Targeted Therapy for Systemic Sclerosis: How Close Are We?: The Antioxidant Pathway
Posted Sep 25 2010 12:00am
The Antioxidant Pathway
An oxidant–antioxidant imbalance has been suggested as another etiopathogenic mechanism in SSc, especially in the development of pulmonary fibrosis, and drugs with antioxidant effects have been tested in SSc. In 2005, a randomized controlled trial showed that pirfenidone, an anti-inflammatory drug that has antioxidant and antifibrotic effects, improved vital capacity and prevented acute exacerbations of idiopathic ILD. The design of this study, however, was criticized and pirfenidone is currently rarely used in SSc.
More interest has been shown in N-acetylcysteine, a precursor of the antioxidant glutathione, which has been shown to restore depleted pulmonary glutathione levels in patients with fibrosing alveolitis. Demedts et al. conducted a randomized controlled trial in 182 patients with idiopathic ILD treated with prednisone plus azathioprine, and compared the addition of oral N-acetylcysteine with placebo. The addition of N-acetylcysteine was associated with a lower rate of worsening in pulmonary function at months 6 and 12 and a marked reduction in the number of myelotoxic side effects compared with placebo. Although there are no controlled trials of N-acetylcysteine in patients with SSc, the almost complete lack of toxicity of the agent makes it an attractive coadjuvant treatment for ILD. Furthermore, an observational study of the use of intravenous N-acetylcysteine in patients with SSc and Raynaud phenomenon or digital vasculopathy has shown promising results.
Relaxin is a pregnancy-related hormone that has tissue remodeling and antifibrotic effects owing to its ability to increase degradation of the extracellular matrix. Experimental studies have shown a progression of dermal fibrosis and thickening in a relaxin-gene knockout mouse, and relaxin levels are higher in patients with SSc than controls. In 2000, a phase I/II trial in 68 patients with SSc found that the administration of recombinant human relaxin was associated with reduced skin thickening and improved function. In a more-recent phase III randomized controlled trial in 239 patients with SSc, however, the agent was ineffective and resulted in severe side effects (renal failure, severe hypertension) when it was discontinued. These results clearly restrict the rationale for future trials based on this molecule.