eMedicine Specialties > Pediatrics: General Medicine > Rheumatology

Mixed Connective Tissue Disease

Marisa S Klein-Gitelman, MD, MPH, Associate Professor of Pediatrics, Northwestern University Feinberg School of Medicine; Head, Division of Rheumatology, Children's Memorial Hospital

Updated: Sep 29, 2009

Introduction

Background

In pediatrics, Kasukawa criteria are used most frequently in published series and have more conservative requirements. Mixed connective tissue disease remains a controversial diagnosis. Some rheumatologists view mixed connective tissue disease as a separate disease; 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 mixed connective tissue disease 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 mixed connective tissue disease.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 mixed connective tissue disease as "a core of minor symptoms (ie, 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 mixed connective tissue disease is as an undifferentiated connective tissue disease represented mostly by Raynaud phenomenon and anti-RNP antibody.

Raynaud phenomenon showing demarcation of color difference.

Pathophysiology

Mixed connective tissue disease has features of several autoimmune diseases. 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.

Frequency

United States

In a literature review, Michels counted 224 cases of mixed connective tissue disease.⁵ Pediatric-onset mixed connective tissue disease 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 mixed connective tissue disease occurs in 0.6% of all pediatric rheumatology patients.

International

US data are derived from international data.

Mortality/Morbidity

Literature describes pediatric mixed connective tissue disease 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 mixed connective tissue disease has not been reported. Literature suggests that no specific protection or propensity based on race is noted.

Sex

A female predominance, which is typical of other autoimmune diseases, is noted in mixed connective tissue disease. Three published series on pediatric mixed connective tissue disease 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. A recent 15-year retrospective study concluded the mean age at disease onset was 10.7 years.⁶

Clinical

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

The following lists, published by several authors, are the criteria for making a diagnosis of mixed connective tissue disease:^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 include 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 include 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.

Causes

Specific causes of mixed connective tissue disease remain undefined.⁷

• Research suggests that many factors, including genetics, hormones, and environment, contribute to development of autoimmune syndromes.
• As mentioned in the Introduction, the hallmark of mixed connective tissue disease 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 mixed connective tissue disease (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.

Differential Diagnoses

Other Problems to Be Considered

Dermatomyositis and Polymyositis
Pulmonary Fibrosis, Idiopathic
Scleroderma
Synovitis

Workup

Laboratory Studies

• The initial laboratory evaluation of mixed connective tissue disease (MCTD) 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 liver function test (LFT) results.
    • Patients with nephritis may have elevated creatinine and abnormal electrolyte levels.
    • Patients with nephrosis may have low albumin and high cholesterol levels.
  • Urine analysis
    • Patients with mixed connective tissue disease and nephritis may have protein, RBCs, WBCs, or casts on evaluation of urine.
    • Patients with nephrotic syndrome have high urinary protein levels.
  • Muscle enzymes: Myositis may be found by measurement of creatine kinase, aldolase, aspartate aminotransferase, alanine aminotransferase, and lactic dehydrogenase levels.
  • 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 result is usually positive in high titers.
  • Anti–double-stranded DNA: This test result is usually negative but is occasionally positive in individuals with mixed connective tissue disease.
  • Autoantibody panel, including antibodies against ribonucleoprotein (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 laboratory test findings 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 mixed connective tissue disease 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 mixed connective tissue disease had Hashimoto thyroiditis, and 2.5% had Graves disease, with prevalence rates 556- and 76-fold higher than the general population, respectively.

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.
• Nailfold capillaroscopy can be helpful because it is associated with mixed connective tissue disease, particularly in patients who have more scleroderma features.⁸
• Echocardiography should be considered because patients may have unexpected pulmonary artery hypertension, which should be monitored and treated.

Procedures

• Perform tissue biopsy as indicated to evaluate disease severity.
• In particular, kidney biopsy should be considered when hypocomplementemia is present, even if initial urine evaluations are negative, because some studies suggest that patients with mixed connective tissue disease can have nonclinical nephritis.

