Mixed connective tissue disease is an uncommon, specifically defined syndrome characterized by overlapping clinical features of systemic lupus erythematosus, systemic sclerosis, and polymyositis with very high titers of circulating antinuclear antibody to a ribonucleoprotein antigen. Hand swelling, Raynaud syndrome, polyarthralgia, inflammatory myopathy, esophageal hypomotility, and interstitial lung disease are common. Diagnosis is by the combination of clinical features, antibodies to ribonucleoprotein, and absence of antibodies specific for other systemic rheumatic diseases. Treatment varies with disease severity and organ involvement but usually includes corticosteroids and additional immunosuppressants.
Mixed connective tissue disease (MCTD) occurs worldwide and in all races, with a peak incidence in adolescence. It is reported more frequently in females than males (1).
The cause of MCTD is unknown. In many patients the disease evolves into classic systemic sclerosis or systemic lupus erythematosus (SLE). Thus, there is a lack of consensus among some experts that MCTD should be considered a distinct disease.
General reference
1. Gunnarsson R, Molberg O, Gilboe IM, Gran JT; PAHNOR1 Study Group. The prevalence and incidence of mixed connective tissue disease: a national multicentre survey of Norwegian patients. Ann Rheum Dis. 2011;70(6):1047-1051. doi:10.1136/ard.2010.143792
Symptoms and Signs of MCTD
Raynaud syndrome (Raynaud phenomenon) may precede other manifestations by years. Frequently, the first manifestations resemble early SLE, systemic sclerosis, polymyositis, or even rheumatoid arthritis. Many patients appear to have an undifferentiated connective tissue disease initially. The disease manifestations may progress and become widespread, and the clinical pattern changes over time (1).
Initial, diffuse swelling of the hands is typical but not universal. Skin findings include chilblains, discoid lesions, and a malar rash similar to that in SLE. Diffuse systemic sclerosis–like skin changes and ischemic necrosis or ulceration of the fingertips may develop.
© Springer Science+Business Media
© Springer Science+Business Media
Almost all patients have polyarthralgias, and 75% have frank arthritis. Often the arthritis is nondeforming, but erosive changes and deformities similar to those in rheumatoid arthritis (eg, boutonnière and swan-neck deformities) may be present.
Proximal muscle weakness is common, typically among people who have elevated levels of muscle enzymes (eg, creatine kinase).
Gastrointestinal dysmotility is also reported in MCTD, similar to systemic sclerosis.
Renal involvement (most commonly membranous nephropathy) occurs in approximately 25% of patients and is typically mild; severe involvement, with morbidity or mortality, is atypical for MCTD.
The lungs are affected in up to 75% of patients with MCTD. Pleural effusions and interstitial lung disease are the most common lung manifestations; pulmonary hypertension is a major cause of death and is reported in up 13% of cases (2).
Pericarditis is a common feature. Severe myocarditis leading to heart failure is uncommon but can occur.
Sjögren syndrome may develop.
Symptoms and signs references
1. Ortega-Hernandez OD, Shoenfeld Y. Mixed connective tissue disease: an overview of clinical manifestations, diagnosis and treatment. Best Pract Res Clin Rheumatol. 2012;26(1):61-72. doi:10.1016/j.berh.2012.01.009
2. Wigley FM, Lima JA, Mayes M, McLain D, Chapin JL, Ward-Able C. The prevalence of undiagnosed pulmonary arterial hypertension in subjects with connective tissue disease at the secondary health care level of community-based rheumatologists (the UNCOVER study). Arthritis Rheum. 2005;52(7):2125-2132. doi:10.1002/art.21131
Diagnosis of MCTD
Testing for antinuclear antibodies (ANA) and antibodies to extractable nuclear antigens, including antibodies to U1 ribonucleoprotein, Smith, and anti–double-stranded DNA
Organ involvement determined as clinically indicated
Although the clinical presentation of MCTD is heterogenous, it should be suspected when overlapping features are present in patients appearing to have systemic lupus erythematosus (SLE), systemic sclerosis, or polymyositis. A significant minority of patients may evolve into a well-defined disease such as systemic sclerosis, SLE, or an inflammatory myopathy a few years after the initial MCTD diagnosis (1).
