GTI may help ID who’s at risk for glucocorticoid side effects

Index considers frequency, severity of treatment-related side effects

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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ANCA-associated vasculitis (AAV) patients receiving a cumulative dose of at least 935 mg of glucocorticoids over six months are more likely to see clinically meaningful side effects, according to a study using calculations based on the Glucocorticoid Toxicity Index (GTI).

The findings suggest the GTI, which considers the frequency and severity of glucocorticoid-related side effects, may help identify who’s at a higher risk for side effects in research and clinical settings. The information may come in handy since current AAV guidelines recommend lower glucocorticoid doses or Tavneos (avacopan) as an alternative to glucocorticoids to keep AAV under control and reduce treatment side effects.

The study, “Prospective study of complications and sequelae of glucocorticoid therapy in ANCA-associated vasculitis,” was published in RDM Open by researchers in Germany.

AAV causes inflammation to small blood vessels, driving damage to organs and affecting their function. Treatment to achieve and maintain remission, or no symptoms of AAV appearing for a time, often involves glucocorticoids. These can have substantial side effects, however, particularly at high doses or for long periods of time.

“Severe courses of disease and frequent relapses lead to high cumulative GC [glucocorticoid] doses with a considerable risk for GC-associated side effects,” the researchers wrote. Relapses are periods when symptoms return after being under control.

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Here, the researchers used the GTI to watch for side effects associated with glucocorticoids and how they change over six months. GTI looks both at current toxicity over six months and cumulative toxicity (entire disease duration). A change of 10 points or more is defined as clinically important.

The study included 138 people (55.1% women; mean age 56.8) with a diagnosis of AAV. As for the type of AAV, about half (51.4%) had granulomatosis with polyangiitis, 42 (30.4%) had eosinophilic granulomatosis with polyangiitis, and 25 (18.1%) had microscopic polyangiitis.

The median current exposure to glucocorticoids was 501.5 mg and the mean total cumulative dose was 9,014 mg over a median disease duration of 57 months, or nearly five years. Most patients (79%) remained in remission over that period.

GC-associated complications were common, as only 8% had no GTI score worsening over the entire disease duration. The most common side effects were skin thinning, osteoporosis (bone weakening), and muscle problems. As expected, the higher the exposure to glucocorticoids, the greater the associated toxicity.

About half the patients (50.7%) saw no change in recent glucocorticoid-related toxicity, 29.7% showed an increase in toxicity, and 19.6% had a toxicity reduction over six months.

Increasing toxicity was more common among those with active disease than those in remission (65.5 vs. 20.2%). At the same time, the mean current exposure to glucocorticoids in active disease patients was 1,745 mg versus 240 mg in those in remission.

The GTI increase in about 20% of patients in remission and receiving a low glucocorticoid dose further emphasize “that even low daily GC doses cause toxicity when applied over a longer period of time,” the researchers wrote.

Patients with active disease who received higher glucocorticoid doses were more likely to have weight gain, diabetes, sleep disturbances, and high arterial blood pressure than those in stable remission.

“In contrast, long-term GC toxicities such as skin [thinning] were significantly more common in patients in stable remission due to the high cumulative GC exposure over the entire treatment period,” the researchers wrote.

Moreover, increasing toxicity caused by glucocorticoids was linked to worse patient-reported physical functioning.

There were no significant differences in total cumulative glucocorticoid dose, current six-month exposure, or changes in glucocorticoid-associated toxicity between sexes.

However, cumulative glucocorticoid-associated toxicity was higher in women than men. Osteoporosis was also significantly more common among women, while acne was more frequent in men. Patients 65 or older were more likely to have cataracts, skin thinning, and diabetes. A cumulative dose of 935 mg within about six months was highly predictive of clinically meaningful toxicity.

“Patients with a cumulative GC dose of 935 mg or more showed an 80% likelihood for a clinically meaningful change in GTI,” the researchers wrote. “To our knowledge, [this] has never been reported thus far.” The threshold doesn’t “apply for all GC toxicities” as “osteoporosis and skin atrophy, for instance, will only occur after a long-term GC exposure.”

“Our data support the urgent need to limit GC exposure in AAV patients, which can be achieved by developing and establishing efficacious immunosuppressive agents,” the researchers said.