Highlights
– Clofutriben, a selective 11β‑HSD1 inhibitor, attenuated many biomarker signals of prednisolone‑related toxicity across tested doses in patients with polymyalgia rheumatica (PMR).
– When combined with clofutriben, prednisolone 10 mg/day produced clinical relapses in some patients; increasing prednisolone to 20–30 mg/day restored symptom control without losing toxicity mitigation.
– Short, sequential single‑blind cohorts provide proof‑of‑concept that modulation of intracellular glucocorticoid activation can decouple some efficacy and toxicity pathways—supporting larger randomized trials to define clinical utility.
Background and clinical need
Glucocorticoids are highly effective anti‑inflammatory agents and remain the mainstay treatment for polymyalgia rheumatica (PMR), a common inflammatory condition in older adults characterized by proximal muscle pain, stiffness, elevated inflammatory markers, and substantial functional impairment. However, systemic glucocorticoid therapy causes well‑documented adverse effects—osteoporosis and fractures, metabolic disturbance (weight gain, dyslipidaemia, hyperglycaemia), cardiovascular risk, infections, and adrenal suppression—that limit long‑term use, especially in an older population that already has higher baseline risks.
One strategy to improve the therapeutic index of systemic glucocorticoids is to modulate intracellular glucocorticoid activation. The enzyme 11β‑hydroxysteroid dehydrogenase type 1 (11β‑HSD1) catalyses the conversion of inactive 11‑keto steroids to their active 11‑hydroxy forms in peripheral tissues (for example, cortisone to cortisol) and thereby amplifies local glucocorticoid exposure. Inhibiting 11β‑HSD1 has been explored in metabolic disease and offers a biologically plausible approach to reduce tissue‑specific glucocorticoid effects while preserving systemic anti‑inflammatory action if dosing is adjusted appropriately.
Study design
Buttgereit and colleagues conducted a single‑blind, sequential cohort clinical trial to test the hypothesis that pharmacologic inhibition of 11β‑HSD1 with clofutriben could selectively diminish glucocorticoid toxicity while permitting restoration of anti‑inflammatory efficacy by increasing systemic prednisolone dose.
Key design features:
- Population: Adults with PMR receiving prednisolone.
- Intervention/sequential cohorts: All participants first received prednisolone 10 mg/day plus placebo for 2 weeks (single‑blind). After this baseline period they received clofutriben in addition to prednisolone for 2 weeks with prednisolone doses varying by cohort: 10 mg/day, 15 mg/day, 20 mg/day, or 30 mg/day.
- Blinding: Single‑blind (participants blinded during the placebo period; subsequent use of clofutriben open to investigators for cohort sequential dosing).
- Outcomes: Clinical relapse, patient‑reported symptoms and disability, inflammatory biomarkers, and a broad panel of biomarkers reflecting glucocorticoid‑related adverse effects (bone turnover markers, lipid metabolism, coagulation markers, cardiovascular and adrenal function indices).
- Participant numbers: 49 and 47 participants completed each trial period with evaluable data (reporting indicates two slightly different denominators for the distinct phases/timepoints).
Key findings
The trial provides several interrelated observations of clinical and mechanistic importance.
Clinical efficacy and symptom control
When clofutriben was added while maintaining prednisolone 10 mg/day, five participants experienced clinical relapse. Participants reported more severe symptoms and increased physical disability when prednisolone was 10 mg/day or 15 mg/day coadministered with clofutriben. By contrast, prednisolone 20 mg/day and 30 mg/day given with clofutriben did not produce worsening symptoms or clinical relapses in this short timeframe, suggesting that higher systemic prednisolone dosing can restore anti‑inflammatory efficacy when intracellular activation is blocked.
Inflammatory biomarkers
Inflammatory biomarkers followed a pattern concordant with patient‑reported outcomes: worsening with clofutriben plus lower prednisolone doses (10–15 mg) and normalization with higher prednisolone doses (20–30 mg). The parallel behaviour of clinical and biomarker measures supports a pharmacologic interaction between 11β‑HSD1 inhibition and prednisolone activity.
Biomarkers of glucocorticoid toxicity
Across all prednisolone doses investigated, coadministration of clofutriben mitigated glucocorticoid‑related changes in multiple toxicity‑relevant biomarkers. The investigators reported favourable shifts in markers of bone turnover, lipid metabolism, hypercoagulability, cardiovascular risk indices, and adrenal function. In other words, clofutriben appeared to reduce surrogates of glucocorticoid harm even when systemic prednisolone dose was increased to restore efficacy.
Safety and tolerability
The short duration of each treatment period (2 weeks) limits broad conclusions about safety. Within the trial’s timeframe the main safety signal was clinical relapse in the lowest‑dose prednisolone cohort when clofutriben was coadministered. No relapses were reported in the higher‑dose cohorts. No unexpected acute adverse events were described in the source summary; longer‑term safety for clofutriben in combination with glucocorticoids remains unknown.
