The Prognosis of Mixed Connective Tissue Disease

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Sequential clinical and laboratory features

MCTD evolves with time and patients who have MCTD typically develop new clinical and laboratory characteristics. This became evident from long-term follow-up studies of patients who had anti-U1 snRNP antibodies [5], [9], [11], [12]. Thus, at first presentation, patients who have anti-U1snRNP antibodies may display only one or a few organ manifestations in addition to positive anti-U1 snRNP antibodies; at that time point they may not fulfill the classification criteria for MCTD or any other

Mortality

Long-term follow up studies on mortality in patients who have MCTD are few and often include a limited number of patients, which reflects the rarity of this condition (Table 1). In five series of MCTD with a total of 194 patients, the mortality generally was low (mean, 13%; range, 4–35%) in patients who had a disease duration of 6 to 12 years [4], [8], [9], [16], [17]. These data are from tertiary referral centers, and therefore, may include some patients who were more severely ill. In a

Cause of death

The predominating causes of death in patients who have MCTD are pulmonary hypertension, associated with proliferative vascular disease, and severe infections [5], [15]. In a retrospective study of 23 patients who had clinical and serologic features of MCTD, 5 patients had died at the time of study [9]. This cohort included 2 individuals who were younger than 20 years and 3 patients who were older than 60 years. Pulmonary disease, pulmonary hypertension, and congestive heart failure were the

Morbidity

The data on long-term morbidity in patients who have MCTD in relation to prognosis also are limited. The long-term outcome varies from remission to progressive inflammatory active disease. In most cases, features of inflammation seem to vanish or diminish [12], [15]. The frequency of Raynaud's phenomenon and esophageal hypomotility also was reduced in a long-term follow-up study, whereas sclerodactyly or diffuse sclerosis, pulmonary dysfunction, pulmonary hypertension, and nervous system

Joints

The joints are affected frequently in patients who have MCTD, and various features are present. Common joint symptoms include arthralgia and arthritis; they often are among the first symptoms of disease. The arthritis can be mono-, oligo-, or polyarticular rheumatoid arthritis-like with a symmetric distribution of small joints [3], [21]. The most frequently reported radiologic features of bone and joints are periarticular, marginal bone erosions in 40% to 70% of patients who have MCTD [2], [3],

Muscles

Myositis has been reported as a frequent manifestation in patients who have anti-U1 snRNP antibodies or MCTD. A favorable response to corticosteroids in patients who had anti-U1snRNP antibodies and myositis was seen in one study [25]. In another study, no difference in response to immunosuppressive treatment was observed compared with other inflammatory myopathies [26]. Both of these reports are limited by a small number of patients and the absence of a standardized outcome measure of muscle

Lung involvement

Lung involvement with pulmonary hypertension was reported as the most serious clinical problem in a prospective study of 34 patients who had MCTD with a mean observation time of 6 years [5]. In several studies, pulmonary hypertension was associated with a poor prognosis and was a major cause of death in patients who had MCTD [5], [15], [27]. In one study, pulmonary hypertension was recorded in 65% of those who underwent cardiac catheterization, regardless of clinical symptoms of the lungs [27].

Cardiovascular disease

Epidemiologic studies of cardiac involvement in patients who have myositis and MCTD largely are lacking, which makes conclusions about the frequency and prognosis of clinical and subclinical cardiac manifestations uncertain. In the few published reports, the frequency of cardiac involvement in patients who had MCTD varied between 11% and 85%, depending on patient selection, and definitions of cardiac involvement, and methods used to detect cardiac manifestations [11], [27], [30]. In the study

Digital ulcers

Raynaud's phenomenon is a common initial symptom in MCTD. It may be severe; in occasional patients it is associated with digital necrosis or gangrene of multiple finger tips [34], [35]. The prognosis of Raynaud's phenomenon is not invariably poor because it may improve over time with a reduction in frequency [15].

Gastrointestinal involvement

Gastrointestinal symptoms are common and were reported in 66% to 74% of patients who had MCTD [15], [36], [37]. The most frequently reported symptoms result from esophageal involvement, such as heartburn in 48% and dysphagia in 38% [36]. Sensitive tests, such as esophageal manometry, also detected abnormal motility in asymptomatic patients which indicated an even more frequent involvement of this organ [20], [37]. In comparison with systemic sclerosis, the morphologic and functional

Renal involvement

The frequency of renal involvement varied between 5% and 36% in different cohorts of patients who had MCTD [8], [38]. The most comprehensive histopathologic data of renal involvement comes from a longitudinal study in which 11 of 30 patients had clinically significant proteinuria [38]. The histopathology was dominated by mild mesangial changes and interstitial fibrosis. Active lesions with cellular crescents were detected in only 1 patient. Six patients were classified as having membranous

Osteoporosis

There is an increased risk for osteoporosis as a long-term consequence in other rheumatic diseases, in particular RA and SLE. There is only one report on osteoporosis in patients who had MCTD [39]. This included a report of bone mineral density of the lumbar spine and femoral neck in 58 postmenopausal women who had MCTD with a mean disease duration of 9.1 years (range, 1–16 years). In the lumbar spine, but not in the femoral neck, bone mineral density was decreased in 25.8% (T-score<−2.5). A

Summary

From long-term follow-up studies, it can be concluded that the prognosis for patients who have MCTD varies from a benign, long-term outcome with remission to a severe, progressive disease course. Approximately one third of patients who have MCTD have a benign course and go into remission, one third have an aggressive course, and one third have a partial response with immunosuppressive treatment but still require immunosuppressive therapy after several years. The worst prognosis with a high

Acknowledgments

The author is grateful to Associate Professor Ronald van Vollenhoven for linguistic advice.

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      Severe lung fibrosis is associated with increased mortality [126]. The most severe clinical manifestation, however, is pulmonary hypertension which contributes to premature death in patients who have MCTD [127]. ANA-testing appears to be positive in virtually all patients with positive U1-RNP antibodies [128].

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    This work was supported by the Swedish Rheumatism Association. The author has received unrestricted research grants from Schering Plough and Baxter, an honorarium from Pfizer for teaching courses that were organized by the Swedish Society for Rheumatology, and owns stock in pharmaceutical companies.

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