eMedicine Specialties > Dermatology > Connective Tissue Diseases

Mixed Connective Tissue Disease

Author: Anna Wozniacka, MD, PhD, Adjunct Lecturer, Department of Dermatology, Medical University of Lodz, Poland
Coauthor(s): Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Medicine, Professor of Pediatrics, Professor of Pathology, Professor of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School; Anna Sysa-Jedrzejowska, MD, PhD, Head, Professor, Department of Dermatology and Venereology, Medical University of Lodz, Poland
Contributor Information and Disclosures

Updated: Feb 28, 2007

Introduction

Background

Mixed connective-tissue disease (MCTD) is a disorder in which features of various connective-tissue diseases (CTDs) such as systemic lupus erythematosus (SLE); systemic sclerosis (SSc); dermatomyositis (DM); polymyositis (PM); and, occasionally, Sjögren syndrome can coexist and overlap. The course of the disease is chronic and usually milder than other CTDs. In most cases, MCTD is considered an intermediate stage of a disease that eventually becomes either SLE or SSc. U1-ribonucleoprotein (RNP) antibodies are a specific marker of the disease.

Pathophysiology

A defining feature of MCTD is the presence of antibodies against the U1-RNP complex, but other autoantibodies have also been described in MCTD. Some hypotheses implicate modified self-antigens and/or infectious agents in the pathogenesis of MCTD.

The pathogenesis of MCTD is not completely known. As with other CTDs, MCTD is considered an autoimmune disease to which individuals who express specific HLA antigens such as human leukocyte antigens (HLA) HLA-DR4 or HLA-DQB1 are genetically predisposed. The frequency of HLA-DR4 in patients with MCTD is estimated to be 52%. Its strong HLA association with MCTD was further shown in the significantly increased frequency of the combination of HLA-B15 with HLA-DR4. Thus, the genetic background in patients with MCTD seems to be different from that in patients with SLE or systemic sclerosis. This observation could partly explain the clinical differences between these diseases. The specific nature of the HLA associations that occur in patients with MCTD may vary depending on the ethnicity of the population studied.

Frequency

International

MCTD is uncommon worldwide.

Mortality/Morbidity

  • The prognosis for patients with MCTD is generally better than that of patients with SLE, SSc, and DM.
  • About 4% of patients die, usually as a result of pulmonary hypertension, nephritis, myocarditis, or widespread vasculitis.
  • In one case series, solid tumors developed in approximately 10% of patients.

Sex

  • Women are affected more often than men.
  • The female-to-male ratio is 4:1.

Age

  • The disease usually occurs in individuals aged 30-50 years.
  • MCTD also affects children, in whom the course is more severe because cardiac and renal involvement are more common.
  • MCTD-related thrombocytopenia, which is unusual in adults, may be marked in children.

Clinical

History

Usually, patients with MCTD present with Raynaud phenomenon, which frequently represents the initial manifestation of the disease. The decreasing frequency of attacks limits progressive vascular damage. The course of the entity is often mild, but the clinical appearance and the patient's complaints depend on the symptoms related to the specific forms of the CTD most expressed in the individual patient.

During the course of the disease in some patients, the typical signs and symptoms of SLE develop and fulfill at least 4 of the American Rheumatism Association (ARA) criteria. In other patients, MCTD becomes SSc that spreads to the face, scalp, and trunk, and the fingers become immobile, hard, and shiny.

  • Usually, patients with MCTD present with Raynaud phenomenon.
  • Headaches may occur.
  • Patients may report fatigue.

Physical

Findings at physical examination may include the following:

