Interferon may be tool to guide glucocorticoid dosage in SLE

Australian researchers have generated a five-gene molecular signature for glucocorticoid exposure in SLE.

The study, published in The Lancet Rheumatology, aimed to find a useful tool for glucocorticoid dose titration and monitoring in clinical practice.

While the study found a significant association of the five-gene signature with increasing glucocorticoid dose, there was high interpatient variation for any given glucocorticoid dose.

“Given high interpatient variability, and a lack of association with demographic and laboratory variables, we next examined whether type I interferon status had an effect on glucocorticoid gene signature expression in SLE,” it said.

“A weaker correlation existed between the five-gene signature and glucocorticoid dose in patients with a high type I interferon gene signature (r=0·29, p<0·0001) compared with patients with a low type I interferon gene signature (r=0·42, p<0·0001), suggesting an inhibitory effect of type I interferon on the ability of glucocorticoids to induce these genes in vivo.”

“We also observed higher SLE disease activity index (SLEDAI) score in patients with a high type I interferon gene signature compared with patients with a low type I interferon gene signature, when matched for glucocorticoid dose, suggesting that poorer glucocorticoid-induced gene induction in patients with a high type I interferon gene signature might be associated with poorer efficacy,” the study said.

The researchers, a team including senior investigator Professor Eric Morand from Monash University, said there was “a striking scarcity of evidence with which to guide dosing of glucocorticoids in SLE”.

“A five-gene glucocorticoid signature identified here robustly differentiated the presence of glucocorticoid exposure in patients enrolled in a large randomised clinical trial who were taking more than 25 mg prednisolone per day.”

“Although a clear dose-dependent effect was observed, wide variation among patients was also seen, and the relationship between signature expression and glucocorticoid dose in patients was only sufficient to show a moderate correlation with glucocorticoid dosing overall.”

They said the evidence from their hypothesis-generating research supported the concept that type I interferon might contribute to glucocorticoid resistance in patients with SLE.

However a second gene signature using genes that did not appear to be influenced by type 1 interferon was no better in discriminating glucocorticoid exposure in SLE patients.

A Comment article in the journal said developing a tool to facilitate appropriate glucocorticoid dosage and to screen patients with poor responses to glucocorticoids was important.

“The study inspires us to guide glucocorticoid treatment for patients with SLE based on data at the molecular level, but first the results need to be validated in further studies.”

They said prospective studies in inception cohorts of patients with SLE would be ideal for that purpose.

“The glucocorticoid signature and the effect of interferon should be deeply investigated in various cell types through new methods in the future.”

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