Dermatologic Manifestations of Mixed Connective Tissue Disease 

Updated: May 11, 2019
Author: Robert A Schwartz, MD, MPH; Chief Editor: William D James, MD 

Overview

Background

Mixed connective-tissue disease (MCTD) is a disorder with features of systemic sclerosis (SSc), lupus erythematosus, and polymyositis. U1-ribonucleoprotein (RNP) antibodies are a specific marker of the disease.[1] MCTD is considered a distinct syndrome and should not be confused with other connective-tissue disease overlap syndromes with features of various connective-tissue diseases.[2] The course of MCTD is chronic and usually milder than other connective-tissue diseases. Although MCTD is a distinct clinical entity, a subgroup of patients may evolve into having another connective-tissue disease.[3, 4]

Pathophysiology

A defining feature of mixed connective-tissue disease (MCTD) is the presence of antibodies against the U1-RNP complex, but other autoantibodies have also been described in MCTD.[5] Some hypotheses implicate modified self-antigens and/or infectious agents in the pathogenesis of MCTD. MCTD differs from systemic lupus erythematosus (SLE) in a number of ways; a study of major histocompatibility complex class I polypeptide-related sequence A and human leukocyte antigen (HLA) gene polymorphisms showed the allele frequency of MICA129 Val was significantly increased in MCTD patients compared with controls and with SLE patients.[6]

The U1 small nuclear ribonucleoprotein particle (snRNP) is a target of autoreactive B cells and T cells in MCTD.[7] Understanding the interactions between U1-snRNP and the immune system may prove beneficial.

The pathogenesis of MCTD is not completely known. As with other connective-tissue diseases, MCTD is considered an autoimmune disease to which individuals who express specific HLA antigens such as 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 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. HLA-DRB1 genotypes may have a modulating influence on MCTD in Polish patients.[8]

Etiology

The cause of mixed connective-tissue disease (MCTD) is not completely known. HLA-DR4 is more common in patients with MCTD than in patients with other connective-tissue diseases (see Pathophysiology). A genetic predisposition is confirmed by reports of familial occurrence.

Epidemiology

Frequency

Mixed connective-tissue disease (MCTD) is uncommon worldwide. The incidence of adult-onset mixed connective-tissue disease (MCTD) in Norway was found to be 2.1 per million per year.[9] It has a female predominance. Its incidence and prevalence is lower than for polymyositis, dermatomyositis, systemic sclerosis, and systemic lupus erythematosus. MCTD was documented in about two persons per 100,000 population annually in Olmsted County, Minnesota.[10]

Sex

Women are affected by mixed connective-tissue disease (MCTD) more often than men. The female-to-male ratio is 4:1.

Age

Mixed connective-tissue disease (MCTD) 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.

Prognosis

Prognosis for patients with mixed connective-tissue disease (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.  The prognosis for patients with MCTD is generally better than that of patients with systemic lupus erythematosus, systemic sclerosis, and dermatomyositis.

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.

However, pulmonary involvement is linked with the worst prognosis and high mortality.[11] Pulmonary arterial hypertension is the leading cause of death in these patients in a study of the survival rate and prognostic indicators of MCTD in a Hungarian population, although cardiovascular morbidity and mortality, cancer, and thrombotic events were enhanced during the disease course of MCTD.[12] The presence of antiphospholipid antibodies correlated with an increased risk of mortality. About 4% of patients die, usually as a result of pulmonary hypertension, nephritis, myocarditis, or widespread vasculitis.

MCTD changing to other connective-tissue diseases was uncommon, with mortality found to be unaffected, in a survey in Olmsted County, Minnesota.[10]

Patient Education

Educate mixed connective-tissue disease (MCTD) 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.

 

Presentation

History

Usually, patients with mixed connective-tissue disease (MCTD) present with Raynaud phenomenon, which frequently represents the initial manifestation of the disease.[13] 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 connective-tissue disease most expressed in the individual patient.

During the course of the disease in some patients, the typical signs and symptoms of systemic lupus erythematosus develop and fulfill at least 4 of the American Rheumatism Association (ARA) criteria. In other patients, MCTD becomes systemic sclerosis that spreads to the face, scalp, and trunk, and the fingers become immobile, hard, and shiny.

See the image below.

Sclerodermalike changes on the face. Sclerodermalike changes on the face.

Usually, patients with MCTD present with Raynaud phenomenon. Headaches may occur, and patients may report fatigue. While myalgia and arthralgia are important early symptoms of pediatric-onset MCTD,[14] many adolescent girls report pain along with fatigue.[15] Pediatric MCTD may show findings of arthritis, polymyositis/dermatomyositis, systemic lupus erythematosus, and systemic sclerosis.[16] Raynaud phenomenon should hasten evaluation. Capillary findings should also be evaluated because they may correlate with the development of scleroderma spectrum disorders.

Physical Examination

Mixed connective-tissue disease (MCTD) findings at physical examination may include the following:

Skin[17]

Raynaud phenomenon, sausage-shaped fingers, and swelling of the dorsa of the hands that never becomes sclerodactyly are the most typical features (see the image below).

Sausage-shaped fingers in a patient with Raynaud p Sausage-shaped fingers in a patient with Raynaud phenomenon.

Another MCTD feature can be “mechanic hands”, evident as a thickened, hyperkeratotic, bilaterally symmetric eruptions along the fingers.[18] Nail-fold capillaroscopic findings may be relative common in those with MCTD and mechanic hands.

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 can be seen. Alopecia, facial erythema, periungual telangiectasia, and pigmentary disturbances can also occur. Painful dermal nodules may appear on the hands or elbows.

