Budesonide in the first line treatment of patients with autoimmune hepatitis | Gastroenterología y Hepatología (English Edition)

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This condition is characterized by hypertransaminasemia, elevation of gammaglobulines and the presence of autoantibodies. Histologically, the typical findings are interface hepatitis and lymphoplasmacytic portal infiltrate.<a class="elsevierStyleCrossRef" href="#bib0175">1</a> The exact pathogenesis of AIH is unknown. Nevertheless, different hypotheses point towards environmental agents that may trigger T cells-mediated immune response to liver antigens in a genetically predisposed host.<a class="elsevierStyleCrossRef" href="#bib0180">2</a> Interestingly, although AIH was the first liver disease with a targeted treatment in the early 60s, it is still a challenging scenario where treatment options have not evolved significantly. In fact, this therapeutic armamentarium mainly consists of inducing remission with prednisone associated with a long-term use of steroid-sparing drugs, usually azathioprine.<a class="elsevierStyleCrossRefs" href="#bib0175">1,3</a> However, international guidelines also recommend budesonide as an alternative first line agent in patients without cirrhosis or severe AIH<a class="elsevierStyleCrossRefs" href="#bib0175">1,3</a> (defined as INR >1.5 and <2 and/or total bilirubin>=12mg/dL<a class="elsevierStyleCrossRef" href="#bib0190">4</a>).The aim of this review is to deepen into the current knowledge and available evidence of budesonide as first-line option in the treatment of AIH.General pharmacologic characteristics of glucocorticoidsGlucocorticoids are natural steroid hormones secreted by the adrenal gland, whose production is regulated by the hypothalamic–anterior pituitary–adrenocortical axis, being cortisol the most relevant glucocorticoid. Briefly, corticotrophin-releasing hormone induces the release of adrenocorticotrophic hormone (ACTH) in the anterior pituitary, stimulating the delivery of cortisol from the adrenal gland.<a class="elsevierStyleCrossRef" href="#bib0195">5</a> Moreover, cortisol production is characterized by a circadian pattern, with the highest plasma concentrations in the morning and the lowest at night.<a class="elsevierStyleCrossRef" href="#bib0195">5</a> This hormone exhibits a plethora of effects involving almost every organ, probably being the anti-inflammatory effects the most recognized ones. Thus, synthetic analogues of cortisol have been developed by means of structural modifications in the glucocorticoid nucleus, enhancing the anti-inflammatory effect and decreasing the mineralocorticoid activity and being used for treating a wide range of inflammatory and immune-mediated diseases.<a class="elsevierStyleCrossRef" href="#bib0195">5</a> These modifications confer an increased specificity for the glucocorticoid receptor, with a longer efficacy and an increased lipophilicity. The bioavailability of the drug after oral ingestion ranges from 60 to 100%, with a moderate protein binding to transcortin and albumin, being the free fraction the responsible of both desired and undesired effects.<a class="elsevierStyleCrossRef" href="#bib0200">6</a>PrednisonePrednisone is a prodrug transformed by 11β-hydroxysteroid dehydrogenase-1 into prednisolone, the active drug. After ingestion, plasma concentrations reach its peak in 0.5–3h, with a reported bioavailability of 84+13%.<a class="elsevierStyleCrossRef" href="#bib0200">6</a> Cortisol and prednisolone share a comparable biochemical structure, although the latter presents a double bond C1=C2, contributing to its higher affinity to the glucocorticoid receptor and leading to a 4 times higher activity than cortisol.<a class="elsevierStyleCrossRef" href="#bib0205">7</a>As mentioned before, AIH was the first liver disease with a specific treatment, being prednisone the drug of choice. The evidence comes from the original clinical trials run in the 70s and 80s, where untreated patients had a dismal evolution, while those under corticosteroid therapy improved their liver tests and had longer survivals. A summary of these trials is captured in<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>BudesonideUnder a structural point of view, budesonide is a 17-α substituted steroid obtained by modifying the 6-α-hydroxy-prednisolone nucleus by adding a 16α and 17α acetyl group.<a class="elsevierStyleCrossRef" href="#bib0210">8</a> The introduction of lipophilic constituents at the 17-α and 16-α positions increases tissue penetration and drug potency.<a class="elsevierStyleCrossRef" href="#bib0210">8</a> In fact, it is a potent topical anti-inflammatory agent<a class="elsevierStyleCrossRef" href="#bib0215">9</a> with an affinity for the glucocorticoid receptor 195 times greater than hydrocortisone and 15 times higher than prednisolone.<a class="elsevierStyleCrossRefs" href="#bib0220">10,11</a> Mechanistically, budesonide activates glucocorticoid receptors in the cytoplasm allowing its translocation to the nucleus, preventing the transcription of inflammatory genes by binding to cortisol binding protein and decreasing cytokine production by activating HDCA2.<a class="elsevierStyleCrossRef" href="#bib0230">12</a> When administered orally, the systemic bioavailability of budesonide is around 10%, as the 90% of the drug is cleared in the hepatic first-pass clearance.<a class="elsevierStyleCrossRefs" href="#bib0235">13,14</a> The metabolism of budesonide is predominantly driven by CYP3A4, obtaining the two most relevant metabolites: 6β-OH-budesonide and 16α-OH-prednisolone, both presenting a marginal glucocorticoid activity.<a class="elsevierStyleCrossRef" href="#bib0245">15</a> Although budesonide is not characterized by presenting many drug-to-drug interactions, some drugs should be used cautiously when administered concomitantly. Hence, cytochrome P450 inhibitors such as ketoconazole, azithromycin or protease inhibitors, among others, may increase plasma exposure of budesonide, and the combination should be avoided.<a class="elsevierStyleCrossRef" href="#bib0250">16</a> On the other hand, CYP3A4 inducers (phenobarbital, carbamazepine, phenytoin) reduce budesonide exposure, decreasing its effectiveness.<a class="elsevierStyleCrossRef" href="#bib0250">16</a>Budesonide as first line drug for autoimmune hepatitisThe usefulness of budesonide in the treatment of AIH was formerly evaluated in the seminal study carried out by Danielsson,<a class="elsevierStyleCrossRef" href="#bib0255">17</a> in the early 1990s. However, it was not until 2005 where the first trial evaluating this drug in untreated patients was published.<a class="elsevierStyleCrossRef" href="#bib0260">18</a> In this open one-arm multicenter phase IIa trial, the authors evaluated the ability of budesonide in inducing response in these patients, by measuring the drop of transaminases three months after starting the treatment. The authors showed that budesonide was not only effective in reducing transaminase levels below twice the upper limit of normal, but also reducing IgG and gammaglobulines.<a class="elsevierStyleCrossRef" href="#bib0260">18</a> Furtherly, Manns et al. published the only currently available trial comparing prednisone and budesonide as first line therapies in the management of AIH.<a class="elsevierStyleCrossRef" href="#bib0240">14</a> Budesonide was not only effective, but also superior to prednisone. In fact, 47% of patients treated with budesonide reached the primary endpoint, while only 18.4% of those treated with prednisone did it. These unexpected results may be explained by the unconventional definition of the primary endpoint, as it was a composite one gathering biochemical remission with the absence of adverse events related to corticosteroids. It is worth mentioning that this unusual endpoint was also used in a similar trial done in AIH pediatric patients.<a class="elsevierStyleCrossRef" href="#bib0265">19</a> However, the results were remarkably different, as the primary endpoint was only reached in 16% and 15% of patients treated with budesonide and prednisone, respectively.<a class="elsevierStyleCrossRef" href="#bib0265">19</a>Beyond these trials, the evidence is limited. Delgado et al. published the results of a large retrospective multicenter cohort of AIH patients in Israel.<a class="elsevierStyleCrossRef" href="#bib0270">20</a> Biochemical remission was achieved in 63% of patients treated with budesonide plus azathioprine and 54.9% of patients treated with the combination of prednisone plus azathioprine. However, 15% of these patients included were also diagnosed with overlap syndrome and, notably, budesonide (or the combination of budesonide and azathioprine) was used only in 21 patients. In this regard, a recent work from Turkey retrospectively evaluated this scenario.<a class="elsevierStyleCrossRef" href="#bib0275">21</a> In their work, they included 50 untreated AIH patients: 25 treated with budesonide plus azathioprine and 25 with the combination of prednisone and azathioprine. Although they did not identify differences in biochemical remission, inflammatory activity, indirectly measured by median transaminase levels, was lower than in any other study -or in the real-life setting- and, more importantly, the definition they used did not consider the normalization of IgG (or gammaglobulin), potentially limiting the evaluation of the results. These studies and others evaluating budesonide as first line alternative are summarized in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Despite the good results obtained in phase II and phase III trials, the use of budesonide in naïve AIH patients is rare.<a class="elsevierStyleCrossRefs" href="#bib0280">22,23</a> Of note, an international multicenter survey disclosing the current management of the disease in different worldwide centers with recognized expertise in the treatment of AIH patients, evidenced that budesonide was not used in any center as first line option for the induction of disease remission. The reason for this paucity of use is probably the consequence of the generalized perception of lower efficacy. A recent multicenter Spanish work, presented in the 2021s Spanish Association for the Study of the Liver annual meeting, showed that budesonide use was marginal (only 5.4% of the cohort) and, more importantly, it was significantly inferior to prednisone.<a class="elsevierStyleCrossRef" href="#bib0290">24</a> In terms of efficacy, the authors compared the two cohorts through an Inverse Probability Treatment Weighting (IPTW) propensity score, identifying that those patients treated with budesonide presented a lower probability of reaching biochemical response at 6 months (OR 0.44; CI95% 0.24–0.81; p<0.009), at 12 months (OR 0.43; CI95% 0.23–0.8; p<0.008) and during the follow-up (OR 0.29; CI95% 0.14–0.58; p<0.0001) (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>).<elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="tbl0020"></elsevierMultimedia>Indications and regimen of budesonide as first line drugIn untreated patients diagnosed of non-severe acute or chronic AIH, budesonide is an adequate alternative treatment endorsed by international guidelines.<a class="elsevierStyleCrossRefs" href="#bib0175">1,3</a> The recommended dose is budesonide 3mg three times per day, combined with weight-adjusted azathioprine.<a class="elsevierStyleCrossRef" href="#bib0185">3</a> Once biochemical response is documented, budesonide tapering during the upcoming 6 months is recommended, until reaching a dose of 3mg daily. Once biochemical remission is consolidated, budesonide withdrawal can be considered while maintaining AZA treatment. However, due to the short life of budesonide, it is unclear whether this reduction scheme is reasonable.<a class="elsevierStyleCrossRef" href="#bib0175">1</a>While budesonide is an alternative in the non-severe scenario, it cannot be considered in the presence of acute liver failure or cirrhosis. First, because there is no evidence of its efficacy, as these patients were not included in the former trial. Second, because the presence of portosystemic shunts in patients with cirrhosis may decrease budesonide efficacy and increase the risk of adverse events by bypassing the liver.<a class="elsevierStyleCrossRef" href="#bib0295">25</a> Finally, some reports have warned about the increased risk of portal thrombosis in cirrhotic patients treated with budesonide, discouraging its use.<a class="elsevierStyleCrossRef" href="#bib0185">3</a>Budesonide safety profileBecause of the marginal use of budesonide in untreated patients, the extent of information about the safety profile in this specific scenario is scant. In the original trial, patients treated with budesonide presented a significant lower rate of adverse events (AEs) compared to patients on prednisone.