Publications by authors named "Miguel Jiménez Pérez"

27 Publications

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Comprehensive analysis and insights gained from long-term experience of the Spanish DILI Registry.

J Hepatol 2021 Jul 1;75(1):86-97. Epub 2021 Feb 1.

UGC Aparato Digestivo and Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.

Background & Aims: Prospective drug-induced liver injury (DILI) registries are important sources of information on idiosyncratic DILI. We aimed to present a comprehensive analysis of 843 patients with DILI enrolled into the Spanish DILI Registry over a 20-year time period.

Methods: Cases were identified, diagnosed and followed prospectively. Clinical features, drug information and outcome data were collected.

Results: A total of 843 patients, with a mean age of 54 years (48% females), were enrolled up to 2018. Hepatocellular injury was associated with younger age (adjusted odds ratio [aOR] per year 0.983; 95% CI 0.974-0.991) and lower platelet count (aOR per unit 0.996; 95% CI 0.994-0.998). Anti-infectives were the most common causative drug class (40%). Liver-related mortality was more frequent in patients with hepatocellular damage aged ≥65 years (p = 0.0083) and in patients with underlying liver disease (p = 0.0221). Independent predictors of liver-related death/transplantation included nR-based hepatocellular injury, female sex, higher onset aspartate aminotransferase (AST) and bilirubin values. nR-based hepatocellular injury was not associated with 6-month overall mortality, for which comorbidity burden played a more important role. The prognostic capacity of Hy's law varied between causative agents. Empirical therapy (corticosteroids, ursodeoxycholic acid and MARS) was prescribed to 20% of patients. Drug-induced autoimmune hepatitis patients (26 cases) were mainly females (62%) with hepatocellular damage (92%), who more frequently received immunosuppressive therapy (58%).

Conclusions: AST elevation at onset is a strong predictor of poor outcome and should be routinely assessed in DILI evaluation. Mortality is higher in older patients with hepatocellular damage and patients with underlying hepatic conditions. The Spanish DILI Registry is a valuable tool in the identification of causative drugs, clinical signatures and prognostic risk factors in DILI and can aid physicians in DILI characterisation and management.

Lay Summary: Clinical information on drug-induced liver injury (DILI) collected from enrolled patients in the Spanish DILI Registry can guide physicians in the decision-making process. We have found that older patients with hepatocellular type liver injury and patients with additional liver conditions are at a higher risk of mortality. The type of liver injury, patient sex and analytical values of aspartate aminotransferase and total bilirubin can also help predict clinical outcomes.
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http://dx.doi.org/10.1016/j.jhep.2021.01.029DOI Listing
July 2021

Clinical Characteristics and Outcome of Drug-Induced Liver Injury in the Older Patients: From the Young-Old to the Oldest-Old.

Clin Pharmacol Ther 2021 Apr 6;109(4):1147-1158. Epub 2020 Dec 6.

Biomedical Research Network Center for Hepatic and Digestive Diseases (CIBERehd), Carlos III Health Institute, Madrid, Spain.

Older patients with hepatotoxicity have been scarcely studied in idiosyncratic drug-induced liver injury (DILI) cohorts. We sought the distinctive characteristics of DILI in older patients across age groups. A total of 882 DILI patients included in the Spanish DILI Registry (33% ≥ 65 years) were categorized according to age: "young" (< 65 years); "young-old" (65-74 years); "middle-old" (75-84 years); and "oldest-old" (≥ 85 years). All elderly groups had an increasingly higher comorbidity burden (P < 0.001) and polypharmacy (P < 0.001). There was a relationship between jaundice and hospitalization (P < 0.001), and both were more prevalent in the older age groups, especially in the oldest-old (88% and 69%, respectively), and the DILI episode was more severe (P = 0.029). The proportion of females decreased across age groups from the young to the middle-old, yet in the oldest-old there was a distinct female predominance. Pattern of liver injury shifted towards cholestatic with increasing age among top culprit drugs amoxicillin-clavulanate, atorvastatin, levofloxacin, ibuprofen, and ticlopidine. The best cutoff point for increased odds of cholestatic DILI was 65 years. Older patients had increased non-liver-related mortality (P = 0.030) as shown by the predictive capacity of the Model for End-Stage Liver Disease score (odds ratio (OR) = 1.116; P < 0.001), and comorbidity burden (OR = 4.188; P = 0.001) in the 6-month mortality. Older patients with DILI exhibited an increasingly predominant cholestatic phenotype across a range of culprit drugs, other than amoxicillin-clavulanate, with increased non-liver-related mortality and require a different approach to predict outcome. The oldest DILI patients exhibited a particular phenotype with more severe DILI episodes and need to be considered when stratifying older DILI populations.
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http://dx.doi.org/10.1002/cpt.2108DOI Listing
April 2021

Incidence and prevalence of acute hepatitis E virus infection in patients with suspected Drug-Induced Liver Injury in the Spanish DILI Registry.

Liver Int 2021 07 16;41(7):1523-1531. Epub 2020 Nov 16.

Unidad de Gestión Clínica de Aparato Digestivo, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain.

Background And Aims: Drug-induced liver injury (DILI) presents with a wide phenotypic spectrum requiring an extensive differential diagnosis. Hepatitis E virus (HEV) is not systematically ruled out during acute hepatitis assessment in Spain. The aims of this study were to establish the role of HEV infection and its phenotypic presentation in patients initially suspected of DILI and to determine the anti-HEV seroprevalence rate.

Methods: An analysis of 265 patients with suspected DILI and considered for enrolment in the Spanish DILI Registry and 108 controls with normal liver profiles was undertaken. Anti-HEV Immunoglobulin (Ig) G antibodies were analysed in serum from all subjects. In those with serum samples extracted within 6 months from liver damage onset (n = 144), HEV antigen (Ag) and anti-HEV IgM antibodies were tested in duplicate by ELISA. In addition, RT-PCR was performed externally in eight patients.