Calcinosis cutis also may be seen.[19] Cutaneous ulceration due to subcutaneous dystrophic calcification associated with mixed connective-tissue disease (MCTD) may occur.[20]

Eyes

Dry eye, or keratoconjunctivitis sicca, is common with MCTD; Sjögren syndrome is often underdiagnosed in individuals with MCTD.[21]

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.

Patients may be first evident with signs and symptoms of synovitis.[22]

Muscles

Myalgia, myositis, and muscle weakness are common features.

Gastrointestinal tract

Dysphagia and dysfunction of esophageal motility resemble that occurring in systemic sclerosis.

Other abnormalities of the gut include esophagitis, constipation, diarrhea, and malabsorption.[23]

Correlated pulmonary function data and high-resolution CT scan findings of interstitial lung disease in 50 consecutive patients with MCTD suggests but does not prove a strong association between esophageal motor dysfunction and interstitial lung disease.[24]

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.

Interstitial lung disease was identified in juvenile MCTD in one quarter of patients studied by high-resolution CT scanning.[25] In most of them, it was subtle and without clinical correlation.

MCTD interstitial lung disease characteristics are nonspecific but seem to link pulmonary hypertension and progressive interstitial lung disease.[26]

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.

An assessment of cognitive functions in patients with MCTD showed cognitive deficits observed in MCTDs were connected with nervous system involvement.[27]

Heart[28]

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.

 

DDx

Diagnostic Considerations

Also consider Kikuchi disease.[29]

Different connective-tissue diseases, especially early and particularly in childhood, may be challenging to diagnose. Months or years may pass before an accurate diagnosis can be made.[30] The 2013 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Systemic Sclerosis (SSc) on defined subgroups of systemic sclerosis (SSc) and in mixed connective-tissue disease (MCTD) as an SSc-related disease were found to be more sensitive than the American College of Rheumatology 1980 criteria.[31] However, there remain concerns with regard to distinguishing systemic sclerosis from MCTD.

Differential Diagnoses

 

Workup

Laboratory Studies

Abnormal laboratory results are dependent on the spectrum of connective tissue disease symptoms, which can be similar to those recognized in systemic lupus erythematosus, systemic sclerosis (SSc), dermatomyositis, and polymyositis. For example, antiphospholipid antibodies were documented in 13.3% of patients with mixed connective-tissue disease (MCTD) in one survey.[32]

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:

  • Proteinuria

  • Hematuria

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.[33]

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 mixed connective-tissue disease (MCTD).

Screening for connective-tissue disease–associated antibodies can be accomplished using an automated immunoassay.[34] An immunoassay that detects antibodies to a mixture of 17 antigens is an alternative to indirect immunofluorescence; combining them is best.

The presence of a high titer of immunoglobulin G antibodies against U1-ribonucleoprotein (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.[35] 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.[36] Other antibodies such as dsDNA, anti-Ro/SS-A, and anti-La/SS-B occur incidentally.[37]

See the image below.

Indirect immunofluorescence testing shows the typi Indirect immunofluorescence testing shows the typical speckled pattern for ribonucleoprotein antibodies on a HEp-2 substrate.

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.

See the image below.

Direct immunofluorescence testing shows epidermal Direct immunofluorescence testing shows epidermal nuclear immunoglobulin G staining.

Pulmonary function testing 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 in mixed connective-tissue disease (MCTD) are not conclusive.

 

Treatment

Medical Care

Medical care for mixed connective-tissue disease (MCTD) 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.[38]

Consultations

Because of different presenting symptoms associated with mixed connective-tissue disease (MCTD), consultation with the following specialists should be considered:

  • A dermatologist should evaluate the skin lesions.

  • An internal medicine specialist should evaluate organ involvement.

Activity

Mixed connective-tissue disease (MCTD) patients have restricted mobility if joint and muscle pain is significant.

Complications

Approximately 10% of patients with mixed connective-tissue disease (MCTD) have an increased risk of cancer development during the course of disease. Many affected patients receive immunosuppressive therapy, which may put them at increased risk of nontuberculous mycobacterial and other infections.[39, 40]

Prevention

Deterrence and prevention of mixed connective-tissue disease (MCTD) includes photoprotection.

 

Medication

Medication Summary

Mixed connective-tissue disease (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. Midrange doses of systemic corticosteroids have been used in conjunction with immunosuppressive agents. 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.

Corticosteroids, systemic

Class Summary

These agents decrease autoimmune reactions, possibly by suppressing key components of the immune system. They are often used to treat collagen vascular diseases.

Prednisolone (Prelone Syrup, Pediapred Oral Solution, Delta-Cortef)

Prednisolone is a synthetic adrenocortical steroid with predominantly glucocorticoid properties. It decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reducing capillary permeability.

Immunosuppressants

Class Summary

These agents inhibit key factors that mediate immune reactions, which in turn decrease inflammatory responses.

Cyclosporine (Sandimmune, Gengraf, Neoral)

Cyclosporine is a 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 months; stabilization of disease may take 3-4 months. Bioavailability is 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.

Nonsteroidal anti-inflammatory drugs

Class Summary

NSAIDs provide symptomatic relief for arthralgia, myalgia, edema, and tenderness.

Naproxen (Naprosyn, Anaprox)

Naproxen is used for relief of mild to moderate pain; it inhibits inflammatory reactions and pain by decreasing the activity of cyclo-oxygenase, which decreases prostaglandin synthesis.

Corticosteroids, topical

Class Summary

Topical corticosteroids are moderate or potent agents with anti-inflammatory and immunosuppressive properties. They can decrease epidermal proliferation.

Fluticasone (Cutivate)

Fluticasone has extremely potent vasoconstrictive and anti-inflammatory activities. It has a weak inhibitory affect on the 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. Fluticasone is of medium potency.