Systemic lupus erythematosus Flashcards
Lupus is in a family of overlapping autoimmune diseases, what other autoimmune diseases are in the family?
Rheumatoid arthritis Sjogren's syndrome Dermatomyositis Polymyositis Systemic sclerosis
What is the distribution of lupus like in terms of gender and age?
M:F 1:9 Presentation 15-40 years
In what races is there increased prevalence of lupus
Afro-caribbean, asian and chinese
What does lupus principally effect?
Joints and skin
Lungs
Kidneys
Haematology
What genetic associations does lupus have?
Multiple genes implicated Complement deficiency e.g. C1q and C3 Fc receptors, IRF5, CTLA4, MHC class II HLA genes
How does lupus normally present?
Malaise Fatigue Fever Weight loss Lymphadenopathy
What specific features are there of lupus presentation?
Butterfly rash
Alopecia
Arthralgia
Long history of Raynaud’s phenomenon
What other features are there of lupus?
Inflammation of kidney, CNS, heart and lungs
Accelerated atherosclerosis
Vasculitis
Why is lupus a very difficult disease to diagnose?
It affects so many different systems
How do lupus patients appear?
The disease makes patients feel incredibly unwell
They have rashes- nose/chin, it may look a bit like acne- localised inflammation but isn’t itchy or painful.
Some rashes can become depigmented- this happens when inflammation extends to the dermis
Depigmentation and scarring is irreversible- however this is usually quite rare
What are the immune systems of SLE patients like normally?
They tend to be overactive- particularly humoral
How is apoptosis affected in lupus?
SLE patients have a defect in apoptosis
Normally we clear dead cells in a non-inflammatory way however patients with SLE can’t do this
There is impaired clearance that is associated with inflammation. Apoptotic cells linger in the body and expose nuclear antigens on their surface.
Auroantibodies
What happens to the nuclear antigens that are exposed on the surface?
Autoantibodies are generated against them
What is the defect in apoptosis combined with and what does this lead to?
B cell hyperactivity- overactive B cells are exposed to autoantigens and plasma cells begin to produce autoantibodies that circulate and form immune complexes.
Due to the B cell hyperactivity, what happens to the immune complexes formed?
They deposit in tissues (mainly kidneys and skin) and activate complement in the tissue
Give a brief summary of autoantibody production in lupus?
Abnormal clearance of apoptotic cell material
Dendritic cell uptake of autoantigens and activation of B cells
B cell Ig class switching and affinity mutation
IgG autoantibodies
Immune complexes
Complement activation and cytokine generation etc
What is the first thing you do to diagnose SLE?
First thing you do is send serum to check for anti-nuclear antibodies (ANA)- useful but not diagnostic
How does ANA testing work?
Serum is placed on a glass slide with cells suspended on it and if ANAs are present they will bind to nuclear antigens.
To tell whether they have bound, you add fluorescently labelled monoclonal antibody that binds to the ANA and observe pattern of attachment
What are the different patterns of ANA and what do they mean?
Homogenous- Abs to DNA- SLE
Speckled- Abs to Ro, La, Sm and RNP- SLE overlap syndromes
Nucleolar- topoisomerase- scleroderma
Centromere- limited cutaneous scleroderma
How does usefulness of Anti-dsDNA and Sm testing differ to ANA?
More specific but less sensitibe
What is anti-Ro and/or La testing used for?
Common in subacute cutaneous LE
Neonatal lupus syndrome and Sjogren’s
What other tests are used to diagnose lupus?
INcreased complement consumption
Anti-cardiolipin antibodies
Lupus anticoagulant
Beta1 glycoprotein
Haematology- Lympopaenia, normochromic anaemia Leukopaenia, AIHA, thrombocytopenia Renal- Proteinuria, haematuria Active urinary sediment
How does complement consumption change in lupus?
Patients with active lupus form immune complexes and they fix complement and consume it, so if you measure complement in the blood (c3 and c4) it will be low in active lupus
What is happening in autoimmune haemolytic anaemia?
Antibodies are binding to red cell surface and are being taken out in the spleen
How do you assess severity of lupus?
Identify pattern of organ involvement
Monitor function of affected organs
Identify pattern of autoantibodies expressed
What do you monitor in terms of renal and lungs/CVS
Renal- BP, U and E, urine sediment and prot:crea ratio
Lungs/CVS- Lung function and ECG
What else do you monitor function of?
Skin, haematology and eyes
What pattern of autoantibodies preempts renal disease?
High titre anti-dsDNA and anti-Sm autoantibodies
What signs of disease activity are there in terms of clinical and laboratory markers?
Clinical- Weight loss, fatigue and malaise Alopecia Rash Laboratory- ESR Increased complement consumption Increased anti-dsDNA Other Abs e.g. ANA and CRP poor indicators
What is the importance in picking up disease activity early?
You could prevent organ damage
How is lupus classified into 3 groups?
Based on severity:
Mild- Joint and/or skin involvement
Moderate- Inflammation of other organs, pleuritis, pericarditis, mild nephritis
Severe- Severe inflammation in vital organs
What does severe lupus consist of?
Severe nephritis CNS disease Pulmonary disease Cardiac involvement AIHA, thrombocytopenia and TTP
How do you treat mild disease?
Paracetamol +/- NSAID- monitor renal function
Hydroxychloroquine- arthropathy, cutaneous manifestations and mild disease activity
Topical corticosteroids
What are the indications of moderate disease?
Failure of hydroxychloroquine/NSAID
Organ/life threatening disease
How do you treat moderate disease?
Corticosteroids: High initial dose to suppress disease activity IV methylprednisolone 3x 0.5-1g per 24hr Initial oral dose for 4 weeks Reduce slowly over 2-3 months to 10mg/d Reduce slowly to 1mg per month
Why do you give steroid sparing agents as well as steroids when treating moderate disease?
High dose steroids are very toxic so may give steroids with steroid sparing agents so you can lower dose
How do you treat severe disease?
Azathioprine: Moderate to severe disease 2.5mg/kg/day Effective steroid sparing agent 20% neutropenia Regular FBC and biochem monitoring
Cyclophosphamide-
Severe organ involvement, IV pulsed or oral Rx
BM suppression, infertility and cystitis
What new treatment is there for severe disease?
Mycophenolate mofetil:
Reversible inhibitor of inosine monophosphate dehydrogenase which is a rate-limiting enzyme in de novo purine synthesis- lymphocytes are dependent on this
Rituximab:
Anti-CD20 mAb therapy that leads to depletion of B cells
It is effective in lupus nephritis
What effect does mycophenolate mofetil and rituximab have on fertility?
None but it is teratogenic so shouldn’t try to conceive
What is the prognosis and survival like in severe lupus?
15 year survival:
No nephritis- 85%
Nephritis- 60%
Worse if black, male or low socio-economic status
What is the mortality pattern of lupus like?
There is the bimodal mortality pattern as there is an early peak in mortality and then a later peak as well
What causes the early and late peaks in mortality?
Early- Renal failure CNS disease Infection Late- Myocardial infarction Stroke
What could the blood film of a patient with SLE show?
Schistocytes (fragments)- microangiopathic haemolytic anaemia Spherocytes Tear drop cells Few leukocytes Few platelets
What could the renal biopsy of a patient with SLE show?
Hypercellular- loads more cells than in a normal glomerulus
Mesangial proliferation
Crescent development- inflammatory cells that have migrated into glomerulus
