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1.
S D Med ; 72(5): 214-216, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31454474

RESUMO

Cirrhosis resulting from autoimmune hepatitis is associated with an increased risk of hepatocellular carcinoma. A common treatment for autoimmune hepatitis, azathioprine, is also associated with the development of many other cancers, predominantly lymphomas. The strongest association is seen for post-transplant lymphoma and hepatosplenic T-cell lymphoma in Crohn's disease and ulcerative colitis patients; there is also an association with a variety of cutaneous malignancies. A relationship between azathioprine and sarcoma has not been demonstrated, though there have been sporadic case reports. We report here the development of leiomyosarcoma in a patient who was treated with azathioprine for autoimmune hepatitis without cirrhosis.


Assuntos
Azatioprina/efeitos adversos , Colite Ulcerativa , Doença de Crohn , Imunossupressores/efeitos adversos , Leiomiossarcoma , Azatioprina/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Leiomiossarcoma/induzido quimicamente
2.
Clin Exp Rheumatol ; 37(5): 858-861, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31074729

RESUMO

OBJECTIVES: To study the efficacy in terms of muscle strength, and corticosteroid tapering as well as the prevalence of adverse effects in patients with the antisynthetase syndrome (ASyS) treated with azathioprine (AZA) compared to those treated with methotrexate (MTX). METHODS: We compared the clinical outcomes in ASyS patients treated with AZA versus MTX including change in corticosteroid dose, strength, and creatine kinase (CK) as well as the prevalence of adverse effects. RESULTS: Among 169 patients with ASyS, 102 were treated at some point exclusively with either AZA or MTX (± corticosteroids). There were no significant differences in the rate of muscle strength recovery, CK decrease or corticosteroid tapering between those ASyS patients treated with MTX versus AZA. The prevalence of adverse events in patients treated with AZA and MTX was similar (29% vs. 25%, p>0.05); elevated liver enzymes (17% AZA vs. 12% MTX) and gastrointestinal involvement (10% AZA vs. 8% MTX) were the most common adverse events. While no patients treated with AZA developed lung complications, two of the patients treated with MTX experienced reversible pneumonitis with MTX cessation. CONCLUSIONS: AZA and MTX showed similar efficacy and adverse events in patients with ASyS. Pneumonitis is a rare but important event in patients receiving MTX.


Assuntos
Azatioprina , Metotrexato , Miosite/tratamento farmacológico , Corticosteroides , Azatioprina/efeitos adversos , Azatioprina/uso terapêutico , Creatina Quinase/sangue , Humanos , Metotrexato/efeitos adversos , Metotrexato/uso terapêutico , Força Muscular/efeitos dos fármacos , Força Muscular/fisiologia
3.
BMC Infect Dis ; 19(1): 404, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31077135

RESUMO

BACKGROUND: Symptomatic primary Epstein-Barr virus infection is a usually self-limiting illness in adolescents. We present a case of an adolescent who had been receiving azathioprine for inflammatory bowel disease for four years and developed a life-threatening primary Epstein-Barr virus infection successfully treated with rituximab. CASE PRESENTATION: An 11-year-old girl presented with chronic, bloody diarrhea. Endoscopic biopsies confirmed a diagnosis of chronic ulcerative colitis with features of Crohn's disease. Azathioprine was initiated after one year due to active colitis. She responded well and remission was achieved. At the age of 16 years she developed a life-threatening Epstein-Barr virus infection including severe multiple organ failure and was critically ill for 4 weeks in the intensive care unit. Natural killer cells were virtually absent in the lymphocyte subset analysis. Azathioprine was stopped on admission. She was initially treated with corticosteroids, acyclovir and intravenous immunoglobulin. Approximately 30 days after admission, she developed signs of severe hepatitis and pneumonitis and received weekly rituximab infusions for 8 weeks. Primary immunodeficiency was excluded by whole exome sequencing in two independent laboratories. Persistent viremia stopped when the natural killer cell count started to rise, approximately 90 days after the cessation of azathioprine. CONCLUSIONS: We found 17 comparable cases in the literature. None of the previous cases reported in the literature, who had been treated with azathioprine and developed either a severe or a fatal Epstein-Barr virus infection, underwent full genetic and prospective immunological workup to rule out known primary immunodeficiencies. Recently, azathioprine has been shown to cause rather specific immunosuppression, resulting in natural killer cell depletion. Our case demonstrates that slow recovery from azathioprine-induced natural killer cell depletion, 3 months after the stopping of azathioprine, coincided with the clearance of viremia and clinical recovery. Finally, our choice of treating the patient with rituximab, as previously used for patients with a severe immunosuppression and Epstein-Barr virus viremia, appeared to be successful in this case. We suggest testing for Epstein-Barr virus serology before starting azathioprine and measuring natural killer cell counts during the treatment to identify patients at risk of developing an unusually severe primary Epstein-Barr virus infection.


