What is Mixed Connective Tissue Disease (MCTD) in the context of scleroderma and Rheumatoid Arthritis (RA)?

Mixed Connective Tissue Disease (MCTD) in the Context of Scleroderma and Rheumatoid Arthritis

Mixed Connective Tissue Disease (MCTD) is a distinct autoimmune disorder characterized by overlapping features of multiple connective tissue diseases, including systemic sclerosis (scleroderma), rheumatoid arthritis, systemic lupus erythematosus, and polymyositis/dermatomyositis, with high titers of anti-U1-ribonucleoprotein (anti-U1-RNP) antibodies as the defining serological marker.

Definition and Characteristics

• MCTD is a rare systemic autoimmune rheumatic disease (SARD) that combines clinical features from multiple connective tissue disorders, particularly scleroderma, rheumatoid arthritis, systemic lupus erythematosus, and polymyositis/dermatomyositis 1
• The hallmark laboratory finding is the presence of high-titer anti-U1-RNP antibodies, which are essential for diagnosis 2, 1
• MCTD was first described in 1972 by Sharp et al., though its classification as a distinct entity has been debated due to its overlap features 1

Clinical Manifestations

• Early manifestations typically include Raynaud's phenomenon, inflammatory arthritis (similar to RA), puffy fingers (similar to scleroderma), myalgia and/or myositis, and occasionally trigeminal neuropathy 1
• As the disease progresses, patients may develop more specific features of the component diseases:
  • Scleroderma-like features: skin thickening, esophageal dysmotility, and pulmonary fibrosis 3
  • RA-like features: inflammatory polyarthritis affecting small joints 1
  • Myositis features: muscle weakness and elevated muscle enzymes 4
• Interstitial lung disease (ILD) is present in 40-80% of MCTD patients, with non-specific interstitial pneumonia (NSIP) being the most common radiological pattern 5
• Pulmonary hypertension and ILD are the two main causes of mortality in MCTD 1

Diagnosis

• Diagnosis relies on the presence of high-titer anti-U1-RNP antibodies along with clinical features of multiple connective tissue diseases 1
• Antinuclear antibody (ANA) testing typically shows a coarse speckled pattern 1
• Several classification criteria exist, though none are universally accepted 6
• Early diagnosis is challenging due to the disease's rarity, heterogeneous presentation, and evolving clinical features 1

Screening and Monitoring for ILD in MCTD

• All patients diagnosed with MCTD should undergo screening with high-resolution computed tomography (HRCT) and pulmonary function tests (PFTs) including spirometry and diffusing capacity for carbon monoxide (DLCO) at diagnosis 5
• For patients with an SSc phenotype, follow-up should include:
  • PFTs every 6 months
  • Annual HRCT for the first 3-4 years after diagnosis 5
• For patients with other phenotypes, annual clinical examination and PFTs are recommended, with HRCT if abnormalities are detected 5
• Risk factors for MCTD-associated ILD include esophageal dysfunction, dysphagia, Raynaud's phenomenon, anti-Smith or anti-Ro-52 antibodies, rheumatoid factor, and no history of arthritis 5
• High anti-ribonucleoprotein antibody titers at baseline strongly predict ILD progression 5

Treatment of MCTD-ILD

• For MCTD-associated ILD, mycophenolate is the preferred first-line therapy 5, 7
• Additional first-line options include azathioprine and tocilizumab 5, 7
• Short-term glucocorticoids (≤3 months) may be used, but should be used cautiously in patients with an SSc phenotype due to increased risk of renal crisis 5
• For MCTD-ILD that progresses despite first-line therapy, treatment options include:
  • Mycophenolate (if not used initially)
  • Rituximab
  • Nintedanib
  • Tocilizumab
  • Cyclophosphamide 5, 7
• For rapidly progressive ILD in MCTD, pulse intravenous methylprednisolone is conditionally recommended as first-line treatment, along with rituximab, cyclophosphamide, IVIG, mycophenolate, calcineurin inhibitors, or JAK inhibitors 5, 7
• Upfront combination therapy is conditionally recommended over monotherapy for rapidly progressive ILD 5, 7

Prognosis and Complications

• Signs of fibrosis on HRCT are associated with increased mortality, with one study showing a mortality rate of 20.8% in patients with severe pulmonary fibrosis compared to 3.3% in those with normal HRCT 5
• Although ILD in MCTD is typically modest in extent, nearly 50% of patients will experience progression 5
• Progression is generally slow but may continue for several years after diagnosis 5
• Rare but serious neurological complications include transverse myelopathy and longitudinal extensive transverse myelopathy 4
• Scleroderma renal crisis can occur in MCTD patients with predominant scleroderma features, requiring prompt treatment with ACE inhibitors 3

Key Differences from Pure Scleroderma or RA

• Unlike pure scleroderma, MCTD typically has inflammatory features (arthritis, myositis) that are more responsive to immunosuppressive therapy 1
• Unlike pure RA, MCTD frequently has vascular manifestations (Raynaud's) and is associated with higher risk of pulmonary hypertension 1
• Treatment approaches differ: while methotrexate is commonly used in RA, it is not a preferred agent for MCTD-ILD 5, 7
• The presence of high-titer anti-U1-RNP antibodies distinguishes MCTD from both pure scleroderma and RA 1