Systemic lupus erythematosus

Question 1

Lupus is in a family of overlapping autoimmune diseases, what other autoimmune diseases are in the family?

Answer 1

Rheumatoid arthritis
Sjogren's syndrome
Dermatomyositis
Polymyositis
Systemic sclerosis

Question 2

What is the distribution of lupus like in terms of gender and age?

Answer 2

M:F 1:9 Presentation 15-40 years

Question 3

In what races is there increased prevalence of lupus

Answer 3

Afro-caribbean, asian and chinese

Question 4

What does lupus principally effect?

Answer 4

Joints and skin
Lungs
Kidneys
Haematology

Question 5

What genetic associations does lupus have?

Answer 5

Multiple genes implicated
Complement deficiency e.g. C1q and C3
Fc receptors, IRF5, CTLA4, MHC class II HLA genes

Question 6

How does lupus normally present?

Answer 6

Malaise
Fatigue
Fever 
Weight loss
Lymphadenopathy

Question 7

What specific features are there of lupus presentation?

Answer 7

Butterfly rash
Alopecia
Arthralgia
Long history of Raynaud’s phenomenon

Question 8

What other features are there of lupus?

Answer 8

Inflammation of kidney, CNS, heart and lungs
Accelerated atherosclerosis
Vasculitis

Question 9

Why is lupus a very difficult disease to diagnose?

Answer 9

It affects so many different systems

Question 10

How do lupus patients appear?

Answer 10

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

Question 11

What are the immune systems of SLE patients like normally?

Answer 11

They tend to be overactive- particularly humoral

Question 12

How is apoptosis affected in lupus?

Answer 12

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

Question 13

What happens to the nuclear antigens that are exposed on the surface?

Answer 13

Autoantibodies are generated against them

Question 14

What is the defect in apoptosis combined with and what does this lead to?

Answer 14

B cell hyperactivity- overactive B cells are exposed to autoantigens and plasma cells begin to produce autoantibodies that circulate and form immune complexes.

Question 15

Due to the B cell hyperactivity, what happens to the immune complexes formed?

Answer 15

They deposit in tissues (mainly kidneys and skin) and activate complement in the tissue

Question 16

Give a brief summary of autoantibody production in lupus?

Answer 16

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

Question 17

What is the first thing you do to diagnose SLE?

Answer 17

First thing you do is send serum to check for anti-nuclear antibodies (ANA)- useful but not diagnostic

Question 18

How does ANA testing work?

Answer 18

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

Question 19

What are the different patterns of ANA and what do they mean?

Answer 19

Homogenous- Abs to DNA- SLE
Speckled- Abs to Ro, La, Sm and RNP- SLE overlap syndromes
Nucleolar- topoisomerase- scleroderma
Centromere- limited cutaneous scleroderma

Question 20

How does usefulness of Anti-dsDNA and Sm testing differ to ANA?

Answer 20

More specific but less sensitibe

Question 21

What is anti-Ro and/or La testing used for?

Answer 21

Common in subacute cutaneous LE

Neonatal lupus syndrome and Sjogren’s

Question 22

What other tests are used to diagnose lupus?

Answer 22

INcreased complement consumption
Anti-cardiolipin antibodies
Lupus anticoagulant
Beta1 glycoprotein

Haematology-
Lympopaenia, normochromic anaemia
Leukopaenia, AIHA, thrombocytopenia 
Renal- 
Proteinuria, haematuria
Active urinary sediment

Question 23

How does complement consumption change in lupus?

Answer 23

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

Question 24

What is happening in autoimmune haemolytic anaemia?

Answer 24

Antibodies are binding to red cell surface and are being taken out in the spleen

Question 25

How do you assess severity of lupus?

Answer 25

Identify pattern of organ involvement Monitor function of affected organs Identify pattern of autoantibodies expressed

Question 26

What do you monitor in terms of renal and lungs/CVS

Answer 26

Renal- BP, U and E, urine sediment and prot:crea ratio | Lungs/CVS- Lung function and ECG

Question 27

What else do you monitor function of?

Answer 27

Skin, haematology and eyes

Question 28

What pattern of autoantibodies preempts renal disease?

Answer 28

High titre anti-dsDNA and anti-Sm autoantibodies

Question 29

What signs of disease activity are there in terms of clinical and laboratory markers?

Answer 29

``` 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 ```

Question 30

What is the importance in picking up disease activity early?

Answer 30

You could prevent organ damage

Question 31

How is lupus classified into 3 groups?

Answer 31

Based on severity: Mild- Joint and/or skin involvement Moderate- Inflammation of other organs, pleuritis, pericarditis, mild nephritis Severe- Severe inflammation in vital organs

Question 32

What does severe lupus consist of?

Answer 32

``` Severe nephritis CNS disease Pulmonary disease Cardiac involvement AIHA, thrombocytopenia and TTP ```

Question 33

How do you treat mild disease?

Answer 33

Paracetamol +/- NSAID- monitor renal function Hydroxychloroquine- arthropathy, cutaneous manifestations and mild disease activity Topical corticosteroids

Question 34

What are the indications of moderate disease?

Answer 34

Failure of hydroxychloroquine/NSAID | Organ/life threatening disease

Question 35

How do you treat moderate disease?

Answer 35

``` 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 ```

Question 36

Why do you give steroid sparing agents as well as steroids when treating moderate disease?

Answer 36

High dose steroids are very toxic so may give steroids with steroid sparing agents so you can lower dose

Question 37

How do you treat severe disease?

Answer 37

``` 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

Question 38

What new treatment is there for severe disease?

Answer 38

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

Question 39

What effect does mycophenolate mofetil and rituximab have on fertility?

Answer 39

None but it is teratogenic so shouldn't try to conceive

Question 40

What is the prognosis and survival like in severe lupus?

Answer 40

15 year survival: No nephritis- 85% Nephritis- 60% Worse if black, male or low socio-economic status

Question 41

What is the mortality pattern of lupus like?

Answer 41

There is the bimodal mortality pattern as there is an early peak in mortality and then a later peak as well

Question 42

What causes the early and late peaks in mortality?

Answer 42

``` Early- Renal failure CNS disease Infection Late- Myocardial infarction Stroke ```

Question 43

What could the blood film of a patient with SLE show?

Answer 43

``` Schistocytes (fragments)- microangiopathic haemolytic anaemia Spherocytes Tear drop cells Few leukocytes Few platelets ```

Question 44

What could the renal biopsy of a patient with SLE show?

Answer 44

Hypercellular- loads more cells than in a normal glomerulus Mesangial proliferation Crescent development- inflammatory cells that have migrated into glomerulus