RESUMEN
Despite great therapeutic advances in the field of biologics, small synthetic molecules such as thiopurines, including azathioprine, mercaptopurine, and thioguanine, remain an important therapeutic pillar in the treatment of inflammatory bowel disease, other autoimmune disorders, and cancer. This review presents the latest guidelines for thiopurine administration, highlighting the importance of individualized therapy guided by pharmacogenomics. It emphasizes dose adjustment based on nudix hydrolase 15 (NUDT15) and thiopurine S-methyltransferase (TPMT) genotype, along side thiopurine S-methyltransferase activity and thiopurine metabolic profile. In addition, the article takes a critical look at emerging research in the field of thiopurine pharmaco genomics featuring novel genetic markers and technological developments in genetic testing. Finally, the potential of integrated approaches that combine genetic, meta bolic, and clinical factors to further individualize thiopurine therapy is highlighted.
Asunto(s)
Enfermedades Inflamatorias del Intestino , Mercaptopurina , Metiltransferasas , Medicina de Precisión , Humanos , Medicina de Precisión/métodos , Metiltransferasas/metabolismo , Metiltransferasas/genética , Mercaptopurina/uso terapéutico , Mercaptopurina/administración & dosificación , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/genética , Azatioprina/administración & dosificación , Farmacogenética , Pirofosfatasas/genética , Pirofosfatasas/metabolismo , Enfermedades Autoinmunes/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Genotipo , Tioguanina , Hidrolasas NudixRESUMEN
Vitiligo is an acquired chronic loss of skin pigmentation characterized by white and frequent symmetric patches, for which corticosteroids are the mainstay of treatment. Regular intake of steroids for prolonged periods is frequently associated with severe and sometimes irreversible adverse events. This study was designed to compare the effectiveness and safety profiles of azathioprine versus psoralen+ultraviolet light A (PUVA)-solar light (SOL; sunlight) to determine which agent reduces the length and adverse effects of vitiligo therapy in a better manner. This single-center, randomized, open-label, prospective case-control study recruited 100 patients. Oral mini-pulse (OMP) corticosteroid therapy was administered to all patients during the first month of the study. The first group of patients (group A) continued with azathioprine 50-mg tablet twice a day (BID), and the second group (group B) was given PUVA-SOL for 2 months with concurrent OMP. Disease activity was monitored. At the end of the study period, 58% (group A) and 50% (group B) of patients had their improved vitiligo area severity index (VASI) scores by 25%-50%. Similarly, 36% (group A) and 50% (group B) of patients improved their VASI score by more than 50%. On the global physician assessment scale, 42% (group A) and 54% (group B) patients had a good to excellent response. Based on these findings, both azathioprine and PUVA-SOL were considered as good steroid-sparing agents, primarily if used with an initial phase of concomitant oral corticosteroids.
Asunto(s)
Azatioprina , Terapia PUVA , Vitíligo , Humanos , Vitíligo/tratamiento farmacológico , Masculino , Femenino , Adulto , Estudios Prospectivos , Terapia PUVA/métodos , Azatioprina/uso terapéutico , Azatioprina/administración & dosificación , Azatioprina/efectos adversos , Persona de Mediana Edad , Estudios de Casos y Controles , Adulto Joven , Resultado del Tratamiento , Inmunosupresores/uso terapéutico , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Adolescente , Índice de Severidad de la EnfermedadRESUMEN
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a severe autoimmune disease that often involves the upper and lower respiratory tracts. In recent years, numerous studies have found a significant increase in the incidence of cancer among AAV patients, but the association between lung cancer and AAV remains inconclusive, with relatively low clinical attention. This review summarizes the current literature on the risk of lung cancer in patients with ANCA-associated vasculitis (AAV), detailing the potential mechanisms by which AAV may contribute to lung cancer, and further elucidates the inherent carcinogenic risks of immunosuppressants.There is a correlation between AAV and lung cancer, which is related to T cell senescence and damage, as well as the abnormal expression of cytokines such as IL-6 and IL-10. In AAV patients, the use of cyclophosphamide and azathioprine (AZA) alone has a clear carcinogenic risk, with frequent use of CYC potentially posing a high risk for lung cancer. Although TNF inhibitors (TNFi) combined with CYC have carcinogenic risks, there is insufficient evidence to link them directly to an increased risk of lung cancer. For patients at high risk for lung cancer, the judicious use of immunosuppressants, timely computed tomography (CT), and lung cancer screening can reduce the risk of lung cancer in AAV patients.
Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Inmunosupresores , Neoplasias Pulmonares , Humanos , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/inmunología , Inmunosupresores/uso terapéutico , Inmunosupresores/efectos adversos , Ciclofosfamida/uso terapéutico , Ciclofosfamida/efectos adversos , Azatioprina/uso terapéutico , Azatioprina/efectos adversosRESUMEN
The mechanism underlying intestinal fibrosis, the main complication of inflammatory bowel disease (IBD), is not yet fully understood, and there is no therapy to prevent or reverse fibrosis. We evaluated, in in vitro cellular models, the ability of different classes of drugs currently used in IBD to counteract two pivotal processes of intestinal fibrosis, the differentiation of intestinal fibroblasts to activated myofibroblasts using CCD-18Co cells, and the epithelial-to-mesenchymal transition (EMT) of intestinal epithelial cells using Caco-2 cells (IEC), both being processes induced by transforming growth factor-ß1 (TGF-ß1). The drugs tested included mesalamine, azathioprine, methotrexate, prednisone, methylprednisolone, budesonide, infliximab, and adalimumab. The expression of fibrosis and EMT markers (collagen-I, α-SMA, pSmad2/3, occludin) was assessed by Western blot analysis and by immunofluorescence. Of the drugs used, only prednisone, methylprednisolone, budesonide, and adalimumab were able to antagonize the pro-fibrotic effects induced by TGF-ß1 on CCD-18Co cells, reducing the fibrosis marker expression. Methylprednisolone, budesonide, and adalimumab were also able to significantly counteract the TGF-ß1-induced EMT process on Caco-2 IEC by increasing occludin and decreasing α-SMA expression. This is the first study that evaluates, using in vitro cellular models, the direct antifibrotic effects of drugs currently used in IBD, highlighting which drugs have potential antifibrotic effects.
Asunto(s)
Budesonida , Transición Epitelial-Mesenquimal , Fibrosis , Enfermedades Inflamatorias del Intestino , Factor de Crecimiento Transformador beta1 , Humanos , Células CACO-2 , Transición Epitelial-Mesenquimal/efectos de los fármacos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/patología , Enfermedades Inflamatorias del Intestino/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Budesonida/farmacología , Adalimumab/farmacología , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Metilprednisolona/farmacología , Mesalamina/farmacología , Prednisona/farmacología , Miofibroblastos/efectos de los fármacos , Miofibroblastos/metabolismo , Antiinflamatorios/farmacología , Infliximab/farmacología , Infliximab/uso terapéutico , Azatioprina/farmacología , Metotrexato/farmacología , Intestinos/efectos de los fármacos , Intestinos/patología , Diferenciación Celular/efectos de los fármacosRESUMEN
The thiopurine drugs-azathioprine and mercaptopurine-are purine antimetabolites used for the treatment of autoimmune hepatitis. These drugs undergo metabolism through genetically determined pathways, which influences their effectiveness and toxicity. There is scarce information regarding the clinical effects of measuring drug metabolites in these patients. The goal of the study is to test the clinical significance of measuring thiopurine metabolites in patients unsuccessfully treated with thiopurines. Clinical and laboratory data collected for patients who were treated for autoimmune hepatitis between 2015 and 2018, and did not achieve full remission under thiopurine therapy and had thiopurine metabolite levels measured due to lack of response and suspicious side effects were chosen. We compared clinical and laboratory data before and after the therapy change. The study included 25 tests of thiopurine metabolites in 21 patients. Six tests had therapeutic levels. Three tests showed high levels leading to lowering the drug dose. In 11 cases, levels of 6-thioguanine nucleotide were low; the dose was not changed in 3 of these, and the dose was increased in the remaining 8. Shunting was observed in 5 cases, 2 of which were mild and the dose was not changed. In the remaining 3, the dose was decreased, and allopurinol was added. Significant improvements in liver enzymes were observed following dose adjustments. We showed that, in cases of suboptimal response to thiopurine treatment, measuring thiopurine metabolites had an important role in optimizing therapy. In most patients, changing the dose led to a significant improvement with no need to switch to secondline therapies.
Asunto(s)
Azatioprina , Hepatitis Autoinmune , Inmunosupresores , Mercaptopurina , Humanos , Hepatitis Autoinmune/tratamiento farmacológico , Hepatitis Autoinmune/metabolismo , Hepatitis Autoinmune/sangre , Femenino , Masculino , Mercaptopurina/análogos & derivados , Mercaptopurina/uso terapéutico , Mercaptopurina/metabolismo , Mercaptopurina/sangre , Persona de Mediana Edad , Azatioprina/uso terapéutico , Adulto , Inmunosupresores/uso terapéutico , Anciano , Resultado del Tratamiento , Nucleótidos de Guanina/sangre , Estudios Retrospectivos , Monitoreo de Drogas/métodos , Tionucleótidos/sangreRESUMEN
This case involves a man with longstanding Crohn's disease on azathioprine therapy who developed a rare manifestation of tuberculosis, presenting as a subcutaneous tuberculous abscess and tuberculous spondylitis. The patient's immunocompromised state due to azathioprine raised the risk for opportunistic infections. The unique aspects include the absence of disseminated tuberculosis and the development of tuberculous paraspinal and subcutaneous abscesses in a patient with Crohn's disease. The case underscores the importance of vigilance for rare infections in immunosuppressed individuals and highlights the need for tuberculosis screening before initiating immunosuppressive therapies. The patient was successfully treated with antituberculous medication, emphasising the importance of a tailored approach in managing such cases.
