ConditionBones, joints & muscles
Overlap Syndromes
Overlap syndromes are conditions in which a person meets the criteria for, or has clear features of, two or more connective tissue (autoimmune rheumatic) diseases at the same time, such as lupus, systemic sclerosis (scleroderma), myositis, Sjogren's syndrome or rheumatoid arthritis. The best-known example is mixed connective tissue disease. Symptoms often include Raynaud's phenomenon, swollen fingers, joint pain and muscle weakness. Treatment targets whichever organs are involved.
Also called: Overlap connective tissue disease, rheumatic overlap syndrome, autoimmune overlap syndrome, overlap myositis
At a glance
- What it is
- Features of two or more autoimmune connective tissue diseases in one person.
- Examples
- Mixed connective tissue disease, lupus-RA ("rhupus"), scleroderma-myositis, antisynthetase syndrome.
- Common symptoms
- Raynaud's, puffy fingers, joint pain, muscle weakness, fatigue, rashes, breathlessness.
- Key tests
- Autoantibodies (anti-U1 RNP, anti-PM/Scl, anti-Ku, antisynthetase antibodies), organ screening.
- Treatment
- Hydroxychloroquine, steroids, immunosuppressants tailored to involved organs.
- Important risk
- Lung involvement, including pulmonary hypertension and interstitial lung disease.
When to get help
Call 911 or go to the ER
- Sudden or severe breathlessness, chest pain or coughing blood
- Severe muscle weakness with trouble swallowing or breathing
- A finger or toe that turns black or has a painful ulcer that is spreading
See a doctor within a day or two
- Increasing breathlessness on exertion, dry cough or swelling of the legs
- New weakness climbing stairs, rising from a chair or lifting your arms
- Blood or protein in the urine, swelling of the legs or face
- High blood pressure with headache in someone with scleroderma features
Book a routine appointment
- Fingers that turn white or blue in the cold plus joint pain, puffy hands or fatigue
- Tight, thickening skin on the fingers or face
- Dry eyes and mouth with joint pain
- A positive ANA blood test with symptoms that do not fit one disease
What overlap syndromes are
Connective tissue diseases are autoimmune conditions in which the immune system attacks the body's own tissues, including skin, joints, muscles, blood vessels and internal organs. The main ones are lupus, systemic sclerosis, myositis, Sjogren's syndrome and rheumatoid arthritis. Each has typical features and antibodies, but they share many symptoms, and some people have a mix. Recognizing an overlap matters because it changes which organs need monitoring and which treatments work best.
Types of overlap syndromes
| Syndrome | Diseases combined | Typical features and antibodies |
|---|---|---|
| Mixed connective tissue disease (MCTD) | Lupus, scleroderma and myositis features | Raynaud's, puffy hands, arthritis, myositis; high anti-U1 RNP |
| "Rhupus" | Lupus and rheumatoid arthritis | Erosive arthritis plus lupus features |
| Scleroderma-myositis overlap | Systemic sclerosis and myositis | Skin thickening, muscle weakness; anti-PM/Scl, anti-Ku |
| Antisynthetase syndrome | Myositis with lung and joint disease | Interstitial lung disease, "mechanic's hands", arthritis, fever; anti-Jo-1 |
| Sjogren's overlap | Sjogren's with lupus, RA or scleroderma | Dry eyes and mouth plus other features |
| Undifferentiated connective tissue disease | Features not meeting any single disease | Positive ANA, Raynaud's, joint pain; many remain stable |
Symptoms
- Raynaud's phenomenon: fingers turning white, blue, then red in cold or stress; often the first sign
- swollen, puffy fingers and hands
- joint pain and swelling
- muscle weakness and aching (myositis, as in dermatomyositis)
- fatigue and low-grade fever
- skin changes: thickening, rashes, sun sensitivity, red patches on knuckles
- dry eyes and mouth
- difficulty swallowing or heartburn
- shortness of breath or dry cough from lung involvement
- hair loss and mouth ulcers
Organ involvement to watch for
- Lungs: interstitial lung disease and pulmonary arterial hypertension are major causes of illness and death in MCTD and scleroderma overlaps.