Results: Out of 144 patients, 12 (8%) were positive for anti-HEV IgM, mean age was 61 years. Underlying hepatic diseases (OR = 23.4, P < .001) and AST peak >20 fold upper limit of normal (OR = 10.9, P = .002) were associated with the diagnosis of acute hepatitis E. The overall anti-HEV IgG seroprevalence rate was 35%, evenly distributed between patients with suspected DILI (34%), and controls (39%).

Conclusions: HEV seroprevalence and acute hepatitis E rates are relatively high in Spain. A search for active HEV infection is therefore advised in patients assessed for suspicion of DILI, particularly in patients with underlying liver diseases and high transaminase levels.
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http://dx.doi.org/10.1111/liv.14713DOI Listing
July 2021

Application of artificial intelligence in the diagnosis and treatment of hepatocellular carcinoma: A review.

World J Gastroenterol 2020 Oct;26(37):5617-5628

UGC de Aparato Digestivo, Unidad de Hepatología-Trasplante Hepático, Hospital Regional Universitario de Málaga, Málaga 29010, Spain.

Although artificial intelligence (AI) was initially developed many years ago, it has experienced spectacular advances over the last 10 years for application in the field of medicine, and is now used for diagnostic, therapeutic and prognostic purposes in almost all fields. Its application in the area of hepatology is especially relevant for the study of hepatocellular carcinoma (HCC), as this is a very common tumor, with particular radiological characteristics that allow its diagnosis without the need for a histological study. However, the interpretation and analysis of the resulting images is not always easy, in addition to which the images vary during the course of the disease, and prognosis and treatment response can be conditioned by multiple factors. The vast amount of data available lend themselves to study and analysis by AI in its various branches, such as deep-learning (DL) and machine learning (ML), which play a fundamental role in decision-making as well as overcoming the constraints involved in human evaluation. ML is a form of AI based on automated learning from a set of previously provided data and training in algorithms to organize and recognize patterns. DL is a more extensive form of learning that attempts to simulate the working of the human brain, using a lot more data and more complex algorithms. This review specifies the type of AI used by the various authors. However, well-designed prospective studies are needed in order to avoid as far as possible any bias that may later affect the interpretability of the images and thereby limit the acceptance and application of these models in clinical practice. In addition, professionals now need to understand the true usefulness of these techniques, as well as their associated strengths and limitations.
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http://dx.doi.org/10.3748/wjg.v26.i37.5617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545389PMC
October 2020

Drug-Induced Liver Injury After Liver Transplantation.

Liver Transpl 2020 09;26(9):1167-1176

Unidad de Gestión Clínica de Aparato Digestivo, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Instituto de Investigación Biomédica de Málaga, Malaga, Spain.

Drug-induced liver injury (DILI) is an adverse reaction to many drugs in common use that in a liver transplantation (LT) recipient may cause graft dysfunction and may even lead to graft loss and the need for retransplantation. However, several potential clinical scenarios, such as graft rejection and infection, can confound the diagnosis of suspected DILI in the setting of LT. This makes causal assessment of a new liver injury more uncertain and has traditionally precluded collection of bona fide cases of DILI affecting LT patients in prospective DILI registries and cohorts. Although no studies have yet determined a greater susceptibility of the transplant patient to DILI, these patients nevertheless present certain risk factors that can theoretically increase the risk of DILI. These include the fact that these patients are polymedicated, use drugs that are potentially hepatotoxic, and can have coexisting hepatitis B or C viruses in addition to other factors found in nontransplant patients, such as genetic variants. Therefore, awareness is crucial of any potential hepatotoxic effect of drugs used in the LT recipient and their possible implication in any case of liver dysfunction. In the present article, we review the most common drugs used in LT recipients from a liver safety perspective and address the main pitfalls in attributing causality in this clinical setting. We also affirm the need for further research and collaboration in this somewhat neglected topic in the field of DILI.
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http://dx.doi.org/10.1002/lt.25804DOI Listing
September 2020

Effectiveness, safety/tolerability of OBV/PTV/r ± DSV in patients with HCV genotype 1 or 4 with/without HIV-1 co-infection, chronic kidney disease (CKD) stage IIIb-V and dialysis in Spanish clinical practice - Vie-KinD study.

PLoS One 2019 24;14(9):e0221567. Epub 2019 Sep 24.

Infectious Diseases Unit, Hospital Universitario Reina Sofía de Córdoba, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, Córdoba, Spain.

Background And Aims: Limited data are available on the effectiveness and tolerability of direct-acting antivirals (DAAs) therapies in the real world for HCV-infected patients with comorbidities. This study aimed to describe the effectiveness of OBV/PTV/r ± DSV (3D/2D regimen) with or without ribavirin (RBV) in HCV or HCV/HIV co-infected patients with GT1/GT4 and CKD (IIIb-V stages), including those under hemodialysis and peritoneal dialysis in routine clinical practice in Spain in 2015.

Material And Methods: Non-interventional, retrospective, multicenter data collection study in 31 Spanish sites. Socio-demographic, clinical variables, study treatment characteristics, effectiveness and tolerability data were collected from medical records.

Results: Data from 135 patients with a mean age (SD) of 58.3 (11.4) years were analyzed: 92.6% GT1 (81.6% GT1b and 17.6% GT1a) and 7.4% GT4, 14 (10.4%) HIV/HCV co-infected, 19.0% with fibrosis F3 and 28.1% F4 by FibroScan®, 52.6% were previously treated with pegIFN and RBV. 11.1%, 14.8% and 74.1% of patients had CKD stage IIIb, IV and V respectively. 68.9% of patients were on hemodialysis; 8.9% on peritoneal dialysis and 38.5% had history of renal transplant. A total of 125 (96.2%) of 135 patients were treated with 3D, 10 (7.4%) with 2D and 30.4% received RBV. The overall intention-to-treat (ITT) sustained virologic response at week 12 (SVR12) was 92.6% (125/135) and the overall modified-ITT (mITT) SVR12 was 99.2% (125/126). The SVR12 rates (ITT) per sub-groups were: HCV mono-infected (91.7%), HCV/HIV co-infected (100%), GT1 (92.0%), GT4 (100%), CKD stage IIIb (86.7%), stage IV (95%) and stage V (93%). Among the 10 non-SVR there was only 1 virologic failure (0.7%); 4 patients had missing data due lost to follow up (3.0%) and 5 patients discontinued 3D/2D regimen (3.7%): 4 due to severe adverse events (including 3 deaths) and 1 patient´s decision.

