Genetic profiling and the future of therapies in dermatology

The precise etiology of numerous dermatological diseases and conditions remains unknown; however, they all share inflammation as a causative factor. A recent study1 identified how precision medicine and genetic profiling can be used to better target inflammatory skin conditions and help clinicians make optimal treatment decisions.

Precision medicine is a breakthrough approach that allows clinicians to tailor treatments to a subpopulation of patients who share a common susceptibility to a particular disease or similar response to a particular drug. Ongoing research in genetic profiling has led to the development of therapies for a number of common and rare dermatological diseases, including psoriasis vulgaris, atopic dermatitis and other clinically and histopathologically inconspicuous rashes.

“We are now in a time where the number of therapeutic drugs for dermatology is really exploding in the field of immunomodulation. As with other diseases, rashes arise from a broad spectrum of genetic pathology and as such do not always fall into neat categories. The goal is to be able to more accurately identify the molecular pathology of a particular rash and link it to specific drugs. In our research, we ultimately try to get a very personal portrait of a given patient’s inflammatory disease so that we can give them the right medication,” said Raymond J. Cho, MD, PhD, associate professor of dermatology, University of California, San Francisco (UCSF), California, and senior co-author of the study along with Jeffrey B. Cheng, MD, PhD, also at UCSF.

Single-cell ribonucleic acid sequencing has helped increase the precision for researchers looking at the details of the complex mix of the immune and stromal cell roles in inflammatory skin diseases, Cho said, allowing them to focus on more targeted treatment regimens for their patients.

In his recent study, Cho and colleagues prepared single-cell CD45+ immune cell transcriptomes from skin biopsies of 31 patients (7 atopic dermatitis, 8 psoriasis vulgaris, 2 lichen planus, 1 bullous pemphigoid, 6 clinically and histopathologically indeterminate rashes, and 7 healthy controls).

The results showed active proliferative expansion of the Treg (regulatory T-cell) and Trm (resident-memory T-cell) components and universal T-cell depletion in human rashes, with a relative attenuation of antigen-presenting cells. In addition, the memory T cells of the skin showed the greatest transcriptional dysregulation in both atopic dermatitis and psoriasis, while atopic dermatitis also showed recurrent abnormalities in ILC. [KK1] and CD8+ cytotoxic lymphocytes. The transcript signatures that distinguish these types of rashes include genes previously involved in T helper cell (TH2)/TH17 diatheses, separated into unbiased functional networks and precisely identified disease class in untrained validation datasets. These gene signatures were able to classify clinicopathologically ambiguous rashes with diagnoses consistent with therapeutic response.

According to Cho, the study results describe how advanced molecular profiling can be used to differentiate various inflammatory skin diseases, including common diseases such as psoriasis and atopic dermatitis, as well as better diagnose rarer and much more difficult cases.

“A finer analysis of immune cell populations may reveal novel cell-type-specific differences in gene activity between inflamed and healthy skin, or between different classes of skin disease. In our study, we were able to define the major classes of inflammatory skin conditions in humans at the molecular level and described a quantitative method to classify indeterminate cases of pathological inflammation,” said Cho.

In the future, for those patients who don’t fall into a very neat category in an obvious way, Cho said a biopsy or some other form of molecular testing could be done to help clinicians better understand what triggers them genetically. in their immune system. Regardless of the clarity of classification, eventually all patients could be profiled to potentially help predict drug response.

“We want to take unusual cases and classify them for therapy – patients that are not right in the middle of an obvious category, probably about 10% of patients. Then we would eventually want to predict treatment success for the remaining 90% of patients,” Cho said.

Psoriasis and atopic dermatitis are common and often difficult to treat skin conditions, sometimes requiring multiple therapeutic approaches to optimally treat patients. In more than 7.5 million people in the United States, even mild cases of psoriasis can trigger inflammatory processes that can lead to serious comorbidities, such as disabling arthritis and the full range of metabolic syndrome. Atopic dermatitis affects about 26 million people in the United States and can cause relentless itching, resulting in excoriations, oozing and cracked skin, and in severe cases, insomnia.

Both diseases are anti-inflammatory, but according to Cho, research has shown how different biochemical pathways trigger inflammation in the 2 conditions, leading to new biological treatments that specifically target different inflammatory pathways and immune cytokine molecules. However, the conditions can’t always be easily distinguished based on knowledge of symptoms or clinical examination, or even using tissue analysis, said Cho, who challenged even well-trained and experienced dermatologists, leading to misdiagnosis and inappropriate treatment.

From the spectrum of dermatological diseases, Cho believes that the 2 areas where the benefit of genetic profiling is currently most felt are more genetically heterogeneous diseases such as atopic dermatitis and rashes that do not easily fit into a specific clinical category. Some rashes seem to have the clinical aspects of both eczema and psoriasis, and according to Cho, about 10% of the rashes seen by clinicians don’t fit comfortably into a fixed category.

On the way to making genetic testing and personalized medicine more mainstream in dermatology practice, researchers need to identify very high-resolution molecular markers and try to understand how they influence clinical parameters such as prognosis and drug response.

“At the moment, the work to identify the highest resolution markers is very painstaking and we need to look very specifically at T cells and antigen-producing cells to see some of the defects that correlate with disease progression and response. Currently there is no set of markers good enough to be used for different diseases,” Cho said.

To help clinicians better categorize challenging and more ambiguous cases, Cho and his colleagues created a proof-of-principle online web interface tool called RashX. The system is designed to allow the global clinical research community to enter and match genetic information about their challenging rash patients with those in the system’s database, which are linked to specific skin diagnoses, and hopefully learn more about the genetic pathology of individual frustrating cases.

According to Cho, RashX’s publicly available framework enables scientists and clinicians around the world to analyze and contribute their own patient-level data, leading to more accurate classification, diagnosis and treatment of challenging cases.

“If you have a patient with a very strange clinical presentation and you may not understand the genesis of inflammation, please contact us as we would be happy to discuss such cases with you. For very unusual cases, we may be able to learn something new about how these unusual rashes develop,” Cho said.

Disclosures: None relevant


1. Liu, Y, Wang H, Taylor M, Cook C, et al. Classification of human chronic inflammatory skin disease based on unicellular immune profiling. Sci Immunol.2022;7(70):eabl9165. doi:10.1126/sciimmunol.abl9165

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