideline declare no conflict of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Need for guidelines" ] 2 => array:2 [ "identificador" => "sec0015" "titulo" => "Definitions" ] 3 => array:2 [ "identificador" => "sec0020" "titulo" => "Objectives" ] 4 => array:2 [ "identificador" => "sec0025" "titulo" => "Methodology" ] 5 => array:3 [ "identificador" => "sec0030" "titulo" => "Induction of remission in patients with active ulcerative colitis" "secciones" => array:2 [ 0 => array:3 [ "identificador" => "sec0035" "titulo" => "Severe UC flare (of any anatomical extension) (Algorithm 1)" "secciones" => array:7 [ …7] ] 1 => array:3 [ "identificador" => "sec0075" "titulo" => "Mild and moderate UC flare (Algorithm 2)" "secciones" => array:5 [ …5] ] ] ] 6 => array:3 [ "identificador" => "sec0105" "titulo" => "Maintenance treatment of patients with ulcerative colitis in remission" "secciones" => array:2 [ 0 => array:3 [ "identificador" => "sec0110" "titulo" => "Maintenance of remission obtained after a mild–moderate flare" "secciones" => array:2 [ …2] ] 1 => array:2 [ "identificador" => "sec0125" "titulo" => "Maintenance of the remission obtained after a severe flare (Algorithms 5 and 6)" ] ] ] 7 => array:3 [ "identificador" => "sec0130" "titulo" => "Other treatments" "secciones" => array:2 [ 0 => array:3 [ "identificador" => "sec0135" "titulo" => "Possible treatments" "secciones" => array:1 [ …1] ] 1 => array:3 [ "identificador" => "sec0145" "titulo" => "Complementary treatments" "secciones" => array:2 [ …2] ] ] ] 8 => array:2 [ "identificador" => "sec0160" "titulo" => "Future perspectives" ] 9 => array:2 [ "identificador" => "sec0165" "titulo" => "Help boxes" ] 10 => array:2 [ "identificador" => "sec0170" "titulo" => "Conflicts of interest of the authors of the guideline" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2012-09-23" "fechaAceptado" => "2012-10-02" "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "◊" "nota" => "GETECCU (Grupo Español de Trabajo de Enfermedad de Crohn y Colitis Ulcerosa or Spanish Group for Working on Crohn's Disease and Ulcerative Colitis)." ] 1 => array:2 [ "etiqueta" => "a" "nota" => "The term aggressive is not the most adequate when referring to a treatment: what must predominate is the benefit-risk balance, and on many occasions, the most effective treatment, and even the most efficient treatment, may be the one that is apparently most aggressive." ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:2 [ 0 => array:4 [ "etiqueta" => "Appendix A" "titulo" => "Composition of the committees of the guideline" "identificador" => "sec0175" "apendiceSeccion" => array:5 [ 0 => array:4 [ …4] 1 => array:4 [ …4] 2 => array:4 [ …4] 3 => array:4 [ …4] 4 => array:4 [ …4] ] ] 1 => array:3 [ "etiqueta" => "Appendix B" "identificador" => "sec0210" "apendiceSeccion" => array:2 [ 0 => array:4 [ …4] 1 => array:4 [ …4] ] ] ] ] ] "multimedia" => array:154 [ 0 => array:7 [ "identificador" => "tbl0660" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "Source: Lennard-Jonnes.<a class="elsevierStyleCrossRef" href="#bib0005">1</a>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] "descripcion" => array:1 [ "en" => "Lennard-Jones diagnostic criteria." ] ] 1 => array:7 [ "identificador" => "tbl0665" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "Abbreviations: Hb, haemoglobin; bpm, beats per minute.Source: Silverberg et al.<a class="elsevierStyleCrossRef" href="#bib0010">2</a>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] "descripcion" => array:1 [ "en" => "Montreal Classification for ulcerative colitis." ] ] 2 => array:7 [ "identificador" => "tbl0670" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "Assessment of the index:Mild flare: when all the variables are in the “mild” category.Severe flare: when all the variables are in “severe”.When there are variables in both categories, it is a moderate flare.Abbreviations: bpm, beats per minute.Source: Truelove and Witts.<a class="elsevierStyleCrossRef" href="#bib0030">6</a>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "At the moment of the examination or in 2 of the last 4 days." ] ] ] "descripcion" => array:1 [ "en" => "Original Truelove–Witts index." ] ] 3 => array:7 [ "identificador" => "tbl0675" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "Assessment of the index:Inactive: <11.Mild flare: 11–15.Moderate flare: 16–21.Severe flare: 22–27.Abbreviation: bpm: beats per minute." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] "descripcion" => array:1 [ "en" => "Modified Truelove–Witts index." ] ] 4 => array:7 [ "identificador" => "tbl0680" "etiqueta" => "Table 5" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "Sources: Schroeder et al.<a class="elsevierStyleCrossRef" href="#bib0110">22</a> and D’Haens et al.<a class="elsevierStyleCrossRef" href="#bib0100">20</a>" "tablatextoimagen" => array:2 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] 1 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] "descripcion" => array:1 [ "en" => "Mayo index (DAI)." ] ] 5 => array:7 [ "identificador" => "tbl0685" "etiqueta" => "Table 6" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "Seo activity index; total A−total B+200=…………Source: Seo et al.<a class="elsevierStyleCrossRef" href="#bib0115">23</a>" "tablatextoimagen" => array:2 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] 1 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] "descripcion" => array:1 [ "en" => "Seo index." ] ] 6 => array:7 [ "identificador" => "tbl0690" "etiqueta" => "Table 7" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "Assessment of the index:Maximum score: 21 points.Score <10 during 2 consecutive days indicates a clinical response (in the original reference to cyclosporine, severe refractory flare).Source: Lichtiger et al.<a class="elsevierStyleCrossRef" href="#bib0120">24</a>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] "descripcion" => array:1 [ "en" => "Lichtiger's index." ] ] 7 => array:7 [ "identificador" => "tbl0695" "etiqueta" => "Table 8" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "Assessment of the index:Simple, clinical index; its interpretation and correlation to more complex indices, such as Power-Tuck, are adequate.Source: Walmsley et al.<a class="elsevierStyleCrossRef" href="#bib0125">25</a>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] "descripcion" => array:1 [ "en" => "Simple activity index (Walmsley index)." ] ] 8 => array:7 [ "identificador" => "tbl0700" "etiqueta" => "Table 9" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "Assessment of the index:Severe flare: ≥65 points.Moderate flare: 35–64 points.Mild flare: 10–34 points.Remission (without activity): <10.Source: Turner et al.<a class="elsevierStyleCrossRef" href="#bib0130">26</a>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] "descripcion" => array:1 [ "en" => "PUCAI index." ] ] 9 => array:7 [ "identificador" => "tbl0705" "etiqueta" => "Table 10" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "a" "nota" => "In some patients and sites, an ultrasound can be carried out that can provide very relevant data, but the CT scan is the test of choice when bowel perforation or an intraabdominal infectious complication is suspected." ] 1 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "b" "nota" => "If the site has an IGRA test (such as Quantiferon©), it is also advisable in this situation of immunosupression." ] ] ] "descripcion" => array:1 [ "en" => "Review of the diagnostic information prior to the treatment of the severe flare." ] ] 10 => array:7 [ "identificador" => "tbl0710" "etiqueta" => "Table 11" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] "descripcion" => array:1 [ "en" => "Summary of the general treatment of the severe flare." ] ] 11 => array:7 [ "identificador" => "tbl0715" "etiqueta" => "Table 12" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "Assessment of the index (estimated probability of failure with the medical treatment):Score index: probability of no response to the medical treatment.0–1: 11%.2–3: 43%.≥4: 85%.Source: Ho et al.<a class="elsevierStyleCrossRef" href="#bib0310">62</a>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] "descripcion" => array:1 [ "en" => "Probability of response to steroids (Ho index)." ] ] 12 => array:7 [ "identificador" => "tbl0720" "etiqueta" => "Table 13" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "a" "nota" => "In conditions of immunosuppression, a Mantoux test is not very sensitive, and in conditions of a severe flare, it may not be possible to wait and apply a booster. As mentioned above, if there is an IGRA at the site (for example, Quantiferon©), it would be an advisable additional measure." ] ] ] "descripcion" => array:1 [ "en" => "Measures prior to starting the treatment with infliximab." ] ] 13 => array:7 [ "identificador" => "tbl0725" "etiqueta" => "Table 14" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] "descripcion" => array:1 [ "en" => "Measures prior to starting the treatment with cyclosporine." ] ] 14 => array:7 [ "identificador" => "tbl0730" "etiqueta" => "Table 15" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:2 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] 1 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] "descripcion" => array:1 [ "en" => "Follow-up measures for the treatment with cyclosporine." ] ] 15 => array:7 [ "identificador" => "tbl0735" "etiqueta" => "Table 16" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] "descripcion" => array:1 [ "en" => "Pharmacological interactions of cyclosporine." ] ] 16 => array:7 [ "identificador" => "tbl0740" "etiqueta" => "Table 17" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "Note: For example, prednisone is 4 times more potent than hydrocortisone (i.e., 5mg of prednisone are equal to 20mg of hydrocortisone) and methylprednisolone is a little more powerful than prednisone (4mg of the former are equal to 5 of the latter).Source: Gasull et al.<a class="elsevierStyleCrossRef" href="#bib0745">149</a>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] "descripcion" => array:1 [ "en" => "Equivalences in the doses of systemic steroids." ] ] 17 => array:5 [ "identificador" => "fig0005" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "fx1.jpeg" "Alto" => 2920 "Ancho" => 2188 "Tamanyo" => 236103 ] ] ] 18 => array:5 [ "identificador" => "fig0010" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "fx2.jpeg" "Alto" => 3391 "Ancho" => 2625 "Tamanyo" => 374064 ] ] ] 19 => array:5 [ "identificador" => "fig0015" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "fx3.jpeg" "Alto" => 2392 "Ancho" => 2187 "Tamanyo" => 205312 ] ] ] 20 => array:5 [ "identificador" => "fig0020" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => 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=> "tbl0090" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 41 => array:5 [ "identificador" => "tbl0095" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 42 => array:5 [ "identificador" => "tbl0100" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 43 => array:5 [ "identificador" => "tbl0105" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 44 => array:5 [ "identificador" => "tbl0110" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 45 => array:5 [ "identificador" => "tbl0115" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 46 => array:5 [ "identificador" => "tbl0120" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 47 => array:5 [ "identificador" => "tbl0125" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 48 => array:5 [ "identificador" => "tbl0130" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 49 => array:5 [ "identificador" => "tbl0135" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 50 => array:5 [ "identificador" => "tbl0140" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 51 => array:5 [ "identificador" => "tbl0145" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 52 => array:5 [ "identificador" => "tbl0150" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 53 => array:5 [ "identificador" => "tbl0155" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 54 => array:5 [ "identificador" => "tbl0160" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 55 => array:5 [ "identificador" => "tbl0165" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 56 => array:5 [ "identificador" => "tbl0170" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 57 => array:5 [ "identificador" => "tbl0175" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 58 => array:5 [ "identificador" => "tbl0180" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 59 => array:5 [ "identificador" => "tbl0185" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 60 => array:5 [ "identificador" => "tbl0190" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 61 => array:5 [ "identificador" => "tbl0195" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 62 => array:5 [ "identificador" => "tbl0200" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 63 => array:5 [ "identificador" => "tbl0205" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 64 => array:5 [ "identificador" => "tbl0210" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 65 => array:5 [ "identificador" => "tbl0215" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 66 => array:5 [ "identificador" => "tbl0220" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 67 => array:5 [ "identificador" => "tbl0225" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 68 => array:5 [ "identificador" => "tbl0230" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 69 => array:5 [ "identificador" => "tbl0235" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 70 => array:5 [ "identificador" => "tbl0240" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 71 => array:5 [ "identificador" => "tbl0245" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 72 => array:5 [ "identificador" => "tbl0250" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 73 => array:5 [ "identificador" => "tbl0255" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 74 => array:5 [ "identificador" => "tbl0260" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 75 => array:5 [ "identificador" => "tbl0265" "tipo" => 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=> "tbl0285" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 80 => array:5 [ "identificador" => "tbl0290" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 81 => array:5 [ "identificador" => "tbl0295" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 82 => array:5 [ "identificador" => "tbl0300" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 83 => array:5 [ "identificador" => "tbl0305" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 84 => array:5 [ "identificador" => "tbl0310" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 85 => array:5 [ "identificador" => "tbl0315" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 86 => array:5 [ "identificador" => "tbl0320" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 87 => array:5 [ "identificador" => "tbl0325" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 88 => array:5 [ "identificador" => "tbl0330" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 89 => array:5 [ "identificador" => "tbl0335" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 90 => array:5 [ "identificador" => "tbl0340" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 91 => array:5 [ "identificador" => "tbl0345" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 92 => array:5 [ "identificador" => "tbl0350" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 93 => array:5 [ "identificador" => "tbl0355" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 94 => array:5 [ "identificador" => "tbl0360" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 95 => array:5 [ "identificador" => "tbl0365" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 96 => array:5 [ "identificador" => "tbl0370" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 97 => array:5 [ "identificador" => "tbl0375" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 98 => array:5 [ "identificador" => "tbl0380" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 99 => array:5 [ "identificador" => "tbl0385" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 100 => array:5 [ "identificador" => "tbl0390" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 101 => array:5 [ "identificador" => "tbl0395" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 102 => array:5 [ "identificador" => "tbl0400" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 103 => array:5 [ "identificador" => "tbl0405" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 104 => array:5 [ "identificador" => "tbl0410" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 105 => array:5 [ "identificador" => "tbl0415" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 106 => array:5 [ "identificador" => "tbl0420" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 107 => array:5 [ "identificador" => "tbl0425" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 108 => array:5 [ "identificador" => "tbl0430" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 109 => array:5 [ "identificador" => "tbl0435" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 110 => array:5 [ "identificador" => "tbl0440" "tipo" => 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…1] ] ] ] ] 118 => array:5 [ "identificador" => "tbl0480" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 119 => array:5 [ "identificador" => "tbl0485" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 120 => array:5 [ "identificador" => "tbl0490" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 121 => array:5 [ "identificador" => "tbl0495" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 122 => array:5 [ "identificador" => "tbl0500" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 123 => array:5 [ "identificador" => "tbl0505" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 124 => array:5 [ "identificador" => "tbl0510" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 125 => array:5 [ "identificador" => "tbl0515" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 126 => array:5 [ "identificador" => "tbl0520" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 127 => array:5 [ "identificador" => "tbl0525" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 128 => array:5 [ "identificador" => "tbl0530" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 129 => array:5 [ "identificador" => "tbl0535" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ 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=> true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 134 => array:5 [ "identificador" => "tbl0560" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 135 => array:5 [ "identificador" => "tbl0565" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 136 => array:5 [ "identificador" => "tbl0570" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 137 => array:5 [ "identificador" => "tbl0575" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 138 => array:5 [ "identificador" => "tbl0580" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 139 => array:5 [ "identificador" => "tbl0585" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 140 => array:5 [ "identificador" => "tbl0590" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 141 => array:5 [ "identificador" => "tbl0595" 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…1] ] ] ] ] 149 => array:5 [ "identificador" => "tbl0635" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 150 => array:5 [ "identificador" => "tbl0640" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 151 => array:5 [ "identificador" => "tbl0645" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 152 => array:5 [ "identificador" => "tbl0650" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:2 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] 1 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] 153 => array:5 [ "identificador" => "tbl0655" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ …1] "imagenFichero" => array:1 [ …1] ] ] ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:149 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ …1] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ …1] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ …1] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ …1] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 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Clinical guide

The GETECCU clinical guideline for the treatment of ulcerative colitis: A guideline created using GRADE methodology

Guía clínica GETECCU del tratamiento de la Colitis Ulcerosa elaborada con la metodología GRADE

Fernando Gomollóna,

Corresponding author

fgomollon@gmail.com

Corresponding author.