Conclusions: These results have shown that 3D/2D regimens are effective and tolerable in patients with advanced CKD including those in dialysis with GT 1 or 4 chronic HCV mono-infection and HIV/HCV coinfection in a real-life cohort. The overall SVR12 rates were 92.6% (ITT) and 99.2% (mITT) without clinically relevant changes in eGFR until 12 weeks post-treatment. These results are consistent with those reported in clinical trials.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0221567PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759177PMC
March 2020

Sunlight exposure in inflammatory bowel disease outpatients: Predictive factors and correlation with serum vitaminD.

Gastroenterol Hepatol 2019 Dec 28;42(10):604-613. Epub 2019 Aug 28.

Unidad de Gestión Clínica de Aparato Digestivo, Hospital Regional de Málaga, Málaga, España; Facultad de Medicina, Universidad de Málaga, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, España.

Introduction: Sunlight exposure is the main source of vitaminD. Our aim was to describe both sun exposure and sun protection behaviour in a series of patients with inflammatory bowel disease (IBD), and to study their potential association with vitaminD concentration.

Patients And Methods: A cross sectional, observational study. The clinical-demographic variables were obtained via clinical interviews and medical history review. The sunlight exposure assessment was carried out using the Sun Exposure Questionnaire and the concentration of 25-hydroxy vitaminD (25OHD) was measured by an electro-chemiluminescence immunoassay. Questionnaires were conducted on quality of life, physical activity, weekly vitaminD intake and sun protection behaviour.

Results: 149 patients were included. In 69% of patients, deficient or insufficient 25OHD values were recorded. 67% showed low sun exposure. A modest significant correlation was observed between the total score of the solar exposure questionnaire and the 25OHD concentration in the complete series (r=0.226, P=.006) and in the summer (r=0.274, P=.01). The sun protection behaviour questionnaire score did not influence the 25OHD concentration. In the multivariate analysis, only the presence of clinical activity was associated with low sun exposure (OR=3.23).

Discussion: Sun exposure according to the questionnaire used was low, was associated with the presence of clinical activity and was weakly correlated with serum 25OHD concentration. More studies are needed to explore the use of individual questionnaires for sun exposure and its relationship with vitaminD in patients with IBD.
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http://dx.doi.org/10.1016/j.gastrohep.2019.07.002DOI Listing
December 2019

Vitamin D in Inflammatory Bowel Disease: Biological, Clinical and Therapeutic Aspects.

Curr Drug Metab 2019 ;20(5):390-398

Clinical Management Unit of Digestive Diseases, Regional University Hospital of Malaga, Malaga, Spain; Faculty of Medicine, University of Malaga, Malaga, Spain.

Background: Vitamin D has an immunoregulatory action in Inflammatory Bowel Disease (IBD) as well as other immune-mediated disorders. Its influence on intestinal permeability, innate and adaptive immunity, and the composition and diversity of the microbiota contribute to the maintenance of intestinal homeostasis. Patients with IBD have a greater prevalence of vitamin D deficiency than the general population, and a possible association between this deficit and a worse course of the disease. However, intervention studies in patients with IBD have proved inconclusive.

Objective: To review all the evidence concerning the role of vitamin D as an important factor in the pathophysiology of IBD, review the associations found between its deficiency and the prognosis of the disease, and draw conclusions for the practical application from the main intervention studies undertaken.

Methods: Structured search and review of basic, epidemiological, clinical and intervention studies evaluating the influence of vitamin D in IBD, following the basic principles of scientific data.

Results: Vitamin D deficiency is associated with disease activity, quality of life, the consumption of social and healthcare resources, and the durability of anti-TNFα biological treatment. Determination of new metabolites of vitamin D, measurement of its absorption capacity and questionnaires about sun exposure could help identify groups of IBD patients with a special risk of vitamin D deficiency.

Conclusion: Well-designed intervention studies are needed in IBD, with probably higher objective plasma doses of vitamin D to establish its efficacy as a therapeutic agent with immunomodulatory properties. Meanwhile, vitamin D deficiency should be screened for and corrected in affected patients in order to achieve adequate bone and phosphocalcic metabolism.
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http://dx.doi.org/10.2174/1389200220666190520112003DOI Listing
December 2019

Vitamin D deficiency in outpatients with inflammatory bowel disease: prevalence and association with clinical-biological activity.

Rev Esp Enferm Dig 2019 Jan;111(1):46-54

UGC Aparato Digestivo, Hospital Regional Universitario de Málaga, España.

Introduction: there are few data on the prevalence of vitamin D deficiency in patients with inflammatory bowel disease (IBD) in Spain. A deficiency could be associated with a worse course of the disease.

Aim: to determine the prevalence of 25-hydroxyvitamin D (25OHD) deficiency in a cohort of outpatients with IBD and assess its association with clinical and biological activity, quality of life and psychological symptoms.

Methods: a cross-sectional, single-center observational study was performed. The study variables were obtained via clinical interviews, medical chart review and validated questionnaires (Hospital Anxiety and Depression Scale and Short Quality of Life in Inflammatory Bowel Disease Questionnaire). 25OHD was measured in the same laboratory by an electro-chemiluminescence immunoassay.

