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A rheumatic disease syndrome characterized by overlapping clinical features similar to those of SLE, scleroderma, and polymyositis/dermatomyositis, and by very high titers of circulating antinuclear antibody to a nuclear ribonucleoprotein (RNP) antigen.
Etiology, Pathogenesis, and Prevalence
The etiology is unknown, but certain findings suggest that immune factors may be involved in the pathogenesis: (1) marked hypergammaglobulinemia; (2) persistence of extremely high titers of RNP antibody; (3) mild to moderate hypocomplementemia in 25%; (4) circulating immune complexes during active disease; (5) specific deposition of IgG, IgM, or complement within the walls of blood vessels or muscle fibers and along the glomerular basement membrane; and (6) chronic inflammatory infiltration by lymphocytes and plasma cells in various tissues.
Whether MCTD is a distinct clinical entity still has not been resolved, but a number of features support this assumption: (1) overlapping clinical features suggesting several connective tissue diseases; (2) extremely high titers of RNP antibody, usually in the absence of significant titers of other antinuclear antibodies; (3) normal reticuloendothelial system clearance of immune complexes in most MCTD patients, in contrast to SLE; (4) abnormalities of immunoregulatory T cell circuits in MCTD that differ from those found in other rheumatic diseases; (5) frequent pulmonary hypertension and associated proliferative vasculopathy with minimal fibrosis; and (6) other pathologic changes that may be restricted to MCTD.
Prevalence is unknown; MCTD appears to be seen more commonly than polymyositis/dermatomyositis and less frequently than SLE. About 80% of patients are female. The age range is from 5 to 80 yr, with a mean of 37 yr.
Symptoms, Signs, and Pathology
The typical clinical syndrome is characterized by Raynaud's phenomenon, polyarthralgia or arthritis, swollen hands, inflammatory proximal myopathy, esophageal hypomotility, and pulmonary disease. Raynaud's phenomenon may precede other disease manifestations by years, and frequently the initial findings suggest early SLE, scleroderma, polymyositis/dermatomyositis, or RA. Whatever the initial presentation, there is a tendency for more limited disease to progress and become widespread and for transitions in the clinical pattern to occur over time.
The most frequent skin finding is swelling of the hands, resulting in a sausage appearance of the fingers. Diffuse scleroderma-like changes and ischemic necrosis or ulceration of the fingertips, common in scleroderma, are much less frequent in MCTD. Other skin findings include lupuslike rashes, erythematous patches over the knuckles, violaceous discoloration of the eyelids, diffuse nonscarring alopecia, and squared telangiectasia over the hands and face.
Almost all patients have polyarthralgias, and 75% have frank arthritis. Often the arthritis is nondeforming, but erosive changes and deformities may be present, suggesting RA. Proximal muscle weakness with or without tenderness is common. Electromyograms are typical of inflammatory myopathy, and muscle biopsies show degeneration of muscle fibers and interstitial and perivascular infiltrates of lymphocytes and plasma cells.
Esophageal abnormalities, including decreased lower sphincter pressure, decreased amplitude of peristalsis in the distal 2/3, and a decrease in upper sphincter pressure, occur in 80% of patients, including 70% of asymptomatic patients. Pulmonary involvement also occurs in about 80%, and significant abnormalities of diffusing capacity may develop before the disease is clinically apparent. Chest x-rays may show pleuritis and/or diffuse interstitial infiltrates. In some patients, pulmonary involvement becomes the predominant clinical problem, leading to exertional dyspnea and/or pulmonary hypertension. Pulmonary hypertension and proliferative vascular lesions, which usually develop insidiously, represent serious complications for some. Recent studies using in vivo nailfold capillary microscopy have revealed severe capillary abnormalities characteristic of scleroderma in patients who subsequently developed pulmonary hypertension. Lung biopsies have revealed mainly vascular intimal proliferation and medial hypertrophy severe enough in some cases to cause vascular obliteration.
Pericarditis is the most frequent cardiac finding. Myocarditis also may be present, leading to heart failure. Mitral valve prolapse was identified in 26% of MCTD patients in a recent series. Renal disease occurs in only about 10% of patients, often is mild, but occasionally becomes a major clinical problem; patients have died with progressive renal failure. Renal biopsies usually show mesangial hypercellularity, focal glomerulitis, and membranous glomerulonephritis, while membranoproliferative glomerulonephritis and proliferative vascular lesions are much less frequently seen. Serious neurologic abnormalities, including organic mental syndrome, aseptic meningitis, seizures, multiple peripheral neuropathies, and cerebral infarction or hemorrhage, occur in only about 10% of patients. A trigeminal sensory neuropathy appears to be seen much more frequently in MCTD than in other rheumatic diseases.