<a class="elsevierStyleCrossRef" href="#bib0240">14</a> Specifically, 26% of patients in the budesonide group presented at least one AE during the follow up, being moon face, acne and hirsutism the leading causes. On the other hand, up to 51.5% of patients treated with prednisone developed at least one AE, reporting the same leading causes.<a class="elsevierStyleCrossRef" href="#bib0240">14</a> Interestingly, no patient treated with prednisone presented diabetes as side effect, while 4 patients (15.4%) on budesonide presented this complication.A few years later, a similar trial was carried out in the pediatric population. The authors did not identify differences in the emergence of AEs in budesonide and prednisone cohorts either at 6 or 12 months after treatment initiation.<a class="elsevierStyleCrossRef" href="#bib0265">19</a> The data about AEs emergence in the different published studies is summarized in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>.A recent Dutch study specifically evaluated the risk of developing steroid related AEs in AIH patients – including overlap with Primary Biliary Cholangitis (PBC) or Primary Sclerosing Cholangiits (PSC) – treated with low doses of prednisone or budesonide. There, they reported that prednisone exposure increased the risk of AEs (OR 1.08, CI95% 1.06–1.11), while budesonide, although bordering the statistical significance, did not (OR 1.09, CI95% 1.00–1.2).<a class="elsevierStyleCrossRef" href="#bib0280">22</a> Nevertheless, the authors found that not only prednisone, but also budesonide significantly increased the risk of cataracts and bone fracture. In fact, these latter AEs persisted after correcting for prior prednisone use, suggesting that the use of budesonide does not avert the risk of them.A fearsome side effect of steroids is adrenal insufficiency, as its consequences can be devastating. On this subject, a recent placebo-controlled trial of PBC patients treated with budesonide showed a slight reduction of serum cortisol in patients treated with the drug with respect to those on placebo.<a class="elsevierStyleCrossRef" href="#bib0300">26</a> However, besides some case reports describing anecdotal cases of this complication in the AIH setting,<a class="elsevierStyleCrossRef" href="#bib0305">27</a> the information is very limited and comes from studies ran in the inflammatory bowel disease (IBD) scenario. There, different studies agree with the results from the PBC study<a class="elsevierStyleCrossRef" href="#bib0300">26</a>: budesonide induces a mild reduction in plasma cortisol, but it is not a clinical concern at the usual doses recommended in the treatment of AIH.<a class="elsevierStyleCrossRefs" href="#bib0225">11,28</a> Moreover, other studies analyzing long-term use of budesonide at 3–6mg doses have shown an absence -or very limited- of effect on adrenal function.<a class="elsevierStyleCrossRefs" href="#bib0315">29–31</a>Are calcium and vitamin D supplements necessary?As per guidelines, DEXA (dual-energy X-ray absorptiometry) scan of both vertebrae and hips should be done in patients at risk of osteoporosis at AIH diagnosis, and every 2–3 years in patients with ongoing risk factors.<a class="elsevierStyleCrossRef" href="#bib0185">3</a> In fact, the most prevalent risk factor in AIH patients is the immunosuppressive treatment itself, specifically the prolonged use of corticosteroids. However, the body of evidence mostly comes from the IBD setting<a class="elsevierStyleCrossRef" href="#bib0330">32</a> where a randomized trial comparing prednisone and budesonide in patients with active Crohn's disease showed a significantly higher bone loss in patients treated with prednisone.<a class="elsevierStyleCrossRef" href="#bib0335">33</a> However, this was not confirmed on other studies.<a class="elsevierStyleCrossRef" href="#bib0340">34</a>Prospective long term studies evaluating impact of budesonide in the bone density of patients with AIH are lacking. However, Van den Brand et al.<a class="elsevierStyleCrossRef" href="#bib0280">22</a> recently showed that budesonide exposure significantly increases the risk of bone fracture, reporting an OR 1.14 (CI95% 1.03–1.27). Therefore, considering the ease of use and its favorable profile, as well as the need of prolonged therapy, treatment with vitamin D and calcium is safe and probably a cost-effective approach.DiscussionBudesonide is a potent synthetic corticosteroid with a lower systemic bioavailability because of the high first-hepatic pass clearance. Although this drug is recommended as an effective alternative by the different international societies (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>), its use in the real-life setting is low. Recently, a retrospective multicenter study developed in Spain showed that the probability of achieving biochemical remission in patients treated with budesonide is significantly lower than those treated by prednisone.<a class="elsevierStyleCrossRef" href="#bib0290">24</a> However, these results must be prospectively validated. In terms of safety, the former trial<a class="elsevierStyleCrossRef" href="#bib0240">14</a> showed a lower short-term rate of AEs in patients treated with budesonide. However, recent data show that budesonide also significantly increases the risk of bone fracture and cataract.<a class="elsevierStyleCrossRef" href="#bib0280">22</a>In conclusion, budesonide is a safe and effective drug in the setting of AIH, but further studies are needed in order to improve patient selection for its use as first line induction therapy.Conflict of interestThe authors declare that they have no conflict of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:15 [ 0 => array:3 [ "identificador" => "xres1761314" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1548926" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1761315" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1548927" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Background" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "General pharmacologic characteristics of glucocorticoids" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Prednisone" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Budesonide" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Budesonide as first line drug for autoimmune hepatitis" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Indications and regimen of budesonide as first line drug" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "Budesonide safety profile" ] 11 => array:2 [ "identificador" => "sec0040" "titulo" => "Are calcium and vitamin D supplements necessary?" ] 12 => array:2 [ "identificador" => "sec0045" "titulo" => "Discussion" ] 13 => array:2 [ "identificador" => "sec0050" "titulo" => "Conflict of interest" ] 14 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2021-09-03" "fechaAceptado" => "2021-11-29" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1548926" "palabras" => array:4 [ 0 => "Autoimmune hepatitis" 1 => "Budesonide" 2 => "Prednisone" 3 => "Biochemical remission" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1548927" "palabras" => array:4 [ 0 => "Hepatitis autoinmune" 1 => "Budesonida" 2 => "Prednisona" 3 => "Remisión bioquímica" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Budesonide is a glucocorticoid characterized by its local action, with a low systemic bioavailability. Since the original trial comparing budesonide with prednisone in 2010, it is recommended as an effective alternative for the treatment of non-severe acute or chronic autoimmune hepatitis. In this document, we review the general pharmacologic properties of glucocorticoids, the available evidence for the use of budesonide as first line option for autoimmune hepatitis as well as the safety profile of the drug." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La budesonida es un glucocorticoide que se caracteriza por su acción local, con una baja biodisponibilidad sistémica. Desde el ensayo original publicado en 2010, en el que se comparó la budesonida con prednisona, se recomienda como una alternativa eficaz en el tratamiento de los pacientes con hepatitis autoinmune aguda o crónica no grave. En este documento, revisamos las propiedades farmacológicas generales de los glucocorticoides, la evidencia disponible para el uso de budesonida como fármaco de primera línea en estos pacientes, así como el perfil de seguridad del fármaco." ] ] "multimedia" => array:4 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "TB: total bilirubin; AST: aspartate aminotransferase; PDN: prednisone; AZA: azathioprine; IgG: immunoglobulin G; ULN: upper limit of normal; CALD: chronic active liver disease.Adapted from Lammers et al.<a class="elsevierStyleCrossRef" href="#bib0365">39</a>" "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Study \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Country \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Design \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Criteria \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Patients \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Treatment \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Follow-up \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">End-point \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Results \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Side-effects \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cook et al., 1971<a class="elsevierStyleCrossRef" href="#bib0340">34</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">USA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Unblinded, randomized, controlled trial \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Untreated patients diagnosed of active chronic hepatitis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N=54 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Corticosteroid group (n=22): PDN 15mg/day reduced whenever biochemical liver function test became normal or in the emergence of severe side-effectsControl group (n=27) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">72 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mortality at 72 monthsTB, AST, albumin at 72 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mortality: PDN 3/22 (13.6%) untreated group 15/27 (55.5%) (p<0.01)Albumin was significantly higher in the PDN group compared to the control group at 6, 12, 18 and 24 months.TB was significantly lower in PDN group with respect to the control group at six and 24 months. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PDN: obesity 5/22 (23%), moon face 5/22 (23%), acne 4/22 (18%), Osteoporosis and vertebral collapse 2/22 (9%), Perforated duodenal ulcer 1/22 (5%), acute steroid psychosis 1/22 (5%), terminal bronchopneumonia 1/22 (5%), myositis 1/22 (5%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Soloway et al., 1972<a class="elsevierStyleCrossRef" href="#bib0345">35</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">UK \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Randomized, double-blinded, controlled trial \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hepatic disease documented by clinical, biochemical, and histological abnormalities lasting at least 10 weeks and documented by biopsy, jaundice, or AST >10×ULN or >5×ULN plus IgG >2×ULN \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N=63 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(a) PDN (n=18) 60mg daily for one week, 40mg daily the following week, 30mg daily for two weeks and 20mg daily as maintenance therapy.(b) AZA (n=14) 100mg daily.(c) PDN+AZA (n=14): 30mg daily for 1 week, 20mg daily the following week, 15mg daily for 2 weeks, and 10mg daily as maintenance(d) Placebo (n=17) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3–38 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(1) Remission defined as:(a) clinical normality, return to all customary activitiesPLUS(b) Disappearance of histological signs of disease activity normality or of minor changes indistinguishable from those in nonspecific or chronic persistent hepatitis(2) Mortality \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PDN group: remission 8/18 (44%), mortality 1/18 (6%),PDN+AZA group: remission 3/14 (21%), mortality 1/14 (7%).AZA group: remission 1/14 (7%), mortality 5/14 (36%)Placebo group: mortality: remission 0/17 (0%), mortality 7/17 (41%)Response rate in patients receiving PDN or combined treatment were superior to those receiving AZA or placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PDN: cushingoid appearance 13/18 (72%), serious side effects (vertebral collapse, aseptic necrosis of the femoral head, or cataracts) 3/18 (17%), diabetes requiring insulin 1/18 (6%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Murray-Lyon et al., 1973<a class="elsevierStyleCrossRef" href="#bib0350">36</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">USA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Randomized, double-blind, controlled trial \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Active chronic hepatitis defined by hepatic disease lasting at least for 3 months with AST>100IU/L and/or IgG>1.5g/100mL.Patients previously treated with AZA or corticosteroids were not excluded. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N=47Cirrhosis (n=32) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PDN group (n=22): 5mg every 8hAZA group (n=25): 75mg dailyIn the absence of response or AST persistently >200IU/L, PDN or AZA doses were increased to 20mg or 112.5mg respectively. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Survival at 24 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PDN group: 95% probability of survival at 24 monthsAZA group: 72% probability of survival at 24 monthsSignificant (p<0.005) decrease in bilirubin and globulin in both groupsHigher AST (p<0.05) and IgG (p=0.02) decrease in the first 6 months in patients treated with PDN. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PRD: facial mooning 11/22 (50%), diabetes mellitus 3/22 (14%); hypertension 2/22 (9%), brush fracture of thoracic vertebrae 1/22 (5%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Summerskill et al., 1975<a class="elsevierStyleCrossRef" href="#bib0355">37</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">USA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Multicenter, randomized, double-blind, controlled trial \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hepatic disease documented by clinical, biochemical, and histological abnormalities lasting at least 10 weeks and documented by biopsy, jaundice, or AST >10×ULN or >5×ULN plus IgG >2×ULN \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N=120 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(a) Placebo (n=16)(b) AZA 100mg (n=13)(c) PDN (n=30)(d) PDN+AZA (n=30)(e) PDN at titrated doses attending to biochemical evolution (n=31) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">36 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(1) Remission defined as:(a) Absence of symptoms and return of the patient to customary activitiesPLUS(b) AST <2×ULNPLUS(c) Normalization of immunoserological tests(2) Mortality \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PDN: 24/30 (80%) achieved remission. Mortality 3/30 (10%)PDN+AZA: 24/30 (80%) achieved remission. Mortality 2/31 (7%)Titrated PDN: 23/31 (74%) achieved remission. Mortality 2/31 (7%)Placebo or AZA: 10/29 (34%) achieved remission. Mortality 12/29 (41%). \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PDN: severe cosmetic changes 4/30 (13%), diabetes 4/30/13%), cataracts 2/30 (7%) vertebral collapse 1/30 (3%)PDN/AZA: diabetes 3/30 (10%)Titrated PDN: diabetes 3/31 (10%)Pacebo or AZA: gastrointestinal bleeding 5/29 (17%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tage-Jansen et al., 1982<a class="elsevierStyleCrossRef" href="#bib0360">38</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Denmark \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Multicenter, randomized, unblinded clinical trial \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Patient with biopsy-proven chronic aggressive hepatitis. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N=99* only information for 84 patients \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(a) PDN 10 mg/day if weight <70kg or 15mg/kg if weight >70kg.(b) AZA 10mg/kg. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">38 (12–83 months) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(1) Remission defined as(a) AST<40UI/L(b) IgG<15.1g/L(2) Mortality \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PRD: Remission: 21/47 (45%); mortality: 13/27 (28%)AZA: Remission: 6/37 (37%), mortality: 10/37 (27%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Not reported \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "Clinical trials evaluating prednisone for treating autoimmune hepatitis." ] ] 1 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "AST: aspartate aminotransferase; ALT: alanine aminotransferase; ULN: upper limit of normal; AIH: autoimmune hepatitis; BUD: budesonide; AZA: azathioprine; PDN: prednisone; pat: patients." "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Study \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Country \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Design \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Inclusion criteria \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Patients \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Treatment \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Followup \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Primary endpoint \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Results \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Adverse EVENTS \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Wiegand et al., 2005<a class="elsevierStyleCrossRef" href="#bib0255">17</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Germany, Netherlands \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Multicenter Open label, prospective clinical trial \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Untreated AIH patientsAST and ALT at least >3× ULN \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N=14; finally included N=12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Day 1: 3g twice daily from day 2: 3mg thrice daily.Upon biochemical remission, the dosage was individually reduced to 3mg budesonideNo other immunosuppressive drugs allowed \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Remission defined as drop of AST and ALT <2×ULN. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Complete remission: 7/12Partial response 3/12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Leukocytosis 5/14 (36%)Hypercholesterinaemia 4/14 (29%)Cushing-like symptoms 3/14 (21%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Csepregi et al., 2006<a class="elsevierStyleCrossRef" href="#bib0370">40</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Germany \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Multicenter Open label study. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Naïve or previously treated patients diagnosed of AIH or overlap \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N=18First-line BUD in AIH: N=7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BUD 3mg thrice daily \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Not defined \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Biochemical remission in AIH 4/7No response in AIH: 3/7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Total incidence: 6/18 (33%)Weight gain >3kg 3/18 (17%),Acne 2/18 (11%)Abdominal pain 1/18 (6%)Alopecia 1/18 (6%)Every AE emerged in patients with cirrhosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Manns et al., 2010<a class="elsevierStyleCrossRef" href="#bib0235">13</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Germany, Poland, Ukraine, Hungary, Israel, Sweden \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Prospective, 6-month double-blind, double-dummy, controlled trial \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Untreated AIH patientsAST and ALT at least >2× ULN \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N=207 patientsBUD=102 patPDN=105 pat \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BUD: 9mg/daily.PDN group: 40mg/daily \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Segment A 24 weeksSegment B 24 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Biochemical remission without corticosteroid-related adverse events. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Primary endpoint:BUD: 47/100 (47.0%)PDN: 19/103 (18.4%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BUD: 26/100 (26%)Headache 11.8%Mood alterations 9.8%.Weight gain 5.9%Muscular weakness 4.9%.Hypertension 2.9%Insomnia 1%.PDN: 53/103 (51.5%)Weight gain 19%.Headache 7.6%.Mood alterations 7.6%.Muscular weakness 7.6%.Hypertension 6.7%.Insomnia 4.8% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Efe et al., 2012<a class="elsevierStyleCrossRef" href="#bib0290">24</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Turkey, France, Italy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Multicenter, retrospective study \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Untreated definite or probable AIH defined by simplified AIH criteria (IAIHG)AIH/PBC overlap syndrome according to Chazouilleres criteria.<a class="elsevierStyleCrossRef" href="#bib0195">5</a>ALT or AST levels >3×ULN \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N=18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BUD 9 mg/day+AZA 50mg all patients \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(a) Biochemical remission defined by AST and/or ALT <2×ULN(b) AST/ALT drop >50% after 1 month on treatment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Biochemical remission: 11/18 (61.1%)No response: 7/18 (38.9%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Incidence 11/18 (61%)Weight gain: 6/18 (30%); acne 4/18 (20%); hirsutism: 4/18 (20%); moon face: 2/18 (10%); skin striae: 2/18 (10%); buffalo hump: 2/18 (10%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Woynarowski et al., 2013<a class="elsevierStyleCrossRef" href="#bib0260">18</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Poland \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Multicenter prospective, double-blind, randomized, controlled trial in pediatric AIH patients \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pediatric AIH patients (9–17 years)AST and ALT at least >2× ULN \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N=46BUD=19 patPDN=27 pat \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3mg 3 times daily or 3mg twice daily after biochemical \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Segmentt A 24 weeksSegment B 24 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Biochemical remission without corticosteroid-related adverse events. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Primary endpoint:BUD: 3/19 (16%)PDN: 4/27 (15%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PDN incidence 17/27 (63%); moon face: 12/27 (44%); acne: 7/27 (26%); skin striae: 3/27 (11%)BUD incidence 9/19 (47%), acne 4/19 (21%), moon face 2/19 (11%), skin striae 1/19 (5%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Binicier et al., 2019<a class="elsevierStyleCrossRef" href="#bib0270">20</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Turkey \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Retrospective unicenter study \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Untreated AIH patients \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N=50PDN+AZA=25 patPDN+BUD=25 pat \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PRED/AZA: 30mg/day PRED and AZA.BUD/AZA: 9 mg/day BUD and AZA. