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 first proposed mixed connective tissue disease (MCTD) as a separate autoimmune disorder.¹ The initial definition identified patients with a specific autoantibody profile, high titers of anti-U1 ribonucleoprotein (70-kD) autoantibody (anti-RNP Ab) but without anti-Smith autoantibody (anti-Sm Ab), in association with specific clinical criteria. Alarcon-Segovia and Villareal and Kasukawa et al subsequently suggested 2 alternate sets of criteria.^{2, 3} A comparison of the sensitivity and specificity of the above 3 sets of criteria along with a fourth set of criteria developed by Kahn et al demonstrated that the Kahn and Alarcon-Segovia criteria are the most sensitive and specific for disease diagnosis.⁴

In pediatrics, Kasukawa criteria are used most frequently in published series and have more conservative requirements. MCTD remains a controversial diagnosis; some rheumatologists view MCTD as a separate disease, and others classify the disorder as an undifferentiated connective tissue disease or overlap syndrome, which may have features of lupus, progressive systemic sclerosis, rheumatoid arthritis, and myositis but should not have its own separate name.

Adding support to the concept of MCTD as a distinct entity, in 1993, Mairesse et al described an autoantibody to the constitutive 73-kD heat shock protein found at high levels exclusively in patients with MCTD.⁴ This autoantibody was found in reduced levels in patients with progressive systemic sclerosis and rheumatoid arthritis. The autoantibody was not found in significant quantities in patients with systemic lupus erythematosus (SLE) or myositis. This finding has not been duplicated and must be interpreted with caution. However, the authors redefine MCTD as "a core of minor symptoms (Raynaud phenomenon, puffy fingers, mild myositis and arthritis) associated significantly with anti-U1-68kD antibody, defining an undifferentiated connective tissue (UCTD) disease that may ultimately overlap with features of major connective tissue disease."

Although confusing, perhaps the best way to consider MCTD is as an undifferentiated connective tissue disease represented mostly by Raynaud phenomenon and anti-RNP antibody. This disorder may evolve into one of several major connective tissue diseases or to an overlap syndrome of the major connective tissue diseases. The evolution of this disease requires the physician to carefully assess and constantly reassess the patient in anticipation of change and to provide early intervention with appropriate medical therapy.

Pathophysiology

MCTD has symptoms of several autoimmune diseases. Refer to disease-specific sites for more details (see Juvenile Rheumatoid Arthritis, Neonatal Lupus and Cutaneous Lupus Erythematosus in Children, Systemic Lupus Erythematosus, Systemic Sclerosis, Sjogren Syndrome, Dermatomyositis, and Myositis Ossificans). The following lists, published by several authors, are the criteria for making a diagnosis of MCTD.^{1, 2, 3}

Sharp criteria

• Definite diagnosis requires 4 major criteria with positive anti-U1 RNP greater than 1:4000 and a negative anti-Sm Ab. U1 RNP is the specific RNP protein associated with this syndrome.
• Probable diagnosis requires either 3 major criteria or 2 major criteria (which must come from the first 3 major criteria listed) and 2 minor criteria plus an anti-U1 RNP greater than 1:1000.
• Possible diagnosis requires 3 major criteria without serologic evidence of disease or, if anti-U1 RNP is greater than 1:100, 2 major criteria or 1 major and 3 minor criteria.
• • Major criteria are severe myositis, pulmonary involvement (diffusing capacity of lung for carbon monoxide 70% of normal, pulmonary hypertension, proliferating vascular lesions on lung biopsy), Raynaud phenomenon or esophageal hypomotility, swollen hands or sclerodactyly, and highest observed anti-U1 RNP (>1:10,000) with negative anti-Sm Ab.
  • Minor criteria are alopecia, leukopenia (4000 WBC/mL), anemia (<10 g/dL for females, <12 g/dL for males), pleuritis, pericarditis, arthritis, trigeminal neuralgia, malar rash, thrombocytopenia (<100,000/mL), mild myositis, and history of swollen hands.

