SLE (05.02.2020) Flashcards

1
Q

What disease family is SLE in? What other diseases are in that family?

A

Family of chronic overlapping AI diseases

  • Rheumatoid arthritis
  • Systemic lupus erythematosus
  • Systemic sclerosis
  • Polymyositis
  • Dermatomyositis
  • Sjögren’s syndrome
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2
Q

SLE - general info

A
  • rare (3 in 10,000)
  • mainly affects women (9:1)
  • generally presents at 15-40 years of age
  • increased in afro-carribean and asian population, prevalence varies
  • genetic predisposition and environmental factors
  • Principally affects joints and skin but also lungs, kidneys, haematology
  • Severity from mild joint pain to fulminant & life threatening
  • Clinical features depend on organ affected
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3
Q

Where does SLE sit on a spectrum of connected AI diseases?

A
  • RA (mainly joints)
  • SLE
  • Sjorgen Syndrome
  • Dermatomyositis (mainly muscular)
  • Polymyositis (mainly muscular)
  • scleroderma / systemic sclerosis (features of muscle, skin and joint involvement as well as lung disease)
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4
Q

Genetic associations of SLE

A
  • multiple GWAS studies show that it is a polygenic disease with multiple susceptibility genes (e.g. Fc receptors, IRF5, CTLA4, MHC class II HLA genes)
  • There are some genes, that if you are deficient you will have SLE (C1q and C3) -> complement deficiency
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5
Q

How does SLE clinically present?

A
  • Malaise, fatigue, fever, wt loss
  • Lymphadenopathy

Specific features:
• Butterfly rash, alopecia
• Arthralgia
• Raynaud’s phenomenon

Other features:
• Inflammation kidney, CNS, heart, lungs
• Accelerated atherosclerosis
• Vasculitis

Severe presentations are possible e.g. with myocarditis!

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6
Q

SLE ACR criteria

A
  • Malar rash
  • Discoid rash (sparing of nasal folds)
  • Photosensitivity
  • Oral ulcers
  • Arthritis
  • Serositis: (a) pleuritis or (b) pericarditis
  • Renal disorder e.g. proteinuria > 0.5g/24h
  • Neurological disorder e.g. seizures/ pyschosis
  • Haematological disorder
  • Immunologic disorder e.g anti-dsDNA Abs
  • Antinuclear antibody in raised titre
  • > 4 out of 11
  • > a spectrum of tissues is affected!
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7
Q

Rash in SLE

A
  • not everyone presents with it
  • butterfly shape
  • sparing of nasal folds (distinguishes it from rosacea)
  • some patients may have scarring
  • no pus in the rash
  • there may be areas of erythema around the rash
  • you may have scarring alopecia (this can be traced with local corticosteroid injections)
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8
Q

Pathogenesis of SLE

A
  • genetic predisposition
  • environmental triggers (e.g. virus and TLR but not understood yet; minor infections e.g. UTI can kick off a disease flare; perhaps bacterium) -> this probably happens a number of times
  • then you get b-cell hyperactivity (critical point) chronically activated innate immune system -> witch from innate to adaptive immune response with antibodies and immune complex
  • this goes through cycles but eventually there is irreversible (typically completement induced) tissue injury.
  • Type 3 hypersensitivity
  • also: clearance of apoptotic cells is deficient in SLE
  • nuclear antigens come onto surface - we clear them fast but people with lupus can’t clear them and develop antibodies and immune complexes against them.
  • ABs and immune complexes settle in the skin or kidneys and activate complement - complement mediated tissue damage causes rash and nephritis
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9
Q

What is the genetic haplotype with predisposition to SLE?

A

HLA-DR

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10
Q

What type of hypersensitivity is SLE?

A

Type 3

- immune complex driven

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11
Q

Pathophysiology of SLE (quick)

A
  • abnormal clearance of apoptotic cell material
  • dendritic cell uptake of auto antigens and activation of B-cells
  • B cell Ig-Class switching and affinity maturation
  • IgG autoantibodies
  • immune complexes
  • complement activation, cytokine generation etc.
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12
Q

ANA

A
  • anti nuclear antibody (aABs against apoptotic cells)
  • lab test that may point towards lupus if positive
  • not diagnostic, but an indicator
  • pattern important e.g. speckled or homogenous (indirect immunofluorescence shows where the attachments on the cells are)
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13
Q

Which laboratory tests are used in the diagnosis process of SLE?

A
  • ANA
  • anti-dsDNA and Sm (more specific but less sensitive)
  • Anti-Ro and/or La
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14
Q

What do different patterns in the ANA test indicate?

A
  • Homogenous - Abs to DNA
  • Speckled - Abs to Ro, La, Sm, RNP
  • Nucleolar - topoisomerase - scleroderma
  • Centromere - limited cutaneous scleroderma
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15
Q

anti-dsDNA and Sm

A
  • (more specific but less sensitive) than ANA
  • absence does not exclude lupus (only 30% people with lupus have it)
  • Sm = anti-Smith
  • 20% people with lupus have it; rarely found in healthy individuals or other rheumatoid diseases
  • can be used to confirm lupus
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16
Q

anti-Ro and/or ant-La

A
  • Common in subacute cutaneous LE
  • Neonatal lupus syndrome & Sjögren’s
  • found mostly in people with systemic lupus
  • frequently found in people with lupus and a negative ANA
  • babies of mothers with anti-Ro and anti-La antibodies are at an increased risk of neonatal lupus, an uncommon condition that produces a temporary rash and can lead to congenital heart block
  • > women with lupus who wish to become pregnant should be tested for these antibodies
17
Q

Haematological features of lupus - diagnostics

A
  • Lymphopaenia, normochromic anaemia

* Leukopaenia, AIHA, thrombocytopaenia

18
Q

Renal feature of SLE - diagnostics

A
  • Proteinuria, haematuria

* Active urinary sediment

19
Q

Other tests for SLE (aside form antibodies)

A
  • Increased complement consumption
  • Anti-cardiolipin antibodies
  • Lupus anticoagulant
  • ß1 glycoprotein
20
Q

How do you assess disease severity in SLE?

