Genetic profiling and the future of therapeutics in dermatology

Genetic profiling and the future of therapeutics in dermatology

The precise etiology of a myriad of dermatological diseases and conditions remains unknown; however, 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 diseases and help clinicians make optimal treatment decisions.

Precision medicine is a cutting-edge approach in which clinicians can tailor treatments to a subpopulation of patients who have a common susceptibility to a particular disease or a similar response to a particular drug. Continued research in genetic profiling has fueled the development of therapies for a number of common and rare dermatological diseases, including psoriasis vulgaris, atopic dermatitis, and other untold clinical and histopathological skin rashes.

“We are at a time when the number of therapeutic drugs for dermatology is really exploding in the immunomodulatory field. Similar to other diseases, skin rashes result from a wide range of genetic conditions and as such do not always fall into precise categories. The goal is to be able to more accurately identify the molecular pathology of a given rash and associate it with specific medications. In our research, we are ultimately trying to get a very personalized picture of a given patient’s inflammatory disease so that we can get them the right medication,” said Raymond J. Cho, MD, PhD, Associate Professor of Dermatology, University of California, San Francisco (UCSF), CA, and study co-lead author with Jeffrey B. Cheng, MD, PhD, also at UCSF.

Single-cell ribonucleic acid sequencing has helped increase precision for researchers examining the intricate details of the role of immune and stromal cells in inflammatory skin diseases, Cho said, helping them focus on more targeted treatment regimens for their patients.

In his recent study, Cho and his fellow researchers profiled single-cell CD45+ immune cell transcriptomes from skin biopsies taken from 31 patients (7 atopic dermatitis, 8 psoriasis vulgaris, 2 lichen planus, 1 bullous pemphigoid, 6 rash clinical and histopathologically indeterminate, and 7 healthy controls).

Results showed active expansion of Treg (regulatory T cell) and Trm (resident memory T cell) component proliferation and universal T cell depletion in human skin rashes, with relative attenuation of antigen-presenting cells. Additionally, skin-resident memory T cells showed the greatest transcriptional dysregulation in atopic dermatitis and psoriasis, while atopic dermatitis also showed recurrent abnormalities in ILC. [KK1] and CD8+ cytotoxic lymphocytes. Transcript signatures differentiating these types of rashes included genes previously implicated in T helper (TH2)/TH17 cell diatheses, separated into unbiased functional networks and a precisely identified disease class in validation datasets untrained. These genetic signatures allowed classification of clinicopathologically ambiguous rashes with diagnoses consistent with therapeutic response.

According to Cho, the results of the study describe how advanced molecular profiling can be used to distinguish between different inflammatory skin diseases, including common diseases such as psoriasis and atopic dermatitis, and also to better diagnose rarer cases and many. more difficult.

“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 diseases. In our study, we were able to define the major classes of human inflammatory skin diseases at the molecular level and described a quantitative method to classify indeterminate cases of pathologic inflammation,” Cho said.

In the future, for patients who don’t fall into a very clear-cut category in an obvious way, Cho said a biopsy or other means of molecular testing could be done to help clinicians better understand what makes them genetically activated in their immune system. Regardless of clarity of classification, all patients could eventually be profiled to eventually be able to help predict drug response.

“We want to take unusual cases and classify them for therapy – patients who are not in the middle of an obvious category, probably around 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 diseases, sometimes requiring several therapeutic approaches for optimal patient care. Affecting 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 as well as the full range of metabolic syndrome. Affecting approximately 26 million people in the United States, atopic dermatitis can cause relentless itching leading to excoriation, oozing and cracking of the skin and insomnia in severe cases.

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

Among the spectrum of dermatological diseases, Cho believes that the 2 areas where the benefits of genetic profiling can currently be felt the most include genetically more heterogeneous diseases such as atopic dermatitis and rashes that do not easily fit into one category. specific clinic. Some rashes can appear to have the clinical aspects of eczema and psoriasis, and according to Cho, about 10% of rashes seen by clinicians may not fit comfortably into a defined category.

As part of their move to further integrate genetic testing and personalized medicine into the practice of dermatology, researchers need to identify very high-resolution molecular markers and try to understand how they affect clinical parameters such as prognosis and response to drugs.

“Right now the work of identifying the most high-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 will be correlated with progression and to the disease response. Currently, there is no set of markers good enough to use in various diseases,” Cho said.

To help clinicians better classify difficult and more ambiguous cases, Cho and his colleagues created an online proof-of-principle web interface tool called RashX. The system is designed to give the global clinical research community the ability to enter and match genetic information about their patients with difficult rashes with that in the system’s database, which is linked to diagnoses specific skin conditions, and hopefully learn more about the genetic pathology of frustrating individuals. case.

According to Cho, RashX’s publicly accessible 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 inflammatory genesis, contact us as we would be happy to consult you on such cases. For very unusual cases, we may just 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 diseases based on single cell immune profiling. Sci Immunol.2022;7(70):eabl9165. doi:10.1126/sciimmunol.abl9165

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