, Santiago García-Lópezb, Beatriz Siciliac, Javier P. Gisbertd, Joaquín Hinojosae, on behalf of GETECCU ◊

a Department of Gastroenterology, Hospital Clínico Universitario Lozano Blesa, IIS, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Zaragoza, Spain

b Department of Gastroenterology, Hospital Universitario Miguel Servet, Zaragoza, Spain

c Department of Gastroenterology, Complejo Asistencial Universitario de Burgos, Burgos, Spain

d Department of Gastroenterology, Hospital Universitario de La Princesa, CIBEREHD, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain

e Department of Gastroenterology, Hospital de Manises, Valencia, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">1</span><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Ulcerative colitis &#40;UC&#41; is a chronic inflammatory bowel disease of multifactorial aetiology that mainly affects the colon&#46; There is no single pathognomonic criterion to define it&#44; the diagnosis being based on a series of clinical&#44; endoscopic and histological criteria&#44; as well as on the exclusion of infectious diseases with similar symptoms&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Both its extension and severity vary in time for all patients&#59; hence&#44; the definition of a specific clinical scenario demands taking both the severity and the extension of the disease into account&#44; in accordance with the definitions suggested by the World Gastroenterology Organization &#40;WGO&#41; in the &#8220;Montreal Classification&#8221;&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Moreover&#44; the disease can remain in a situation of clinical remission&#44; requiring the application of different treatment strategies in situations of activity or remission&#46; It has been established that certain maintenance treatments quite significantly reduce the probability of new flares of activity&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Even though it was described at the end of the XIX century&#44; its frequency over different populations has changed notably&#44; especially during the second half of the XX century&#44; together with other immune diseases and with a clear sustained tendency to increase with social and economic development&#46; Because it frequently starts in youth or even in childhood&#44; and its mortality is low&#44; its prevalence is considerably higher &#40;at last 20 or 30 times its incidence&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> In Spain&#44; epidemiological data suggest that up to the 1980s&#44; it was an uncommon disease&#46; However&#44; over the past 30 years&#44; it has reached incidence rates that are very similar to the ones described previously in north European countries and&#44; in fact&#44; in the most recent studies&#44; data are completely similar&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">This disease has been treated with drugs&#44; surgery or both&#46; In the first half of the XX century&#44; treatment procedures&#44; such as sulfasalazine&#44; were introduced empirically&#59; but already in 1955 the first clinical randomized controlled trial was published and showed that hydrocortisone was superior to placebo in the treatment of moderate or severe UC flares&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Up to 1980&#44; observational studies of varying quality were predominant&#46; Henceforth&#44; numerous controlled clinical trials&#44; epidemiological analyses&#44; assessments of diagnostic measures and even complex genetic studies<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> have been carried out with an ever more solid scientific methodology&#46; Currently&#44; there are numerous nutritional&#44; pharmacological&#44; surgical and monitoring and follow-up alternatives available&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;9</span></a> Their application over the broad range of clinical scenarios with such diverse individual and social circumstances is not always easy and is one of the reasons that justify the creation of these guidelines&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2</span><span class="elsevierStyleSectionTitle">Need for guidelines</span><p id="par0015" class="elsevierStylePara elsevierViewall">As this is a common&#44; chronic disease that affects mostly young people and that has a increasing prevalence&#44; the health&#44; economic and social repercussions perfectly justify the need for tools to systematize the treatment of UC&#46; However&#44; we will point out other reasons for its creation in more detail&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">In the first place&#44; the professionals involved in this entity are quite numerous&#46; A partial list would include a gastroenterologist&#44; a surgeon&#44; a primary care physician&#44; a nutritionist&#44; a psychologist&#44; a nurse&#44; a stomatherapist&#44; a rheumatologist&#44; an ophthalmologist and a dermatologist&#46; The need for coordination between these professionals and the patient also justifies the need for a Clinical Practice Guidelines &#40;CPG&#41;&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">There is great evidence<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> that the usual variability of clinical practice affects patients with inflammatory bowel disease &#40;IBD&#41; quite significantly&#44; with important clinical&#44; economical&#44; and social repercussions&#46; In fact&#44; a recent European collaborative study reflected enormous differences in the total cost of the management of the disease&#44; regardless of the country&#39;s per capita income&#44; and&#44; what is clinically most significant&#44; they reflected great differences in the distribution of this cost&#58; the proportion of patients treated surgically was very variable &#40;in UC between 10 and 40&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> This variability also justifies the need for a CPG&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">There are already several publications bearing the word &#8220;guidelines&#8221; in their title&#44; being the most important among them for their rigour and diffusion the British guidelines &#40;British Society of Gastroenterology&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> the American guidelines<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> &#40;American College of Gastroenterology&#41;&#44; the guidelines of the World Gastroenterology Organization&#44;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> the guidelines of the &#8220;Asian Pacific&#8221; consensus group<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> and the European guidelines<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16&#44;17</span></a> &#40;European Crohn and Colitis Organization&#41;&#46; Although these publications&#44; especially the latter&#44; are of great quality and are based on the clinical evidence available&#44; they are actually consensus documents that are more or less elaborate&#46; To our knowledge&#44; there is no CPG in the world created based on a structured and systematic methodology&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">One of the main objectives of the Spanish Working Group on Crohn&#39;s Disease and Ulcerative Colitis &#40;<a href="http://www.geteccu.org/">GETECCU</a>&#41; is to improve the care of patients with inflammatory bowel disease&#44; and strategically&#44; it has established the creation of CPGs that serve as an aid for healthcare professionals&#44; patients&#44; researchers and payers&#46; In the first phase of the project&#44; we focus on the treatment of inflammatory bowel diseases&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3</span><span class="elsevierStyleSectionTitle">Definitions</span><p id="par0040" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0045" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Target population&#58;</span> Patients of any gender and age who are diagnosed with UC according to the internationally accepted criteria by Lennard-Jones<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0660">Table 1</a>&#41;&#46; These criteria are accepted by both the WGO<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> &#40;World Gastroenterology Organization&#41; and the ECCO<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> &#40;European Crohn and Colitis Organization&#41;&#46;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8728;</span><p id="par0050" class="elsevierStylePara elsevierViewall">Complementary guidelines will be developed in the future to specify independent aspects that are relevant to the paediatric population&#44; as well as special clinical scenarios&#46;</p></li></ul></p><elsevierMultimedia ident="tbl0660"></elsevierMultimedia></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel"><span class="elsevierStyleItalic">-</span></span><p id="par0055" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Ulcerative colitis &#40;UC&#41;&#58;</span><ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">&#8728;</span><p id="par0060" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Severity criteria&#58;</span> The ones defined by the Montreal Classification&#44;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> whose validity has recently been ratified by a group of experts<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0665">Table 2</a>&#41;&#58;<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">&#9642;</span><p id="par0065" class="elsevierStylePara elsevierViewall">Ulcerative colitis<ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">&#8226;</span><p id="par0070" class="elsevierStylePara elsevierViewall">Remission</p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">&#8226;</span><p id="par0075" class="elsevierStylePara elsevierViewall">Mild</p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">&#8226;</span><p id="par0080" class="elsevierStylePara elsevierViewall">Moderate</p></li><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">&#8226;</span><p id="par0085" class="elsevierStylePara elsevierViewall">Severe</p></li></ul></p></li><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">&#9642;</span><p id="par0090" class="elsevierStylePara elsevierViewall">Confusing terms such as fulminant colitis or &#8220;very severe&#8221; will be avoided&#46;</p></li><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">&#9642;</span><p id="par0095" class="elsevierStylePara elsevierViewall">The differences between moderate-severe flare in the studies found in literature&#44; especially pharmacological&#8211;biological studies&#44; are not always well established &#40;Box 1&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">&#9642;</span><p id="par0100" class="elsevierStylePara elsevierViewall">We will use the severity scale used in the Montreal Classification&#44;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> which has actually been extrapolated from the index that has been used longer&#44; the Truelove&#8211;Witts index<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0670">Table 3</a>&#41; that in some publications&#44; particularly Spanish publications&#44; has been modified in a semi-quantitative manner &#40;<a class="elsevierStyleCrossRef" href="#tbl0675">Table 4</a>&#41;&#46; Actually&#44; this index has not been validated formally in any study&#44; and its use may be controversial<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> &#40;Box 2&#41;&#46; In fact&#44; there is no reference clinical index of activity&#44; that is why it is necessary to be familiar with many of them in order to interpret the results of the studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20&#44;21</span></a> We provide the most important ones&#58;<ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0065"><span class="elsevierStyleLabel">-</span><p id="par0105" class="elsevierStylePara elsevierViewall">The Mayo Index &#40;DAI&#41;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0680">Table 5</a>&#41;</p><elsevierMultimedia ident="tbl0680"></elsevierMultimedia></li><li class="elsevierStyleListItem" id="lsti0070"><span class="elsevierStyleLabel">-</span><p id="par0110" class="elsevierStylePara elsevierViewall">SEO&#39;s Index<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0685">Table 6</a>&#41;</p><elsevierMultimedia ident="tbl0685"></elsevierMultimedia></li><li class="elsevierStyleListItem" id="lsti0075"><span class="elsevierStyleLabel">-</span><p id="par0115" class="elsevierStylePara elsevierViewall">Lichtiger&#39;s Index<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0690">Table 7</a>&#41;</p><elsevierMultimedia ident="tbl0690"></elsevierMultimedia></li><li class="elsevierStyleListItem" id="lsti0080"><span class="elsevierStyleLabel">-</span><p id="par0120" class="elsevierStylePara elsevierViewall">The Walmsley Index&#44; known as the Simple Activity Index<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0695">Table 8</a>&#41;</p><elsevierMultimedia ident="tbl0695"></elsevierMultimedia></li><li class="elsevierStyleListItem" id="lsti0085"><span class="elsevierStyleLabel">-</span><p id="par0125" class="elsevierStylePara elsevierViewall">PUCAI &#40;Paediatric Ulcerative Colitis Activity Index&#41;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0700">Table 9</a>&#41;&#46; Actually&#44; this is the only index with a correct methodological validation&#44; but it has only been used in paediatric population&#46;</p><elsevierMultimedia ident="tbl0700"></elsevierMultimedia></li></ul></p><elsevierMultimedia ident="tbl0670"></elsevierMultimedia><elsevierMultimedia ident="tbl0675"></elsevierMultimedia></li></ul></p><elsevierMultimedia ident="tbl0665"></elsevierMultimedia></li><li class="elsevierStyleListItem" id="lsti0090"><span class="elsevierStyleLabel">&#8728;</span><p id="par0130" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Extension criteria</span>&#58; The ones defined in the Montreal Classification&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> We must admit the fundamental limit of this classification&#58; the extension may change over time and&#44; in fact&#44; a variable part of proctitis cases will evolve to a more extensive colitis<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a>&#59; however&#44; for the analysis of the therapeutic effect&#44; this is of a minor importance&#44; because the colitis is analyzed at the extension it has <span class="elsevierStyleItalic">at the moment</span> the study is carried out&#58;<ul class="elsevierStyleList" id="lis0035"><li class="elsevierStyleListItem" id="lsti0095"><span class="elsevierStyleLabel">&#9642;</span><p id="par0135" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Extensive UC</span>&#58; involving the rectum beyond the splenic angle&#46;</p></li><li class="elsevierStyleListItem" id="lsti0100"><span class="elsevierStyleLabel">&#9642;</span><p id="par0140" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Left-sided UC</span>&#58; up to the splenic angle&#46;</p></li><li class="elsevierStyleListItem" id="lsti0105"><span class="elsevierStyleLabel">&#9642;</span><p id="par0145" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Ulcerative proctitis</span>&#58; limited involvement of the rectum &#40;the upper limit of the inflammation does not go beyond the recto-sigmoid junction&#41;&#46;</p></li></ul></p></li><li class="elsevierStyleListItem" id="lsti0110"><span class="elsevierStyleLabel">&#8728;</span><p id="par0150" class="elsevierStylePara elsevierViewall">Aside from the fundamental definitions&#44; it is necessary to know other terms of regular use in medical literature about UC&#46; As the definition is arbitrary&#44; it would probably be most adequate follow a consensus&#44; and the most accepted international consensus is the one of the ECCO&#58;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a><ul class="elsevierStyleList" id="lis0040"><li class="elsevierStyleListItem" id="lsti0115"><span class="elsevierStyleLabel">&#9642;</span><p id="par0155" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Remission</span>&#58; full resolution of symptoms&#44; accompanied by mucosal healing &#40;this aspect is not evaluated in many studies&#41;&#46; Not all the trials use exactly the same definition of remission&#44; and when this is relevant&#44; we will specifically point it out in the text &#40;Box 1&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0120"><span class="elsevierStyleLabel">&#9642;</span><p id="par0160" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Response</span>&#58; a significant improvement of clinical and&#47;or endoscopic situation &#40;severe to moderate&#44; severe to mild&#44; moderate to mild&#41; without reaching remission&#46;</p></li><li class="elsevierStyleListItem" id="lsti0125"><span class="elsevierStyleLabel">&#9642;</span><p id="par0165" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Relapse</span>&#58; a new flare in a patient with an established UC after a remission has been achieved&#44; either spontaneously or after medical treatment&#46;</p></li><li class="elsevierStyleListItem" id="lsti0130"><span class="elsevierStyleLabel">&#9642;</span><p id="par0170" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Steroid dependence</span>&#58;<ul class="elsevierStyleList" id="lis0045"><li class="elsevierStyleListItem" id="lsti0135"><span class="elsevierStyleLabel">-</span><p id="par0175" class="elsevierStylePara elsevierViewall">the impossibility of reducing the dose of steroids under 10<span class="elsevierStyleHsp" style=""></span>mg&#47;day of prednisone &#40;or its equivalent&#41; after 3 months of starting the steroid treatment or</p></li><li class="elsevierStyleListItem" id="lsti0140"><span class="elsevierStyleLabel">-</span><p id="par0180" class="elsevierStylePara elsevierViewall">a relapse within the first 3 months after having discontinued the treatment with steroids&#46;</p></li></ul></p></li><li class="elsevierStyleListItem" id="lsti0145"><span class="elsevierStyleLabel">&#9642;</span><p id="par0185" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Steroid resistance</span>&#58; A situation of clinical activity in spite of a 4-week treatment at full doses &#40;0&#46;75<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day of prednisolone or 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day of prednisone&#44; or its equivalent&#41;&#46; This definition is very controversial and will most likely be modified in the future&#46; In fact&#44; in the context of a severe flare&#44; the majority of clinicians will define steroid-resistance as the lack of clinical response after the intravenous administration of steroids at full doses for 7 days&#46; Moreover&#44; there is a growing tendency to place the definition in 5 or even 3 days&#46; To the effects of this CPG&#44; we will use the concept of a month for mild or moderate flares&#44; and 7 days for severe flares&#46;</p></li><li class="elsevierStyleListItem" id="lsti0150"><span class="elsevierStyleLabel">&#9642;</span><p id="par0190" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Pouchitis</span>&#58; inflammation of the ileal pouch created to maintain the intestine-anus continuity after a total colectomy&#46; In many patients it behaves as a chronic illness&#46;</p></li><li class="elsevierStyleListItem" id="lsti0155"><span class="elsevierStyleLabel">&#9642;</span><p id="par0195" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Cuffitis</span>&#58; inflammation of the rectal mucosa cuff that remains in the anal area in some ileo-anal anastomoses&#46;</p></li></ul></p></li></ul></p></li><li class="elsevierStyleListItem" id="lsti0160"><span class="elsevierStyleLabel"><span class="elsevierStyleItalic">-</span></span><p id="par0200" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Pharmacological index</span><ul class="elsevierStyleList" id="lis0050"><li class="elsevierStyleListItem" id="lsti0165"><span class="elsevierStyleLabel">&#8728;</span><p id="par0205" class="elsevierStylePara elsevierViewall">Systemic drugs&#58;<ul class="elsevierStyleList" id="lis0055"><li class="elsevierStyleListItem" id="lsti0170"><span class="elsevierStyleLabel">&#9642;</span><p id="par0210" class="elsevierStylePara elsevierViewall">Salicylates&#58; sulfasalazine&#44; mesalazine</p></li><li class="elsevierStyleListItem" id="lsti0175"><span class="elsevierStyleLabel">&#9642;</span><p id="par0215" class="elsevierStylePara elsevierViewall">Oral steroids&#58;<ul class="elsevierStyleList" id="lis0060"><li class="elsevierStyleListItem" id="lsti0180"><span class="elsevierStyleLabel">-</span><p id="par0220" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Systemic steroids</span>&#58; hydrocortisone&#44; prednisone&#44; methylprednisolone&#44; deflazacort&#44; betamethasone&#44; dexamethasone&#46;</p></li><li class="elsevierStyleListItem" id="lsti0185"><span class="elsevierStyleLabel">-</span><p id="par0225" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Topical action</span>&#58; beclomethasone dipropionate &#40;BDP&#41;&#44; budesonide</p></li></ul></p></li><li class="elsevierStyleListItem" id="lsti0190"><span class="elsevierStyleLabel">&#9642;</span><p id="par0230" class="elsevierStylePara elsevierViewall">Immunomodulating drugs &#40;immunosuppressants&#41;&#58;<ul class="elsevierStyleList" id="lis0065"><li class="elsevierStyleListItem" id="lsti0195"><span class="elsevierStyleLabel">-</span><p id="par0235" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Thiopurine agents</span>&#58; azathioprine&#44; mercaptopurine&#44; thioguanine</p></li><li class="elsevierStyleListItem" id="lsti0200"><span class="elsevierStyleLabel">-</span><p id="par0240" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Methotrexate</span></p></li><li class="elsevierStyleListItem" id="lsti0205"><span class="elsevierStyleLabel">-</span><p id="par0245" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Calcineurinics</span>&#58; cyclosporine&#44; tacrolimus</p></li></ul></p></li><li class="elsevierStyleListItem" id="lsti0210"><span class="elsevierStyleLabel">&#9642;</span><p