Background/Purpose: Approximately 1% of the population rely on chronic glucocorticoid (GC) prescription to control autoimmune and inflammatory conditions. Risk of GC induced adrenal insufficiency (GC-AI) in patients treated with chronic GC was reported to be 48.7% (95% CI 36.9-60.6).  Management of GC-AI requires appropriate monitoring and education to prevent adrenal crisis. Clofutriben is an 11β-hydroxysteroid dehydrogenase (HSD-1) inhibitor in development to prevent/reverse GC toxicity whilst maintaining GC efficacy. We aimed to determine whether co-administration of clofutriben can decrease risk of prednisolone-associated biochemical adrenal insufficiency.

Methods: The interaction of prednisolone and clofutriben on hypothalamic-pituitary-adrenal axis function was studied in patients with polymyalgia rheumatica, who received prednisolone 10 mg daily prior to the trial, and had stable (absent or low) disease activity. Participants entered a 2-week blinded prednisolone 10 mg run-in (n=37) followed by 2-week treatment with prednisolone + clofutriben 6 mg. Prednisolone dose co-administered with clofutriben was 10 mg (n=13), 15 mg (n=12), or 20 mg (n=11). Morning plasma adrenocorticotrophic hormone (ACTH) and serum cortisol were measured prior to dosing at the end of each period. Analysis of variance was conducted on the intent-to-treat dataset.

Results: Patients treated with prednisolone + placebo showed ACTH of 18.4 (95% CI 11.9-24.8) ng/L and cortisol of 7.7 (95% CI 6.1-9.2) mg/dL. When treated with prednisolone + clofutriben, ACTH increased to 32.1 (95% CI 25.6-38.6) ng/L and cortisol increased to 11.0 (95% CI 9.4-12.5).  In patients treated with prednisolone + clofutriben, ACTH and cortisol increased with each prednisolone dose level. Suppressed morning cortisol concentrations (≤5.0 mg/dL) were observed in 34% patients taking prednisolone alone, but only in 14% of patients taking prednisolone + clofutriben. 

Conclusion: In patients with polymyalgia rheumatica chronically treated with prednisolone, clofutriben increased morning ACTH and cortisol concentrations after 2 weeks of therapy, even with prednisolone dose increase. These data support a hypothesis that co-administration of HSD-1 inhibitors with glucocorticoids might mitigate risk of GC-AI.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/hypothalamic-pituitary-adrenal-axis-suppression-by-prednisolone-reversed-by-the-11%ce%b2-hydroxysteroid-dehydrogenase-type-1-inhibitor-clofutriben/