- Heart: pericarditis, myocarditis.
- Kidneys: lupus nephritis, scleroderma renal crisis (rare).
- Esophagus and gut: reflux, swallowing problems, poor absorption.
- Nerves: trigeminal neuralgia in MCTD.
Diagnosis
A rheumatologist makes the diagnosis by combining:
- history and examination: nailfold capillaries, skin, joints, muscle strength, lungs
- antibody tests: ANA, anti-U1 RNP, anti-dsDNA, anti-Smith, anti-Scl-70, anticentromere, anti-PM/Scl, anti-Ku, antisynthetase antibodies, rheumatoid factor, anti-CCP, anti-Ro and anti-La
- muscle tests: CK and aldolase, electromyography, MRI or muscle biopsy
- organ screening: pulmonary function tests, high-resolution chest CT, echocardiogram for pulmonary hypertension, urine tests and kidney function
- nailfold capillaroscopy for scleroderma-pattern changes
Features can evolve over time, so diagnoses sometimes change, for example from undifferentiated disease to a defined condition.
Treatment
Treatment is guided by which organs are affected:
- Raynaud's: keeping warm, stopping smoking, calcium channel blockers, and other vasodilators for severe cases or ulcers.
- Joint and skin symptoms: hydroxychloroquine, NSAIDs (at the label dose, with caution), low-dose steroids, methotrexate.
- Myositis: corticosteroids plus steroid-sparing agents (methotrexate, azathioprine, mycophenolate), IVIG or rituximab.
- Interstitial lung disease: mycophenolate, cyclophosphamide, rituximab, and antifibrotics such as nintedanib.
- Pulmonary arterial hypertension: specialized vasodilator therapy.
- Kidney involvement: immunosuppression as for lupus nephritis; ACE inhibitors for scleroderma renal crisis.
- Reflux: acid-reducing medicines.
Outlook
Many people with overlap syndromes do well with treatment and regular monitoring. Outlook depends on organ involvement, particularly the lungs and heart. Regular screening, including yearly lung function tests and echocardiograms for some patients, allows early treatment of serious complications.
Frequently asked questions
What is an overlap syndrome?
An overlap syndrome is when a person has features of two or more autoimmune connective tissue diseases, such as lupus, scleroderma, myositis, Sjogren's syndrome or rheumatoid arthritis, at the same time. Mixed connective tissue disease is the best-known example.
What is mixed connective tissue disease?
Mixed connective tissue disease is an overlap syndrome combining features of lupus, scleroderma and myositis, with high levels of anti-U1 RNP antibodies. Common symptoms are Raynaud's phenomenon, puffy hands, joint pain, muscle weakness and fatigue.
What is rhupus?
Rhupus is an overlap of rheumatoid arthritis and lupus. People have the erosive joint disease typical of rheumatoid arthritis together with lupus features such as rashes, mouth ulcers, blood count changes or kidney involvement.
How are overlap syndromes treated?
Treatment depends on which organs are involved. Common medicines include hydroxychloroquine, corticosteroids, methotrexate, mycophenolate and biologics. Raynaud's, lung disease and pulmonary hypertension have specific treatments. Regular monitoring by a rheumatologist is essential.
Are overlap syndromes serious?
They can be, especially when the lungs, heart or kidneys are involved. However, many people have mainly joint, skin and Raynaud's symptoms that respond well to treatment. Early diagnosis and screening for organ involvement improve the long-term outlook.
Sources
This guide was written from current patient and clinical guidance, including:
- American College of Rheumatology: Patient fact sheets on mixed connective tissue disease, lupus, scleroderma and myositis
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS): Autoimmune diseases
- Johns Hopkins Lupus Center and Scleroderma Center: Overlap syndromes
- National Organization for Rare Disorders (NORD): Mixed connective tissue disease
- Myositis Association: Overlap myositis