AUTHOR INFORMATION

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Authored by Marisa S Klein-Gitelman, MD, MPH, MS, Assistant Professor, Department of Pediatrics, Section of Immunology-Rheumatology, Northwestern University and Children's Memorial Hospital

Marisa S Klein-Gitelman, MD, MPH, MS, is a member of the following medical societies: American College of Rheumatology

Edited by Barry L Myones, MD, Director of Research, Pediatric Rheumatology Center, Texas Children's Hospital at Houston; Associate Professor, Departments of Pediatrics & Immunology, Pediatric Rheumatology Section, Baylor College of Medicine; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Thomas JA Lehman, MD, Clinical Professor of Pediatrics, Weill-Cornell University; Chief, Department of Pediatrics, Division of Pediatric Rheumatology, Hospital for Special Surgery; Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine; and Barry L Myones, MD, Director of Research, Pediatric Rheumatology Center, Texas Children's Hospital at Houston; Associate Professor, Departments of Pediatrics & Immunology, Pediatric Rheumatology Section, Baylor College of Medicine

Author's Email:	Marisa S Klein-Gitelman, MD, MPH, MS
Editor's Email:	Barry L Myones, MD

eMedicine Journal, May 24 2006, VOLUME 7, Number 5

INTRODUCTION

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Background: Sharp and colleagues first proposed mixed connective tissue disease (MCTD) as a separate autoimmune disorder. 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. A comparison of the sensitivity and specificity of the above 3 sets of criteria along with a fourth set of criteria developed by MF Kahn demonstrated that the Kahn and Alarcon-Segovia criteria are the most sensitive and specific for disease diagnosis.

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. 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). The following lists, published by several authors, are the criteria for making a diagnosis of MCTD.

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 are Raynaud phenomenon and swollen fingers or hands.

Frequency:

• In the US: In a literature review, Michels counted 224 cases of MCTD. 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.

• Internationally: 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%. 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

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History:

• The most frequent presentation of 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
  
  
  
  • Vasculitic rashes (usually palpable purpuric rashes)
  
  
  
  • Dysphagia
  
  
  
  • Fever
  
  
  
  • Rheumatoid nodules
  
  
  
  • Lymphadenopathy
  
  
  
  • Alopecia
  
  
  
  • Telangiectasia
  
  
  

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 MCTD patients (29/53 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

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Acute Lymphoblastic Leukemia
Acute Poststreptococcal Glomerulonephritis
Autoimmune and Chronic Benign Neutropenia
Chronic Fatigue Syndrome
Endocarditis, Bacterial
Evans Syndrome
Fibromyalgia
Juvenile Rheumatoid Arthritis
Nephritis
Nephrotic Syndrome
Pericarditis, Viral
Polyarteritis Nodosa
[Pulmonary Hypertension, Primary]

Sarcoidosis
Splenomegaly
Systemic Lupus Erythematosus
Systemic Sclerosis

Other Problems to be Considered:

Dermatomyositis and Polymyositis
Pulmonary Fibrosis, Idiopathic
Scleroderma
Synovitis

WORKUP

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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 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 MCTD patients 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 radiograph
  
  
  
  • Barium swallow to evaluate esophageal motility
  
  
  
  • Echocardiography 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. It is important to screen for this problem 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:


• • MRI of the brain
  
  
  
  • 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) 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.

Staging: MCTD is not staged.

TREATMENT

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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 MCTD.



• Other consultants depend on the organ systems involved and the level of 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

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Therapeutic interventions for children with MCTD should occur under the direction or with the advice of an experienced physician. A variety of 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/or 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 eMedicine’s topic on Hypertension in the Pediatric Volume.

