Genetic and Immunological Advances in Risk Assessment and Treatment of Psoriatic Diseases

Jul 11, 2024

Photo Credit: TanyaJoy

Immunological and genetic studies are changing the way medical professionals understand psoriatic disease, the risks, and how patients could respond to treatment.

The basic understanding of psoriatic disease is changing based on immunological and genetic studies. Prof. Wilson Liao, MD, University of California San Francisco, CA, reviewed recent genetic and immunology studies aimed at risk assessment, prediction of response to therapy, and basic understanding of the disease.

The largest genetic study to date in psoriasis was a recent meta-analysis of 18 genome-wide association studies totalling 36,466 cases of psoriasis and 458,078 controls, which identified 109 genetic loci associated with psoriasis. These loci are responsible for the TNF/NF-kB, IL-17/IL-23, and aryl hydrocarbon receptor pathways, as well as pathways responsible for antigen presentation and innate immunity related to viral antigens. Furthermore, this study showed that cell types such as fibroblasts, melanocytes, and endothelial, lymphatic, and eccrine cells are also implicated in psoriasis. In pustular psoriasis, multiple genes have been identified in recent years, implicating the IL-1, IL-36, and IL-26 pathways.

How can the assessment of genetics be useful to doctors? Firstly, genetic signatures could be predictive of the development of psoriatic arthritis. To this end, a machine-learning model using 200 gene loci has been developed to predict psoriatic arthritis with an AUROC of approximately 80%⁴. “Hopefully, in the near future, you will open up your electronic medical records seeing a warning message that your patient is at risk,” said Prof. Liao.

Furthermore, genetics have been used to predict responses to therapies. Patients with psoriasis who are positive for HLA-C*06:02 have improved responses to ustekinumab, while patients who are negative for HLA-C*06:02 have increased chances to respond to adalimumab, with mutations in the HLA-DR binding groove responsible for development of anti-drug antibodies to adalimumab and discontinuations of therapy.

Genetics can also be used to determine the relationship between psoriasis and environmental triggers. “Historically, factors like obesity, biomechanical stress, diet, various infections, smoking, and medications are all associated with the onset or worsening of psoriasis, but these have been largely cohort or observational studies,” said Prof. Liao. “It is hard to say whether these factors are causal or merely associated.” The genetic tool called Mendelian randomization can help shed light on the causal nature of various associations. This technique has led to “increasing evidence that obesity, BMI, and smoking, but also Crohn’s disease, type 2 diabetes, and depression are causally linked to the development of psoriasis, and, similarly, vitamin D levels, a person’s fruit intake, and educational attainment are protective against the development of psoriasis,” said Prof. Liao.

Finally, advances in the immunology of the disease also indicate that the current model of psoriasis immunology should be expanded. “We can now build on the basic model of just T cells, antigen-presenting cells, and keratinocytes with our now more expanded understanding of fibroblasts, endothelial cells, and other cell types,” said Prof. Liao. “We have also seen that psoriasis may be triggered by group A Streptococcus, as well as self-lipid, wheat, tobacco, and microbial antigens.”