Connective tissue diseases are multisystem inflammatory conditions associated with autoantibodies and other immunological abnormalities. These include; SLE, antiphospholipid syndrome, diffuse and limited systemic sclerosis, Sjögren’s syndrome, idiopathic inflammatory myopathies, mixed connective tissue disease and the vasculitides.
SLE and vasculitides are covered in separate articles.
Autoantibodies associated with the connective tissue diseases. Antinuclear antibodies (ANA) are positive in many patients with CTDs; however they are not specific for the individual conditions. This is useful as an initial test to support further investigation for specific antibodies. The most strongly associated autoantibodies are given for each condition, with their sensitivities. LSSc- limited systemic sclerosis, DSSc- diffuse systemic sclerosis.
APS is characterized by recurrent arterial or venous thrombosis and/or pregnancy related morbidity, with the presence of antibodies to phospholipid related proteins. APS can be secondary, associated with other autoimmune conditions, commonly SLE. APS occurs in 1-4% of the population.
Diagnosis is based on the detection of anticardiolipin (ACL) antibodies and lupus anticoagulant (LAC). ACL are also seen in 4% of the normal population, rising with age, and in SLE.
Differentials for recurrent thrombosis include genetic coagulopathies such as protein C and S deficiencies, and thrombotic thrombocytopenic purpura.
Systemic sclerosis (Scleroderma)
In systemic sclerosis (SSc) increased fibroblast activity results in abnormal collagen growth and deposition. This results in vascular damage and fibrosis in the skin and visceral organs. The two main forms are limited cutaneous SSc and diffuse SSc. Systemic sclerosis is seen throughout the world, and is more common in females (F:M 4:1) with a peak age of onset at 25-55 years.
Limited cutaneous systemic sclerosis: 70% of cases. Sclerosis affects only the face, forearms and lower legs. Patients may develop features of CREST syndrome: Calcinosis, Raynaud’s, oEsophogeal dysmotility, Sclerodactyly, Telangiectasia.
Diffuse cutaneous systemic sclerosis: 30% of cases. Sclerosis also involves the upper arms, thighs or trunk. Onset is more rapid, and progression is usually faster. Symptoms are worse in the first 3-5 years, and may remit with softening of skin and improved mobility. Internal organ involvement is more common.
Investigation: The diagnosis of SSc is clinical. Antinuclear antibodies are seen in 95% of patients- anticentromere antibodies are associated with LSSc, and antitopoisomerase-1 (Scl-70) antibodies with DSSc.
Chronic graft vs host disease, amyloidosis, acromegaly, nephrogenic systemic fibrosis, scleromyxoedema and carcinoid syndrome can present with similar features. Chemical exposure (including silica, aromatic hydrocarbons) and drugs (including bleomycin) are responsible for a small number of cases.
Management: For skin fibrosis, emollients, topical steroids and physiotherapy to improve mobility. Renal function, lung function, ECG and blood pressure monitoring are important for identifying complications.
In Sjögren’s syndrome, fibrosis and destruction of exocrine glands results in failure of gland function. The aetiology is unknown, but there is an association with HLA DR-3. It may be primary or secondary, occurring with other autoimmune diseases, commonly rheumatoid arthritis, SLE or systemic sclerosis. Prevalence is 3-4% of adults, with a female to male ratio of 9:1. Peak onset is at 30-40 years.
Investigation: Salivary flow rates can be measured, and tear production using Schirmer’s test. A 3cm piece of filter paper is used to measure tear production; wetting of <5mm indicated diminished tear secretion. Labial gland biopsies may be used to show lymphocytic infiltration.
Differential diagnosis includes previous head and neck irradation and anticholinergic drug use. Neoplasia, HIV, CMV and sarcoidosis can also cause gland swelling and histological changes.
Management: treatment is symptomatic. Artificial tears should be used liberally. Pilocarpine can improve oral and eye symptoms. Artificial saliva is available, and good dental hygiene is required.
Idiopathic inflammatory myopathies
The idiopathic inflammatory myopathies are characterized by proximal muscle weakness and autoimmune mediated muscle breakdown. Polymyositis (PM) and dermatomyositis (DM) are the most common of these disorders, but are rare with an incidence of 0.5/100 000, higher in the Afro-Caribbean population and females (2:1). DM is features of PM with skin involvement.
Other causes of a raised CK include; muscle trauma, myositis, rhabdomyolysis, MI, drugs (including statins, lamotrigine, L-dopa) and renal failure.
There are many other causes of myopathy; inclusion body myositis, focal myositis, metabolic (hypocalcaemia, hypokalaemia), endocrine (cortisol excess, thyroid dysfunction), drugs (including penicillamine), motor neurone disease, Guillain–Barré syndrome, myasthenia gravis and infections (HIV, hepatitis B and C, influenza, TB, toxoplasmosis), in addition to those mentioned above.
Mixed connective tissue disease
There is an overlap of features of SLE, SSc and myositis. MCTD is uncommon, but seen more frequently in women, with onset around 30-50 years. For a definite diagnosis, four of the major criteria are required, including raised levels of anti-U1-RNP antibodies.
The major criteria are;
Other features include; alopecia, anaemia, arthritis, cytopenias, pleuritis and pericarditis. Many patients develop other CTDs, commonly SLE and SSc. Complications may occur as for other CTDs; pulmonary hypertension is the commonest cause of death.
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