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 Name	Naproxen (Aleve, Naprelan, Naprosyn, Anaprox) -- For relief of mild to moderate pain; inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which is responsible for prostaglandin synthesis. Available in SR formulation for once daily dosing as Naprelan.
Adult Dose	500-1000 mg/d PO divided bid
Pediatric Dose	7-20 mg/kg/d PO divided bid/tid; not to exceed adult dose
Contraindications	Documented hypersensitivity; gastritis; hepatic or renal insufficiency; coagulopathy; other conditions in which changes in platelet function could be harmful
Interactions	Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Category D in third trimester of pregnancy; acute renal insufficiency, interstitial nephritis, hyperkalemia, hyponatremia, and renal papillary necrosis may occur; patients with preexisting renal disease or compromised renal perfusion risk acute renal failure; leukopenia occurs rarely, is transient, and usually returns to normal during therapy; persistent leukopenia, granulocytopenia, or thrombocytopenia warrants further evaluation and may require discontinuation; occasionally, patient with SLE has a hypersensitivity reaction, most often characterized as a hepatotoxicity, but reaction can include other symptoms and must be kept in mind

Drug Name	Tolmetin (Tolectin) -- For relief of mild to moderate pain; inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which is responsible for prostaglandin synthesis.
Adult Dose	1200-1800 mg/d PO divided tid
Pediatric Dose	15-30 mg/kg/d PO divided tid/qid; not to exceed adult dose
Contraindications	Documented hypersensitivity; gastritis; hepatic or renal insufficiency; coagulopathy; other conditions in which changes in platelet function could be harmful
Interactions	May increase serum concentrations of methotrexate or lithium; aspirin and probenecid may increase serum concentrations; tolmetin and warfarin lead to increased PT and bleeding; drug interactions similar to other NSAIDs may occur (eg, blunting antihypertensive effects of beta-blocking agents); other GI irritants may increase GI adverse reactions
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution with renal or liver disease; avoid during pregnancy; occasionally, patient with SLE has hypersensitivity reaction, most often characterized as hepatotoxicity, but reaction can include other symptoms and must be kept in mind; routinely monitor for gastritis, renal toxicity, hepatic toxicity, and bone marrow suppression, hepatitis, interstitial nephritis, CNS changes

Drug Name	Diclofenac (Voltaren-XR) -- Inhibits prostaglandin synthesis by decreasing activity of enzyme cyclooxygenase, which decreases formation of prostaglandin precursors. Available in SR formulation as Voltaren-XR (100 mg).
Adult Dose	100-200 mg/d PO divided bid
Pediatric Dose	<12 years: Not established >12 years: 2-3 mg/kg/d PO divided bid; not to exceed adult dose
Contraindications	Documented hypersensitivity; gastritis; hepatic or renal insufficiency; coagulopathy; other conditions in which changes in platelet function could be harmful
Interactions	Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Category D in third trimester of pregnancy; acute renal insufficiency, hyperkalemia, hyponatremia, interstitial nephritis, and renal papillary necrosis may occur; increases risk of acute renal failure in patients with preexisting renal disease or compromised renal perfusion; low WBC counts occur rarely and usually return to normal in ongoing therapy; discontinuation of therapy may be necessary with persistent leukopenia, granulocytopenia, or thrombocytopenia; occasionally, patient with SLE has hypersensitivity reaction, most often characterized as hepatotoxicity, but reaction can include other symptoms and must be kept in mind

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

Drug Name	Hydroxychloroquine (Plaquenil) -- Antimalarial drugs inhibit synthesis of DNA, RNA, and proteins by interacting with nucleic acids. Antimalarial drugs have variety of immunosuppressive effects, can act as antioxidants, and interfere with prostaglandins. Hydroxychloroquine sulfate 200 mg is equivalent to 155 mg hydroxychloroquine base and 250 mg chloroquine phosphate.
Adult Dose	200-400 mg/d PO (3-7 mg/kg/d)
Pediatric Dose	3-7 mg/kg/d PO; not to exceed 400 mg/d
Contraindications	Documented hypersensitivity; G-6-PD deficiency; retinal or visual field changes; porphyria; psoriasis
Interactions	Few reported; chloroquine may potentiate possible ocular toxicity; serum levels increase with cimetidine; magnesium trisilicate may decrease absorption
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in hepatic disease, G-6-PD deficiency, psoriasis, and porphyria; not recommended for long-term use in children; perform periodic (ie, 6 mo) ophthalmologic examinations for retinal pigment changes; test periodically for muscle weakness; adverse effects are infrequent and include eye changes, GI symptoms (diarrhea is most prominent), and CNS changes

