What is Mixed Connective Tissue Disease (MCTD)?

Mixed Connective Tissue Disease: A Comprehensive Overview

Mixed Connective Tissue Disease (MCTD) is an autoimmune overlap syndrome characterized by the presence of high-titer anti-U1-RNP antibodies and clinical features of multiple connective tissue diseases, with pulmonary hypertension and interstitial lung disease being the main causes of mortality.

Definition and Diagnostic Features

• MCTD was first described in 1972 as a distinct clinical entity characterized by overlapping features of systemic sclerosis (SSc), systemic lupus erythematosus (SLE), polymyositis, and rheumatoid arthritis, along with the presence of antibodies to U1-RNP 1, 2
• The hallmark serological finding is high-titer anti-U1-RNP antibodies, typically associated with a coarse speckled pattern on antinuclear antibody (ANA) testing 1, 3
• Despite being recognized for over 50 years, debate continues about whether MCTD represents a distinct disease entity or an overlap syndrome 2, 4

Clinical Manifestations

Early Disease Features

• Raynaud's phenomenon (often the initial manifestation) 1, 2
• Puffy fingers or "sausage-like" digits 1
• Inflammatory arthritis affecting multiple joints 1, 2
• Myalgia and/or frank myositis 1
• Trigeminal neuropathy (less common but distinctive) 1

Advanced Disease Features

• Interstitial lung disease (ILD), present in 40-80% of patients 3
• Pulmonary hypertension (a major cause of mortality) 3, 2
• Esophageal dysfunction and dysphagia 3
• Sclerodactyly and other scleroderma-like skin changes 2
• Inflammatory myopathy with muscle weakness 2

Pulmonary Manifestations

• ILD is a major complication with nonspecific interstitial pneumonia (NSIP) being the most common radiological pattern 3
• Nearly 50% of patients with MCTD-ILD experience disease progression, which is generally slow but continues for years after diagnosis 3
• Signs of pulmonary fibrosis on HRCT correlate with increased mortality (20.8% mortality with severe fibrosis vs. 3.3% with normal HRCT) 3
• Pulmonary arterial hypertension is a significant cause of death in MCTD, occurring in up to 38% of patients in long-term follow-up studies 3

Risk Factors for MCTD-ILD

• Esophageal dilatation and motor dysfunction 3
• Dysphagia 3
• Raynaud's phenomenon 3
• Presence of anti-Smith or anti-Ro-52 antibodies 3
• Positive rheumatoid factor 3
• Absence of arthritis history 3
• High anti-RNP antibody titers at baseline (strong predictor of ILD progression) 3

Screening and Monitoring Recommendations

• All patients diagnosed with MCTD should undergo baseline screening with HRCT and pulmonary function tests (PFTs including spirometry and DLCO) 3, 5
• For patients with SSc phenotype:
  • PFTs every 6 months 3, 5
  • Annual HRCT for the first 3-4 years after diagnosis 3, 5
• For other MCTD phenotypes:
  • Annual PFTs 3
  • HRCT if PFTs show abnormalities 3

Treatment Approaches

• No specific clinical practice guidelines exist for MCTD, and treatment is often extrapolated from guidelines for other connective tissue diseases 4
• For MCTD-associated ILD, mycophenolate is considered the preferred first-line therapy 5
• Additional immunosuppressive options include azathioprine, cyclosporine A, and tocilizumab 5, 6
• Short-term glucocorticoids (≤3 months) may be used, but should be used cautiously in patients with SSc phenotype due to increased risk of renal crisis 5
• Prompt and aggressive immunosuppressive therapy is crucial in cases with severe pulmonary involvement 6

Prognosis and Long-term Outcomes

• The early concept that MCTD has a good prognosis has not been supported by long-term follow-up studies 2
• MCTD may evolve into more defined connective tissue diseases like SLE or systemic sclerosis over time 2
• Pulmonary hypertension and scleroderma renal crisis are important causes of death 2
• Patients with severe pulmonary fibrosis have significantly higher mortality rates 3

Diagnostic Challenges

• Diagnosis is difficult due to the rarity of MCTD, lack of validated classification criteria, and heterogeneous clinical presentation 1, 4
• Early disease may be misclassified as other connective tissue diseases or go unrecognized 1
• In longstanding disease, differentiation from overlap syndromes can be challenging 1
• No specific biomarkers beyond anti-U1-RNP are available to guide classification 1

Rare Complications

• MCTD can rarely be complicated by microscopic polyangiitis with anti-neutrophil cytoplasmic antibodies (ANCA), particularly myeloperoxidase-specific ANCA (MPO-ANCA) 6
• Such cases may present with interstitial pneumonia with alveolar hemorrhage and require aggressive immunosuppressive therapy 6