Alarcon-Segovia and Villareal classification

• Serologic criterion is a positive anti-RNP at a titer of 1:1600 or higher.
• Clinical criteria (at least 3) are edema of the hands, Raynaud phenomenon (ie, 2 or 3 color changes), acrosclerosis, synovitis, and myositis (laboratory or biopsy evidence).

Kasukawa criteria

• Diagnosis requires the following 3 conditions: (1) positive in either 1 of 2 common symptoms, (2) positive anti-RNP antibody, and (3) positive in 1 or more findings in 2 of 3 disease categories of A, B, and C. The following are disease findings A, B, and C:
• • SLE-like conditions (polyarthritis, lymphadenopathy, facial erythema, pericarditis or pleuritis, leukopenia [<4000/mL], or thrombocytopenia [<100,000/mL])
  • Progressive systemic sclerosislike findings (sclerodactyly, pulmonary fibrosis, restrictive lung disease [vital capacity <80%] or reduced diffusion capacity [<70%], hypomotility, or dilation of the esophagus)
  • Polymyositislike findings (muscle weakness, increased serum level of myogenic enzymes [creatine kinase], myogenic pattern on electromyogram)
• Common symptoms include Raynaud phenomenon and swollen fingers or hands.

Frequency

United States

In a literature review, Michels counted 224 cases of MCTD.⁵ Pediatric-onset MCTD accounts for an estimated one quarter of all cases. Most large pediatric rheumatology centers in major cities have 5-15 active pediatric cases, although some studies estimate that MCTD occurs in 0.6% of all pediatric rheumatology patients.

International

US data are derived from international data.

Mortality/Morbidity

Literature describes pediatric MCTD from individual case reports to small series. Mortality is 0-50%. The review by Michels found a mortality figure of 7.6%.⁵ More recent data assess pediatric mortality at 3-4 per 1000 population versus adult mortality at 12-23 per 1000 population. Serious organ involvement included 47% of patients with renal disease, 54% with restrictive lung disease, and 29% with GI disease. Although rare, morbidity from cerebral disease, cardiomyopathy, myopericarditis, and pulmonary hypertension has been reported and is associated with a significant risk of mortality.

Race

Ethnic distribution for pediatric MCTD has not been reported. Literature suggests that no specific protection or propensity based on race exists.

Sex

A female predominance, which is typical of other autoimmune diseases, exists. Three published series on pediatric MCTD report 89 of 105 patients to be female, or a female-to-male ratio of approximately 6:1.

Age

Age range for pediatric onset disease is younger than 16 years by definition. No specific age of onset is excluded. The median age at onset is 12 years, based on reported pediatric series. The youngest reported age at onset is 2 years.

CLINICAL

Section 3 of 10  

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

History

• The most frequent presentation of mixed connective tissue disease (MCTD) is a child with polyarthritis, general malaise, and Raynaud phenomenon.
• Patients may present with the following:
• • Sclerodermatous skin (usually limited to fingers but can be more extensive).
  • Sausage-shaped fingers
  • Proximal muscle weakness
  • Rash (finger ulcers or pits, Gottren papules)
  • Vasculitic rashes (usually palpable purpuric rashes)
  • Dysphagia
  • Gastroesophageal reflux disease (GERD) symptoms
  • Fever
  • Rheumatoid nodules
  • Lymphadenopathy
  • Alopecia
  • Telangiectasia
  • Headache

Physical

Detailed physical examination is critical.

• Classification criteria other than autoantibody status rely on clinical examination and diagnostic tests.
• Consider the following to make the diagnosis:
• • Alopecia
  • Pleuritic chest pain
  • Pericardial rub
  • Arthritis
  • Raynaud phenomenon
  • Malar rash
  • Petechial rash
  • Muscle weakness
  • Swollen hands (especially dorsal surface)
  • Trigeminal neuropathy
  • Acrosclerosis or sclerodermatous skin changes
  • Epigastric tenderness

Causes

Specific causes of MCTD remain undefined. Research suggests that many factors, including genetics, hormones, and environment, contribute to development of autoimmune syndromes. As mentioned in the Introduction, the hallmark of MCTD is the presence of autoantibodies to U1 small nuclear ribonucleoproteins, in particular a 70-kDa U1 protein. During cell death or apoptosis, the 70-kDa protein is cleaved by caspase-3 into a small 40-kDa protein. Several research groups have described this apoptotic form. Specific anti-RNP autoantibodies that preferentially bind to the apoptotic form of the U1 protein have been demonstrated in a group of patients with MCTD (29 of 53 tested). Furthermore, the concentration of the autoantibody is high early in the disease and decreases over time, suggesting that it correlates or represents an inciting event in disease onset.