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 Name	Prednisone (Deltasone, Orasone)/Methylprednisolone (Adlone, Solu-Medrol) -- Decreases inflammation by suppression of immune system: decreased lymphocyte volume and activity; decreased PMN migration; decreased or reversal of capillary permeability. High doses, especially over periods longer than 2-3 wk, suppress adrenal function.
Adult Dose	1-2 mg/kg/d PO
Pediatric Dose	1-2 mg/kg/d PO initially in divided doses not to exceed qid, then consolidated to daily dose before tapering total mg/d 30 mg/kg IV not to exceed 1 g/h as methylprednisolone for severe disease; may be administered as 3-d pulse regimen or as part of steroid regimen under guidance of rheumatologist
Contraindications	Documented hypersensitivity; serious infection except septic shock or tuberculous meningitis but including systemic fungal infection and varicella
Interactions	Coadministration with digoxin may increase digitalis toxicity secondary to hypokalemia; estrogens may increase levels of methylprednisolone; phenobarbital, phenytoin, and rifampin may decrease levels of methylprednisolone (adjust dose); monitor patients for hypokalemia with concurrent diuretic use
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Carefully monitor patients on corticosteroids for infection and carefully evaluate in setting of fever with no obvious source; monitor patients for diabetes, osteoporosis, osteonecrosis, hypertension, glaucoma, cataract, altered mood, gastritis; evaluate patients for occult infection, including TB and HIV, prior to starting corticosteroids Sudden discontinuation in patients on chronic steroids even in face of active infection; infection can cause disease flare and sudden discontinuation of steroids may cause Addisonian crisis; carefully consider use of steroids in setting of active infection and discuss with experienced physicians; consider alternate types of immunosuppression in patients who develop diabetes while on corticosteroids and taper steroids carefully; in interim, may require insulin

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 Name	Cyclophosphamide (Cytoxan, Neosar) -- Interferes with normal function of DNA by alkylation and cross-linking strands of DNA and by possible protein modification.
Adult Dose	500-1000 mg/m2 IV every mo; not to exceed 1000 mg/m2
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; severely depressed bone marrow function
Interactions	Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones Chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity
Pregnancy	D - Unsafe in pregnancy
Precautions	Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis

Drug Name	Azathioprine (Imuran) -- Antagonizes purine metabolism and may inhibit synthesis of proteins, RNA, and DNA. May interfere with mitosis and cellular metabolism.
Adult Dose	1-2.5 mg/kg/d PO
Pediatric Dose	1-3 mg/kg/d PO
Contraindications	Documented hypersensitivity; low levels of serum TPMT
Interactions	Toxicity increases with allopurinol; concurrent use with ACE inhibitors may induce severe leukopenia; may increase levels of methotrexate metabolites and decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine
Pregnancy	D - Unsafe in pregnancy
Precautions	Monitor carefully for renal toxicity and hepatotoxicity; caution in patients with liver or renal disease; decrease dose by 25-33% in patients receiving allopurinol and azathioprine