Assuntos
Azatioprina/efeitos adversos , Infecções por Vírus Epstein-Barr/etiologia , Imunossupressores/efeitos adversos , Doenças Inflamatórias Intestinais/complicações , Células Matadoras Naturais , Azatioprina/uso terapêutico , Biópsia , Criança , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/virologia , Feminino , Herpesvirus Humano 4/imunologia , Humanos , Imunossupressores/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Células Matadoras Naturais/efeitos dos fármacos , Contagem de Linfócitos , Estudos Prospectivos , Rituximab/uso terapêutico , Resultado do Tratamento
4.
Actas dermo-sifiliogr. (Ed. impr.) ; 110(3): 227-231, abr. 2019. tab
Artigo em Espanhol | IBECS | ID: ibc-181713

RESUMO

Antecedentes; La dermatitis atópica (DA) es una enfermedad inflamatoria crónica de la piel típicamente infantil cuyas formas graves pueden afectar intensamente la calidad de vida del paciente. Existen formas refractarias al tratamiento convencional en las que es preciso emplear inmunosupresores sistémicos como la azatioprina (AZA) para alcanzar un buen control de la enfermedad. Objetivo: Evaluar la eficacia y la tolerancia de la AZA en niños con DA grave. Pacientes y métodos: Se realizó una revisión retrospectiva de niños con DA grave tratados con AZA entre enero de 2007 y mayo de 2017. Resultados: Se revisaron 11 pacientes (6 varones, 5 mujeres) con una edad promedio de 13 años (rango 8-18 años). La edad media ± DE al inicio del tratamiento fue de 10,9 ± 2,2 años (IC 95% 8,6-13,1). La media de la dosis inicial de AZA fue de 1,8 ± 0,2 mg/kg/d. Evaluamos la respuesta al tratamiento de nuestros pacientes a las 4 semanas, entre la semana 12 y la 16, y a partir de los 6 meses. La media del tratamiento fue de 10,8 ± 5,7 meses. Dos pacientes tuvieron que suspender el tratamiento por efectos adversos. Siete de los 9 pacientes restantes presentaron un aclaramiento completo o casi completo de la DA a los 6 meses de tratamiento. Conclusión: En nuestra experiencia, la AZA es bien tolerada y puede ser considerada como una opción terapéutica en los niños con DA grave refractaria a tratamientos convencionales


Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease that typically affects children. Severe forms may have a profound effect on patients’ quality of life. Some forms are resistant to conventional treatment and require the use of systemic immunosuppressants such as azathioprine (AZA) to adequately manage the disease. Objective: To evaluate the effectiveness and tolerance of AZA in children with severe AD. Patients and methods: We performed a retrospective study of children with severe AD treated with AZA between January 2007 and May 2017. Results: We reviewed the cases of 11 patients (6 boys and 5 girls) with a mean age of 13 years (range, 8-18 years). The mean (SD) age at start of treatment was 10.9 (2.2) years (95% CI 8.6-13.1). The mean initial dosage of AZA was 1.8 (0.2) mg/kg/d. We evaluated treatment response after 4 weeks, 12 to 16 weeks, and 6 months. Mean treatment duration was 10.8 (5.7) months. Treatment had to be suspended in 2 patients because of adverse effects. Seven of the 9 remaining patients presented complete or almost complete clearance of the AD after 6 months of treatment. Conclusion: In our experience, AZA is well tolerated and may be considered as a treatment option in children with severe AD resistant to conventional treatment


