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Postgraduate Medicine Jan 2023Takayasu's arteritis is a rare, chronic, large vessel vasculitis which affects the aorta and its large branches. Early diagnosis is important to prevent serious end... (Review)
Review
Takayasu's arteritis is a rare, chronic, large vessel vasculitis which affects the aorta and its large branches. Early diagnosis is important to prevent serious end organ damage, including to stroke and ischemic heart disease. Studies have demonstrated treatment response with methotrexate, azathioprine, and tumor necrosis factor (TNF) inhibitors. This article aims to describe to the reader key features of Takayasu's arteritis and highlights updated evidence in the diagnosis and management of these patients. We also review the 2021 ACR guidelines for Takayasu's arteritis and correlate them to the updated evidence discussed throughout the review. An extensive literature search was conducted via PUBMED, including the words 'Takayasu's diagnostic criteria,' 'Takayasu's treatment,' 'Takayasu's diagnosis,' 'Takayasu's imaging', and 'Takayasu's diagnostic criteria.' Search was filtered to include clinical trials, randomized controlled trials, systematic reviews, and meta-analyses. Articles in the English language or with English translation and published by the date of 20 December 2021 were included.
Topics: Humans; Takayasu Arteritis; Azathioprine
PubMed: 36588528
DOI: 10.1080/00325481.2022.2159723 -
United European Gastroenterology Journal Nov 2019Autoimmune hepatitis is a rare and chronic liver disease that is characterised by increased serum transaminases and immunoglobulin G, inflammatory liver histology and... (Review)
Review
Autoimmune hepatitis is a rare and chronic liver disease that is characterised by increased serum transaminases and immunoglobulin G, inflammatory liver histology and presence of circulating autoantibodies. An autoimmune hepatitis diagnosis justifies life-long treatment in most patients in order to prevent development of cirrhosis and end-stage liver disease. The cornerstone of treatment is steroid induction therapy followed by maintenance therapy with azathioprine, which is effective in most cases. For patients who do not respond to standard treatment, second-line treatment with other immunosuppressants can be effective. Treatment should be aimed at biochemical remission of the disease, which is defined as normalization of transaminases and immunoglobulin G. Patients should be monitored intensively during the first months of treatment in order to monitor side-effects, assess symptoms and individualise treatment. Specialist consultation should be sought in difficult-to-treat patients. Future studies and networking initiatives should result in optimization of current treatment strategies in autoimmune hepatitis.
Topics: Alanine Transaminase; Aspartate Aminotransferases; Autoantibodies; Azathioprine; Disease Progression; Glucocorticoids; Hepatitis, Autoimmune; Humans; Immunoglobulin G; Immunosuppressive Agents; Induction Chemotherapy; Maintenance Chemotherapy; Mercaptopurine; Mycophenolic Acid; Prednisolone
PubMed: 31700628
DOI: 10.1177/2050640619872408 -
Gut and Liver Jul 2020Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease, characterized by the elevation of aminotransferases, presence of anti-nuclear antibody or anti-smooth... (Review)
Review
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease, characterized by the elevation of aminotransferases, presence of anti-nuclear antibody or anti-smooth muscle antibody, elevated immunoglobulin G (IgG), and interface hepatitis/plasma-lymphocytic inflammation based on histology. Recent epidemiological studies have indicated an increasing trend in the prevalence of AIH worldwide, especially in male patients; this trend may suggest the alteration of environmental triggers of disease onset over time. As no disease-specific biomarker or histological finding is currently available, AIH requires a clinical diagnosis, and a validated diagnostic scoring system with acceptable specificity and sensitivity has been proposed. Regarding treatment, corticosteroids and azathioprine are recommended, and in those who exhibit an incomplete response or those who are intolerant to these drugs, second-line therapy, such as mycophenolate mofetil, is considered. Overall, the long-term outcome is excellent in patients with complete biochemical responses, while life-long maintenance treatment may be required since the cessation of immunosuppressive agents frequently leads to the relapse of the disease. Acute-onset AIH does occur, and the diagnosis is very challenging due to the lack of serum autoantibodies or elevated IgG. The unmet needs include earlier diagnosis, intervention with disseminated clinical practice guidelines, and recognition and improvement of patients' health-related quality of life with the development of novel corticosteroid-free treatment regimens.
