Pediatric Mixed Connective Tissue Disease

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

In pediatrics, Kasukawa criteria are used most frequently in published series and have more conservative requirements. 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.[5, 6]

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.

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.

Mixed connective tissue disease has features of several autoimmune diseases.[7]  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.

Specific causes of mixed connective tissue disease remain undefined.[8]  Research suggests that many factors, including genetics, hormones, and environment, contribute to development of autoimmune syndromes.

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.

United States data

In a literature review, Michels counted 224 cases of mixed connective tissue disease.[9] 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.

US data are derived from international data.

Race-, sex-, and age-related demographics

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.

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 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.[10]

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).

Morbidity/mortality

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%.[9]  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.

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.

Witczak et al studied cardiac function in 50 patients with pediatric mixed connective tissue disease of 15 years’ duration. Both left and right ventricular dysfunction were detected. Left ventricular dysfunction was significantly associated with higher disease activity and longer prednisolone therapy.[11]

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.

Knight et al aimed to characterize the prevalence of depression and anxiety in pediatric systemic lupus erythematosus and mixed connective tissue disease patients and determine their association with healthcare utilization. Depression and anxiety symptoms were prevalent in patients with SLE/MCTD, and suicidal ideation significantly more common in SLE/MCTD than in healthy subjects. Despite prevalent symptoms, there were poor rates of prior mental health treatment, and less frequent PCP visits among those with depression symptoms. The authors concluded that further investigation of barriers to mental health care and interventional strategies for symptomatic youth with SLE/MCTD is needed.[12]

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

Detailed physical examination is critical.[13]  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

Diagnostic criteria

The following lists, published by several authors, are the criteria for making a diagnosis of mixed connective tissue disease.[1, 2, 3, 14]

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.

Japanese consensus panel criteria

A consensus panel in Japan in 2019 offered a revised set of diagnostic criteria for MCTD, which divides the features of the disease into the following four categories:

1. Common manifestations: Raynaud phenomenon, Puffy fingers and/or swollen hands
2. Immunologic manifestation: Anti–U1-RNP antibody positivity
3. Characteristic organ involvement: Pulmonary arterial hypertension, aseptic meningitis, trigeminal neuropathy
4. Overlapping manifestations: (A) SLE-like, (B) systemic sclerosis–like, (C) polymyositis/dermatomyositis-like 

SLE-like manifestations include the following:

• Polyarthritis
• Lymphadenopathy
• Malar rash
• Pericarditis or pleuritis
• Leukopenia (4,000/μL or less) or thrombocytopenia (100,000/μL or less)

Systemic sclerosis–like manifestations include the following:

• Sclerodactyly
• Interstitial lung disease
• Esophageal dysmotility or dilatation

Polymyositis/dermatomyositis-like manifestations include the following:

• Muscle weakness
• Elevated levels of myogenic enzymes
• Myogenic abnormalities on electromyogram

For diagnosis of MCTD, the patient must have the following:

• At least one common manifestation
• Anti–U1-RNP antibodies
• At least one characteristic organ involvement,  or at least one feature of at least two of the three disorders in the overlapping manifestations category (A, B, and C) 

Other conditions to consider in the differential diagnosis of MCTD include the following:

• Pleuritis
• Respiratory distress syndrome
• Stroke

The initial laboratory evaluation of mixed connective tissue disease (MCTD) should include the following:

• Complete blood cell (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, red blood cells (RBCs), white blood cells (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.[15]

• 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.

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.[16] 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.

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.[17, 18, 19]

Echocardiography should be considered because patients may have unexpected pulmonary artery hypertension, which should be monitored and treated.

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.

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.

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.

Class Summary

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.

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.

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).

Class Summary

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.

Class Summary

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.

Class Summary

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.

Azathioprine (Imuran)

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

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.

Class Summary

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.

Calcifediol (Calderol)

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

Class Summary

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.

Class Summary

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.

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.

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.

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.