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Vol. 41. Issue 3.
Pages 205-221 (March 2018)
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Vol. 41. Issue 3.
Pages 205-221 (March 2018)
Review
DOI: 10.1016/j.gastre.2018.03.002
Recommendations of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis (GETECCU) on the use of thiopurines in inflammatory bowel disease
Recomendaciones del Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa (GETECCU) sobre el uso de tiopurinas en la enfermedad inflamatoria intestinal
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Fernando Bermejoa,
Corresponding author
fbermejos1@gmail.com

Corresponding author.
, Mariam Aguasb,c, María Chaparroc,d, Eugeni Domènechc,e, Ana Echarrif, Esther García-Planellag, Iván Guerraa, Javier P. Gisbertc,d, Antonio López-Sanrománh, on behalf of GETECCU
a Servicio de Digestivo, Hospital Universitario de Fuenlabrada, Fuenlabrada, Madrid, Spain
b Servicio de Digestivo, Hospital Universitari La Fe, Valencia, Spain
c Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Spain
d Servicios de Digestivo, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, Spain
e Servicio de Digestivo, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
f Servicio de Digestivo, Complejo Hospitalario Universitario de Ferrol, Ferrol, Spain
g Servicio de Digestivo, Hospital Universitari Santa Creu i Sant Pau, Barcelona, Spain
h Servicio de Digestivo, Hospital Universitario Ramón y Cajal, Madrid, Spain
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Table 1. Most relevant points regarding the efficacy of thiopurine therapy in inflammatory bowel disease.
Table 2. Most relevant points in relation to pre-assessment and start of thiopurine therapy.
Table 3. Most relevant points in relation to adverse effects of thiopurine therapy.
Table 4. Most relevant points in relation to tumour risk and attitude towards thiopurine therapy.
Table 5. Most relevant points in relation to the safety profile of thiopurines in terms of reproduction.
Table 6. Most relevant points in relation to controlling treatment using thiopurine metabolite testing.
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Abstract

Thiopurines (azathioprine and mercaptopurine) are widely used in patients with inflammatory bowel disease. In this paper, we review the main indications for their use, as well as practical aspects on efficacy, safety and method of administration. They are mainly used to maintain remission in steroid-dependent disease or with ciclosporin to control a severe ulcerative colitis flare-up, as well as to prevent postoperative Crohn's disease recurrence, and also in combination therapy with biologics. About 30–40% of patients will not respond to treatment and 10–20% will not tolerate it due to adverse effects. Before they are prescribed, immunisation status against certain infections should be checked. Determination of thiopurine methyltransferase activity (TPMT) is not mandatory but it increases initial safety. The appropriate dose is 2.5mg/kg/day for azathioprine and 1.5mg/kg/day for mercaptopurine. Some adverse effects are idiosyncratic (digestive intolerance, pancreatitis, fever, arthromyalgia, rash and some forms of hepatotoxicity). Others are dose-dependent (myelotoxicity and other types of hepatotoxicity), and their surveillance should never be interrupted during treatment. If therapy fails or adverse effects develop, management can include switching from one thiopurine to the other, reducing the dose, combining low doses of azathioprine with allopurinol and assessing metabolites, before their use is ruled out. Non-melanoma skin cancer, lymphomas and urinary tract tumours have been linked to thiopurine therapy. Thiopurine use is safe during conception, pregnancy and breastfeeding.

Keywords:
Thiopurine
Azathioprine
Mercaptopurine
Inflammatory bowel disease
Crohn's disease
Ulcerative colitis
Metabolites
Resumen

Las tiopurinas (azatioprina y mercaptopurina) se usan frecuentemente en pacientes con enfermedad inflamatoria intestinal. En este documento, revisaremos sus principales indicaciones, así como aspectos prácticos de seguridad, eficacia y modo de empleo. Sus usos principales son el mantenimiento de la remisión en la enfermedad corticodependiente o tras el control de un brote grave de colitis ulcerosa con ciclosporina, la prevención de la recurrencia posquirúrgica en enfermedad de Crohn y el empleo en terapia combinada junto con biológicos. El 30–40% de pacientes no responderá al tratamiento y un 10–20% no tolerará el tratamiento por efectos adversos. Antes de iniciarlas, se recomienda evaluar el estado de inmunización frente a ciertas infecciones; la determinación previa de la actividad de la tiopurina·metiltransferasa (TPMT) no es imprescindible, pero permite mayor seguridad inicial. La dosis adecuada es de 2,5mg/kg/día para azatioprina y de 1,5mg/kg/día para mercaptopurina. Algunos efectos adversos son idiosincrásicos (intolerancia digestiva, pancreatitis, fiebre, artromialgias, exantema y algunos casos de hepatotoxicidad). Otros son dosis-dependientes (mielotoxicidad y otros tipos de hepatotoxicidad) y su vigilancia debe mantenerse mientras dure el tratamiento. Si son ineficaces o aparecen efectos adversos, puede recurrirse al cambio de tiopurina, la reducción de dosis, combinar dosis bajas de azatioprina con alopurinol y determinar metabolitos antes de descartar su uso. Los tumores de piel distintos al melanoma, los linfomas y los tumores del tracto urinario se han relacionado con su administración. Las tiopurinas son fármacos seguros en la concepción, gestación y lactancia.

Palabras clave:
Tiopurina
Azatioprina
Mercaptopurina
Enfermedad inflamatoria intestinal
Enfermedad de Crohn
Colitis ulcerosa
Metabolitos

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