Topics: Autoantibodies; Azathioprine; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Quality of Life
PubMed: 32301319
DOI: 10.5009/gnl19261 -
Leukemia Jul 2022Maintenance therapy (MT) with oral methotrexate (MTX) and 6-mercaptopurine (6-MP) is essential for the cure of acute lymphoblastic leukemia (ALL). MTX and 6-MP interfere... (Review)
Review
Maintenance therapy (MT) with oral methotrexate (MTX) and 6-mercaptopurine (6-MP) is essential for the cure of acute lymphoblastic leukemia (ALL). MTX and 6-MP interfere with nucleotide synthesis and salvage pathways. The primary cytotoxic mechanism involves the incorporation of thioguanine nucleotides (TGNs) into DNA (as DNA-TG), which may be enhanced by the inhibition of de novo purine synthesis by other MTX/6-MP metabolites. Co-medication during MT is common. Although Pneumocystis jirovecii prophylaxis appears safe, the benefit of glucocorticosteroid/vincristine pulses in improving survival and of allopurinol to moderate 6-MP pharmacokinetics remains uncertain. Numerous genetic polymorphisms influence the pharmacology, efficacy, and toxicity (mainly myelosuppression and hepatotoxicity) of MTX and thiopurines. Thiopurine S-methyltransferase (encoded by TPMT) decreases TGNs but increases methylated 6-MP metabolites (MeMPs); similarly, nudix hydrolase 15 (encoded by NUDT15) also decreases TGNs available for DNA incorporation. Loss-of-function variants in both genes are currently used to guide MT, but do not fully explain the inter-patient variability in thiopurine toxicity. Because of the large inter-individual variations in MTX/6-MP bioavailability and metabolism, dose adjustments are traditionally guided by the degree of myelosuppression, but this does not accurately reflect treatment intensity. DNA-TG is a common downstream metabolite of MTX/6-MP combination chemotherapy, and a higher level of DNA-TG has been associated with a lower relapse hazard, leading to the development of the Thiopurine Enhanced ALL Maintenance (TEAM) strategy-the addition of low-dose (2.5-12.5 mg/m/day) 6-thioguanine to the 6-MP/MTX backbone-that is currently being tested in a randomized ALLTogether1 trial (EudraCT: 2018-001795-38). Mutations in the thiopurine and MTX metabolism pathways, and in the mismatch repair genes have been identified in early ALL relapses, providing valuable insights to assist the development of strategies to detect imminent relapse, to facilitate relapse salvage therapy, and even to bring about changes in frontline ALL therapy to mitigate this relapse risk.
Topics: Humans; Mercaptopurine; Methotrexate; Methyltransferases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Thioguanine
PubMed: 35654820
DOI: 10.1038/s41375-022-01591-4 -
Angiogenesis Nov 2022With recent progress in modeling liver organogenesis and regeneration, the lack of vasculature is becoming the bottleneck in progressing our ability to model human...
With recent progress in modeling liver organogenesis and regeneration, the lack of vasculature is becoming the bottleneck in progressing our ability to model human hepatic tissues in vitro. Here, we introduce a platform for routine grafting of liver and other tissues on an in vitro grown microvascular bed. The platform consists of 64 microfluidic chips patterned underneath a 384-well microtiter plate. Each chip allows the formation of a microvascular bed between two main lateral vessels by inducing angiogenesis. Chips consist of an open-top microfluidic chamber, which enables addition of a target tissue by manual or robotic pipetting. Upon grafting a liver microtissue, the microvascular bed undergoes anastomosis, resulting in a stable, perfusable vascular network. Interactions with vasculature were found in spheroids and organoids upon 7 days of co-culture with space of Disse-like architecture in between hepatocytes and endothelium. Veno-occlusive disease was induced by azathioprine exposure, leading to impeded perfusion of the vascularized spheroid. The platform holds the potential to replace animals with an in vitro alternative for routine grafting of spheroids, organoids, or (patient-derived) explants.
Topics: Animals; Azathioprine; Coculture Techniques; Humans; Liver; Microfluidics; Organoids
PubMed: 35704148
DOI: 10.1007/s10456-022-09842-9 -
Gastroenterology Mar 2021Pregnant women with inflammatory bowel disease (IBD) may require biologic or thiopurine therapy to control disease activity. Lack of safety data has led to therapy... (Observational Study)
Observational Study
BACKGROUND & AIMS
Pregnant women with inflammatory bowel disease (IBD) may require biologic or thiopurine therapy to control disease activity. Lack of safety data has led to therapy discontinuation during pregnancy, with health repercussions to mother and child.
METHODS
Between 2007 and 2019, pregnant women with IBD were enrolled in a prospective, observational, multicenter study across the United States. The primary analysis was a comparison of 5 outcomes (congenital malformations, spontaneous abortions, preterm birth, low birth weight, and infant infections) among pregnancies exposed vs unexposed in utero to biologics, thiopurines, or a combination. Bivariate analyses followed by logistic regression models adjusted for relevant confounders were used to determine the independent effects of specific drug classes on outcomes of interest.
