DeSSciphering systemic sclerosis : the skin and its thickness

Systemic sclerosis (SSc) is a rare, clinically heterogeneous, severe multisystem disorder characterised by autoimmunity, fibrosis and vasculopathy [Rodnan et al., 1979; Gabrielli et al., 2009]. It is one of the most disabling and disfiguring diseases among the systemic diseases and compared to other rheumatic diseases, SSc is associated with a high loss of life expectancy [Mok et al., 2011]. Raynaud's phenomenon (RP) as an abnormality of the microcirculation is the initial and heralding symptom of SSc in over 95% of patients. Skin sclerosis and internal organ involvement then mostly manifest with a variable temporal interval after the onset of RP [Walker et al., 2007; Varga et al., 2012]. Aside from the skin, multiple organ systems can be damaged by fibrotic and/or vascular complications including the gastrointestinal tract, the pulmonary parenchyma and circulation, the heart, kidney and the joints [Medsger, 1997; Gabrielli et al., 2009]. Although skin fibrosis is the cardinal feature of the disease, the progressive deterioration of internal organs determines the clinical outcome [Walker et al., 2007; Domsic et al., 2014; Nihtyanova et al., 2014]. The aims of this thesis are (1) to map the time after disease onset in terms of RP to the onset of organ manifestations in SSc and to identify predictors of an early onset of manifestations; (2) to assess the effect of smoking on the manifestation and worsening of SSc organ manifestations and (3) to assess the level of functional ability and to identify factors associated with disability. This thesis is based on the largest worldwide database for SSc, the European Scleroderma Trials and Research group (EUSTAR) registry. By today, more than 15,000 SSc patients are followed prospectively in more than 200 expert centres within the EUSTAR network. We found that organ manifestations exhibit rapid kinetics early after the onset of RP, implying that there is only a short ‘window of opportunity’ to prevent incident organ damage. Furthermore, in every organ system, half of all organ manifestations become evident rather early in the disease, i.e. within the first two years. This implies that severe complications, for instance pulmonary hypertension and interstitial lung disease, are not restricted to late disease. Risk factors, such as the SSc subtype, autoantibody profile and the patient's sex do modify the cumulative incidences of the organ manifestations but do not substantially modify the steep increase in organ complication rates during the first two years after RP onset. These results are of great importance for clinicians, who need to counsel, risk stratify and treat SSc patients early on after the diagnosis. Furthermore, the findings are of great significance for the design of therapeutics aimed to ‘widen’ the still very narrow ‘window of opportunity’. We demonstrated that the known adverse effect of smoking on the bronchial airways and alveoli is also observed in SSc patients. However, we did not observe robust adverse effects of smoking on the progression of SSc-specific pulmonary or cutaneous manifestations. This finding argues against a major role of tobacco-associated free radicals, vasoconstrictor and immunomodulatory effects in the pathogenesis of SSc vasculopathy and fibrosis. Regarding the functional ability, we found that there is a major difference between the factors driving patient perceived levels of disability and those emphasized by physicians in their disease evaluation. The patients perceive dyspnoea, gastrointestinal symptoms, pain, muscle weakness and the presence of digital ulcers as the main factors driving their level of disability. These results that objective disease severity measures as assessed by the physicians do not correlate with patient-perceived disability indicate that the many and multi-faced aetiologies of disability and quality of life in SSc are poorly understood and are therefore a clarion call to further research