Genetic profile and future of therapy 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 detect inflammatory skin diseases and help clinicians make optimal treatment decisions.

Precision medicine is a cutting-edge approach in which physicians 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. Continuing research into genetic profiling has fueled the development of therapies for a number of common and rare dermatological diseases, including psoriasis vulgaris, atopic dermatitis, and other anonymous clinical and histopathological eruptions.

“We are in a moment where the number of therapeutic drugs for dermatology is really exploding in the immunomodulatory area. Similar to other diseases, skin rashes result from a broad spectrum of genetic conditions and as such do not always fall into neat categories. The goal is to be able to more precisely identify the molecular pathology of a given rash and match it to specific drugs. In our research, we are ultimately trying to get a very personalized portrait of a given patient’s inflammatory disease so that we can provide them with the right medication,” said Raymond J. Cho, MD, PhD, associate professor, dermatology, University of California, San Francisco (UCSF), California, and senior study co-author with Jeffrey B. Cheng, MD, PhD, also at UCSF.

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

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

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

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

“More precise 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 major classes of human inflammatory skin diseases 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 obviously fall into a very neat category, Cho said a biopsy or other means of molecular testing could be done to help doctors better understand what makes them genetically activated in their system. immune. Regardless of the clarity of classification, ultimately all patients could be profiled to eventually be able to help predict drug response.

“We want to take unusual cases and classify them for therapeutics: patients who don’t fall right in the middle of an obvious category, probably about 10% of patients. So ultimately we would like 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 multiple therapeutic approaches to optimally manage patients. Affecting more than 7.5 million people in the United States, even mild cases of psoriasis can trigger inflammatory processes that could lead to serious comorbidities such as disabling arthritis and the full range of metabolic syndrome. Affecting an estimated 26 million people in the United States, atopic dermatitis can cause relentless itching resulting in weeping, weeping and cracking of the skin, and insomnia in the most severe cases.

Both diseases are inflammatory, but research has shown how distinct biochemical pathways trigger inflammation in the 2 conditions, according to Cho, leading to new biologic treatments specifically targeting 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 with the help of tissue analysis, Cho said, challenging even well-trained and experienced dermatologists, leading to misdiagnoses and inappropriate treatments.

Of the dermatological disease spectrum, Cho believes that the 2 areas where the benefit of genetic profiling can currently be most felt include more genetically heterogeneous diseases such as atopic dermatitis and skin rashes that do not easily fit into a specific clinical category. Some rashes can appear to have the clinical aspects of both eczema and psoriasis, and according to Cho, about 10 percent of the rashes doctors see may not comfortably fit into a certain category.

On the journey to bring genetic testing and personalized medicine more mainstream into dermatology practice, researchers must identify ultra-high-resolution molecular markers and seek to understand how they affect clinical parameters such as prognosis and drug response.

“Right now, the work to identify 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 related to disease progression and response. Currently, there is no set of markers good enough to be used in a variety of diseases,” said Cho.

To help doctors better categorize difficult and more ambiguous cases, Cho and his colleagues created a proof-of-principle online web interface tool called RashX. The system is designed to provide the global clinical research community with an opportunity to input and compare genetic information about their challenging rash patients with that in the system’s database, which is linked to specific skin diagnoses, and hopefully learn more on the genetic pathology of the individual frustrating cases.

According to Cho, RashX’s publicly available framework allows scientists and physicians from around the world to analyze and contribute their patient-level data, leading to more accurate classification, diagnosis and treatment of difficult cases.

“If you have a patient with a very strange clinical presentation and you may not understand the inflammatory genesis, please contact us as we would like to consult you on these cases. For very unusual cases, we might just learn something new about how these unusual rashes develop,” Cho said.

Information: none relevant


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


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