Assuntos
Humanos , Masculino , Feminino , Criança , Adolescente , Dermatite Atópica/tratamento farmacológico , Azatioprina/efeitos adversos , Avaliação de Eficácia-Efetividade de Intervenções , Azatioprina/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento , Esteroides/administração & dosagem
5.
BMJ Case Rep ; 12(3)2019 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-30936327

RESUMO

Azathioprine (AZA) is an immunosuppressive drug that is widely used in the treatment of autoimmune diseases. Although AZA is used widely, many studies reported that AZA-related hepatotoxicity is rather rare. We aimed to present a case with severe cholestatic hepatitis due to AZA use for Behcet's disease. Three weeks after starting AZA for the treatment of uveitis, the patient was admitted to our clinic with cholestasis and constitutional symptoms. In liver biopsy, findings were in accordance with drug reaction, and the AZA treatment was stopped. After 2 months, bilirubin levels and liver tests results became normal. As a result, given that AZA may cause severe cholestasis, the drug should be stopped if idiosyncrasy or hypersensitivity develops. If there is a debate in the diagnosis, histopathological evaluation of the liver would be the major issue because of the correct diagnosis of the drug toxicity and excluding other aetiologies.


Assuntos
Azatioprina/efeitos adversos , Síndrome de Behçet/tratamento farmacológico , Colestase/induzido quimicamente , Imunossupressores/efeitos adversos , Fígado/patologia , Prurido/induzido quimicamente , Uveíte/tratamento farmacológico , Adulto , Azatioprina/uso terapêutico , Síndrome de Behçet/complicações , Síndrome de Behçet/fisiopatologia , Doença Hepática Induzida por Substâncias e Drogas , Colestase/tratamento farmacológico , Colestase/patologia , Humanos , Imunossupressores/uso terapêutico , Icterícia/induzido quimicamente , Fígado/efeitos dos fármacos , Masculino , Náusea/induzido quimicamente , Prurido/tratamento farmacológico , Prurido/patologia , Resultado do Tratamento , Uveíte/etiologia , Vômito/induzido quimicamente
7.
Drug Metab Pers Ther ; 34(1)2019 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-30840585

RESUMO

Background The thiopurine S-methyltransferase (TPMT)/azathioprine (AZA) gene-drug pair is one of the most well-known pharmacogenetic markers. Despite this, few studies investigated the implementation of TPMT testing and the combined evaluation of genotype and phenotype in multidisciplinary clinical settings where patients are undergoing chronic therapy with AZA. Methods A total of 356 AZA-treated patients for chronic autoimmune diseases were enrolled. DNA was isolated from whole blood and the samples were analyzed for the c.460G>A and c.719A>G variants by the restriction fragment length polymorphism (RFLP) technique and sequenced for the c.238G>C variant. The TPMT enzyme activity was determined in erythrocytes by a high-performance liquid chromatography (HPLC) assay. Results All the patients enrolled were genotyped while the TPMT enzyme activity was assessed in 41 patients. Clinical information was available on 181 patients. We found no significant difference in the odds of having adverse drug reactions (ADRs) in wild-type patients and variant allele carriers, but the latter had an extra risk of experiencing hematologically adverse events. The enzyme activity was significantly associated to genotype. Conclusions TPMT variant allele carriers have an extra risk of experiencing hematologically adverse events compared to wild-type patients. Interestingly, only two out of 30 (6.6%) patients had discordant results between genotype, phenotype and onset of ADRs.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Azatioprina/efeitos adversos , Azatioprina/uso terapêutico , Genótipo , Metiltransferases/genética , Fenótipo , Doenças Autoimunes/enzimologia , Doenças Autoimunes/genética , Cromatografia Líquida de Alta Pressão , Doença Crônica , Eritrócitos/efeitos dos fármacos , Feminino , Humanos , Itália , Masculino , Metiltransferases/metabolismo
8.
Lupus ; 28(4): 565-568, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30862250

