Skin involvement in early diffuse cutaneous systemic sclerosis: an unmet clinical need

Abstract

Diffuse cutaneous systemic sclerosis (dcSSc) is associated with high mortality resulting from early internal-organ involvement. Clinicians therefore tend to focus on early diagnosis and treatment of potentially life-threatening cardiorespiratory and renal disease. However, the rapidly progressive painful, itchy skin tightening that characterizes dcSSc is the symptom that has the greatest effect on patients' quality of life, and there is currently no effective disease-modifying treatment for it. Considerable advances have been made in predicting the extent and rate of skin-disease progression (which vary between patients), including the development of techniques such as molecular analysis of skin biopsy samples. Risk stratification for progressive skin disease is especially relevant now that haematopoietic stem-cell transplantation is a treatment option, because stratification will inform the balance of risk versus benefit for each patient. Measurement of skin disease is a major challenge. Results from clinical trials have highlighted limitations of the modified Rodnan skin score (the current gold standard). Alternative patient-reported and other potential outcome measures have been and are being developed. Patients with early dcSSc should be referred to specialist centres to ensure best-practice management, including the management of their skin disease, and to maximize opportunities for inclusion in clinical trials.

Fig. 1. Skin involvement in diffuse cutaneous systemic sclerosis.

a | Flexion contractures of the fingers in early diffuse cutaneous systemic sclerosis (dcSSc). b | Superficial cutaneous ulceration in early dcSSc. c | Late-stage dcSSc with persisting contracture (note the scar from carpal tunnel decompression, performed soon after the onset of symptoms of dcSSc). Images copyright of Northern Care Alliance NHS Foundation Trust.

Fig. 2. Conceptual framework for skin-score trajectory and clinical diversity in diffuse cutaneous systemic sclerosis.

Although at a group level, cohort studies and clinical trials of systemic sclerosis (SSc) almost always show improvement in average skin score over 1–3 years, this group-level behaviour does not reflect differences in modified Rodnan skin score (mRSS) change over time for individual patients. Operationally, SSc can be differentiated into three subgroups, characterized by high peak mRSS followed by regression, high peak mRSS without disease regression or lower peak mRSS tending to improve over 2–5 years of follow-up. This pattern of subgroups is likely to reflect interplay between the effectors of progression and fibrosis and the counteracting influence of the mechanisms that determine spontaneous regression, which is a hallmark of normal skin wound healing. Molecular and cellular determinants of these processes are likely to interact and to underlie the distinct patterns of skin disease, and might also determine the development and severity of internal-organ complications in SSc. Greater understanding of the biological basis of heterogeneity in skin-score change could facilitate clinical trial design and a more stratified approach to patient care. Notably, in normal skin, wound-healing mediators such as TGFβ regulate both profibrotic mechanisms and processes involved in regression of fibrosis, such as induction of matrix-degrading metalloproteinases. The balance between these processes of activation and regression and the persistence of local mediators of fibrosis might underlie the distinct skin-score trajectories observed for individual patients with SSc^,,.

Fig. 3. Management of skin disease in patients with early diffuse cutaneous systemic sclerosis.

Early recognition and referral to a specialist centre are the first principles of management. Pending specialist review, ‘general measures’ should be initiated. In most patients, immunosuppressant therapy should be prescribed. If at all possible, patients should be offered the opportunity to participate in a clinical trial. For patients who continue to progress, haematopoietic stem-cell transplantation should be considered.