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Dermatology > CONNECTIVE TISSUE DISEASES
Mixed Connective Tissue Disease
Article Last Updated: Feb 28, 2007
AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Anna Wozniacka, MD, PhD, Adjunct Lecturer, Department of Dermatology, Medical University of Lodz, Poland
Anna Wozniacka is a member of the following medical societies: European Academy of Dermatology and Venereology
Coauthor(s):
Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Medicine, Professor of Pediatrics, Professor of Pathology, Professor of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School;
Anna Sysa-Jedrzejowska, MD, PhD, Head, Professor, Department of Dermatology and Venereology, Medical University of Lodz, Poland
Editors: Russell Hall, MD, Chief, Professor, Department of Internal Medicine, Division of Dermatology, Duke University; Michael J Wells, MD, Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center; Van Perry, MD, Assistant Professor, Department of Medicine, Division of Dermatology, University of Texas Health Science Center; Glen H Crawford, MD, Assistant Clinical Professor, Department of Dermatology, University of Pennsylvania School of Medicine; Chief, Division of Dermatology, The Pennsylvania Hospital; William D James, MD, Paul R Gross Professor of Dermatology, University of Pennsylvania School of Medicine; Vice-Chair, Program Director, Department of Dermatology, University of Pennsylvania Health System
Author and Editor Disclosure
Synonyms and related keywords:
MCTD, CTD, Sharp syndrome, Sharp's syndrome, systemic lupus erythematosus, SLE, systemic sclerosis, SSc, dermatomyositis, DM, polymyositis, PM, Sjögren syndrome, U1-ribonucleoprotein antibodies, U1-RNP
Background
Mixed connective-tissue disease (MCTD) is a disorder in which features of various connective-tissue diseases (CTDs) such as systemic lupus erythematosus (SLE); systemic sclerosis (SSc); dermatomyositis (DM); polymyositis (PM); and, occasionally, Sjögren syndrome can coexist and overlap. The course of the disease is chronic and usually milder than other CTDs. In most cases, MCTD is considered an intermediate stage of a disease that eventually becomes either SLE or SSc. U1-ribonucleoprotein (RNP) antibodies are a specific marker of the disease.
Pathophysiology
A defining feature of MCTD is the presence of antibodies against the U1-RNP complex, but other autoantibodies have also been described in MCTD. Some hypotheses implicate modified self-antigens and/or infectious agents in the pathogenesis of MCTD.
The pathogenesis of MCTD is not completely known. As with other CTDs, MCTD is considered an autoimmune disease to which individuals who express specific HLA antigens such as human leukocyte antigens (HLA) HLA-DR4 or HLA-DQB1 are genetically predisposed. The frequency of HLA-DR4 in patients with MCTD is estimated to be 52%. Its strong HLA association with MCTD was further shown in the significantly increased frequency of the combination of HLA-B15 with HLA-DR4. Thus, the genetic background in patients with MCTD seems to be different from that in patients with SLE or systemic sclerosis. This observation could partly explain the clinical differences between these diseases. The specific nature of the HLA associations that occur in patients with MCTD may vary depending on the ethnicity of the population studied.
Frequency
International
MCTD is uncommon worldwide.
Mortality/Morbidity
- The prognosis for patients with MCTD is generally better than that of patients with SLE, SSc, and DM.
- About 4% of patients die, usually as a result of pulmonary hypertension, nephritis, myocarditis, or widespread vasculitis.
- In one case series, solid tumors developed in approximately 10% of patients.
Sex
- Women are affected more often than men.
- The female-to-male ratio is 4:1.
Age
- The disease usually occurs in individuals aged 30-50 years.
- MCTD also affects children, in whom the course is more severe because cardiac and renal involvement are more common.
- MCTD-related thrombocytopenia, which is unusual in adults, may be marked in children.
History
Usually, patients with MCTD present with Raynaud phenomenon, which frequently represents the initial manifestation of the disease. The decreasing frequency of attacks limits progressive vascular damage. The course of the entity is often mild, but the clinical appearance and the patient's complaints depend on the symptoms related to the specific forms of the CTD most expressed in the individual patient.
During the course of the disease in some patients, the typical signs and symptoms of SLE develop and fulfill at least 4 of the American Rheumatism Association (ARA) criteria. In other patients, MCTD becomes SSc that spreads to the face, scalp, and trunk, and the fingers become immobile, hard, and shiny.
- Usually, patients with MCTD present with Raynaud phenomenon.
- Headaches may occur.
- Patients may report fatigue.
Physical
Findings at physical examination may include the following:
- Skin
- Raynaud phenomenon, sausage-shaped fingers, and swelling of the dorsa of the hands that never becomes sclerodactyly are the most typical features (see Image 2).