Tests for antinuclear antibodies (ANA) and antibody to U1 ribonucleoprotein (RNP) antigen are done first. Almost all patients have high titers of ANA by indirect immunofluorescence testing; the ANA produces a speckled pattern. Antibodies to U1 RNP are present, usually at very high titers. Antibodies to the ribonuclease-resistant Smith (Sm) component of extractable nuclear antigen (anti-Sm antibodies) and to double-stranded DNA (negative in MCTD by definition) are measured to exclude SLE. The presence of anti-RNP antibodies is not sufficient to make the diagnosis of MCTD; typical clinical findings are also required.
Rheumatoid factor is frequently present, and titers may be high. The erythrocyte sedimentation rate and C-reactive protein levels are frequently elevated.
Pulmonary hypertension should be assessed for with pulmonary function testing and echocardiography, as in patients with systemic sclerosis. Further evaluation depends on symptoms and signs, including manifestations of myositis, renal involvement, or pulmonary involvement.
Creatine kinase, MRI, electromyography, or muscle biopsy can help confirm the presence of myositis as part of MCTD.
Diagnosis reference
1. Reiseter S, Gunnarsson R, Corander J, et al. Disease evolution in mixed connective tissue disease: results from a long-term nationwide prospective cohort study. Arthritis Res Ther. 2017;19(1):284. Published 2017 Dec 21. doi:10.1186/s13075-017-1494-7
Treatment of MCTD
General management and initial pharmacologic therapy are extrapolated from approaches used for other systemic rheumatic diseases and are guided by the dominant clinical phenotype (ie, in a manner similar to that for SLE, systemic sclerosis, or myositis) (1).
myositis or systemic sclerosis, treatment is as for those diseases.
Patients with Raynaud syndrome
All patients should be closely monitored for atherosclerosis. Patients on long-term corticosteroid therapy should receive osteoporosis prophylaxis. If combination immunosuppressive therapy is used, patients should be given prophylaxis for opportunistic infections, such as Pneumocystis jirovecii (see prevention of Pneumocystis jirovecii pneumonia), and vaccines against common infections (eg, streptococcal pneumonia, influenza, COVID-19).
Some experts encourage screening for pulmonary hypertension on a periodic basis with pulmonary function testing and/or echocardiography every 1 to 2 years, depending on symptoms.
Treatment reference
1. Gunnarsson R, Hetlevik SO, Lilleby V, Molberg Ø. Mixed connective tissue disease. Best Pract Res Clin Rheumatol. 2016;30(1):95-111. doi:10.1016/j.berh.2016.03.002
Prognosis for MCTD
The overall 10-year survival rate is approximately 96% (1), but prognosis depends largely on which manifestations predominate. Patients with features of systemic sclerosis and polymyositis have a worse prognosis. Patients are at increased risk of atherosclerosis.
Causes of death include pulmonary hypertension, renal failure, myocardial infarction, colonic perforation, disseminated infection, and cerebral hemorrhage.
Some patients have sustained remissions for many years without treatment.
Prognosis reference
1. Hajas A, Szodoray P, Nakken B, et al. Clinical course, prognosis, and causes of death in mixed connective tissue disease. J Rheumatol. 2013;40(7):1134-1142. doi:10.3899/jrheum.121272
Key Points
MCTD consists of features of SLE, systemic sclerosis, and/or polymyositis.
ANA and antibodies to U1 RNP are present and anti-Sm and anti-DNA antibodies are absent, but the presence of anti-RNP antibodies alone is not sufficient to make the diagnosis.
Anticipate pulmonary hypertension.
Treat mild disease with NSAIDs or antimalarials and more severe disease with corticosteroids and other immunosuppressants.
