New biomarkers can help in the targeted treatment of the chronic skin disease sarcoidosis

Sarcoidosis is a rare systemic disease that affects an estimated 200,000 people in the United States, more often black people and more women than men, especially when it causes a chronic skin disease. Thanks to new research from scientists at the Perelman School of Medicine, who Journal of Clinical Investigations.

Using skin, lung and blood samples from patients with sarcoidosis and other patients with granulomas (nodules), the team found that so-called innate lymphoid cells type 1 (ILC1) are present in much higher concentrations in the granulomas of patients with sarcoidosis.

They also found that targeting a signaling pathway called CXCR4, which is activated in these cells, can inhibit the formation of granulomas. These findings suggest that doctors may be able to diagnose sarcoidosis by measuring patients’ ILC1 levels and may even be able to treat the disease with already available drugs that inhibit the CXCR4 signaling pathway.

“In addition to the challenge of diagnosing sarcoidosis, the first-line treatment for sarcoidosis patients has been extensive immunosuppression with steroids, which is tantamount to using a blunt instrument to treat sarcoidosis,” said Thomas Leung, MD, Ph.D., assistant professor of dermatology at Pennsylvania University.

“By identifying the cause of the disease, we may have found a better way to diagnose the disease as well as a potential treatment that avoids serious side effects.”

Sarcoidosis is characterized by the formation of granulomas, or clumps of immune cells, in organs, including the skin. The granulomas in the skin can form large clumps and often appear on the face. These lesions can interfere with breathing and severely affect patients’ interpersonal interactions and quality of life.

Importantly, granulomas can also form inside and around vital organs such as the heart, lungs and eyes, causing chronic inflammation and permanent scarring of the organs and sometimes death.

Diagnosing sarcoidosis still presents enormous challenges for clinicians because there is no single test to confirm sarcoidosis, said study co-author Misha Rosenbach, MD, professor of dermatology at Paul R. Gross College and director of the Cutaneous Sarcoidosis and Granulomatosis Clinic at Pennsylvania State University.

“Knowing that innate lymphoid cells type 1 are a biomarker for sarcoidosis should lead to more timely diagnosis of patients,” said Rosenbach.

The researchers first compared samples of affected and unaffected skin from sarcoidosis patients with samples from patients with skin granulomas caused by other, unrelated diseases. ILC1 levels were particularly high in the skin tissues of sarcoidosis. This was also the case when the researchers examined lung granulomas from sarcoidosis.

What really made researchers think ILC1 might be the cause, however, was the 12-fold increase in the amount of ILC1 circulating in the blood of sarcoidosis patients. ILC1 levels appeared to change as patients were treated.

“ILC1 is an important part of the body’s inflammatory response,” Leung said. “However, as with anything, in the human body, getting the balance right is critical, and a 12-fold difference between patients with sarcoidosis and those without the disease is significant and made us suspicious of these cells.”

The study authors then developed a mouse model to study the biology of granulomas and found that ILC1 cells are necessary for granuloma formation. This led to the researchers’ final tests, in which they investigated whether controlling ILC1 and its associated inflammatory pathway CXCR4 could prevent granuloma formation in mice with sarcoidosis. Both approaches resulted in fewer granulomas forming compared to control groups.

“We found that CXCR4 signaling is critical for the development of tissue granulomas and that blocking this signal can inhibit granuloma formation,” said Leung. “CXCR4 inhibitors are already available in the clinic as an injection and are used to safely mobilize stem cells prior to stem cell transplants.”

“I’m excited to work with Misha Rosenbach and the Sarcoidosis Clinic at Penn to conduct a clinical trial to investigate whether repurposing these drugs could be the first targeted treatment for sarcoidosis. Drug repurposing is more efficient than developing a new drug because the safety and nuances of the drug are already well known.”

George Cotsarelis, MD, chief of the Department of Dermatology and Milton Bixler Hartzell Chair in Dermatology at Pennsylvania University, emphasized that dermatology plays a key role in this type of research.

“We have been saying for decades that the skin is a ‘window’ to the body,” he said. “Examining the skin is an efficient method for investigating systemic multi-organ diseases.”