Overlap syndromes

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Last reviewed: 21 Apr 2025

Last updated: 14 Nov 2023

Overlap syndromes refers to a group of conditions that have clinical features of, and meet classification criteria for, more than one well-characterized rheumatic disease.

The spectrum of overlap syndromes includes mixed connective tissue disease (MCTD); antisynthetase syndrome; and polymyositis/scleroderma (PM/Scl) overlap syndrome.

MCTD is a distinct clinical entity characterized by overlapping features of systemic lupus erythematosus, scleroderma, myositis, and rheumatoid arthritis in the setting of a high titer of autoantibodies to U1 ribonucleoprotein.

Antisynthetase syndromes form a distinct group characterized by antibodies directed against various aminoacyl-tRNA synthetase enzymes with overlapping clinical features of myositis, arthritis, and interstitial lung disease.

PM/Scl syndrome is characterized by overlapping features of scleroderma and polymyositis, PM/Scl antibody, Raynaud phenomenon, tendon inflammation, and interstitial lung disease.

Treatment of overlap syndromes is tailored to the active clinical manifestations and ranges from supportive therapy to cytotoxic immunosuppressive regimens.

Definition

"Overlap syndromes" refers to a diverse group of conditions that have clinical features of, and meet classification criteria for, more than 1 well-characterized rheumatic disease. They usually present subacutely with clinical manifestations that can include different organ systems. The pattern of organ involvement reflects the characteristic features of the well-defined rheumatic diseases occurring together.

History and exam

Key diagnostic factors

digital pallor/pain
arthritis/arthralgia
swollen hands
sclerodactyly
nail fold vascular changes
dyspnea or cough
GERD and heartburn
myalgias or myositis

Full details

Other diagnostic factors

hematuria
lymphadenopathy
alopecia
skin rashes
proximal muscle weakness
trigeminal neuralgia
headaches
neuropsychiatric disease including psychosis and seizures
peripheral neuropathy
fever

Full details

Risk factors

female sex
age 20 to 40 years
presence of specific HLA genotypes

Full details

Diagnostic tests

1st tests to order

CBC
erythrocyte sedimentation rate
CRP
serum BUN and creatinine
rheumatoid factor
antinuclear antibodies
anti-cyclic citrullinated peptide (anti-CCP) antibody
urinalysis
anti-U1 ribonucleoprotein
anti-Jo-1

Full details

Tests to consider

creatine kinase
anti-double-stranded DNA
Smith antigen
anti-SS-A and anti-SS-B
additional antibody tests (anti-Scl 70, anticentromere antibodies, anti-RNA polymerase III, anti-PM/Scl antibodies)
pulmonary function tests (spirometry, lung volumes and diffusion capacity measurement)
CXR
high-resolution CT scan of chest
echocardiogram
right-heart catheterization
barium swallow
upper gastrointestinal endoscopy ± biopsy
plain x-ray of affected joint(s)
electromyography
nerve conduction studies
muscle biopsy
lung biopsy
renal biopsy

Full details

Emerging tests

anti-Ku antibodies
other antisynthetase antibodies (PL7, PL12, OJ, EJ, KS, Ha and others)

Treatment algorithm

ONGOING

all patients

Contributors

Authors

Larry Young, MD

Associate Professor of Medicine

Division of Rheumatology

Miller School of Medicine

University of Miami

Miami

Disclosures

LY declares that he has no competing interests.

Carlos Lozada, MD

Associate Professor of Medicine

Division of Rheumatology and Immunology

Miller School of Medicine

University of Miami

Miami

Disclosures

CL declares that he has no competing interests.

Acknowledgements

Dr Larry Young and Dr Carlos Lozada would like to gratefully acknowledge Dr Robert Hoffman, a previous contributor to this topic.

Disclosures

RH has received NIH grants greater than 6 figures USD. RH is the author of some studies referenced in this topic. RH declares that he has no competing interests.

Peer reviewers

Robert Ortmann, MD

Associate Professor and Director

Division of Rheumatology and Immunology

University of Arkansas for Medical Sciences

Little Rock

Disclosures

RO declares that he has no competing interests.

Alan Bridges, MD

Professor and Vice Chair

Department of Medicine

University of Wisconsin Hospital

Madison

Disclosures

AB declares that he has no competing interests.

Simon Bowman, PhD, FRCP

Consultant Rheumatologist and Honorary Senior Clinical Lecturer in Rheumatology

Selly Oak Hospital

Birmingham

Disclosures

SB declares that he has no competing interests.

References

Our in-house evidence and editorial teams collaborate with international expert contributors and peer reviewers to ensure that we provide access to the most clinically relevant information possible.

Key articles

Ungprasert P, Crowson CS, Chowdhary VR, et al. Epidemiology of mixed connective tissue disease, 1985-2014: a population-based study. Arthritis Care Res (Hoboken). 2016 Dec;68(12):1843-8.Full text Abstract

Hoffman Robert W. 152 - Overlap syndromes. In: Hochberg Marc C, Silman Alan J, Smolen Josef S. et al., eds. Rheumatology. 6th ed. Maryland Heights, MO: Mosby; 2015, 1264-9.

Kasukawa R, Tojo T, Miyawaki S, et al. Preliminary diagnostic criteria for classification of mixed connective tissue disease. In: Kasukawa R, Sharp GC, eds. Mixed connective tissue disease and anti-nuclear antibodies. Amsterdam, the Netherlands: Elsevier; 1987:41-7.

Reference articles

A full list of sources referenced in this topic is available to users with access to all of BMJ Best Practice.

Differentials
- Systemic lupus erythematosus (SLE)
- Polymyositis
- Scleroderma
More Differentials
Guidelines
- 2022 Guideline for vaccinations in patients with rheumatic and musculoskeletal diseases
More Guidelines
Patient information
Rheumatoid arthritis
Acid reflux, heartburn, and gastroesophageal reflux disease (GERD)
More Patient information
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Overlap syndromes

Summary

Definition

History and exam

Key diagnostic factors

Other diagnostic factors

Risk factors

Diagnostic tests

1st tests to order

Tests to consider

Emerging tests

Treatment algorithm

all patients

Contributors

Authors

Larry Young, MD

Disclosures

Carlos Lozada, MD

Disclosures

Acknowledgements

Disclosures

Peer reviewers

Robert Ortmann, MD

Disclosures

Alan Bridges, MD

Disclosures

Simon Bowman, PhD, FRCP

Disclosures

References

Key articles

Reference articles

A full list of sources referenced in this topic is available to users with access to all of BMJ Best Practice.

Differentials

Guidelines

Patient information

Log in or subscribe to access all of BMJ Best Practice

Log in or subscribe to access all of BMJ Best Practice

Log in to access all of BMJ Best Practice