Treatment of Scleroderma with Joint, Skin, and Lung Involvement
Start mycophenolate mofetil (MMF) as first-line therapy for patients with active systemic sclerosis affecting skin, joints, and interstitial lung disease, as it addresses both skin fibrosis and ILD simultaneously. 1, 2, 3
Primary Treatment Strategy
First-Line Immunosuppressive Therapy
Mycophenolate mofetil (MMF) is the recommended initial treatment, having surpassed cyclophosphamide as the preferred first-line agent for both skin and lung manifestations in systemic sclerosis. 1, 2, 4
MMF produces a mean modified Rodnan skin score (mRSS) improvement of approximately -4.90 points while simultaneously benefiting interstitial lung disease. 4
The 2023 EULAR recommendations specifically designate MMF as the novel first-line intervention for active skin fibrosis and SSc-ILD based on its ability to soften skin, modify disease trajectory, and address pulmonary involvement. 1, 3
The American Thoracic Society provides a strong recommendation for MMF use in SSc-ILD based on high-quality evidence. 5
Alternative First-Line Option
Methotrexate 25 mg per week can be used as an alternative if MMF is not tolerated or if musculoskeletal involvement is predominant, producing approximately 5-point improvement in mRSS. 4
However, the evidence for methotrexate's efficacy on joint involvement specifically remains limited despite musculoskeletal symptoms being a major patient concern. 1
Adding Antifibrotic Therapy
When to Add Nintedanib
Nintedanib should be added if ILD is fibrotic and progressing despite immunosuppression with MMF, particularly when forced vital capacity (FVC) is <80% of predicted. 3
The combination of nintedanib plus MMF may provide synergistic benefit by addressing both inflammatory/immune-mediated and fibrotic disease components. 3
The American Thoracic Society suggests nintedanib use for SSc-ILD, and the combination of nintedanib plus mycophenolate warrants consideration. 5
Pirfenidone is a possible alternative antifibrotic agent, though evidence is less robust. 1
Second-Line Biologic Options
If disease progresses on MMF or if MMF is contraindicated:
Rituximab (anti-CD20 biologic) is incorporated into 2023 EULAR recommendations as a novel option for treating skin fibrosis and SSc-ILD. 1, 3
Tocilizumab (anti-IL-6 biologic) is similarly recommended for patients who fail to achieve adequate response to MMF. 1, 3
The American Thoracic Society suggests both rituximab and tocilizumab for SSc-ILD treatment. 5
Be aware that rituximab carries rare risks including pneumonitis, worsening ILD, infections, and hypogammaglobulinemia. 2
Cyclophosphamide as Alternative
Cyclophosphamide (oral 1-2 mg/kg/day or IV 600-750 mg/m²/month) remains an option for more severe or rapidly progressive disease, improving both skin involvement and ILD. 3
The Scleroderma Lung Study demonstrated cyclophosphamide produced a placebo-adjusted mean increase in FVC of 2.5% and total lung capacity of 4.1%, with better dyspnea scores. 3
However, cyclophosphamide carries higher toxicity, including increased risk of treatment-related mortality and morbidity, making it less favorable as first-line. 3
The American Thoracic Society suggests cyclophosphamide for SSc-ILD but acknowledges MMF as the stronger recommendation. 5
High-Risk Disease: Consider AHSCT
Autologous hematopoietic stem cell transplantation (AHSCT) should be contemplated for patients with very high-risk features: modified Rodnan skin score >24 or moderate skin disease with worsening ILD despite conventional immunosuppression. 3
AHSCT can improve survival in patients with early diffuse cutaneous SSc at high risk of mortality, particularly those with very high skin scores or moderate skin involvement with worsening ILD. 1
This procedure must be performed in specialized centers with expertise in HSCT for systemic sclerosis, after rigorous benefit-to-risk assessment by multidisciplinary experts. 3
Critical Baseline Screening Required
Before initiating treatment:
Pulmonary function tests (PFTs) with DLCO to detect subclinical ILD, as ILD is present in approximately 65% of SSc patients and accounts for 40% of deaths. 4, 6
High-resolution CT (HRCT) of the chest as the primary tool to diagnose ILD and assess extent of fibrosis. 4, 7
Echocardiogram to screen for pulmonary arterial hypertension. 4
Blood pressure monitoring to establish baseline for scleroderma renal crisis surveillance. 4
Monitoring Strategy on MMF
Perform serial PFTs every 3-6 months to track forced vital capacity (FVC). 2, 4
Repeat HRCT at defined intervals to assess fibrosis progression. 2, 4
Monitor mRSS at each visit to quantify skin improvement. 4
Watch for progression indicators: worsening dyspnea, declining FVC >10%, or new HRCT changes. 2, 4
Critical Pitfalls to Avoid
Corticosteroid Use
Avoid corticosteroids as monotherapy for stable disease, as they are associated with substantial long-term morbidity in fibrotic lung disease and no demonstrated survival benefit in definite pulmonary fibrosis. 2, 4
Corticosteroids increase risk of scleroderma renal crisis in early diffuse cutaneous SSc. 4
If steroids must be used chronically, keep doses ≤15 mg/day prednisone equivalent to minimize scleroderma renal crisis risk. 2
Reserve high-dose IV methylprednisolone only for rapidly progressive ILD with acute respiratory failure or acute exacerbation of ILD. 2
Joint Involvement Considerations
Despite musculoskeletal involvement being common and highly ranked by patients as a major concern, there is a lack of good quality evidence for the impact of corticosteroids, tocilizumab, or rituximab specifically on joint involvement. 1
Some case series suggested effectiveness of abatacept on joint involvement, but a phase 2 trial showed no significant differences in swollen and tender joint counts at 12 months, though clinically meaningful treatment differences were observed in HAQ DI. 1
Do not assume that improvement in skin score alone signifies overall disease control; ILD may progress independently and requires separate monitoring and targeted antifibrotic therapy when indicated. 3