Researchers identify a potential “Achilles heel” of psoriasis

Psoriasis is a chronic immune-mediated inflammatory skin disease affecting more than 8 million Americans and nearly 125 million people worldwide.

Characterized by painful, scaly, and inflamed skin lesions, the disease often begins in adolescence or early adulthood and persists through life.

Although highly effective therapies are now available, psoriasis remains incurable, and lesions commonly recur in the same skin location after treatment is stopped.

“Even when the skin appears clinically clear, tissue resident memory T cells, or TRMs, can persist within the tissue and drive disease relapse,” explained Rundong Jiang, Ph.D. student, first author of the study and a researcher at Michigan Medicine.

“Understanding how these cells survive long term has been a major unanswered question in psoriasis research.”

A new study from researchers at Michigan Medicine provides important insight into how one of the most widely used classes of psoriasis therapies, IL-23 blockade, achieves durable disease control.

By mapping the immune landscape of psoriasis lesions before, during, and after treatment, the team identified how these therapies reshape the inflammatory environment over time and uncovered mechanisms that may explain both prolonged remission and eventual disease recurrence.

Exploring how IL 23-blockade works

Anti-IL-23 therapies, including widely used drugs such as Skyrizi, have transformed the treatment of psoriasis. However, exactly how these therapies produce long-lasting disease control within the skin itself has remained incompletely understood.

“Although these drugs are highly successful clinically, we still did not fully understand how they work within the tissue microenvironment of psoriasis lesions,” said Rundong Jiang.

“We wanted to define the cellular and molecular mechanisms responsible for their durable effects.”

Using high-resolution single-cell analyses, the researchers found that pathogenic immune cells remain embedded within the epidermis, the outermost layer of the skin, where they can persist for years or even decades.

“What was remarkable is that IL-23 blockade, particularly at higher doses, profoundly reduced these TRM cells within the epidermis,” said Johann E. Gudjonsson, M.D., Ph.D., senior author of the study.

“These cells appear to function as a reservoir for disease recurrence."

The study also identified additional signaling pathways that may help sustain these residual pathogenic cells including IL-7 and IL-34 signaling.

These findings suggest that combining IL-23 blockade with therapies targeting survival pathways in TRMs could potentially drive deeper and more durable remission.

“We think we may now understand why these drugs are so effective, but also why the disease eventually returns,” Gudjonsson said.

“Current therapies dramatically suppress the inflammatory response, but they may not completely eliminate the cells capable of reigniting disease.”

Towards deeper remission and potentially disease reset

The team’s next goal is to determine whether these residual TRM populations can be more completely eliminated or functionally reprogrammed to achieve prolonged remission or potentially reset the disease state.

“We’re still quite a way from that goal,” Gudjonsson cautioned, “but this study provides an important roadmap for how we might eventually get there.”