Abigail Medford

Background: Individuals with Down syndrome (DS) have T cell dysregulation with abnormally elevated baseline pro-inflammatory and multiple overly activated immune cell types. Thus, they are much more likely to develop autoimmune inflammatory conditions.¹ Psoriasis is a chronic autoimmune skin disorder marked by abnormal skin cell proliferation that frequently manifests in individuals with DS. The incidence of psoriasis in North America is 1-3%, and around 8% in individuals with DS.² The presentation varies depending on the variant of psoriasis, but all forms of psoriasis share 3 identifying skin characteristics: erythema, thickening, and scale.³ Psoriasis is thought to result from excessive adaptive immune system activation. While there is no cure for psoriasis, pharmaceuticals can help control the symptoms. However, some patients respond well to therapy while others do not. Currently, topical agents are the first line of treatment for patients with mild psoriasis, including topical corticosteroids, vitamin D equivalents, calcineurin inhibitors, and keratolytics. Light therapy can also be helpful. For more severe forms of psoriasis, biologics that inhibit TNF-α, p40IL-12/23, IL-17, and p19IL-23, as well as an oral phosphodiesterase 4 inhibitor, are recommended.³

Objective: This review explored the intersection of psoriasis in the Down syndrome population, highlighting important clinical presentation, etiology, and current and emerging therapeutics.

Search Methods: An online search in the PubMed database used the keywords “psoriasis,” “Down syndrome,” and “immunology.” Most of the citations used restricted the search from 2017 to 2024.

Results: The Type-I Interferon (IFN) pathway is hyperactive in patients with DS.⁴ IFN binds to its receptors encoded on chromosome 21. Chromosome 21 triplication leads to overexpression of IFN receptors and heightened IFN sensitivity. Thus, JAK/STAT (JAK Kinase) inhibitors are emerging as a very effective first-line treatment, particularly tofacitinib, currently being tested in phase III clinical trial.⁴  miR-150 dysregulation is implicated in many of the comorbidities seen within the DS population.^5-9 A hypoxic environment is created during psoriasis in which keratinocytes show a decrease in miR-150 expression and a marked increase in vascular endothelial growth factor‐A (VEGFA) and HIF-1α expression in lesioned psoriatic tissues.¹⁰ This upregulation of VEGFA and HIF-1α modulates the proliferation of HaCaT cells and HKCs and accelerates angiogenesis in the skin. Conversely, overexpression of miR-150 leads to downregulating VEGFA and HIF-1α and decreasing cell proliferation. The expression of HIF-1α and VEGFA are both inversely correlated with miR-150, respectively. Data indicated that miR-150-dependent HIF-1α and VEGFA regulation could be a target to control psoriasis, considering that these factors are involved in the angiogenesis and proliferation of keratinocytes.¹⁰ VEGFA inhibition was shown to downregulate blood vessel area and endothelial cells in plaques of psoriasis ex vivo with severe disease and high VEGFA levels, making its case as an effective therapy adjunct.¹¹ Thus, miR-150-dependent HIF-1α and VEGFA regulation could also be a future target for psoriasis treatment.

Conclusions: Current data implicate IFN signaling pathway, miR-150, VEGFA, and HIF1-a as potential targets for psoriasis treatment in DS. Thus, more research is warranted to close the gap between the pathogenesis of psoriasis and its manifestations and higher incidence in the DS population.

Work Cited:

1. Espinosa JM. Down Syndrome and COVID-19: A Perfect Storm? Cell Rep Med. May 19 2020;1(2):100019. doi:10.1016/j.xcrm.2020.100019
2. Marmon S, De Souza A, Strober BE. Psoriasis and Down syndrome: a report of three cases and a potential pathophysiologic link. Dermatol Online J. 2012;18(6):13. Published 2012 Jun 15.
3. Armstrong AW, Read C. Pathophysiology, Clinical Presentation, and Treatment of Psoriasis: A Review. JAMA. May 19 2020;323(19):1945-1960. doi:10.1001/jama.2020.4006
4. O’Connor C, Byrne B, Roche D, et al. Biological and <scp>JAK</scp> inhibitor therapy outcomes for severe psoriasis in trisomy 21. The Journal of Dermatology. 2023;50(10):1339-1342. doi:10.1111/1346-8138.16851
5. Chia SY, Vipin A, Ng KP, et al. Upregulated Blood miR-150-5p in Alzheimer’s Disease Dementia Is Associated with Cognition, Cerebrospinal Fluid Amyloid-β, and Cerebral Atrophy. J Alzheimers Dis. 2022;88(4):1567-1584. doi:10.3233/JAD-220116
6. Ekta, Gupta M, Kaur A, Singh TG, Bedi O. Pathobiological and molecular connections involved in the high fructose and high fat diet induced diabetes associated nonalcoholic fatty liver disease. Inflamm Res. Sep 2020;69(9):851-867. doi:10.1007/s00011-020-01373-7
7. Chen W, Yan X, Yang A, Xu A, Huang T, You H. miRNA-150-5p promotes hepatic stellate cell proliferation and sensitizes hepatocyte apoptosis during liver fibrosis. Epigenomics. Jan 2020;12(1):53-67. doi:10.2217/epi-2019-0104
8. Tan IL, Coutinho de Almeida R, Modderman R, et al. Circulating miRNAs as Potential Biomarkers for Celiac Disease Development. Front Immunol. 2021;12:734763. doi:10.3389/fimmu.2021.734763
9. Bueno LCM, Paim LR, Minin EOZ, et al. Increased Serum Mir-150-3p Expression Is Associated with Radiological Lung Injury Improvement in Patients with COVID-19. Viruses. Jun 23 2022;14(7)doi:10.3390/v14071363
10. Li Y, Su J, Li F, Chen X, Zhang G. MiR-150 regulates human keratinocyte proliferation in hypoxic conditions through targeting HIF-1α and VEGFA: Implications for psoriasis treatment. PLoS One. 2017;12(4):e0175459. doi:10.1371/journal.pone.0175459
11. Luengas‐Martinez A, Ismail D, Paus R, Young SH. Inhibition of vascular endothelial growth factor‐A downregulates angiogenesis in psoriasis: A pilot study. Skin Health and Disease. 2023;3(5)doi:10.1002/ski2.245