Analysis of 754 Cases of Antithyroid Drug-Induced Agranulocytosis Over 30 Years in Japan

ATDs are associated with a variety of side effects that include rare but potentially life-threatening complications.

“ATDs are associated with a variety of side effects that include rare but potentially life-threatening complications [4,115,116] .”

Agranulocytosis occurs in about 0.1-0.15% of patients, usually within the first 3 months of ATD treatment.

“It occurs in about 0.1-0.15% of patients (usually within the first 3 months of treatment) [116] .”

Eighty-nine percent of the reported patients developed agranulocytosis, and 11% developed pancytopenia or aplastic anemia.

“Eighty-nine percent developed agranulocytosis, and 11% developed pancytopenia or aplastic anemia.”

Thirty of the events (4%) were fatal.

“Thirty of the events (4%) were fatal.”

Two of the three recent reports were from Japan and one from Denmark; in both countries the majority of patients are treated with MMI, so data are more limited for PTU-associated agranulocytosis.

“Two studies were from Japan and one was from Denmark.In both countries the majority of patients are treated with MMI, so data are more limited for PTU-associated agranulocytosis.”

The second study was based on a national database for adverse drug reactions, which may have included some patients reported in the first study.

“The second study was based on a national database for adverse drug reactions, which may have included some patients reported in the first study (128).”

The average age of patients developing agranulocytosis was slightly older (45 vs. 40 years), an observation that has been made by others.

“The average age of patients developing agranulocytosis was slightly older (45 vs. 40 years), an observation that has been made by others.”

Seventy-two percent of patients developed agranulocytosis within 60 days of starting ATD, and 85% within 90 days.

“Seventy-two percent developed agranulocytosis within 60 days of starting ATD, and 85% within 90 days.”

At the onset of agranulocytosis, the average MMI dose was 25 mg/d and the average PTU dose was 217 mg/d.

“At the onset of agranulocytosis, the average MMI dose was 25 mg/d and the average PTU dose was 217 mg/d.”

Three recent reports of large numbers of ATD-treated patients who developed hematologic complications provide information on risk factors, treatment, and outcomes.

“Three recent reports of large numbers of ATD-treated patients who developed hematologic complications provide information on risk factors, treatment, and outcomes (127-129).”

A total of 754 Graves' disease patients who developed ATD-induced hematologic complications were reported, for an estimated incidence of 0.1%-0.15%.

“A total of 754 GD patients who developed ATD-induced hematologic complications were reported, for an estimated incidence of 0.1%-0.15%.”

In 7% of patients, agranulocytosis occurred later than 4 months after starting ATD, but some of these patients had discontinued the medication for long periods and developed agranulocytosis after a second or subsequent exposure.

“In 7% of patients, agranulocytosis occurred later than 4 months after starting ATD, but some of these patients had discontinued the medication for long periods of time and developed agranulocytosis after a second or subsequent exposure.”

Of the 754 reported patients, 725 received MMI, 28 received PTU, and one received both drugs.

“Of them, 725 patients received MMI, 28 received PTU, and one received both drugs.”

In patients with ATD-induced agranulocytosis who had at least one prior granulocyte count measured, 21% had a normal WBC count within a week and 53% within 2 weeks before developing agranulocytosis.

“In a recent analysis of 211 patients with ATD-induced agranulocytosis who had at least one prior granulocyte count measured, 21% had a normal WBC count within a week and 53% within 2 weeks before developing agranulocytosis (128).”

Most side effects of MMI are dose-related and occur within the first 3 months of treatment.

“Because most side effects of MMI are dose-related and occur within the first 3 months of treatment (128), high doses of MMI (e.g., >30 mg for an adolescent or adult) should rarely be used initially.”

In adults, agranulocytosis is dose dependent with MMI and rarely occurs at low doses (e.g., 5-10 mg/d).

“In adults, agranulocytosis is dose dependent with MMI and rarely occurs at low doses (e.g., 5-10 mg/d) (128,324,335).”

Agranulocytosis has been reported in about 0.3% of adult patients taking MMI or PTU.

“Agranulocytosis has been reported in about 0.3% of adult patients taking MMI or PTU (128,324,335).”

When agranulocytosis develops, 95% of the time it occurs in the first 100 days of therapy.

“When agranulocytosis develops, 95% of the time it occurs in the first 100 days of therapy (128,324,335).”

Both agranulocytosis and liver failure developing during MMI and PTU therapy mostly occur during the initial 3 months of therapy, but this risk can recur when the drug is reintroduced after a relatively long period.

“Another aspect to consider is that both agranulocytosis and liver failure developing during MMI and PTU therapy mostly occur during the initial 3 months of therapy (128), but this risk can recur when the drug is reintroduced after a relatively long period of time (177).”