Interpretation and mechanistic plausibility
The results are mechanistically coherent. 11β‑HSD1 inhibition reduces intracellular regeneration of active glucocorticoids in peripheral tissues. This can reduce local glucocorticoid effects that mediate many adverse metabolic and musculoskeletal outcomes. However, for inflammatory control—particularly in tissues where glucocorticoid activation contributes to anti‑inflammatory signalling—blocking intracellular activation may reduce efficacy unless systemic (circulating) active glucocorticoid concentrations are increased to compensate. The trial’s finding that higher prednisolone doses (20–30 mg/day) restored clinical control while preserving biomarker improvements is consistent with this concept: raising systemic exposure can offset loss of intracellular regeneration but leave tissue‑specific toxicity signals attenuated because 11β‑HSD1–mediated local amplification remains blocked.
Clinical and research implications
This study provides a proof‑of‑concept that pharmacologic modulation of intracellular glucocorticoid activation could create a therapeutic window in which anti‑inflammatory efficacy is maintained while some downstream adverse effects are reduced. For clinical practice this raises several important considerations:
- Patients on prednisone (the inactive prodrug) may be particularly susceptible to 11β‑HSD1 inhibition because conversion to active prednisolone relies on this enzyme. Clinicians must be cautious if combining 11β‑HSD1 inhibitors with prednisone without adjusting glucocorticoid regimen.
- Dose adjustment of systemic glucocorticoid may be necessary when an 11β‑HSD1 inhibitor is started to avoid under‑treatment of inflammation; conversely, clinicians may be able to achieve equivalent anti‑inflammatory effects with a lower cumulative toxicity profile over time.
- Older adults with PMR—who are both glucocorticoid‑responsive and at high risk for steroid adverse effects—are an attractive target population for further trials of this strategy.
Limitations
Interpretation must be tempered by several important limitations of the trial:
- Short treatment periods (2 weeks on each regimen) restrict conclusions about sustained efficacy, long‑term toxicity mitigation, and safety.
- The sequential single‑blind design and relatively small cohorts are vulnerable to bias and not equivalent to randomized, double‑blind controlled trials for establishing clinical efficacy or safety.
- No detailed numerical effect sizes, confidence intervals or formal statistical power calculations are presented in the brief summary—full trial publication should be consulted for quantitative interpretation.
- Biomarker changes are surrogate endpoints; whether these translate into clinically meaningful reductions in fractures, cardiovascular events, diabetes incidence, or infection risk requires longer outcomes studies.
Expert commentary and next steps
The trial led by Buttgereit et al. (2025) is an important early translational step. It demonstrates feasibility and provides mechanistic signals justifying larger, controlled trials. Essential next steps include randomized, double‑blind studies with longer follow‑up that are designed to answer clinically relevant questions: can clofutriben (or other 11β‑HSD1 inhibitors) reduce cumulative steroid‑related morbidity (for example, new osteoporosis or fractures, new diabetes, cardiovascular events) without increasing rates of disease relapse or steroid‑refractory inflammation? What is the optimal prednisolone dosing strategy when 11β‑HSD1 is inhibited? Studies should include elderly patients with comorbidities and quantitatively prespecified endpoints for both efficacy and hard clinical harms.
Conclusion
This single‑blind, sequential cohort trial suggests that selective inhibition of 11β‑HSD1 with clofutriben can blunt biochemical and surrogate markers of prednisolone toxicity while permitting restoration of clinical efficacy through prednisolone dose escalation. The findings support the biological premise that intracellular glucocorticoid activation contributes disproportionately to some toxicity pathways and that its inhibition may expand the therapeutic index of systemic glucocorticoids. Larger, randomized, longer‑duration clinical trials are warranted to determine whether this strategy can safely reduce long‑term glucocorticoid harm in PMR and other steroid‑treated disorders.
Funding and trial registration
For funding, trial registration, detailed methods, numerical results, and full safety data, readers should consult the primary report: Buttgereit F, Everding A, Andreica I, et al. Ann Rheum Dis. 2025 Nov 11. PMID: 41224552.
References
1. Buttgereit F, Everding A, Andreica I, Kellner HL, Schuch F, Weyand C, Stewart PM, Merkel PA, Dejaco C, Czerwiec FS, Desai K, Katz DA. 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. Ann Rheum Dis. 2025 Nov 11:S0003-4967(25)04454-1. doi: 10.1016/j.ard.2025.10.015. Epub ahead of print. PMID: 41224552.
2. Tomlinson JW, Walker EA, Bujalska IJ, Draper N, Lavery GG, Cooper MS, Hewison M, Stewart PM. 11beta‑Hydroxysteroid dehydrogenase type 1: a tissue‑specific regulator of glucocorticoid action. Endocr Rev. 2004 Oct;25(5):831–66. PMID: 15355933.
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