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Rheumatoid Arthritis
Published in Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide, Clinical Innovation in Rheumatology, 2023
Brent A. Luedders, Ted R. Mikuls, James R. O’Dell, Bryant R. England
Insights from the human genome project inspired the precision medicine approach. In RA, a better understanding of the human genome and how it interacts with medications could allow us to tailor therapies. This is already being utilized in a minority of RA patients who may be treated with azathioprine. Deficiency of the enzyme thiopurine S-methyltransferase (TPMT), which is responsible for metabolism of azathioprine, is associated with an increased risk for hematologic toxicity from azathioprine,114 and in patients with known deficient activity, there have been recommendations to either choose alternative agents or start at a reduced dose.115 Broader precision medicine RA treatment through pharmacogenomics may be on the horizon. A systematic review and meta-analysis identified more than twenty-five single nucleotide polymorphisms (SNPs) corresponding to genes involved in T cell function, NFκB, and TNF signaling that were predictive of response to anti-TNF treatment.116 These and additional SNPs may also be leveraged to predict response to other existing and yet-to-be-developed DMARDs. While currently focused on selecting the best therapy, pharmacogenomics also provides the opportunity to inform providers and patients on the selection of the optimal medication dose as well as the risks of adverse effects.
Paediatric clinical pharmacology
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
Thiopurine methyltransferase (TPMT). TPMT is a cytosolic enzyme metabolising thiopurine drugs. The phenotypic distribution of TPMT activity may be measured in red blood and is trimodal in healthy adult volunteers: 89% have high activity, 11 % have an intermediate activity, and approximately 1 individual in 300 has severely compromised enzyme activity. This polymorphism is inherited as an autosomal recessive trait [36]. Three major point mutations in the TPMT gene (localised in chromosome 6p22.3) are responsible for the low TPMT activity and identified in the genotyping process.
Pharmacology, Pharmacogenetics, and Pharmacoepidemiology: Three P’s of Individualized Therapy
Published in Brian Leyland-Jones, Pharmacogenetics of Breast Cancer, 2020
Thiopurine methyltransferase (TPMT) is an enzyme that converts thiopurine prodrugs, such as mercaptopurine, into inactive methylated metabolites. Prior to inactivation, mercaptopurine is converted into a variety of active nucleotide metabolites that are incorporated into DNA and RNA, thereby inducing an antileukemic effect. Patients with an inherited TPMT deficiency suffer severe, potentially fatal hematopoietic toxicity when exposed to standard doses of mercaptopurine (and other thiopurine prodrugs such as azathioprine and thioguanine). More than 95% of the clinically relevant TPMT mutations are accounted for by three nonsynonymous SNPs (TPMT*2, TPMT*3A, and TPMT*3C) (22). TPMT activity is inherited as an autosomal codominant trait with approximately 95% of the population homozygous for the wild-type allele TPMT*1 (that have full enzyme activity), 10% heterozygous for the polymorphism (that have intermediate levels of enzyme activity), and 1 in 300 individuals will carry two mutant TPMT alleles (that do not express functional TPMT) (23). Using a pharmacogenetic test, developed at St. Jude Hospital, patients are often classified according to their levels of TPMT activity into normal, intermediate, and deficient. This test has a concordance rate of 100% between genotype and phenotype with studies revealing no long- term outcome changes related to dosage individualization based on the TPMT status of a patient (24) (Fig.3). This illustrates how the clinical application of pharmacogenetics can be used to minimize toxicity without compromising efficacy.
A rare case of Azathioprine-induced leukopenia in an European woman
Published in Acta Clinica Belgica, 2022
Wautier Séverine, De Koninck Xavier, Coche Jean-Charles
A 26-year-old European woman with febrile neutropenia was admitted to our department. The patient was diagnosed with Crohn’s disease after presenting terminal ileitis and caecal fistula a few months prior to hospitalisation. Despite initiating antibiotic therapy and subsequent budesonide administration, the patient complained of abdominal cramps and intense pain. Moreover, genetic testing did not detect thiopurine S‐methyltransferase (TPMT) variants TPMT*2, TPMT*3B, and TPMT*3 C. Subsequently, the patient was administered AZA (2.5 mg/kg); the white blood cell count was measured fortnightly during the initial 2 months of AZA administration. The patient showed grade III leukopenia and severe neutropenia [660 neutrophils/mm3 (reference range: 2000–7500/mm3)] in week 6 of AZA treatment. Consequently, AZA treatment was discontinued. However, the patient presented fever and abdominal pain after two days and was subsequently hospitalised. Blood sampling confirmed neutropenia with mild thrombocytopenia and anaemia (Figure 1). There were no abnormal circulating cells or vitamin deficiency. Furthermore, viral serology was negative for HIV, HBV, HCV, EBV, CMV, and parvovirus B19.
Safety considerations when using drugs to treat pruritus
Published in Expert Opinion on Drug Safety, 2020
Kayla Fourzali, Gil Yosipovitch
Azathioprine is a purine analog that interferes with DNA production and therefore B and T cell proliferation. It has been shown to have antipruritic effects in AD and intractable pruritus [68,72]. Adverse effects include the potential for severe leukopenias, for which laboratory monitoring of blood counts is recommended. A systemic hypersensitivity reaction characterized by severe gastrointestinal symptoms, fever, malaise, and potential for hypotensive shock occurs in a subset of patients within the first several weeks of treatment. Signs of this reaction warrant the immediate discontinuation of therapy [73]. Of particular concern with this medication is the apparent increased risk of malignancy, particularly for non-melanoma skin cancer, which increases with dosage, duration of use and sun exposure [73]. Of note, reduced activity of the thiopurine methyl-transferase (TPMT) due to genetic polymorphisms is common in the general population in particular in African Americans and affect the toxicity of azathioprine and risk of associated severe myelosuppression. Thus, baseline TPMT levels should be obtained prior to initiating therapy, with dosage adjustments accordingly or avoidance of this medication if very low or absent [66].
An update on treatment of ulcerative colitis
Published in Expert Opinion on Orphan Drugs, 2019
Thiopurines induce adverse events in up to 30% of cases, requiring drug cessation in 20%-40% of these cases, with an estimated number needed to harm (NNH) of 14 [34]. The toxicity may be dose-independent (idiosyncratic or allergic) or dose-dependent. The most common are nausea, vomiting, bone marrow suppression, pancreatitis, cutaneous eruption, and hepatitis. In addition, thiopurines increase the risk of opportunistic infection, non-melanoma skin cancers and lymphomas [35]. Prior to initiation of treatment an evaluation of thiopurine methyltransferase (TPMT) assay is recommended to identify patients at risk of severe dose-dependent myelosuppression. In addition, the evaluation of the level of thiopurine metabolites, namely, 6-thioguanine nucleotide (6-TGN) is helpful to optimize dose and efficacy [35].