The connective tissue disease systemic sclerosis (SSc) - or scleroderma - has many debilitating manifestations and few reliably effective treatments. Research at HSS is hoping to help change that.
Scleroderma causes a condition called fibrosis, which is the growth of excessive connective tissue. This excess tissue can create painful skin conditions and affect major organs of the body, including the heart and lungs.
There are certain proteins – called cytokines – that signal other cells to launch molecular actions that create fibrosis. Two cytokines known to be involved in triggering fibrosis are transforming growth factor beta and platelet-derived growth factor. Both of those cytokines are active in the same cellular pathway called the tyrosine kinase pathway. There are drugs that can block tyrosine kinase cellular activity. These drugs are called tyrosine kinase inhibitors or TKIs. The theory behind using TKIs to treat scleroderma is that blocking relevant tyrosine kinase cellular activity can block the development of fibrosis.
HSS has been testing a TKI called imatinib mesylate, or just imatinib, also known commercially as Gleevec™. Earlier studies of human skin cells and animal models using imatinib suggested that the drug may have the potential ability to reduce fibrosis. Testing then proceeded to clinical trials at HSS.
Attending Rheumatologist and Director of the HSS Vasculitis and Scleroderma Program, Robert F. Spiera, MD, and his team, including Assistant Attending Physician, Jessica K. Gordon, MD, have led the testing of TKIs to treat scleroderma at HSS.
The first 12 month clinical trial of imatinib started with 30 patients who had diffuse systemic sclerosis. The patents received daily treatment with Gleevec, at a target dose of 400 mg daily, for one year. 24 patients completed the year’s trial.
After 12 months, the patients showed an average 22% improvement on a standard test called the Modified Rodnan Skin Score (MRSS). Pulmonary function remained stable even in patients who had lung involvement entering the trial.
Side effects are a concern when treating with Gleevec, but during the trial, acceptable safety and tolerability of the drug was demonstrated.
The patients who completed the first 12-month study were then eligible to continue treatment in an additional 24-month extension of the clinical trial. 17 patients did continue. 76% were female. 65% were Caucasian. They ranged in age from 18 to 61, with a median age of 48. The patients were treated daily with the same target dose of 400 mg of Gleevec for another year.
During the first 12 month trial, the patients’ MRSS scores had already improved. Further improvement was seen during the additional 24 months of treatment. The group’s median MRSS score at the start of the extension was 24, which improved to 18 at the end of the two years of treatment. These results must be interpreted cautiously however, as patients with scleroderma can have improvements in their skin score spontaneously, especially with longer duration of disease.
When a patient’s health changes during a clinical trial, or they show side effects in reaction to the drug being tested, it is called an adverse event or AE. During the 24-month extension, 92 AEs were recorded, 43% of which were felt to be at least possibly related to the drug treatment. The most frequently noted side effects were muscle pain, fatigue, nausea, and edema.
Gleevec was developed – and is still used – to treat leukemia and gastrointestinal stromal tumors. The clinical trials at HSS are called “open label” because doctors are prescribing the drug to treat a different condition than its established purpose.
The testing of Gleevec for use in scleroderma at HSS has been a long, careful process. Evaluation of results in human trials are closely monitored for safety and efficacy. With effective drug treatment options being so limited for scleroderma, the recognition of acceptable safety and tolerability coupled with the demonstration of possible benefit suggest further, larger testing. Eventually, larger, placebo-controlled studies can be done to better define the value of this therapy.
A new second-generation TKI has now been developed. It is called nilotinib. HSS doctors are also studying its use in treating scleroderma. Learn more about a pilot study of the new TKI.
It is very important that doctors and patients be extremely cautious about TKIs and understand not only are there risks for serious side effects, but the drugs do not help all patients. Treatment with Gleevec is still being carefully tested but what is already well known is that it is not for everyone, and treatment should not be attempted just because there are so few reliable options.
Larger double blinded randomized clinical trials ultimately are necessary to really define the benefits and risks of a treatment.
Weill-Cornell Medical Center:
Cynthia Magro, MD
Horatio F. Wildman, MD