Other findings that may be present in patients with MCTD include Sj?gren's syndrome, Hashimoto's thyroiditis, fever, lymphadenopathy (often of massive proportions), splenomegaly, hepatomegaly, intestinal involvement similar to that seen in scleroderma, and persistent hoarseness.
Laboratory Findings
Almost all patients with MCTD have high titers (often >1:1000) of fluorescent antinuclear antibodies (ANA), which produce a speckled pattern. Antibodies to extractable nuclear antigen (ENA) are usually detected at very high titers (>1:100,000) by hemagglutination. The ANA and hemagglutination reactions are typically eliminated by digestion with ribonuclease (RNase), since the ENA component to which antibodies are directed in MCTD is an RNase-sensitive nuclear ribonucleoprotein (RNP) antigen. By immunodiffusion it can be confirmed that antibody to RNP is present, while antibody to the RNase-resistant Sm component of ENA is usually absent. High titers of antibody to RNP usually persist for years, but may significantly decline or become undetectable in patients who are in prolonged remission.
The nature of the RNP and Sm antigens has now been further elucidated. Antibodies to RNP immunoprecipitate U1 small nuclear ribonucleic acid (snRNA)-protein complexes and react with 70K, A, and C proteins. Antibodies to Sm immunoprecipitate complexes containing U1, U2, U4, U5, and U6 snRNAs and react with proteins designated B/B' and D. Recent studies have shown that autoantibodies to the 70K protein are strongly associated with MCTD but are rare in SLE. Immunogenetic studies have linked U1 70K-positive MCTD with HLA-DR4 but not with HLA-DR3 as is found in patients with SLE.
Antibodies to native DNA and LE cells are infrequent in MCTD. Rheumatoid agglutinins are frequently positive, and titers often are high. The ESR is frequently elevated, and 75% of patients have diffuse hypergammaglobulinemia often ranging from 2 to 5 gm/dL. Levels of serum complement are slightly to moderately reduced in only about 25% of patients. Serum levels of creatine kinase and aldolase usually are elevated when active myositis is present.
Moderate anemia and leukopenia occur in 30 to 40% of patients with MCTD. Clinically significant Coombs-positive hemolytic anemia and thrombocytopenia are uncommon. However, in one report of childhood MCTD, severe thrombocytopenia was more common, and 2 children required splenectomy because they were only partially responsive to corticosteroids. Hematuria, casts, and proteinuria are detected on urinalysis when glomerulonephritis occurs.
Diagnosis 
MCTD should be considered when additional overlapping features are present in patients appearing to have SLE, scleroderma, polymyositis, RA, juvenile RA, Sj?gren's syndrome, vasculitis, idiopathic thrombocytopenic purpura, lymphoma, or "viral pericarditis." MCTD occasionally may present as a fever of unknown origin. Since the characteristic serologic finding of high titers of antibody to RNP only is much more frequently associated with MCTD than with other rheumatic diseases, detection of RNP antibody permits a presumptive diagnosis early in the evolution of the disease when clinical manifestations are limited. If RNP antibody is detected at a high titer, a thorough evaluation of the muscle, esophageal, and pulmonary systems (especially diffusing capacity) frequently will reveal abnormalities even when the patients are asymptomatic with respect to these systems.
Prognosis
The overall mortality in 5 reports (194 patients) was 13%, with the mean disease duration varying from 6 to 12 yr. Causes of death have included proliferative vascular lesions with pulmonary hypertension, renal failure, myocardial infarction, colonic perforation, disseminated infection, and cerebral hemorrhage. Sustained remissions for many years on little or no maintenance corticosteroid therapy have now been observed in some patients.
Treatment
General medical management and drug therapy are similar to the approach used in SLE. Most patients are responsive to corticosteroids, particularly if treated early in the course of the disease. Mild disease often is controlled by salicylates, other nonsteroidal anti-inflammatory drugs, antimalarials, or very low doses of corticosteroids. Severe major organ involvement usually requires larger doses of corticosteroids; eg, an initial dose of 1 mg/kg of prednisone. Even in patients whose disease is progressive and widespread, more prolonged high-dose corticosteroid therapy, sometimes in combination with cytotoxic drugs, may be associated with clinical improvement. However, with disease of longer duration resulting in greater functional impairment, the response may not be so complete, and drug toxicity may contribute to serious and sometimes fatal complications. In general, the scleroderma-like features of MCTD are the least likely to respond to treatment.
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