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Biochemical remission defined by AST and ALT normalization \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Biochemical remission defined as transaminases normalization:-PDN+AZA: 17/25 (68%)-BUD+AZA: 18/25 (72%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PDN/AZA incidence: 9/25 (60%), acne 4/25 (16%), moon face 4/24 (16%), hirsutism 3/25 (12%), striae 2/25 (8%), myopathy 1/25 (4%), buffalo hump 1/25 (4%).BUD/AZA Incidence 5/25 (20%) Acne 2/25 (8%), hirsutism 1/25 (4%), myopathy 1/25 (4%), moon face 1/25 (4%), buffalo hump 1/25 (4%), striae 2/25 (4%). \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "Clinical trials & retrospective studies evaluating budesonide for the treatment of autoimmune hepatitis." ] ] 2 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Guideline \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Drug \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Induction dose \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Tappering \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Azathioprine (yes/no) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Duration of treatment \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AASLD 2020<a class="elsevierStyleCrossRef" href="#bib0185">3</a></td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Prednisone \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20–40mg daily \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tapper to 5–10mg daily \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">At least 2 years \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Budesonide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3mg thrice daily \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tapper to 3mg daily \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ESPGHAN 2019<a class="elsevierStyleCrossRef" href="#bib0375">41</a></td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Prednisone \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 mg/kg daily (maximum 60 mg/day) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tapper to 2.5–5mg daily \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">At least 2–3 years \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Budesonide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Undefined \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Undefined \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Undefined \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Undefined \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hellenic 2018<a class="elsevierStyleCrossRef" href="#bib0380">42</a></td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Prednisone \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Prednisolone 0.5–1mg/kg daily \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Individualized according to response and side-effectsComplete PDN withdrawal after 6–8 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">At least 3 years \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Budesonide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9mg daily \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Not defined \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EASL 2015<a class="elsevierStyleCrossRef" href="#bib0175">1</a></td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Prednisone \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.5–1mg/kg daily \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(a) From 60 to 20mg-10mg weekly(b) From 20mg to 10mg-2.5–5mg biweekly(c) From 10mg-Individualized according to response \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">At least three years and 24 months after biochemical remission \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Budesonide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9mg daily \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Not clearly defined \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BSG 2011<a class="elsevierStyleCrossRef" href="#bib0385">43</a></td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Prednisone \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">30mg daily \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5mg weekly until 10mg daily \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">At least 2 years and 12 months after biochemical remission \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Budesonide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9mg daily \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Not defined \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Not defined \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "International guidelines recommendations for the treatment of autoimmune hepatitis." ] ] 3 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at4" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "IQR: interquartile range." "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Centres \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">21 Spanish centers</th></tr><tr title="table-row"><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Study period \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">2009–2020</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Budesonide \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Prednisone \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Number of patients \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">151 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">218 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Women (n, %) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">107 (70.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">154 (70.6) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Age (years, median, IQR) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">62,2 (46.3–71.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">62,4 (50.7–72.1) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cirrhosis (n, %) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 (5.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">38 (17.5) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Induction dose (median, IQR) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9 (9–9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">50 (30–60) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Azathioprine (n, %) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">132 (88.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">184 (86) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "Baseline characteristics of the patients included in the study by Díaz-González et al.<a class="elsevierStyleCrossRef" href="#bib0290">24</a>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:43 [ 0 => array:3 [ "identificador" => "bib0175" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "EASL clinical practice guidelines: autoimmune hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A.W. 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Budesonide in the first line treatment of patients with autoimmune hepatitis

Budesonida en primera línea de tratamiento de pacientes con hepatitis autoinmune

Ignasi Olivasa, Marina Cobrerosb, María-Carlota Londoñoa, Álvaro Díaz-Gonzálezb,

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alvaro.diaz@scsalud.es

Corresponding author.

a Liver Unit, Hospital Clínic of Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERehd, Universitat de Barcelona, Barcelona, Spain

b Digestive Diseases Department, Marqués de Valdecilla University Hospital, Instituto de investigación sanitaria Valdecilla (IDIVAL), Santander, Spain

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        "autoresLista" => "Ignasi Olivas, Marina Cobreros, Mar&#237;a-Carlota Londo&#241;o, &#193;lvaro D&#237;az-Gonz&#225;lez"
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            "nombre" => "Marina"
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            "nombre" => "&#193;lvaro"
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            "email" => array:1 [
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                "identificador" => "cor0005"
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        "afiliaciones" => array:2 [
          0 => array:3 [
            "entidad" => "Liver Unit&#44; Hospital Cl&#237;nic of Barcelona&#44; Institut d&#8217;Investigacions Biom&#232;diques August Pi i Sunyer &#40;IDIBAPS&#41;&#44; CIBERehd&#44; Universitat de Barcelona&#44; Barcelona&#44; Spain"
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            "entidad" => "Digestive Diseases Department&#44; Marqu&#233;s de Valdecilla University Hospital&#44; Instituto de investigaci&#243;n sanitaria Valdecilla &#40;IDIVAL&#41;&#44; Santander&#44; Spain"
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    "titulosAlternativos" => array:1 [
      "es" => array:1 [
        "titulo" => "Budesonida en primera l&#237;nea de tratamiento de pacientes con hepatitis autoinmune"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Background</span><p id="par0005" class="elsevierStylePara elsevierViewall">Autoimmune hepatitis &#40;AIH&#41; is a chronic inflammatory liver disease endowed with a progressive course&#46; This condition is characterized by hypertransaminasemia&#44; elevation of gammaglobulines and the presence of autoantibodies&#46; Histologically&#44; the typical findings are interface hepatitis and lymphoplasmacytic portal infiltrate&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">1</span></a> The exact pathogenesis of AIH is unknown&#46; Nevertheless&#44; different hypotheses point towards environmental agents that may trigger T cells-mediated immune response to liver antigens in a genetically predisposed host&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">2</span></a> Interestingly&#44; although AIH was the first liver disease with a targeted treatment in the early 60s&#44; it is still a challenging scenario where treatment options have not evolved significantly&#46; In fact&#44; this therapeutic armamentarium mainly consists of inducing remission with prednisone associated with a long-term use of steroid-sparing drugs&#44; usually azathioprine&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">1&#44;3</span></a> However&#44; international guidelines also recommend budesonide as an alternative first line agent in patients without cirrhosis or severe AIH<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">1&#44;3</span></a> &#40;defined as INR &#62;1&#46;5 and &#60;2 and&#47;or total bilirubin<span class="elsevierStyleHsp" style=""></span>&#62;&#61;<span class="elsevierStyleHsp" style=""></span>12<span class="elsevierStyleHsp" style=""></span>mg&#47;dL<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">4</span></a>&#41;&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">The aim of this review is to deepen into the current knowledge and available evidence of budesonide as first-line option in the treatment of AIH&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">General pharmacologic characteristics of glucocorticoids</span><p id="par0015" class="elsevierStylePara elsevierViewall">Glucocorticoids are natural steroid hormones secreted by the adrenal gland&#44; whose production is regulated by the hypothalamic&#8211;anterior pituitary&#8211;adrenocortical axis&#44; being cortisol the most relevant glucocorticoid&#46; Briefly&#44; corticotrophin-releasing hormone induces the release of adrenocorticotrophic hormone &#40;ACTH&#41; in the anterior pituitary&#44; stimulating the delivery of cortisol from the adrenal gland&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">5</span></a> Moreover&#44; cortisol production is characterized by a circadian pattern&#44; with the highest plasma concentrations in the morning and the lowest at night&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">5</span></a> This hormone exhibits a plethora of effects involving almost every organ&#44; probably being the anti-inflammatory effects the most recognized ones&#46; Thus&#44; synthetic analogues of cortisol have been developed by means of structural modifications in the glucocorticoid nucleus&#44; enhancing the anti-inflammatory effect and decreasing the mineralocorticoid activity and being used for treating a wide range of inflammatory and immune-mediated diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">5</span></a> These modifications confer an increased specificity for the glucocorticoid receptor&#44; with a longer efficacy and an increased lipophilicity&#46; The bioavailability of the drug after oral ingestion ranges from 60 to 100&#37;&#44; with a moderate protein binding to transcortin and albumin&#44; being the free fraction the responsible of both desired and undesired effects&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">6</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Prednisone</span><p id="par0020" class="elsevierStylePara elsevierViewall">Prednisone is a prodrug transformed by 11&#946;-hydroxysteroid dehydrogenase-1 into prednisolone&#44; the active drug&#46; After ingestion&#44; plasma concentrations reach its peak in 0&#46;5&#8211;3<span class="elsevierStyleHsp" style=""></span>h&#44; with a reported bioavailability of 84<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>13&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">6</span></a> Cortisol and prednisolone share a comparable biochemical structure&#44; although the latter presents a double bond C1<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>C2&#44; contributing to its higher affinity to the glucocorticoid receptor and leading to a 4 times higher activity than cortisol&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">7</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">As mentioned