RESUMO

Organizing pneumonia is an inflammatory lung entity that presents with a huge variety of clinical, radiological and pathological patterns. Organizing pneumonia can be idiopathic or secondary to other diseases. Corticosteroid therapy is usually the first-line treatment showing clinical improvement in most cases. This report presents the case of a 56-year-old woman with systemic lupus erythematosus who was diagnosed with an organizing pneumonia and showed a poor response to steroid and azathioprine treatment. We considered the use of belimumab, which resulted in excellent clinical and radiological outcomes.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Bronquiolite Obliterante/tratamento farmacológico , Bronquiolite Obliterante/etiologia , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/complicações , Anticorpos Antinucleares/sangue , Anticorpos Monoclonais Humanizados/administração & dosagem , Azatioprina/administração & dosagem , Azatioprina/efeitos adversos , Azatioprina/uso terapêutico , Bronquiolite Obliterante/sangue , Progressão da Doença , Tolerância a Medicamentos , Feminino , Seguimentos , Humanos , Imunossupressores/administração & dosagem , Leucocitose/sangue , Pulmão/diagnóstico por imagem , Pulmão/patologia , Lúpus Eritematoso Sistêmico/sangue , Pessoa de Meia-Idade , Prednisolona/administração & dosagem , Prednisolona/uso terapêutico , Testes de Função Respiratória , Tomógrafos Computadorizados , Resultado do Tratamento
9.
Biomed Res Int ; 2019: 7604939, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30834274

RESUMO

Background: In inflammatory bowel disease (IBD) patients there are reports of the occurrence of hepatobiliary manifestations, so the aim of this study was to evaluate the hepatobiliary manifestations in patients with Crohn's disease (CD) and ulcerative colitis (UC) from an IBD reference center. Methods: Cross-sectional study in an IBD reference center, with interviews and review of medical charts, between July 2015 and August 2016. A questionnaire addressing epidemiological and clinical characteristics was used. Results: We interviewed 306 patients, and the majority had UC (53.9%) and were female (61.8%). Hepatobiliary manifestations were observed in 60 (19.6%) patients with IBD. In the greater part of the patients (56.7%) hepatobiliary disorders were detected after the diagnosis of IBD. In UC (18.2%) patients, the hepatobiliary disorders identified were 11 (6.7%) non-alcoholic fatty liver disease, 9 (5.5%) cholelithiasis, 6 (3.6%) primary sclerosing cholangitis (PSC), 3 (1.8%) hepatotoxicity associated with azathioprine, 1 (0.6%) hepatitis B, and 1 (0.6%) hepatic fibrosis. In CD (21.3%) patients, 11 (7.8%) had cholelithiasis, 11 (7.8%) non-alcoholic fatty liver disease, 4 (2.8%) PSC, 3 (2.1%) hepatotoxicity, 1 (0.7%) hepatitis B, (0.7%) hepatitis C, 1 (0.7%) alcoholic liver disease, and 1 (0.7%) autoimmune hepatitis (AIH). There was one case of PSC/AIH overlap syndrome. Conclusion: The frequency of hepatobiliary disorders was similar in both forms of IBD in patients evaluated. The most common nonspecific hepatobiliary manifestations in IBD patients were non-alcoholic liver disease and cholelithiasis. The most common specific hepatobiliary disorder was PSC in patients with extensive UC or ileocolonic CD involvement; this was seen more frequently in male patients.


