AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Sharp and colleagues (1972) first recognized mixed connective-tissue disease (MCTD) among a group of patients with overlapping clinical features of systemic lupus erythematosus (SLE), scleroderma, and myositis, with the presence of a distinctive antibody against what now is known to be U1-ribonucleoprotein (RNP). This disease has been more completely characterized in recent years and is now recognized to consist of the following core clinical and laboratory features: Raynaud phenomenon, swollen hands, arthritis/arthralgia, acrosclerosis, esophageal dysmotility, myositis, pulmonary hypertension, high level of anti–U1-RNP antibodies, and antibodies against U1-70 kd small nuclear ribonucleoprotein (snRNP).

Pathophysiology

Pathophysiologic abnormalities that are believed to play a role in MCTD include the following:

• B lymphocyte hyperactivity, resulting in high levels of anti–U1-RNP and anti–U1-70 kd autoantibodies
• T lymphocyte activation with the presence of anti–U1-70 kd–reactive T lymphocytes circulating in the peripheral blood of patients with MCTD
• Apoptotic modification of the U1-70 kd antigen
• Immune response against apoptotically modified self-antigens
• Genetic association with major histocompatibility genes human leukocyte antigen (HLA)–DRB1*04/*15
• Vascular endothelial proliferation with widespread lymphocytic and plasmacytic infiltration of tissues

Frequency

United States

Careful epidemiological studies have not been performed in the United States. MCTD appears to be more prevalent than dermatomyositis (1-2 cases per 100,000 population) but is less prevalent than SLE (15-50 cases per 100,000 population).

International

In an epidemiological survey in Japan, MCTD has a reported prevalence of 2.7 cases per 100,000 population.

Mortality/Morbidity

• Recent long-term outcome studies have established pulmonary hypertension as the most common disease-related cause of death.
• Immunoglobulin G (IgG) anticardiolipin antibodies are a marker for development of pulmonary hypertension.
• Infections are a major cause of death.

Race

MCTD has been reported in all races.

Sex

The female-to-male ratio is approximately 10:1.

Age

Onset typically occurs in people aged 15-25 years.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Manifestation 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)
• 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)

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. 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. Use of corticosteroids and immunosuppressive agents further increases the risk of infection.
• Corticosteroids may mask serious intra-abdominal processes, including appendicitis, vasculitis, pancreatitis, and bowel perforations.
• 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 can 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.

Causes

• The fundamental cause of MCTD remains unknown.
• The loss of T lymphocyte and B lymphocyte tolerance—initiated by cryptic self-antigens, abnormalities of apoptosis, or molecular mimicry by infectious agents—is proposed current theories of pathogenesis.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Pleuritis
Respiratory distress syndrome
Stroke

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• CBC count
• Urinalysis
• Routine blood chemistry
• Antinuclear antibodies
• • High-titer speckled pattern fluorescent antinuclear antibody (FANA) is typical of MCTD.
  • FANA is not specific for MCTD.
• Anti–U1-RNP antibodies are present in high titer.
• • Anti-RNP antibodies are required for diagnosis of MCTD.
  • The presence of anti–U1-70 kd is characteristic of MCTD.
• Other antibodies
• • Antiphospholipid antibodies (including anticardiolipin antibodies and lupus anticoagulant) may be associated with pulmonary hypertension. In MCTD, however, these apparently may not be associated with clotting events.
  • Rheumatoid factor frequently is detected.
  • Other lupus-specific antibodies (eg, anti-Sm and anti–double stranded DNA antibodies) are absent.
  • Scleroderma-specific antibodies are absent, including anticentromere, anti–Scl-70 (topoisomerase), and anti–PM-1 (Pm-Scl).
• Amylase and lipase - To assess for pancreatitis

Imaging Studies

• Chest radiograph - To assess for infiltrates, effusion, or cardiomegaly
• Echocardiogram - Used to evaluate for effusion, chest pain, pulmonary hypertension, or valvular disease
• Ultrasound/CT scan - Used to evaluate abdominal pain (indicated for evidence of serositis, pancreatitis, or visceral perforation related to vasculitis)
• MRI - Used to assess neuropsychiatric signs or symptoms

Other Tests

• ECG and/or cardiac enzymes - To assess for myocardial ischemia and myocarditis
• Cerebral spinal fluid (CFS) analysis - To monitor for infection, stroke, or neuropsychiatric manifestations

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• The overall goal of therapy is to control symptoms and maintain function. Target medical therapy to specific organ involvement and extent of disease activity. Monitoring for development of complications, such as pulmonary hypertension or infection, is important.

Consultations

• Whenever possible, a rheumatologist experienced in diagnosis and treatment of the disease should co-manage all patients with MCTD.
• Consultation with other specialists or subspecialists may be indicated for the evaluation and/or treatment of specific aspects of disease, such as pulmonary hypertension.

Diet

• Patients with hypertension, esophageal reflux, malabsorption, or other sclerodermatous-type bowel involvement may need special considerations.
• Because atherosclerotic heart disease remains a major risk for all patients, advocate a heart-healthy diet. However, no specific dietary manipulations have been demonstrated to be effective in treating MCTD.

