History and exam
Key diagnostic factors
common
presence of risk factors
Risk factors include female sex (female to male ratio approximately 10:1) and age between 20 and 40 years.
digital pallor/pain
Approximately 90% of patients with mixed connective tissue disease have Raynaud's phenomenon (RP) on presentation.[6]
RP may also be an isolated condition, but abnormal nail fold capillaroscopy suggests eventual development of underlying rheumatic condition. Only infrequently is RP complicated by findings of digital ischaemia or infarcts in overlap syndromes.
arthritis/arthralgia
Joint symptoms are present in almost all patients with mixed connective tissue disease and are a common presenting symptom. Frank arthritis develops in 50% to 60% of patients during follow-up. Small-joint polyarthritis is the most common pattern of involvement, but deformities are uncommon.
swollen hands
Very common at presentation in mixed connective tissue disease, and may progress to entire hand swelling.
sclerodactyly
Common in mixed connective tissue disease, but tends to occur as a later manifestation of disease.[5]
nail fold vascular changes
Abnormal nail fold capillaroscopy (pattern of blood vessels visible under low magnification in the nail bed) has predictive value for an underlying rheumatic disease in patients presenting with Raynaud's phenomenon.
Patterns of giant capillaries and loss of the normal architecture with dropout of vessels may suggest underlying mixed connective tissue disease, systemic sclerosis, or polymyositis.[17][18]
dyspnoea or cough
Pulmonary involvement in mixed connective tissue disease will eventually affect up to 66% of patients.[13][14] Both interstitial lung disease and pulmonary hypertension may be seen.
Among patients with antisynthetase syndrome, interstitial lung disease is even more common, occurring in 86% of patients.[15][16]
Physical examination may demonstrate signs of elevated right-sided heart pressures or bibasilar rales. Pleural effusions occur uncommonly.
GORD and heartburn
On presentation, 47% of patients with mixed connective tissue disease already have symptoms of oesophageal dysmotility, with reflux symptoms, dysphagia, and regurgitation. Ultimately seen in 65% of patients during follow-up. Much less commonly, patients develop symptoms due to pancreatitis, mesenteric ischaemia, or malabsorption.
uncommon
myalgias or myositis
Myalgias occur in 25% to 50% of mixed connective tissue disease patients, but myositis is less common, usually without frank weakness on physical examination.
Myositis is a key component of antisynthetase syndrome.[21]
Other diagnostic factors
common
haematuria
Renal involvement in 25% of patients with mixed connective tissue disease (MCTD); rare in other overlap syndromes. In MCTD, focal proliferative glomerulonephritis is the most common cause. Rarely, membranous glomerulonephritis with nephrotic syndrome occurs. Renal biopsy is indicated in patients with significant abnormalities on urinalysis and in some cases of declining renal function.
lymphadenopathy
Reported to occur in 25% to 50% of patients with mixed connective tissue disease, often as a presenting sign that improves with time.
alopecia
Has been reported in 40% of mixed connective tissue disease patients.
uncommon
skin rashes
Many different types may occur in 50% to 60% of patients; in mixed connective tissue disease (MCTD), malar rashes and discoid lesions similar to those characteristic of systemic lupus erythematosus may be seen occasionally.
Acrosclerosis with telangiectasias and occasionally calcinosis may be seen, but truncal sclerodermatous skin changes are very rare.
Skin changes typical of dermatomyositis, including Gottron's papules and a heliotrope rash, may occur in MCTD, but the nodules of rheumatoid arthritis are rarely seen.[6]
proximal muscle weakness
Patients may develop an inflammatory myositis. Patients with these symptoms, or those with suspected muscular involvement, require serum muscle enzymes, possibly followed by an electromyogram/nerve conduction study and muscle biopsy.
trigeminal neuralgia
Very rarely may be the presenting feature of mixed connective tissue disease, presenting as neuropathic pain or anaesthesia over the distribution of 1 or more of the branches of the trigeminal nerve.
headaches
May be seen due to aseptic meningitis in mixed connective tissue disease.
neuropsychiatric disease including psychosis and seizures
Rare manifestations of mixed connective tissue disease.
peripheral neuropathy
Predominantly sensory polyneuropathy may be seen and should be further evaluated with nerve conduction studies and electromyography.
fever
Low-grade fever due to mixed connective tissue disease is uncommon. A careful search for infection is therefore mandatory.
Risk factors
strong
female sex
age 20 to 40 years
Although overlap syndromes can occur at any age, patients with mixed connective tissue disease generally present between 20 and 40 years of age; patients with antisynthetase syndrome typically present later in life.
weak
presence of specific HLA genotypes
Genotypes HLA-DR4 and HLA-DR2 are associated with mixed connective tissue disease.[11]
Prevalence of certain HLA subtypes is increased in other autoimmune diseases, including systemic lupus erythematosus (HLA-DR2 and HLA-DR3) and scleroderma (HLA-DR2, DQA1*0501, and DQB1*0301).
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