What is Systemic Lupus Erythematosus (SLE) overlap syndrome?

Systemic Lupus Erythematosus (SLE) Overlap Syndrome

SLE overlap syndrome is a distinct clinical entity where patients simultaneously fulfill classification criteria for SLE and at least one other connective tissue disease, resulting in a unique constellation of symptoms, serological profiles, and treatment considerations that differ from isolated SLE. 1

Definition and Characteristics

SLE overlap syndrome occurs when a patient meets diagnostic criteria for both SLE and another autoimmune connective tissue disease, either concurrently or sequentially. These overlapping conditions commonly include:

• Systemic sclerosis (scleroderma)
• Polymyositis/dermatomyositis
• Sjögren's syndrome
• Rheumatoid arthritis
• Mixed connective tissue disease

The prevalence of these overlaps varies:

• SLE-myositis overlap: 3.4-6.3% of SLE patients 2
• SLE with autoimmune thyroid disease: common association
• SLE with autoimmune hepatitis: 2.7-4.7% of SLE patients 3

Clinical Manifestations

The clinical presentation of SLE overlap syndrome typically includes:

1. Core SLE features:

   • Mucocutaneous manifestations (rash, photosensitivity)
   • Arthritis
   • Serositis
   • Hematologic abnormalities
   • Renal involvement
   • Neurological manifestations

2. Additional features based on overlap disease:

   • With scleroderma: Raynaud's phenomenon, skin thickening, pulmonary fibrosis
   • With myositis: Proximal muscle weakness, elevated muscle enzymes
   • With Sjögren's: Sicca symptoms (dry eyes, dry mouth)
   • With rheumatoid arthritis: Erosive arthritis (referred to as "rhupus")

Immunologic Profile

SLE overlap syndromes often have distinctive serological patterns:

• Anti-U1-RNP antibodies: Particularly elevated in mixed connective tissue disease overlap 4, 2
• Anti-Ro/SSA and anti-La/SSB antibodies: Common in Sjögren's overlap
• Anti-topoisomerase I (Scl-70): Associated with scleroderma overlap 4
• Anti-Jo-1 and other anti-synthetase antibodies: Present in myositis overlap
• Anti-cardiolipin antibodies: Found in 68% of SLE patients with pulmonary hypertension 3

Organ System Involvement

Overlap syndromes can affect multiple organ systems with varying severity:

1. Pulmonary involvement:

   • Pulmonary arterial hypertension is particularly common in mixed connective tissue disease (occurring in up to 38% of patients) 3
   • Interstitial lung disease is more frequent in scleroderma and myositis overlap

2. Renal involvement:

   • Lupus nephritis patterns may be modified by the overlapping disease
   • Patients with SLE-AIH overlap show higher IgG levels and poorer prognosis 3

3. Hepatic involvement:

   • SLE-autoimmune hepatitis overlap occurs in 2.7-4.7% of SLE patients 3
   • May present with elevated liver enzymes and autoimmune hepatitis features

4. Gastrointestinal involvement:

   • Esophageal dysfunction is common in scleroderma overlap and mixed connective tissue disease 3
   • Dysphagia occurs in up to 80% of patients with Sjögren's overlap 3

5. Musculoskeletal involvement:

   • More severe arthritis in rhupus syndrome
   • Proximal muscle weakness in myositis overlap

Diagnostic Approach

The diagnosis of SLE overlap syndrome requires:

1. Comprehensive autoantibody testing:

   • ANA (antinuclear antibodies)
   • Disease-specific antibodies (anti-dsDNA, anti-Sm for SLE)
   • Overlap-specific antibodies (anti-RNP, anti-Ro/SSA, anti-La/SSB, anti-Jo1)

2. Organ-specific assessments:

   • Pulmonary function tests and HRCT for lung involvement
   • Echocardiography for cardiac involvement
   • Renal function tests and urinalysis
   • Muscle enzymes (CK, aldolase) for myositis
   • Nailfold capillaroscopy for scleroderma features

3. Histopathological evaluation when indicated:

   • Kidney biopsy for lupus nephritis
   • Liver biopsy for autoimmune hepatitis overlap
   • Muscle biopsy for inflammatory myopathies

Treatment Considerations

Treatment of SLE overlap syndrome must address both SLE and the overlapping condition:

1. Core therapies:

   • Hydroxychloroquine is the cornerstone treatment for all SLE patients, including those with overlap syndromes 5
   • Corticosteroids for acute flares and disease control

2. Disease-modifying agents:

   • Mycophenolate mofetil or cyclophosphamide for severe organ involvement
   • Azathioprine as a steroid-sparing agent
   • Methotrexate particularly for arthritis features

3. Biologic therapies:

   • Belimumab for active SLE features
   • Rituximab (anti-CD20) may be beneficial in refractory cases 1
   • Caution with anti-TNF agents as they may trigger SLE flares 1

4. Overlap-specific considerations:

   • For SLE-AIH overlap: combined immunosuppression with corticosteroids and azathioprine 3
   • For SLE-scleroderma: careful blood pressure monitoring due to risk of renal crisis with high-dose steroids 6

Prognosis and Monitoring

The prognosis of SLE overlap syndrome varies depending on the specific overlap and organ involvement:

• SLE-AIH overlap has a poorer prognosis than isolated AIH 3
• SLE-scleroderma overlap may have more severe organ involvement 6
• Regular monitoring of disease activity and organ function is essential
• Vaccination against pneumococcal infection is recommended due to increased infection risk 3

Clinical Pitfalls

1. Misdiagnosis: Failing to recognize the overlap component can lead to inadequate treatment
2. Treatment conflicts: Some therapies beneficial for one component may worsen another
3. Infection risk: Increased susceptibility to infections, particularly pneumococcal, requires preventive strategies 3
4. Organ damage: Overlapping conditions may accelerate organ damage, requiring more aggressive monitoring and treatment

Understanding SLE overlap syndrome is crucial for appropriate management and improving outcomes in this complex subset of patients with autoimmune disease.