Drug Name	Methotrexate (Rheumatrex) -- An antimetabolite that interferes with enzyme dihydrofolate reductase, leading to depletion of DNA precursors and inhibition of DNA and purine synthesis, particularly adenosine.
Adult Dose	5-30 mg PO/IV/SC qwk
Pediatric Dose	5-20 mg/m2 PO/IV/SC qwk; many pediatric rheumatologists increase dose (not to exceed 30 mg/m2; approximately equivalent to 1 mg/kg)
Contraindications	Documented hypersensitivity; alcoholism; hepatic insufficiency; documented immunodeficiency syndromes; preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia); renal insufficiency
Interactions	Oral aminoglycosides may decrease absorption and blood levels of concurrent PO methotrexate (MTX); charcoal lowers MTX levels; coadministration with etretinate may increase hepatotoxicity of MTX; folic acid or derivatives contained in some vitamins may decrease response to MTX Coadministration with NSAIDs may be fatal; indomethacin and phenylbutazone can increase MTX plasma levels; may decrease phenytoin serum levels Probenecid, salicylates, procarbazine, and sulfonamides, including TMP/SMZ, may increase effects and toxicity of MTX; may increase plasma levels of thiopurines
Pregnancy	X - Contraindicated in pregnancy
Precautions	Monitor CBC counts monthly and liver and renal function every 1-3 mo during therapy (monitor more frequently during initial dosing, dose adjustments, or when risk of elevated MTX levels [eg, dehydration]); MTX has toxic effects on hematologic, renal, GI, pulmonary, and neurologic systems; discontinue if significant drop in blood counts; aspirin, NSAIDs, or low-dose steroids may be administered concomitantly with MTX (possibility of increased toxicity with NSAIDs, including salicylates, has not been tested)

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 Name	Calcium carbonate (Oystercal, Caltrate) -- Used as antacid and for prevention of calcium depletion.
Adult Dose	1200 mg/d PO
Pediatric Dose	<6 months: 360 mg/d PO 6-12 months: 540 mg/d PO 1-10 years: 800 mg/d PO 11-18 years: Administer as in adults
Contraindications	Renal calculi; hypercalcemia; hypophosphatemia; renal or cardiac disease; digitalis toxicity
Interactions	May decrease effects of tetracyclines, atenolol, salicylates, iron salts, and fluoroquinolones; large intakes of dietary fiber may decrease calcium absorption and levels
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in renal disease; cardiac disease; and sarcoidosis

Drug Name	Calcifediol (Calderol) -- Vitamin D regulates calcium homeostasis, promoting absorption of calcium by gut, resorption of calcium by kidney, and increasing bone mineral metabolism.
Adult Dose	20-100 mcg/d PO; titrate to obtain normal serum calcium and phosphorus levels
Pediatric Dose	Suggested doses: <30 kg: 20 mcg PO 3 times per wk >30 kg: 50 mcg PO 3 times per wk
Contraindications	Documented hypersensitivity; hypercalcemia
Interactions	Effects enhanced by thiazide diuretics and reduced by cholestyramine and colestipol; may precipitate arrhythmia in conjunction with digitalis
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Pregnancy category C per manufacturer; expert analysis category A; category D if dosage exceeds RDA; adequate dietary calcium needed for clinical response; maintain adequate fluid intake; calcium-phosphate product (serum calcium times phosphorus) not to exceed 70; avoid use with renal function impairment and secondary hyperparathyroidism; avoid hypercalcemia

Drug Category: Rheostatic agents -- 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 Name	Pentoxifylline (Trental) -- Methylxanthine used as hemorheologic agent by improving flow properties of blood by decreasing viscosity, which improves oxygenation to peripheral tissues. Precise mode of action is not defined; however, produces dose-related hemorheologic effects, lowering blood viscosity and improving erythrocyte flexibility. Another benefit is ability to increase leukocyte deformability and to inhibit neutrophil adhesion and activation.
Adult Dose	400 mg PO tid with meals
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; recent cerebrovascular or retinal hemorrhage; serious adverse reaction to caffeine, theophylline, theobromine, or other methylxanthines
Interactions	Coadministration with cimetidine or theophylline increases effect, toxic potential, or both; increases effect of antihypertensives; patients taking warfarin should undergo more frequent monitoring of PTs
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Patients taking warfarin should undergo more frequent monitoring of PTs; frequently examine and monitor patients at increased risk for bleeding or with history of bleeding for change in hemoglobin or hematocrit levels

FOLLOW-UP

Section 8 of 11

Further Inpatient Care:

• Admit patients with 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 known intervention exists to deter disease onset or to alter progression 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, 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. Also, see eMedicine's patient education articles, Fibromyalgia and Chronic Fatigue Syndrome.