before&#44; AIH was the first liver disease with a specific treatment&#44; being prednisone the drug of choice&#46; The evidence comes from the original clinical trials run in the 70s and 80s&#44; where untreated patients had a dismal evolution&#44; while those under corticosteroid therapy improved their liver tests and had longer survivals&#46; A summary of these trials is captured in<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Budesonide</span><p id="par0030" class="elsevierStylePara elsevierViewall">Under a structural point of view&#44; budesonide is a 17-&#945; substituted steroid obtained by modifying the 6-&#945;-hydroxy-prednisolone nucleus by adding a 16&#945; and 17&#945; acetyl group&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">8</span></a> The introduction of lipophilic constituents at the 17-&#945; and 16-&#945; positions increases tissue penetration and drug potency&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">8</span></a> In fact&#44; it is a potent topical anti-inflammatory agent<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">9</span></a> with an affinity for the glucocorticoid receptor 195 times greater than hydrocortisone and 15 times higher than prednisolone&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">10&#44;11</span></a> Mechanistically&#44; budesonide activates glucocorticoid receptors in the cytoplasm allowing its translocation to the nucleus&#44; preventing the transcription of inflammatory genes by binding to cortisol binding protein and decreasing cytokine production by activating HDCA2&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">12</span></a> When administered orally&#44; the systemic bioavailability of budesonide is around 10&#37;&#44; as the 90&#37; of the drug is cleared in the hepatic first-pass clearance&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">13&#44;14</span></a> The metabolism of budesonide is predominantly driven by CYP3A4&#44; obtaining the two most relevant metabolites&#58; 6&#946;-OH-budesonide and 16&#945;-OH-prednisolone&#44; both presenting a marginal glucocorticoid activity&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">15</span></a> Although budesonide is not characterized by presenting many drug-to-drug interactions&#44; some drugs should be used cautiously when administered concomitantly&#46; Hence&#44; cytochrome P450 inhibitors such as ketoconazole&#44; azithromycin or protease inhibitors&#44; among others&#44; may increase plasma exposure of budesonide&#44; and the combination should be avoided&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">16</span></a> On the other hand&#44; CYP3A4 inducers &#40;phenobarbital&#44; carbamazepine&#44; phenytoin&#41; reduce budesonide exposure&#44; decreasing its effectiveness&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">16</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Budesonide as first line drug for autoimmune hepatitis</span><p id="par0035" class="elsevierStylePara elsevierViewall">The usefulness of budesonide in the treatment of AIH was formerly evaluated in the seminal study carried out by Danielsson&#44;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">17</span></a> in the early 1990s&#46; However&#44; it was not until 2005 where the first trial evaluating this drug in untreated patients was published&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">18</span></a> In this open one-arm multicenter phase IIa trial&#44; the authors evaluated the ability of budesonide in inducing response in these patients&#44; by measuring the drop of transaminases three months after starting the treatment&#46; The authors showed that budesonide was not only effective in reducing transaminase levels below twice the upper limit of normal&#44; but also reducing IgG and gammaglobulines&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">18</span></a> Furtherly&#44; Manns et al&#46; published the only currently available trial comparing prednisone and budesonide as first line therapies in the management of AIH&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">14</span></a> Budesonide was not only effective&#44; but also superior to prednisone&#46; In fact&#44; 47&#37; of patients treated with budesonide reached the primary endpoint&#44; while only 18&#46;4&#37; of those treated with prednisone did it&#46; These unexpected results may be explained by the unconventional definition of the primary endpoint&#44; as it was a composite one gathering biochemical remission with the absence of adverse events related to corticosteroids&#46; It is worth mentioning that this unusual endpoint was also used in a similar trial done in AIH pediatric patients&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">19</span></a> However&#44; the results were remarkably different&#44; as the primary endpoint was only reached in 16&#37; and 15&#37; of patients treated with budesonide and prednisone&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">19</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Beyond these trials&#44; the evidence is limited&#46; Delgado et al&#46; published the results of a large retrospective multicenter cohort of AIH patients in Israel&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">20</span></a> Biochemical remission was achieved in 63&#37; of patients treated with budesonide plus azathioprine and 54&#46;9&#37; of patients treated with the combination of prednisone plus azathioprine&#46; However&#44; 15&#37; of these patients included were also diagnosed with overlap syndrome and&#44; notably&#44; budesonide &#40;or the combination of budesonide and azathioprine&#41; was used only in 21 patients&#46; In this regard&#44; a recent work from Turkey retrospectively evaluated this scenario&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">21</span></a> In their work&#44; they included 50 untreated AIH patients&#58; 25 treated with budesonide plus azathioprine and 25 with the combination of prednisone and azathioprine&#46; Although they did not identify differences in biochemical remission&#44; inflammatory activity&#44; indirectly measured by median transaminase levels&#44; was lower than in any other study -or in the real-life setting- and&#44; more importantly&#44; the definition they used did not consider the normalization of IgG &#40;or gammaglobulin&#41;&#44; potentially limiting the evaluation of the results&#46; These studies and others evaluating budesonide as first line alternative are summarized in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">Despite the good results obtained in phase II and phase III trials&#44; the use of budesonide in na&#239;ve AIH patients is rare&#46;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">22&#44;23</span></a> Of note&#44; an international multicenter survey disclosing the current management of the disease in different worldwide centers with recognized expertise in the treatment of AIH patients&#44; evidenced that budesonide was not used in any center as first line option for the induction of disease remission&#46; The reason for this paucity of use is probably the consequence of the generalized perception of lower efficacy&#46; A recent multicenter Spanish work&#44; presented in the 2021s Spanish Association for the Study of the Liver annual meeting&#44; showed that budesonide use was marginal &#40;only 5&#46;4&#37; of the cohort&#41; and&#44; more importantly&#44; it was significantly inferior to prednisone&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">24</span></a> In terms of efficacy&#44; the authors compared the two cohorts through an Inverse Probability Treatment Weighting &#40;IPTW&#41; propensity score&#44; identifying that those patients treated with budesonide presented a lower probability of reaching biochemical response at 6 months &#40;OR 0&#46;44&#59; CI95&#37; 0&#46;24&#8211;0&#46;81&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;009&#41;&#44; at 12 months &#40;OR 0&#46;43&#59; CI95&#37; 0&#46;23&#8211;0&#46;8&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;008&#41; and during the follow-up &#40;OR 0&#46;29&#59; CI95&#37; 0&#46;14&#8211;0&#46;58&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;0001&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Indications and regimen of budesonide as first line drug</span><p id="par0050" class="elsevierStylePara elsevierViewall">In untreated patients diagnosed of non-severe acute or chronic AIH&#44; budesonide is an adequate alternative treatment endorsed by international guidelines&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">1&#44;3</span></a> The recommended dose is budesonide 3<span class="elsevierStyleHsp" style=""></span>mg three times per day&#44; combined with weight-adjusted azathioprine&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">3</span></a> Once biochemical response is documented&#44; budesonide tapering during the upcoming 6 months is recommended&#44; until reaching a dose of 3<span class="elsevierStyleHsp" style=""></span>mg daily&#46; Once biochemical remission is consolidated&#44; budesonide withdrawal can be considered while maintaining AZA treatment&#46; However&#44; due to the short life of budesonide&#44; it is unclear whether this reduction scheme is reasonable&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">1</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">While budesonide is an alternative in the non-severe scenario&#44; it cannot be considered in the presence of acute liver failure or cirrhosis&#46; First&#44; because there is no evidence of its efficacy&#44; as these patients were not included in the former trial&#46; Second&#44; because the presence of portosystemic shunts in patients with cirrhosis may decrease budesonide efficacy and increase the risk of adverse events by bypassing the liver&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">25</span></a> Finally&#44; some reports have warned about the increased risk of portal thrombosis in cirrhotic patients treated with budesonide&#44; discouraging its use&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">3</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Budesonide safety profile</span><p id="par0060" class="elsevierStylePara elsevierViewall">Because of the marginal use of budesonide in untreated patients&#44; the extent of information about the safety profile in this specific scenario is scant&#46; In the original trial&#44; patients treated with budesonide presented a significant lower rate of adverse events &#40;AEs&#41; compared to patients on prednisone&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">14</span></a> Specifically&#44; 26&#37; of patients in the budesonide group presented at least one AE during the follow up&#44; being moon face&#44; acne and hirsutism the leading causes&#46; On the other hand&#44; up to 51&#46;5&#37; of patients treated with prednisone developed at least one AE&#44; reporting the same leading causes&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">14</span></a> Interestingly&#44; no patient treated with prednisone presented diabetes as side effect&#44; while 4 patients &#40;15&#46;4&#37;&#41; on budesonide presented this complication&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">A few years later&#44; a similar trial was carried out in the pediatric population&#46; The authors did not identify differences in the emergence of AEs in budesonide and prednisone cohorts either at 6 or 12 months after treatment initiation&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">19</span></a> The data about AEs emergence in the different published studies is summarized in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">A recent Dutch study specifically evaluated the risk of developing steroid related AEs in AIH patients &#8211; including overlap with Primary Biliary Cholangitis &#40;PBC&#41; or Primary Sclerosing Cholangiits &#40;PSC&#41; &#8211; treated with low doses of prednisone or budesonide&#46; There&#44; they reported that prednisone exposure increased the risk of AEs &#40;OR 1&#46;08&#44; CI95&#37; 1&#46;06&#8211;1&#46;11&#41;&#44; while budesonide&#44; although bordering the statistical significance&#44; did not &#40;OR 1&#46;09&#44; CI95&#37; 1&#46;00&#8211;1&#46;2&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">22</span></a> Nevertheless&#44; the authors found that not only prednisone&#44; but also budesonide significantly increased the risk of cataracts and bone fracture&#46; In fact&#44; these latter AEs persisted after correcting for prior prednisone use&#44; suggesting that the use of budesonide does not avert the risk of them&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">A