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Mixed Connective Tissue Disease
Background: In 1972, 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, very high titers of antiribonucleoprotein (68-kD) autoantibody (anti-RNP Ab) but without anti-Smith autoantibody (anti-Sm Ab), in association with specific clinical criteria. In 1987, Alarcon-Segovia and Villareal and Kasukawa et al subsequently suggested 2 alternate sets of criteria. 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 some 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 very 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 that may evolve in 1 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 for early intervention with appropriate medical therapy.

Pathophysiology: MCTD has symptoms of several autoimmune diseases. The following lists are the criteria for diagnosing MCTD as published by several authors.

Sharp (1972) 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 observed or sclerodactyly, and highest observed anti-U1 RNP (>1:10,000) with negative anti-Sm Ab.
    • Minor criteria are alopecia, leukopenia (4000 WBC/cc), anemia (<10 g/dL for females, <12 g/dL for males), pleuritis, pericarditis, arthritis, trigeminal neuralgia, malar rash, thrombocytopenia (<100,000/cc), mild myositis, and history of swollen hands.

Alarcon-Segovia/Villareal classification

  • Serologic criterion is a positive anti-RNP at a titer of 1:1600 or higher.
  • Clinical criteria are (at least 3) 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:
    • Systemic lupus erythematosuslike conditions (polyarthritis, lymphadenopathy, facial erythema, pericarditis or pleuritis, leukopenia [<4000/cc], or thrombocytopenia [<100,000/cc])
    • 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 1997 literature review, Michels counted 224 cases of MCTD. Most large pediatric rheumatology centers in major cities have 5-15 active pediatric cases.

Mortality/Morbidity: The 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%. Serious organ involvement included 47% of patients with renal disease, 54% with restrictive lung disease, and 29% with GI disease. Although rare, morbidity due to cerebral disease, cardiomyopathy, myopericarditis, and pulmonary hypertension has been reported.

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

Sex: A female predominance, which is typical of other autoimmune diseases, exists. No specific estimate of the male-to-female ratio exists.

Age: Age range has been reported to be 5-18 years. No specific age of onset is excluded. The median age at onset is 12 years.

History:

  • The most frequent presentation of MCTD is a child with polyarthritis, general malaise, and Raynaud phenomenon.
  • The patient may present with the following:
    • Sclerodermatous skin
    • Sausage-shaped fingers
    • Proximal muscle weakness
    • Rash
    • Vasculitic rashes (usually palpable purpuric rashes)
    • Dysphagia
    • Fever
    • Rheumatoid nodules
    • Lymphadenopathy
    • Alopecia
    • Telangiectasia

Physical: A 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 the development of the syndrome.

Other Problems to be Considered:

Dermatomyositis and Polymyositis
Pulmonary Fibrosis, Idiopathic
Scleroderma
Synovitis

Lab Studies:

  • Initial laboratory evaluation should include the following:
    • Complete blood count with platelets and reticulocyte count: Leukopenia, thrombocytopenia, or hemolytic anemia is a common finding. 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: Measurement of acute phase reactants can include erythrocyte sedimentation rate or C-reactive protein.
  • Diagnostic laboratory studies include the following:
    • Antinuclear antibody: This test is usually positive in very 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 either 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 very 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 very sensitive to detecting anti-RNP antibodies.

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.)
  • High-resolution CT scan of the lung may be necessary to determine if pulmonary fibrosis exists based on chest radiograph, pulmonary function tests, and clinical symptoms.
  • Other imaging studies should be guided by clinical manifestations and may include the following:
    • MRI of the brain
    • Renal ultrasonography and/or nuclear medicine evaluation of renal function
    • Plain films to evaluate arthritis

Other Tests:

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

Procedures:

  • Perform tissue biopsy as indicated to evaluate disease severity.

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

Staging: MCTD is not staged.

Medical Care:

  • The most important tools in the care of the patient are careful and frequent clinical and laboratory evaluations to test for new disease manifestations, tailor the medical regimen, and provide prompt attention to disease flare.
  • 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.

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. The 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 with 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, the patient 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 dependent on whether the patient has another disease manifesting with MCTD. Because of the rarity of this disease, advise the patient to consult with a physician with experience in the treatment of MCTD.
 

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. Used for their analgesic and anti-inflammatory properties treating arthralgia and arthritis. 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 as Naprelan.
Adult Dose 500-1000 mg/d PO divided bid
Pediatric Dose 7-20 mg/kg/d PO divided bid/tid
Larger children: Not to exceed adult dose guidelines
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
Larger children: Not to exceed adult dose guidelines
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 a hypersensitivity reaction, most often characterized as a 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, and CNS changes as well as other listed adverse effects for each specific agent
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 recommended
>12 years: 2-3 mg/kg/d PO divided bid
Larger children: Not to exceed adult dose guidelines
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.