DIFFERENTIALS

Section 4 of 10  

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

Other Problems to be Considered

Dermatomyositis and Polymyositis
Pulmonary Fibrosis, Idiopathic
Scleroderma
Synovitis

WORKUP

Section 5 of 10  

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

Lab Studies

• Initial laboratory evaluation should include the following:
• • CBC count with platelets and reticulocyte count: leukopenia, thrombocytopenia, and hemolytic anemia are common findings. If the patient has a combination of these findings, carefully consider the possibility of leukemia.
  • Complete chemistry panel to evaluate electrolytes, liver, and kidney function
  • • Unsuspected autoimmune hepatitis may be found based on elevated LFTs.
    • Nephritic patients may have elevated creatinine and abnormal electrolytes.
    • Patients with nephrosis may have low albumin and high cholesterol.
  • Urine analysis
  • • Patients with mixed connective tissue disease (MCTD) and nephritis may have protein, RBCs, WBCs, or casts on evaluation of urine.
    • Patients with nephrotic syndrome have high urinary protein.
  • Muscle enzymes: Myositis may be found by measurement of creatine kinase, aldolase, aspartate aminotransferase, alanine aminotransferase, and lactic dehydrogenase.
  • Acute phase reactants: Measure acute phase reactants with erythrocyte sedimentation rate or C-reactive protein.
• Diagnostic laboratory studies include the following:
• • Antinuclear antibody: This test is usually positive in high titers.
  • Anti–double-stranded DNA: This test is usually negative but is occasionally positive in individuals with MCTD.
  • Autoantibody panel including antibodies against RNP, Smith, Ro(SSA), La(SSB), Scl-70, phospholipids, cardiolipin and histone, total hemolytic complement, C3, C4, quantitative immunoglobulins, and thyroid studies.
  • • Other than anti-RNP and anti-Sm, these lab tests may be positive or negative depending on the characteristics of the individual patient's disease.
    • By definition, anti-RNP should be positive, and anti-Sm should be negative. Anti-Sm and anti-RNP antibodies can be measured by double diffusion, counterimmunoelectrophoresis, passive hemagglutination, and enzyme immunoassay. The double diffusion assay uses crude antigens, and positivity is based on the identity of precipitation lines for test standard and test sera. This test is specific but not sensitive.
    • Purified Sm proteins are available for testing; however, RNP antigen has not been separated from Sm and is detected as a complex.
    • Counterimmunoelectrophoresis and passive hemagglutination improve the ability to distinguish anti-Sm from anti-RNP by modifying the antigen extract.
    • The antigen for anti-Sm antibodies is treated with RNase, removing RNP from the preparation.
    • A decrease in titer of approximately 5 tubes (or more) dilution from before and after RNase digestion is characteristic of MCTD sera.
    • The antigens in the enzyme immunoassay are prepared by immunoaffinity chromatography using human autoantibodies and murine monoclonal antibodies to separate Sm from the RNP/Sm antigen complex and are sensitive to detecting anti-RNP antibodies.
  • Thyroid studies (thyroid stimulating hormone [TSH], free T4, thyroid autoantibody screen). In one study of 1517 adult patients with rheumatic diseases, 21% of the patients with MCTD had Hashimoto thyroiditis, and 2.5% had Graves disease, with prevalence rates 556- and 76-fold higher, respectively, than the general population.