id="par0250" class="elsevierStylePara elsevierViewall">Biological agents&#58; infliximab&#44; adalimumab&#46;</p></li><li class="elsevierStyleListItem" id="lsti0215"><span class="elsevierStyleLabel">&#9642;</span><p id="par0255" class="elsevierStylePara elsevierViewall">Heparin&#46;</p></li></ul></p></li><li class="elsevierStyleListItem" id="lsti0220"><span class="elsevierStyleLabel">&#8728;</span><p id="par0260" class="elsevierStylePara elsevierViewall">Topical drugs<ul class="elsevierStyleList" id="lis0070"><li class="elsevierStyleListItem" id="lsti0225"><span class="elsevierStyleLabel">&#9642;</span><p id="par0265" class="elsevierStylePara elsevierViewall">Mesalazine</p></li><li class="elsevierStyleListItem" id="lsti0230"><span class="elsevierStyleLabel">&#9642;</span><p id="par0270" class="elsevierStylePara elsevierViewall">Steroids<ul class="elsevierStyleList" id="lis0075"><li class="elsevierStyleListItem" id="lsti0235"><span class="elsevierStyleLabel">-</span><p id="par0275" class="elsevierStylePara elsevierViewall">Oral administration&#58; beclomethasone&#44; budesonide</p></li><li class="elsevierStyleListItem" id="lsti0240"><span class="elsevierStyleLabel">-</span><p id="par0280" class="elsevierStylePara elsevierViewall">Rectal administration&#58;<ul class="elsevierStyleList" id="lis0080"><li class="elsevierStyleListItem" id="lsti0245"><span class="elsevierStyleLabel">&#8226;</span><p id="par0285" class="elsevierStylePara elsevierViewall">High systemic bioavailability&#58; hydrocortisone&#44; prednisolone&#44; triamcinolone&#44; methylprednisolone and betamethasone</p></li><li class="elsevierStyleListItem" id="lsti0250"><span class="elsevierStyleLabel">&#8226;</span><p id="par0290" class="elsevierStylePara elsevierViewall">Low systemic bioavailability&#58; budesonide&#44; beclomethasone and prednisolone-metasulphobenzoate</p></li></ul></p></li></ul></p></li></ul></p></li><li class="elsevierStyleListItem" id="lsti0255"><span class="elsevierStyleLabel">&#8728;</span><p id="par0295" class="elsevierStylePara elsevierViewall">Other treatment techniques&#58;<ul class="elsevierStyleList" id="lis0085"><li class="elsevierStyleListItem" id="lsti0260"><span class="elsevierStyleLabel">&#9642;</span><p id="par0300" class="elsevierStylePara elsevierViewall">Aphaeresis&#58; leucocyte aphaeresis&#44; granulocyte aphaeresis</p></li></ul></p></li></ul></p></li></ul></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">4</span><span class="elsevierStyleSectionTitle">Objectives</span><p id="par0305" class="elsevierStylePara elsevierViewall">The objectives were defined by the Elaboration Committee &#40;see <a class="elsevierStyleCrossRefs" href="#sec0175">Appendices</a>&#41;&#44; following the GRADE working methodology&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> In summary&#44; after choosing the three clinical scenarios to which recommendations may be applied &#40;induction of remission in severe colitis&#44; induction of remission in mild-to-moderate colitis&#44; and maintenance of remission&#41;&#59; in each of the scenarios&#44; the possible variables of result were explained and defined in a numeric scale from 1 to 9 &#40;1&#8211;3&#58; are not included&#59; 4&#8211;6&#58; important but not critical&#59; and 7&#8211;9&#58; critical for decision-making&#41; by the nine members of the Elaboration Committee&#46; After being classified in order of importance&#44; variables with an average score above 4 were included as result variables&#46; In all the critical variables&#44; the degree of internal agreement of the Committee was excellent&#44; with unanimity in the score or with a maximum variability of one point&#46; After this previous process&#44; the following were defined as CPG <span class="elsevierStyleItalic">objectives</span>&#58;<ul class="elsevierStyleList" id="lis0090"><li class="elsevierStyleListItem" id="lsti0265"><span class="elsevierStyleLabel">&#9642;</span><p id="par0310" class="elsevierStylePara elsevierViewall">To establish recommendations based on available tests for the <span class="elsevierStyleItalic">induction treatment in the severe UC flare</span> prioritizing the following assessment variables&#58;</p></li></ul><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><ul class="elsevierStyleList" id="lis0095"><li class="elsevierStyleListItem" id="lsti0270"><span class="elsevierStyleLabel">&#9642;</span><p id="par0315" class="elsevierStylePara elsevierViewall">To establish recommendations for the <span class="elsevierStyleItalic">induction treatment in the mild&#8211;moderate UC flare</span> prioritizing the following assessment variables&#58;</p></li></ul><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><ul class="elsevierStyleList" id="lis0100"><li class="elsevierStyleListItem" id="lsti0275"><span class="elsevierStyleLabel">&#9642;</span><p id="par0320" class="elsevierStylePara elsevierViewall">To establish recommendations for the <span class="elsevierStyleItalic">maintenance treatment of UC in remission</span> prioritizing the following assessment variables&#58;</p></li></ul><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">5</span><span class="elsevierStyleSectionTitle">Methodology</span><p id="par0325" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0105"><li class="elsevierStyleListItem" id="lsti0280"><span class="elsevierStyleLabel">&#8728;</span><p id="par0330" class="elsevierStylePara elsevierViewall">For the elaboration of the CPG&#44; AGREE methodology was followed&#44; which is described in detail on the web page&#58; <a href="http://www.agreecollaboration.org/">www&#46;agreecollaboration&#46;org</a>&#46; Briefly&#44; an interdisciplinary working team was formed&#44; structured in a Design Committee &#40;general for the different CPG promoted by <a href="http://www.geteccu.org/">GETECCU</a>&#41;&#44; an Elaboration Committee &#40;for the three first CPG&#41;&#44; a Working Committee &#40;specific for this CPG&#41;&#44; an Internal Review Committee &#40;for the three first CPG&#41; and an External Review Committee &#40;specific for this CPG&#41;&#46; The External Review Committee included gastroenterologists&#44; surgeons&#44; primary care physicians&#44; nurses and patients&#46; A more detailed composition of all these committees is presented in the guidelines&#8217; <a class="elsevierStyleCrossRefs" href="#sec0175">Appendices</a>&#46; Throughout the entire process&#44; both in the formation of the team as well as in the areas in which it was necessary&#44; the methodological support of the specialized Cochrane Collaboration staff was available&#46; After the objectives were defined by the Elaboration Committee&#44; the Working Committee carried out a Systematic Literature Review&#44; specifically directed at answering the key questions posed previously&#46; After the information was obtained&#44; it underwent an evaluation process&#44; following the GRADE methodology&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> Thus&#44; the quality of the studies was evaluated considering the study&#39;s design&#44; their consistency and the direct and indirect evidence&#46; Considering a combination of the four components&#44; quality was defined as <span class="elsevierStyleItalic">High</span> &#40;very unlikely that new studies change the estimation&#41;&#44; <span class="elsevierStyleItalic">Moderate</span> &#40;it is likely that new studies change the reliability of the result&#41;&#44; <span class="elsevierStyleItalic">Low</span> &#40;it is very likely that new studies will have an impact on the result&#39;s reliability and that they might modify it&#41; and <span class="elsevierStyleItalic">Very low</span> &#40;any estimated results are very doubtful&#41;&#46; Aside from the essential factors mentioned&#44; for the overall estimation of quality of the evidence&#44; other factors such as the number of patients studied&#44; the strength of the associations that were found&#44; the presence of dose&#8211;response gradients &#40;in pharmacological studies&#41; and the acknowledgement or not of possible confounding factors identified by the evaluators were taken into account&#46; In any case&#44; all of these factors are considered cumulatively and with a specific methodology that may be consulted in the references&#46; In order to establish <span class="elsevierStyleItalic">recommendations</span>&#44; we considered not only the quality of the evidence&#44; but we also carried out a weighing between the potential benefits of the intervention&#44; its risks&#44; and its applicability in the population that will be treated and&#44; finally&#44; its costs&#46; Even without having analyzed formal cost-effectiveness analyses&#44; costs are always considered from a global standpoint and are compared&#44; not only considering direct costs&#44; but also the indirect costs and the context &#40;regarding the costs of alternatives&#41;&#46; The <span class="elsevierStyleItalic">recommendations</span> issued are classified into four degrees&#58; <span class="elsevierStyleItalic">recommendation or we recommend</span>&#44; which implies strongly advising the clinician&#58; <span class="elsevierStyleItalic">Do it</span>&#59; <span class="elsevierStyleItalic">suggestion or we suggest</span> which means to advise the clinical <span class="elsevierStyleItalic">probably do it</span>&#59; <span class="elsevierStyleItalic">suggestion against or we do no suggest</span> which implies the same as <span class="elsevierStyleItalic">probably don&#8217;t do it&#59;</span> and <span class="elsevierStyleItalic">we recommend avoiding or we do not recommend</span> which strongly and clearly indicates <span class="elsevierStyleItalic">don&#8217;t do it&#46;</span> This type of classification is both easily understandable and flexible&#44; because it can be adapted to the very different clinical scenarios possible&#46;</p></li><li class="elsevierStyleListItem" id="lsti0285"><span class="elsevierStyleLabel">&#8728;</span><p id="par0335" class="elsevierStylePara elsevierViewall">The Systematic Literature Review was carried out with free and conditioned searches in the following databases&#58; PUBMED&#44; EMBASE&#44; TRIPDATABASE&#44; and COCHRANE COLLABORATION&#44; as well as in textbooks and by cross-referencing several studies&#46; A review was carried out for each one of the questions asked&#46; Furthermore&#44; cross references were carried out in specialty texts and in all the recent reviews&#46; In all the cases in which a systematic review was already published&#44; it was used if its methodology was deemed adequate by the Working Committee&#44; following the criteria of the Cochrane Foundation&#46; If there were doubts about the methodology&#44; the source data were reviewed&#44; and if there were several systematic reviews&#44; the choice was made firstly based on methodological criteria&#44; and secondly&#44; on time criteria &#40;the most recent cases were preferred in case of methodological equivalence&#41;&#46; Only documents published completely were evaluated&#46; Nonetheless&#44; at the moment of the final writing of the Guidelines&#44; the Writing Committee considered some results reported formally during the last national and international congresses on some specific points that will be specified in the text&#46; The limit for the inclusion of studies is February 2011&#46; In the reference list&#44; we only include key studies&#44; systematic reviews and quotes after these&#46;</p></li><li class="elsevierStyleListItem" id="lsti0290"><span class="elsevierStyleLabel">&#8728;</span><p id="par0340" class="elsevierStylePara elsevierViewall">This CPG will be of free and universal access&#46; It will be published in several formats &#40;hard and soft copy&#41; and will be available freely on the Internet to be accessed accessible by any professional and&#47;or patient&#46;</p></li><li class="elsevierStyleListItem" id="lsti0295"><span class="elsevierStyleLabel">&#8728;</span><p id="par0345" class="elsevierStylePara elsevierViewall">The information will be presented answering general questions posed in three formats&#58; review of the evidence&#44; summarized explanatory text and decision algorithms&#46; In sum&#44; the evidence is presented answering each one of the questions asked&#44; whereas the explanatory texts are articulated around the six specific algorithms that have been elaborated&#46;</p></li><li class="elsevierStyleListItem" id="lsti0300"><span class="elsevierStyleLabel">&#8728;</span><p id="par0350" class="elsevierStylePara elsevierViewall">The strategic decisions about the CPG will be taken by GETECCU&#44; represented by its Board of Directors&#44; and by the Guidelines Elaboration Committee named to this effect&#46;</p></li><li class="elsevierStyleListItem" id="lsti0305"><span class="elsevierStyleLabel">&#8728;</span><p id="par0355" class="elsevierStylePara elsevierViewall">The costs are covered by GETECCU&#44; who has obtained a GRANT &#40;with no restrictions&#41; from MSD&#46;</p></li><li class="elsevierStyleListItem" id="lsti0310"><span class="elsevierStyleLabel">&#8728;</span><p id="par0360" class="elsevierStylePara elsevierViewall">The conflicts of interest of the authors are explained in Appendix&#46;</p></li></ul></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">6</span><span class="elsevierStyleSectionTitle">Induction of remission in patients with active ulcerative colitis</span><p id="par0365" class="elsevierStylePara elsevierViewall">Any situation in which the patient has symptoms and&#47;or signs indicating disease activity is considered an active colitis&#46; In case of doubt&#44; endoscopy and histology are reference techniques for defining the symptoms&#46; For severity and extension we used the Montreal Classification<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0665">Table 2</a>&#41;&#46; The key information necessary for the clinician is summarized in algorithms 1&#44; 2 and their corresponding explanatory text&#46; The review of the evidence is presented by answering the questions elaborated by the working group&#46;</p><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">6&#46;1</span><span class="elsevierStyleSectionTitle">Severe UC flare &#40;of any anatomical extension&#41; &#40;<a class="elsevierStyleCrossRef" href="#enun0005">Algorithm 1</a>&#41;</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">6&#46;1&#46;1</span><span class="elsevierStyleSectionTitle">Steroids</span><p id="par0370" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0110"><li class="elsevierStyleListItem" id="lsti0315"><span class="elsevierStyleLabel">-</span><p id="par0375" class="elsevierStylePara elsevierViewall">Are steroids effective in induction of remission in patients with a severe UC flare&#63;</p></li></ul>Text of the guidelines&#58;<elsevierMultimedia ident="tbl0020"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0025"></elsevierMultimedia>Formulation of the recommendation<elsevierMultimedia ident="tbl0030"></elsevierMultimedia>Comment by the elaborating group&#58;<elsevierMultimedia ident="tbl0035"></elsevierMultimedia></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">6&#46;1&#46;2</span><span class="elsevierStyleSectionTitle">Immunomodulators</span><p id="par0380" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0115"><li class="elsevierStyleListItem" id="lsti0320"><span class="elsevierStyleLabel">-</span><p id="par0385" class="elsevierStylePara elsevierViewall">Is cyclosporine effective in induction of remission in patients with a severe UC flare&#63; and in a situation of steroid resistance&#63;</p></li></ul>Text of the guidelines&#58;<elsevierMultimedia ident="tbl0040"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0045"></elsevierMultimedia>Formulation of the recommendation<elsevierMultimedia ident="tbl0050"></elsevierMultimedia>Comment by the elaborating group<elsevierMultimedia ident="tbl0055"></elsevierMultimedia><ul class="elsevierStyleList" id="lis0120"><li class="elsevierStyleListItem" id="lsti0325"><span class="elsevierStyleLabel">-</span><p id="par0390" class="elsevierStylePara elsevierViewall">Is tacrolimus effective in induction of remission in patients with a severe UC flare&#63; and in a situation of steroid resistance&#63;</p></li></ul>Text of the guidelines&#58;<elsevierMultimedia ident="tbl0060"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0065"></elsevierMultimedia>Formulation of the recommendation<elsevierMultimedia ident="tbl0070"></elsevierMultimedia>Comment by the elaborating group<elsevierMultimedia ident="tbl0075"></elsevierMultimedia></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">6&#46;1&#46;3</span><span class="elsevierStyleSectionTitle">Biological treatments</span><p id="par0395" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0125"><li class="elsevierStyleListItem" id="lsti0330"><span class="elsevierStyleLabel">-</span><p id="par0400" class="elsevierStylePara elsevierViewall">Is infliximab effective in induction of remission in patients with a severe UC flare&#63; and in a situation of steroid resistance&#63;</p></li></ul>Text of the guidelines&#58;<elsevierMultimedia ident="tbl0080"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0085"></elsevierMultimedia>Formulation of the recommendation<elsevierMultimedia ident="tbl0090"></elsevierMultimedia>Comment by the elaborating group<elsevierMultimedia ident="tbl0095"></elsevierMultimedia></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">6&#46;1&#46;4</span><span class="elsevierStyleSectionTitle">Heparin</span><p id="par0405" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0130"><li class="elsevierStyleListItem" id="lsti0335"><span class="elsevierStyleLabel">-</span><p id="par0410" class="elsevierStylePara elsevierViewall">Is heparin &#40;at anti-coagulant doses&#41; effective in induction of remission in patients with a severe UC flare&#63;</p></li></ul>Text of the guidelines&#58;<elsevierMultimedia ident="tbl0100"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0105"></elsevierMultimedia>Formulation of the recommendation<elsevierMultimedia ident="tbl0110"></elsevierMultimedia>Comment by the elaborating group<elsevierMultimedia ident="tbl0115"></elsevierMultimedia></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">6&#46;1&#46;5</span><span class="elsevierStyleSectionTitle">Antibiotics</span><p id="par0415" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0135"><li class="elsevierStyleListItem" id="lsti0340"><span class="elsevierStyleLabel">-</span><p id="par0420" class="elsevierStylePara elsevierViewall">Are antibiotics effective in induction of remission in patients with a severe UC flare&#63;</p></li></ul>Text of the guidelines&#58;<elsevierMultimedia ident="tbl0120"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0125"></elsevierMultimedia>Formulation of the recommendation<elsevierMultimedia ident="tbl0130"></elsevierMultimedia>Comment by the elaborating group<elsevierMultimedia ident="tbl0135"></elsevierMultimedia></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">6&#46;1&#46;6</span><span class="elsevierStyleSectionTitle">Surgery</span><p id="par0425" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0140"><li class="elsevierStyleListItem" id="lsti0345"><span class="elsevierStyleLabel">-</span><p id="par0430" class="elsevierStylePara elsevierViewall">Is surgery effective in induction of remission in patients with a severe UC flare&#63;</p></li></ul></p><p id="par0435" class="elsevierStylePara elsevierViewall">Colectomy was established as treatment for UC when there were no medical alternatives&#46; Gradually&#44; with technical advances in anaesthesia and in postoperative control&#44; colectomy reached mortality rates that are clearly below the spontaneous course of the flare&#46; The absence of controlled studies in this field is one of the clearest examples of situations that are self-evident&#44; but impossible to demonstrate&#46; There is no reasonable doubt that colectomy is a very effective treatment in severe UC flares&#44; a scenario for which&#44; in the absence of medical treatment&#44; mortality rates of 22&#8211;77&#37; were described&#46; Even if we do not have controlled studies either&#44; the results of the Oxford series in the 1960s and 1970s in studies conducted by Sidney Truelove in the steroid era<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a> are very convincing&#46; The best results were obtained when a fixed day was set a priori in which the patient with no response to steroids was intervened &#40;in the Oxford series&#44; this was decided to be on the fifth day of treatment&#59; in the Scandinavian series&#44; it was decided to be a little later&#44; but it yielded very similar results<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a>&#41;&#46; It is curious to see how&#44; after introducing new medical alternatives such as cyclosporine or infliximab&#44; most experts emphasize on making an early decision &#40;third&#44; fifth&#44; seventh or tenth day&#44; according to the authors&#41;&#46; On some occasions&#44; surgery is the <span class="elsevierStyleItalic">best</span> choice&#58; perforation&#44; severe haemorrhage that is not controlled with endoscopic treatment&#44; toxic megacolon of more than 72<span class="elsevierStyleHsp" style=""></span>h duration&#46; In others&#44; it is probably the <span class="elsevierStyleItalic">preferred</span> choice&#58; e&#46;g&#46;&#44; severe colitis with a very prolonged clinical history and&#47;or a previous diagnosis of dysplasia&#46; In most cases&#44; however&#44; it is just a <span class="elsevierStyleItalic">back-up</span> option and it is only indicated if the previous medical treatment has failed&#46; In any case&#44; uncontrolled but extensive experience suggests that in the severe UC flare treatment&#44; the collaboration of a surgical team from the moment the patient is <span class="elsevierStyleItalic">admitted</span> helps make more coherent decisions every time&#44; taking into consideration several treatment options&#46;<span class="elsevierStyleVsp" style="height:0.5px"></span>Summary