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, and 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 an addisonian crisis; carefully consider use of steroids in setting of active infection and discuss with physicians who have experience with this difficult clinical situation; consider alternate types of immunosuppression in patients who develop diabetes while on corticosteroids and taper steroids carefully; in interim, use of insulin may be required

Drug Category: Immunosuppressive agents -- Evaluate children with signs of active nephritis to determine 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, cyclosporin) when standard therapies have failed. Other treatments under study include hormonal therapy, biologic agents that target cytokine production, and anti-DNA antibodies. For the patient 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
  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 weekly
Pediatric Dose 5-20 mg/m2 PO/IV/SC weekly; 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 D - Unsafe in pregnancy
Precautions Monitor CBCs monthly and liver and renal function q1-3mo 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: Antihypertensive agents -- Treat hypertension aggressively. If hypertension is a consequence of steroid therapy, consider immunomodulating medications as steroid-sparing agents to help control hypertension. Calcium channel blockers also are used in treatment of Raynaud phenomenon.

Drug Name
 		 Nifedipine (Adalat, Procardia) -- Relaxes coronary smooth muscle and produces coronary vasodilation, which improves myocardial oxygen delivery. Useful to treat hypertension and Raynaud phenomenon.
Adult Dose 10 mg PO tid or 30-60 mg/d PO (SR form) initially; not to exceed 180 mg/d
Pediatric Dose Infants and children: 0.25-0.5 mg/kg/dose PO initially; not to exceed 10 mg repeated q4-8h
Adolescents: Administer as in adults
Contraindications Documented hypersensitivity
Interactions Caution with coadministration of any agent that can lower BP (eg, beta-blockers, opioids); H2 blockers (cimetidine) may increase toxicity
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Do not use SL dosing; caution in patients with CHF, aortic stenosis, severe left ventricular dysfunction, hepatic or renal impairment, hypertrophic cardiomyopathy, concomitant therapy with beta-blockers or digoxin, or edema; may worsen symptoms in patients with angina
Drug Name
 		 Enalapril (Vasotec) -- A competitive inhibitor of ACE, preventing production of angiotensin II, a potent vasoconstrictor, which results in increase in plasma renin activity and reduction in aldosterone secretion by adrenal gland. Useful in treatment of hypertension and to decrease risk of hypertensive crisis in patients with scleroderma manifestations. Also alters GFR, reducing urinary protein losses in nephrotic patients.
Adult Dose 2.5-5 mg/d PO increased prn to 10-40 mg/d in 1-2 divided doses
Pediatric Dose Infants and children: 0.1 mg/kg/d PO in 1-2 divided doses; increase, not to exceed 0.5 mg/kg/d prn
Adolescents: Administer as in adults
Contraindications Documented hypersensitivity
Interactions NSAIDs may reduce hypotensive effects; ACE inhibitors may increase digoxin, lithium, and allopurinol levels; rifampin decreases enalapril levels; probenecid may increase enalapril levels; hypotensive effects of ACE inhibitors may be enhanced when administered concurrently with diuretics
Pregnancy D - Unsafe in pregnancy
Precautions Safety for use during first trimester of pregnancy has not been established; unsafe for ensuing pregnancy; caution in patients with renal impairment, RAS, CHF, valvular stenosis, or hyperkalemia; experience in children is limited
Drug Name
 		 Propranolol (Inderal, Betachron E-R) -- Nonselective beta-adrenergic blocker that competitively blocks response to beta1 and beta2 adrenergic stimulation, which results in decreases in heart rate, myocardial contractility, myocardial oxygen consumption, and BP.
Adult Dose 40 mg/d PO bid or 60-80 mg/d PO as SR capsule; increase dose q3-7d to usual dose of 320 mg or less divided bid/tid doses or qd as SR capsule; not to exceed 640 mg/d
Pediatric Dose 0.5-1 mg/kg/d PO in divided doses q6-12h; increase gradually q3-7d with usual dose of 1-5 mg/kg/d
Contraindications Documented hypersensitivity; uncompensated CHF; bradycardia, cardiogenic shock; A-V conduction abnormalities
Interactions Coadministration with aluminum salts, barbiturates, NSAIDs, penicillins, calcium salts, cholestyramine, and rifampin may decrease propranolol effects; calcium channel blockers, cimetidine, loop diuretics, and MAOIs may increase toxicity of propranolol; toxicity of hydralazine, haloperidol, benzodiazepines, and phenothiazines may increase with propranolol
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions May reduce symptoms of hypoglycemia; use with caution in patients with diabetes; do not use after IV verapamil since it may potentiate effect; abrupt discontinuation may lead to exacerbation of angina or MI in patients with history of angina

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: 1200 mg/d PO
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 Administer as in adults
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 and/or toxic potential; 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

Further Inpatient Care:

  • Admit patients with MCTD to the hospital for diagnostic evaluation or for chemotherapy as warranted. Most often this is an outpatient workup.

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.

Transfer:

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

Deterrence/Pevention:

  • No known intervention exists to deter disease onset or to alter progression other than the medical management of disease manifestations as described.

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.

Prognosis:

  • Prognosis generally is 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.
  • 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:

  • The patient and family must have a thorough understanding of the disease, potential severity, and complications due to the disease and the therapy. Treatment of the individual with MCTD is difficult, especially for adolescent patients. The physician and parents and/or caregivers should expect issues including depression and noncompliance to occur and must be prepared to work together with the patient toward a better outcome.

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