What Risk Factors Are Associated With Antithyroid Drug-Induced Agranulocytosis?
What Risk Factors Are Associated With Antithyroid Drug-Induced Agranulocytosis?
What risk factors are associated with agranulocytosis in patients receiving propylthiouracil or methimazole?
The antithyroid drugs (ATDs) propylthiouracil (PTU) and methimazole are associated with a rare incidence of agranulocytosis, which is characterized by fever, malaise, gingivitis, oropharyngeal infection, and/or absolute granulocyte count < 500/mm. A retrospective study found an incidence of agranulocytosis of 0.35% and 0.37% with methimazole and PTU, respectively.
A transient granulocytopenia (granulocyte count, < 1500/mm) may occur in patients with Graves' disease, some patients of African descent, and in some patients who receive ATDs; this must be distinguished from ATD-induced agranulocytosis. Agranulocytosis usually occurs within 90 days of treatment initiation but can occur a year or more later. It may also occur after renewed exposure following previous uneventful use.
Some studies have found a relationship between ATD-induced agranulocytosis and dose. Tsuboi and colleagues determined that patients receiving an initial methimazole dose of 30 mg had a significantly higher incidence of agranulocytosis compared with those who received an initial dose of 15 mg. Patients receiving an initial lower dose had an incidence 10 times lower than those receiving a higher dose. Similarly, Cooper and colleagues found that patients receiving a methimazole dose > 40 mg daily had over 8 times higher risk for agranulocytosis than patients receiving lower doses. A relationship between PTU and dose is less clear.
In a retrospective review of 21,800 patients receiving ATDs (duration, 15.7 ± 8.4 months), Bahrami found that the majority of agranulocytosis occurred within the first few weeks of ATD therapy. However, it could occur at any time and was not associated with age, sex, or duration of therapy. In addition, no patients receiving a methimazole dose < 20 mg daily developed agranulocytosis.
Some studies found a higher incidence in patients older than 40 years and more fatal outcomes in patients younger than 65 years. Other studies did not find an association between ATD-induced agranulocytosis and patient age.
Risk may be associated with genetics. The human leukocyte antigen class II genes containing the DRB1*08032 allele were found to be associated with methimazole-induced agranulocytosis. This suggests that the mechanism may be autoimmune mediated.
Patients should have a baseline differential white blood cell count established prior to PTU or methimazole initiation. Routine monitoring is controversial and not recommended by some authorities. Tajiri and Noguchi suggested that clinicians should consider normal white blood cell agranulocytosis at least during the first 3 months of ATD therapy, and granulocyte count measurement in patients with a white blood cell count < 4.0 x 10/L.
Patients receiving PTU or methimazole should be educated about the signs and symptoms of agranulocytosis. One small retrospective review found that 100% of patients with ATD-induced agranulocytosis reported fever and 89% reported a sore throat. Patients who display signs or symptoms of agranulocytosis should discontinue the antithyroid agent and seek immediate medical attention.
Question
What risk factors are associated with agranulocytosis in patients receiving propylthiouracil or methimazole?
|
|
Response from Joanna Maudlin Pangilinan, PharmD, BCOP Pharmacist, Comprehensive Cancer Center, University of Michigan Health System, Ann Arbor, Michigan |
The antithyroid drugs (ATDs) propylthiouracil (PTU) and methimazole are associated with a rare incidence of agranulocytosis, which is characterized by fever, malaise, gingivitis, oropharyngeal infection, and/or absolute granulocyte count < 500/mm. A retrospective study found an incidence of agranulocytosis of 0.35% and 0.37% with methimazole and PTU, respectively.
A transient granulocytopenia (granulocyte count, < 1500/mm) may occur in patients with Graves' disease, some patients of African descent, and in some patients who receive ATDs; this must be distinguished from ATD-induced agranulocytosis. Agranulocytosis usually occurs within 90 days of treatment initiation but can occur a year or more later. It may also occur after renewed exposure following previous uneventful use.
Some studies have found a relationship between ATD-induced agranulocytosis and dose. Tsuboi and colleagues determined that patients receiving an initial methimazole dose of 30 mg had a significantly higher incidence of agranulocytosis compared with those who received an initial dose of 15 mg. Patients receiving an initial lower dose had an incidence 10 times lower than those receiving a higher dose. Similarly, Cooper and colleagues found that patients receiving a methimazole dose > 40 mg daily had over 8 times higher risk for agranulocytosis than patients receiving lower doses. A relationship between PTU and dose is less clear.
In a retrospective review of 21,800 patients receiving ATDs (duration, 15.7 ± 8.4 months), Bahrami found that the majority of agranulocytosis occurred within the first few weeks of ATD therapy. However, it could occur at any time and was not associated with age, sex, or duration of therapy. In addition, no patients receiving a methimazole dose < 20 mg daily developed agranulocytosis.
Some studies found a higher incidence in patients older than 40 years and more fatal outcomes in patients younger than 65 years. Other studies did not find an association between ATD-induced agranulocytosis and patient age.
Risk may be associated with genetics. The human leukocyte antigen class II genes containing the DRB1*08032 allele were found to be associated with methimazole-induced agranulocytosis. This suggests that the mechanism may be autoimmune mediated.
Patients should have a baseline differential white blood cell count established prior to PTU or methimazole initiation. Routine monitoring is controversial and not recommended by some authorities. Tajiri and Noguchi suggested that clinicians should consider normal white blood cell agranulocytosis at least during the first 3 months of ATD therapy, and granulocyte count measurement in patients with a white blood cell count < 4.0 x 10/L.
Patients receiving PTU or methimazole should be educated about the signs and symptoms of agranulocytosis. One small retrospective review found that 100% of patients with ATD-induced agranulocytosis reported fever and 89% reported a sore throat. Patients who display signs or symptoms of agranulocytosis should discontinue the antithyroid agent and seek immediate medical attention.
Source...