Results: the study included 224 patients. The prevalence of vitamin D deficiency in Crohn's disease and ulcerative colitis was 33.3% and 20.3%, respectively. In Crohn's disease, vitamin D deficiency was associated with a higher clinical activity (p < 0.001) and a higher concentration of fecal calprotectin (p = 0.01). In ulcerative colitis, it was associated with clinical activity (p < 0.001), the use of steroids during the last six months (p = 0.001) and hospital admission during the previous year (p = 0.003). A sub-analysis of 149 patients failed to detect an association between vitamin D and quality of life or the scores of the Hospital Anxiety and Depression Scale.

Conclusions: vitamin D deficiency is common in patients with inflammatory bowel disease. An association was found between vitamin D concentration and clinical activity indexes, as well as fecal calprotectin levels in Crohn's disease.
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http://dx.doi.org/10.17235/reed.2018.5714/2018DOI Listing
January 2019

Herbal and Dietary Supplement-Induced Liver Injuries in the Spanish DILI Registry.

Clin Gastroenterol Hepatol 2018 09 4;16(9):1495-1502. Epub 2018 Jan 4.

Unidad de Gestión Clínica de Aparato Digestivo, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, CIBERehd, Málaga, Spain.

Background & Aims: There have been increasing reports of liver injury associated with use of herbal and dietary supplements, likely due to easy access to these products and beliefs among consumers that they are safer or more effective than conventional medications. We aimed to evaluate clinical features and outcomes of patients with herbal and dietary supplement-induced liver injuries included in the Spanish DILI Registry.

Methods: We collected and analyzed data on demographic and clinical features, along with biochemical parameters, of 32 patients with herbal and dietary supplement-associated liver injury reported to the Spanish DILI registry from 1994 through 2016. We used analysis of variance to compare these data with those from cases of liver injury induced by conventional drugs or anabolic androgenic steroid-containing products.

Results: Herbal and dietary supplements were responsible for 4% (32 cases) of the 856 DILI cases in the registry; 20 cases of DILI (2%) were caused by anabolic androgenic steroids. Patients with herbal and dietary supplement-induced liver injury were a mean age of 48 years and 63% were female; they presented a mean level of alanine aminotransferase 37-fold the upper limit of normal, 28% had hypersensitivity features, and 78% had jaundice. Herbal and dietary supplement-induced liver injury progressed to acute liver failure in 6% of patients, compared with none of the cases of anabolic androgenic steroid-induced injury and 4% of cases of conventional drugs. Liver injury after repeat exposure to the same product that caused the first DILI episode occurred in 9% of patients with herbal and dietary supplement-induced liver injury vs none of the patients with anabolic androgenic steroid-induced injury and 6% of patients with liver injury from conventional drugs.

Conclusion: In an analysis of cases of herbal and dietary supplement-induced liver injury in Spain, we found cases to be more frequent among young women than older patients or men, and to associate with hepatocellular injury and high levels of transaminases. Herbal and dietary supplement-induced liver injury is more severe than other types of DILI and re-exposure is more likely. Increasing awareness of the hepatoxic effects of herbal and dietary supplements could help physicians make earlier diagnoses and reduce the risk of serious liver damage.
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http://dx.doi.org/10.1016/j.cgh.2017.12.051DOI Listing
September 2018

Efficacy and safety of vedolizumab as a treatment option for moderate to severe refractory ulcerative colitis in two patients after liver transplant due to primary sclerosing cholangitis.

Rev Esp Enferm Dig 2017 Sep;109(9):659-662

UGC Aparato Digestivo, Hospital Regional Universitario de Málaga, España.

Vedolizumab is a humanized IgG1 monoclonal antibody that selectively blocks the lymphocyte integrin α4β7 and prevents its interaction with endothelial adhesion molecules and subsequent transmigration to the gastrointestinal tract. The drug was approved in 2014 for the induction and maintenance treatment of ulcerative colitis and moderate to severe Crohn's disease that is refractory or intolerant to conventional treatment with corticoids and immunosuppressants and/or anti-TNFα drugs. However, inflammatory bowel disease has a variable behavior following liver transplant. One third of patients with ulcerative colitis associated with primary sclerosing cholangitis are expected to deteriorate despite receiving immunosuppression to prevent rejection. There is limited experience with anti-TNFα agents in patients with inflammatory bowel disease in the setting of liver transplantation and the studies to date involve a limited number of cases. The efficacy and safety data of vedolizumab in this situation are unreliable and very preliminary. We present two cases with the aim to present the efficacy and safety of vedolizumab after one year of treatment in two patients who underwent a transplant due to primary sclerosing cholangitis. One case had de novo post-transplant ulcerative colitis refractory to two anti-TNFα drugs (golimumab and infliximab). The other patient had a colostomy due to fulminant colitis and developed severe ulcerative proctitis refractory to infliximab after reconstruction with an ileorectal anastomosis.
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http://dx.doi.org/10.17235/reed.2017.5024/2017DOI Listing
September 2017

Medium to long-term efficacy and safety of oral tacrolimus in moderate to severe steroid refractory ulcerative colitis.

Rev Esp Enferm Dig 2017 Aug;109(8):559-565

UGC Aparato Digestivo, Hospital Regional Universitario de Málaga.

Background And Objective: Oral tacrolimus is an effective drug that induces clinical remission in patients with moderate to severe ulcerative colitis refractory to steroids. However, there is little data with regard to its medium to long-term efficacy and safety. The aim of this study was to assess the medium to long-term efficacy and safety of oral tacrolimus in this challenging clinical situation.

Methods: This was a retrospective observational review of the clinical charts of 34 patients with moderate to severe ulcerative colitis refractory to steroids treated with oral tacrolimus at our hospital (July 2001-July 2016). Remission was defined as a Lichtiger index score < 3 and response was defined as a score < 10 with a reduction of at least three points compared to the baseline score.