- More than one half of patients have abnormal capillaries in the nail fold.
- Small-vessel vasculitis with palpable purpura is present in about 25% of patients. Occasionally, vascular disturbances may be severe and lead to peripheral gangrene and leg ulcers.
- Other skin manifestations are not universally expressed. Erythematous plaques similar to those seen in patients with chronic cutaneous (discoid) lupus erythematosus (DLE) can be seen. Alopecia, facial erythema, periungual telangiectasia, and pigmentary disturbances can also occur. Painful dermal nodules may appear on the hands or elbows.
- Joints
- About 60% of patients complain of arthralgia.
- Arthritis without any visible joint deformation can occur.
- Any joint may be involved.
- Patients usually complain of morning stiffness.
- Muscles: Myalgia, myositis, and muscle weakness are common features.
- Gastrointestinal tract
- Dysphagia and dysfunction of esophageal motility resemble that occurring in SSc.
- Other abnormalities of the gut include esophagitis, constipation, diarrhea, and malabsorption.
- Lungs
- Pleuropulmonary manifestations are common. The incidence varies from 20-85%.
- Pleuropulmonary complications include pleural effusion, interstitial pulmonary fibrosis, pulmonary arterial hypertension, pulmonary vasculitis, pulmonary thromboembolic phenomena, aspiration pneumonia, serositis, and hypoventilatory failure.
- Kidneys
- The incidence of renal involvement is only about 5%.
- Nephritis is associated with a poor prognosis. In addition to myocarditis, pulmonary hypertension, and widespread vasculitis, nephritis is considered a common cause of death.
- Nervous system
- Nervous system involvement is rare.
- Aseptic meningitis, trigeminal neuropathy, and psychosis are the prominent neurologic features.
- Sporadic cases with autonomic neuropathy are described.
- Heart: Cardiac involvement is often clinically insignificant, but the rate varies from 11-85% depending on patient selection and methods used to detect cardiac manifestations. Pericarditis, pulmonary hypertension, mitral valve prolapse, myocarditis, conduction disturbances, and abnormal left ventricular diastolic filling pattern are the most frequently observed problems.
- Lymph nodes: Lymph node enlargement is seldom a feature, but it may be present.
Causes
The cause is not completely known.
- HLA-DR4 is more common in patients with MCTD than in patients with other CTDs (see Pathophysiology).
- A genetic predisposition is confirmed by reports of familial occurrence.
Dermatomyositis
Systemic Sclerosis
Lab Studies
- Abnormal laboratory results are dependent on the spectrum of CTD symptoms, which can be similar to those recognized in SLE, SSc, DM, and PM.
- The complete blood cell count may reveal the following:
- Anemia
- Thrombocytopenia (unusual in adults but may be marked in children)
- Decreased white blood cell count
- Urine analysis may be helpful in detecting the following:
- An assessment of kidney function may show the following results:
- Elevated creatinine level
- Elevated urea level
- Muscle enzyme tests may demonstrate the following:
- Elevated aldolase level
- Elevated creatine kinase (CK) level: CK is an enzyme in muscle cells that may be released into blood stream upon damage of myocytes. CK consists of 3 isoenzymes designated MM, MB, and BB. Adult skeletal muscle contains mainly CK-MM, cardiac muscle CK-MB, and smooth muscle CK-BB.
- Tests for myocarditis may reveal elevated cardiac isoform troponin-I (cTnI) levels, which has the highest specificity for cardiac muscle and is the most reliable serum marker for detection of myocardial damage in patients with inflammatory muscle disease.
- The erythrocyte sedimentation rate may be increased.
- Hypergammaglobulinemia may be present.
Imaging Studies
- Radiologic, manometric, videoendoscopic, and scintigraphic examination may reveal abnormal esophageal motility.
- Technetium Tc 99m-pyrophosphate scintigraphy permits detection of left ventricular global and regional wall abnormalities.
- Gadolinium diethylenetriaminepentaacetic–enhanced MRI is used to distinguish active myocardial inflammation from myocardial damage in humans with myocarditis with viral infections, sarcoidosis, or ischemic myocardial damage.
- Chest x-ray films may show pleural thickening, fibrosis, and pericarditis.
- Echocardiography can reveal pericarditis.
- Angiography shows obstruction of the small blood vessels in some cases.
Other Tests
- Electromyography findings can reveal muscle destruction.
- ECG is the basic method to detect arrhythmias, conduction defects, and ST-T changes.
- Immunologic findings may be helpful in diagnosing MCTD.
