Introduction:
These diseases share overlapping clinical features, characterised
by dysregulation of immune responses, autoantibody production often directed at
components of the cell nucleus, and widespread tissue damage.
Systemic lupus erythematosus
Systemic lupus erythematosus (SLE) is a rare multisystem
connective tissue disease, mainly occurring in women (90%), with a peak onset
in the second and third decades. Prevalence is 0.2% in Afro- Caribbeans and
0.03% in Caucasians.
Several autoantibodies are associated with SLE. Many of the target
autoantigens are intracellular and intranuclear components. It is likely that
the wide spectrum of autoantibody production results from polyclonal B- and
T-cell activation. Although the triggers that
lead to autoantibody production in SLE are unknown, one mechanism may
be exposure of intracellular antigens on the cell surface during apoptosis.
Clinical features
Fever, weight loss and mild lymphadenopathy occur during flaresof
disease activity; fatigue, malaise and fibromyalgia-like symptomsare not
particularly associated with active disease.
Arthritis: This is a common symptom, occurring in 90% of patients
and often associated with early morning stiffness. Tenosynovitis may also be a
feature but clinically apparent synovitis with joint swelling is rare.
Raynaud’s phenomenon: Arthralgia or arthritis in combination with Raynaud’s
phenomenon is the most common presentation of SLE. Raynaud’s phenomenon in a
teenage girl with no other associated symptoms is likely to be idiopathic ‘primary’
Raynaud’s. By contrast, onset in a male, or in a woman over the age of 30 yrs,
suggests underlying connective tissue disease.
Skin: Three types of rash are characteristic:
● The classic butterfly (malar) facial rash: raised and
painful or pruritic, and spares the nasolabial folds.
● The subacute cutaneous lupus
erythematosus (SCLE) rash: migratory, non-scarring and either annular or
psoriaform.
● The discoid lupus rash: characterised by
hyperkeratosis and follicular plugging, with scarring alopecia if it occurs on
the scalp.
Other skin manifestations include periungual erythema, vasculitis and
livedo reticularis, which is also a common feature of the antiphospholipid
syndrome.
Kidney: The typical renal lesion is a proliferative
glomerulonephritis, characterised by haematuria, proteinuria and casts on urine
microscopy.
Cardiovascular: Pericarditis is the most common feature. Myocarditis
and Libman–Sacks endocarditis (sterile fibrin containing vegetations) also
occur. Atherosclerosis, stroke and myocardial infarction are increased due to
the adverse effects of inflammation on the endothelium, chronic steroid therapy
and the procoagulant effects of antiphospholipid antibodies.
Lung: Pleurisy can cause pleuritic chest pain, a rub or a
pleural effusion. Alveolitis, lung fibrosis and diaphragmatic paralysis can also
occur.
Neurological: Cerebral lupus causes visual hallucinations, chorea, organic
psychosis, transverse myelitis and lymphocytic meningitis.
Haematological: Neutropenia, lymphopenia, thrombocytopenia and
haemolytic anaemia occur.
GI: Oral ulcers are common. Mesenteric vasculitis can
cause bowel infarction.
Investigations
Blood should be sent for haematology, biochemistry, ANA,
antibodies to extractable nuclear antigens, and complement levels. Patients
with active SLE almost always test positive for ANA, but ANA-negative SLE occurs
very rarely with antibodies to the Ro antigen. Anti-dsDNA antibodies are
characteristic of severe active SLE but only occur in ~30% of cases. Patients
with active disease tend to have low C3 and C4, but this may reflect inherited
complement deficiency that predisposes to SLE. Studies of other family members
help to differentiate inherited deficiency from complement consumption. A
raised ESR, leucopenia and lymphopenia are typical of active SLE, as are anaemia,
haemolytic anaemia and thrombocytopenia. CRP is often normal in active SLE,
except in the presence of serositis; elevated CRP suggests coexisting
infection.
Management
Patients should avoid sun exposure and should apply high-factor sun
blocks.
Mild disease: Disease restricted to skin and joints may require only
analgesics, NSAIDs and hydroxychloroquine. Short courses of oral prednisolone
may be needed for flares of disease (e.g. synovitis, pleuro-pericarditis).
Life-threatening
disease (e.g. renal, cerebral, cardiac):
This requires high-dose corticosteroids (IV methylprednisolone) in combination with
IV cyclophosphamide, repeated at intervals of 2–3 wks.