Assuntos
Eliminação Hepatobiliar , Doenças Inflamatórias Intestinais/diagnóstico , Fígado/fisiopatologia , Adulto , Azatioprina/efeitos adversos , Colelitíase/diagnóstico , Colelitíase/fisiopatologia , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/fisiopatologia , Doença de Crohn/diagnóstico , Doença de Crohn/fisiopatologia , Estudos Transversais , Feminino , Hepatite B/diagnóstico , Hepatite B/fisiopatologia , Hepatite C/diagnóstico , Hepatite C/fisiopatologia , Hepatite Autoimune/diagnóstico , Hepatite Autoimune/fisiopatologia , Humanos , Doenças Inflamatórias Intestinais/classificação , Doenças Inflamatórias Intestinais/fisiopatologia , Hepatopatias/classificação , Hepatopatias/patologia , Hepatopatias Alcoólicas/diagnóstico , Hepatopatias Alcoólicas/fisiopatologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Adulto Jovem
10.
BMJ Case Rep ; 12(2)2019 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-30755430

RESUMO

We present a case of haemophagocytic lymphohistiocytosis (HLH) in the context of disseminated cytomegalovirus (CMV) viraemia in a 50-year-old man with well-controlled HIV infection and ulcerative colitis (UC), for which he was receiving azathioprine. Peak CMV viral load was 371 000 copies/ml with evidence of end-organ CMV in the lungs and colon. A bone marrow biopsy showed evidence of haemophagocytosis of platelets, neutrophils and erythrocytes. The azathioprine was stopped, and he received intravenous ganciclovir and corticosteroids with suppression of the CMV viral load and resolution of the HLH.


Assuntos
Antivirais/uso terapêutico , Azatioprina/efeitos adversos , Colite Ulcerativa/tratamento farmacológico , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/diagnóstico , Corticosteroides/uso terapêutico , Azatioprina/uso terapêutico , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/imunologia , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/imunologia , Ganciclovir/uso terapêutico , Infecções por HIV/imunologia , Humanos , Hospedeiro Imunocomprometido , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/imunologia , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
12.
Eur J Clin Pharmacol ; 75(3): 335-342, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30610277

RESUMO

PURPOSE: The thiopurines azathioprine and 6-mercaptopurine are frequently used for remission maintenance in patients with inflammatory bowel diseases. However, there are therapy failures, and it is unclear whether clinical and laboratory parameters can be used to predict thiopurine metabolite concentrations (as a surrogate for adequate remission maintenance therapy) and clinical outcome in these patients. METHODS: In this retrospective analysis of clinical routine patient data, multivariate statistical models based on Linear Mixed Models regression and Generalized Estimating Equations logistic regression were developed. The adequacy of the models was assessed using Pearson's correlation and a receiver operating characteristic curve. RESULTS: This study included 273 patients and 1158 thiopurine metabolite measurements as well as routine laboratory and clinical data. In the statistical models, thiopurine metabolite concentrations and the odds of non-remission based on different clinical and laboratory parameters were computed. Correlation (r2) between predicted and measured thiopurine metabolites were 0.40 (p < 0.001) for 6-thioguanine nucleotides and 0.53 (p < 0.001) for 6-methyl-mercaptopurine nucleotides, respectively. The model for remission classified data sets in remission and non-remission with a sensitivity of 63% and a specificity of 73%. The area under the receiver operating characteristic curve of the model was 0.72. CONCLUSIONS: Although the models are not yet accurate enough to be used in clinical routine, model-based prediction of thiopurine metabolite concentrations and of outcome is feasible. Until more accurate models are developed and validated, traditional therapeutic drug monitoring of thiopurine metabolites in patients with inflammatory bowel diseases under thiopurine therapy stays the best tool to individualize therapy.


