Can scleroderma cause fibrosis?

Scleroderma and Fibrosis Development

Yes, scleroderma directly causes fibrosis in multiple organ systems, with fibrosis being a hallmark pathological feature of the disease that significantly contributes to morbidity and mortality. 1

Pathophysiology of Fibrosis in Scleroderma

Scleroderma (systemic sclerosis) is characterized by a pathogenic triad that includes:

1. Vasculopathy - Small vessel damage
2. Inflammation and autoimmunity - Immune system dysregulation
3. Fibrosis - Excessive collagen deposition in skin and internal organs 1

The fibrotic process in scleroderma involves:

• Progressive replacement of normal tissue with excessive collagen
• Activation of fibroblasts leading to extracellular matrix overproduction
• TGF-beta overexpression driving the fibrotic process 2

Organ Systems Affected by Fibrosis in Scleroderma

Skin Fibrosis

• Primary clinical manifestation used to classify disease subtypes:
  • Limited cutaneous SSc (lcSSc): Fibrosis distal to elbows/knees
  • Diffuse cutaneous SSc (dcSSc): Fibrosis both distal and proximal to knees/elbows and/or trunk 1

Pulmonary Fibrosis

• Interstitial lung disease (ILD) occurs in 40-75% of scleroderma patients
• Progressive in approximately 15-18% of cases
• Leading cause of death in scleroderma patients 1, 3
• Characterized by:
  • Nonspecific interstitial pneumonia (NSIP) pattern most common
  • Usual interstitial pneumonia (UIP) pattern less common 1
  • Decreased diffusing capacity (DLCO) on pulmonary function tests

Cardiac Fibrosis

• Autopsy studies reveal active myocarditis in 25% of cases and focal fibrosis in another 25% 1
• Cardiac fibrosis can lead to dilated cardiomyopathy
• In the EUSTAR cohort, 26% of fatal scleroderma cases were attributable to heart failure 1

Muscle Fibrosis

• Recent studies highlight that fibrosis is a prevalent histopathologic feature in muscle biopsies
• "Fibrosing myopathy" is associated with:
  • Diffuse scleroderma
  • Lower muscle enzymes
  • Nonirritable myopathy
  • Higher risk of cardiopulmonary complications and cardiac death 4

Clinical Implications of Fibrosis

• Fibrosis is responsible for many of the clinical manifestations and complications of scleroderma
• Pulmonary fibrosis progresses to severe restrictive lung disease in about 15% of patients 3
• Risk factors for developing progressive pulmonary fibrosis include:
  • Diffuse cutaneous scleroderma
  • Anti-Scl-70 antibodies
  • Low pulmonary function at presentation
  • Evidence of lung inflammation 3

Diagnostic Approaches for Fibrosis

• High-resolution CT (HRCT) scanning is essential for detecting lung fibrosis
• Pulmonary function tests with DLCO measurement
• Echocardiography for cardiac evaluation
• Muscle biopsy may reveal fibrosis in cases of suspected muscle involvement 1, 3

Treatment Considerations

• Early detection and intervention are critical to limit progression of fibrosis
• Treatment approaches target the inflammatory and fibrotic pathways:
  • Immunosuppressive agents (cyclophosphamide, mycophenolate mofetil)
  • Targeted therapies (nintedanib, tocilizumab)
  • Anti-TGF-beta approaches show promise in experimental models 2

Pitfalls and Caveats

• Fibrosis may be present and progressing even in asymptomatic patients
• Isolated decrease in DLCO may be an early sign of developing pulmonary fibrosis
• Patients with limited scleroderma and an isolated decrease in DLCO have a 20% risk of developing pulmonary arterial hypertension within 5 years 1
• Fibrosis in scleroderma can occur in multiple organs simultaneously, requiring comprehensive evaluation

In conclusion, fibrosis is not merely a complication but a fundamental pathological process in scleroderma, affecting multiple organ systems and significantly contributing to the disease burden and mortality.