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

Mixed connective-tissue disease (MCTD) was first recognized by Sharp and colleagues (1972) 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).¹

MCTD 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
• 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/*15²
• Vascular endothelial proliferation with widespread lymphocytic and plasmacytic infiltration of tissues
• Activation of Toll-like receptors in a pattern that may differ from that of lupus

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.³
• 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. The clinical manifestations of MCTD are similar among various ethnic groups.

Sex

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

Age

The onset of MCTD can occur at any age but 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

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)
• 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. 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.⁴
• 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.

Causes

• The fundamental cause of MCTD remains unknown. Autoimmunity to components of the U1-70 kd snRNP are a hallmark of disease. Anti-RNP antibodies can precede overt clinical manifestations of MCTD, but overt disease generally develops within one year of anti-RNP antibody induction.
• The loss of T-lymphocyte and B-lymphocyte tolerance, due to (1) cryptic self-antigens, (2) abnormalities of apoptosis, or (3) molecular mimicry by infectious agents, and driven by U1-RNA-induced innate immune responses, are 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
• Muscle enzymes if myositis is suspected clinically
• Antinuclear antibodies
• • High-titer speckled pattern fluorescent antinuclear antibody (FANA) is typical of mixed connective-tissue disease (MCTD).
  • FANA is not specific to MCTD.
• High titers of anti–U1-RNP antibodies
• • Anti-RNP antibodies are required for diagnosis of MCTD.
  • The presence of anti–U1-70 kd is characteristic of MCTD.
• Other immune studies
• • Antiphospholipid antibodies (including anticardiolipin antibodies and lupus anticoagulant) may be associated with pulmonary hypertension. In MCTD, however, the presence of these antibodies has not been associated with clotting events.
  • Rheumatoid factor is frequently detected.
  • Other lupus-specific antibodies (eg, anti–double-stranded DNA antibodies) are absent.
  • Scleroderma-specific antibodies, including anticentromere, anti–Scl-70 (topoisomerase), and anti–PM-1 (Pm-Scl), are absent.
  • C3 and C4 complement levels are more likely to be depleted in lupus than in MCTD
• Amylase and lipase - To assess for pancreatitis if clinically indicated

Imaging Studies

• Chest radiography - To assess for infiltrates, effusion, or cardiomegaly
• Echocardiography - Used to evaluate for effusion, chest pain, pulmonary hypertension, or valvular disease (An exercise echocardiography may increase the sensitivity to identify pulmonary hypertension.)
• Ultrasonography/CT scanning - 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

• Pulmonary function testing - To screen for declining diffusing capacity of lung for carbon monoxide (DLCO), possibly indicating pulmonary hypertension
• 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
• Six-minute walk - To assess for cardiopulmonary insufficiency, possibly indicating pulmonary hypertension

Procedures

• Right-sided heart catheterization is the criterion standard for diagnosis of pulmonary hypertension.

Staging

• MCTD can enter sustained remission later in the clinical course. Anti-RNP autoantibodies typically become undetectable in patients in remission.

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 to 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 mixed connective-tissue disease (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 consideration.
• Because atherosclerotic heart disease remains a major risk in 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)

These agents reduce pain and inflammation and allow for improvement in mobility and function. Mild mixed connective-tissue disease (MCTD) may be controlled with NSAIDs. Arthritis/arthralgia can often be controlled with NSAIDs and hydroxychloroquine. Low-dose oral corticosteroids or low-dose methotrexate is reserved for more refractory synovitis.

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

Although increased cost can be a negative factor, COX-2 inhibitors may be more effective in reducing the incidence of costly and potentially fatal GI bleeding than traditional NSAIDs. COX-2 inhibitors and many traditional NSAIDs may increase the risk of atherosclerotic cardiovascular endpoints.

Drug Category: Proton pump inhibitors

Esophageal reflux symptoms can be controlled effectively with these agents.