Results And Conclusions: Seven patients (20.58%) required colectomy during the follow-up period (mean 65 months). Nine patients required rescue with infliximab (four patients during the first six months of follow-up and the other five after the first six months). The short to medium clinical efficacy combining both remission and clinical response was 82% at six months. Kaplan-Meier analysis showed that the percentage of patients free from colectomy and additional sequential rescue therapy was 75% at 54 months (median follow-up). The early introduction of thiopurines (< 2 months from start of tacrolimus) showed no significant improvement in prognosis (p = 0.72). Fifty-three per cent of patients experienced adverse effects, none of whom required treatment withdrawal. No severe infections were noted during the follow-up.
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http://dx.doi.org/10.17235/reed.2017.4899/2017DOI Listing
August 2017

Inflammatory Bowel Disease: New Therapeutic Options in the Post Anti-TNFα Era.

Curr Drug Metab 2017 ;18(7):666-679

UGC de Aparato Digestivo, Hospital Regional Universitario de Málaga, Málaga. Spain.

Background: Inflammatory bowel diseases are chronic bowel disorders the causes of which have not been fully elucidated, though they all sharean immunological basis. They have an important impact on both quality of life of the patient and on healthcare services.

Method: The incorporation of biological agents against tumour necrosis factor (TNF) alpha some 15 years ago represented a revolution in the management of patients with disease that did not respond to conventional treatment, enabling an overall improvement in the quality of life of many of these patients.

Results: Nonetheless, these agents are not effective in an appreciable percentage of patients (primary lack of response), can lose their efficacy over time even though they were initially effective (loss of secondary response), and can also be burdened by varied and sometimes severe adverse effects (e.g., infusion reactions, infections, neoplasms). Consequently, basic research over recent years has provided us with promising new pharmacological agents aimed at targets other than TNF alpha (IL12/23, anti-adhesion molecules, Janus kinase inhibitors, anti- Smad7, blockade of sphingosine-1-phosphate receptors).

Conclusion: This paper reviews some of the key aspects of these new drugs, including their mechanism of action, some incipient pharmacokinetic and metabolic data, their efficacy and their safety. These new agents will take on an important role in the coming years in the management of patients with moderate-to-severe forms of inflammatory bowel disease.
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http://dx.doi.org/10.2174/1389200218666170406120203DOI Listing
September 2018

Human immunodeficiency virus-infected liver transplant recipients with incidental hepatocellular carcinoma: A prospective multicenter nationwide cohort study.

Liver Transpl 2017 05;23(5):645-651

Hospital Clínic-IDIBAPS, University of Barcelona, Barcelona, Spain.

There is a lack of data on incidental hepatocellular carcinoma (iHCC) in the setting of liver transplantation (LT) in human immunodeficiency virus (HIV)-infected patients. This study aims to describe the frequency, histopathological characteristics, and outcomes of HIV+ LT recipients with iHCC from a Spanish multicenter cohort in comparison with a matched cohort of LT patients without HIV infection. A total of 15 (6%) out of 271 patients with HIV infection who received LT in Spain from 2002 to 2012 and 38 (5%) out of the 811 HIV- counterparts presented iHCC in liver explants (P = 0.58). Patients with iHCC constitute the present study population. All patients also had hepatitis C virus (HCV)-related cirrhosis. There were no significant differences in histopathological features of iHCC between the 2 groups. Most patients showed a small number and size of tumoral nodules, and few patients had satellite nodules, microvascular invasion, or poorly differentiated tumors. After a median follow-up of 49 months, no patient developed hepatocellular carcinoma (HCC) recurrence after LT. HIV+ LT recipients tended to have lower survival than their HIV- counterparts at 1 (73% versus 92%), 3 (67% versus 84%), and 5 years (50% versus 80%; P = 0.06). There was also a trend to a higher frequency of HCV recurrence as a cause of death in the former (33% versus 10%; P = 0.097). In conclusion, among LT recipients for HCV-related cirrhosis, the incidence and histopathological features of iHCC in HIV+ and HIV- patients were similar. However, post-LT survival was lower in HIV+ patients probably because of a more aggressive HCV recurrence. Liver Transplantation 23 645-651 2017 AASLD.
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http://dx.doi.org/10.1002/lt.24741DOI Listing
May 2017

Metabolic complications in liver transplant recipients.

World J Gastroenterol 2016 Jul;22(28):6416-23

Miguel Jiménez-Pérez, Rocío González-Grande, Edith Omonte Guzmán, Víctor Amo Trillo, Juan Miguel Rodrigo López, UGC de Aparato Digestivo, Unidad de Hepatología-Trasplante Hepático, Hospital Universitario Regional de Málaga, 29010 Málaga, Spain.

The metabolic syndrome (MS), which includes obesity, dyslipidaemia, hypertension and hyperglycaemia according to the most widely accepted definitions now used, is one of the most common post-transplant complications, with a prevalence of 44%-58%. The MS, together with the immunosuppression, is considered the main risk factor for the development of cardiovascular disease (CVD) in transplant recipients, which in turn accounts for 19%-42% of all deaths unrelated to the graft. The presence of MS represents a relative risk for the development of CVD and death of 1.78. On the other hand, non-alcoholic fatty liver disease (NAFLD), considered as the manifestation of the MS in the liver, is now the second leading reason for liver transplantation in the United States after hepatitis C and alcohol. NAFLD has a high rate of recurrence in the liver graft and a direct relation with the worsening of other metabolic disorders, such as insulin resistance or diabetes mellitus. Consequently, it is vitally important to identify and treat as soon as possible such modifiable factors as hypertension, overweight, hyperlipidaemia or diabetes in transplanted patients to thus minimise the impact on patient survival. Additionally, steroid-free regimens are favoured, with minimal immunosuppression to limit the possible effects on the development of the MS.
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http://dx.doi.org/10.3748/wjg.v22.i28.6416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4968123PMC
July 2016

Treatment of chronic hepatitis C with direct-acting antivirals: The role of resistance.

