Systemic Lupus Erythematosus

• Acute onset, chronic, relapsing and remitting, often febrile illness charaterised principally by injury to the skin, joints, kidney and serosal membranes
• Prevalence of 1 in 2500
• M:F ratio, 9:1
• Usually arises in 20-30 age group

 

Aetiology/pathogenesis

 

• Fundamental defect is a failure of the mechanisms that maintain self-tolerance
• Produce antibodies which recognise cytoplasmic, nuclear and cell surface antigens
• ANA’s can be split into four categories;
  • Antibodies to DNA
  • Antibodies to histones
  • Antibodies to non-histone proteins bound to RNA
    Antibodies to nucleolar antigens
• ANA recognised by indirect immunofluorescence. Four basic patterns have been recognised;
  • Homogenous or diffuse nuclear staining – antibodies to histones, chromatin and less commonly dsDNA
  • Peripheral nuclear staining – indicative of antibodies recognising dsDNA
  • Speckled pattern – common pattern. Reflects the presence of antibodies to non-DNA nuclear components e.g. anti-Sm, anti-Ro, anti-La
  • Nucleolar pattern – represents antibodies to nucleolar RNA. Most commonly seen in patients with systemic sclerosis
• Generally ANA is recognised in virtually every patient with SLE, therefore test is very sensitive
• 5-15% of normal individuals have these autoantibodies
• Anti-Sm is virtually diagnostic for SLE
• Anti-phospholipid autoantibodies are present in around 50% of SLE patients
• Some of the autoantibodies interfere with in vitro clotting tests such as partial thromboplastin time. These antibodies are referred to as lupus anticoagulant but despite having a circulating anticoagulant which delaying in vitro clotting time, these patients have a hypercoagulable state. They have venous and arterial thrombosis, which may be associated with recurrent miscarriages and focal cerebral or ocular ischaemia
• The above clinical symptoms when associated with SLE are called secondary antiphospholipid antibody syndrome. If patients develop these symptoms in the absence of SLE it is called primary antiphospholipid antibody syndrome

 

 

 

Genetic factors

 

• Familial tendency to inherit disease
• Higher concordance in mono than dizygotic twins
• Association with HLA-DQ
• Inherited deficiencies in Complement components – C2, C4, C1q
• Best animal model of disease is the (NZWxNZB)F1

 

Environmental factors

 

• Drugs such as hydralazine, procainamide and D-penicillamine can induce an SLE-like disease in humans
• Exposure to ultraviolet light can exacerbate disease (may induce apoptosis or promote IL-1 production by keratinocytes)
• Role of sex hormones – more common in women, exacerbations in pregnancy and during normal menses

 

Immunological factors

 

• Production of autoantibodies driven by a antigen specific CD4+ T cell response
• Defective clearance of apoptotic cells
• Dysregulation of cytokine release particularly interferrons
• Most of the visceral injury is mediated by immune complexes (Type III hypersensitivity)

 

Diagnosis criteria (American college of rheumatology)  - require to have 4 of the following;

• Maler rash
• Discoid rash
• Photosensitivity
• Oral ulcers
• Arthritis
• Serositis (pericarditis or pleuritis)
• Renal disorder
• Neurological disorder – seizures, psychosis
• Haematological disorder – anaemia, lymphopenia, thrombocytopenia
• Immunological disorder – anti-dsDNA, anti-Sm, anti-phospholipid
• Antinuclear antibodies

 

Morphology

 

• Most characteristic lesions due to deposition if immune complexes and are found in the skin, blood vessels, connective tissue and kidney
• An acute necrotising vasculitis involving small arteries or arterioles can present in any tissue
• In chronic stages vessels can undergo fibrous thickening with luminal narrowing
• Kidney
  • Injury due to immune complex deposition
  • Immune complexes are believed to form in situ
  • Other injury may be thrombotic due to anti-phospholipid antibodies
• Skin
  • Skin is involved in the majority of patients
  • Erythema generally affects butterfly area of the face but a similar rash can also be seen in the limbs and trunk
  • Erythema accentuated by sunlight exposure
  • Histology shows liquifactive degeneration of the basal layer of the epidermis with odema at the dermal junction. In the dermis there is mononuclear infiltration and Ig and complement deposition at the dermoepidermal junction
• Joints
  • Joint involvement frequently involves a nonerosive synovitis with little deformity (distinguishing it from that seen in RA)
  • In acute phase there can be neutrophils and fibrin found in the synovium and a perivascular mononuclear infiltrate around the subsynovial tissue
• CNS
  • Neuropsychiatric symptoms due to a noninflammatory occlusion of small blood vessels by intimal proliferation. Believed to result from anti-phopholipid antibody mediated damage of the endothelium
  • Other studies suggest that antibodies which recognise a synaptic membrane protein might be involved in CNS symptoms
• Serosal involvement
  • Inflammation of the serosa may be acute, subacute or chronic
  • Fibrinous exudates may be seen in acute inflammation. Fibrous tissue might be present in chronic inflammation
• Cardiovascular system
  • Most manifested in the form of pericarditis
  • Myocarditis due to mononuclear cell infiltration is less common
  • Libman-Saks endocarditis – non bacterial deposits on heart valves
  • Coronary atherosclerosis is common, unclear whether it is caused by immune complexes and anti-phospolipid mediated damage or due to an increased incidence in traditional risk factors in SLE patients
• Spleen
  • May be moderately enlarged with a thickened capsule
  • Numerous plasma cells are present in the pulp
• Lungs
  • Most common manifestations are pleuritis and pleural effusions
  • Less commonly there may be alveolar injury in the form of oedema and haemorrhage
  • May also result in chronic interstitial fibrosis
• Other organs
  • Acute vasculitis may be seen in the portal tracts of the liver accompanied by lymphocytic infiltration creating non-specific portal triaditis
  • Lupus erythematous (LE) bodies (a phagocyte which had engulfed the denatured nucleus of an injured cell) may be present in the bone marrow
  • Lymph nodes may be enlarged and contain hyperactive follicles

 

Clinical Course

 

• May present as a fever of unknown origin
• Presenting manifestation may be anaemia or thrombocytopenia
• Patients are prone to infections, partly due to their immune dysregulation and their treatment with immune suppressants
• Flare ups and remissions can occur for years or decades
• During flare ups, hypocomplementaemia can occur
• 80% 10 year survival rate. Death generally due to renal complications and intercurrent infections. Coronary artery disease is also an increasing cause of death
• Patients treated with immunosuppressants and steroids also incur the usual risks associated with such therapies

 

• Two syndromes have been identified in which cutaneous involvement in the predominant feature;

·        Chronic Discoid Lupus Erythematosis

• • Skin lesions mimic SLE but systemic manifestations are rare

 

·        Subacute Cutaneous Lupus Erythematosis

• • Differs from chronic discoid lupus in that the rash is generally widespread, superficial and non-scarring
  • Mild systemic components
  • Associated with HLA-DR3 and anti-Ro antibodies