Assuntos
Azatioprina/sangue , Monitoramento de Medicamentos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Mercaptopurina/sangue , Modelos Estatísticos , Adulto , Área Sob a Curva , Azatioprina/efeitos adversos , Azatioprina/uso terapêutico , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Mercaptopurina/efeitos adversos , Mercaptopurina/uso terapêutico , Metiltransferases/genética , Metiltransferases/metabolismo , Valor Preditivo dos Testes , Estudos Retrospectivos , Resultado do Tratamento
13.
Clin Nephrol ; 91(3): 172-179, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30686286

RESUMO

AIM: Maintenance therapy for lupus nephritis (LN) remains controversial. This meta-analysis of randomized controlled trials (RCTs) describes the comparative benefits and safety of mycophenolate mofetil (MMF) versus azathioprine (AZA) as maintenance therapy in patients with LN. MATERIALS AND METHODS: RCTs that compared the maintenance regimens of MMF and AZA in the treatment of LN were included. Outcomes were mortality, end-stage renal disease (ESRD), renal relapse, doubling of serum creatinine, and adverse effects. We performed the meta-analysis using Review Manager software (version 5.3). RESULTS: Seven RCTs were included in the meta-analysis. There were no significant differences between the MMF and AZA groups in regards to mortality, relapse, ESRD, doubling of serum creatinine, infection, or gastrointestinal upset. However, the MMF group incurred lower risks of leukopenia (RR = 0.16, 95% CI = 0.06 - 0.40; p = 0.0001) and amenorrhea (RR = 0.23, 95% CI = 0.09 - 0.59, p = 0.002) compared with the AZA group. CONCLUSION: MMF seems more effective than AZA as maintenance therapy for LN although the differences did not reach statistical significance. Furthermore, the MMF group incurred lower risk of leukopenia than AZA. However, more RCTs are needed to confirm the conclusion.


Assuntos
Azatioprina/uso terapêutico , Imunossupressores/uso terapêutico , Nefrite Lúpica/tratamento farmacológico , Ácido Micofenólico/uso terapêutico , Azatioprina/efeitos adversos , Creatinina/sangue , Progressão da Doença , Humanos , Imunossupressores/efeitos adversos , Falência Renal Crônica/etiologia , Nefrite Lúpica/sangue , Nefrite Lúpica/complicações , Quimioterapia de Manutenção , Ácido Micofenólico/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva , Taxa de Sobrevida
14.
BMC Gastroenterol ; 19(1): 11, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30646848

RESUMO

BACKGROUND: Mitochondrial neurogastrointestinal encephalopathy (MNGIE), due to mutations in TYMP, often presents with gastrointestinal symptoms. Two sisters, initially managed for Crohn's disease based upon clinical, imaging and pathological findings, were later found to have MNGIE. The cases provide novel clinicopathological insight, for two further reasons: both sisters remain ambulant and in employment in their late 20s and 30s; diagnosis in one sister was made after a suspected azathioprine-precipitated acute illness. CASE PRESENTATION: A 25-year-old female presented with diarrhoea, vomiting, abdominal pain, and bloating. Faecal calprotectin, colonic biopsies and magnetic resonance enterography were consistent with a diagnosis of Crohn's disease. Azathioprine initiation preceded admission with a sore throat, headache, myalgia, and pyrexia. Withdrawal led to rapid clinical improvement. MRI brain revealed persistent, extensive white matter changes. Elevated plasma and urine thymidine and deoxyuridine, and genetic testing for TYMP variants, confirmed MNGIE. Testing of the patient's sister, also diagnosed with Crohn's disease, revealed identical variants. In this context, retrospective review of colonic biopsies identified histological findings suggestive of MNGIE. CONCLUSIONS: Azathioprine interference in nucleic acid metabolism may interact with the mitochondrial DNA depletion of MNGIE. Nucleotide supplementation, proposed for treatment by manipulating mitochondrial nucleoside pools, may require caution. The late onset and mild phenotype observed confirms presentation can occur later in life, and may reflect residual thymidine phosphorylase activity. Clinicians should consider measuring plasma thymidine levels in suspected Crohn's disease to rule out MNGIE, particularly if white matter abnormalities are identified on neuroimaging.