  • Skin
    • Raynaud phenomenon, sausage-shaped fingers, and swelling of the dorsa of the hands that never becomes sclerodactyly are the most typical features (see Image 2).
    • More than one half of patients have abnormal capillaries in the nail fold.
    • Small-vessel vasculitis with palpable purpura is present in about 25% of patients. Occasionally, vascular disturbances may be severe and lead to peripheral gangrene and leg ulcers.
    • Other skin manifestations are not universally expressed. Erythematous plaques similar to those seen in patients with chronic cutaneous (discoid) lupus erythematosus (DLE) can be seen. Alopecia, facial erythema, periungual telangiectasia, and pigmentary disturbances can also occur. Painful dermal nodules may appear on the hands or elbows.
  • Joints
    • About 60% of patients complain of arthralgia.
    • Arthritis without any visible joint deformation can occur.
    • Any joint may be involved.
    • Patients usually complain of morning stiffness.
  • Muscles: Myalgia, myositis, and muscle weakness are common features.
  • Gastrointestinal tract
    • Dysphagia and dysfunction of esophageal motility resemble that occurring in SSc.
    • Other abnormalities of the gut include esophagitis, constipation, diarrhea, and malabsorption.
  • Lungs
    • Pleuropulmonary manifestations are common. The incidence varies from 20-85%.
    • Pleuropulmonary complications include pleural effusion, interstitial pulmonary fibrosis, pulmonary arterial hypertension, pulmonary vasculitis, pulmonary thromboembolic phenomena, aspiration pneumonia, serositis, and hypoventilatory failure.
  • Kidneys
    • The incidence of renal involvement is only about 5%.
    • Nephritis is associated with a poor prognosis. In addition to myocarditis, pulmonary hypertension, and widespread vasculitis, nephritis is considered a common cause of death.
  • Nervous system
    • Nervous system involvement is rare.
    • Aseptic meningitis, trigeminal neuropathy, and psychosis are the prominent neurologic features.
    • Sporadic cases with autonomic neuropathy are described.
  • Heart: Cardiac involvement is often clinically insignificant, but the rate varies from 11-85% depending on patient selection and methods used to detect cardiac manifestations. Pericarditis, pulmonary hypertension, mitral valve prolapse, myocarditis, conduction disturbances, and abnormal left ventricular diastolic filling pattern are the most frequently observed problems.
  • Lymph nodes: Lymph node enlargement is seldom a feature, but it may be present.

Causes

The cause is not completely known.

  • HLA-DR4 is more common in patients with MCTD than in patients with other CTDs (see Pathophysiology).
  • A genetic predisposition is confirmed by reports of familial occurrence.

More on Mixed Connective Tissue Disease

Overview: Mixed Connective Tissue Disease
Differential Diagnoses & Workup: Mixed Connective Tissue Disease
Treatment & Medication: Mixed Connective Tissue Disease
Follow-up: Mixed Connective Tissue Disease
Multimedia: Mixed Connective Tissue Disease
References
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References

  1. Aringer M, Steiner G, Smolen JS. Does mixed connective tissue disease exist? Yes. Rheum Dis Clin North Am. Aug 2005;31(3):411-20, v. [Medline].

  2. Gourley I, Bell AL, Biggart D. Kikuchi''s disease as a presenting feature of mixed connective tissue disease. Clin Rheumatol. Jan 1995;14(1):104-7. [Medline].

  3. Grader-Beck T, Wigley FM. Raynaud's phenomenon in mixed connective tissue disease. Rheum Dis Clin North Am. Aug 2005;31(3):465-81, vi. [Medline].

  4. Hall S, Hanrahan P. Muscle involvement in mixed connective tissue disease. Rheum Dis Clin North Am. Aug 2005;31(3):509-17, vii. [Medline].

  5. Hof D, Raats JM, Pruijn GJ. Apoptotic modifications affect the autoreactivity of the U1 snRNP autoantigen. Autoimmun Rev. Jul 2005;4(6):380-8. [Medline].

  6. Hoffman RW, Greidinger EL. Mixed connective tissue disease. Curr Opin Rheumatol. Sep 2000;12(5):386-90. [Medline].

  7. Jablonska S, Blaszczyk M. Scleroderma overlap syndromes. Adv Exp Med Biol. 1999;455:85-92. [Medline].

  8. Kozuka T, Johkoh T, Honda O, et al. Pulmonary involvement in mixed connective tissue disease: high- resolution CT findings in 41 patients. J Thorac Imaging. Apr 2001;16(2):94-8. [Medline].

  9. Lundberg IE. Cardiac involvement in autoimmune myositis and mixed connective tissue disease. Lupus. 2005;14(9):708-12. [Medline].

  10. Maddison PJ. Mixed connective tissue disease: overlap syndromes. Baillieres Best Pract Res Clin Rheumatol. Mar 2000;14(1):111-24. [Medline].

