History

Manifestations of mixed connective-tissue disease (MCTD) can be protean. Most patients experience Raynaud phenomenon, arthralgia/arthritis, swollen hands, sclerodactyly or acrosclerosis, and mild myositis. The following may be revealed by history or physical examination:

Raynaud phenomenon (96% cumulatively, 74% at presentation); see the image below
Arthralgia/arthritis (96% cumulatively, 68% at presentation)
Esophageal hypomotility (66% cumulatively, 9% at presentation)
Pulmonary dysfunction (66% cumulatively, rare at presentation)
Swollen hands (66% cumulatively, 45% at presentation)
Myositis (51% cumulatively, 2% at presentation)
Rash (53% cumulatively, 13% at presentation)
Leukopenia (53% cumulatively, 9% at presentation)
Sclerodactyly (49% cumulatively, 11% at presentation)
Pleuritis/pericarditis (43% cumulatively, 19% at presentation)
Pulmonary hypertension (23% cumulatively, rare at presentation)

Raynaud phenomenon is a common feature of mixed connective tissue disease.

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The experience with a large single-center cohort of MCTD patients suggests that the following three clinical subclusters of MCTD manifestations may exist^[31]:

Predominantly vascular manifestations, including Raynaud phenomenon, pulmonary hypertension, and antiphospholipid syndrome with thromboses (this group is at the greatest risk of mortality)
A polymyositislike picture, including interstitial lung disease, esophageal dysmotility, and myositis
Erosive polyarthritis with anti–cyclic citrullinated peptide (anti-CCP) antibodies and sclerodactyly

Physical

Physical examination is helpful in confirming or identifying features of MCTD. Seek the following features on examination:

Fever should prompt a careful search for infection; however, infection may be present in the absence of fever and is one of the primary disease-related causes of mortality and/or morbidity in MCTD; the use of corticosteroids and immunosuppressive agents further increases the risk of infection ^[32]
Corticosteroids may mask serious intra-abdominal processes, including appendicitis, vasculitis, pancreatitis, and bowel perforation
Cardiopulmonary symptoms or findings should prompt a careful evaluation for pulmonary hypertension
Capillary microscopy can assist in finding sclerodermatous-type nailfold changes
Severe Raynaud phenomenon may result in digital vascular infarcts and ulcerations
Pericarditis may be occult and can progress rapidly to cardiac tamponade
Trigeminal neuralgia is common in MCTD
Secondary Sjögren syndrome occurs in 25% of patients with MCTD and may cause both ocular symptoms and oral dryness

Protein-losing gastroenteropathy is a rare feature of MCTD, but may be the initial manifestation of the disorder. Patients present with generalized edema, ascites, and pleural and pericardial effusions due to to hypoproteinemia from leakage of serum protein into the gastrointestinal tract.^[33]

Differential Diagnoses

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Media Gallery

Raynaud phenomenon is a common feature of mixed connective tissue disease.
Chest radiograph in a patient with pulmonary hypertension reveals enlarged pulmonary arteries.

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Author

Eric L Greidinger, MD Associate Professor, Department of Medicine, Division of Rheumatology and Immunology, University of Miami, Leonard M Miller School of Medicine, Miami Veterans Affairs Medical Center

Eric L Greidinger, MD is a member of the following medical societies: American College of Physicians, American College of Rheumatology

Disclosure: Received research grant from: Corbus Pharmaceuticals; Eli Lilly & Company; Horizon Pharmaceuticals; INFLARX GBMH, Mitsubishi Pharmaceuticals, Reatta Pharmaceuticals, Swedish Orphan Biovitrum AB.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Elliot Goldberg, MD Dean of the Western Pennsylvania Clinical Campus, Professor, Department of Medicine, Lewis Katz School of Medicine at Temple University

Elliot Goldberg, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology

Disclosure: Nothing to disclose.

Chief Editor

Herbert S Diamond, MD Visiting Professor of Medicine, Division of Rheumatology, State University of New York Downstate Medical Center; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital

Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, Phi Beta Kappa

Disclosure: Nothing to disclose.

Additional Contributors

Bryan L Martin, DO Associate Dean for Graduate Medical Education, Designated Institutional Official, Associate Medical Director, Director, Allergy Immunology Program, Professor of Medicine and Pediatrics, Ohio State University College of Medicine

Bryan L Martin, DO is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, American College of Osteopathic Internists, American College of Physicians, American Medical Association, American Osteopathic Association

Disclosure: Nothing to disclose.

Acknowledgements

Robert W Hoffman, DO, FACP, FACR Chief, Division of Rheumatology and Immunology, Professor, Departments of Medicine and Microbiology & Immunology, University of Miami, Leonard M Miller School of Medicine

Robert W Hoffman, DO, FACP, FACR is a member of the following medical societies: American Association for the Advancement of Science, American Association of Immunologists, American College of Physicians, American College of Rheumatology, and Clinical Immunology Society

Disclosure: Nothing to disclose.