World J Gastroenterol 2016 Aug;22(29):6573-81

Miguel Jiménez-Pérez, UGC de Aparato Digestivo, Unidad de Hepatología-Trasplante Hepático, Hospital Universitario Regional de Málaga, 29010 Malaga, Spain.

The use of direct-acting antivirals (DAAs) to treat chronic hepatitis C has resulted in a significant increase in rates of sustained viral response (around 90%-95%) as compared with the standard treatment of peginterferon/ribavirin. Despite this, however, the rates of therapeutic failure in daily clinical practice range from 10%-15%. Most of these cases are due to the presence of resistant viral variants, resulting from mutations produced by substitutions of amino acids in the viral target protein that reduce viral sensitivity to DAAs, thus limiting the efficacy of these drugs. The high genetic diversity of hepatitis C virus has resulted in the existence of resistance-associated variants (RAVs), sometimes even before starting treatment with DAAs, though generally at low levels. These pre-existing RAVs do not appear to impact on the sustained viral response, whereas those that appear after DAA therapy could well be determinant in virological failure with future treatments. As well as the presence of RAVs, virological failure to treatment with DAAs is generally associated with other factors related with a poor response, such as the degree of fibrosis, the response to previous therapy, the viral load or the viral genotype. Nonetheless, viral breakthrough and relapse can still occur in the absence of detectable RAVs and after the use of highly effective DAAs, so that the true clinical impact of the presence of RAVs in therapeutic failure remains to be determined.
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http://dx.doi.org/10.3748/wjg.v22.i29.6573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970473PMC
August 2016

Definition and risk factors for chronicity following acute idiosyncratic drug-induced liver injury.

J Hepatol 2016 09 13;65(3):532-42. Epub 2016 May 13.

Unidad de Gestión Clínica de Aparato Digestivo, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain.

Background & Aims: Chronic outcome following acute idiosyncratic drug-induced liver injury (DILI) is not yet defined. This prospective, long-term follow-up study aimed to analyze time to liver enzyme resolutions to establish the best definition and risk factors of DILI chronicity.

Methods: 298 out of 850 patients in the Spanish DILI registry with no pre-existing disease affecting the liver and follow-up to resolution or ⩾1year were analyzed. Chronicity was defined as abnormal liver biochemistry, imaging test or histology one year after DILI recognition.

Results: Out of 298 patients enrolled 273 (92%) resolved ⩽1year from DILI recognition and 25 patients (8%) were chronic. Independent risk factors for chronicity were older age [OR: 1.06, p=0.011], dyslipidemia [OR: 4.26, p=0.04] and severe DILI [OR: 14.22, p=0.005]. Alanine aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin (TB) median values were higher in the chronic group during follow-up. Values of ALP and TB >1.1 x upper limit of normal (xULN) and 2.8 xULN respectively, in the second month from DILI onset, were found to predict chronic DILI (p<0.001). Main drug classes involved in chronicity were statins (24%) and anti-infectives (24%). Histological examination in chronic patients demonstrated two cases with ductal lesion and seven with cirrhosis.

Conclusions: One year is the best cut-off point to define chronic DILI or prolonged recovery, with risk factors being older age, dyslipidemia and severity of the acute episode. Statins are distinctly related to chronicity. ALP and TB values in the second month could help predict chronicity or very prolonged recovery.

Lay Summary: Drug-induced liver injury (DILI) patients who do not resolve their liver damage during the first year should be considered chronic DILI patients. Risk factors for DILI chronicity are older age, dyslipidemia and severity of the acute episode. Chronic DILI is not a very common condition; normally featuring mild liver profile abnormalities and not being an important clinical problem, with the exception of a small number of cases of early onset cirrhosis.
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http://dx.doi.org/10.1016/j.jhep.2016.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458366PMC
September 2016

New approaches in the treatment of hepatitis C.

World J Gastroenterol 2016 Jan;22(4):1421-32

Rocío González-Grande, Miguel Jiménez-Pérez, González Arjona, José Mostazo Torres, Liver Transplantation and Hepatology Unit, UGC de Aparato Digestivo, Hospital Regional Universitario, 29010 Malaga, Spain.

About 130-170 million people, is estimated to be infected with the hepatitis C virus (HCV). Chronic HCV infection is one of the leading causes of liver-related death and in many countries it is the primary reason for having a liver transplant. The main aim of antiviral treatment is to eradicate the virus. Until a few years ago the only treatment strategy was based on the combination of pegylated interferon and ribavirin (PEG/RBV). However, in genotypes 1 and 4 the rates of viral response did not surpass 50%, reaching up to 80% in the rest. In 2011 approval was given for the first direct acting antiviral agents (DAA), boceprevir and telaprevir, for treatment of genotype 1, in combination with traditional dual therapy. This strategy managed to increase the rates of sustained viral response (SVR) in both naive patients and in retreated patients, but with greater toxicity, interactions and cost, as well as being less safe in patients with advanced disease, in whom this treatment can trigger decompensation or even death. The recent, accelerated incorporation since 2013 of new more effective DAA, with pan-genomic properties and excellent tolerance, besides increasing the rates of SVR (even up to 100%), has also created a new scenario: shorter therapies, less toxicity and regimens free of PEG/RBV. This has enabled their almost generalised applicability in all patients. However, it should be noted that most of the scientific evidence available is based on expert opinion, case-control series, cohort studies and phase 2 and 3 trials, some with a reduced number of patients and select groups. Few data are currently available about the use of these drugs in daily clinical practice, particularly in relation to the appearance of side effects and interactions with other drugs, or their use in special populations or persons with the less common genotypes. This situation suggests the need for the generalised implementation of registries of patients receiving antiviral therapy. The main inconvenience of these new drugs is their high cost. This necessitates selection and prioritization of candidate patients to receive them, via strategies established by the various national organs, in accordance with the recommendations of scientific societies.
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http://dx.doi.org/10.3748/wjg.v22.i4.1421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4721977PMC
January 2016

Management of hepatitis B virus infection after liver transplantation.

