MICA: Evaluation of the selective endothelin A-receptor antagonist zibotentan as a treatment for renal disease in systemic sclerosis (scleroderma)

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Systemic sclerosis (SSc), also called scleroderma, is a serious rheumatic disease. Although skin thickening, or hardening, occurs in almost all cases, justifying the term "scleroderma", the disease is much more than "skin-deep" since it often causes damage many internal organs including the heart, lungs, kidney, bowel and blood vessels. It is important because, although uncommon, it causes more deaths than any other rheumatic disease, with around half of the patients diagnosed with scleroderma eventually dying as a direct result of the condition. It also causes many severe non-life threatening problems such as pain, loss of hand function and disability. The kidneys are often affected in scleroderma and this can occur in two main ways. First, around 1 in 8 cases of severe systemic sclerosis develop kidney failure associated with very high blood pressure. This is called a scleroderma renal crisis (SRC). Although previously usually fatal, most patients now survive SRC but up to half can have long term renal failure and require dialysis or transplantation. In addition to SRC, scleroderma also affects kidneys in a second way that is much more frequent. Due to long term blood vessel damage and scarring (or fibrosis) scleroderma causes long term (chronic) renal damage. Although less immediately life-threatening than SRC this chronic renal damage may impact on long term survival and quality of life, and have a major effect on medication or the severity of other scleroderma complications.The present application will assess the potential benefit of using a novel drug to block a specific protein called endothelin that may be driving the renal abnormalities in systemic sclerosis. Endothelin is produced by blood vessel lining cells and high levels appear to damage tissues including the kidneys. It exerts its effect through two specific cell surface receptors termed ET-A and ET-B. Endothelin levels are increased in SRC and there is evidence for increased endothelin activity in several complications of systemic sclerosis. Zibotentan is a very potent drug that blocks one receptor for endothelin, the ET-A receptor. This is important as other receptors, specifically the ET-B receptor, may be important for normal kidney function. Thus blocking ET-A is expected to improve outcome in SRC and may also reverse or prevent less severe forms of renal disease. We will explore this by first defining the best measures of renal disease in systemic sclerosis and then undertake a clinical trial of zibtentan compared with control in cases of SSc that have moderate kidney disease. In parallel we will assess the benefit of adding zibotentan to standard treatments for SRC that include routine use of other blood pressure lowering drugs such as ACE inhibitors. Together the results of this work will define the benefit of blocking ET-A, whilst retaining the likely beneficial effects of ET-B signalling, and may have relevance for complications of scleroderma outside the kidney, and to other commoner medical conditions.