State-of-the-art evidence in the treatment of systemic sclerosis

Abstract

Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease with multi-organ involvement, fibrosis and vasculopathy. Treatment in SSc, including early diffuse cutaneous SSc (dcSSc) and the use of organ-specific therapies, has improved, as evident from randomized clinical trials. Treatments for early dcSSc include immunosuppressive agents such as mycophenolate mofetil, methotrexate, cyclophosphamide, rituximab and tocilizumab. Patients with rapidly progressive early dcSSc might be eligible for autologous haematopoietic stem cell transplantation, which can improve survival. Morbidity from interstitial lung disease and pulmonary arterial hypertension is improving with the use of proven therapies. Mycophenolate mofetil has surpassed cyclophosphamide as the initial treatment for SSc-interstitial lung disease. Nintedanib and possibly perfinidone can be considered in SSc pulmonary fibrosis. Pulmonary arterial hypertension is frequently treated with initial combination therapy (for example, with phosphodiesterase 5 inhibitors and endothelin receptor antagonists) and, if necessary, the addition of a prostacyclin analogue. Raynaud phenomenon and digital ulcers are treated with dihydropyridine calcium channel blockers (especially nifedipine), then phosphodiesterase 5 inhibitors or intravenous iloprost. Bosentan can reduce the development of new digital ulcers. Trial data for other manifestations are mostly lacking. Research is needed to develop targeted and highly effective treatments, best practices for organ-specific screening and early intervention, and sensitive outcome measurements.

Fig. 1. Treatment effect on skin in SSc.

This figure illustrates the effects of immunosuppressive treatments on the skin in systemic sclerosis (SSc). Modified Rodnan skin score (mRSS) is measured on a scale of 0 to 51 points. The size of each circle reflects the effect size of the treatment (taking into consideration sample size and standard deviation), mirroring the change in mRSS from the smallest (the effect of tocilizumab treatment) to the largest (the effect of autologous haematopoietic stem cell transplantation (AHSCT), as seen in the ASTIS trial). MMF, mycophenolate mofetil.

Fig. 2. Overview of management of lung fibrosis in SSc.

The pathway for patients with systemic sclerosis (SSc) requires screening and early detection of interstitial lung disease (ILD) together with staging and risk stratification. Treatment generally involves immunosuppression and supportive measures together with anti-fibrotic therapies in appropriate cases (Table 2). In established lung fibrosis, use of a simple staging system can help with treatment decision-making but longitudinal monitoring of lung function tests and CT imaging is important to detect progressive disease and assess treatment response. AHSCT, autologous haematopoietic stem cell transplantation; HRCT, high-resolution CT; PFT, pulmonary function testing.

Fig. 3. Pulmonary hypertension treatment algorithm in SSc.

Treatment of pulmonary arterial hypertension (PAH) in patients with systemic sclerosis (SSc) is guided by risk stratification, which uses information from clinical assessments and imaging. Risk is graded using the REVEAL 2.0 calculator (involving 14 variables): a REVEAL score ≤6 corresponds with a low risk, a score of 7 or 8 corresponds to an intermediate risk and a score ≥9 indicates a high risk. Four groups of pulmonary hypertension-specific therapies can be considered in the treatment of SSc-PAH: endothelin receptor (ETR) antagonists, phosphodiesterase 5 (PDE5) inhibitors, soluble guanylate cyclase (sGC) stimulators, and prostacyclin analogues and receptor agonists. Combination oral therapy with an ETR antagonist and a PDE5 inhibitor is often first-line treatment in SSc-PAH. Historically, initial monotherapy with one oral agent was recommended, but now this approach is used only in selected low-risk patients. BMPR2, bone morphogenetic protein receptor type 2; mPAP, mean pulmonary arterial pressure; PVR, pulmonary vascular resistance.

Fig. 4. Management of Raynaud phenomenon and digital ulcers in SSc.

Treatment of Raynaud phenomenon and digital ulcers is similar, although some drugs might prevent digital ulcers but not enhance their healing. This algorithm suggests different lines of treatment and the strength of each recommendation according to the scientific evidence available: strong (green), possible (yellow) and based on weak or historical evidence (red). CCB, calcium channel blocker; PDE5, phosphodiesterase 5; SSc systemic sclerosis. *Effective in digital ulcer healing. ^‡Effective in digital ulcer prevention.