Haemorrhagic cystitis and Pneumocystis pneumonia
are important complications of this treatment. Mycophenolate mofetil (MMF) is a
less toxic alternative to cyclophosphamide.
Maintenance therapy: Azathioprine, methotrexate and MMF are used for
maintenance. Patients with thrombosis and the antiphospholipid syndrome require
lifelong warfarin.
Systemic sclerosis
Systemic sclerosis (scleroderma) is a generalised multisystem
connective tissue disorder. The peak age of onset is in the fourth and fifth
decades, and it has a 4 : 1 female : male ratio. It is subdivided into diffuse
cutaneous systemic sclerosis (DCSS) and limited cutaneous systemic sclerosis
(LCSS). Many patients with LCSS have features that are grouped into the ‘CREST’
syndrome (calcinosis, Raynaud’s, oesophageal
involvement, sclerodactyly, telangiectasia).
The aetiology of systemic sclerosis is unknown. Early in the disease,
there is skin infiltration by T lymphocytes and abnormal fibroblast activation,
leading to increased production of collagen in the dermis. This results in
symmetrical thickening, tightening and
induration of the skin, and then sclerodactyly in the fingers. In
addition to skin changes, there is arterial and arteriolar narrowing due to
intimal proliferation and vessel wall inflammation. Endothelial injury causes
release of vasoconstrictors and platelet activation, resulting in further
ischaemia.
American Rheumatism
Association criteria for SLE
Features
Characteristics
Malar rash - Fixed erythema, flat
or raised, sparing nasolabial folds
Discoid rash - Erythematous raised
patches, keratotic scarring, follicular plugging
Photosensitivity - Rash on sunlight
exposure
Oral ulcers - Oral or
nasopharyngeal; may be painless
Arthritis - Non-erosive, ≥ 2 peripheral joints
Serositis - Pleuritis or pericarditis
Renal disorder - Persistent
proteinuria > 0.5 g/day or cellular casts
Neurological - Seizures or
psychosis, without provoking drugs/metabolic derangement
Haematological disorder
- Haemolytic anaemia or leucopenia (< 4 × 109/L) or
Lymphopenia (< 1 × 109/L) or thrombocytopenia (< 100 × 109/L) not due to
drugs
Immunological - Raised anti-DNA
antibodies or antibody to Sm
antigen or positive
antiphospholipid antibodies
ANA disorder - Abnormal ANA titre by
immunofluorescence SLE is diagnosed if any 4 of these 11 features are present
serially or simultaneously.
Clinical features
Skin: The skin of the fingers becomes tight, shiny and
thickened. Raynaud’s phenomenon occurs early in the disease. In the distal
extremities, the combination of intimal fibrosis
and vasculitis may cause tissue ischaemia, skin ulceration and
localised infarcts. Subcutaneous calcium deposition can cause nodules on the
fingers (calcinosis). Involvement of the face causes thinning and radial
furrowing of the lips. Telangiectasia may be present. Skin involvement
restricted to sites distal to the elbow or knee (apart from the face) is
classified as LCSS or CREST syndrome; more proximal involvement is classified
as DCSS.
Musculoskeletal
features: Arthralgia, morning stiffness and
flexor tenosynovitis are common. Restricted hand function is usually due to
skin rather than joint disease.
GI features: Smooth muscle atrophy and fibrosis in the lower oesophagus
lead to acid reflux with erosive oesophagitis; this may in turn progress to
further fibrosis. Dysphagia may also occur. Involvement of the stomach causes
early satiety and occasionally outlet obstruction. Small intestine involvement
may lead to malabsorption due to bacterial overgrowth and intermittent bloating
or pain. Dilatation of the large or small bowel due to autonomic neuropathy may
cause pseudo-obstruction.
Cardiorespiratory
features: Pulmonary involvement is a major cause
of morbidity and mortality. Pulmonary fibrosis mainly affects patients with
diffuse disease. Pulmonary hypertension is a complication of long-standing
limited disease, characterised by rapidly
progressive dyspnoea and right heart failure.
Renal features: One of the main causes of death is hypertensive renal
crisis characterised by rapidly developing malignant hypertension and renal
failure. It is much more common in patients with diffuse disease.
Investigations
The diagnosis is primarily a clinical one. ANA is positive in 70%.
