A new clinical study published in theAnnals of the Rheumatic Diseasesfound that adding the investigational drug clofutriben to corticosteroid therapy may lower steroid-related toxicity in patients with polymyalgia rheumatica (PMR). While corticosteroids are effective, their long-term use is limited by cumulative side effects. In short-term testing, clofutriben reduced toxicity biomarkers enough to potentially allow doubling or tripling of steroid doses while maintaining improved safety. While remarkably effective at controlling inflammation and pain, glucocorticoids like prednisolone are also notorious for severe side effects, including osteoporosis, metabolic dysfunction, cardiovascular risks, and adrenal suppression. These toxicities often limit their long-term usefulness, leaving patients with few alternatives. In the newly published proof-of-concept trial, this research tested whether the 11β-hydroxysteroid dehydrogenase type 1 (HSD-1) inhibitor clofutriben could protect against steroid-related toxicity by reducing intracellular exposure to active glucocorticoids, without sacrificing the therapeutic benefit. The study enrolled adults diagnosed with PMR, who first received prednisolone 10 mg per day with placebo for 2 weeks. They then continued treatment for another 2 weeks with clofutriben added at prednisolone doses of 10, 15, 20, or 30 mg per day. Of the participants, 49 completed the placebo phase and 47 completed the clofutriben phase with evaluable results. When clofutriben was combined with only 10 mg of prednisolone, 5 patients experienced clinical relapse, and participants reported worsening symptoms and physical disability. Similar effects were seen at 15 mg. However, at higher doses of 20 mg and 30 mg, no relapses occurred, and symptom control matched or exceeded the initial treatment phase using prednisolone 10 mg alone. Inflammatory biomarkers followed the same pattern, demonstrating stable disease activity at the higher steroid doses. Across all steroid dose levels, clofutriben substantially reduced biological markers linked to prednisolone toxicity, including bone turnover impairment, abnormal lipid metabolism, cardiovascular stress indicators, hypercoagulability signalling, and adrenal suppression. Overall, these results suggests that HSD-1 inhibition reduces harm more strongly than it reduces therapeutic benefit. The trial represents the first proof in a rheumatic disease population that an HSD-1 inhibitor can both prevent and reverse steroid-associated toxicity. With data from larger trials, a fixed-dose steroid-clofutriben combination could replace current prednisolone prescriptions. Buttgereit, F., Everding, A., Andreica, I., Kellner, H. L., Schuch, F., Weyand, C., Stewart, P. M., Merkel, P. A., Dejaco, C., Czerwiec, F. S., Desai, K., & Katz, D. A. (2025). Effects of clofutriben, a selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor, on the efficacy and toxicity of prednisolone in patients with polymyalgia rheumatica: a single-blind controlled trial with sequential cohorts. Annals of the Rheumatic Diseases.https://doi.org/10.1016/j.ard.2025.10.015