IL-17A Inhibition and Neuroendocrine Signaling in Psoriasis

Psoriasis is increasingly recognized as a systemic inflammatory disease with effects extending beyond the skin to metabolic, cardiovascular, and neuroendocrine pathways. While IL-17A inhibition has become a cornerstone of treatment for moderate-to-severe disease, its broader physiologic consequences remain incompletely defined.

One area of interest is the hypothalamic pituitary adrenal (HPA) axis, a central regulator of stress responses and immune modulation that may be dysregulated in patients with psoriasis. New prospective data provide insight into how IL-17A blockade with secukinumab intersects with this system.

Published in Clinical Immunology, investigators report results from a 16-week randomized controlled trial evaluating endocrine and stress-related biomarkers in adults with moderate to severe psoriasis treated with secukinumab. The single-center study enrolled 105 patients receiving either standard-dose 300 mg therapy or a reduced 75 mg dose, allowing assessment of dose-related effects on immune and neuroendocrine markers.

Immune and Endocrine Signals Tracked Longitudinally
At baseline, participants had active disease with a mean Psoriasis Area and Severity Index (PASI) score of 14.2 and a mean Dermatology Life Quality Index of 10.2. Plasma IL-17A and HPA axis hormones, including cortisol, adrenocorticotropic hormone, dehydroepiandrosterone, and prolactin, were measured every four weeks through Week 16. Perceived stress was assessed in parallel using the Perceived Stress Scale.

As expected, circulating IL-17A levels increased substantially during secukinumab therapy in both dosing groups. By Week 16, mean IL-17A concentrations rose from approximately 6 pg/mL at baseline to more than 40 pg/mL, with no significant differences between doses. This pattern is consistent with reduced cytokine clearance when IL-17A is bound by secukinumab and is interpreted as a pharmacodynamic effect rather than evidence of ongoing inflammation.

Cortisol Rises Without Correlation to Skin Outcomes
More novel were the observed changes in HPA axis hormones. Cortisol levels increased significantly over the treatment period in both dosing groups, rising by approximately 33% from baseline to Week 16. Modest changes were observed in adrenocorticotropic hormone and dehydroepiandrosterone, while prolactin levels remained unchanged. Importantly, cortisol changes did not correlate with improvements in PASI or quality-of-life scores, despite marked clinical response in the higher-dose group.

This dissociation suggests that HPA axis activation during secukinumab therapy is unlikely to be a primary mediator of cutaneous improvement. Rather, it appears to represent a parallel physiologic effect accompanying IL-17A inhibition, reinforcing that therapeutic efficacy is driven predominantly through immune mechanisms.

Stress–Hormone Relationships and Interpretation
At baseline, higher perceived stress correlated inversely with cortisol levels, consistent with prior reports of a blunted HPA axis in stressed patients with psoriasis. During treatment, this relationship shifted toward neutrality and became positive in one subgroup at Week 16. Although intriguing, these findings warrant caution, given modest subgroup sizes and limited duration.

Whether these changes reflect partial normalization of stress biology or treatment-related activation of the HPA axis remains unresolved. The short follow-up precludes conclusions about durability or clinical relevance.

Clinical Context and Next Steps
The observed cortisol increase was dose independent and not associated with short-term adverse signals. However, sustained HPA axis activation has been linked elsewhere to metabolic and skeletal risks, which are already elevated in psoriasis populations. Key limitations include reliance on plasma biomarkers without mechanistic validation and absence of a non–IL-17 comparator group.

Overall, this study expands understanding of the systemic effects of IL-17A inhibition, documenting measurable HPA axis activation during secukinumab therapy that appears independent of skin response. The findings highlight the value of evaluating biologic therapies through a broader physiologic lens and underscore the need for longer-term and comparative studies.

Reference
Krefting F, Hölsken S, Sondermann W, Schedlowski M. Hypothalamic pituitary adrenal axis hormone changes during IL-17A inhibition with secukinumab in patients with psoriasis. Clin Immunol. 2026;282:110611. doi:10.1016/j.clim.2025.110611