A
  1. Identify pattern of organ involvement
  2. Monitor function of affected organs
    • Renal - BP, U & E, urine sediment + Prot:Crea ratio
    • Lungs/CVS - lung function, echocardiography
    • Skin, haematology, eyes
  3. Identify pattern of autoantibodies expressed
    • Anti-dsDNA, anti-Sm - renal disease
    • Anti-cardiolipin antibodies
21
Q

How can you assess the signs of disease activity and pre-empt severe attacks?

A

Clinical features
• Wt loss, fatigue, malaise, hair loss (e.g. how is the fatigue? Are you feeling better or worse?)
• Alopecia (e.g. how is your alopecia compared to when I last saw you?)
• Rash (is it different?)

Laboratory markers
•  ESR (raised in high disease activity)
•  Increased complement consumption 
•  Increased anti-dsDNA 
•  Other Abs e.g ANA and CRP poor indicators
22
Q

CRP and ESR in active SLE

A
  • CRP is normal!! (in RA it would go up with ESR)

- ESR is increased

23
Q

Serum complement test

A
  • A serum complement test measures the levels of proteins consumed during the inflammatory process.
  • Thus, low complement levels reflect that inflammation is taking place within the body.
  • Variations in complement levels exist in different individuals simply due to genetic factors.
24
Q

Mild SLE

A

joint +/- skin involvement

25
Q

Moderate SLE

A

Joint +/- skin involvement

Inflammation of other organs:

  • pleuritis
  • pericarditis
  • mild nephritis
26
Q

Severe SLE

A
-  severe inflammation in vital organs
	• severe nephritis		          
	• CNS disease
	• pulmonary disease
	• cardiac involvement
	• AIHA, Thrombocytopaenia, TTP
27
Q

How do you treat mild SLE?

A

A. Paracetamol +/- NSAID
• Monitor renal function

B. Hydroxychloroquine
• arthropathy
• cutaneous manifestations
• mild disease activity

C. Topical corticosteroids (for rash but not face)

28
Q

SE of steroids

A
  • skin thinning
  • weight gain
  • diabetes
  • osteoporosis
  • acne

=> you cannot give too many steroids to patients because of the SE profile.

29
Q

How do you treat moderate SLE?

A

Indication:
• failure of hydroxychloroquine/NSAID
• organ/life threatening disease

Corticosteroids
• high initial dose to suppress disease activity
(0.5-1.5mg/kg/day)
• iv methylprednisolone 3 x 0.5-1g per 24h• initial oral dose for 4 weeks
• reduce slowly over 2-3 mths to 10 mg/d
• reduce slowly at 1mg per month

30
Q

How do you treat sever SLE?

A

Azathioprine
• moderate to severe disease 2.5 mg/kg/day
• effective steroid-sparing agent
• 20% neutropenia (3/1000 severe BM suppression)
• regular FBC & biochemistry monitoring

Cyclophosphamide
• severe organ involvement, iv pulsed or oral Rx
• eg. nephritis - 6 x 1 monthly iv pulses
• BM suppression, infertility, cystitis (acrolein) -> quite problematic if you think of the age group that is affected by SLE
• given in much more severe disease where the benefit is better than the risk

Mycophenolate mofetil
• Reversible inhibitor of inosine monophosphate dehydrogenase
• Rate-limiting enzyme in de novo purine synthesis
• Lymphocytes – dependent upon de novo purine synthesis

Rituximab
• Anti-CD20 mAb therapy
• Leads to depletion of B cells
• Effective in lupus nephritis	
• Binds to B-cells, less b cells in the circulation. Used in lymphoma

Belimumab
• Belimumab blocks Blys -> reduces the activity of B-cells; tries to switch off B-cell hyperactivity.

31
Q

What is important in SLE treatment?

A

DO NOT UNDE-TREAT THE PATIENTS!!

  • aggressive treatment
  • do not be scared to treat them because you are really scared of the drugs
32
Q

Prognosis and survival

A
  • 15 year survival : no nephritis 85%
    nephritis 60%
  • Prognosis also worse if black, male, low socio-economic status
33
Q

What has a big influence of 15-year survival with SLE?

A

Kidney involvement/nephritis: no nephritis 85%; nephritis 60%

34
Q

Bimodal mortality pattern in SLE

A

Early Active lupus
Renal failure
CNS disease
Infection

Late Myocardial infarction

35
Q

CHD and SLE

A
  • acccelaerated/more severe atherosclerosis
  • The atherosclerosis plaques are more likely to have stroke, MI
  • Women are still protected form CVS disease for some time.
  • mortality in later stages of SLE
36
Q

What are the main components of SLE treatment?

A
  • Symptomatic
  • Immune-modulating
  • Immunosuppressive