Asunto(s)
Absceso , Antituberculosos , Enfermedad de Crohn , Tuberculosis de la Columna Vertebral , Humanos , Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/tratamiento farmacológico , Masculino , Absceso/microbiología , Absceso/tratamiento farmacológico , Tuberculosis de la Columna Vertebral/tratamiento farmacológico , Tuberculosis de la Columna Vertebral/complicaciones , Tuberculosis de la Columna Vertebral/diagnóstico , Antituberculosos/uso terapéutico , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Azatioprina/uso terapéutico , Azatioprina/efectos adversos , Huésped Inmunocomprometido , Adulto , Persona de Mediana EdadRESUMEN
Background: Azathioprine is one of the earliest immunosuppressants prescribed for several autoimmune diseases. Yet there is a lack of research on the impact of azathioprine on pulp healing following the pulp capping procedure. Aim: This study aimed to investigate the effect of azathioprine on the healing ability of mechanically exposed dogs' dental pulps following direct pulp capping with mineral trioxide aggregate (MTA), bio-aggregates (BA), and Calcium hydroxide (Ca(OH)2). Methods: Four mongrel dogs were randomly assigned to two groups (two dogs/30 teeth in each group): immunosuppressed (group I) and control (group II). Group I received azathioprine for two months before surgical treatments and until the dogs were euthanized. Fifteen class V buccal cavities were performed in each dog. Each group was randomly divided into three subgroups (10 teeth each) based on the pulp capping substance. The pulps in subgroups A, B, and C were immediately capped with MTA, BA, and Ca(OH)2, respectively. Inflammation and dentine bridge development were histopathologically evaluated and scored at one and two months. The data were statistically analyzed. Results: The immunosuppressed group exhibited statistically greater inflammatory cell count and decreased dentine bridge thickness, compared to the control group in all subgroups (p < 0.05). Conclusion: Azathioprine has an adverse effect on the healing of exposed dogs' dental pulp following direct pulp capping with MTA, BA, and Ca(OH)2. Therefore, patients using azathioprine as an immunosuppressive medication may experience delayed healing of mechanically exposed pulps following capping with MTA, BA, or Ca(OH)2.
Asunto(s)
Azatioprina , Compuestos de Calcio , Hidróxido de Calcio , Recubrimiento de la Pulpa Dental , Inmunosupresores , Óxidos , Silicatos , Animales , Perros , Azatioprina/farmacología , Azatioprina/uso terapéutico , Recubrimiento de la Pulpa Dental/veterinaria , Óxidos/farmacología , Inmunosupresores/uso terapéutico , Inmunosupresores/farmacología , Silicatos/farmacología , Compuestos de Calcio/farmacología , Hidróxido de Calcio/farmacología , Hidróxido de Calcio/uso terapéutico , Enfermedades de los Perros/tratamiento farmacológico , Compuestos de Aluminio/farmacología , Pulpa Dental/efectos de los fármacos , Combinación de Medicamentos , Masculino , Cicatrización de Heridas/efectos de los fármacos , Materiales de Recubrimiento Pulpar y Pulpectomía/farmacología , FemeninoRESUMEN
BACKGROUND: Alopecia areata (AA) is an autoimmune pathology manifested by loss of hair. OBJECTIVE: To evaluate and compare the efficacy and safety of tofacitinib and azathioprine in patients with AA and variants. METHODS: In this double-blind randomized controlled trail (RCT) carried out at the Department of Dermatology, Medical Teaching Institute-Lady Reading Hospital (MTI-LRH), Peshawar, Pakistan, patients aged ≥ 12 years diagnosed with AA, alopecia totalis (AT) or alopecia universalis (AU) with minimum 50% scalp hair loss for a period ≥ 06 years were included. Patients were randomly assigned to receive oral tofacitinib 5 mg twice daily (Group I) or oral azathioprine 2 mg/kg body weight once daily (Group II). The primary endpoint was Severity of Alopecia Tool (SALT) score, evaluated at baseline and 06 months follow-up. Safety was consistently assessed during the study. RESULTS: A total of 104 patients underwent random allocation into either the tofacitinib group (n = 52) or the azathioprine group (n = 52). The mean (SD) age of patients was 20.23 (7.14) years and 22.26 (8.07) years, while the mean (SD) disease duration was 6.59 (4.01) years and 7.98 (4.40) years in in Group I and II, respectively. Overall, 40 (38.5%) patients were adolescents while 70 (67.3%) were male. 52 (50%) had AA, 37 (35.5%) had AT and 15 (14.5%) had AU. Mean baseline SALT score in tofacitinib group was 91.02 ± 10.21 and azathioprine group was 91.02 ± 10.63, which at 06 months follow-up improved to 14.1 ± 24.6 and 63.9 ± 33.9, respectively (difference, 11.5 points; 95% confidence interval, 38.3-61.3, p < 0.0001). Overall, no major adverse effects and no difference among the minor adverse effects in the two groups (04 adverse events for tofacitinib group and 08 for azathioprine group: p = 0.23) was observed. CONCLUSIONS: Efficacy of tofacitinib was significantly higher than azathioprine, whilst both drugs were well-tolerated in patients with AA and variants.