Imaging Studies

• Initial imaging studies should include the following:
• • Chest radiography should be performed.
  • Barium swallow should be performed to evaluate esophageal motility.
  • Echocardiography should be performed to evaluate myocardial and valvular function and to obtain an estimate of pulmonary artery pressure. Obtain baseline echocardiogram to look for evidence of myocarditis, valvulitis, and pulmonary hypertension. Of particular importance, monitor for pulmonary hypertension over time. Early diagnosis may lead to better response to treatments with corticosteroids. Currently, the use of sildenafil is under investigation to determine therapeutic benefit.
• In addition to chest radiography, pulmonary function tests, and clinical symptoms, high-resolution CT scan of the lung may be necessary to determine if pulmonary fibrosis exists. The presence of interstitial lung disease is often missed. Screening for this problem is important as it is more readily treated early in the disease course.
• Other imaging studies should be guided by clinical manifestations and may include the following:
• • Brain MRI
  • Renal ultrasonography, nuclear medicine evaluation of renal function, or both
  • Plain films to evaluate arthritis
• Inhaled aerosol clearance times of Tc 99m–labeled diethylene-triamine penta-acetate (Tc 99m–DTPA) should be obtained to evaluate pulmonary interstitial fibrosis and improvement after treatment.

Other Tests

• Obtain baseline pulmonary function tests, including diffusing capacity of lung for carbon monoxide.

Procedures

• Perform tissue biopsy as indicated to evaluate disease severity.

Histologic Findings

No specific histologic findings aid in the diagnosis of MCTD as a separate autoimmune disease. For example, nephritis in MCTD is usually indistinguishable from lupus nephritis.

Staging

MCTD is not staged.

TREATMENT

Section 6 of 10  

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

Medical Care

• The most important tools in patient care are tailoring the medical regimen, promptly attending to disease flare, and performing careful and frequent clinical and laboratory evaluations to test for new disease manifestations.
• Strongly consider annual echocardiogram, pulmonary function tests, and barium swallow.

Surgical Care

No specific surgical care is required.

Consultations

• A rheumatologist should be an integral part of the medical care team supporting the patient with mixed connective tissue disease (MCTD).
• Other consultants depend on the organ systems involved and the disease severity.

Diet

• Diet restrictions are driven by medical therapy and disease manifestations. Prescribe a low-fat, calcium-sufficient diet with no added salt for patients receiving corticosteroids.
• Recognize and evaluate nontraditional remedies along with traditional medications for safety and efficacy.

Activity

• Encourage the patient with MCTD to maintain a healthy lifestyle.
• Limitations should occur only secondary to serious organ involvement that prevents performance of activities.
• Advise patients with MCTD to avoid fatigue.
• Advise patients with MCTD to avoid significant cold exposures or to dress accordingly to decrease Raynaud symptoms.

MEDICATION

Section 7 of 10  

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

Therapeutic interventions for children with mixed connective tissue disease (MCTD) should occur under the direction or with the advice of an experienced physician. Various medications are used to treat individuals with MCTD and are chosen depending on disease manifestations. Goals of therapy are to control disease manifestations, allowing the child to have a good quality of life without major disease exacerbations, and to prevent serious organ damage that adversely affects function or life span. At the same time, the physician is challenged to prevent intolerable adverse effects from the therapeutic regimen.

Prior to treatment, identify diagnostic criteria and exclude other possible diagnoses. For those patients who do not have sufficient findings to fulfill diagnostic criteria, determine a course of action based on medical judgment and set time aside to answer all questions with the patient, family, and caregivers. Because they may be helpful, offer literature and support groups.

Many of these drugs have serious adverse effects, contraindications, and drug interactions. A high risk of infection, infertility, and future cardiovascular disease exists. Most medications are contraindicated during pregnancy. Advise patients with MCTD who are pregnant to consult an obstetrician and a rheumatologist with experience in treating other patients in similar conditions. The most important tool in the treatment of individuals with MCTD is meticulous and frequent reevaluation of patients. Reevaluation includes clinical and laboratory evaluation, allowing prompt recognition and treatment of disease flare that is essential to positive outcome.

