What are the recommended treatments for managing scleroderma?

Management of Scleroderma

First-Line Systemic Treatment

Mycophenolate mofetil (MMF) is the first-line treatment for systemic sclerosis with skin involvement, addressing both skin thickening and potential interstitial lung disease simultaneously. 1

• MMF has surpassed cyclophosphamide as the initial treatment of choice and is the most commonly prescribed first-line drug for diffuse cutaneous SSc, with a mean modified Rodnan skin score (mRSS) improvement of -4.90 points 1
• Methotrexate 25 mg per week is an alternative first-line treatment if MMF is not tolerated or if musculoskeletal involvement is predominant, with approximately 5-point improvement in mRSS 1
• For early diffuse SSc specifically, methotrexate may be considered for skin manifestations 1

Critical Baseline Screening

Before initiating treatment, perform comprehensive organ assessment:

• Pulmonary function tests (PFTs) with DLCO to detect subclinical interstitial lung disease, which is present in many patients at diagnosis 1
• High-resolution CT (HRCT) of the chest as the primary tool to diagnose ILD 1
• Echocardiogram to screen for pulmonary arterial hypertension 1
• Blood pressure monitoring to establish baseline for scleroderma renal crisis surveillance 1
• Modified Rodnan skin score (mRSS) assessment at 17 anatomical sites, with scores 0-3 at each site for a maximum of 51 points 1

Organ-Specific Management

Interstitial Lung Disease

Cyclophosphamide should be considered for SSc-related interstitial lung disease despite its known toxicity. 2

• Cyclophosphamide given orally at 1–2 mg/kg per day improved lung function tests, dyspnoea score, and quality of life over 12 months, with placebo-corrected mean improvement in forced vital capacity of 2.5% and total lung capacity of 4.1% 2
• Cyclophosphamide improved the transitional dyspnoea index and HAQ disability index compared to placebo 2
• MMF addresses potential ILD progression as part of first-line therapy 1

Raynaud's Phenomenon and Digital Ulcers

• Dihydropyridine-type calcium channel blockers, such as oral nifedipine, are first-line therapy for Raynaud's phenomenon 3
• Phosphodiesterase-5 (PDE-5) inhibitors should be considered for SSc-related Raynaud's phenomenon and digital ulcers 3
• Intravenous iloprost should be considered for severe Raynaud's phenomenon that fails to respond to oral therapy 3
• Fluoxetine may be used as an alternative treatment option 3

Gastrointestinal Involvement

• Proton pump inhibitors (PPI) should be used for prevention of gastro-oesophageal reflux, oesophageal ulcers, and strictures 1
• Prokinetic drugs should be used for symptomatic motility disturbances including dysphagia, GORD, early satiety, bloating, and pseudo-obstruction 1

Scleroderma Renal Crisis

• ACE inhibitors should be used in treatment of scleroderma renal crisis if it develops 1

Pulmonary Arterial Hypertension

• Treatment options include endothelin receptor antagonists, prostacyclin analogues, PDE-5 inhibitors, and riociguat 3

Localized Scleroderma (Morphea) Management

For active, potentially disfiguring or disabling forms of linear morphea, methotrexate at 15 mg/m²/week combined with systemic corticosteroids during the initial inflammatory phase is first-line therapy. 3, 4

Treatment Algorithm by Subtype

• Limited, superficial lesions (circumscribed morphea): Topical treatments are generally sufficient 4
• Linear, deep, generalized, or pansclerotic morphea: Systemic therapy with methotrexate and corticosteroids is indicated 4
• Medium-dose UVA1 therapy is effective in improving skin softness and reducing thickness 3, 4
• Topical imiquimod has been shown to decrease skin thickening by upregulating interferons that inhibit collagen production 4

Second-Line Options for Morphea

• Mycophenolate mofetil (MMF) at 500-1000 mg/m² is recommended as second-line therapy for MTX-refractory or MTX-intolerant patients 4
• MTX should be maintained for at least 12 months after achieving clinical improvement before tapering 4
• MTX or alternative disease-modifying drugs should be withdrawn once the patient is in remission and off steroids for at least 1 year 4

Monitoring Strategy

Regular Assessments

• PFTs should be performed every 3-6 months to track forced vital capacity (FVC) 1
• mRSS should be assessed at each visit to quantify skin improvement (minimal clinically important difference is 3.5-5.3 points) 1
• Repeat HRCT should be performed at defined intervals to assess fibrosis progression 1
• For localized scleroderma, use the Localized Scleroderma Cutaneous Assessment Tool (LoSCAT) for standardized assessment 3, 4
• Close monitoring for medication side effects is essential, particularly with MTX which may cause nausea, headache, and transient hepatotoxicity 4

Advanced Therapies for Severe Disease

Hematopoietic Stem Cell Transplantation

• For rapidly progressive SSc with skin and/or lung involvement, hematopoietic stem cell transplantation may be considered in selected patients 3
• High skin scores (mRSS >24) or moderate scores with progressive ILD are criteria for considering autologous hematopoietic stem cell transplantation in patients with early diffuse cutaneous SSc 1
• A high mRSS (>24) at baseline is associated with increased risk of mortality and lower rates of survival without progression 1

Alternative Immunosuppressive Therapies

• Cyclophosphamide has been shown to improve skin changes in SSc patients 2
• Other agents such as mycophenolate mofetil, azathioprine, or ciclosporine A are used to treat skin involvement, though their efficacy has not been studied as extensively 2
• B-cell depleting agents, such as Rituximab, are being increasingly utilized for cutaneous scleroderma with positive outcomes 5
• Intravenous immunoglobulins (IVIG) have demonstrated potential benefit for refractory cases with advanced skin fibrosis 5

Critical Pitfalls to Avoid

Corticosteroids should be avoided as monotherapy, as they are associated with substantial long-term morbidity in fibrotic lung disease and increase risk of scleroderma renal crisis in early diffuse cutaneous SSc. 1

• If steroids are used, patients must be carefully monitored for blood pressure and renal function 1
• Inadequate treatment duration leads to relapse; treatment should be continued for sufficient time 4
• Skin disease should not be underestimated, as it is associated with significant physical and psychological morbidity 1, 4
• Caution is necessary when using cyclosporine as it may decrease renal function and induce hypertension 3
• Patients with systemic sclerosis should be referred to a specialized center due to the heterogeneity of the disease, the complexity of diagnostic evaluation, and the wide array of available treatment options 3