Asunto(s)
Alopecia Areata , Alopecia , Azatioprina , Piperidinas , Pirimidinas , Humanos , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Pirimidinas/uso terapéutico , Piperidinas/administración & dosificación , Piperidinas/efectos adversos , Piperidinas/uso terapéutico , Masculino , Alopecia Areata/tratamiento farmacológico , Alopecia Areata/diagnóstico , Método Doble Ciego , Femenino , Azatioprina/administración & dosificación , Azatioprina/efectos adversos , Azatioprina/uso terapéutico , Adolescente , Adulto , Adulto Joven , Alopecia/tratamiento farmacológico , Resultado del Tratamiento , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Administración Oral , Niño , Pirroles/administración & dosificación , Pirroles/efectos adversos , Índice de Severidad de la Enfermedad , Inmunosupresores/efectos adversos , Inmunosupresores/administración & dosificaciónRESUMEN
BACKGROUND AND OBJECTIVE: Thioguanine (TG), azathioprine (AZA), and mercaptopurine (MP) are thiopurine prodrugs commonly used to treat diseases, such as leukemia and inflammatory bowel disease (IBD). 6-thioguanine nucleotides (6-TGNs) have been commonly used for monitoring treatment. High levels of 6-TGNs in red blood cells (RBCs) have been associated with leukopenia, the cutoff levels that predict this side effect remain uncertain. Thiopurines are metabolized and incorporated into leukocyte DNA. Measuring levels of DNA-incorporated thioguanine (DNA-TG) may be a more suitable method for predicting clinical response and toxicities such as leukopenia. Unfortunately, most methodologies to assay 6-TGNs are unable to identify the impact of NUDT15 variants, effecting mostly ethnic populations (e.g., Chinese, Indian, Malay, Japanese, and Hispanics). DNA-TG tackles this problem by directly measuring thioguanine in the DNA, which can be influenced by both TPMT and NUDT15 variants. While RBC 6-TGN concentrations have traditionally been used to optimize thiopurine therapy due to their ease and affordability of measurement, recent developments in liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques have made measuring DNA-TG concentrations in lymphocytes accurate, reproducible, and affordable. The objective of this systematic review was to assess the current evidence of DNA-TG levels as marker for thiopurine therapy, especially with regards to NUDT15 variants. METHODS: A systematic review and meta-analysis were performed on the current evidence for DNA-TG as a marker for monitoring thiopurine therapy, including methods for measurement and the illustrative relationship between DNA-TG and various gene variants (such as TPMT, NUDT15, ITPA, NT5C2, and MRP4). PubMed and Embase were systematically searched up to April 2024 for published studies, using the keyword "DNA-TG" with MeSH terms and synonyms. The electronic search strategy was augmented by a manual examination of references cited in articles, recent reviews, editorials, and meta-analyses. A meta-analysis was performed using R studio 4.1.3. to investigate the difference between the coefficients (Fisher's z-transformed correlation coefficient) of DNA-TG and 6-TGNs levels. A meta-analysis was performed using RevMan version 5.4 to investigate the difference in DNA-TG levels between patients with or without leukopenia using randomized effect size model. The risk of bias was assessed using the Newcastle-Ottowa quality assessment scale. RESULTS: In this systematic review, 21 studies were included that measured DNA-TG levels in white blood cells for either patients with ALL (n = 16) or IBD (n = 5). In our meta-analysis, the overall mean difference between patients with leukopenia (ALL + IBD) versus no leukopenia was 134.15 fmol TG/µg DNA [95% confidence interval (CI) (83.78-184.35), P < 0.00001; heterogeneity chi squared of 5.62, I2 of 47%]. There was a significant difference in DNA-TG levels for patients with IBD with and without leukopenia [161.76 fmol TG/µg DNA; 95% CI (126.23-197.29), P < 0.00001; heterogeneity chi squared of 0.20, I2 of 0%]. No significant difference was found in DNA-TG level between patients with ALL with or without leukopenia (57.71 fmol TG/µg DNA [95% CI (- 22.93 to 138.35), P < 0.80]). DNA-TG monitoring was found to be a promising method for predicting relapse rates in patients with ALL, and DNA-TG levels are likely a better predictor for leukopenia in patients with IBD than RBC 6-TGNs levels. DNA-TG levels have been shown to correlate with various gene variants (TPMT, NUDT15, ITPA, and MRP4) in various studies, points to its potential as a more informative marker for guiding thiopurine therapy across diverse genetic backgrounds. CONCLUSIONS: This systematic review strongly supports the further investigation of DNA-TG as a marker for monitoring thiopurine therapy. Its correlation with treatment outcomes, such as relapse-free survival in ALL and the risk of leukopenia in IBD, underscores its role in enhancing personalized treatment approaches. DNA-TG effectively identifies NUDT15 variants and predicts late leukopenia in patients with IBD, regardless of their NUDT15 variant status. The recommended threshold for late leukopenia prediction in patients with IBD with DNA-TG is suggested to be between 320 and 340 fmol/µg DNA. More clinical research on DNA-TG implementation is mandatory to improve patient care and to improve inclusivity in thiopurine treatment.