- Indirect immunofluorescence: The presence of a high titer of immunoglobulin G antibodies against U1-RNP as the only autoantibodies strongly supports a diagnosis of MCTD. These antibodies are directed against small ribonucleoproteins, which are referred to as extractable nuclear antigens. The fluorescent antinuclear antibody test typically reveals a speckled pattern of staining on HEp-2 substrate. More sophisticated analysis identifies the target protein as the 68- to 70-kd U1-RNP complex. Recent studies revealed that antibodies directed to an apoptotic-specific epitope on 70K are more specifically associated with MCTD than other anti-70K antibodies. Other antibodies such as dsDNA, anti-Ro/SS-A, and anti-La/SS-B occur incidentally.
- Direct immunofluorescence: Performed on lesional skin of patients with MCTD, this may reveal epidermal nuclear immunoglobulin G staining. This staining is thought to be related to the high titers of U1-RNP antibodies in the patient's sera. In some cases, the lupus band test might be positive, with linear deposits of immunoglobulins, fibrin, and/or complement components present at the basement membrane. Immunoglobulin M is usually the main compound.
- Pulmonary function tests may reveal ventilator disorders of the restrictive type, such as diminished vital capacity, normal residual volume, and total lung capacity. Respiratory function tests are usually consistent with radiographic findings (see Imaging Studies).
Histologic Findings
The histologic findings are not conclusive.
Medical Care
Medical care must be individualized and based on the severity and type of organ involvement. Plasmapheresis may be a successful treatment because of the removal of immune complexes in serum and improvement of visceral circulation.
Consultations
Because of different presenting symptoms, consultation with the following specialists should be considered:
- A dermatologist should evaluate the skin lesions.
- An internal medicine specialist should evaluate organ involvement.
Activity
The patient's mobility is restricted if joint and muscle pain is significant.
MCTD is a chronic and usually mild disease, which can be treated symptomatically or with corticosteroids or immunosuppressives if the severity of disease justifies it. Combined treatment allows dose reduction of systemic steroids (corticosteroid-sparing effect). Treatment depends on internal organ involvement. Usually middle doses of systemic corticosteroids are effective in most cases. Anti-inflammatory agents are helpful for arthralgia, myalgia, and swelling of the hands. Skin lesions can be treated with topical corticosteroids. In all cases, photoprotection is recommended.
Drug Category: Corticosteroids, systemic
These agents decrease autoimmune reactions, possibly by suppressing key components of the immune system. They are often used to treat collagen vascular diseases.
| Drug Name | Prednisolone (Prelone Syrup, Pediapred Oral Solution, Delta-Cortef) |
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| Description | Synthetic adrenocortical steroid with predominantly glucocorticoid properties. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reducing capillary permeability. |
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| Adult Dose | 0.5-1 mg/kg/d PO, taper gradually as symptoms resolve |
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| Pediatric Dose | 0.14-2 mg/kg/d (4-60 mg/m2/d) PO divided tid/qid |
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| Contraindications | Documented hypersensitivity; viral, fungal, connective-tissue, or mycobacterial skin infections; peptic ulcer disease; hepatic dysfunction; GI disease |
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| Interactions | Coadministration with estrogens may decrease clearance; when used with digoxin, digitalis toxicity secondary to hypokalemia may increase; phenobarbital, phenytoin, and rifampin may increase the metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics; coadministration with ritonavir may significantly increase serum concentrations of prednisone; concomitant therapy with montelukast may result in severe peripheral edema; clarithromycin may increase risk of psychotic symptoms |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
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| Precautions | Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use |
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Drug Category: Immunosuppressants
These agents inhibit key factors that mediate immune reactions, which in turn decrease inflammatory responses.
| Drug Name | Cyclosporine (Sandimmune, Gengraf, Neoral) |
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| Description | Cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions (eg, delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft-vs-host disease) in a variety of organs. For children and adults, base dosing on ideal body weight. Onset of action is 1-2 mo; stabilization of disease may take 3-4 mo. Bioavailability not necessarily equal in different formulations; use caution. In severe disease, higher doses (transplant dosing) increases risk of adverse events and may be beyond the scope of practice for a general dermatologist. |
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| Adult Dose | Initial: 2.5 mg/kg/d PO divided bid; base dose on clinical response and tolerability; may increase dose by 0.5-0.75 mg/kg/d after 2 mo then monthly (not to exceed 4 mg/kg/d); decrease dose by 25-50% to control adverse events
Maintenance: Decrease to lowest possible dose to control disease |
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| Pediatric Dose | Administer as in adults |
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| Contraindications | Documented hypersensitivity; uncontrolled hypertension or malignancies; abnormal renal function; concomitant with PUVA or to a lesser extent UVB radiation, other immunosuppressive agents, coal tar, or radiation therapy may increase risk of skin cancer; patients potassium-sparing diuretics |
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| Interactions | Carbamazepine, phenytoin, isoniazid, rifampin, and phenobarbital may decrease concentrations; azithromycin, itraconazole, nicardipine, ketoconazole, fluconazole, erythromycin, verapamil, grapefruit juice, diltiazem, aminoglycosides, acyclovir, amphotericin B, and clarithromycin may increase toxicity; concurrent lovastatin increases risk of acute renal failure, rhabdomyolysis, myositis, and myalgias; concomitant vaccinations may be less effective |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
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| Precautions | Baseline laboratory studies should include creatinine (on 2 occasions), BUN, CBC count, magnesium, potassium, uric acid, and lipid levels; evaluate CBC count, uric acid level, potassium level, lipid level, magnesium level, and renal and liver function often; evaluate BP frequently; if sustained HTN, sustained increase in serum creatinine level by 25% or more, or an abrupt increase in creatinine level by 50% or more, reduce dose; if change in creatinine level or HTN does not reverse after 2 (creatinine) or multiple (HTN) dose modifications, discontinue drug; caution in elderly patients or those with hyperkalemia; may increase risk of infection, lymphoma, and skin cancer; reserve IV use only for those who cannot take the PO form |
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Drug Category: Nonsteroidal anti-inflammatory drugs
NSAIDs provide symptomatic relief for arthralgia, myalgia, edema, and tenderness.
