Disease modification in systemic sclerosis: the search for the Holy Grail

Abstract

Descriptions of a systemic sclerosis (SSc)-like illness can be found in the writings of Hippocrates (460– 370 BC), however the first welldocumented case was reported by Carlo Cursio in 1755. He described a 17-year-old female patient from Naples (Italy) who presented with “an excessive tension and hardness of her skin all over her body, by which she found herself so bound and straiten’d, that she could hardly move her limbs.” She was treated with warm milk, vapor baths, “bleeding from her foot” and quicksilver, and reportedly her skin became soft and flexible after a period of 11 months [1]. Not all patients with SSc are as fortunate. More than 250 years have since passed and there is no treatment for SSc. The etiology of SSc is unknown and the complex pathogenesis is not clearly understood. The initial stage of the disease is characterized by an early inflammatory infiltrate, microvascular dysfunction and dysregulated immunity, which is superseded by overwhelming fibrosis [2]. Treatment studies for SSc are few and difficult to conduct owing to a low disease prevalence, a complicated pathogenesis unique to individual patients (even with a similar disease phenotype) and suboptimal primary outcome measures, such as the modified Rodnan skin score (mRSS), which may not correlate well with disease activity and severity in all patients. Trials with agents such as imatinib, IFN-g, IFN-a, d-penicillamine, relaxin and minocycline, which target only the fibrotic component of the disease, have shown improvement in open-label studies for the treatment of SSc. However, when randomized studies were carried out, a similar benefit was not observed. Agents that potentially target other pathogenic