fearsome side effect of steroids is adrenal insufficiency&#44; as its consequences can be devastating&#46; On this subject&#44; a recent placebo-controlled trial of PBC patients treated with budesonide showed a slight reduction of serum cortisol in patients treated with the drug with respect to those on placebo&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">26</span></a> However&#44; besides some case reports describing anecdotal cases of this complication in the AIH setting&#44;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">27</span></a> the information is very limited and comes from studies ran in the inflammatory bowel disease &#40;IBD&#41; scenario&#46; There&#44; different studies agree with the results from the PBC study<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">26</span></a>&#58; budesonide induces a mild reduction in plasma cortisol&#44; but it is not a clinical concern at the usual doses recommended in the treatment of AIH&#46;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">11&#44;28</span></a> Moreover&#44; other studies analyzing long-term use of budesonide at 3&#8211;6<span class="elsevierStyleHsp" style=""></span>mg doses have shown an absence -or very limited- of effect on adrenal function&#46;<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">29&#8211;31</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Are calcium and vitamin D supplements necessary&#63;</span><p id="par0080" class="elsevierStylePara elsevierViewall">As per guidelines&#44; DEXA &#40;dual-energy X-ray absorptiometry&#41; scan of both vertebrae and hips should be done in patients at risk of osteoporosis at AIH diagnosis&#44; and every 2&#8211;3 years in patients with ongoing risk factors&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">3</span></a> In fact&#44; the most prevalent risk factor in AIH patients is the immunosuppressive treatment itself&#44; specifically the prolonged use of corticosteroids&#46; However&#44; the body of evidence mostly comes from the IBD setting<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">32</span></a> where a randomized trial comparing prednisone and budesonide in patients with active Crohn&#39;s disease showed a significantly higher bone loss in patients treated with prednisone&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">33</span></a> However&#44; this was not confirmed on other studies&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">34</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Prospective long term studies evaluating impact of budesonide in the bone density of patients with AIH are lacking&#46; However&#44; Van den Brand et al&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">22</span></a> recently showed that budesonide exposure significantly increases the risk of bone fracture&#44; reporting an OR 1&#46;14 &#40;CI95&#37; 1&#46;03&#8211;1&#46;27&#41;&#46; Therefore&#44; considering the ease of use and its favorable profile&#44; as well as the need of prolonged therapy&#44; treatment with vitamin D and calcium is safe and probably a cost-effective approach&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Discussion</span><p id="par0090" class="elsevierStylePara elsevierViewall">Budesonide is a potent synthetic corticosteroid with a lower systemic bioavailability because of the high first-hepatic pass clearance&#46; Although this drug is recommended as an effective alternative by the different international societies &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#44; its use in the real-life setting is low&#46; Recently&#44; a retrospective multicenter study developed in Spain showed that the probability of achieving biochemical remission in patients treated with budesonide is significantly lower than those treated by prednisone&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">24</span></a> However&#44; these results must be prospectively validated&#46; In terms of safety&#44; the former trial<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">14</span></a> showed a lower short-term rate of AEs in patients treated with budesonide&#46; However&#44; recent data show that budesonide also significantly increases the risk of bone fracture and cataract&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">22</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">In conclusion&#44; budesonide is a safe and effective drug in the setting of AIH&#44; but further studies are needed in order to improve patient selection for its use as first line induction therapy&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conflict of interest</span><p id="par0100" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflict of interest&#46;</p></span></span>"
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        ]
        8 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "Budesonide as first line drug for autoimmune hepatitis"
        ]
        9 => array:2 [
          "identificador" => "sec0030"
          "titulo" => "Indications and regimen of budesonide as first line drug"
        ]
        10 => array:2 [
          "identificador" => "sec0035"
          "titulo" => "Budesonide safety profile"
        ]
        11 => array:2 [
          "identificador" => "sec0040"
          "titulo" => "Are calcium and vitamin D supplements necessary&#63;"
        ]
        12 => array:2 [
          "identificador" => "sec0045"
          "titulo" => "Discussion"
        ]
        13 => array:2 [
          "identificador" => "sec0050"
          "titulo" => "Conflict of interest"
        ]
        14 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2021-09-03"
    "fechaAceptado" => "2021-11-29"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1548926"
          "palabras" => array:4 [
            0 => "Autoimmune hepatitis"
            1 => "Budesonide"
            2 => "Prednisone"
            3 => "Biochemical remission"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1548927"
          "palabras" => array:4 [
            0 => "Hepatitis autoinmune"
            1 => "Budesonida"
            2 => "Prednisona"
            3 => "Remisi&#243;n bioqu&#237;mica"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Budesonide is a glucocorticoid characterized by its local action&#44; with a low systemic bioavailability&#46; Since the original trial comparing budesonide with prednisone in 2010&#44; it is recommended as an effective alternative for the treatment of non-severe acute or chronic autoimmune hepatitis&#46; In this document&#44; we review the general pharmacologic properties of glucocorticoids&#44; the available evidence for the use of budesonide as first line option for autoimmune hepatitis as well as the safety profile of the drug&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La budesonida es un glucocorticoide que se caracteriza por su acci&#243;n local&#44; con una baja biodisponibilidad sist&#233;mica&#46; Desde el ensayo original publicado en 2010&#44; en el que se compar&#243; la budesonida con prednisona&#44; se recomienda como una alternativa eficaz en el tratamiento de los pacientes con hepatitis autoinmune aguda o cr&#243;nica no grave&#46; En este documento&#44; revisamos las propiedades farmacol&#243;gicas generales de los glucocorticoides&#44; la evidencia disponible para el uso de budesonida como f&#225;rmaco de primera l&#237;nea en estos pacientes&#44; as&#237; como el perfil de seguridad del f&#225;rmaco&#46;</p></span>"
      ]
    ]
    "multimedia" => array:4 [
      0 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at1"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">TB&#58; total bilirubin&#59; AST&#58; aspartate aminotransferase&#59; PDN&#58; prednisone&#59; AZA&#58; azathioprine&#59; IgG&#58; immunoglobulin G&#59; ULN&#58; upper limit of normal&#59; CALD&#58; chronic active liver disease&#46;</p><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Adapted from Lammers et al&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">39</span></a></p>"
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Country&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Design&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Criteria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Follow-up&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">End-point&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Results&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Side-effects&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cook et al&#46;&#44; 1971<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">34</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">USA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Unblinded&#44; randomized&#44; controlled trial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Untreated patients diagnosed of active chronic hepatitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>54&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Corticosteroid group &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>22&#41;&#58; PDN 15<span class="elsevierStyleHsp" style=""></span>mg&#47;day reduced whenever biochemical liver function test became normal or in the emergence of severe side-effectsControl group &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>27&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">72 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mortality at 72 monthsTB&#44; AST&#44; albumin at 72 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mortality&#58; PDN 3&#47;22 &#40;13&#46;6&#37;&#41; untreated group 15&#47;27 &#40;55&#46;5&#37;&#41; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41;Albumin was significantly higher in the PDN group compared to the control group at 6&#44; 12&#44; 18 and 24 months&#46;TB was significantly lower in PDN group with respect to the control group at six and 24 months&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PDN&#58; obesity 5&#47;22 &#40;23&#37;&#41;&#44; moon face 5&#47;22 &#40;23&#37;&#41;&#44; acne 4&#47;22 &#40;18&#37;&#41;&#44; Osteoporosis and vertebral collapse 2&#47;22 &#40;9&#37;&#41;&#44; Perforated duodenal ulcer 1&#47;22 &#40;5&#37;&#41;&#44; acute steroid psychosis 1&#47;22 &#40;5&#37;&#41;&#44; terminal bronchopneumonia 1&#47;22 &#40;5&#37;&#41;&#44; myositis 1&#47;22 &#40;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Soloway et al&#46;&#44; 1972<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">35</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">UK&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Randomized&#44; double-blinded&#44; controlled trial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hepatic disease documented by clinical&#44; biochemical&#44; and histological abnormalities lasting at least 10 weeks and documented by biopsy&#44; jaundice&#44; or AST <span class="elsevierStyleUnderline">&#62;</span>10&#215;ULN or <span class="elsevierStyleUnderline">&#62;</span>5&#215;ULN plus IgG <span class="elsevierStyleUnderline">&#62;</span>2&#215;ULN&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>63&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#40;a&#41; PDN &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>18&#41; 60<span class="elsevierStyleHsp" style=""></span>mg daily for one week&#44; 40<span class="elsevierStyleHsp" style=""></span>mg daily the following week&#44; 30<span class="elsevierStyleHsp" style=""></span>mg daily for two weeks and 20<span class="elsevierStyleHsp" style=""></span>mg daily as maintenance therapy&#46;&#40;b&#41; AZA &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>14&#41; 100<span class="elsevierStyleHsp" style=""></span>mg daily&#46;&#40;c&#41; PDN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>AZA &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>14&#41;&#58; 30<span class="elsevierStyleHsp" style=""></span>mg daily for 1 week&#44; 20<span class="elsevierStyleHsp" style=""></span>mg daily the following week&#44; 15<span class="elsevierStyleHsp" style=""></span>mg daily for 2 weeks&#44; and 10<span class="elsevierStyleHsp" style=""></span>mg daily as maintenance&#40;d&#41; Placebo &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>17&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#8211;38 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#40;1&#41; Remission defined as&#58;<span class="elsevierStyleHsp" style=""></span>&#40;a&#41; clinical normality&#44; return to all customary activitiesPLUS<span class="elsevierStyleHsp" style=""></span>&#40;b&#41; Disappearance of histological signs of disease activity normality or of minor changes indistinguishable from those in nonspecific