Histologic Findings

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

Staging

• Mixed connective tissue disease is not staged.

Treatment

Medical Care

• The most important tools in treatment of mixed connective tissue disease (MCTD) include tailoring the medical regimen, promptly attending to disease flare, and performing careful and frequent clinical and laboratory evaluations to test for new disease manifestations.
• Some patients have physical findings and laboratory studies that more closely resemble lupus (particularly double-stranded DNA and hypocomplementemia), and treatment should be tailored to treat a lupuslike disease.
• Strongly consider annual echocardiography, pulmonary function testing, 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.
• 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 mixed connective tissue disease to maintain a healthy lifestyle.
• Limitations should occur only secondary to serious organ involvement that prevents performance of activities.
• Advise patients with mixed connective tissue disease to avoid fatigue.
• Advise patients with mixed connective tissue disease to avoid significant cold exposures or to dress accordingly to decrease Raynaud symptoms.

Medication

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 mixed connective tissue disease 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 mixed connective tissue disease 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 mixed connective tissue disease 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 systemic lupus erythematosus (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 mixed connective tissue disease. Because of the rarity of this disease, advise the patient to consult a physician with experience in the treatment of mixed connective tissue disease. Patients with hypertension should be aggressively treated. 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.

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 nonsteroidal anti-inflammatory drugs (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.

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.

Dosing

Adult

500-1000 mg/d PO divided bid

Pediatric

7-20 mg/kg/d PO divided bid/tid; not to exceed adult dose

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

Contraindications

Documented hypersensitivity; gastritis; hepatic or renal insufficiency; coagulopathy; other conditions in which changes in platelet function could be harmful

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

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

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.

Dosing

Adult

1200-1800 mg/d PO divided tid

Pediatric

<2 years: Not established
>2 years: 15-30 mg/kg/d PO divided tid/qid; not to exceed adult dose

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

Contraindications

Documented hypersensitivity; gastritis; hepatic or renal insufficiency; coagulopathy; other conditions in which changes in platelet function could be harmful

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studies in humans; may use if benefits outweigh risk to fetus

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

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).

Dosing

Adult

100-200 mg/d PO divided bid

Pediatric

<12 years: Not established
>12 years: 2-3 mg/kg/d PO divided bid; not to exceed adult dose

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

Contraindications

Documented hypersensitivity; gastritis; hepatic or renal insufficiency; coagulopathy; other conditions in which changes in platelet function could be harmful

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

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

Antimalarials

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

Hydroxychloroquine (Plaquenil)

Antimalarial drugs inhibit synthesis of DNA, RNA, and proteins by interacting with nucleic acids. Antimalarial drugs have various 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.

Dosing

Adult

200-400 mg/d PO (3-7 mg/kg/d)

Pediatric

3-7 mg/kg/d PO; not to exceed 400 mg/d

Interactions

Few reported; chloroquine may potentiate possible ocular toxicity; serum levels increase with cimetidine; magnesium trisilicate may decrease absorption

Contraindications

Documented hypersensitivity; G-6-PD deficiency; retinal or visual field changes; porphyria; psoriasis

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

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

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 mixed connective tissue disease and pulmonary artery hypertension.

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.

Dosing

Adult

1-2 mg/kg/d PO

Pediatric

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/d as methylprednisolone for severe disease; may be administered as 3-d pulse regimen or as part of steroid regimen under guidance of rheumatologist

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

Contraindications

Documented hypersensitivity; serious infection except septic shock or tuberculous meningitis but including systemic fungal infection and varicella

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

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

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.

Cyclophosphamide (Cytoxan, Neosar)

Interferes with normal function of DNA by alkylation and cross-linking strands of DNA and by possible protein modification.

Dosing

Adult

500-1000 mg/m² IV every mo; not to exceed 1000 mg/m²

Pediatric

Administer as in adults

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

Contraindications

Documented hypersensitivity; severely depressed bone marrow function

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis

Azathioprine (Imuran)

Antagonizes purine metabolism and may inhibit synthesis of proteins, RNA, and DNA. May interfere with mitosis and cellular metabolism.

