What are the characteristic skin manifestations of systemic sclerosis and what is the first‑line treatment for active skin disease?

Skin Manifestations of Systemic Sclerosis

Characteristic Skin Manifestations

Skin fibrosis is the dominant clinical feature of systemic sclerosis, with nearly all patients experiencing cutaneous involvement that determines disease classification and prognosis. 1, 2

Classification by Skin Extent

• Diffuse cutaneous SSc (dcSSc): Skin thickening extends both distal AND proximal to elbows/knees, including truncal involvement, with rapid disease progression and earlier widespread internal organ involvement 1, 2

• Limited cutaneous SSc (lcSSc): Skin fibrosis confined to areas distal to elbows/knees without truncal involvement, though face and neck may be affected, with more insidious onset 1, 2

• SSc sine scleroderma: A small subset (1.5-8%) lacks definite skin involvement but develops major internal organ complications 2

Specific Cutaneous Features

• Skin thickening/sclerosis: Assessed using the modified Rodnan skin score (mRSS), which evaluates 17 anatomical sites (fingers, hands, forearms, arms, chest, abdomen, thighs, legs, feet) with scores of 0-3 per site (total range 0-51) 3, 2

• Raynaud phenomenon: Present in nearly all patients (>95%) 1, 2

• Digital ulcers: Affect approximately 50% of SSc patients 1, 2

• Puffy fingers: May be an early "prescleroderma" manifestation 2

• Telangiectasias and calcinosis: Common additional cutaneous features 4

Disease Progression Pattern

• In dcSSc, the mRSS typically increases over the first 4 years of disease, then may regress somewhat thereafter, though many patients deviate from this pattern 1, 3

• High mRSS (>24) at baseline is associated with increased mortality risk and lower survival without progression 3

• Skin scores correlate inversely with survival and serve as valuable markers of disease severity 5

---

First-Line Treatment for Active Skin Disease

Mycophenolate mofetil (MMF) is the first-line immunosuppressive treatment for active skin fibrosis in early diffuse cutaneous systemic sclerosis. 6, 7

Treatment Algorithm for Skin Fibrosis

Step 1: Initial Assessment

• Establish disease duration from first non-Raynaud phenomenon feature (treatment trials typically focus on patients within 2-5 years of onset) 1
• Calculate baseline mRSS to quantify skin involvement 3
• Screen for high-risk features: anti-RNA polymerase III antibodies, rapidly progressive skin involvement, tendon friction rubs 2, 8

Step 2: First-Line Therapy

• Mycophenolate mofetil: The established first-line immunosuppressive for skin fibrosis in early dcSSc 6, 7
• This recommendation is based on its ability to soften skin and change the natural history of early diffuse cutaneous disease 1

Step 3: Alternative Immunosuppressive Options

• Cyclophosphamide: Can improve both skin manifestations and interstitial lung disease 1
• Rituximab (B-cell depleting agent): Increasingly utilized for cutaneous scleroderma with positive outcomes 7
• Intravenous immunoglobulins (IVIG): Demonstrated potential benefit for refractory cases with advanced skin fibrosis 7

Step 4: Disease-Modifying Therapy for High-Risk Patients

• Autologous hematopoietic stem cell transplantation (AHSCT): Reserved for patients with early dcSSc at high risk of mortality, specifically those with very high skin scores (mRSS) OR moderate skin involvement with worsening interstitial lung disease 1, 3
• AHSCT can improve survival as well as skin, function, and ILD outcomes 1
• This represents the most aggressive intervention with ability to reset the immune system and achieve remission in severe cases 7

Treatment of Vascular Manifestations

Raynaud Phenomenon

• First-line: Dihydropyridine calcium channel blockers, especially nifedipine 1
• Second-line: Phosphodiesterase 5 inhibitors OR intravenous iloprost 1

Digital Ulcers

• Prevention: Bosentan (dual endothelin receptor antagonist) can reduce development of new digital ulcers 1, 5
• Treatment: Same stepwise approach as Raynaud phenomenon (calcium channel blockers, then phosphodiesterase 5 inhibitors or IV iloprost) 1

---

Critical Clinical Caveats

Monitoring Requirements

• The minimal clinically important difference in mRSS is 3.5 to 5.3 points, meaning changes below this threshold may not represent true clinical improvement 1, 3

• Blood pressure must be monitored regularly in early dcSSc patients, especially those with anti-RNA polymerase III antibodies, to detect scleroderma renal crisis early 1, 2

• Screen for interstitial lung disease at diagnosis and regularly thereafter, as ILD is common (40-75%) and progressive in 15-18% of patients 1, 2

Treatment Pitfalls to Avoid

• Avoid high-dose glucocorticoids in patients with early dcSSc, tendon friction rubs, or rapidly progressive skin involvement, as steroids are themselves a risk factor for scleroderma renal crisis 8

• Treatment for early lcSSc remains uncertain with insufficient evidence to guide therapy 1

• Predicting which early dcSSc patients will improve or worsen during treatment is difficult, making risk stratification essential before considering aggressive interventions like AHSCT 1, 9

Emerging Therapies

• Novel approaches under investigation include anti-interleukin 6, Janus kinase inhibitors, transforming growth factor β inhibition, and CAR T-cell therapy for refractory disease 6, 7