or chronic persistent hepatitis&#40;2&#41; Mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PDN group&#58; remission 8&#47;18 &#40;44&#37;&#41;&#44; mortality 1&#47;18 &#40;6&#37;&#41;&#44;PDN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>AZA group&#58; remission 3&#47;14 &#40;21&#37;&#41;&#44; mortality 1&#47;14 &#40;7&#37;&#41;&#46;AZA group&#58; remission 1&#47;14 &#40;7&#37;&#41;&#44; mortality 5&#47;14 &#40;36&#37;&#41;Placebo group&#58; mortality&#58; remission 0&#47;17 &#40;0&#37;&#41;&#44; mortality 7&#47;17 &#40;41&#37;&#41;Response rate in patients receiving PDN or combined treatment were superior to those receiving AZA or placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PDN&#58; cushingoid appearance 13&#47;18 &#40;72&#37;&#41;&#44; serious side effects &#40;vertebral collapse&#44; aseptic necrosis of the femoral head&#44; or cataracts&#41; 3&#47;18 &#40;17&#37;&#41;&#44; diabetes requiring insulin 1&#47;18 &#40;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Murray-Lyon et al&#46;&#44; 1973<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">36</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">USA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Randomized&#44; double-blind&#44; controlled trial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Active chronic hepatitis defined by hepatic disease lasting at least for 3 months with AST<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleUnderline">&#62;</span><span class="elsevierStyleHsp" style=""></span>100<span class="elsevierStyleHsp" style=""></span>IU&#47;L and&#47;or IgG<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>1&#46;5<span class="elsevierStyleHsp" style=""></span>g&#47;100<span class="elsevierStyleHsp" style=""></span>mL&#46;Patients previously treated with AZA or corticosteroids were not excluded&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>47Cirrhosis &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>32&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PDN group &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>22&#41;&#58; 5<span class="elsevierStyleHsp" style=""></span>mg every 8<span class="elsevierStyleHsp" style=""></span>hAZA group &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>25&#41;&#58; 75<span class="elsevierStyleHsp" style=""></span>mg dailyIn the absence of response or AST persistently <span class="elsevierStyleUnderline">&#62;</span>200<span class="elsevierStyleHsp" style=""></span>IU&#47;L&#44; PDN or AZA doses were increased to 20<span class="elsevierStyleHsp" style=""></span>mg or 112&#46;5<span class="elsevierStyleHsp" style=""></span>mg respectively&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Survival at 24 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PDN group&#58; 95&#37; probability of survival at 24 monthsAZA group&#58; 72&#37; probability of survival at 24 monthsSignificant &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;005&#41; decrease in bilirubin and globulin in both groupsHigher AST &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; and IgG &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;02&#41; decrease in the first 6 months in patients treated with PDN&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PRD&#58; facial mooning 11&#47;22 &#40;50&#37;&#41;&#44; diabetes mellitus 3&#47;22 &#40;14&#37;&#41;&#59; hypertension 2&#47;22 &#40;9&#37;&#41;&#44; brush fracture of thoracic vertebrae 1&#47;22 &#40;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Summerskill et al&#46;&#44; 1975<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">37</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">USA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Multicenter&#44; randomized&#44; double-blind&#44; controlled trial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hepatic disease documented by clinical&#44; biochemical&#44; and histological abnormalities lasting at least 10 weeks and documented by biopsy&#44; jaundice&#44; or AST &#62;10&#215;ULN or &#62;5&#215;ULN plus IgG &#62;2&#215;ULN&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>120&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#40;a&#41; Placebo &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>16&#41;&#40;b&#41; AZA 100<span class="elsevierStyleHsp" style=""></span>mg &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>13&#41;&#40;c&#41; PDN &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>30&#41;&#40;d&#41; PDN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>AZA &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>30&#41;&#40;e&#41; PDN at titrated doses attending to biochemical evolution &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>31&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">36 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#40;1&#41; Remission defined as&#58;<span class="elsevierStyleHsp" style=""></span>&#40;a&#41; Absence of symptoms and return of the patient to customary activitiesPLUS<span class="elsevierStyleHsp" style=""></span>&#40;b&#41; AST <span class="elsevierStyleUnderline">&#60;</span>2&#215;ULNPLUS<span class="elsevierStyleHsp" style=""></span>&#40;c&#41; Normalization of immunoserological tests&#40;2&#41; Mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PDN&#58; 24&#47;30 &#40;80&#37;&#41; achieved remission&#46; Mortality 3&#47;30 &#40;10&#37;&#41;PDN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>AZA&#58; 24&#47;30 &#40;80&#37;&#41; achieved remission&#46; Mortality 2&#47;31 &#40;7&#37;&#41;Titrated PDN&#58; 23&#47;31 &#40;74&#37;&#41; achieved remission&#46; Mortality 2&#47;31 &#40;7&#37;&#41;Placebo or AZA&#58; 10&#47;29 &#40;34&#37;&#41; achieved remission&#46; Mortality 12&#47;29 &#40;41&#37;&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PDN&#58; severe cosmetic changes 4&#47;30 &#40;13&#37;&#41;&#44; diabetes 4&#47;30&#47;13&#37;&#41;&#44; cataracts 2&#47;30 &#40;7&#37;&#41; vertebral collapse 1&#47;30 &#40;3&#37;&#41;PDN&#47;AZA&#58; diabetes 3&#47;30 &#40;10&#37;&#41;Titrated PDN&#58; diabetes 3&#47;31 &#40;10&#37;&#41;Pacebo or AZA&#58; gastrointestinal bleeding 5&#47;29 &#40;17&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tage-Jansen et al&#46;&#44; 1982<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">38</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Denmark&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Multicenter&#44; randomized&#44; unblinded clinical trial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Patient with biopsy-proven chronic aggressive hepatitis&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>99&#42; only information for 84 patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#40;a&#41; PDN 10 mg&#47;day if weight &#60;70<span class="elsevierStyleHsp" style=""></span>kg or 15<span class="elsevierStyleHsp" style=""></span>mg&#47;kg if weight <span class="elsevierStyleUnderline">&#62;</span>70<span class="elsevierStyleHsp" style=""></span>kg&#46;&#40;b&#41; AZA 10<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">38 &#40;12&#8211;83 months&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#40;1&#41; Remission defined as<span class="elsevierStyleHsp" style=""></span>&#40;a&#41; AST<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>40<span class="elsevierStyleHsp" style=""></span>UI&#47;L<span class="elsevierStyleHsp" style=""></span>&#40;b&#41; IgG<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>15&#46;1<span class="elsevierStyleHsp" style=""></span>g&#47;L&#40;2&#41; Mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PRD&#58; Remission&#58; 21&#47;47 &#40;45&#37;&#41;&#59; mortality&#58; 13&#47;27 &#40;28&#37;&#41;AZA&#58; Remission&#58; 6&#47;37 &#40;37&#37;&#41;&#44; mortality&#58; 10&#47;37 &#40;27&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Not reported&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Clinical trials evaluating prednisone for treating autoimmune hepatitis&#46;</p>"
        ]
      ]
      1 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at2"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">AST&#58; aspartate aminotransferase&#59; ALT&#58; alanine aminotransferase&#59; ULN&#58; upper limit of normal&#59; AIH&#58; autoimmune hepatitis&#59; BUD&#58; budesonide&#59; AZA&#58; azathioprine&#59; PDN&#58; prednisone&#59; pat&#58; patients&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Country&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Design&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Inclusion criteria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Followup&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Primary endpoint&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Results&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Adverse EVENTS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Wiegand et al&#46;&#44; 2005<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">17</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Germany&#44; Netherlands&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Multicenter Open label&#44; prospective clinical trial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Untreated AIH patientsAST and ALT at least &#62;3&#215; ULN&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>14&#59; finally included <span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Day 1&#58; 3<span class="elsevierStyleHsp" style=""></span>g twice daily from day 2&#58; 3<span class="elsevierStyleHsp" style=""></span>mg thrice daily&#46;Upon biochemical remission&#44; the dosage was individually reduced to 3<span class="elsevierStyleHsp" style=""></span>mg budesonideNo other immunosuppressive drugs allowed&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Remission defined as drop of AST and ALT <span class="elsevierStyleUnderline">&#60;</span>2&#215;ULN&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Complete remission&#58; 7&#47;12Partial response 3&#47;12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Leukocytosis 5&#47;14 &#40;36&#37;&#41;Hypercholesterinaemia 4&#47;14 &#40;29&#37;&#41;Cushing-like symptoms 3&#47;14 &#40;21&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Csepregi et al&#46;&#44; 2006<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">40</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Germany&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Multicenter Open label study&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Na&#239;ve or previously treated patients diagnosed of AIH or overlap&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>18First-line BUD in AIH&#58; <span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">BUD 3<span class="elsevierStyleHsp" style=""></span>mg thrice daily&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Not defined&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Biochemical remission in AIH 4&#47;7No response in AIH&#58; 3&#47;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Total incidence&#58; 6&#47;18 &#40;33&#37;&#41;Weight gain &#62;3<span class="elsevierStyleHsp" style=""></span>kg 3&#47;18 &#40;17&#37;&#41;&#44;Acne 2&#47;18 &#40;11&#37;&#41;Abdominal pain 1&#47;18 &#40;6&#37;&#41;Alopecia 1&#47;18 &#40;6&#37;&#41;Every AE emerged in patients with cirrhosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Manns et al&#46;&#44; 2010<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">13</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Germany&#44; Poland&#44; Ukraine&#44; Hungary&#44; Israel&#44; Sweden&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prospective&#44; 6-month double-blind&#44; double-dummy&#44; controlled trial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Untreated AIH patientsAST and ALT at least &#62;2&#215; ULN&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>207 patientsBUD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>102 patPDN<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>105 pat&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">BUD&#58; 9<span class="elsevierStyleHsp" style=""></span>mg&#47;daily&#46;PDN group&#58; 40<span class="elsevierStyleHsp" style=""></span>mg&#47;daily&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Segment A 24 weeksSegment B 24 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Biochemical remission without corticosteroid-related adverse events&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Primary endpoint&#58;BUD&#58; 47&#47;100 &#40;47&#46;0&#37;&#41;PDN&#58; 19&#47;103 &#40;18&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">BUD&#58; 26&#47;100 &#40;26&#37;&#41;Headache 11&#46;8&#37;Mood alterations 