As in individuals with SLE, patients may require little or no medication or may require long-term immunosuppression. Some of the medications patients require can be found below. Other specific medications may be applicable if the patient has another disease manifesting with MCTD. Because of the rarity of this disease, advise the patient to consult a physician with experience in the treatment of MCTD. Patients with hypertension should be treated aggressively. If hypertension is a consequence of corticosteroid therapy, consider immunomodulating medications as steroid-sparing agents to help control hypertension. Calcium channel blockers used to treat hypertension may also be used to treat Raynaud phenomenon. For more information, see Hypertension.

Drug Category: Nonsteroidal anti-inflammatory drugs

For children who present with mild disease, treat symptomatically and monitor closely for signs of disease progression. Treat individuals with arthritis and musculoskeletal pain with NSAIDs.

Select a specific agent based on patient response to medication, history of previous drug allergy or reaction, and ease of use. These medications have analgesic and anti-inflammatory properties to treat arthralgia and arthritis and are available with slightly different safety and efficacy profiles.

Drug Category: Antimalarials

Patients in whom major disease manifestation is lupus, rash, and other minor symptoms can be treated with hydroxychloroquine.

Drug Category: Corticosteroids

Use corticosteroids to treat children with hypocomplementemia and elevated levels of anti-DNA antibodies, children with active myositis, and children with significant manifestations of scleroderma. Dose varies with intensity of disease activity. Consider daily prednisone (1 mg/kg/d) or higher-dose alternate-day prednisone (5 mg/kg/d, not to exceed 150-250 mg depending on size of patient). Alternatively, lower-dose daily prednisone (0.5 mg/kg) may be used in conjunction with intermittent high-dose IV methylprednisolone (30 mg/kg/dose, not to exceed 1 g) on a weekly basis. Of note, recent case reports suggest that 3 days of pulse IV methylprednisolone followed by moderate-to-high dose oral steroids improved pulmonary artery pressures in a patient with MCTD and pulmonary artery hypertension.

Drug Category: Immunosuppressive agents

Evaluate children with signs of active nephritis to determine World Health Organization (WHO) classification category of their nephritis. For patients with class IV nephritis and some patients with class III nephritis, treat with corticosteroids and cyclophosphamide. Use azathioprine for individuals with milder nephritis. Use methotrexate for persons with arthritis not controlled by NSAIDs and for persons with fibrosis, especially sclerodermatous skin. Consider cyclophosphamide for individuals with severe systemic involvement of other vital organs, especially brain and lung. Consider other agents (eg, mycophenolate mofetil, cyclosporine) when standard therapies have failed. Other treatments under study include hormonal therapy, biologic agents that target cytokine production, and anti-DNA antibodies. For patients with severe persistent disease, autologous and stem cell transplantation is under study.

Drug Category: Calcium and vitamin D therapies

All patients who are on corticosteroids or who have arthritis are at greater risk for osteopenia and its complications. Diet and appropriate supplementation with vitamin D and calcium are important tools for bone health in these patients.

Drug Category: Rheostatic agents

These agents are used to improve peripheral blood flow and to improve delivery of oxygen to tissue suffering from peripheral vascular disease. In individuals with MCTD, used to decrease symptoms and damage from Raynaud phenomenon.

Drug Category: Phosphodiesterase (type 5) Enzyme Inhibitor

These agents increase peripheral vasodilation and may be helpful in treating symptoms associated with Raynaud disease.

FOLLOW-UP

Section 8 of 10  

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

Further Inpatient Care

• Admit patients with mixed connective tissue disease (MCTD) to the hospital for diagnostic evaluation or for chemotherapy as warranted. Most often, this is an outpatient evaluation.

Further Outpatient Care

• Observe the patient at regular intervals of 1-3 months depending on disease severity and manifestations. Obtain appropriate laboratory tests during these visits depending on disease manifestations and medication adverse effects.
• Laboratory data may include lupus serology, renal evaluation, muscle enzymes, and hematologic evaluation.
• Use physical or occupational therapy as needed for musculoskeletal symptoms.
• Continue to monitor for early evidence of pulmonary hypertension, interstitial lung disease, esophageal dysmotility, and osteoporosis.

In/Out Patient Meds

• See Medical Care.

