New research confirms link between perceived stress and psoriasis flare-ups

The study shows how stress triggers relapses. It was presented at the EADV Congress 2024 and scientifically confirms the correlation for the first time in vivo.

First scientifically validated in vivo evidence

The researchers induced psoriatic lesions in human skin xenografts in mice. After remission was achieved with topical dexamethasone, the mice were exposed to sound or mock stress for 24 hours.
Within 14 days, 100 per cent of the mice exposed to sound had a recurrence of psoriasis lesions, accompanied by remarkable changes in the immunological markers associated with the disease.
Aprepitant, a neurokinin-1 receptor (NK1-R) antagonist, was effective in preventing a stress-induced psoriasis flare in 80 per cent of cases and normalised most inflammatory markers.
The research team believes that these results will pave the way for future advances in the understanding and treatment of stress-induced psoriasis. Further research is planned into the clinical potential of NK1-R antagonists to refine treatment strategies and better help patients.
The results of this study will be presented for the first time at the 2024 Congress of the European Academy of Dermatology and Venerology (EADV).

Sound and psoriatic lesions

In the study, psoriatic lesions were induced in healthy human skin xenografts on mice with severe combined immunodeficiency (SCID)/beige (n=25) by injecting autologous, in vitro IL-2-preactivated mononuclear cells from peripheral blood. After achieving remission of the lesions with topical dexamethasone, mice were exposed to either sound or sham irradiation for 24 hours. Recurrence of psoriatic lesions was then monitored for the following 14 days.

Remarkably, acoustic stress led to a relapse of the psoriatic lesions within 14 days in all human skin xenografts. This was accompanied by significant changes in psoriasis-related skin phenomena, including increased epidermal thickness, K16 expression, keratinocyte proliferation, antimicrobial peptide expression, and immune activation of intraepidermal cells.

Sonic stress increases pro-inflammatory mediators and biomarkers

Further analyses showed that sonic stress significantly increased the presence of immune cells in the skin and increased pro-inflammatory mediators such as CXCL10, IL-22, IL-15, IL-17A/F, IFN-γ and TNFα. Furthermore, biomarkers of neurogenic inflammation, such as nerve growth factor (NGF) and substance P (SP), were upregulated. Sonic stress also led to increased tryptase levels, indicating mast cell activation, and to increased expression of NK-1R, the receptor for SP.

‘Psychoemotional stress triggers the release of pro-inflammatory neuropeptides such as SP, leading to neurogenic skin inflammation by activating immune cells, particularly through mast cell degranulation. This is further exacerbated by corticotropin-releasing hormone (CRH) and NGF, which intensify inflammation and promote hyperproliferation of keratinocytes, thereby triggering and exacerbating psoriatic lesions in susceptible individuals.’ (Professor Amos Gilhar, lead researcher, The Skin Research Laboratory, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel)

Aprepitant prevents relapses

The research team also tested the effectiveness of aprepitant, an FDA-approved anti-emetic, a neurokinin-1 receptor (NK1-R) antagonist, in preventing a stress-related psoriasis flare-up. Aprepitant prevented a relapse in 80 per cent of cases and normalised most inflammatory markers.

‘Aprepitant is a promising potential therapy for stress-related psoriasis flare-ups,’ said Professor Gilhar, who warned, however, against its use outside of the approved indications and the need for further safety data.

‘Aprepitant selectively targets the SP-induced component of neurogenic inflammation, but has no effect on other mediators such as NGF and CRH. Combining NK-1R antagonists with other treatments may prove more effective.’

With regard to the further implications of the study, Professor Gilhar adds:

‘Consistent with previous research on stress in mice, our study in the humanised psoriasis mouse model identifies the SP/NK-1R pathway as a promising target for therapeutic intervention in psoriasis that is triggered or worsened by stress. It also points to other possible targets, including NGF, mast cell activation/degranulation and CRH/CRH-R1 signalling.’

The study highlights the complex link between the nervous system and the immune response in psoriasis. ‘Understanding how stress impacts psoriasis allows us to refine our treatment approaches to better help patients,’ continued Professor Gilhar. ‘In the future, our team plans to explore the clinical potential of NK-1R antagonists and the role of stress in the treatment of psoriasis.’

Sources

Keren, A., Zeltzer, A. A., Bertolini, M., Paus, R., & Gilhar, A. (2024). Psoriatic lesions in human skin xenotransplants in vivo are triggered by perceived stress and can be suppressed by the neurokinin-1 receptor antagonist aprepitant. Presented at European Academy of Dermatology and Venereology (EADV) Congress 2024.
European Commission. (2024). Two itchy-skin diseases that can go much deeper. Retrieved from https://projects.research-and-innovation.ec.europa.eu/en/horizon-magazine/two-itchy-skin-diseases-can-go-much-deeper
National Institute of Arthritis and Musculoskeletal and Skin Diseases. (2024). Psoriasis. Retrieved from https://www.niams.nih.gov/health-topics/psoriasis#:~:text=Psoriasis%20is%20a%20chronic%20(long,can%20be%20affected%20as%20well.
Rousset, L., & Halioua, B. (2018). Stress and psoriasis. International journal of dermatology, 57(10), 1165–1172. https://doi.org/10.1111/ijd.14032.