Dosing

Adult

1-2.5 mg/kg/d PO

Pediatric

1-3 mg/kg/d PO

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

Contraindications

Documented hypersensitivity; low levels of serum TPMT

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

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

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.

Dosing

Adult

5-30 mg PO/IV/SC qwk

Pediatric

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)

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

Contraindications

Documented hypersensitivity; alcoholism; hepatic insufficiency; documented immunodeficiency syndromes; preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia); renal insufficiency

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

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)

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.

Calcium carbonate (Oystercal, Caltrate)

Used as antacid and for prevention of calcium depletion.

Dosing

Adult

1200 mg/d PO

Pediatric

<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

Interactions

May decrease effects of tetracyclines, atenolol, salicylates, iron salts, and fluoroquinolones; large intakes of dietary fiber may decrease calcium absorption and levels

Contraindications

Renal calculi; hypercalcemia; hypophosphatemia; renal or cardiac disease; digitalis toxicity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studies in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in renal disease; cardiac disease; and sarcoidosis

Calcifediol (Calderol)

Vitamin D regulates calcium homeostasis, promoting absorption of calcium by gut, resorption of calcium by kidney, and increasing bone mineral metabolism.

Dosing

Adult

20-100 mcg/d PO; titrate to obtain normal serum calcium and phosphorus levels

Pediatric

Suggested doses:
<30 kg: 20 mcg PO 3 times per wk
>30 kg: 50 mcg PO 3 times per wk

Interactions

Effects enhanced by thiazide diuretics and reduced by cholestyramine and colestipol; may precipitate arrhythmia in conjunction with digitalis

Contraindications

Documented hypersensitivity; hypercalcemia

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

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

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 mixed connective tissue disease, used to decrease symptoms and damage from Raynaud phenomenon.

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.

Dosing

Adult

400 mg PO tid with meals

Pediatric

Not established

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

Contraindications

Documented hypersensitivity; recent cerebrovascular or retinal hemorrhage; serious adverse reaction to caffeine, theophylline, theobromine, or other methylxanthines

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studies in humans; may use if benefits outweigh risk to fetus

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

Phosphodiesterase (type 5) Enzyme Inhibitor

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

Sildenafil (Revatio)

Inhibits phosphodiesterase type 5 in smooth muscle of pulmonary vasculature in which phosphodiesterase type 5 is responsible for the degradation of cGMP. Increased cGMP concentration results in pulmonary vasculature relaxation; vasodilation in the pulmonary bed and the systemic circulation (to a lesser degree) may occur. The systemic vasodilation may be helpful to reduce Raynaud disease symptoms.

Dosing

Adult

20 mg PO qd initially; may increase, not to exceed 20 mg tid

Pediatric

Data limited; safety and efficacy has not been established
20 mg PO qd initially; may increase, not to exceed 20 mg bid
Not appropriate for small children

Interactions

Potentiates vasodilatory effect of NO, resulting in potentially fatal drop in blood pressure; coadministration with ketoconazole, erythromycin, or cimetidine increases plasma sildenafil concentrations; coadministration with rifampin decreases plasma levels of sildenafil; coadministration with bosentan increases bosentan levels by 50% and reduces sildenafil levels by 63%

Contraindications

Documented hypersensitivity; concurrent or intermittent using of organic nitrates in any form

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Adverse effects include headaches (16%), flushing (10%), upset stomach (7%), nasal congestion (4%), and a blue haze at the periphery of vision (3%); adverse effects occur more often in men taking the 100-mg dose; serious adverse effects occur in patients with severe heart disease and those who are taking nitrates; rates of MI were 1.7 and 1.4 per 100 man-years for sildenafil and placebo groups; sudden vision loss caused by nonarteritic anterior ischemic optic neuropathy (NAION) has been associated with phosphodiesterase type 5 inhibitors following use for ED, analysis is ongoing to determine causality

Follow-up

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.

Inpatient & Outpatient Medications

• See Medical Care.