  11. Oh YB, Jun JB, Kim CK, et al. Mixed connective tissue disease associated with skin defects of livedoid vasculitis. Clin Rheumatol. 2000;19(5):381-4. [Medline].

  12. Peller JS, Gabor GT, Porter JM, Bennett RM. Angiographic findings in mixed connective tissue disease. Correlation with fingernail capillary photomicroscopy and digital photoplethysmography findings. Arthritis Rheum. Jul 1985;28(7):768-74. [Medline].

  13. Pope JE. Other manifestations of mixed connective tissue disease. Rheum Dis Clin North Am. Aug 2005;31(3):519-33, vii. [Medline].

  14. Seguchi M, Soejima Y, Tateishi A, et al. Mixed connective tissue disease with multiple organ damage: successful treatment with plasmapheresis. Intern Med. Dec 2000;39(12):1119-22. [Medline].

  15. Sharp GC, Irvin WS, Tan EM, et al. Mixed connective tissue disease--an apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am J Med. Feb 1972;52(2):148-59. [Medline].

  16. Weber P, Ganser G, Frosch M, et al. Twenty-four hour intraesophageal pH monitoring in children and adolescents with scleroderma and mixed connective tissue disease. J Rheumatol. Nov 2000;27(11):2692-5. [Medline].

  17. Yang YH, Tsai MJ, Lin SC, et al. Childhood mixed connective tissue disease. J Formos Med Assoc. Feb 2000;99(2):158-61. [Medline].

  18. Zdrojewicz Z, Budzyn-Koziol E, Pulawska J. [Mixed connective tissue disease--etiology, pathogenesis, clinical significance, treatment]. Postepy Hig Med Dosw. 1999;53(5):751-66. [Medline].

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Further Reading

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Keywords

MCTD, CTD, Sharp syndrome, Sharp's syndrome, systemic lupus erythematosus, SLE, systemic sclerosis, SSc, dermatomyositis, DM, polymyositis, PM, Sjögren syndrome, U1-ribonucleoprotein antibodies, U1-RNP

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Contributor Information and Disclosures

Author

Anna Wozniacka, MD, PhD, Adjunct Lecturer, Department of Dermatology, Medical University of Lodz, Poland
Anna Wozniacka, MD, PhD is a member of the following medical societies: European Academy of Dermatology and Venereology
Disclosure: Nothing to disclose.

Coauthor(s)

Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Medicine, Professor of Pediatrics, Professor of Pathology, Professor of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

Anna Sysa-Jedrzejowska, MD, PhD, Head, Professor, Department of Dermatology and Venereology, Medical University of Lodz, Poland
Disclosure: Nothing to disclose.

Medical Editor

Russell Hall, MD, Chief, Professor, Department of Internal Medicine, Division of Dermatology, Duke University
Russell Hall, MD is a member of the following medical societies: American Academy of Dermatology, American Dermatological Association, American Federation for Medical Research, American Society for Clinical Investigation, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

Pharmacy Editor

Michael J Wells, MD, Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center
Michael J Wells, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, and Texas Medical Association
Disclosure: Nothing to disclose.

Managing Editor

Van Perry, MD, Assistant Professor, Department of Medicine, Division of Dermatology, University of Texas Health Science Center
Van Perry, MD is a member of the following medical societies: American Academy of Dermatology and American Society for Laser Medicine and Surgery
Disclosure: Nothing to disclose.

CME Editor

Glen H Crawford, MD, Assistant Clinical Professor, Department of Dermatology, University of Pennsylvania School of Medicine; Chief, Division of Dermatology, The Pennsylvania Hospital
Glen H Crawford, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Phi Beta Kappa, and Society of USAF Flight Surgeons
Disclosure: Nothing to disclose.

Chief Editor

William D James, MD, Paul R Gross Professor of Dermatology, University of Pennsylvania School of Medicine; Vice-Chair, Program Director, Department of Dermatology, University of Pennsylvania Health System
William D James, MD is a member of the following medical societies: American Academy of Dermatology and Society for Investigative Dermatology
Disclosure: elsevier Royalty Other; american college of physicians Honoraria Other

 
 
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