Drug Category: Antimalarial agents

Mild MCTD can often be controlled with hydroxychloroquine. Hydroxychloroquine may also help prevent disease flares.

Drug Category: Corticosteroids

These agents are reserved for more active or severe disease. They are used in moderate-to-high doses for major organ involvement. They are often used in combination with other drugs.

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 are used for vasodilation and possible antiplatelet effects.

Drug Category: Phosphodiesterase (type 5) Enzyme Inhibitor

Phosphodiesterase inhibitors can ameliorate symptoms of pulmonary hypertension and Raynaud phenomenon in patients with MCTD. These agents may not be as durable as other drug classes in improving pulmonary hypertension, but the adverse-effect profile of phosphodiesterase inhibitors is often more favorable than prostaglandin or anti-endothelin therapies.

Drug Category: Endothelin Receptor Antagonist

These agents may be helpful for managing pulmonary hypertension in patients with MCTD. The risk of liver toxicity with endothelin receptor antagonists dictates that these drugs must be prescribed by experts.

Drug Category: Prostaglandins

These agents may be useful for managing pulmonary hypertension in patients with MCTD, although dose titration and administration should be managed by an expert in this drug.

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). Recent reports suggest that, in contrast to primary or scleroderma-associated pulmonary hypertension, a subset of MCTD patients with pulmonary hypertension may respond well to aggressive immunosuppression with cytotoxic agents.

FOLLOW-UP

Section 8 of 10  

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

Further Inpatient Care

• Patients with mixed connective-tissue disease (MCTD) 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 consultations 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 are typically 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 another rheumatic disease.
• Most patients with MCTD have a favorable outcome.
• Pulmonary hypertension is the most common 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 mixed connective-tissue disease (MCTD), and the correct diagnosis. Failure to make a correct diagnosis, to treat the disease correctly, or to seek subspecialty consultations are all potential legal pitfalls that 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

1. 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].
2. Hoffman RW, Rettenmaier LJ, Takeda Y, et al. 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].
3. Burdt MA, Hoffman RW, Deutscher SL, et al. Long-term outcome in mixed connective tissue disease: longitudinal clinical and serologic findings. Arthritis Rheum. May 1999;42(5):899-909. [Medline].
4. Jais X, Launay D, Yaici A, et al. Immunosuppressive therapy in lupus- and mixed connective tissue disease-associated pulmonary arterial hypertension: a retrospective analysis of twenty-three cases. Arthritis Rheum. Feb 2008;58(2):521-31. [Medline].
5. 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.
6. 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. [Medline].
7. Hoffman RW. Undifferentiated and mixed connective tissue disease. In: Wallace D, Hahn B, eds. Dubois Systemic Lupus Erythematosus. Lippincott, P: In press.
8. Hoffman RW. Mixed connective tissue disease, overlap syndromes and Sjogren's syndrome. In: Lahita RG, ed. Systemic Lupus Erythematosus. 4^th ed. San Diego, Calif: Academic Press; 2004.
9. Hoffman RW. T cells in the pathogenesis of systemic lupus erythematosus. Clin Immunol. Oct 2004;113(1):4-13. [Medline].
10. Hoffman RW, Cassidy JT, Takeda Y, et al. 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].
11. Hoffman RW, Greidinger EL. Mixed connective tissue disease. Curr Opin Rheumatol. Sep 2000;12(5):386-90. [Medline].
12. Maldonado ME, Perez M, Pignac-Kobinger J, et al. Clinical and immunologic manifestations of mixed connective tissue disease in a Miami population compared to a Midwestern US Caucasian population. J Rheumatol. Mar 2008;35(3):429-37. [Medline].
13. Perkins K, Hoffman RW, Bezruczko N. A Rasch analysis for classification of systemic lupus erythematosus and mixed connective tissue disease. J Appl Meas. 2008;9(2):136-50. [Medline].
14. 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: Aug 7, 2008