of the evidence<elsevierMultimedia ident="tbl0140"></elsevierMultimedia>Formulation of the recommendation&#58;<elsevierMultimedia ident="tbl0145"></elsevierMultimedia>Comment by the elaborating group&#58;<elsevierMultimedia ident="tbl0150"></elsevierMultimedia></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">6&#46;1&#46;7</span><span class="elsevierStyleSectionTitle">Parenteral nutrition</span><p id="par0440" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0145"><li class="elsevierStyleListItem" id="lsti0350"><span class="elsevierStyleLabel">-</span><p id="par0445" class="elsevierStylePara elsevierViewall">Is parenteral nutrition effective in induction of remission in patients with a severe UC flare&#63;</p></li></ul></p><p id="par0450" class="elsevierStylePara elsevierViewall">There are not enough studies to create a GRADE table in the case of parenteral nutrition either&#46; However&#44; we can state several basic principles&#44; either due to the existence of controlled studies&#44; or the existence of direct and&#47;or experimental data&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a><ul class="elsevierStyleList" id="lis0150"><li class="elsevierStyleListItem" id="lsti0355"><span class="elsevierStyleLabel">&#8226;</span><p id="par0455" class="elsevierStylePara elsevierViewall">In contrast with what was suggested in the first half of the XX century&#44; absolute diet does not have any primary therapeutic effectiveness and hence&#44; except in cases of absolute oral intolerance&#44; intestinal obstruction or extreme severity&#44; oral nutrition must not be discontinued&#46;</p></li><li class="elsevierStyleListItem" id="lsti0360"><span class="elsevierStyleLabel">&#8226;</span><p id="par0460" class="elsevierStylePara elsevierViewall">Parenteral nutrition has no primary efficacy in the treatment of UC&#44; and generally&#44; enteral nutrition must be preferred&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a> Moreover&#44; it is more expensive and it entails a higher risk of infection and thromboembolic phenomena when compared to enteral nutrition&#46;</p></li><li class="elsevierStyleListItem" id="lsti0365"><span class="elsevierStyleLabel">&#8226;</span><p id="par0465" class="elsevierStylePara elsevierViewall">In case a complete caloric and nutritional supply cannot be assured&#44; enteral nutrition must be used&#44; either as a supplement or even as the sole source of nutrition&#46;</p></li><li class="elsevierStyleListItem" id="lsti0370"><span class="elsevierStyleLabel">&#8226;</span><p id="par0470" class="elsevierStylePara elsevierViewall">In case of severe flares&#44; a relatively extensive hospital stay should be foreseen&#46; There are studies from the 1980s&#44;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a> corroborated in years as recent as 2008<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a>&#59; showing that hospitalized patients are discharged &#40;on average&#41; in a worse nutritional condition than the one they had on admission&#46; Moreover&#44; numerous experimental and clinical tests confirm that an adequate nutrition is necessary for the correct functioning of the immune system&#46; In patients with severe UC&#44; the risk of nosocomial infections&#44; either opportunistic or not&#44; is very high due to several factors&#58; hospitalization&#44; use of tubes and catheters&#44; an increased intestinal permeability &#40;rupture of the mucous barrier&#41;&#44; malnourishment and the use of immunomodulating drugs being the most important&#46; The measures for the control of infections will help reduce the risk&#44; but we can ensure a greater medical impact by assuring a proper nutrition&#46; Also&#44; we can decrease the negative effects of some drugs&#44; keeping a good nutritional status &#40;calcium and vitamin D to prevent osteoporosis&#59; prevention of hypercholesterolemia and hypomagnesaemia in case cyclosporine is used&#41;&#46;</p></li></ul><span class="elsevierStyleVsp" style="height:0.5px"></span>Summary of the evidence&#58;<elsevierMultimedia ident="tbl0155"></elsevierMultimedia>Formulation of the recommendation&#58;<elsevierMultimedia ident="tbl0160"></elsevierMultimedia>Comment by the elaborating group&#58;<elsevierMultimedia ident="tbl0165"></elsevierMultimedia><span class="elsevierStyleEnunciation" id="enun0005"><span class="elsevierStyleLabel">Algorithm 1</span><p id="par0475" class="elsevierStylePara elsevierViewall">Severe flare&#58; algorithm and explanatory text<elsevierMultimedia ident="fig0005"></elsevierMultimedia></p></span></p><p id="par0480" class="elsevierStylePara elsevierViewall">Treatment of severe UC flare is summarized in <a class="elsevierStyleCrossRef" href="#enun0005">Algorithm 1</a>&#46; When the diagnosis of severe UC flare is established&#44; in most cases hospitalization is a prudent strategy&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;13&#44;17&#44;61</span></a> From the first moment&#44; a strategy must be proposed that includes immediate measures&#44; the options in case these fail and also the possible treatment in the mid and long term&#46; Therefore&#44; all the diagnostic information must be reviewed &#40;<a class="elsevierStyleCrossRef" href="#tbl0705">Table 10</a>&#41; by re-evaluating all the data that may be of interest when it comes to making decisions in each specific case&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a></p><elsevierMultimedia ident="tbl0705"></elsevierMultimedia><p id="par0485" class="elsevierStylePara elsevierViewall">In most cases&#44; the initial treatment &#40;except if there is an absolute contraindication due to previous severe toxicity &#40;for instance&#44; steroid-associated psychosis&#41; or a situation of surgical urgency&#41; will be based on the administration of intravenous steroids&#44; with a dose equivalent to 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg of prednisone per day&#46; It can be administered in a single or fragmented dose&#44; or even in continuous infusion&#46; Furthermore&#44; the treatment with other measures must be completed in order to prevent thromboembolism&#44; obtain an adequate nutrition and&#44; in selected cases&#44; administer antibiotics &#40;<a class="elsevierStyleCrossRef" href="#tbl0710">Table 11</a>&#41;&#46; The clinical follow-up must be&#44; at minimum&#44; daily&#44; and preferably jointly managed with the surgeon&#46; It is practical to include in the diagnostic evaluation those tests that inform us about the risks of the side effects of infliximab&#44; cyclosporine or azathioprine&#44; as they may allow to start the treatments with a greater safety&#44; and if found to be necessary&#44; instituting the necessary preventive measures&#46;</p><elsevierMultimedia ident="tbl0710"></elsevierMultimedia><p id="par0490" class="elsevierStylePara elsevierViewall">It is advisable to set&#44; from the first day&#44; a time point for evaluating the response&#44; and it is most adequate to do it between the third and fifth day after starting the treatment&#46; In fact&#44; currently most authors tend to recommend an initial evaluation at 72<span class="elsevierStyleHsp" style=""></span>h&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a> At that moment&#44; the patient may have reached remission &#40;in which case&#44; he&#47;she will progressively move from the treatment phase to the maintenance phase&#41; or not&#46; If remission has not been obtained&#44; there are several indices &#40;for example&#44; Ho&#39;s index&#44;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a><a class="elsevierStyleCrossRef" href="#tbl0715">Table 12</a>&#41; that allow us to predict the probability of response if the steroid treatment were to be extended&#46; A recent simple model&#44; evaluated prospectively in a hospital&#44; suggests that with four parameters &#40;rectal bleeding&#44; CRP&#44; platelet count and the number of bowel movements&#41; evaluated by the third day&#44; it may be decided with great precision if it is necessary to switch to another treatment or not&#46; If this were to be confirmed in other sites&#44; this model may allow us to make decisions with data available at any other site with great ease&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a> On occasions&#44; the situation is very clear&#44; and a new medical treatment &#40;infliximab or cyclosporine&#41; is initiated between the third and fifth days&#46; In other patients&#44; the situation is not that clear&#44; and it is preferred to carry out a re-evaluation between the fifth and seventh days after starting on steroids&#46; If remission has not been reached by the seventh day it is best to start the alternative treatment&#46;</p><elsevierMultimedia ident="tbl0715"></elsevierMultimedia><p id="par0495" class="elsevierStylePara elsevierViewall">When steroids fail&#44; there are mainly three options&#58; cyclosporine&#44; infliximab and surgery&#46; The lack of comparative studies hinders us from being specific&#46; In this decision node&#44; the opinion of the well-informed patient is very important&#44; with the collaboration of relatives and associated people&#44; and it is absolutely necessary to rule out other causes of refractoriness&#44; especially a colon infection by <span class="elsevierStyleItalic">CMV</span><a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">64</span></a> and by <span class="elsevierStyleItalic">Clostridium difficile</span> &#40;by means of the study of signs of infection by <span class="elsevierStyleItalic">CMV</span> in a rectal biopsy&#44; and by looking for specific toxins in faeces&#44; respectively&#41;&#46; The following favour surgery&#58; a prolonged history of the disease and&#47;or the presence of dysplasia in previous controls&#44; as well as two clinical situations&#58; toxic megacolon and massive haemorrhage&#46; However&#44; in almost all cases&#44; a medical option can be tried&#46; If the patient has suffered a severe flare while already on treatment with thiopurines &#40;drugs that would be necessary in the post-cyclosporine maintenance treatment&#41;&#44; it would&#44; probably&#44; be most indicated to use infliximab&#46; In the rest of the cases&#44; the choice may be between cyclosporine<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> or infliximab&#44;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> a decision in which the team&#39;s experience and other local factors &#40;the possibility of determining blood levels of cyclosporine&#44; for example&#41; are determinant&#46; The general recommendations for the use of infliximab<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">65</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0720">Table 13</a>&#41; or cyclosporine<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> must be followed &#40;<a class="elsevierStyleCrossRefs" href="#tbl0725">Tables 14&#8211;16</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0720"></elsevierMultimedia><elsevierMultimedia ident="tbl0725"></elsevierMultimedia><elsevierMultimedia ident="tbl0730"></elsevierMultimedia><elsevierMultimedia ident="tbl0735"></elsevierMultimedia><p id="par0500" class="elsevierStylePara elsevierViewall">In any of the medical options chosen&#44; a new moment of evaluation must be planned&#44; and probably&#44; it would be most reasonable to carry out an evaluation after seven days of having started the new treatment&#46; At this point&#44; there are no set norms&#46; If there is a worsening or an absolute lack of improvement&#44; in most cases&#44; the most reasonable course of action is surgery&#59; if there is remission&#44; we may move on to the maintenance regimen&#46; Nonetheless&#44; it is very common for intermediate situations to take place&#44; in which all the possibilities must be evaluated&#46; Thus&#44; it has been described that in spite of the failure with cyclosporine&#44; some patients may avoid surgery by using infliximab&#44;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a> and also&#44; less frequently&#44; the opposite path has been taken&#46;</p><p id="par0505" class="elsevierStylePara elsevierViewall">In all the decision nodes&#44; the opinion of the patient&#44; or that of his&#47;her relatives and&#47;or friends&#44; the opinion of the surgeon and the opinion of the gastroenterologist must be considered carefully&#46; We cannot emphasize enough on how relevant it is to share all the information with the patient from the start&#46;</p></span></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">6&#46;2</span><span class="elsevierStyleSectionTitle">Mild and moderate UC flare &#40;<a class="elsevierStyleCrossRef" href="#enun0010">Algorithm 2</a>&#41;</span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">6&#46;2&#46;1</span><span class="elsevierStyleSectionTitle">Salicylates</span><p id="par0510" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0155"><li class="elsevierStyleListItem" id="lsti0375"><span class="elsevierStyleLabel">-</span><p id="par0515" class="elsevierStylePara elsevierViewall">Is the treatment with oral salicylates effective in induction of remission in patients with a mild&#8211;moderate UC flare&#63;</p></li></ul>Text of the guidelines&#58;<elsevierMultimedia ident="tbl0170"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0175"></elsevierMultimedia>Formulation of the recommendation<elsevierMultimedia ident="tbl0180"></elsevierMultimedia>Comment by the elaborating group&#58;<elsevierMultimedia ident="tbl0185"></elsevierMultimedia><ul class="elsevierStyleList" id="lis0160"><li class="elsevierStyleListItem" id="lsti0380"><span class="elsevierStyleLabel">-</span><p id="par0520" class="elsevierStylePara elsevierViewall">Is the combined treatment with oral and topical salicylates more effective than oral treatment alone in induction of remission in patients with a mild&#8211;moderate UC flare&#63;</p></li></ul>Text of the guidelines&#58;<elsevierMultimedia ident="tbl0190"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0195"></elsevierMultimedia>Formulation of the recommendation<elsevierMultimedia ident="tbl0200"></elsevierMultimedia>Comment by the elaborating group<elsevierMultimedia ident="tbl0205"></elsevierMultimedia><ul class="elsevierStyleList" id="lis0165"><li class="elsevierStyleListItem" id="lsti0385"><span class="elsevierStyleLabel">-</span><p id="par0525" class="elsevierStylePara elsevierViewall">Is the treatment with topical salicylates alone effective in induction of remission in patients with a mild&#8211;moderate flare of left-sided UC&#63;</p></li></ul>Text of the guidelines&#58;<elsevierMultimedia ident="tbl0210"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0215"></elsevierMultimedia></p><p id="par0530" class="elsevierStylePara elsevierViewall">Formulation of the recommendation<elsevierMultimedia ident="tbl0220"></elsevierMultimedia>Comment by the elaborating group&#58;<elsevierMultimedia ident="tbl0225"></elsevierMultimedia><ul class="elsevierStyleList" id="lis0170"><li class="elsevierStyleListItem" id="lsti0390"><span class="elsevierStyleLabel">-</span><p id="par0535" class="elsevierStylePara elsevierViewall">Is treatment with topical salicylates more effective than oral treatment in induction of remission in patients with left-sided UC flare&#63;</p></li></ul>Text of the guidelines&#58;<elsevierMultimedia ident="tbl0230"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0235"></elsevierMultimedia>Formulation of the recommendation<elsevierMultimedia ident="tbl0240"></elsevierMultimedia>Comment by the elaborating group<elsevierMultimedia ident="tbl0245"></elsevierMultimedia></p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">6&#46;2&#46;2</span><span class="elsevierStyleSectionTitle">Steroids</span><p id="par0540" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0175"><li class="elsevierStyleListItem" id="lsti0395"><span class="elsevierStyleLabel">-</span><p id="par0545" class="elsevierStylePara elsevierViewall">Are systemic oral steroids effective in induction of remission in patients with mild&#8211;moderate UC flares&#63;</p></li></ul>Text of the guidelines&#58;<elsevierMultimedia ident="tbl0250"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0255"></elsevierMultimedia>Formulation of the recommendation&#58;<elsevierMultimedia ident="tbl0260"></elsevierMultimedia>Comment by the elaborating group&#58;<elsevierMultimedia ident="tbl0265"></elsevierMultimedia><ul class="elsevierStyleList" id="lis0180"><li class="elsevierStyleListItem" id="lsti0400"><span class="elsevierStyleLabel">-</span><p id="par0550" class="elsevierStylePara elsevierViewall">Are the new oral steroids of low bioavailability effective in induction of remission in patients with mild&#8211;moderate UC flares&#63;</p></li></ul>Text of the guidelines&#58;<elsevierMultimedia ident="tbl0270"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0275"></elsevierMultimedia>Formulation of the recommendation<elsevierMultimedia ident="tbl0280"></elsevierMultimedia>Comment by the elaborating group<elsevierMultimedia ident="tbl0285"></elsevierMultimedia><ul class="elsevierStyleList" id="lis0185"><li class="elsevierStyleListItem" id="lsti0405"><span class="elsevierStyleLabel">-</span><p id="par0555" class="elsevierStylePara elsevierViewall">Is the treatment with rectal steroids effective in induction of remission in patients with a mild&#8211;moderate flare of left-sided UC&#63;</p></li></ul>Text of the guidelines&#58;<elsevierMultimedia ident="tbl0290"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0295"></elsevierMultimedia>Formulation of the recommendation<elsevierMultimedia ident="tbl0300"></elsevierMultimedia>Comment by the elaborating group<elsevierMultimedia ident="tbl0305"></elsevierMultimedia><ul class="elsevierStyleList" id="lis0190"><li class="elsevierStyleListItem" id="lsti0410"><span class="elsevierStyleLabel">-</span><p id="par0560" class="elsevierStylePara elsevierViewall">Are low bioavailability rectal steroids more effective than those of high bioavailability in the induction of remission in patients with mild&#8211;moderate UC flares&#63;</p></li></ul>Text of the guidelines&#58;<elsevierMultimedia ident="tbl0310"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0315"></elsevierMultimedia>Formulation of the recommendation&#58;<elsevierMultimedia ident="tbl0320"></elsevierMultimedia>Comment by the elaborating group&#58;<elsevierMultimedia ident="tbl0325"></elsevierMultimedia><ul class="elsevierStyleList" id="lis0195"><li class="elsevierStyleListItem" id="lsti0415"><span class="elsevierStyleLabel">-</span><p id="par0565" class="elsevierStylePara elsevierViewall">Are topical salicylates more effective than rectal steroids in the induction of remission in patients with a mild&#8211;moderate UC flare&#63;</p></li></ul>Text of the guidelines&#58;<elsevierMultimedia ident="tbl0330"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0335"></elsevierMultimedia>Formulation of the recommendation<elsevierMultimedia ident="tbl0340"></elsevierMultimedia>Comment by the elaborating group&#58;<elsevierMultimedia ident="tbl0345"></elsevierMultimedia></p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">6&#46;2&#46;3</span><span class="elsevierStyleSectionTitle">Immunomodulators</span><p id="par0570" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0200"><li class="elsevierStyleListItem" id="lsti0420"><span class="elsevierStyleLabel">-</span><p id="par0575" class="elsevierStylePara elsevierViewall">Are thiopurine immunomodulators effective in induction of remission in patients with a moderate flare of steroid-dependent and&#47;or steroid-resistant UC&#63;</p></li></ul>Text of the guidelines&#58;<elsevierMultimedia ident="tbl0350"></elsevierMultimedia>Summary of the evidence&#58;<elsevierMultimedia ident="tbl0355"></elsevierMultimedia>Formulation of the recommendation&#58;<elsevierMultimedia ident="tbl0360"></elsevierMultimedia>Comment by the elaborating group&#58;<elsevierMultimedia ident="tbl0365"></elsevierMultimedia><ul class="elsevierStyleList" id="lis0205"><li class="elsevierStyleListItem" id="lsti0425"><span class="elsevierStyleLabel">-</span><p id="par0580" class="elsevierStylePara elsevierViewall">Is methotrexate effective in induction of remission in patients with a moderate flare of steroid-dependent UC&#63;</p></li></ul>Text of the guidelines&#58;<elsevierMultimedia ident="tbl0370"></elsevierMultimedia>Summary of the evidence&#58;<elsevierMultimedia ident="tbl0375"></elsevierMultimedia>Formulation of the recommendation&#58;<elsevierMultimedia ident="tbl0380"></elsevierMultimedia>Comment by the elaborating group&#58;<elsevierMultimedia ident="tbl0385"></elsevierMultimedia></p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">6&#46;2&#46;4</span><span class="elsevierStyleSectionTitle">Biological therapies</span><p id="par0585" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0210"><li class="elsevierStyleListItem" id="lsti0430"><span class="elsevierStyleLabel">-</span><p id="par0590" class="elsevierStylePara elsevierViewall">Is infliximab effective in induction of remission in patients with a moderate flare of steroid-dependent and&#47;or steroid-resistant UC&#63;</p></li></ul>Text of the guidelines&#58;<elsevierMultimedia ident="tbl0390"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0395"></elsevierMultimedia>Formulation of the recommendation&#58;<elsevierMultimedia ident="tbl0400"></elsevierMultimedia>Comment by the elaborating group&#58;<elsevierMultimedia ident="tbl0405"></elsevierMultimedia><ul class="elsevierStyleList" id="lis0215"><li class="elsevierStyleListItem" id="lsti0435"><span class="elsevierStyleLabel">-</span><p id="par0595" class="elsevierStylePara elsevierViewall">Is adalimumab effective in induction of remission in patients with a moderate flare of steroid-dependent and&#47;or steroid-resistant UC&#63;</p></li></ul>Text of the guidelines&#58;<elsevierMultimedia ident="tbl0410"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0415"></elsevierMultimedia>Formulation of the recommendation&#58;<elsevierMultimedia ident="tbl0420"></elsevierMultimedia>Comment