Assuntos
Doença de Crohn/diagnóstico , Gastroenteropatias/diagnóstico , Gastroenteropatias/patologia , Encefalomiopatias Mitocondriais/diagnóstico , Encefalomiopatias Mitocondriais/patologia , Adulto , Idade de Início , Azatioprina/efeitos adversos , Desoxiuridina/sangue , Desoxiuridina/urina , Diagnóstico Diferencial , Feminino , Humanos , Fenótipo , Mutação Puntual , Estudos Retrospectivos , Timidina/sangue , Timidina/urina , Timidina Fosforilase/genética , Substância Branca/patologia
15.
Dig Dis Sci ; 64(3): 875-879, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30542812

RESUMO

BACKGROUND: Thiopurines are classically used in Crohn's disease (CD). Treatment fails in a proportion of patients either due to adverse events (AE) or lack of efficacy. Increasing use of anti-TNFα biologic drugs may have had impact on thiopurines usage. AIM: To evaluate the evolving use of azathioprine (AZA) monotherapy in the era of biologics. METHODS: The study retrospectively analyzed clinical records of all CD patients who started treatment with AZA monotherapy at our center since 1990. Dates of starting AZA and treatment failure (TF) were collected. We defined AZA TF if it was withdrawn due to lack of efficacy or AE, or biologics were added. RESULTS: A total of 383 patients were included: 46.5% were males and mean age was 31 (range 17-84) years. Median follow-up was 43 (range 0.2-289) months. Overall, 147 patients (38%) experienced TF. Median cumulative survival time of AZA was 126 (95% CI 105-147) months. Proportion of patients with AZA TF increased along time: 7 patients in 1990-1995 (4.7% of all TF); 8 in 1996-2000 (5.4%); 22 in 2001-2005(15%); 41 in 2006-2010 (28%); 69 in 2011-2014 (47%) (p = 0.04). 7%, 21%, 4%, 45%, and 33.3% of patients moved to biologics in each period, respectively (χ2 = 13.07; p < 0.05). Seventy-four patients (18.4%) stopped AZA due to AE, and 73(19%) due to lack of efficacy. Regarding AZA indication, prevention of postoperative recurrence obtained better results than steroid dependency (p = 0.001); perianal fistulizing CD predicted poorer outcomes (p = 0.002). CONCLUSION: An important proportion of CD patients under AZA monotherapy experienced TF in our experience. Although AZA monotherapy remains useful for CD in the era of biologics, current clinical practice is shifting to anti-TNFα biologic drugs in an increasing proportion of patients.


Assuntos
Azatioprina/uso terapêutico , Doença de Crohn/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Imunossupressores/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Azatioprina/efeitos adversos , Produtos Biológicos/uso terapêutico , Doença de Crohn/diagnóstico , Doença de Crohn/imunologia , Feminino , Fármacos Gastrointestinais/efeitos adversos , Humanos , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Espanha , Fatores de Tempo , Falha de Tratamento , Adulto Jovem
16.
Transplant Proc ; 50(10): 3925-3927, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30577288

RESUMO

BACKGROUND: Azathioprine (AZA) is the drug recommended for the continuation of immunosuppressive treatment after renal transplant in women during pregnancy. CASE REPORT: A 37-year-old Japanese female developed agranulocytosis and severe alopecia after initiation of AZA (50 mg), used as an alternative to mycophenolate mofetil (MMF, 1000 mg) therapy in anticipation of a planned pregnancy. Within 4 days of the initiation of AZA therapy, the patient developed a high fever, leucopenia, and cranial alopecia. Genetic testing revealed a homozygous polymorphism of NUDT15 (rs116855232, NM_018283.3:c.415C>T: p.Arg139Cys), which has previously been identified as a risk factor for AZA-related complications in patients with inflammatory bowel disease. CONCLUSION: Genetic screening for NUDT15 could contribute to the prevention of serious adverse reactions to AZA and provide the opportunity for personalized medicine. Identification of a safe alternative to MMF during pregnancy after a renal transplant is a problem to be resolved in the future.