World J Gastroenterol 2015 Nov;21(42):12083-90

Miguel Jiménez-Pérez, Rocío González-Grande, José Mostazo Torres, Carolina González Arjona, Liver Transplantation and Hepatology Unit, UGC de Aparato Digestivo Hospital Regional Universitario, 29010 Malaga, Spain.

Chronic hepatitis B virus (HBV) infection is responsible for up to 30% of cases of liver cirrhosis and up to 53% of cases of hepatocellular carcinoma. Liver transplantation (LT) is the best therapeutic option for patients with end-stage liver failure caused by HBV. The success of transplantation, though, depends on receiving prophylactic treatment against post-transplant viral reactivation. In the absence of prophylaxis, liver transplantation due to chronic hepatitis B (CHB) is associated with high rates of viral recurrence and poor survival. The introduction of treatment with hepatitis B immunoglobulins (HBIG) during the 1990s and later the incorporation of oral antiviral drugs have improved the prognosis of these patients. Thus, LT for CHB is now a universally accepted option, with an estimated 5 years survival of around 85% vs the 45% survival seen prior to the introduction of HBIG. The combination of lamivudine plus HBIG has for many years been the most widely used prophylactic regimen. However, with the appearance of new more potent oral antiviral agents associated with less resistance (e.g., entecavir and tenofovir) for the treatment of CHB, new prophylactic strategies are being designed, either in combination with HBIG or alone as a monotherapy. These advances have allowed for more personalized prophylaxis based on the individual risk profile of a given patient. In addition, the small pool of donors has required the use of anti-HBc-positive donors (with the resulting possibility of transmitting HBV from these organs), which has been made possible by suitable prophylactic regimens.
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http://dx.doi.org/10.3748/wjg.v21.i42.12083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4641126PMC
November 2015

Human immunodeficiency virus infection does not worsen prognosis of liver transplantation for hepatocellular carcinoma.

Hepatology 2016 Feb 4;63(2):488-98. Epub 2016 Jan 4.

Hospital Clínic-IDIBAPS, University of Barcelona, Barcelona, Spain.

Unlabelled: The impact of human immunodeficiency virus (HIV) infection on patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC) is uncertain. This study aimed to assess the outcome of a prospective Spanish nationwide cohort of HIV-infected patients undergoing LT for HCC (2002-2014). These patients were matched (age, gender, year of LT, center, and hepatitis C virus (HCV) or hepatitis B virus infection) with non-HIV-infected controls (1:3 ratio). Patients with incidental HCC were excluded. Seventy-four HIV-infected patients and 222 non-HIV-infected patients were included. All patients had cirrhosis, mostly due to HCV infection (92%). HIV-infected patients were younger (47 versus 51 years) and had undetectable HCV RNA at LT (19% versus 9%) more frequently than non-HIV-infected patients. No significant differences were detected between HIV-infected and non-HIV-infected recipients in the radiological characteristics of HCC at enlisting or in the histopathological findings for HCC in the explanted liver. Survival at 1, 3, and 5 years for HIV-infected versus non-HIV-infected patients was 88% versus 90%, 78% versus 78%, and 67% versus 73% (P = 0.779), respectively. HCV infection (hazard ratio = 7.90, 95% confidence interval 1.07-56.82) and maximum nodule diameter >3 cm in the explanted liver (hazard ratio = 1.72, 95% confidence interval 1.02-2.89) were independently associated with mortality in the whole series. HCC recurred in 12 HIV-infected patients (16%) and 32 non-HIV-infected patients (14%), with a probability of 4% versus 5% at 1 year, 18% versus 12% at 3 years, and 20% versus 19% at 5 years (P = 0.904). Microscopic vascular invasion (hazard ratio = 3.40, 95% confidence interval 1.34-8.64) was the only factor independently associated with HCC recurrence.

Conclusions: HIV infection had no impact on recurrence of HCC or survival after LT. Our results support the indication of LT in HIV-infected patients with HCC.
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http://dx.doi.org/10.1002/hep.28321DOI Listing
February 2016

[Peristomal pyoderma gangrenosum after rectal adenocarcinoma in the context of colonic and complex perianal Crohn's disease].

Gastroenterol Hepatol 2016 May 18;39(5):338-41. Epub 2015 Jun 18.

Unidad de Gestión Clínica de Aparato Digestivo, Hospital Regional Universitario de Málaga, Málaga, España.

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http://dx.doi.org/10.1016/j.gastrohep.2015.05.001DOI Listing
May 2016

Management of recurrent hepatitis C virus after liver transplantation.

World J Gastroenterol 2014 Nov;20(44):16409-17

Miguel Jiménez-Pérez, Rocío González-Grande, Liver transplantation and hepatology unit, UGC de Aparato Digestivo Hospital Regional Universitario, 29010 Málaga, Spain.

Chronic hepatitis C virus (HCV) infection is the leading cause of death from liver disease and the leading indication for liver transplantation (LT) in the United States and Western Europe. LT represents the best therapeutic alternative for patients with advanced chronic liver disease caused by HCV or those who develop hepatocarcinoma. Reinfection by HCV of the graft is universal and occurs in 95% of transplant patients. This reinfection can compromise graft function and patient survival. In a few cases, the histological recurrence is minimal and non-progressive; however, in most patients it follows a more rapid course than in immunocompetent persons, and frequently evolves into cirrhosis with graft loss. In fact, the five-year and ten-year survival of patients transplanted because of HCV are 75% and 68%, respectively, compared with 85% and 78% in patients transplanted for other reasons. There is also a pattern of recurrence that is very severe, but rare (< 10%), called fibrosing cholestatic hepatitis, which often involves rapid graft loss. Patients who present a negative HCV viremia after antiviral treatment have better survival. Many studies published over recent years have shown that antiviral treatment of post-transplant HCV hepatitis carried out during the late phase is the best option for improving the prognosis of these patients. Until 2011, PEGylated interferon plus ribavirin was the standard of care, resulting in a sustained virological response in around 30% of recipients. The addition of protease inhibitors, such as boceprevir or telaprevir, to the standard of care, or the use of other direct-acting antiviral drugs may involve therapeutic changes in the context of HCV recurrence. This may result a better prognosis for these patients, particularly those with severe recurrence or factors predicting rapid progression of fibrosis. However, the use of these agents in LT still requires clarification in terms of safety and efficacy.
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http://dx.doi.org/10.3748/wjg.v20.i44.16409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248184PMC
November 2014

Use of Hy's law and a new composite algorithm to predict acute liver failure in patients with drug-induced liver injury.