Asunto(s)
Monitoreo de Drogas , Nucleótidos de Guanina , Mercaptopurina , Tioguanina , Tionucleótidos , Humanos , Azatioprina/uso terapéutico , Azatioprina/farmacocinética , Biomarcadores/sangre , ADN/genética , Monitoreo de Drogas/métodos , Nucleótidos de Guanina/sangre , Mercaptopurina/farmacocinética , Mercaptopurina/uso terapéutico , Mercaptopurina/sangre , Hidrolasas Nudix , Pirofosfatasas/genética , Pirofosfatasas/metabolismo , Tioguanina/farmacocinética , Tionucleótidos/sangreRESUMEN
Aims: This study aimed to investigate the impact of genetic polymorphisms of thiopurine methyltransferase (TPMT) and NUDT15 on pharmacokinetics profile of mercaptopurine in healthy adults in China. Methods: Blood samples were obtained from 45 healthy adult volunteers who were administered azathioprine. Genomic DNA was extracted and sequenced for TPMT and NUDT15. The plasma concentrations of 6-mercaptopurine (6-MP) were determined by ultra-performance liquid chromatography-tandem mass spectrometry. Finally, pharmacokinetic parameters were calculated based on the time-concentration curve. Results: Among the 45 healthy adult volunteers enrolled in the study, two TPMT allelic variants and three NUDT15 allelic variants were detected. In total, six genotypes were identified, including TPMT*1/*1&NUDT15*1/*1, TPMT*1/*1&NUDT15*1/*2, TPMT*1/*1&NUDT15*1/*9, TPMT*1/*1&NUDT15*2/*5, TPMT*1/*6&NUDT15*1/*2, and TPMT*1/*3&NUDT15*1/*2. The results indicated that Area Under Curve (AUC) of 6-MP in volunteers with TPMT*1/*3&NUDT15*1/*2 and TPMT*1/*6&NUDT15*1/*2 were 1.57-1.62-fold higher than in individuals carrying the wild type (TPMT*1/*1&NUDT15*1/*1). Compared with wild type, the half-life (T1/2) of TPMT*1/*6&NUDT15*1/*2 was extended by 1.98 times, whereas T1/2 of TPMT*1/*3&NUDT15*1/*2 decreased by 67%. The maximum concentration (Cmax) of TPMT*1/*3&NUDT15*1/*2 increased significantly by 2.15-fold, whereas the corresponding clearance (CL/F) decreased significantly by 58.75%. Conclusion: The findings of this study corroborate the notion that various genotypes of TPMT and NUDT15 can impact the pharmacokinetics of mercaptopurine, potentially offering foundational insights for personalized mercaptopurine therapy.
Asunto(s)
Genotipo , Voluntarios Sanos , Mercaptopurina , Metiltransferasas , Pirofosfatasas , Humanos , Metiltransferasas/genética , Metiltransferasas/metabolismo , Adulto , Pirofosfatasas/genética , Pirofosfatasas/metabolismo , Masculino , Mercaptopurina/farmacocinética , Mercaptopurina/metabolismo , Femenino , Alelos , Polimorfismo Genético/genética , China , Polimorfismo de Nucleótido Simple/genética , Pueblo Asiatico/genética , Adulto Joven , Persona de Mediana Edad , Azatioprina/farmacocinética , Azatioprina/metabolismo , Hidrolasas NudixRESUMEN
Ulcerative colitis (UC) is a chronic inflammatory bowel disease usually treated by azathioprine. It is a well-established risk factor for colorectal cancers and extraintestinal malignancies. Nevertheless, the risk of myeloid leukemia in patients with UC is less known. We report a case of a 51-year-old patient, with a history of extensive ulcerative colitis, who was treated with azathioprine at a dose of 2.5 mg/kg/day. Seven years later, he presented an increased count of white blood cells at 25,400/µL and of platelets at 1,382,000/µL. Peripheral blood smear showed 1% blasts and 20% myelemia. The karyotype showed the Philadelphia chromosome and the RT-PCR revealed the BCR-ABL transcript. Thus, chronic myeloid leukemia (CML) was confirmed and imatinib was prescribed. This case reported a rare and serious event in a UC patient and illustrates the importance of closely monitoring this population.