Transfer

• Because patients with mixed connective tissue disease 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 mixed connective tissue disease depend on the organ systems involved and the adverse effects and risks of immunosuppressive therapy.
• Patients with mixed connective tissue disease 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 mixed connective tissue disease 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 mixed connective tissue disease have had renal disease and considerable morbidity and mortality from major organ manifestations. It appears that, in mixed connective tissue disease, 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 mixed connective tissue disease 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

Medicolegal 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 mixed connective tissue disease benefit most from evaluation and treatment by a pediatric rheumatologist.

Multimedia

Media file 1: Raynaud phenomenon showing demarcation of color difference.

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. Tsai YY, Yang YH, Yu HH, Wang LC, Lee JH, Chiang BL. Fifteen-year experience of pediatric-onset mixed connective tissue disease. Clin Rheumatol. Sep 16 2009;[Medline].

7. Sharp G. The origin of mixed connective tissue disease: a stimulus for autoimmune disease research. Lupus. 2009;18(12):1031-2. [Medline].

8. Ingegnoli F, Zeni S, Gerloni V, Fantini F. Capillaroscopic observations in childhood rheumatic diseases and healthy controls. Clin Exp Rheumatol. Nov-Dec 2005;23(6):905-11. [Medline].

9. Biro E, Szekanecz Z, Czirjak L, et al. Association of systemic and thyroid autoimmune diseases. Clin Rheumatol. Mar 2006;25(2):240-5. [Medline].

10. 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].

11. Ito S, Nakamura T, Kurosawa R, Miyamae T, Imagawa T, Mori M. Glomerulonephritis in children with mixed connective tissue disease. Clin Nephrol. Sep 2006;66(3):160-5. [Medline].

12. 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].

13. 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].

14. 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].

15. 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].

16. 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].

Keywords

mixed connective tissue disease, MCTD, autoimmune disorder, Raynaud phenomenon, puffy fingers, mild myositis, arthritis, anti-U1-68kD antibody, undifferentiated connective tissue disease, UCTD, lupus, rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus, myositis, alopecia, leukopenia, anemia, pleuritis, pericarditis, trigeminal neuralgia, malar rash, thrombocytopenia, gastroesophageal reflux, GERD, treatment, diagnosis

Contributor Information and Disclosures

Author

Marisa S Klein-Gitelman, MD, MPH, Associate Professor of Pediatrics, Northwestern University Feinberg School of Medicine; Head, Division of Rheumatology, Children's Memorial Hospital
Marisa S Klein-Gitelman, MD, MPH is a member of the following medical societies: American College of Rheumatology
Disclosure: Nothing to disclose.

Medical Editor

Barry L Myones, MD, Associate Professor, Departments of Pediatrics and Immunology, Pediatric Rheumatology Section, Baylor College of Medicine; Director of Research, Pediatric Rheumatology Center, Texas Children's Hospital
Barry L Myones, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American College of Rheumatology, American Heart Association, American Society for Microbiology, Clinical Immunology Society, and Texas Medical Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Thomas JA Lehman, MD, FAAP, FACR, Clinical Professor of Pediatrics, Department of Pediatrics, Division of Pediatric Rheumatology, Weill-Cornell University; Chief, Hospital for Special Surgery
Thomas JA Lehman, MD, FAAP, FACR is a member of the following medical societies: PM American Allergy Society
Disclosure: Nothing to disclose.

CME Editor

Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine
Daniel Rauch, MD, FAAP is a member of the following medical societies: Ambulatory Pediatric Association, American Academy of Pediatrics, and Society of Hospital Medicine
Disclosure: Baxter Honoraria Consulting

Chief Editor

Lawrence K Jung, MD, Chief, Division of Pediatric Rheumatology, Children's National Medical Center
Lawrence K Jung, MD is a member of the following medical societies: American Association for the Advancement of Science, American Association of Immunologists, American College of Rheumatology, Clinical Immunology Society, and New York Academy of Sciences
Disclosure: Nothing to disclose.

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