RESULTS
Among 1490 completed pregnancies, there were 1431 live births. One-year infant outcomes were available in 1010. Exposure was to thiopurines (n = 242), biologics (n = 642), or both (n = 227) vs unexposed (n = 379). Drug exposure did not increase the rate of congenital malformations, spontaneous abortions, preterm birth, low birth weight, and infections during the first year of life. Higher disease activity was associated with risk of spontaneous abortion (hazard ratio, 3.41; 95% confidence interval, 1.51-7.69) and preterm birth with increased infant infection (odds ratio, 1.73; 95% confidence interval, 1.19-2.51).
CONCLUSIONS
Biologic, thiopurine, or combination therapy exposure during pregnancy was not associated with increased adverse maternal or fetal outcomes at birth or in the first year of life. Therapy with these agents can be continued throughout pregnancy in women with IBD to maintain disease control and reduce pregnancy-related adverse events. ClinicalTrials.gov, Number: NCT00904878.
Topics: Adult; Anti-Inflammatory Agents; Azathioprine; Biological Products; Colitis, Ulcerative; Crohn Disease; Drug Therapy, Combination; Female; Humans; Infant, Newborn; Intestinal Mucosa; Mercaptopurine; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Prenatal Exposure Delayed Effects; Prospective Studies; United States
PubMed: 33227283
DOI: 10.1053/j.gastro.2020.11.038 -
Actas Dermo-sifiliograficas Jun 2020Pemphigus vulgaris (PV) is an uncommon, serious disease that is treated with systemic corticosteroids and corticosteroid-sparing agents.
BACKGROUND
Pemphigus vulgaris (PV) is an uncommon, serious disease that is treated with systemic corticosteroids and corticosteroid-sparing agents.
OBJECTIVES
To describe and analyze the demographic and clinical characteristics of patients with PV.
MATERIAL AND METHODS
Retrospective cohort study of adults diagnosed with PV over a period of 12years.
RESULTS
PV presented with mucosal lesions in 20 of the 32 patients studied (63%); the most common site was the oral mucosa followed by the vulva. Mucosal involvement was more common in women (P=.03). Lesions were found at more than 1 mucosal site in patients whose disease began in the mucosa, independently of age or sex (P=.003). Disease onset before the age of 40years was associated with generalized skin lesions (P=.003), a need for corticosteroid-sparing therapy (P=.05), and refractory PV (P=.02). Azathioprine was the most widely prescribed corticosteroid-sparing agent (in 22 patients). Eight patients (25%) were dependent on corticosteroids and disease recurred in 26 (81%). Complete remission, with or without treatment, was achieved in 15 patients (47%). Patients remained disease-free for a median of 14months, and 2 patients died (6%).
CONCLUSION
Onset before the age of 40 years could be a sign of poor prognosis in patients with PV, as it was significantly associated with a higher risk of generalized skin involvement, a need for corticosteroid-sparing therapy, and refractory disease.
Topics: Adrenal Cortex Hormones; Adult; Azathioprine; Female; Humans; Pemphigus; Retrospective Studies; Skin Diseases
PubMed: 32466985
DOI: 10.1016/j.ad.2019.10.004 -
Journal of Clinical Oncology : Official... Sep 2019Infant acute lymphoblastic leukemia (ALL) is characterized by () gene rearrangements and coexpression of myeloid markers. The Interfant-06 study, comprising 18 national... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Infant acute lymphoblastic leukemia (ALL) is characterized by () gene rearrangements and coexpression of myeloid markers. The Interfant-06 study, comprising 18 national and international study groups, tested whether myeloid-style consolidation chemotherapy is superior to lymphoid style, the role of stem-cell transplantation (SCT), and which factors had independent prognostic value.
MATERIALS AND METHODS
Three risk groups were defined: low risk (LR): germline; high risk (HR): -rearranged and older than 6 months with WBC count 300 × 10/L or more or a poor prednisone response; and medium risk (MR): all other -rearranged cases. Patients in the MR and HR groups were randomly assigned to receive the lymphoid course low-dose cytosine arabinoside [araC], 6-mercaptopurine, cyclophosphamide (IB) or experimental myeloid courses, namely araC, daunorubicin, etoposide (ADE) and mitoxantrone, araC, etoposide (MAE).
RESULTS
A total of 651 infants were included, with 6-year event-free survival (EFS) and overall survival of 46.1% (SE, 2.1) and 58.2% (SE, 2.0). In West European/North American groups, 6-year EFS and overall survival were 49.4% (SE, 2.5) and 62.1% (SE, 2.4), which were 10% to 12% higher than in other countries. The 6-year probability of disease-free survival was comparable for the randomized arms (ADE+MAE 39.3% [SE 4.0; n = 169] IB 36.8% [SE, 3.9; n = 161]; log-rank = .47). The 6-year EFS rate of patients in the HR group was 20.9% (SE, 3.4) with the intention to undergo SCT; only 46% of them received SCT, because many had early events. rearrangement was the strongest prognostic factor for EFS, followed by age, WBC count, and prednisone response.