MISCELLANEOUS

Section 9 of 11

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 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.

TEST QUESTIONS

Section 10 of 11

CME Question 1: A child with Raynaud phenomenon and arthritis presents for evaluation. Which of the following laboratory tests does not support the diagnosis of mixed connective tissue disease (MCTD)?

A: Positive antinuclear antibody
B: Positive anti-Smith antibody
C: Positive antiphospholipid antibody
D: Positive antiribonucleoprotein antibody
E: Positive anti-DNA antibody

The correct answer is B: According to criteria for MCTD, the presence of anti-Smith antibody suggests the diagnosis of systemic lupus erythematosus. For example, the Sharp criteria specify that the anti-Smith antibody must be negative for definite diagnosis.

CME Question 2: Mixed connective tissue disease (MCTD) is most likely to have the symptoms of which of the following diseases?

A: Lupus
B: Scleroderma
C: Arthritis
D: Myositis
E: All of the above

The correct answer is E: A thorough evaluation of all possible disease manifestations is most important in the diagnosis and treatment of MCTD. Patients may present with subtle findings, and the character of the disease can change over time.

Pearl Question 1 (T/F): Girls are most likely to have mixed connective tissue disease (MCTD).

The correct answer is True: While girls are more likely to have MCTD, boys can and do present with this disease.

Pearl Question 2 (T/F): The antinuclear antibody (ANA) in mixed connective tissue disease (MCTD) is most often strongly positive.

The correct answer is True: Most patients with MCTD have a strongly positive ANA. Occasionally, the amount of ANA is so high that a specific titer cannot be measured. The presence of a strongly positive ANA should prompt the clinician to consider this diagnosis.

Pearl Question 3 (T/F): Patients with mixed connective tissue disease (MCTD) are very ill.

The correct answer is False: Patients with MCTD can have a severe, moderate, or mild disease course.

Pearl Question 4 (T/F): Patients with (MCTD) always have Raynaud phenomenon.

The correct answer is False: Although most patients with MCTD have significant Raynaud phenomenon, this process is not required for diagnosis according to current diagnostic criteria.

BIBLIOGRAPHY

Section 11 of 11

• 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.
• Biro E, Szekanecz Z, Czirjak L, et al: Association of systemic and thyroid autoimmune diseases. Clin Rheumatol 2006 Mar; 25(2): 240-5[Medline].
• Bodolay E, Szekanecz Z, Devenyi K, et al: Evaluation of interstitial lung disease in mixed connective tissue disease (MCTD). Rheumatology (Oxford) 2005 May; 44(5): 656-61[Medline].
• 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.
• 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 1993 Dec; 95(6): 595-600[Medline].
• Michels H: Course of mixed connective tissue disease in children. Ann Med 1997 Oct; 29(5): 359-64[Medline].
• Mier R, Ansell B, Hall MA, et al: Long term follow-up of children with mixed connective tissue disease. Lupus 1996 Jun; 5(3): 221-6[Medline].
• Mier RJ, Shishov M, Higgins GC, et al: Pediatric-onset mixed connective tissue disease. Rheum Dis Clin North Am 2005 Aug; 31(3): 483-96, vii[Medline].
• 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 1972 Feb; 52(2): 148-59[Medline].
• Singsen BH, Bernstein BH, Kornreich HK, et al: Mixed connective tissue disease in childhood. A clinical and serologic survey. J Pediatr 1977 Jun; 90(6): 893-900[Medline].
• Tiddens HA, van der Net JJ, de Graeff-Meeder ER, et al: Juvenile-onset mixed connective tissue disease: longitudinal follow-up. J Pediatr 1993 Feb; 122(2): 191-7[Medline].

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