by the elaborating group&#58;<elsevierMultimedia ident="tbl0425"></elsevierMultimedia></p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">6&#46;2&#46;5</span><span class="elsevierStyleSectionTitle">Aphaeresis</span><p id="par0600" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0220"><li class="elsevierStyleListItem" id="lsti0440"><span class="elsevierStyleLabel">-</span><p id="par0605" class="elsevierStylePara elsevierViewall">Is the treatment with aphaeresis effective in induction of remission in patients with a moderate flare of steroid-dependent UC&#63;</p></li></ul>Text of the guidelines&#58;<elsevierMultimedia ident="tbl0430"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0435"></elsevierMultimedia>Formulation of the recommendation<elsevierMultimedia ident="tbl0440"></elsevierMultimedia>Comment by the elaborating group&#58;<elsevierMultimedia ident="tbl0445"></elsevierMultimedia><span class="elsevierStyleEnunciation" id="enun0010"><span class="elsevierStyleLabel">Algorithm 2</span><p id="par0610" class="elsevierStylePara elsevierViewall">Mild to moderate flare&#58; algorithm and explanatory text<elsevierMultimedia ident="fig0010"></elsevierMultimedia></p></span></p><p id="par0615" class="elsevierStylePara elsevierViewall">We had to group patients this way&#44; as clinical trials use this classification system&#46; Of course&#44; within the same global definition&#44; an almost infinite number of possible clinical scenarios are included &#40;Box 1&#41;&#46; The clinician will recommend very different actions with very mild or almost severe situations&#58; all of them fit the definition&#46; Aside from severity&#44; the clinician needs information about the extension of the disease and &#40;fundamentally&#41; about the response and tolerance to treatments of the specific patient in previous flares&#46; Hence&#44; there are patients who tolerate topical therapy very poorly&#44; or patients in whom mesalazine causes a paradoxical reaction with increased diarrhoea&#46; Once more&#44; we are forced to emphasize on the extraordinary practical importance of a complete medical history&#46; Being the flare mild or moderate&#44; the attitude will be completely different in proctitis&#44; in which the local treatment will be basic&#44; and the rest of colitis in which a combined local and oral treatment will be the norm&#46; Of course&#44; just as between the mildest flare and the most intense moderate flare there is a whole continuum&#59; the limits of the treatment in terms of extension are not absolutely rigid&#58; it may be acceptable to treat a case of proctosigmoiditis exclusively with topical treatment&#44; and it may also be acceptable to treat an extensive colitis exclusively with oral medication&#46;</p><p id="par0620" class="elsevierStylePara elsevierViewall">Just as we have reviewed in detail&#44; the clinician has a variety of treatment measures that&#44; generally&#44; he&#47;she uses in an escalated manner&#58; more simple measures and with less risks in the milder flares that broadens if no response is obtained&#46; A strategy of using the less <span class="elsevierStyleItalic">aggressive</span><a class="elsevierStyleCrossRef" href="#fn0005"><span class="elsevierStyleSup">a</span></a> options first is only acceptable if a strategy in the mid and long term that involves knowing the patient&#39;s response to the treatment in a <span class="elsevierStyleItalic">reasonable</span> time frame has been planned from the beginning&#46; Actually&#44; it is impossible to define a uniform timeframe exactly&#44; due to the enormous inter-individual variability&#46; Generally speaking&#44; the milder the clinical case&#44; the greater the interval may be before knowing the patient&#39;s response&#44; but in no case must it be over one month&#44; in order to be able to choose other treatment systems if the one we have recommended fails&#46; Nowadays we have to bear in mind some factors that may make follow-up easier&#46; First&#44; the communication with the patient does not always have to be in person&#44; as the telephone and the Internet can perfectly work for maintaining a contact that is much more fluent&#44; rapid and simple&#46; Second&#44; within the Units of Inflammatory Disease&#44; the nursing staff has an increasingly more important role&#44; and among their missions it may be included to more closely monitor the patients&#8217; situation&#46; In fact&#44; software tools have been developed that have proven to be helpful in gaining more control in controlled trials&#46; In the entire process&#44; the patient&#39;s participation is fundamental&#44; and therefore&#44; all efforts must be made to transmit the information and to listen to the patient&#39;s point of view&#46;</p><p id="par0625" class="elsevierStylePara elsevierViewall">The therapeutic tools that are managed in most of the mild to moderate active flares are salicylates&#44; low bioavailability steroids and systemic steroids&#46; Furthermore&#44; one can choose between rectal and oral routes&#44; and a combination of both&#46; The algorithm suggests a reasonable path&#44; especially if we start from a mild flare&#44; by progressively adopting more <span class="elsevierStyleItalic">aggressive</span> measures&#44; sequentially&#46; However&#44; depending on the patient&#39;s medical history and the severity of the flare&#44; the clinician may recommend to directly starting the treatment regimen in a much more advanced point&#46; Thus&#44; for example&#44; if a patient who is receiving 3<span class="elsevierStyleHsp" style=""></span>g daily of maintenance oral mesalazine&#44; with an extensive colitis&#44; and that presents with a UC flare since a week ago with five bloody bowel movements daily&#44; fever and asthenia&#44; after ruling out infection&#44; it is reasonable to directly begin the treatment with oral steroids&#44; completing the treatment with topical salicylates in the case of intense rectal symptoms being present&#46; Moreover&#44; of course&#44; in this case&#44; follow-up will be carried out in only one week&#39;s time&#44; aside from leaving open communication channels with the patient in case there was a previous worsening&#46; That is&#44; depending on the clinical scenario&#44; the history and the specific experiences of the patient&#44; both the patient and the healthcare professionals must come to an agreement that modulates the recommendations of the general algorithm&#46;</p></span></span></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">7</span><span class="elsevierStyleSectionTitle">Maintenance treatment of patients with ulcerative colitis in remission</span><p id="par0630" class="elsevierStylePara elsevierViewall">Colitis in remission is defined as the one in which the patient have a complete resolution of the symptoms accompanied by mucosal healing defined with clinical and endoscopic indices&#46; In routine daily clinical practice&#44; endoscopic assessment is usually not considered necessary&#44; as the clinical assessment of the patients has a sensitivity of 86&#37; and a specificity of 76&#37; and would be defined as the presence of at least 3 bowel movements&#47;day or maybe even better&#44; the recovery of the patient&#39;s prior normal bowel rhythm&#44; without rectal bleeding or defecation urgency&#46;</p><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">7&#46;1</span><span class="elsevierStyleSectionTitle">Maintenance of remission obtained after a mild&#8211;moderate flare</span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">7&#46;1&#46;1</span><span class="elsevierStyleSectionTitle">UC not treated with steroids &#40;<a class="elsevierStyleCrossRef" href="#enun0015">Algorithm 3</a>&#41;</span><p id="par0635" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0225"><li class="elsevierStyleListItem" id="lsti0445"><span class="elsevierStyleLabel">-</span><p id="par0640" class="elsevierStylePara elsevierViewall">Is treatment with oral salicylates effective in maintenance of remission in patients after a mild&#8211;moderate UC flare treated with salicylates&#63;</p></li></ul>Text of the guidelines&#58;<elsevierMultimedia ident="tbl0450"></elsevierMultimedia>Summary of the evidence&#58;<elsevierMultimedia ident="tbl0455"></elsevierMultimedia>Formulation of the recommendation&#58;<elsevierMultimedia ident="tbl0460"></elsevierMultimedia>Comment by the elaborating group&#58;<elsevierMultimedia ident="tbl0465"></elsevierMultimedia><ul class="elsevierStyleList" id="lis0230"><li class="elsevierStyleListItem" id="lsti0450"><span class="elsevierStyleLabel">-</span><p id="par0645" class="elsevierStylePara elsevierViewall">Is the treatment with topical salicylates effective in the maintenance of remission in patients after a mild&#8211;moderate flare of left sided UC treated with salicylates&#63;</p></li></ul>Text of the guidelines&#58;<elsevierMultimedia ident="tbl0470"></elsevierMultimedia>Summary of the evidence&#58;<elsevierMultimedia ident="tbl0475"></elsevierMultimedia>Formulation of the recommendation&#58;<elsevierMultimedia ident="tbl0480"></elsevierMultimedia>Comment by the elaborating group&#58;<elsevierMultimedia ident="tbl0485"></elsevierMultimedia><span class="elsevierStyleEnunciation" id="enun0015"><span class="elsevierStyleLabel">Algorithm 3</span><p id="par0650" class="elsevierStylePara elsevierViewall">Maintenance treatment after induction of remission with mesalazine and&#47;or topical steroids&#58; algorithm and explanatory text<elsevierMultimedia ident="fig0015"></elsevierMultimedia></p></span></p><p id="par0655" class="elsevierStylePara elsevierViewall">In patients in whom it has not been necessary to use systemic steroids to control the disease&#44; the maintenance treatment with salicylates must always be tried as the first option&#46; There are many years of experience with sulfasalazine and it is a perfectly useful drug&#44; as long as the patient is not a male who is trying to conceive&#46; However&#44; due to safety and convenience&#44; most patients receive treatment with mesalazine&#46; As it is a long-term treatment&#44; the essential point is to achieve good compliance&#44; and for this&#44; it is probably very useful to use a single daily dose&#44; regardless of the pharmaceutical formulation chosen&#46; Fortunately&#44; there are several formulations available nowadays in Spain&#58; 400<span class="elsevierStyleHsp" style=""></span>mg tablets&#44; 500<span class="elsevierStyleHsp" style=""></span>mg tablets&#44; 1<span class="elsevierStyleHsp" style=""></span>g sachets of microgranules&#44; 1&#46;2<span class="elsevierStyleHsp" style=""></span>g tablets and 1&#46;5<span class="elsevierStyleHsp" style=""></span>g sachets of microgranules&#46; The patient&#39;s preferences are very important in the selection of one or another form&#44; in order to facilitate compliance&#46; There are also differences in the cost that may be substantial and that could prompt the clinician to recommend one form or another&#46;</p><p id="par0660" class="elsevierStylePara elsevierViewall">In the distal forms&#44; the proofs about the efficacy of the maintenance treatment are somewhat weaker&#44; and it is not always easy to achieve good compliance&#46; In fact&#44; given the scarce evidence available in the long term&#44; most authors recommend to maintain treatment only for 6 months if it is the first episode of proctitis&#44; and if it has been mild&#59; and to extend its duration in cases of refractoriness or frequent relapses&#46; It should be assessed how hard it is for patients to permanently adhere to a topical treatment&#44; which is always&#44; at the very least&#44; inconvenient&#46; Adaptation to each circumstance is key in this case&#44; and the information that is well transmitted to the patient is essential to come to an agreement on a treatment in each case&#46;</p></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">7&#46;1&#46;2</span><span class="elsevierStyleSectionTitle">Steroid-dependent&#47;steroid-resistant UC &#40;<a class="elsevierStyleCrossRef" href="#enun0020">Algorithm 4</a>&#41;</span><p id="par0665" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0235"><li class="elsevierStyleListItem" id="lsti0455"><span class="elsevierStyleLabel">-</span><p id="par0670" class="elsevierStylePara elsevierViewall">Is the treatment with thiopurine immunomodulators effective in the maintenance of remission in patients after a mild&#8211;moderate flare of steroid-dependent UC&#63;</p></li></ul>Text of the guidelines&#58;<elsevierMultimedia ident="tbl0490"></elsevierMultimedia>Summary of the evidence<elsevierMultimedia ident="tbl0495"></elsevierMultimedia>Formulation of the recommendation&#58;<elsevierMultimedia ident="tbl0500"></elsevierMultimedia>Comment by the elaborating group&#58;<elsevierMultimedia ident="tbl0505"></elsevierMultimedia><ul class="elsevierStyleList" id="lis0240"><li class="elsevierStyleListItem" id="lsti0460"><span class="elsevierStyleLabel">-</span><p id="par0675" class="elsevierStylePara elsevierViewall">Is methotrexate effective in the maintenance of remission in patients after a mild&#8211;moderate flare of steroid-dependent&#47;resistant UC&#63;</p></li></ul>Text of the guidelines&#58;<elsevierMultimedia ident="tbl0510"></elsevierMultimedia>Summary of the evidence&#58;<elsevierMultimedia ident="tbl0515"></elsevierMultimedia>Formulation of the recommendation&#58;<elsevierMultimedia ident="tbl0520"></elsevierMultimedia>Comment by the elaborating group&#58;<elsevierMultimedia ident="tbl0525"></elsevierMultimedia><ul class="elsevierStyleList" id="lis0245"><li class="elsevierStyleListItem" id="lsti0465"><span class="elsevierStyleLabel">-</span><p id="par0680" class="elsevierStylePara elsevierViewall">Is the treatment with infliximab effective in the maintenance of remission in patients after a mild&#8211;moderate flare of steroid-dependent&#47;resistant UC&#63;</p></li></ul>Text of the guidelines&#58;<elsevierMultimedia ident="tbl0530"></elsevierMultimedia>Summary of the evidence&#58;<elsevierMultimedia ident="tbl0535"></elsevierMultimedia>Formulation of the recommendation&#58;<elsevierMultimedia ident="tbl0540"></elsevierMultimedia>Comment by the elaborating group&#58;<elsevierMultimedia ident="tbl0545"></elsevierMultimedia><span class="elsevierStyleEnunciation" id="enun0020"><span class="elsevierStyleLabel">Algorithm 4</span><p id="par0685" class="elsevierStylePara elsevierViewall">Maintenance treatment after induction of remission with systemic steroids&#58; algorithm and explanatory text<elsevierMultimedia ident="fig0020"></elsevierMultimedia></p></span></p><p id="par0690" class="elsevierStylePara elsevierViewall">If it is a first flare&#44; and control has been obtained without an excessive difficulty &#40;hospitalization has not been necessary&#44; the response to steroids has been obtained quickly&#41;&#44; it is worth to try a maintenance treatment based on the use of mesalazine &#40;oral&#44; and in some cases oral and rectal&#41;&#46; However&#44; if the flare has required hospitalization or if the control has been slow and laborious&#44; or if the patient already meets criteria for steroid-dependence&#44; the most reasonable option is to use thiopurines &#40;azathioprine or mercaptopurine&#41;&#46; Once again&#44; it is necessary to create awareness for the patient about the importance of compliance&#46; Moreover&#44; regular controls must be instituted to monitor the appearance of a possible toxicity&#46; In case thiopurines failing&#44; either due to toxicity or to lack of efficacy&#44; there are mainly two options&#46; Up until relatively recently&#44; the trend was to recommend the patient elective surgery&#46; However&#44; infliximab has been available for several years&#44; and it obtains a significant response rate in this subgroup of patients&#46; Choosing between both alternatives requires knowing each patient&#39;s circumstances&#44; as the clinical scenarios are rather variable&#46; Nowadays&#44; in most cases&#44; the treatment with infliximab is tried first&#44; and only in some circumstances &#40;for example&#44; a long medical history with low-grade dysplasia in the last colonoscopy&#41; is surgery preferred as the first line of treatment&#46; The use of biological agents has represented a very clear advance in these patients&#44; but there are still numerous uncertainties that the clinician must solve in each case&#58; Should we administer immunomodulators simultaneously&#63; If so&#44; for how long&#63; Is there any moment in which we must suppress the biological agent&#63; Only over the next years will useful information be collected to respond to these questions&#46;</p><p id="par0695" class="elsevierStylePara elsevierViewall">In some of these patients&#44; there is no response to immunomodulators or to biological agents&#44; and both the clinician and the patient him&#47;herself are reluctant to proceed with surgery because the presentation is not very severe&#46; With the data currently available&#44; this is probably the niche in which aphaeresis has a place&#46; If used&#44; it is recommended to do so within clinical trials&#44; or at least in observational studies&#44; so as to contribute to gathering information that will clarify the exact role that aphaeresis has in these patients&#46; It would also be an option&#44; in patients who respond initially to infliximab but who later lose the response&#44; to try to use adalimumab&#46; Observational studies suggest this&#46;</p></span></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">7&#46;2</span><span class="elsevierStyleSectionTitle">Maintenance of the remission obtained after a severe flare &#40;<a class="elsevierStyleCrossRefs" href="#enun0025">Algorithms 5 and 6</a>&#41;</span><p id="par0700" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0250"><li class="elsevierStyleListItem" id="lsti0470"><span class="elsevierStyleLabel">-</span><p id="par0705" class="elsevierStylePara elsevierViewall">Is the maintenance treatment with thiopurine immunomodulators effective in patients with severe UC who have obtained remission with infliximab&#63; &#40;<a class="elsevierStyleCrossRef" href="#enun0025">Algorithm 5</a>&#41;</p></li></ul>Text of the guidelines&#58;<elsevierMultimedia ident="tbl0550"></elsevierMultimedia>Summary of the evidence&#58;<elsevierMultimedia ident="tbl0555"></elsevierMultimedia>Formulation of the recommendation&#58;<elsevierMultimedia ident="tbl0560"></elsevierMultimedia>Comment by the elaborating group&#58;<elsevierMultimedia ident="tbl0565"></elsevierMultimedia><ul class="elsevierStyleList" id="lis0255"><li class="elsevierStyleListItem" id="lsti0475"><span class="elsevierStyleLabel">-</span><p id="par0710" class="elsevierStylePara elsevierViewall">Is the maintenance treatment with <span class="elsevierStyleItalic">infliximab</span> effective in patients with severe UC who have obtained remission with infliximab&#63; &#40;<a class="elsevierStyleCrossRef" href="#enun0025">Algorithm 5</a>&#41;&#46;</p></li></ul>Text of the guidelines&#58;<elsevierMultimedia ident="tbl0570"></elsevierMultimedia>Summary of the evidence&#58;<elsevierMultimedia ident="tbl0575"></elsevierMultimedia>Recommendation&#58;<elsevierMultimedia ident="tbl0580"></elsevierMultimedia>Comment by the elaborating group&#58;<elsevierMultimedia ident="tbl0585"></elsevierMultimedia><span class="elsevierStyleEnunciation" id="enun0025"><span class="elsevierStyleLabel">Algorithm 5</span><p id="par0715" class="elsevierStylePara elsevierViewall">Maintenance treatment after induction of remission with infliximab&#58; algorithm and explanatory text<elsevierMultimedia ident="fig0025"></elsevierMultimedia></p></span></p><p id="par0720" class="elsevierStylePara elsevierViewall">When remission with infliximab has been obtained&#44; we find ourselves with 2 different scenarios&#44; according to whether the patient has taken thiopurines before or not&#46; If the patient had not received them&#44; the rational course of action would be to use the combination of infliximab and thiopurines for a period of time &#40;perhaps six months to a year&#41; and then try to withdraw infliximab&#46; Not enough studies have been published&#44; but some experts warn against this possibility&#44; because when relapses appear&#44; when trying to control them again by reintroducing infliximab&#44; failure could be frequent&#46; If the patient had already been treated with thiopurines&#44; he&#47;she must continue the treatment with infliximab as maintenance&#46; Although it is not reflected in the algorithm&#44; we may also distinguish two different situations in this scenario&#46; The first would be when thiopurines had been withdrawn due to a prior severe toxicity&#46; In this case&#44; it is clear that maintenance should be made with infliximab as monotherapy&#46; It could be discussed whether to combine mesalazine as&#44; although there are no specific inconveniences for the association&#44; no advantages have been shown either&#46; The second situation would be those patients in whom thiopurines had failed&#46; In this case&#44; they also require maintenance with infliximab&#44; but it seems reasonable to maintain the association with thiopurines at least for six months in order to reduce the immunogenicity of the anti-TNF agent&#46; In the long term&#44; in every case&#44; the real &#40;cost&#41; or possible &#40;risks&#41; disadvantages of biological agents must be weighed against their advantages &#40;perhaps a greater response rate&#41;&#46; There are no data that allow us to establish a uniform recommendation in these patients&#46; In any case&#44; all the changes must be made with the patient in remission&#44; and very likely at the moment of making decisions&#44; in a subgroup of patients who require these complex medications for the control&#44; remission must be defined clinically&#44; through laboratory tests&#44; endoscopically&#44; and maybe even histologically&#46;</p><p id="par0725" class="elsevierStylePara elsevierViewall">If&#44; in the course of the disease of these patients&#44; there