Anti-topoisomerase I (anti-Scl-70) antibodies occur in 30% of those with
diffuse systemic sclerosis, and anti-centromere antibodies occur in 60% of
those with CREST syndrome.
Management and prognosis
Raynaud’s and digital
ulcers: Patients should avoid cold
exposure; conventional or heated mittens can be effective. Calcium antagonists (e.g.
nifedipine, amlodipine) and angiotensin II receptor antagonists (e.g.
valsartan) promote vasodilatation, and epoprostenol infusions may be helpful
for severe digital ischaemia. Prompt antibiotics are required for infected skin
ulcers.
Oesophageal reflux: This should be treated with proton pump inhibitors
(PPIs) and prokinetic agents such as metoclopramide.
Hypertension: This should be treated aggressively with ACE inhibitors.
Pulmonary
hypertension: This is managed with the oral
endothelin 1 antagonist bosentan, but if severe may require heart–lung transplantation.
Mixed connective tissue disease
This is an overlap connective tissue disease with features of SLE,
systemic sclerosis and myositis. Most patients have antiribonucleoprotein (anti-RNP)
antibodies, although these can also occur in SLE without overlap features.
Sjögren’s syndrome
This idiopathic autoimmune disorder is characterised by
lymphocytic infiltration of salivary and lachrymal glands, leading to glandular
fibrosis and exocrine failure. It predominantly affects women and has a peak
onset between the ages of 40 and 60 yrs.
There is an association with HLA-B8 and DR3. The disease may be primary
or secondary in association with other autoimmune diseases such as RA, SLE or
primary biliary cirrhosis.
Clinical features
● Dry eyes (keratoconjunctivitis sicca) due to a lack of
tears.
● Dry
mouth (xerostomia).
● Vaginal dryness.
● Other features: fatigue, non-erosive arthritis and
Raynaud’s phenomenon.
● There is a 40-fold increase in lifetime risk of
lymphoma.
Investigations
The diagnosis can be established by the Schirmer test, which
measures the flow of tears using an absorbent paper strip placed in the lower
eyelid; a normal result is > 6
mm of wetting over 5 mins. If the diagnosis is in doubt, lip biopsy may
identify lymphocytic infiltration of the minor salivary glands.
● ESR: usually elevated.
● Autoantibodies: RF, ANA, anti-Ro (SS-A) and anti-La
(SS-B).
Management
Treatment is largely symptomatic:
● Artificial tears and lubricants for dry eyes.
● Artificial saliva for xerostomia.
● Lubricants such as K-Y jelly for vaginal dryness.
● Corticosteroids for extraglandular and musculoskeletal
manifestations.
Polymyositis and dermatomyositis
These rare connective tissue disorders are characterised by muscle
weakness and inflammation. The onset is usually between 40 and 60 yrs of age.
There is a threefold increased risk of malignancy in patients with
dermatomyositis and polymyositis.
Clinical features
Polymyositis: Presents with symmetrical proximal muscle weakness, usually
affecting the lower limbs first. Patients report difficulty rising from a
chair, climbing stairs and lifting, sometimes in combination with muscle pain.
The onset is typically gradual, over a few
weeks. Systemic features of fever, weight loss and fatigue are common.
Respiratory or pharyngeal muscle involvement leading to ventilatory
failure/aspiration is ominous and requires urgent treatment.
Interstitial lung disease occurs in up to 30%, most of whom have
antisynthetase (Jo-1) antibodies.
Dermatomyositis: Presents similarly but in combination with characteristic
cutaneous manifestations. Gottron’s papules are scaly erythematous/violaceous
plaques or papules occurring over the extensor surfaces of the fingers. A
characteristic heliotrope rash may develop – a violaceous discoloration of the eyelid
associated with periorbital oedema.
Investigations
Muscle biopsy shows typical features of fibre necrosis and
inflammatory cell infiltration. MRI can help identify areas of abnormal muscle.
CK is usually raised and tracks disease activity. ANA and anti-Jo1 antibodies
may be positive. EMG may confirm the presence
of myopathy and exclude neuropathy.
Management
Oral corticosteroids (e.g. prednisolone) are the mainstay of
initial treatment. Patients with severe weakness or respiratory or pharyngeal involvement
may require IV methylprednisolone. Additional immunosuppressive
therapy (e.g. azathioprine or methotrexate) is often
required.
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