Mixed Connective Tissue Disease
Overlap autoimmune syndrome with features of SLE, systemic sclerosis, and polymyositis, defined by the presence of high-titre anti-U1 RNP antibodies. Raynaud phenomenon, swollen hands, arthritis, myositis, and ILD are the most common manifestations.
Key Facts
MCTD is characterised by overlapping features of SLE, SSc, and PM with high-titre anti-U1 RNP antibodies (defining feature) Most common features: Raynaud phenomenon (90%), swollen/puffy hands, arthritis, myositis, ILD Pulmonary hypertension and ILD are the main causes of morbidity and mortality F:M ratio 9:1; peak onset 15-35 years Treatment guided by predominant organ manifestation: corticosteroids, methotrexate, mycophenolate, or anti-TNF as appropriate Many patients evolve over time to a more defined CTD (usually SSc or SLE) Renal involvement is uncommon (unlike SLE); if present, usually membranous nephropathy
Overview
Key Facts
MCTD remains a controversial entity – some experts consider it a transitional state rather than a distinct disease. The anti-U1 RNP antibody is the serological hallmark.
Epidemiology
- Rare; exact prevalence unknown (~0.01% estimated)
- F:M 9:1; peak onset 15-35 years
Pathophysiology
- Anti-U1 RNP antibodies target spliceosomal proteins
- Features reflect the overlap nature: vasculopathy (SSc component), immune complex disease (SLE component), muscle inflammation (PM component)
- Many patients evolve to a more defined CTD over 5-10 years
Clinical Presentation
Common Features
- Raynaud phenomenon (>90%): often the first manifestation
- Puffy/swollen hands ("sausage fingers"): very characteristic early feature
- Arthritis: polyarthritis, may be deforming (Jaccoud-like)
- Myositis: proximal weakness, elevated CK
- Oesophageal dysmotility: dysphagia, GORD
- Sclerodactyly: tight skin on fingers
- Serositis: pleurisy, pericarditis
- ILD: NSIP pattern
Less Common
- Pulmonary arterial hypertension: major cause of mortality
- Trigeminal neuropathy: sensory neuropathy of CN V (relatively specific)
- Membranous nephropathy: renal involvement less common than in SLE
- Cytopenias: leucopenia, thrombocytopenia
Red Flags
- Dyspnoea → screen for PAH and ILD
- Evolving features towards a defined CTD → reassess diagnosis
Differential Diagnosis
| Diagnosis | Key Features | Investigation |
|---|---|---|
| SLE | Anti-dsDNA, nephritis, malar rash | ANA, dsDNA, C3/C4 |
| Systemic sclerosis | Anti-Scl-70/anti-centromere, extensive fibrosis | Specific antibodies |
| Dermatomyositis | Skin rash, anti-Mi-2 | CK, biopsy |
| Undifferentiated CTD | Overlap features without meeting any criteria | Serology panel |
Diagnosis / Investigation
Bloods
- Anti-U1 RNP: high-titre positive (defining; essential for diagnosis)
- ANA: positive (speckled pattern)
- Anti-dsDNA: usually negative (helps distinguish from SLE)
- CK: elevated if myositis component
- FBC: cytopenias possible
- ESR/CRP: often elevated
Organ Assessment
- PFTs + HRCT: ILD screening
- Echocardiogram: PAH screening
- Barium swallow/manometry: oesophageal dysmotility
- U&Es, urine ACR: renal assessment
- EMG/MRI: if myositis suspected
Management
Treatment Guided by Predominant Feature
- Arthritis: NSAIDs, hydroxychloroquine, methotrexate
- Myositis: prednisolone + methotrexate/azathioprine
- Raynaud: nifedipine, iloprost
- ILD: mycophenolate mofetil, cyclophosphamide
- PAH: endothelin receptor antagonists, PDE5 inhibitors, prostacyclins
- Serositis: NSAIDs, corticosteroids
- Hydroxychloroquine: for all patients (as in SLE)
Monitoring
- Regular PFTs and echocardiogram (PAH/ILD screening)
- CK monitoring if myositis
- Annual organ assessment
Referral
- All suspected MCTD → rheumatology
- PAH → specialist centre
- ILD → respiratory medicine
Prognosis
- 10-year survival: ~80%
- PAH is the leading cause of mortality
- Evolution: many patients evolve to a defined CTD (SSc most common, then SLE)
- Renal crisis: uncommon (unlike SSc)
- Prognosis generally better than SSc or SLE in many series
- Anti-U1 RNP titres do not reliably predict disease course
Other Relevant Information
MCTD Features by CTD Component
| SLE Features | SSc Features | PM Features |
|---|---|---|
| Arthritis | Raynaud | Proximal weakness |
| Serositis | Sclerodactyly | Elevated CK |
| Cytopenias | Oesophageal dysmotility | Myopathic EMG |
| Lymphadenopathy | ILD | Muscle biopsy |