How Our Understanding of Inflammatory Skin Disease Has Evolved From the 4 Humors to Targeted Therapies

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Once thought of as the result of an imbalance in bodily humors, inflammatory skin diseases are now understood to arise from types of immune responses, opening the door to targeted therapies and personalized medicine, according to speakers at the American Academy of Dermatology (AAD) 2023 Annual Meeting.

It’s an exciting time to be a medical dermatologist, said Mehdi Rashighi, MD, of the University of Massachusetts Medical School. The field has witnessed an explosion of FDA-approved targeted treatments for inflammatory skin diseases such as vitiligo and alopecia areata (AA), and there will hopefully soon be other drugs to manage diseases that for thousands of years have never had any good treatments—in part, because their mechanisms were not understood.

Two millennia ago, Hippocrates classified skin diseases as either idiopathic, originating from the skin, or exanthematic, resulting from imbalances in the 4 humors: blood, yellow bile, black bile, and phlegm. This was the accepted dogma until the mid-19th century saw the advent of germ theory, followed by the introduction of pathology and histopathology.

The late 1970s brought a turning point as the works of A. Bernard Ackerman, MD, “used some histological patterns to classify different inflammatory skin diseases, and this is something that we’re still using when we teach our residents,” Rashighi said. Since then, therapeutic strategies for immune-mediated diseases have evolved from broad-spectrum immune modulators to the small-molecule Janus kinase (JAK) inhibitors that have racked up approvals in the past year.

Hippocrates’ model of the 4 humors has now been supplanted by the equilibrium model of the 4 types of immune responses. A dysregulated type 1 immune response can produce vitiligo or AA; type 2, atopic dermatitis (AD) and prurigo nodularis; type 3, psoriasis and hidradenitis suppurativa; and type 4, contact dermatitis.

“We are at the point where we have convergence of multiple disciplines, and that’s going to enable us to understand the pathogenesis of inflammatory skin diseases at an unprecedented high granularity, not only helping us to divide different inflammatory skin diseases but also a better understanding of the heterogeneity,” Rashighi predicted, “and that’s going to enable us to essentially develop much more personalized and more targeted effective treatments.”

Next, Matthew Vesely, MD, PhD, of Yale School of Medicine, delved further into the use of immunological profiles to diagnose and treat inflammatory skin disease. Classification of disease began with the microscope and has since evolved to RNA sequencing, now down to the level of the single cell. By adding the power of molecular diagnostics, he explained, we can now define disease in terms of patterns of inflammation that share critical immune features.

For instance, vitiligo and AA present completely differently, but we’re now starting to treat them in a similar manner with the goal of blocking the signaling of the interferon-γ cytokines involved in their pathogenesis. We’re also hearing so much about JAK inhibitors because many critical cytokines in the pathogenesis of disease share the signaling cascade of the JAK/STAT pathway.

Despite these sometimes overlapping patterns of immune responses, Vesely said, diseases are heterogenous in their immune pathways, so we need to dive deeper to enhance our understanding. “How we classify disease immunologically may allow us to have more robust targeted therapies,” he closed.

The aim of targeted therapy is to use personalized approaches to select the best treatment, which was the focus of the next speaker, William Damsky, MD, PhD, of Yale School of Medicine. It is exciting to have an expanding armamentarium of new therapies, but choosing among them is still mostly done by trial and error, which is inefficient. His work aims to use biopsy staining to answer questions of molecular heterogeneity that can help inform choice of treatment based on patients’ unique disease biology.

For instance, his team took a retrospective look at patients with atopic dermatitis who had varying levels of response to dupilumab. They found that those with complete response tended to express a lot of IL-13, whereas nonresponders tended to produce other cytokines like interferon-γ. A prospective study of patients with psoriasis and AD to confirm these results is ongoing.

He prefers the method of biopsy staining because it is easily replicable and does not require specialized infrastructure, but he mentioned several innovative approaches underway, including dermal biomarker patches and skin scraping analysis services.

“A lot of people are thinking about this, and it’s a really sort of exciting frontier in personalized medicine,” he concluded.

In response to an audience question about the role of the practicing dermatologist amid these immunohistochemical advances, Vesely affirmed that the dermatologist will always remain central, but the addition of these tools can allow us to “better classify disease up front, molecularly and immunologically, and then choose the right treatment in the first place.”