Genes reveal which patients will benefit from scleroderma drug

Systemic sclerosis, also known as scleroderma, is a rare autoimmune connective tissue disorder that's difficult to treat. However, thanks to new research at Northwestern University Feinberg School of Medicine and Dartmouth's Geisel School of Medicine, doctors may be able to treat some patients more effectively.

Characterized by thickening of the skin, scleroderma can also cause significant complications in the joints and internal organs - particularly the esophagus, lower gastrointestinal tract, lungs, heart and kidneys. There is no cure - and the one drug commonly used to treat the disease, mycophenolate mofetile (MMF) does not work for all patients. In the absence of a biomarker to inform therapeutic medical decisions, patients are exposed to ineffective and potentially toxic medications.

In the first study of its kind in scleroderma, Monique Hinchcliff, M.D., assistant professor of medicine at the Feinberg School, associate director of the Northwestern Scleroderma Program, and a physician at Northwestern Memorial Hospital, and Michael Whitfield, associate professor of genetics at the Geisel School of Medicine, together have shown that gene expression signatures can accurately identify patients who will positively respond to a particular therapy.

The paper was recently published electronically in the Journal of Investigative Dermatology.

"There is the potential for adverse reactions including death with scleroderma therapies, and delay in initiating appropriate therapy can be harmful," Hinchcliff said. "Selecting effective treatment for each patient is the major issue facing physicians treating scleroderma patients."

Whitfield's and Hinchcliff's findings revealed that patients whose conditions improve with MMF therapy all share a particular gene expression pattern in skin.

During the clinical trial, patients who improved during MMF therapy were classified in the inflammatory gene expression subset, while patients who did not improve were classified in the normal-like or fibroproliferative gene expression subsets. This fits the initial hypothesis since MMF impairs lymphocyte proliferation.

Systemic sclerosis or systemic scleroderma is an autoimmune or connective tissue disease. It is characterized by thickening of the skin caused by accumulation of collagen, and by injuries to the smallest arteries. There are two overlapping forms. Limited cutaneous scleroderma is limited to the skin on the face, hands and feet. Diffuse cutaneous scleroderma covers more of the skin, and is at risk of progressing to the visceral organs, including the kidneys, heart, lungs and gastrointestinal tract are affected.

Survival is determined by the severity of visceral disease. Prognosis is difficult to predict until the disease differentiates into recognizable subsets. Patients with limited cutaneous scleroderma have a good prognosis, with 10-year survival of 75%, although <10% develop pulmonary arterial hypertension after 10 to 20 years. Patients with diffuse cutaneous scleroderma have a 10-year survival of 55%. Death is most often from pulmonary, heart and kidney involvement, although survival has greatly improved with effective treatment for kidney failure. Immunosuppressive drugs are used, although glucocorticoids have limited application.