is failure with infliximab in spite of its &#8220;intensification&#8221; &#40;either due to toxicity&#44; or due to a loss of response&#41;&#44; surgery must be proposed&#46; The treatment with adalimumab is worth trying as compassionate use&#44; because a series of observational studies suggest that this alternative may be effective in up to 2&#47;3 of the patients&#46;<ul class="elsevierStyleList" id="lis0260"><li class="elsevierStyleListItem" id="lsti0480"><span class="elsevierStyleLabel">-</span><p id="par0730" class="elsevierStylePara elsevierViewall">Is the maintenance treatment with azathioprine effective in patients with severe UC who have obtained remission with cyclosporine&#63; &#40;<a class="elsevierStyleCrossRef" href="#enun0030">Algorithm 6</a>&#41;</p></li></ul>Text of the guidelines&#58;<elsevierMultimedia ident="tbl0590"></elsevierMultimedia>Summary of the evidence&#58;<elsevierMultimedia ident="tbl0595"></elsevierMultimedia>Formulation of the recommendation&#58;<elsevierMultimedia ident="tbl0600"></elsevierMultimedia>Comment by the elaborating group&#58;<elsevierMultimedia ident="tbl0605"></elsevierMultimedia><ul class="elsevierStyleList" id="lis0265"><li class="elsevierStyleListItem" id="lsti0485"><span class="elsevierStyleLabel">-</span><p id="par0735" class="elsevierStylePara elsevierViewall">Is the maintenance treatment with cyclosporine effective in patients with severe UC who have obtained remission with cyclosporine&#63; &#40;<a class="elsevierStyleCrossRef" href="#enun0030">Algorithm 6</a>&#41;&#46;</p></li></ul>Text of the guidelines&#58;<elsevierMultimedia ident="tbl0610"></elsevierMultimedia>Summary of the evidence&#58;<elsevierMultimedia ident="tbl0615"></elsevierMultimedia>Formulation of the recommendation&#58;<elsevierMultimedia ident="tbl0620"></elsevierMultimedia>Comment by the elaborating group&#58;<elsevierMultimedia ident="tbl0625"></elsevierMultimedia><ul class="elsevierStyleList" id="lis0270"><li class="elsevierStyleListItem" id="lsti0490"><span class="elsevierStyleLabel">-</span><p id="par0740" class="elsevierStylePara elsevierViewall">Is the maintenance treatment with tacrolimus effective in patients with severe UC who have obtained remission with tacrolimus&#63; &#40;<a class="elsevierStyleCrossRef" href="#enun0030">Algorithm 6</a>&#41;&#46;</p></li></ul>Text of the guidelines&#58;<elsevierMultimedia ident="tbl0630"></elsevierMultimedia>Summary of the evidence&#58;<elsevierMultimedia ident="tbl0635"></elsevierMultimedia>Formulation of the recommendation&#58;<elsevierMultimedia ident="tbl0640"></elsevierMultimedia>Comment by the elaborating group&#58;<elsevierMultimedia ident="tbl0645"></elsevierMultimedia><span class="elsevierStyleEnunciation" id="enun0030"><span class="elsevierStyleLabel">Algorithm 6</span><p id="par0745" class="elsevierStylePara elsevierViewall">Maintenance treatment after induction of remission with cyclosporine &#40;or tacrolimus&#41;&#58; algorithm and explanatory text<elsevierMultimedia ident="fig0030"></elsevierMultimedia></p></span></p><p id="par0750" class="elsevierStylePara elsevierViewall">Even though they have been used occasionally in other circumstances&#44; in most cases&#44; the use of cyclosporine or tacrolimus &#40;from this moment onwards we will refer only to cyclosporine&#41; is limited to severe flares that are refractory to steroids&#44; and in some exceptional cases in which steroids are contraindicated&#46; If remission is achieved&#44; cyclosporine cannot be maintained indefinitely&#44; as there is the risk of inducing irreversible renal toxicity&#46; The alternative that is most used has been to maintain cyclosporine during a limited time &#40;most groups recommend three months&#44; although in Spain&#44; several sites maintain it only for four weeks&#41;&#44; associated to down-titrated steroids and to thiopurines&#46; Together&#44; the data available suggest that thiopurines reduce the need for colectomy in the mid and long term in this subgroup of patients with a reasonable toxicity&#46; However&#44; occasionally&#44; the severe flare has been produced in a patient that was already being treated with thiopurines&#46; In this specific case&#44; clinicians are left with three options&#58; to directly recommend elective surgery &#40;an alternative that may have been assessed before&#44; in the control of the severe refractory flare controlled with cyclosporine&#41;&#44; start the maintenance treatment with infliximab&#44; or try thiopurines once again&#46; Of course&#44; maintaining only thiopurines does not seem the most logical course of action&#44; although it may be possible that in some specific circumstances&#44; changing the patter of inflammation may recover its efficacy&#46; In most cases&#44; the patients and the healthcare professionals will have to choose between infliximab and surgery&#44; and the decision will be made depending on the individual circumstances &#40;duration of the disease&#44; prior toxicity to drugs&#41;&#44; of each patient&#39;s expectations &#40;fear of surgery&#44; accessibility to medical control&#41; and of the local experience of the working group&#46; When infliximab is chosen&#44; which is a very reasonable decision in many cases&#44; it is very reasonable to maintain thiopurines&#44; at least during a minimum period of time that could be of 6&#8211;12 months&#46;</p></span></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">8</span><span class="elsevierStyleSectionTitle">Other treatments</span><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">8&#46;1</span><span class="elsevierStyleSectionTitle">Possible treatments</span><span id="sec0140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">8&#46;1&#46;1</span><span class="elsevierStyleSectionTitle">Probiotics</span><p id="par0755" class="elsevierStylePara elsevierViewall">The literature about probiotics and UC is very difficult to interpret&#44; as&#58; &#40;a&#41; the type and formulation of the different probiotics used in the different studies vary greatly&#59; &#40;b&#41; comparisons to placebo are scarce&#44; and in many of the studies&#44; the arm with probiotics also receives treatment with other drugs &#40;particularly amino-salicylates&#41; and &#40;c&#41; the published results are incredibly heterogeneous&#46; Therefore&#44; currently there is no solid evidence in favour or against the use of probiotics in UC&#44; except for the case of pouchitis &#40;an entity that is not the subject of these CPG&#41;&#46; Some recent data suggest that VSL3 may be of use in UC<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">138</span></a> in situations of a mild-moderate flare&#44; both as isolated treatment and as complementary treatment to mesalazine&#44; but these must be confirmed in spite of being a part of the basic treatment regimen&#46;</p></span></span><span id="sec0145" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">8&#46;2</span><span class="elsevierStyleSectionTitle">Complementary treatments</span><span id="sec0150" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">8&#46;2&#46;1</span><span class="elsevierStyleSectionTitle">Anaemia</span><p id="par0760" class="elsevierStylePara elsevierViewall">The treatment of anaemia and iron deficiency without anaemia is an essential part in the management of UC&#46; There is a Guideline of International Consensus&#44;<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">139</span></a> to which the reader is referred&#46; It is never normal for patients to have anaemia or iron deficiency&#44; and one of our goals must be to normalize haematological parameters by sensibly using transfusions&#44; intravenous iron or oral iron according to the circumstances&#46;</p></span><span id="sec0155" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">8&#46;2&#46;2</span><span class="elsevierStyleSectionTitle">Other</span><p id="par0765" class="elsevierStylePara elsevierViewall">In the treatment of UC&#44; there may be some special circumstances that are not outlined in these CPG&#46; In the vast majority of these scenarios&#44; the evidence available is scarce or of low quality&#44; although on occasions&#44; there are more than enough data for establishing a recommendation&#46; As it is not a subject of these Guidelines&#44; we recommend the readers to refer to the ECCO Consensus&#44; to their chapter about special situations in UC&#46;<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">140</span></a> It may also be useful to consult the ECCO consensus for the prevention of infectious complications&#46;<a class="elsevierStyleCrossRef" href="#bib0705"><span class="elsevierStyleSup">141</span></a> The use of biological therapies is considered when there are other recent reference documents&#46;<a class="elsevierStyleCrossRef" href="#bib0710"><span class="elsevierStyleSup">142</span></a> Moreover&#44; the information about fertility&#44; pregnancy and birth in patients with IBD has been critically examined in another very recent consensus document&#46;<a class="elsevierStyleCrossRef" href="#bib0715"><span class="elsevierStyleSup">143</span></a></p></span></span></span><span id="sec0160" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">9</span><span class="elsevierStyleSectionTitle">Future perspectives</span><p id="par0770" class="elsevierStylePara elsevierViewall">Currently&#44; it seems unlikely that in a reasonable time frame &#40;perhaps until 2013&#44; at least&#41; the practical clinician will have more pharmacological options available for the treatment of UC&#46; This does not mean that improvements that are directly applicable to the patients cannot be produced&#46; Our opinion is that they may be produced&#44; prompted by&#58;<ul class="elsevierStyleList" id="lis0275"><li class="elsevierStyleListItem" id="lsti0495"><span class="elsevierStyleLabel">&#8226;</span><p id="par0775" class="elsevierStylePara elsevierViewall">The application&#44; in the daily practice&#44; of the recommendations contained in Clinical Practice Guidelines&#44; such as these ones&#46;</p></li><li class="elsevierStyleListItem" id="lsti0500"><span class="elsevierStyleLabel">&#8226;</span><p id="par0780" class="elsevierStylePara elsevierViewall">Acknowledging the importance of the maintenance treatment as a form of avoiding the appearance of flares and of substantially improving the patients&#8217; quality of life&#46;</p></li><li class="elsevierStyleListItem" id="lsti0505"><span class="elsevierStyleLabel">&#8226;</span><p id="par0785" class="elsevierStylePara elsevierViewall">The study of barriers for a good treatment compliance&#44; which is a problem that is at the root of many treatment failures&#44; in order to be able to face this problem directly&#46; This point is very important in the group of patients with UC&#44; but it is even more so when topical treatments are necessary&#46;</p></li><li class="elsevierStyleListItem" id="lsti0510"><span class="elsevierStyleLabel">&#8226;</span><p id="par0790" class="elsevierStylePara elsevierViewall">The permanent education of patients to progressively acquire a shared responsibility in the long-term management of their disease&#46; As this is a chronic entity&#44; patients are better placed to control the problem&#44; and only with knowledge of the disease and of the treatment possibilities will they be able to do so&#46;</p></li><li class="elsevierStyleListItem" id="lsti0515"><span class="elsevierStyleLabel">&#8226;</span><p id="par0795" class="elsevierStylePara elsevierViewall">New controlled and observational studies will provide critical information about the use of the therapeutic means that are already available&#46; Specifically&#44; at this moment at least 3 key studies are already advanced&#58; a study about cyclosporine versus infliximab in severe UC flares&#44; of which only its publication is pending &#40;although it has already been reported in congresses&#44; as we pointed out previously&#41;&#44; another study about the efficacy of the combination of infliximab and thiopurines in the induction and maintenance of remission of UC&#44; of which also only the publication is pending&#59; and a study about the efficacy of granulocyte aphaeresis in the situation of steroid-dependence&#59; this last one is still in the patient recruitment phase&#46; Moreover&#44; we expect the publication of a yet undetermined number of observational studies&#44; especially regarding the cumulative experience with infliximab that would provide information about the duration of the response&#44; possibilities of intensification and long-term toxicity&#46; Jointly&#44; all these data will make it necessary to review these guidelines in a maximum time frame of three years&#46; Above all&#44; we believe that these data will allow us to advance in the individualization of the treatment&#44; by allowing to stratify patients&#44; not just by the global clinical scenario&#44; but also by other circumstances&#46;</p></li><li class="elsevierStyleListItem" id="lsti0520"><span class="elsevierStyleLabel">&#8226;</span><p id="par0800" class="elsevierStylePara elsevierViewall">Of course&#44; the basic and clinical research will allow for an ever better definition of the different subgroups of patients&#44; which would also make the individualized application of the treatments easier&#46;</p></li></ul></p></span><span id="sec0165" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">10</span><span class="elsevierStyleSectionTitle">Help boxes</span><p id="par0805" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Box 1&#58; Severity and extension&#44; problematic definitions</span></p><p id="par0810" class="elsevierStylePara elsevierViewall">Few of us would have difficulties in distinguishing a living being from a non living being&#44; yet stating an exact definition of life is not at all an easy task&#46;<a class="elsevierStyleCrossRef" href="#bib0720"><span class="elsevierStyleSup">144</span></a> A similar paradox is produced practically every time we face a patient with ulcerative colitis &#40;UC&#41;&#46; For the patients&#44; it is easy to know if they are doing well&#44; not so well&#44; poorly or very badly&#59; and for the expert clinician it would not be very difficult to know &#8211; at least in appearance &#8211; if the patient is doing well&#44; not so well&#44; poorly or very badly&#46; However&#44; the problem arises when&#44; in order to be able to compare two patients or two moments in the same patient&#44; we have to use some sort of objective index&#46; UC is a complex disease&#44; with very variable intestinal and extraintestinal symptoms&#59; and with repercussions in laboratory findings and&#47;or endoscopically that are also very diverse and changing&#46; Furthermore&#44; it is frequent to find severe discrepancies between clinical data&#44; data from laboratory tests&#44; and&#47;or endoscopic data&#46; The first technical approximation to this issue was done by Sidney Truelove and Lloyd Witts in the classic clinical trial about hydrocortisone in colitis&#46;<a class="elsevierStyleCrossRef" href="#bib0725"><span class="elsevierStyleSup">145</span></a> From that moment on&#44; numerous clinical&#44; biological&#44; endoscopic and histological indices have been used&#46; Curiously&#44; few have been validated formally&#44; and the vast majority lack sufficient reproducibility&#46; There is also an important limitation for the daily use of these classifications&#58; the human brain is not fond of complex classifications&#46;<a class="elsevierStyleCrossRef" href="#bib0730"><span class="elsevierStyleSup">146</span></a> In order to create these CPG&#44; we were forced to classify patients into two great situations of severity&#58; mild to moderate versus severe&#46; This is the only way of systematizing the information currently available in literature&#46; The broadness of the mild-moderate concept is especially troublesome&#44; as it spans from a patient who has 3 bowel movements per day and mild abdominal discomfort &#40;if his&#47;her normal situation is one bowel movement per day without any discomfort&#41; to a patient who has 5 bowel movements with blood&#44; that force him&#47;her to get up at night&#44; and who has an important asthenia linked to an anaemia with a haemoglobin of 11&#46;2<span class="elsevierStyleHsp" style=""></span>g&#47;dL&#46; In fact&#44; it is possible that the former has mild symptoms and is not taking any treatment&#44; while the latter has intense symptoms in spite of already receiving a combination of oral mesalazine&#44; rectal mesalazine and oral steroids&#46; For their inclusion in the clinical trial&#44; both patients are in the same group&#59; for the clinician it is obvious that the first patient would receive oral mesalazine&#44; which would soothe him&#47;her and the clinician would then follow-up one month later&#59; however&#44; for the second patient&#44; the clinician may seriously consider using infliximab&#46; It is not feasible to collect all of these possibilities into a few simple algorithms&#44; nor do all circumstances fit in the GRADE tables&#44; as complex as these may be&#46; These GUIDELINES intend to make the work easier&#44; but of course&#44; they cannot replace the clinician&#46;</p><p id="par0815" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Box 2&#58; Activity indices</span></p><p id="par0820" class="elsevierStylePara elsevierViewall">The variable clinical course of inflammatory bowel diseases makes the concept of activity of the disease essential&#46; However&#44; there is no single definition of activity&#44; as there are several different viewpoints &#40;for example&#44; the patient versus clinician versus investigator&#41; and different consequences of the disease that are to be measured&#58; biochemical changes&#44; histological lesion&#44; radiological lesion&#44; endoscopic lesion&#44; clinical symptoms&#44; quality of life&#44; financial repercussion&#44; morbidity&#44; mortality and others&#46; The need to have a practical definition arose in the clinical trial of hydrocortisone compared to placebo&#44; carried out by Sidney Truelove and Lloyd Witts between 1952 and 1955&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> To be able to evaluating the result of the treatment&#44; they created a very simple classification that distinguished the extremes &#40;mild versus severe&#41;&#44; with an intermediate category&#44; with parameters that were all clinical or in terms of laboratory tests&#46; The simplicity of the classification&#44; and the fact that it was the first&#44; led it to be imposed both in clinical practice and in many studies&#46; However&#44; it has never been validated with a formal methodology &#40;its internal reliability&#44; reproducibility and external reliability are unknown&#41;&#46; During the 56 years that have elapsed since then&#44; numerous indices have appeared that are clinical&#44; clinical&#8211;biological&#44; endoscopic&#44; histological&#44; of quality of life&#44; of work repercussion and of other types that have been used in very different studies&#46; In fact&#44; it is often very difficult to compare the results of several studies&#44; because they use different measuring systems&#44; and because even when they use the same&#44; the cut-off points chosen for the definitions are not always the same&#46; When the different options are analyzed with a methodological rigour&#44; the results are discouraging&#58; there is no correlation between laboratory values and endoscopy&#44; between endoscopy and clinical presentation&#44; between histology and laboratory tests&#44; between the patient&#39;s and doctor&#39;s viewpoint&#44; etc&#46; Curiously&#44; the last ones in arriving at the problem&#44; the paediatric gastroenterologists expert in inflammatory bowel disease&#44; have applied a more rigourous methodology from the beginning&#44; and have developed the PUCAI &#40;Paediatric Ulcerative Colitis Activity Index&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0735"><span class="elsevierStyleSup">147</span></a> probably the first index that has been validated correctly&#46; For the purposes of these guidelines there is one more issue&#58; even if we wanted to be rigourous with the indices&#44; we could not&#44; because the studies were made before the indices in many cases&#46; Therefore&#44; we decided to use the Montreal classification&#44; which divides the possible situations of activity into four&#58; remission&#44; mild&#44; moderate and severe&#46; Data from most studies can be extrapolated to this type of classification&#46; Of course&#44; some confusion may arise&#44; especially at the limits &#40;Box 1&#41;&#46; Many studies analyze not only clinical indices&#44; but also endoscopic and at times&#44; histological indices&#46; Also&#44; in this case&#44; we have been forced to simplify sometimes&#44; assuming a possible loss of quality of the data&#44; compensated on many occasions by the great number of patients included&#46; Although we admit that in the future&#44; the concepts of remission &#40;for example&#44; recently it has been proposed to define remission as the absolute absence of clinical symptoms and mucosal healing demonstrated in colonoscopy<a class="elsevierStyleCrossRef" href="#bib0740"><span class="elsevierStyleSup">148</span></a>&#41; will always include objective parameters &#40;endoscopic&#44; histological or biological&#41;&#44; the definitions of response and remission are almost always clinical&#44; because the studies analyzed&#44; in many cases&#44; do not allow for another approach&#46; Finally&#44; we have to point out that in the case of a severe flare&#44; the variables chosen by the Committee are clearly definable&#58; mortality or the need for colectomy&#59; which makes the studies more easily comparable&#46;</p><p id="par0825" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Box 3&#58; Practical considerations about the doses of immunomodulating drugs</span></p><p id="par0830" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Steroids</span>&#58; Systemic steroids have been used by