Overlap Syndrome

🧩 Overlap Syndrome describes conditions where two or more autoimmune connective tissue diseases coexist in the same patient. This creates a blended clinical picture — for example, features of lupus, rheumatoid arthritis, scleroderma, and myositis appearing together. Accurate diagnosis requires a strong index of suspicion and specific autoantibody testing (e.g. anti-U1 RNP, anti-PM/Scl).

🔬 Definition

• Overlap syndrome occurs when features of distinct systemic rheumatic diseases coexist in a single patient.
• Most commonly involves combinations of SLE, scleroderma, myositis, and RA.
• Represents an area of clinical and serological overlap rather than a single distinct entity.
• Autoantibody profiles often help define the subtype and guide management.

🧠 Pathophysiology

• Loss of immune tolerance leads to autoantibody production and immune complex formation.
• Shared genetic predisposition (e.g. HLA-DR4, DRB1 alleles) and environmental triggers (viral infections, UV light) play contributory roles.
• Pathology reflects mixed tissue inflammation — synovitis, vasculitis, myositis, and fibrosis in varying proportions.

🌈 Common Overlap Syndromes

• Mixed Connective Tissue Disease (MCTD)
  • Overlap of SLE, systemic sclerosis, polymyositis, and RA.
  • Characterised by anti-U1 ribonucleoprotein (anti-RNP) antibodies.
  • Typical features: Raynaud’s phenomenon, swollen hands, myositis, arthritis, and oesophageal dysmotility.
• Anti-Synthetase Syndrome
  • Autoantibodies against aminoacyl-tRNA synthetases (e.g. anti-Jo-1).
  • Triad: myositis, arthritis, interstitial lung disease (ILD).
  • Additional features: “Mechanic’s hands” (hyperkeratotic cracks on fingers), fever, Raynaud’s.
• Scleroderma–Polymyositis Overlap
  • Linked to anti-PM/Scl antibodies.
  • Features of limited or diffuse scleroderma with inflammatory myopathy.
  • ILD and tendon friction rubs common; Raynaud’s almost universal.

🩺 Clinical Presentation

• Usually subacute onset with multisystem involvement.
• Common features: arthralgia, proximal muscle weakness, digital ulcers, sclerodactyly, rashes, and Raynaud’s.
• Internal organ involvement (lung, renal, cardiac, GI) depends on the overlap components.
• Can evolve over time — early disease may resemble one entity and later manifest features of another.

🔍 Key Investigations

• Autoantibody Testing: ANA, ENA (anti-RNP, anti-Jo-1, anti-PM/Scl, anti-centromere, anti-Scl-70).
• Muscle Enzymes: CK, aldolase (elevated in myositis).
• Inflammatory Markers: ESR, CRP.
• Organ Screening: CXR or HRCT for ILD, ECHO for pulmonary hypertension, urinalysis for lupus nephritis.

💊 Management Principles

• Individualised according to dominant disease and organ involvement.
• Immunosuppressants: Methotrexate, azathioprine, or mycophenolate mofetil for inflammatory arthritis and myositis.
• Corticosteroids: For active inflammation; use lowest effective dose and taper slowly.
• Biologics: Rituximab or cyclophosphamide may be considered for refractory disease or major organ involvement.
• Supportive Care: Physiotherapy, pulmonary rehab, calcium/vitamin D, and screening for steroid complications.
• Monitoring: Serial lung function tests and ECHO in those with ILD or pulmonary hypertension.

🧠 Teaching tip: Overlap syndromes remind us that autoimmune disease is rarely “textbook.” Always think of an overlap if a patient’s presentation doesn’t fit neatly into one diagnosis — for instance, Raynaud’s + proximal weakness + arthritis. Check for anti-RNP or PM/Scl antibodies early — they often reveal the unifying diagnosis. 🔬

📚 References

• UpToDate: Overview of Mixed Connective Tissue Disease
• StatPearls: Mixed Connective Tissue Disease
• Rheumatology (Oxford): Autoantibody-defined overlap syndromes