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Azatioprina , Colitis Ulcerosa , Mesilato de Imatinib , Inmunosupresores , Leucemia Mielógena Crónica BCR-ABL Positiva , Humanos , Colitis Ulcerosa/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Persona de Mediana Edad , Azatioprina/efectos adversos , Azatioprina/uso terapéutico , Masculino , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Mesilato de Imatinib/uso terapéutico , Mesilato de Imatinib/efectos adversos , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéuticoRESUMEN
BACKGROUND: Immunosuppressive therapies as azathioprine (AZA), mycophenolate mofetil (MMF) and rituximab (RTX) are widely prescribed as first-line treatment to prevent relapses in NMOSD. However, the rate of response to these traditional therapies is unknown in Argentina. We aimed to describe and compare treatment failure rates in NMOSD patients included in the Argentinean MS and NMOSD registry (RelevarEM, NCT03375177). METHODS: A retrospective cohort study was conducted in NMOSD patients included in RelevarEM (a nationwide, longitudinal, observational, non-mandatory registry of MS and NMOSD in Argentina). NMOSD patients were defined based on validate diagnostic criteria. Only NMOSD patients who received AZA or MMF for at least 6 months or RTX for at least 1 month were included. Patients who were receiving AZA, MMF, or RTX and then switched to another 1 of these 3 therapies were included if the above-mentioned criteria for each drug were fulfilled. Data on patient demographics, clinical, neuroradiological findings, and treatments administered were collected. Treatment failure was defined as any new attack/relapse that occurred despite immunosuppressive treatment. RESULTS: We included 139 NMOSD patients who were receiving AZA (n = 105), MMF (n = 5) or RTX (n = 29) with a mean follow-up time of 41.3 ± 11.4 months and median of EDSS at treatment initiation of 3. We observed a reduction in the annualized relapse rate from pre-treatment to post-treatment of 51.1 %, 48.4 %, and 79.1 % respectively with a Hazard Risk relative to RTX (95 % CI) of 1.67 (1.34-3.54, p = 0.01) for AZA and 2.01 (1.86-4.43, p = 0.008) for MMF. AZA, MMF and RTX failure was observed in 45/105 (42.8 %), 2/5 (40 %) and 3/29 (10.3 %) patients, respectively. CONCLUSIONS: Treatment failure rates were higher for AZA and MMF than RTX in Argentinean NMOSD patients in a real-world setting. High-efficacy treatment increases the opportunity to prevent attacks of NMOSD.
Asunto(s)
Azatioprina , Inmunosupresores , Ácido Micofenólico , Neuromielitis Óptica , Sistema de Registros , Rituximab , Insuficiencia del Tratamiento , Humanos , Neuromielitis Óptica/tratamiento farmacológico , Femenino , Argentina , Adulto , Masculino , Inmunosupresores/uso terapéutico , Rituximab/uso terapéutico , Rituximab/administración & dosificación , Estudios Retrospectivos , Azatioprina/uso terapéutico , Persona de Mediana Edad , Ácido Micofenólico/uso terapéutico , Estudios LongitudinalesRESUMEN
BACKGROUND: Thymoma presents with several autoimmune manifestations and is associated with secondary autoimmune regulator (AIRE) deficiency. Pneumonitis has recently been described as an autoimmune manifestation associated with thymoma presenting with similar clinical, radiographic, histological, and autoantibody features as seen in patients with inherited AIRE deficiency who suffer from Autoimmune PolyEndocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED) syndrome. OBJECTIVES: To treat two patients with biopsy-proven thymoma-associated pneumonitis with lymphocyte-directed immunomodulation. METHODS: Two patients with thymoma were enrolled on IRB-approved protocols at the NIH Clinical Center. We performed history and physical examination; laboratory, radiographic, histologic and pulmonary function evaluations; and measurement of the lung-directed autoantibodies KCNRG and BPIFB1 prior to and at 1- and 6-months following initiation of lymphocyte-directed immunomodulation with azathioprine with or without rituximab. RESULTS: Combination T- and B-lymphocyte-directed immunomodulation resulted in improvement of clinical, functional, and radiographic parameters at 6-month follow-up evaluations in both patients with sustained remission up to 12-36 months following treatment initiation. CONCLUSION: Lymphocyte-directed immunomodulation remitted autoimmune pneumonitis in two patients with thymoma.