| Drug Name | Naproxen (Naprosyn, Anaprox) |
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| Description | For relief of mild to moderate pain; inhibits inflammatory reactions and pain by decreasing activity of cyclo-oxygenase, which decreases prostaglandin synthesis. |
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| Adult Dose | HCl formulation: 250-500 mg PO bid
Sodium formulation: 275-550 mg PO bid
May increase to 1.5 g/d of naproxen base for limited periods |
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| Pediatric Dose | <2 years: Not established
>2 years: 2.5-5 mg/kg/dose PO; not to exceed 15 mg/kg/d |
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| Contraindications | Documented hypersensitivity including to aspirin or other NSAIDs; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency |
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| Interactions | Coadministration with aspirin increases risk of 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; may increase phenytoin levels when administered concurrently |
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| Pregnancy | B - Usually safe but benefits must outweigh the risks.
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| 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 have risk of 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 |
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Drug Category: Corticosteroids, topical
Topical corticosteroids are moderate or potent agents with anti-inflammatory and immunosuppressive properties. They can decrease epidermal proliferation.
| Drug Name | Fluticasone (Cutivate) |
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| Description | Extremely potent vasoconstrictive and anti-inflammatory activities. Weak inhibitory affect on hypothalamic-pituitary-adrenocortical axis when applied topically. Other more potent topical corticosteroids may be useful for unresponsive inflammatory skin lesions. Less potent nonfluorinated topical corticosteroids may be useful in patients with less aggressive skin disease. Medium potency. |
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| Adult Dose | Apply sparingly to affected area bid; not to exceed 50 g/wk |
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| Pediatric Dose | <3 months: Not established
>3 months: Apply as in adults; use with caution |
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| Contraindications | Documented hypersensitivity; viral, fungal, or bacterial skin infections |
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| Interactions | None reported |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
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| Precautions | Prolonged use, application over large surface areas, and use of potent steroids or occlusive dressings may increase systemic absorption and cause Cushing syndrome, reversible HPA-axis suppression, hyperglycemia, or glycosuria; fluorinated topical corticosteroids should not be applied to face, groin, or axilla or under occlusion in the typical patient because of possible cutaneous atrophy and telangiectasia |
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Deterrence/Prevention:
- Deterrence and prevention includes photoprotection.
Complications:
- Approximately 10% of patients with MCTD have an increased risk of cancer development during the course of disease.
Prognosis:
- Prognosis for patients with MCTD is better than for patients who have only one form of overlapping disease. Many patients will later progress to scleroderma or lupus; some will remain undifferentiated. In addition, myositis of MCTD may have a better prognosis than other forms of myositis.
- In one case series, solid tumors developed in approximately 10% of patients.
- Nephritis is associated with a poor prognosis. It is considered a common cause of death.
Patient Education:
- Educate patients regarding photoprotection. Patients should avoid sun exposure, which is a triggering and aggravating factor.
- Patients with Raynaud phenomenon should be instructed to avoid exposure to cold.
Medical/Legal Pitfalls
- Sclerodermiformis may appear as SSc.
| Media file 2:
Sausage-shaped fingers in a patient with Raynaud phenomenon. |
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Media type: Photo
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| Media file 3:
Direct immunofluorescence testing shows epidermal nuclear immunoglobulin G staining. |
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Media type: Image
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| Media file 4:
Indirect immunofluorescence testing shows the typical speckled pattern for ribonucleoprotein antibodies on a HEp-2 substrate. |
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Media type: Image
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Mixed Connective Tissue Disease excerpt Article Last Updated: Feb 28, 2007
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