several routes &#40;oral&#44; intravenous&#44; rectal&#41; and in many different formulations and products&#46; If we consider prednisone as the reference steroid &#40;it is the one most commonly used&#41;&#44; the standard dose for treatment start is 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&#44; orally&#46; In order to adjust the doses of other steroids&#44; we have to take into account the potency equivalences between them &#40;<a class="elsevierStyleCrossRef" href="#tbl0740">Table 17</a>&#41;&#44; the route of administration that may vary the bioavailability significantly&#44; and that there may be differences in the toxicity and individual effects of the different products&#46; The IV steroid that is most used is methylprednisolone&#44; which is more potent than prednisone &#40;4<span class="elsevierStyleHsp" style=""></span>mg of methylprednisolone are equal to 5<span class="elsevierStyleHsp" style=""></span>mg of prednisone&#59; not considering the obvious difference in bioavailability&#41;&#46; The initial dose is usually maintained for two weeks&#44; although depending on the response&#44; it may be acceptable from one week up to four&#46; When the dose is reduced&#44; there are several guidelines for down-titrating the dose&#46; The most usual practice is to remove 10<span class="elsevierStyleHsp" style=""></span>mg from the daily dose of prednisone weekly until reaching 20<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#44; and from that point&#44; remove 5<span class="elsevierStyleHsp" style=""></span>mg from the daily dose weekly until discontinuing it&#46; It is usually not justified to maintain the treatment for more than three months without having considered and tried an alternative treatment&#46;</p><elsevierMultimedia ident="tbl0740"></elsevierMultimedia><p id="par0835" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Cyclosporine</span>&#58; Cyclosporine is used exclusively in the severe or moderate flare that is refractory to steroids&#44; and its administration must not be extended for more than three to six months due to the risk of irreversible toxicity&#44; particularly renal toxicity&#46; Although defenders of the oral route are not lacking&#44; the studies justifying its use have almost all been carried out initially using the intravenous route&#46; Initially&#44; a dose of 4<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day was chosen&#44; although later an individual adjustment may be needed depending on the blood levels obtained and of toxicity&#46; In a randomized study&#44; it was shown that 2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day were as effective as 4&#59; although actually&#44; in both groups&#44; the mean final dose that was administered was very similar because adjustments by levels and toxicity were allowed&#46; With the data available&#44; it seems prudent to begin with 2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day and up-titration if no toxicity is produced&#44; and the levels considered therapeutic are not reached&#46;</p><p id="par0840" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Tacrolimus</span>&#58; The doses used are of 0&#46;01&#8211;0&#46;02<span class="elsevierStyleHsp" style=""></span>mg&#47;kg when it is used intravenously&#44; and of 0&#46;1&#8211;0&#46;2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg when it is used orally&#59; adjusting individually according to the blood levels&#44; the toxicity and the response&#46;</p><p id="par0845" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Azathioprine and mercaptopurine</span>&#58; The mean dose of azathioprine is of 2&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day and the mean dose of mercaptopurine is of 1&#8211;1&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&#46; However&#44; there is great individual variability in the response and toxicity&#44; which is why the doses may be adjusted in terms of the effectiveness and toxicity&#46; If they are available&#44; metabolite levels may be used as a guide&#44; at least in selected patients&#46; However&#44; in most sites&#44; adjustments have to be carried out considering the clinical presentation&#44; the total leukocytes&#44; transaminases and other analytical parameters&#46; Their usefulness cannot be ruled out completely if they have been maintained for a period of less than 6 months&#46;</p></span><span id="sec0170" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">11</span><span class="elsevierStyleSectionTitle">Conflicts of interest of the authors of the guideline</span><p id="par0850" class="elsevierStylePara elsevierViewall">This guide has been possible to some extent by an unrestricted grant of MSD&#46; MSD was not involved in any part of the development or scientific aspects of the guide&#46;</p><p id="par0855" class="elsevierStylePara elsevierViewall">F&#46; Gomoll&#243;n has received grants for assistance to scientific meetings from Abbott and MSD&#46; He has also received consultancy fees from FAES-FARMA&#44; Abbott and MSD&#46; He has also received research support from MSD&#46;</p><p id="par0860" class="elsevierStylePara elsevierViewall">S&#46; Garc&#237;a-L&#243;pez has received grants for assistance to scientific meetings from Abbott&#44; MSD&#44; FAES-FARMA&#44; Ferring and Shire&#46; He has also received consultancy fees from Abbott and MSD&#46;</p><p id="par0865" class="elsevierStylePara elsevierViewall">B&#46; Sicilia has received grants for assistance to scientific meetings from Abbott and MSD&#46;</p><p id="par0870" class="elsevierStylePara elsevierViewall">Javier P&#46; Gisbert has received grants for assistance to scientific meetings from Abbott and MSD&#46; He has also received consultancy fees from FAES-FARMA&#44; Abbott and MSD&#46;</p><p id="par0875" class="elsevierStylePara elsevierViewall">Joaquin Hinojosa has received grants for assistance to scientific meetings from Abbott and MSD&#46; He has also received consultancy fees from FAES-FARMA&#44; Abbott and MSD&#46;</p><p id="par0880" class="elsevierStylePara elsevierViewall">The rest of the authors of the guideline declare no conflict of interest&#46;</p></span></span>"
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          "titulo" => "Need for guidelines"
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          "titulo" => "Induction of remission in patients with active ulcerative colitis"
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              "titulo" => "Severe UC flare &#40;of any anatomical extension&#41; &#40;Algorithm 1&#41;"
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              "titulo" => "Mild and moderate UC flare &#40;Algorithm 2&#41;"
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          "titulo" => "Maintenance treatment of patients with ulcerative colitis in remission"
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              "titulo" => "Maintenance of remission obtained after a mild&#8211;moderate flare"
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              "titulo" => "Maintenance of the remission obtained after a severe flare &#40;Algorithms 5 and 6&#41;"
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              "titulo" => "Complementary treatments"
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          "titulo" => "Future perspectives"
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        "etiqueta" => "&#9674;"
        "nota" => "<p class="elsevierStyleNotepara">GETECCU &#40;Grupo Espa&#241;ol de Trabajo de Enfermedad de Crohn y Colitis Ulcerosa or Spanish Group for Working on Crohn&#39;s Disease and Ulcerative Colitis&#41;&#46;</p>"
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        "etiqueta" => "a"
        "nota" => "<p class="elsevierStyleNotepara">The term <span class="elsevierStyleItalic">aggressive</span> is not the most adequate when referring to a treatment&#58; what must predominate is the benefit-risk balance&#44; and on many occasions&#44; the most effective treatment&#44; and even the most efficient treatment&#44; may be the one that is apparently most <span class="elsevierStyleItalic">aggressive</span>&#46;</p>"
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              1 => array:4 [ …4]
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          "leyenda" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Source</span>&#58; Lennard-Jonnes&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p>"
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          "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; Hb&#44; haemoglobin&#59; bpm&#44; beats per minute&#46;</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Source</span>&#58; Silverberg et al&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Montreal Classification for ulcerative colitis&#46;</p>"
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          "leyenda" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Assessment of the index</span>&#58;</p><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Mild flare&#58; when all the variables are in the &#8220;mild&#8221; category&#46;</p><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Severe flare&#58; when all the variables are in &#8220;severe&#8221;&#46;</p><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">When there are variables in both categories&#44; it is a moderate flare&#46;</p><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; bpm&#44; beats per minute&#46;</p><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Source</span>&#58; Truelove and Witts&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p>"
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          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Assessment of the index</span>&#58;</p><p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Inactive&#58; &#60;11&#46;</p><p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Mild flare&#58; 11&#8211;15&#46;</p><p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Moderate flare&#58; 16&#8211;21&#46;</p><p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">Severe flare&#58; 22&#8211;27&#46;</p><p id="spar0095" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviation</span>&#58; bpm&#58; beats per minute&#46;</p>"
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          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Modified Truelove&#8211;Witts index&#46;</p>"
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          "leyenda" => "<p id="spar0105" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Sources</span>&#58; Schroeder et al&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> and D&#8217;Haens et al&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p>"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">Mayo index &#40;DAI&#41;&#46;</p>"
        ]
      ]
      5 => array:7 [
        "identificador" => "tbl0685"
        "etiqueta" => "Table 6"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0115" class="elsevierStyleSimplePara elsevierViewall">Seo activity index&#59; total A<span class="elsevierStyleHsp" style=""></span>&#8722;<span class="elsevierStyleHsp" style=""></span>total B<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>200<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8230;&#8230;&#8230;&#8230;</p><p id="spar0120" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Source</span>&#58; Seo et al&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a></p>"
          "tablatextoimagen" => array:2 [
            0 => array:2 [
              "tabla" => array:1 [ …1]
              "imagenFichero" => array:1 [ …1]
            ]
            1 => array:2 [
              "tabla" => array:1 [ …1]
              "imagenFichero" => array:1 [ …1]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0110" class="elsevierStyleSimplePara elsevierViewall">Seo index&#46;</p>"
        ]
      ]
      6 => array:7 [
        "identificador" => "tbl0690"
        "etiqueta" => "Table 7"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0130" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Assessment of the index</span>&#58;</p><p id="spar0135" class="elsevierStyleSimplePara elsevierViewall">Maximum score&#58; 21 points&#46;</p><p id="spar0140" class="elsevierStyleSimplePara elsevierViewall">Score &#60;10 during 2 consecutive days indicates a clinical response &#40;in the original reference to cyclosporine&#44; severe refractory flare&#41;&#46;</p><p id="spar0145" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Source</span>&#58; Lichtiger et al&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a></p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [ …1]
              "imagenFichero" => array:1 [ …1]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0125" class="elsevierStyleSimplePara elsevierViewall">Lichtiger&#39;s index&#46;</p>"
        ]
      ]
      7 => array:7 [
        "identificador" => "tbl0695"
        "etiqueta" => "Table 8"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0155" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Assessment of the index</span>&#58;</p><p id="spar0160" class="elsevierStyleSimplePara elsevierViewall">Simple&#44; clinical index&#59; its interpretation and correlation to more complex indices&#44; such as Power-Tuck&#44; are adequate&#46;</p><p id="spar0165" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Source</span>&#58; Walmsley et al&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a></p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [ …1]
              "imagenFichero" => array:1 [ …1]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0150" class="elsevierStyleSimplePara elsevierViewall">Simple activity index &#40;Walmsley index&#41;&#46;</p>"
        ]
      ]
      8 => array:7 [
        "identificador" => "tbl0700"
        "etiqueta" => "Table 9"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0175" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Assessment of the index</span>&#58;</p><p id="spar0180" class="elsevierStyleSimplePara elsevierViewall">Severe flare&#58; &#8805;65 points&#46;</p><p id="spar0185" class="elsevierStyleSimplePara elsevierViewall">Moderate flare&#58; 35&#8211;64 points&#46;</p><p id="spar0190" class="elsevierStyleSimplePara elsevierViewall">Mild flare&#58; 10&#8211;34 points&#46;</p><p id="spar0195" class="elsevierStyleSimplePara elsevierViewall">Remission &#40;without activity&#41;&#58; &#60;10&#46;</p><p id="spar0200" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Source</span>&#58; Turner et al&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a></p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [ …1]
              "imagenFichero" => array:1 [ …1]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0170" class="elsevierStyleSimplePara elsevierViewall">PUCAI index&#46;</p>"
        ]
      ]
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        "identificador" => "tbl0705"
        "etiqueta" => "Table 10"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [ …1]
              "imagenFichero" => array:1 [ …1]
            ]
          ]
          "notaPie" => array:2 [
            0 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara">In some patients and sites&#44; an ultrasound can be carried out that can provide very relevant data&#44; but the CT scan is the test of choice when bowel perforation or an intraabdominal infectious complication is suspected&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0015"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara">If the site has an IGRA test &#40;such as Quantiferon&#169;&#41;&#44; it is also advisable in this situation of immunosupression&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0205" class="elsevierStyleSimplePara elsevierViewall">Review of the diagnostic information prior to the treatment of the severe flare&#46;</p>"
        ]
      ]
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        "identificador" => "tbl0710"
        "etiqueta" => "Table 11"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [ …1]
              "imagenFichero" => array:1 [ …1]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0210" class="elsevierStyleSimplePara elsevierViewall">Summary of the general treatment of the severe flare&#46;</p>"
        ]
      ]
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        "identificador" => "tbl0715"
        "etiqueta" => "Table 12"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0220" class="elsevierStyleSimplePara elsevierViewall">Assessment of the index &#40;estimated probability of failure with the medical treatment&#41;&#58;</p><p id="spar0225" class="elsevierStyleSimplePara elsevierViewall">Score index&#58; probability of no response to the medical treatment&#46;</p><p id="spar0230" class="elsevierStyleSimplePara elsevierViewall">0&#8211;1&#58; 11&#37;&#46;</p><p id="spar0235" class="elsevierStyleSimplePara elsevierViewall">2&#8211;3&#58; 43&#37;&#46;</p><p id="spar0240" class="elsevierStyleSimplePara elsevierViewall">&#8805;4&#58; 85&#37;&#46;</p><p id="spar0245" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Source</span>&#58; Ho et al&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a></p>"
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            0 => array:2 [
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0215" class="elsevierStyleSimplePara elsevierViewall">Probability of response to steroids &#40;Ho index&#41;&#46;</p>"
        ]
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        "identificador" => "tbl0720"
        "etiqueta" => "Table 13"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [ …1]
              "imagenFichero" => array:1 [ …1]
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          ]
          "notaPie" => array:1 [
            0 => array:3 [
              "identificador" => "tblfn0020"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara">In conditions of immunosuppression&#44; a Mantoux test is not very sensitive&#44; and in conditions of a severe flare&#44; it may not be possible to wait and apply a booster&#46; As mentioned above&#44; if there is an IGRA at the site &#40;for example&#44; Quantiferon&#169;&#41;&#44; it would be an advisable additional measure&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0250" class="elsevierStyleSimplePara elsevierViewall">Measures prior to starting the treatment with infliximab&#46;</p>"
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        "identificador" => "tbl0725"
        "etiqueta" => "Table 14"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [ …1]
              "imagenFichero" => array:1 [ …1]
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          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0255" class="elsevierStyleSimplePara elsevierViewall">Measures prior to starting the treatment with cyclosporine&#46;</p>"
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        "identificador" => "tbl0730"
        "etiqueta" => "Table 15"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "tablatextoimagen" => array:2 [
            0 => array:2 [
              "tabla" => array:1 [ …1]
              "imagenFichero" => array:1 [ …1]
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            1 => array:2 [
              "tabla" => array:1 [ …1]
              "imagenFichero" => array:1 [ …1]
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        "descripcion" => array:1 [
          "en" => "<p id="spar0260" class="elsevierStyleSimplePara elsevierViewall">Follow-up measures for the treatment with cyclosporine&#46;</p>"
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        "identificador" => "tbl0735"
        "etiqueta" => "Table 16"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [ …1]
              "imagenFichero" => array:1 [ …1]
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          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0265" class="elsevierStyleSimplePara elsevierViewall">Pharmacological interactions of cyclosporine&#46;</p>"
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        "identificador" => "tbl0740"
        "etiqueta" => "Table 17"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0275" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Note</span>&#58; For example&#44; prednisone is 4 times more potent than hydrocortisone &#40;i&#46;e&#46;&#44; 5<span class="elsevierStyleHsp" style=""></span>mg of prednisone are equal to 20<span class="elsevierStyleHsp" style=""></span>mg of hydrocortisone&#41; and methylprednisolone is a little more powerful than prednisone &#40;4<span class="elsevierStyleHsp" style=""></span>mg of the former are equal to 5 of the latter&#41;&#46;</p><p id="spar0280" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Source</span>&#58; Gasull et al&#46;<a class="elsevierStyleCrossRef" href="#bib0745"><span class="elsevierStyleSup">149</span></a></p>"
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            0 => array:2 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0270" class="elsevierStyleSimplePara elsevierViewall">Equivalences in the doses of systemic steroids&#46;</p>"
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        "mostrarDisplay" => true
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            "Alto" => 2920
            "Ancho" => 2188
            "Tamanyo" => 236103
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        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => false
        "mostrarDisplay" => true
        "figura" => array:1 [
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        "mostrarFloat" => false
        "mostrarDisplay" => true
        "figura" => array:1 [
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        "mostrarDisplay" => true
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        "mostrarDisplay" => true
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        "mostrarDisplay" => true
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Article information