Activity

Convincing data support the value of an active lifestyle and an exercise program tailored to the needs of patients with arthritis of various types. This approach also appears to be appropriate in MCTD.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Nonsteroidal anti-inflammatory drugs (NSAIDs)

Reduce pain and inflammation and allow for improvement in mobility and function. Mild disease may be controlled with NSAIDs. Arthritis/arthralgia often can be controlled with NSAIDs and hydroxychloroquine. Low-dose oral corticosteroids or low-dose methotrexate are reserved for more refractory synovitis.

Drug Category: Cyclooxygenase-2 (COX-2) inhibitors

Although increased cost can be a negative factor, the incidence of costly and potentially fatal GI bleeds clearly is less with COX-2 inhibitors than with traditional NSAIDs. Ongoing analysis of cost avoidance of GI bleeds will further define the populations that will find COX-2 inhibitors the most beneficial.

Drug Category: Proton pump inhibitors

Esophageal reflux symptoms can be controlled effectively with these agents.

Drug Category: Antimalarial agents

Mild disease often can be controlled with hydroxychloroquine. Also may help prevent disease flares.

Drug Category: Corticosteroids

Reserved for more active or severe disease. Used in moderate-to-high doses for major organ involvement. Often used in combination with other drugs.

Drug Category: Prostaglandins

May be useful for secondary pulmonary hypertension in MCTD.

Drug Category: Cytotoxic agents

Major organ involvement may require moderate-to-high divided daily doses of corticosteroids and cytotoxic agents (eg, PO or pulse IV cyclophosphamide).

Drug Category: Calcium channel blocking agents

Avoiding exposure to cold temperatures and using long-acting calcium channel blocking agents may control Raynaud phenomenon. Calcium channel blocking agents used for vasodilation and possible antiplatelet effects.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Patients may require admission pending assessment for suspected infection or complications related to disease or treatment.
• Admit patients to appropriate service with rheumatology care if available. Obtain subspecialty consultation as indicated.

Further Outpatient Care

• See patients with stable disease and no recent changes in medications approximately every 2-4 months and perform routine laboratory evaluation, including CBC count and chemistry studies.
• Patients with active disease typically are seen approximately every 3-6 weeks, depending on the severity of disease.

Prognosis

• Cases of MCTD with typical clinical or serologic features occasionally evolve into scleroderma, SLE, or other rheumatic disease.
• Most patients have a favorable outcome.
• Pulmonary hypertension is the most frequent disease-associated cause of death.
• Careful monitoring and aggressive treatment may improve the outcome of pulmonary hypertension.

Patient Education

• Education about MCTD and its treatment is essential.
• Active participation in the decision-making process empowers patients in their own care.
• Education about disease decreases the risk of patients developing learned helplessness and improves functional outcomes.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• In several studies, several years have elapsed between the onset of symptoms of rheumatic diseases, including MCTD, and the correct diagnosis. Failure to make a correct diagnosis, to treat the disease correctly, or to seek subspecialty consultation are all potential legal pitfalls the physician should consider.

Special Concerns

• Monitor patients carefully during pregnancy because they are at increased risk of fetal loss.
• Corticosteroids are the mainstay of therapy during pregnancy.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Alarcon-Segovia D, Villareal M. Classification and diagnostic criteria for mixed connective tissue disease. In: Kasukawa R, Sharp GC, eds. Mixed Connective Tissue Disease and Anti-Nuclear Antibodies. Amsterdam:. Excerpta Medica;1987:33-40.
• Burdt MA, Hoffman RW, Deutscher SL. Long-term outcome in mixed connective tissue disease: longitudinal clinical and serologic findings. Arthritis Rheum. May 1999;42(5):899-909. [Medline].
• Greidinger EL, Zang Y, Jaimes K, et al. A murine model of mixed connective tissue disease induced with U1 small nuclear RNP autoantigen. Arthritis Rheum. Feb 2006;54(2):661-9.
• Hoffman RW, Rettenmaier LJ, Takeda Y. Human autoantibodies against the 70-kd polypeptide of U1 small nuclear RNP are associated with HLA-DR4 among connective tissue disease patients. Arthritis Rheum. May 1990;33(5):666-73. [Medline].
• Hoffman RW, Cassidy JT, Takeda Y. U1-70-kd autoantibody-positive mixed connective tissue disease in children. A longitudinal clinical and serologic analysis. Arthritis Rheum. Nov 1993;36(11):1599-602. [Medline].
• Hoffman RW, Greidinger EL. Mixed connective tissue disease. Curr Opin Rheumatol. Sep 2000;12(5):386-90. [Medline].
• Hoffman RW. Mixed connective tissue disease, overlap syndromes and Sjogren's syndrome. In: Lahita RG, ed. Systemic Lupus Erythematosus.4th ed. San Diego, Calif:. Academic Press;2004.
• Hoffman RW. Undifferentiated and mixed connective tissue disease. In: D Wallace and B Hahn eds. Dubois Systemic Lupus Erythematosus. Lippincott, P. In press.
• Hoffman RW. T cells in the pathogenesis of systemic lupous erythematosus. Clin Immunol. 2004;113:4-13. [Medline].
• Sharp GC, Irvin WS, Tan EM. 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].
• Smolen JS, Steiner G. Mixed connective tissue disease: to be or not to be?. Arthritis Rheum. May 1998;41(5):768-77. [Medline].

Article Last Updated: Nov 7, 2006