CONCLUSION
Early intensification with postinduction myeloid-type chemotherapy courses did not significantly improve outcome for infant ALL compared with the lymphoid-type course IB. Outcome for infant ALL in Interfant-06 did not improve compared with that in Interfant-99.
Topics: Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Cytarabine; Daunorubicin; Disease-Free Survival; Etoposide; Female; Gene Rearrangement; Germ-Line Mutation; Histone-Lysine N-Methyltransferase; Humans; Infant; Infant, Newborn; Male; Mercaptopurine; Mitoxantrone; Myeloid-Lymphoid Leukemia Protein; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Survival Rate; Treatment Outcome
PubMed: 31283407
DOI: 10.1200/JCO.19.00261 -
Xenobiotica; the Fate of Foreign... Jan 2020The thiopurine drugs azathioprine and mercaptopurine are effective in the treatment of disorders of immune regulation and acute lymphoblastic leukaemia. Although... (Review)
Review
The thiopurine drugs azathioprine and mercaptopurine are effective in the treatment of disorders of immune regulation and acute lymphoblastic leukaemia. Although developed in the 1950s, thiopurines remained relevant in the anti-tumour necrosis factor biologic era, finding widespread use as a co-immunomodulator. Step changes in the management of patients treated with thiopurines have reduced the incidence of severe, sometimes life-threatening toxicity. Testing for thiopurine methyltransferase (TPMT) deficiency directs a safe initial dose for therapy. The introduction of red cell thioguanine nucleotide (TGN) monitoring provides a basis for dose adjustment and the identification of patients with high levels of red cell methylmercaptopurine (MMP) and an increase in the MMP:TGN ratio. These patients are at risk for hepatotoxicity and where TGN levels are sub-therapeutic, non-response to therapy. Switching thiopurine hypermethylators to low-dose thiopurine and allopurinol combination therapy resolves hepatoxicity and increases sub-therapeutic TGN levels to regain clinical response. variants are a common cause of severe myelotoxicity in Asian populations where the frequency of TPMT deficiency is low. There is increasing evidence that testing for NUDT15 and TPMT deficiency in all populations prior to the start of thiopurine therapy is clinically useful and should be the first step in personalising thiopurine therapy.
Topics: Azathioprine; Drug Hypersensitivity; Erythrocytes; Female; Genotype; Humans; Male; Mercaptopurine; Methyltransferases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Purine-Pyrimidine Metabolism, Inborn Errors; Purines
PubMed: 31682552
DOI: 10.1080/00498254.2019.1688424 -
Nature Communications Sep 2023Temozolomide (TMZ) is a standard treatment for glioblastoma (GBM) patients. However, TMZ has moderate therapeutic effects due to chemoresistance of GBM cells through...
Temozolomide (TMZ) is a standard treatment for glioblastoma (GBM) patients. However, TMZ has moderate therapeutic effects due to chemoresistance of GBM cells through less clarified mechanisms. Here, we demonstrate that TMZ-derived 5-aminoimidazole-4-carboxamide (AICA) is converted to AICA ribosyl-5-phosphate (AICAR) in GBM cells. This conversion is catalyzed by hypoxanthine phosphoribosyl transferase 1 (HPRT1), which is highly expressed in human GBMs. As the bona fide activator of AMP-activated protein kinase (AMPK), TMZ-derived AICAR activates AMPK to phosphorylate threonine 52 (T52) of RRM1, the catalytic subunit of ribonucleotide reductase (RNR), leading to RNR activation and increased production of dNTPs to fuel the repairment of TMZ-induced-DNA damage. RRM1 T52A expression, genetic interruption of HPRT1-mediated AICAR production, or administration of 6-mercaptopurine (6-MP), a clinically approved inhibitor of HPRT1, blocks TMZ-induced AMPK activation and sensitizes brain tumor cells to TMZ treatment in mice. In addition, HPRT1 expression levels are positively correlated with poor prognosis in GBM patients who received TMZ treatment. These results uncover a critical bifunctional role of TMZ in GBM treatment that leads to chemoresistance. Our findings underscore the potential of combined administration of clinically available 6-MP to overcome TMZ chemoresistance and improve GBM treatment.
Topics: Animals; Humans; Mice; AMP-Activated Protein Kinases; Drug Resistance, Neoplasm; Glioblastoma; Hypoxanthines; Mercaptopurine; Ribonucleotide Reductases; Temozolomide; Hypoxanthine Phosphoribosyltransferase
PubMed: 37737247
DOI: 10.1038/s41467-023-41663-2