Evidence-based management of rapidly progressing systemic sclerosis

Systemic sclerosis has the highest case-specific mortality of any of the auto-immune rheumatic diseases, as well as causing major morbidity. It is a major clinical challenge and one that has previously provoked substantial nihilism due to the limited therapeutic options available and the perceived lack of evidence for clinical effectiveness of those treatments that are currently in use. However, this situation is changing; there are emerging data supporting efficacy for some treatment approaches for this patient group together with a growing number of exciting potential novel approaches to treatment that are moving into the clinical arena. Some of the recent clinical trials are reviewed and discussed in detail.

The major mortality and much of the morbidity of systemic sclerosis (SSc) arises through the development of specific complications of the disease including organ-based complications such as cardiopulmonary, renal or gastrointestinal manifestations. The frequency and diverse nature of these complications makes systematic assessment and long-term follow up essential to good management of SSc. In addition, it is essential that accurate baseline assessment of each case is undertaken to define the extent and pattern of disease and to ascertain the likelihood of progression and risk of severe life-threatening complications. Current approaches to assessment and follow-up of severe progressive SSc are summarised below.

Assessment of skin disease

Skin fibrosis is a hallmark feature of SSc. Depending on the extent of skin sclerosis, the disease is classified into two major subsets – limited cutaneous SSc (limited SSc) when only skin distal to the elbows and knees (with or without face involvement) is affected and diffuse cutaneous SSc (diffuse SSc) when the skin thickening includes distal areas and also spreads proximally. These patients are also at risk from other complications of SSc.

The majority of cases of rapidly progressive SSc can be classified to the diffuse subset as there is almost always progression to involve proximal limbs or trunk. Nevertheless, it is important to consider that almost all cases will, at some point, have had less extensive skin involvement. For this reason, determining the duration of disease, as defined by the first non-Raynaud disease sign or symptom (such as joint pain and swelling, reflux disease and digital ulcer) is critical to assessment of cases of SSc. In addition, tendon friction rubs (TFRs), a ’leathery crepitus’ on palpation of knees, wrists, fingers and ankles during motion is a significant predictor of developing diffuse SSc . Before presenting the evidence for efficacy of the different agents in treatment of scleroderma skin disease, it is important to consider its relation to internal organ involvement in SSc patients and current methods of assessment that have shed insight onto the natural history of skin sclerosis in diffuse SSc.

Patients with early diffuse SSc tend to have worsening of their skin thickness over the first 1–3 years after disease onset. During this phase of skin thickening, patients develop internal organ involvement ( Table 1 ). In addition, worsening skin thickness is a predictor of morbidity and mortality. Therefore, current efforts are directed in the early diagnosis of internal organ involvement and institute therapies. Fig. 1 summarises our current diagnostic approach in patients with SSc. After 1–3 years of worsening skin thickening, the skin tends to soften irrespective of treatment . This has been noted both in clinical practice and randomised controlled trials (RCTs) of diffuse SSc . Although softening of skin is associated with improved survival , this relationship between change in skin score and internal organ involvement is not straightforward, which questions its validity as a primary outcome in trials assessing treatment efficacy. With that background, the modified Rodnan skin score (MRSS), a measure of skin thickness has been used as the primary outcome measure in most of these trials, as it is feasible, reliable, valid and responsive to change in multicentre clinical trials and is routinely performed in clinical practice at scleroderma centres. It assesses skin thickness in 17 body surface areas (face, chest, abdomen, and right and left fingers, hands, forearms, upper arms, thighs, lower legs and feet) . Each area was assessed for thickness on a 0–3 scale (0 = normal, 1 = mild but definite thickening, 2 = moderate skin thickening and 3 = severe skin thickening). The total score (the sum of scores from all 17 body areas) ranges from 0 to 51; a score of ≥20 is associated with poor prognosis.

Table 1

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