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Inmunomodulación , Timoma , Humanos , Timoma/inmunología , Timoma/complicaciones , Timoma/diagnóstico , Femenino , Masculino , Rituximab/uso terapéutico , Autoanticuerpos/inmunología , Persona de Mediana Edad , Neoplasias del Timo/inmunología , Neoplasias del Timo/complicaciones , Neoplasias del Timo/diagnóstico , Neumonía/etiología , Neumonía/inmunología , Neumonía/diagnóstico , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/etiología , Adulto , Azatioprina/uso terapéutico , Linfocitos B/inmunología , Resultado del Tratamiento , Linfocitos T/inmunologíaRESUMEN
PURPOSE: Drug-induced liver injury is becoming an increasingly important topic in drug research and clinical practice. Due to a lack of experimental animal models, predicting drug-induced liver injury in humans is challenging. Azathioprine (AZA) is a classical immunosuppressant with hepatotoxic adverse effects. The present study aimed to address the hepatoprotective effect of carvedilol (CAR) against AZA-induced hepatocellular injury via assessing redox-sensitive signals. METHOD: To achieve this purpose, rats were allocated into four groups: control, CAR only, AZA only, and CAR plus AZA groups. The induction of hepatic injury was induced by a single intraperitoneal injection of AZA at a dose of 50 mg/kg on the 6th day of the experiment. Each experimental protocol was approved and supervised by the Ethics Committee for Animal Experiments. RESULTS: The results of the present study revealed that CAR administration significantly diminished AZA-induced hepatic dysfunction, as evidenced by relief of hepatic function biomarkers and histopathological aberration induced by AZA injection. Besides, CAR restored oxidant/antioxidant balance as well as NRF2 expression. In addition, CAR suppressed inflammatory response induced by AZA challenge as evidenced by downregulation of TLR4, TNF-α, MPO, and eNOS/iNOS levels in hepatic tissue. Moreover, CAR recovered apoptotic/anti-apoptotic status by modulation of caspase-3/Bcl2 expression. CONCLUSION: Taken together, CAR protects against AZA-induced hepatic injury via antioxidant, anti-inflammatory, and anti-apoptotic activities. These findings revealed that CAR could be a good candidate for hepatic injury protection and can be added to AZA therapeutic regimen to reduce their adverse effect.
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Apoptosis , Azatioprina , Carvedilol , Enfermedad Hepática Inducida por Sustancias y Drogas , Hígado , Oxidación-Reducción , Animales , Carvedilol/farmacología , Carvedilol/uso terapéutico , Apoptosis/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Masculino , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Azatioprina/toxicidad , Ratas Wistar , Ratas , Inmunosupresores/toxicidad , Estrés Oxidativo/efectos de los fármacosRESUMEN
BACKGROUND: Azathioprine (AZA) is a widely used immunosuppressant drug. Leukopenia is a serious adverse effect of the drug which often necessitates dose reduction or drug withdrawal. Predictors of leukopenia include genetic and nongenetic factors. Genetic polymorphism of AZA-metabolizing enzyme, thiopurine S-methyltransferase (TPMT) is well established. There is inconclusive evidence about the role of Nudix hydrolase (NUDT15) gene polymorphism. This case-control study assessed the association of genetic polymorphisms of NUDT15 and TPMT with leukopenia induced by AZA. MATERIALS AND METHODS: Cases were patients on AZA who developed leukopenia (white blood cell count <4000/µl) within 1 year of treatment initiation that necessitated dose reduction or drug withdrawal. Age and gender-matched patients without leukopenia within 1 year of treatment with AZA served as controls. TPMT (3 loci: c238G to C, c460G to A, c719A to G) and NUDT15 (c 415C to T, rs116855232) genotyping were done using TPMT strip assay and polymerase chain reaction-restriction fragment length polymorphism, respectively. Genotype frequencies were noted, and the odds ratio was calculated to determine the association between genotypes and leukopenia. RESULTS: Twenty-nine subjects (15 cases and 14 controls) were enrolled. Statistically significant differences were not observed in the TPMT genotype (*1/*1 and *1/*3C) (P = 0.23) between cases and controls. NUDT15 genotypes (*1/*1 and *1/*3) (P = 0.65) also showed no statistically significant difference between cases and controls. CONCLUSION: The above genotypes do not appear to be associated with AZA-induced leukopenia in an eastern Indian population.
