Connective Tissue Diseases

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.

Connective Tissue Diseases



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.

Antiphospholipid syndrome

 

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.

 

Clinical features:

  • Arterial thrombosis: may result in cerebral ischaemia, or peripheral ischaemia. Thrombosis occurs in vessels of any size, without evidence of vasculitis.
  • Venous thrombosis: may present with DVT or PE.
  • Foetal complications: recurrent spontaneous pregnancy loss, commonly in the second trimester.
  • Thrombocytopenia: occurs in one third with APS. Rarely severe enough to cause bleeding.

 

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.

 

Management:

  • Avoid other thrombotic risk factors; smoking, oestrogen containing contraceptives. Treat hypertension, hyperlipidaemia and diabetes.
  • Asymptomatic: if there is no history of thrombosis, but antibody tests are positive, low dose aspirin.
  • Thrombosis: lifelong anticoagulation with warfarin, with INR 2-3.
  • Recurrent foetal loss: warfarin should be stopped before conception, and heparin given throughout pregnancy; this increases the live birth rate to around 80%.

 

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.

 

Features:

  • Localised skin fibrosis appears as an area of increased or reduced pigmentation with erythema and skin thickening. Patches may occur at any site, most commonly on the trunk and limbs. Sclerodactyly, microstomia and flexion contractures may result.
  • Joint pain and swelling, myalgia, restriction of movement and muscle atrophy.
  • Cardiovascular: Raynaud’s phenomenon occurs in most cases of SSc. Myocardial fibrosis can cause arrhythmias and cardiac failure.
  • Pulmonary: fibrosing alveolitis affects 25% with limited and 40% with diffuse SSc. Pulmonary hypertension affects 20%, often secondary to fibrosis. Primary pulmonary hypertension is more common in LSSc. Pulmonary disease is the most frequent cause of death in SSc.
  • Renal: scleroderma renal crisis causes rapidly progressive renal failure, often with accelerated hypertension, oliguria, oedema and proteinuria. Scleroderma renal crisis occurs in up to 20% with DSSc and 5% with LCSSc.
  • GI: SSc can affect any part of the GI tract. Commonly, oesophageal dysmotility causes heartburn and dysphagia and hypomotility in the bowel causes constipation.

 

 

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.

 

Sjögren’s syndrome

 

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.

 

Features;

  • Ocular: reduced tear secretion results in destruction of cornea and conjunctival epithelium. Eyes feel dry, painful and gritty. There is increased risk of bacterial conjunctivitis.
  • Oral: dry mouth (xerostomia) results in difficulties swallowing and talking. Dental caries and oral candidiasis are common.
  • Other exocrine glands: vaginal dryness can cause dyspareunia, decreased GI mucous secretion can cause oesophagitis or gastritis.
  • Systemic features: constitutional symptoms- fatigue, weight loss, fever. Arthritis and raynaud’s phenomenon are common. Interstitial lung disease, interstitial nephritis and vasculitis may occur.
  • Malignancy: B cell lymphomas are more common than in the general population.
  • Pregnancy: Sjogren’s syndrome is associated with anti-Ro and anti-La antibodies. These can cause congenital heart block and neonatal lupus in pregnancy.

 

 

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.

 

Diagnostic criteria:

  • Muscle weakness: symmetrical proximal muscle weakness over weeks/months
  • Elevated serum muscle enzymes, CK and aldolase
  • Typical EMG findings: myopathic potentials (low amplitude, short duration, polyphasic), fibrillation, increased insertion activity
  • Typical muscle biopsy findings
  • In DM, typical dermatological features: Gottron’s papules on fingers, elbows, knees and medial malleoli; heliotrope sign around eyes; erythematous or poikilodermatous rash

Clinical features:

  • Muscle weakness: develops insidiously, symmetrical and diffuse affecting the proximal muscles of the neck, shoulders, trunk, hips and thighs. Weakness of diaphragm and intercostals may cause SOB
  • Myalgia occurs in 50%
  • Atrophy and contractures occur in chronic disease, especially PM
  • Cutaneous features: the rash of DM may precede weakness by weeks or months. Gottron’s papules (erythematous or violaceous papules or plaques) occur over MCPs and PIPs, and occasionally on extensor surfaces of knees, wrists, elbows or medial malleoli. Seen in 80%. Heliotrope rash around the eyes is seen in 50%. A macular rash may occur over the upper chest, neck, shoulders, extremities, face and scalp.
  • Systemic manifestations: fevers, fatigue, weight loss, interstitial pulmonary fibrosis (20%), oesophageal dysphagia (30%), hypertension and pericardial effusions (20%) are the more common systemic features
  • Association with malignancy: 15% in DM and 9% in PM, usually in first 1-2 years after onset. There is an increase in many malignancies, commonly ovarian, breast, lung, stomach, colon and bladder cancers.

 

Investigation:

  • Muscle enzymes: creatinine kinase (CK) is often elevated
  • Autoantibodies: Antinuclear antibodies are positive in 80%. Anti-Jo1 is more specific, but only positive in 30%.
  • Muscle biopsy: if diagnosis is not clear, or if failure to respond to treatment

 

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.

 

Treatment:

  • Corticosteroids: oral prednisolone at 60-80mg/day until symptoms improve, after which the dose can be gradually reduced over six months
  • Immunosuppressive agents are considered if steroids are ineffective
  • Exercise programmes can improve fatigue and weakness

 

 

 

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;

  • Myositis
  • Pulmonary involvement
  • Raynaud’s phenomenon,
  • Swollen hands
  • Sclerodactyly
  • Raised anti-U1-RNP antibodies.

 

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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