Assuntos
Azatioprina/efeitos adversos , Imunossupressores/efeitos adversos , Transplante de Rim , Pirofosfatases/genética , Adulto , Agranulocitose/induzido quimicamente , Alopecia/induzido quimicamente , Feminino , Rejeição de Enxerto/prevenção & controle , Homozigoto , Humanos , Transplante de Rim/métodos , Polimorfismo de Nucleotídeo Único/genética , Gravidez , Fatores de Risco
18.
Medicine (Baltimore) ; 97(34): e11814, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30142769

RESUMO

Azathioprine (AZA) 2 to 2.5 mg/kg/d is recommended for European patients with Crohn disease (CD), but several Asian studies reported that low dose of AZA was also effective to treat CD. To confirm those observations, we perform this prospective observational study to compare the efficacy and safety of low and standard doses of AZA in the treatment of active CD.This was a prospective, open-labeled observational study. Two hundred twenty-six active CD patients were divided into 2 groups and treated with AZA 1.5 or 2.0 mg/kg/d respectively, combined with steroid therapy. Patients were followed up for 96 weeks. The complete remission (CR) rate, response rate, relapse rate, and adverse effect rate were assessed at weeks 24, 48, and 96 by intention-to-treat (ITT) analysis.Azathioprine 1.5 mg/kg/d showed no significant difference compared with AZA 2 mg/kg/d in CR rate, response rate and relapse rate by ITT analysis at week 24, 48, or 96 (all P > .05). Their adverse effect rates had no significant difference either (P > .05). Up to 21.7% (49/226) of the patients reported adverse events and 69.4% (34/49) of them were myelosuppresion.Azathioprine 1.5 mg/kg/d combined with steroids is as effective as AZA 2.0 mg/kg/d to induce remission of active CD in the first 6 months, and to maintain remission of inactive CD in the first 2 years, without increasing the recurrence of active CD after clinical remission. The most common adverse effect is myelosuppression.


Assuntos
Azatioprina/administração & dosagem , Doença de Crohn/tratamento farmacológico , Imunossupressores/administração & dosagem , Adulto , Azatioprina/efeitos adversos , Feminino , Seguimentos , Glucocorticoides/uso terapêutico , Humanos , Imunossupressores/efeitos adversos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Indução de Remissão , Resultado do Tratamento
19.
Transplant Proc ; 50(6): 1878-1880, 2018 Jul - Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30056920

RESUMO

Recipients of allotransplants are more susceptible to viral infections, among which the human papilloma virus infection is an independent factor inducing precancerous lesions and cancers of both the anogenital and the cervicocephalic region. MATERIALS AND METHODS: The study included a group of 69 allogenic kidney transplantation recipients aged 20 to 70, who were treated with cyclosporine, azathioprine, and prednisone. The patients in whom the macroscopic examination of the oral mucosa revealed lesions were qualified for a biopsy. The infection with human papilloma virus (HPV) was confirmed by a histopathological examination and genotyping with the use of polymerase chain reaction (PCR) and Hybrid Capture II test. RESULTS: Papillomatous lesions in the oral cavity occurred in 36.1% of the research group participants. The HPV16 virus was the most common genotype in this group of patients (25%). The pathologic changes in the oral cavity were predominantly situated on the gingivae. In the group of transplant recipients, clinical changes resulting from HPV infection occurred within a period of 2 years following the transplantation. Cyclosporine used in the immunosuppression scheme has correlated in as many as 53.7% of cases of allogenic kidney transplant recipients with the appearance of clinical signs and symptoms of HPV infection. In 50% of cases there was a correlation with acute kidney transplant rejection. When induction therapy (anti-thymocyte globulin [ATG] and muromonab-CD3 [OKT3]) was applied, at least 1 oral cavity lesion in each case of allogenic transplant recipients was reported. CONCLUSIONS: Typing of HPV with the use of molecular methods should be a standard diagnostic technique.


Assuntos
Imunossupressores/efeitos adversos , Transplante de Rim , Boca/virologia , Infecções por Papillomavirus/etiologia , Adulto , Idoso , Azatioprina/efeitos adversos , Ciclosporina/efeitos adversos , Feminino , Humanos , Imunossupressão/métodos , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Papillomaviridae , Infecções por Papillomavirus/epidemiologia , Prednisona/efeitos adversos
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