Mixed connective-tissue disease (MCTD) was first recognized by Sharp and colleagues (1972) in a group of patients with overlapping clinical features of systemic lupus erythematosus (SLE), scleroderma, and myositis, with the presence of a distinctive antibody against what now is known to be U1-ribonucleoprotein (RNP).[1, 2]
MCTD has been more completely characterized in recent years and is now recognized to consist of the following core clinical and laboratory features[3, 4] :
Pathophysiologic abnormalities that are believed to play a role in MCTD include the following:
In a study of a nationwide MCTD cohort in Norway, Flåm and colleagues found that HLA-B*08 and DRB1*04:01 were risk alleles for MCTD, while DRB1*04:04, DRB1*13:01 and DRB1*13:02 were protective. Risk alleles for SLE, systemic sclerosis, and polymyositis/dermatomyositis were distinct from those for MCTD.[7]
The fundamental cause of MCTD remains unknown. Autoimmunity to components of the U1-70 kd snRNP is a hallmark of disease. Anti-RNP antibodies can precede overt clinical manifestations of MCTD, but overt disease generally develops within 1 year of anti-RNP antibody induction.
The loss of T-lymphocyte and B-lymphocyte tolerance, due to cryptic self-antigens, abnormalities of apoptosis, or molecular mimicry by infectious agents, and driven by U1-RNA-induced innate immune responses, are proposed current theories of pathogenesis.
A population-based study from Olmsted County, Minnesota found that MCTD occurred in about 2 persons per 100,000 per year. Diagnosis was frequently delayed with a median of 3.6 years elapsing from first symptom to fulfillment of diagnostic criteria.[8]
Long-term outcome studies have established pulmonary hypertension as the most common disease-related cause of death.[9] Immunoglobulin G (IgG) anticardiolipin antibodies are a marker for development of pulmonary hypertension. Infections are also a major cause of death.
Cardiac disease, most often pericarditis, is also common in MCTD patients, with prevalence estimates ranging from 13% to 65%. Other cardiac abnormalities include conduction abnormalities, pericardial effusion, mitral valve prolapse, diastolic dysfunction, and accelerated atherosclerosis. In three prospective studies with 13-15 years of follow-up, MCTD patients had an overall mortality rate of 10.4%, and 20% of these deaths were directly attributable to cardiac causes.[10]
MCTD has been reported in all races. The clinical manifestations of MCTD are similar among various ethnic groups; however, one study observed ethnic differences in the frequency of end-organ involvement.[11]
The female-to-male ratio of MCTD is approximately 3:1.
The onset of MCTD is typically at 15-25 years of age, but can occur at any age.
Most patients with MCTD have a favorable outcome. Cases of MCTD with typical clinical or serologic features occasionally evolve into scleroderma, SLE, or another rheumatic disease.
Pulmonary hypertension is the most common disease-associated cause of death. Careful monitoring and aggressive treatment may improve the outcome of pulmonary hypertension.
Careful epidemiological studies have not been performed in the United States. MCTD appears to be more prevalent than dermatomyositis (1-2 cases per 100,000 population) but is less prevalent than SLE (15-50 cases per 100,000 population).
In an epidemiological survey in Japan, MCTD has a reported prevalence of 2.7 cases per 100,000 population. More recently, a population-based study in Norway found the point prevalence rate to be 3.8 cases per 100,000 adult population, with a female-to-male ratio of 3.3.[12]
Clinical Presentation
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