Researchers find gene mutations in scleroderma patients that could point to new treatments

Researchers have discovered cancer-like genetic mutations in the affected cells of people with scleroderma that point the way to potential new ways to treat the debilitating and sometimes fatal skin and connective tissue disease.

“Of all rheumatic diseases, scleroderma has the worst outcomes,” says lead researcher Mohamed Osman, a rheumatologist and assistant professor at the Faculty of Medicine and Dentistry.

“By uncovering some of the mechanisms that link abnormal DNA damage responses to fibrosis and inflammation, we hope to uncover new mechanisms that we can use to better treat patients in the clinic.”

According to Osman, one in 2,500 people suffers from scleroderma. Also known as “systemic sclerosis,” scleroderma causes hardening of the skin due to overproduction of collagen. In severe cases, fibrosis (scarring or thickening) of vascular and organ tissues such as the lungs, kidneys, and gastrointestinal tract can result, which can be fatal. In some patients, the disease begins as Raynaud’s disease, a disease that causes spasms in the arteries of the hands and feet.

Women and smokers are at higher risk than others of developing scleroderma, but the cause is unknown. Scleroderma patients have an increased risk of lung, breast, ovarian or colon cancer. Medications, diet, and exercise can slow progression and relieve symptoms, but there is no cure.

Although scleroderma is generally thought of as an inflammatory autoimmune disease, immunosuppressive treatments — which shut down or turn off the immune system and are typically used for other autoimmune diseases — are not as effective in scleroderma.

“This is a preliminary study that gives us many insights into the pathogenesis of this disease and explains why we are seeing inflammation that does not respond as well to immunosuppressive therapy, which has been a mystery until now,” says Osman.

Immunosuppression versus Immunotherapy

The researchers examined tissues from eight patients, taking samples of scleroderma-affected skin and mouth swabs as controls. Using a next-generation sequencing platform, they sequenced all of the exons in the genome, known as the exome. Exons are the parts of genes that contain the code for making proteins.

They found nearly 2,000 mutations, including “clock-like” mutations that promote premature aging and cancer, and 25 oncogenes that have carcinogenic potential. At the same time, they found that some of the mutations that are always present in cancer were not seen in the scleroderma cells.

Based on these new findings, the researchers believe that immunotherapy treatments, such as those used for some types of cancer, could prove effective. Immunotherapy boosts specific parts of the immune system to target specific cells.

“Our study shows that there is a parallel between the mutations that drive cancer and the mutations that drive the development of scleroderma,” says co-researcher Robert Gniadecki, professor and director of the Department of Dermatology.

“The endpoint in cancer is aggressive tumor growth and in scleroderma it is fibrosis. The immune response is at the heart of both processes.”

Osman and Gniadecki plan to continue their work by examining cells from additional patients. The two first met in an airport lounge after a conference and during the conversation they realized that while they work in different disciplines – rheumatology and dermatology – they share a common interest in solving the mystery of scleroderma. They are now working together in a combined dermatology and rheumatology clinic, where they treat patients and carry out the joint research project.

The research, published in the Journal of Autoimmunity, funded by the Arthritis Society and Scleroderma Canada. Osman is a member of the Women and Children’s Health Research Institute.