ISSN: 02105705
Original language: English

DOI:10.1016/j.gastrohep.2012.11.002

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2023 December	81	6	87
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2023 September	115	4	119
2023 August	27	1	28
2023 July	51	6	57
2023 June	56	1	57
2023 May	68	1	69
2023 April	53	2	55
2023 March	83	18	101
2023 February	60	10	70
2023 January	77	29	106
2022 December	57	13	70
2022 November	47	21	68
2022 October	46	27	73
2022 September	55	19	74
2022 August	51	17	68
2022 July	58	21	79
2022 June	55	28	83
2022 May	57	19	76
2022 April	51	17	68
2022 March	69	13	82
2022 February	72	15	87
2022 January	70	14	84
2021 December	56	21	77
2021 November	68	26	94
2021 October	91	38	129
2021 September	48	16	64
2021 August	50	24	74
2021 July	37	19	56
2021 June	30	12	42
2021 May	71	11	82
2021 April	84	17	101
2021 March	72	30	102
2021 February	74	14	88
2021 January	79	22	101
2020 December	75	15	90
2020 November	83	22	105
2020 October	62	13	75
2020 September	74	25	99
2020 August	70	17	87
2020 July	43	7	50
2020 June	39	12	51
2020 May	58	18	76
2020 April	47	18	65
2020 March	46	16	62
2020 February	58	23	81
2020 January	52	23	75
2019 December	55	14	69
2019 November	71	52	123
2019 October	58	9	67
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2018 May	46	4	50
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2018 March	31	0	31
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2017 December	30	1	31
2017 November	64	0	64
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2017 September	45	5	50
2017 August	64	1	65
2017 July	35	5	40
2017 June	72	4	76
2017 May	89	2	91
2017 April	56	4	60
2017 March	83	5	88
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2017 January	54	3	57
2016 December	71	7	78
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2015 January	4	1	5
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2014 June	1	0	1
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2014 March	1	2	3
2014 February	0	1	1
2014 January	0	4	4
2013 December	1	1	2
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