Overlap syndrome

Overview

Overlap syndrome refers to a medical condition in which features of two or more autoimmune connective tissue diseases occur simultaneously in the same individual. These syndromes are characterized by overlapping clinical, serological, and pathological features of diseases such as systemic lupus erythematosus (SLE), systemic sclerosis (scleroderma), polymyositis, dermatomyositis, and rheumatoid arthritis. Unlike mixed connective tissue disease (MCTD), which is defined by a specific antibody profile (anti-U1 RNP), overlap syndrome does not require a specific serologic marker and includes patients who meet the classification criteria for more than one defined autoimmune disease.

Overlap syndromes are important to recognize because they can have a unique clinical course and may require a tailored therapeutic approach based on the specific diseases involved. These conditions are chronic, systemic, and often involve inflammation of the skin, joints, muscles, and internal organs, such as the lungs, kidneys, or gastrointestinal tract.

Causes

The exact cause of overlap syndrome is unknown, but it is believed to result from a combination of genetic predisposition, environmental triggers, and immune dysregulation. As with other autoimmune diseases, the immune system mistakenly attacks the body’s own tissues, leading to inflammation and damage.

Potential Contributing Factors

• Genetic predisposition: Family history of autoimmune diseases increases risk

• Environmental exposures: Infections, smoking, UV light, or certain medications

• Hormonal influences: Autoimmune diseases are more common in women, suggesting a role for estrogen

• Immune system abnormalities: Dysregulation leading to the production of autoantibodies and chronic inflammation

Symptoms

The symptoms of overlap syndrome vary depending on which autoimmune diseases are present. Patients may show features of two or more disorders concurrently or sequentially over time. Commonly affected systems include the skin, joints, muscles, lungs, and gastrointestinal tract.

General Symptoms

• Fatigue

• Fever

• Weight loss

• Malaise

Organ-Specific and Disease-Specific Symptoms

• From Systemic Lupus Erythematosus (SLE): Butterfly rash, arthritis, nephritis, photosensitivity

• From Systemic Sclerosis: Skin thickening, Raynaud’s phenomenon, esophageal dysmotility, pulmonary fibrosis

• From Polymyositis/Dermatomyositis: Proximal muscle weakness, elevated muscle enzymes, skin rashes (e.g., heliotrope rash, Gottron’s papules)

• From Rheumatoid Arthritis: Symmetric joint inflammation, morning stiffness, joint erosions

Diagnosis

Diagnosis of overlap syndrome is complex and relies on the identification of clinical features and laboratory evidence supporting more than one autoimmune condition. The absence of a specific serologic hallmark (as in MCTD) makes diagnosis more reliant on fulfilling classification criteria for individual diseases.

Clinical Evaluation

• Detailed patient history, including symptom onset and pattern

• Thorough physical examination assessing skin, joints, muscle strength, and systemic signs

Laboratory Tests

• Antinuclear antibody (ANA): Usually positive

• Autoantibody profile: Includes anti-dsDNA, anti-Smith, anti-RNP, anti-centromere, anti-Scl-70, anti-Jo-1, RF, anti-CCP

• Inflammatory markers: ESR, CRP

• Muscle enzymes: Creatine kinase (CK), aldolase if myositis is suspected

• Organ-specific labs: Renal function, liver enzymes, urinalysis

Imaging and Procedures

• X-rays or MRI: For joint or muscle involvement

• High-resolution CT scan: For interstitial lung disease

• Muscle or skin biopsy: When myositis or scleroderma is suspected

Treatment

Treatment of overlap syndrome is tailored to the specific diseases involved and the severity of organ involvement. The goal is to control inflammation, manage symptoms, and prevent long-term complications. A multidisciplinary team approach is often necessary.

Medications

• Nonsteroidal anti-inflammatory drugs (NSAIDs): For joint and muscle pain

• Corticosteroids: Prednisone is commonly used to control inflammation in active disease

• Immunosuppressive agents: Methotrexate, azathioprine, mycophenolate mofetil, or cyclophosphamide, depending on organ involvement

• Biologic therapies: Rituximab or other targeted agents may be used in refractory cases

• Antimalarials: Hydroxychloroquine for lupus-related symptoms and skin issues

Supportive Therapies

• Physical and occupational therapy to maintain joint and muscle function

• Pulmonary rehabilitation for lung involvement

• Speech and swallowing therapy for esophageal issues

Monitoring and Prevention

• Regular lab tests to monitor disease activity and medication side effects

• Cancer screening in dermatomyositis or other high-risk conditions

• Osteoporosis prevention in patients on long-term steroids

Prognosis

The prognosis of overlap syndrome depends on the specific autoimmune diseases involved, the severity of organ damage, and how early treatment is initiated. Many patients achieve good disease control with proper management, though relapses may occur.

Patients with significant internal organ involvement, such as interstitial lung disease or renal complications, may have a more guarded prognosis. Long-term follow-up with rheumatology and other specialists is essential for monitoring disease progression and managing comorbidities.

With individualized care, most people with overlap syndrome can lead productive lives and maintain a good quality of life.