9&#46;8&#37;&#46;Weight gain 5&#46;9&#37;Muscular weakness 4&#46;9&#37;&#46;Hypertension 2&#46;9&#37;Insomnia 1&#37;&#46;PDN&#58; 53&#47;103 &#40;51&#46;5&#37;&#41;Weight gain 19&#37;&#46;Headache 7&#46;6&#37;&#46;Mood alterations 7&#46;6&#37;&#46;Muscular weakness 7&#46;6&#37;&#46;Hypertension 6&#46;7&#37;&#46;Insomnia 4&#46;8&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Efe et al&#46;&#44; 2012<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">24</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Turkey&#44; France&#44; Italy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Multicenter&#44; retrospective study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Untreated definite or probable AIH defined by simplified AIH criteria &#40;IAIHG&#41;AIH&#47;PBC overlap syndrome according to Chazouilleres criteria&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">5</span></a>ALT or AST levels &#62;3&#215;ULN&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">BUD 9 mg&#47;day<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>AZA 50<span class="elsevierStyleHsp" style=""></span>mg all patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#40;a&#41; Biochemical remission defined by AST and&#47;or ALT <span class="elsevierStyleUnderline">&#60;</span>2&#215;ULN&#40;b&#41; AST&#47;ALT drop &#62;50&#37; after 1 month on treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Biochemical remission&#58; 11&#47;18 &#40;61&#46;1&#37;&#41;No response&#58; 7&#47;18 &#40;38&#46;9&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Incidence 11&#47;18 &#40;61&#37;&#41;Weight gain&#58; 6&#47;18 &#40;30&#37;&#41;&#59; acne 4&#47;18 &#40;20&#37;&#41;&#59; hirsutism&#58; 4&#47;18 &#40;20&#37;&#41;&#59; moon face&#58; 2&#47;18 &#40;10&#37;&#41;&#59; skin striae&#58; 2&#47;18 &#40;10&#37;&#41;&#59; buffalo hump&#58; 2&#47;18 &#40;10&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Woynarowski et al&#46;&#44; 2013<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">18</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Poland&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Multicenter prospective&#44; double-blind&#44; randomized&#44; controlled trial in pediatric AIH patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pediatric AIH patients &#40;9&#8211;17 years&#41;AST and ALT at least &#62;2&#215; ULN&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>46BUD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>19 patPDN<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>27 pat&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3<span class="elsevierStyleHsp" style=""></span>mg 3 times daily or 3<span class="elsevierStyleHsp" style=""></span>mg twice daily after biochemical&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Segmentt A 24 weeksSegment B 24 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Biochemical remission without corticosteroid-related adverse events&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Primary endpoint&#58;BUD&#58; 3&#47;19 &#40;16&#37;&#41;PDN&#58; 4&#47;27 &#40;15&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PDN incidence 17&#47;27 &#40;63&#37;&#41;&#59; moon face&#58; 12&#47;27 &#40;44&#37;&#41;&#59; acne&#58; 7&#47;27 &#40;26&#37;&#41;&#59; skin striae&#58; 3&#47;27 &#40;11&#37;&#41;BUD incidence 9&#47;19 &#40;47&#37;&#41;&#44; acne 4&#47;19 &#40;21&#37;&#41;&#44; moon face 2&#47;19 &#40;11&#37;&#41;&#44; skin striae 1&#47;19 &#40;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Binicier et al&#46;&#44; 2019<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">20</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Turkey&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Retrospective unicenter study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Untreated AIH patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>50PDN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>AZA<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>25 patPDN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>BUD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>25 pat&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PRED&#47;AZA&#58; 30<span class="elsevierStyleHsp" style=""></span>mg&#47;day PRED and AZA&#46;BUD&#47;AZA&#58; 9 mg&#47;day BUD and AZA&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Biochemical remission defined by AST and ALT normalization&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Biochemical remission defined as transaminases normalization&#58;<span class="elsevierStyleHsp" style=""></span>-<span class="elsevierStyleHsp" style=""></span>PDN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>AZA&#58; 17&#47;25 &#40;68&#37;&#41;<span class="elsevierStyleHsp" style=""></span>-<span class="elsevierStyleHsp" style=""></span>BUD<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>AZA&#58; 18&#47;25 &#40;72&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PDN&#47;AZA incidence&#58; 9&#47;25 &#40;60&#37;&#41;&#44; acne 4&#47;25 &#40;16&#37;&#41;&#44; moon face 4&#47;24 &#40;16&#37;&#41;&#44; hirsutism 3&#47;25 &#40;12&#37;&#41;&#44; striae 2&#47;25 &#40;8&#37;&#41;&#44; myopathy 1&#47;25 &#40;4&#37;&#41;&#44; buffalo hump 1&#47;25 &#40;4&#37;&#41;&#46;BUD&#47;AZA Incidence 5&#47;25 &#40;20&#37;&#41; Acne 2&#47;25 &#40;8&#37;&#41;&#44; hirsutism 1&#47;25 &#40;4&#37;&#41;&#44; myopathy 1&#47;25 &#40;4&#37;&#41;&#44; moon face 1&#47;25 &#40;4&#37;&#41;&#44; buffalo hump 1&#47;25 &#40;4&#37;&#41;&#44; striae 2&#47;25 &#40;4&#37;&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Clinical trials &#38; retrospective studies evaluating budesonide for the treatment of autoimmune hepatitis&#46;</p>"
        ]
      ]
      2 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at3"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Guideline&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Drug&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Induction dose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Tappering&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Azathioprine &#40;yes&#47;no&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Duration of treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AASLD 2020<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">3</span></a></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prednisone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20&#8211;40<span class="elsevierStyleHsp" style=""></span>mg daily&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tapper to 5&#8211;10<span class="elsevierStyleHsp" style=""></span>mg daily&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">At least 2 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Budesonide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3<span class="elsevierStyleHsp" style=""></span>mg thrice daily&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tapper to 3<span class="elsevierStyleHsp" style=""></span>mg daily&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ESPGHAN 2019<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">41</span></a></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prednisone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2 mg&#47;kg daily &#40;maximum 60 mg&#47;day&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tapper to 2&#46;5&#8211;5<span class="elsevierStyleHsp" style=""></span>mg daily&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">At least 2&#8211;3 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Budesonide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Undefined&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Undefined&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Undefined&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Undefined&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hellenic 2018<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">42</span></a></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prednisone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prednisolone 0&#46;5&#8211;1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg daily&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Individualized according to response and side-effectsComplete PDN withdrawal after 6&#8211;8 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">At least 3 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Budesonide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9<span class="elsevierStyleHsp" style=""></span>mg daily&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Not defined&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EASL 2015<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">1</span></a></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prednisone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;5&#8211;1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg daily&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#40;a&#41; From 60 to 20<span class="elsevierStyleHsp" style=""></span>mg<span class="elsevierStyleHsp" style=""></span>-<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>mg weekly&#40;b&#41; From 20<span class="elsevierStyleHsp" style=""></span>mg to 10<span class="elsevierStyleHsp" style=""></span>mg<span class="elsevierStyleHsp" style=""></span>-<span class="elsevierStyleHsp" style=""></span>2&#46;5&#8211;5<span class="elsevierStyleHsp" style=""></span>mg biweekly&#40;c&#41; From 10<span class="elsevierStyleHsp" style=""></span>mg<span class="elsevierStyleHsp" style=""></span>-<span class="elsevierStyleHsp" style=""></span>Individualized according to response&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">At least three years and 24 months after biochemical remission&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Budesonide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9<span class="elsevierStyleHsp" style=""></span>mg daily&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Not clearly defined&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">BSG 2011<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">43</span></a></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prednisone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30<span class="elsevierStyleHsp" style=""></span>mg daily&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5<span class="elsevierStyleHsp" style=""></span>mg weekly until 10<span class="elsevierStyleHsp" style=""></span>mg daily&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">At least 2 years and 12 months after biochemical remission&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Budesonide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9<span class="elsevierStyleHsp" style=""></span>mg daily&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Not defined&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Not defined&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">International guidelines recommendations for the treatment of autoimmune hepatitis&#46;</p>"
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      3 => array:8 [
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        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
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          0 => array:3 [
            "identificador" => "at4"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">IQR&#58; interquartile range&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Centres&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">21 Spanish centers</th></tr><tr title="table-row"><th class="td-with-role" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Study period&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">2009&#8211;2020</th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Budesonide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Prednisone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Number of patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">151&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">218&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Baseline characteristics of the patients included in the study by D&#237;az-Gonz&#225;lez et al&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">24</span></a></p>"
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                            0 => "A&#46;W&#46; Lohse"
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                            3 => "J&#46; Drenth"
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Article information

ISSN: 24443824
Original language: English

DOI:10.1016/j.gastre.2021.11.003

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