Transfer

• Because patients with MCTD often have complicated medical issues, refer to a tertiary medical center for evaluation and treatment.

Deterrence/Prevention

• No intervention to deter disease onset or to alter progression is known other than the medical management of disease manifestations as described and screening for new disease manifestations.

Complications

• Complications of MCTD depend on the organ systems involved and the adverse effects and risks of immunosuppressive therapy.
• Patients with MCTD are at risk for infections, cardiovascular disease, and complications observed in lupus, progressive systemic sclerosis, and myositis (see Pathophysiology).

Prognosis

• Prognosis is generally considered similar to that of pediatric lupus. Initial descriptions of MCTD did not include renal disease, and the prognosis was believed to be considerably better than for the major connective tissue diseases. However, patients who fit the criteria for MCTD have had renal disease and considerable morbidity and mortality from major organ manifestations. It appears that, in MCTD, children fare better than adults.
• Individual patients appear to have severe or mild disease courses.
• Prognosis also depends on which disease manifestations are more prominent (eg, myocarditis, pulmonary disease, renal disease).

Patient Education

• Patient and family must have a thorough understanding of the disease, potential severity, and complications from the disease and therapy. Treatment of the individual with MCTD is difficult, especially for adolescent patients. The physician, parents, and/or caregivers should expect issues including depression and noncompliance. They must be prepared to work together with the patient toward a better outcome.
• For excellent patient education resources, visit eMedicine's Muscle Disorders Center.

MISCELLANEOUS

Section 9 of 10  

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

Medical/Legal Pitfalls

• Pitfalls exist because of the complicated nature of this illness. Primary health care providers are urged to seek the advice of a subspecialist in the diagnosis and treatment of mixed connective tissue disease (MCTD).

Special Concerns

• Patients are often on potentially teratogenic medications; these women should avoid pregnancy. Children with MCTD benefit most from evaluation and treatment by a pediatric rheumatologist.

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. 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. 1987:33-40.
3. Kasukawa R, Tojo T, Miyawaki S. Preliminary diagnostic criteria for classification of mixed connective tissue disease. In: Kasukawa R, Sharp GC, eds. Mixed Connective Tissue Disease and Anti-nuclear Antibodies. 1987:41-7.
4. Mairesse N, Kahn MF, Appelboom T. Antibodies to the constitutive 73-kd heat shock protein: a new marker of mixed connective tissue disease?. Am J Med. Dec 1993;95(6):595-600. [Medline].
5. Michels H. Course of mixed connective tissue disease in children. Ann Med. Oct 1997;29(5):359-64. [Medline].
6. Biro E, Szekanecz Z, Czirjak L, et al. Association of systemic and thyroid autoimmune diseases. Clin Rheumatol. Mar 2006;25(2):240-5. [Medline].
7. Bodolay E, Szekanecz Z, Devenyi K, et al. Evaluation of interstitial lung disease in mixed connective tissue disease (MCTD). Rheumatology (Oxford). May 2005;44(5):656-61. [Medline].
8. Mier R, Ansell B, Hall MA, et al. Long term follow-up of children with mixed connective tissue disease. Lupus. Jun 1996;5(3):221-6. [Medline].
9. Mier RJ, Shishov M, Higgins GC, et al. Pediatric-onset mixed connective tissue disease. Rheum Dis Clin North Am. Aug 2005;31(3):483-96, vii. [Medline].
10. Mier RJ, Shishov M, Higgins GC, Rennebohm RM, Wortmann DW, Jerath R. Pediatric-onset mixed connective tissue disease. Rheum Dis Clin North Am. Aug 2005;31(3):483-96, vii. [Medline].
11. Singsen BH, Bernstein BH, Kornreich HK, et al. Mixed connective tissue disease in childhood. A clinical and serologic survey. J Pediatr. Jun 1977;90(6):893-900. [Medline].
12. Tiddens HA, van der Net JJ, de Graeff-Meeder ER, et al. Juvenile-onset mixed connective tissue disease: longitudinal follow-up. J Pediatr. Feb 1993;122(2):191-7. [Medline].

Article Last Updated: Aug 7, 2007