SLE (05.02.2020) Flashcards
What disease family is SLE in? What other diseases are in that family?
Family of chronic overlapping AI diseases
- Rheumatoid arthritis
- Systemic lupus erythematosus
- Systemic sclerosis
- Polymyositis
- Dermatomyositis
- Sjögren’s syndrome
SLE - general info
- 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
Where does SLE sit on a spectrum of connected AI diseases?
- 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)
Genetic associations of SLE
- 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
How does SLE clinically present?
- 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!
SLE ACR criteria
- 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!
Rash in SLE
- 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)
Pathogenesis of SLE
- 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
What is the genetic haplotype with predisposition to SLE?
HLA-DR
What type of hypersensitivity is SLE?
Type 3
- immune complex driven
Pathophysiology of SLE (quick)
- 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.
ANA
- 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)
Which laboratory tests are used in the diagnosis process of SLE?
- ANA
- anti-dsDNA and Sm (more specific but less sensitive)
- Anti-Ro and/or La
What do different patterns in the ANA test indicate?
- Homogenous - Abs to DNA
- Speckled - Abs to Ro, La, Sm, RNP
- Nucleolar - topoisomerase - scleroderma
- Centromere - limited cutaneous scleroderma
anti-dsDNA and Sm
- (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
anti-Ro and/or ant-La
- 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
Haematological features of lupus - diagnostics
- Lymphopaenia, normochromic anaemia
* Leukopaenia, AIHA, thrombocytopaenia
Renal feature of SLE - diagnostics
- Proteinuria, haematuria
* Active urinary sediment
Other tests for SLE (aside form antibodies)
- Increased complement consumption
- Anti-cardiolipin antibodies
- Lupus anticoagulant
- ß1 glycoprotein
How do you assess disease severity in SLE?
- Identify pattern of organ involvement
- Monitor function of affected organs
• Renal - BP, U & E, urine sediment + Prot:Crea ratio
• Lungs/CVS - lung function, echocardiography
• Skin, haematology, eyes - Identify pattern of autoantibodies expressed
• Anti-dsDNA, anti-Sm - renal disease
• Anti-cardiolipin antibodies
How can you assess the signs of disease activity and pre-empt severe attacks?
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
CRP and ESR in active SLE
- CRP is normal!! (in RA it would go up with ESR)
- ESR is increased
Serum complement test
- 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.
Mild SLE
joint +/- skin involvement
Moderate SLE
Joint +/- skin involvement
Inflammation of other organs:
- pleuritis
- pericarditis
- mild nephritis
Severe SLE
- severe inflammation in vital organs • severe nephritis • CNS disease • pulmonary disease • cardiac involvement • AIHA, Thrombocytopaenia, TTP
How do you treat mild SLE?
A. Paracetamol +/- NSAID
• Monitor renal function
B. Hydroxychloroquine
• arthropathy
• cutaneous manifestations
• mild disease activity
C. Topical corticosteroids (for rash but not face)
SE of steroids
- skin thinning
- weight gain
- diabetes
- osteoporosis
- acne
=> you cannot give too many steroids to patients because of the SE profile.
How do you treat moderate SLE?
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
How do you treat sever SLE?
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.
What is important in SLE treatment?
DO NOT UNDE-TREAT THE PATIENTS!!
- aggressive treatment
- do not be scared to treat them because you are really scared of the drugs
Prognosis and survival
- 15 year survival : no nephritis 85%
nephritis 60% - Prognosis also worse if black, male, low socio-economic status
What has a big influence of 15-year survival with SLE?
Kidney involvement/nephritis: no nephritis 85%; nephritis 60%
Bimodal mortality pattern in SLE
Early Active lupus
Renal failure
CNS disease
Infection
Late Myocardial infarction
CHD and SLE
- 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
What are the main components of SLE treatment?
- Symptomatic
- Immune-modulating
- Immunosuppressive