Gastroenterology 2014 Jul 1;147(1):109-118.e5. Epub 2014 Apr 1.

Unidad de Gestión Clínica de Enfermedades Digestivas, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain.

Background & Aims: Hy's Law, which states that hepatocellular drug-induced liver injury (DILI) with jaundice indicates a serious reaction, is used widely to determine risk for acute liver failure (ALF). We aimed to optimize the definition of Hy's Law and to develop a model for predicting ALF in patients with DILI.

Methods: We collected data from 771 patients with DILI (805 episodes) from the Spanish DILI registry, from April 1994 through August 2012. We analyzed data collected at DILI recognition and at the time of peak levels of alanine aminotransferase (ALT) and total bilirubin (TBL).

Results: Of the 771 patients with DILI, 32 developed ALF. Hepatocellular injury, female sex, high levels of TBL, and a high ratio of aspartate aminotransferase (AST):ALT were independent risk factors for ALF. We compared 3 ways to use Hy's Law to predict which patients would develop ALF; all included TBL greater than 2-fold the upper limit of normal (×ULN) and either ALT level greater than 3 × ULN, a ratio (R) value (ALT × ULN/alkaline phosphatase × ULN) of 5 or greater, or a new ratio (nR) value (ALT or AST, whichever produced the highest ×ULN/ alkaline phosphatase × ULN value) of 5 or greater. At recognition of DILI, the R- and nR-based models identified patients who developed ALF with 67% and 63% specificity, respectively, whereas use of only ALT level identified them with 44% specificity. However, the level of ALT and the nR model each identified patients who developed ALF with 90% sensitivity, whereas the R criteria identified them with 83% sensitivity. An equal number of patients who did and did not develop ALF had alkaline phosphatase levels greater than 2 × ULN. An algorithm based on AST level greater than 17.3 × ULN, TBL greater than 6.6 × ULN, and AST:ALT greater than 1.5 identified patients who developed ALF with 82% specificity and 80% sensitivity.

Conclusions: When applied at DILI recognition, the nR criteria for Hy's Law provides the best balance of sensitivity and specificity whereas our new composite algorithm provides additional specificity in predicting the ultimate development of ALF.
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http://dx.doi.org/10.1053/j.gastro.2014.03.050DOI Listing
July 2014

[Pulmonary toxicity associated with sirolimus therapy in liver transplantation].

Gastroenterol Hepatol 2006 Dec;29(10):616-8

Unidad de Hepatología-Trasplante Hepático, Servicio de Aparato Digestivo, Hospital Universitario Carlos Haya, Málaga, España.

Sirolimus is a potent immunosuppressive drug that began to be used in the last few years. This drug was initially used in renal transplantation but its use in other solid organ transplantations such as liver, heart, lung and pancreas, has been increasing. Sirolimus is indicated in rescue therapies and to reduce the secondary toxic effects of calcineurin inhibitors. However, this drug has been associated with infrequent but severe pulmonary toxicity and cases of interstitial pneumonitis, bronchiolitis obliterans with organizing pneumonia, and alveolar proteinosis have been described. We present the case of a male liver transplant recipient who developed interstitial pneumonitis associated with sirolimus use.
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http://dx.doi.org/10.1157/13095205DOI Listing
December 2006

[Tacrolimus in the treatment of refractory moderate-to-severe inflammatory bowel disease].

Gastroenterol Hepatol 2006 Jun-Jul;29(6):327-33

Servicio de Aparato Digestivo, Hospital Regional Universitario Carlos Haya, Málaga, Spain.

Introduction: The primary endpoint of this study was to evaluate the efficacy of oral tacrolimus in patients with active moderate-to-severe luminal IBD, mainly those refractory to steroids. Secondary endpoints were surgery requirements during follow-up, the percentage of patients achieving steroid withdrawal, and treatment safety.

Patients And Method: Nineteen patients were included. The main indication for tacrolimus therapy was steroid resistance. The mean duration of treatment was 11 (range 3- 13) and 15 (range 4-44) months in patients with UC and CD, respectively. Remission was evaluated at weeks 4, 8 and 24 from the start of treatment, using the Harvey-Bradshaw index and the Truelove-Witts criteria for CD and UC patients, respectively, and acute- phase reactants (Serum erythrocyte sedimentation rate and C-reactive protein). Steroid withdrawal, need for surgery, and previous and concomitant medication were also evaluated.

Results: Overall, 47%, 66% and 41% of the patients were in complete remission at weeks 4, 8 and 24, respectively. Steroid withdrawal was achieved in 50% of the patients. Among patients who could not undergo complete steroid withdrawal, steroid therapy was reduced to a mean prednisone dose of 12.5 mg /day (range 10-15 mg). Surgery was required in 16% (mean follow-up of 38 months). Adverse effects occurred in 63% patients, who improved with dose reduction; none of the patients required tacrolimus withdrawal.

Conclusions: Oral tacrolimus could be a safe, effective and useful option in patients with refractory IBD.
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http://dx.doi.org/10.1157/13089714DOI Listing
September 2006