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Azatioprina , Inmunosupresores , Leucopenia , Metiltransferasas , Pirofosfatasas , Humanos , Leucopenia/inducido químicamente , Leucopenia/genética , Azatioprina/efectos adversos , Pirofosfatasas/genética , Metiltransferasas/genética , Estudios de Casos y Controles , Femenino , Masculino , India , Adulto , Inmunosupresores/efectos adversos , Persona de Mediana Edad , Polimorfismo Genético , Genotipo , Polimorfismo de Nucleótido Simple , Adulto Joven , Hidrolasas NudixRESUMEN
PURPOSE OF REVIEW: Chronic spontaneous urticaria (CSU) patients sometimes do not respond to second-generation antihistamine, and 10-50% patients do not even respond to four-fold the usual dose of nonsedating H1 antihistamine, which further leads to repeated courses of oral corticosteroids to abate the symptoms. There are third-line agents approved by EAACI guidelines, which include omalizumab and cyclosporine. Certain patients are even resistant to the third-line agents. In this review, various other treatment options will be discussed in patients of refractory CSU. RECENT FINDINGS: Recently, we demonstrated azathioprine as a possible third-line option, which was found noninferior to cyclosporine in antihistamine refractory CSU. There have been trials, studies, case series and reports, which suggest other putative options for refractory CSU management. SUMMARY: Studies on the management of refractory CSU are accumulating thereby expanding the armamentarium of dermatologists and allergologist against difficult-to-treat urticaria patients.
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Urticaria Crónica , Ciclosporina , Omalizumab , Humanos , Urticaria Crónica/tratamiento farmacológico , Omalizumab/uso terapéutico , Ciclosporina/uso terapéutico , Azatioprina/uso terapéutico , Resistencia a Medicamentos , Inmunosupresores/uso terapéutico , Antialérgicos/uso terapéutico , Corticoesteroides/uso terapéutico , Guías de Práctica Clínica como Asunto , Urticaria/tratamiento farmacológicoRESUMEN
Thiopurines, an effective therapy for Crohn's disease (CD), often lead to adverse events (AEs). Gene polymorphisms affecting thiopurine metabolism may predict AEs. This retrospective study in CD patients (n = 114) with TPMT activity > 5 Units/Red Blood Cells analyzed TPMT (c.238 G > C, c.460 G > A, c.719 A > G), ITPA (c.94 C > A, IVS2 + 21 A > C), and NUDT15 (c.415 C > T) polymorphisms. All patients received azathioprine (median dose 2.2 mg/kg) with 41.2% experiencing AEs, mainly myelotoxicity (28.1%). No NUDT15 polymorphisms were found, 7% had TPMT, and 31.6% had ITPA polymorphisms. AEs led to therapy modifications in 41.2% of patients. Multivariate analysis identified advanced age (OR 1.046, p = 0.007) and ITPA IVS2 + 21 A > C (OR 3.622, p = 0.015) as independent predictors of AEs. IVS2 + 21 A > C was also associated with myelotoxicity (OR 2.863, p = 0.021). These findings suggest that ITPA IVS2 + 21 A > C polymorphism and advanced age predict AEs during thiopurine therapy for CD with intermediate-normal TPMT activity.
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Azatioprina , Enfermedad de Crohn , Metiltransferasas , Pirofosfatasas , Humanos , Enfermedad de Crohn/genética , Enfermedad de Crohn/tratamiento farmacológico , Pirofosfatasas/genética , Femenino , Masculino , Adulto , Estudios Retrospectivos , Azatioprina/efectos adversos , Azatioprina/uso terapéutico , Metiltransferasas/genética , Persona de Mediana Edad , Adulto Joven , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Adolescente , Variantes Farmacogenómicas/genética , Polimorfismo de Nucleótido Simple/genética , Polimorfismo Genético/genética , Mercaptopurina/efectos adversos , Mercaptopurina/uso terapéutico , Análisis Multivariante , Anciano , Factores de Riesgo , Hidrolasas Nudix , Inosina TrifosfatasaRESUMEN
INTRODUCTION/AIMS: The impact of treatment expectations on active treatment outcomes has not been specifically investigated in neuromuscular disorders. We thus explored in myasthenia gravis (MG) the contribution of patients' pre-treatment expectations combined with an immunosuppressant drug on treatment outcomes. METHODS: This pilot correlational study involved 17 patients with generalized MG, scheduled to start immunosuppressant azathioprine. At baseline, a healthcare professional administered: (i) the Stanford Expectations of Treatment Scale; (ii) a structured checklist paper form asking patients which side-effects they expected to develop after starting azathioprine, coupled with a standardized framing of statements. Quantitative Myasthenia Gravis (QMG) score and daily dose of concomitant drugs were assessed by neurologists as clinical outcomes. Clinical outcomes and side-effects were re-assessed at 3 and 6 months, and clinical outcomes were monitored at 18 months. RESULTS: Clinically significant improvement in the QMG scores was achieved at 3 or 6 months. The level of state anxiety appeared to act as moderator of pre-treatment negative expectations (strong, positive, indicative correlation, rs = .733, p = .001). The latter were, in turn, associated with the fulfillment of side-effects that patients expected to develop with the new treatment (moderate, positive, indicative correlation, rs = .699, p = .002). No significant correlation emerged between positive and negative expectations. DISCUSSION: Our findings show a very quick clinical response and also suggest that patients' expectations and anxiety contributed to treatment outcomes, highlighting the importance of promoting safety messages and education strategies around newly introduced treatments. Future goals include evaluating a larger cohort that includes a matched control group.