SLE Flashcards
Describe the typical patient with SLE
A woman of child bearing age 90%
- highest prevalence is in women of African-American and Afro-caribbean origin.
- lowest prevalence is in white men
Describe the basic pathogenesis of SLE
Gene-environment interactions result in abnormal immune responses that generate pathogenic autoantibodies and immune complexes* that deposit in tissue, activate complement, cause inflammation and over time lead to irreversible organ damage.
- abnormal immune responses vary between individuals
- patients often have low C3/C4 - early complements are important for immune complex clearance
What are environmental risk factors for SLE
Smoking
EBV infection
Sunlight exposure
Silica exposure (most important in African Americans)
What are musculoskeletal manifestations of SLE
Symmetrical migratory polyarthirits, usually not erosive
Myositis
Ischaemic bone necrosis
Arthralgias/myalgia
What are skin manifestations of SLE
Photosensitive malar rash (butterfly distribution) and photosensitive rash in other sun exposed areas
Discoid lupus erythematosus
Alopecia
Oral ulcers
Subacute cutaneous lupus erythematous (looks a bit like a fungal rash)
What are the renal manifestations of lupus
Minimal mesangial lupus nephritis Mesangial proliferative lupus nephritis Focal lupus nephritis Diffuse lupus nephritis Membranous lupus nephritis Advanced sclerotic lupus nephritis
What are the neurological manifestations of lupus
Cognitive dysfunction Headache (usually bad during flares) Mood disturbance and psychosis Myelopathy Mono/poly neuropathy Seizures Stroke/Tia (need to determine whether from vasculitis or atherosclerosis)
What are pulmonary manifestations of SLE?
Pleuritis with or without pleural effusion Interstitial fibrosis Pulmonary hypertension Pulmonary haemorrage Shrinking lung syndrome Lupus pneumonitis
What are the cardiac manifestations of SLE
Pericarditis
Myocarditis
Libman-Sacks endocarditis (fibrinous/sterile infective endocarditis)
Accelerated atherosclerosis with increased rates of MI at relatively young age
What are haematologic manifestations of SLE
Anaemia of chronic disease Haemolytic anaemia - positive Coombe's test Leukopenia (predominantly lymphopenia) Thrombocytopenia - ITP - TTP ** - if red cell fragments and thrombocytopenia Lymphadenopathy Splenectomy Anti-phospholipid syndrome
What are the GI manifestations of SLE
Nausea Vomitting Diarrhea Raised LFTs Intestinal vasculitis Autoimmune peritonitis Lupus enteritis (more common in Asians, thickened bowel loops)
What are ocular manifestations of SLE
Sicca syndrome Retinal vasculitis Optic neuritis Anterior uveitis Episcleritis Scleritis
What autoantibodies and markers can be used to monitor disease severity in SLE
Anti-Ds DNA
Complement (C3/C4) - low in flares
ANA does not correspond to disease severity
What autoantibodies are important to screen in women of childbearing age with SLE and why
Anti-Ro - higher rates of neonatal lupus with congenital heart block (need fetal hr monitoring regularly)
Anti-phospholipid antibodies - high rates of thrombosis and fetal loss
What is the best screening test for lupus?
ANA - 98% of those with SLE have positive but less specific (5-15% of normal population are also positive)
- probability of SLE with a neg ANA is
What are the immunological features of SLE?
ANA (sensitive) Anti-dsDNA (specific) Anti-Sm (specific, less sensitive) - more common in African Americans and renal lupus Anti-Ro and anti-La (SSA and SSB) - also associated with Sjogrens - associated with congenital lupus and heart block Low Complement - C3, C4, CH50 Direct Coombe's test positive (not necessarily haemolytic anaemia) Anti-RNP - 30% SLE - alone - suggestive of MCTD
What is the recommended treatment for mild lupus
Hydroxychloroquine (for all) plus either NSAIDs or low dose steroids
- sometimes MTX, Leflunomide used if bad joint symptoms
What is the recommended treatment for severe lupus?
Induction with pulse Methylpred and cyclophosphamide or mycophenolate
Followed by maintainance tapering steroids and mycophenolate or azathioprine
Treatment for moderate SLE (significant symptoms but not organ threatening)
Hydroxychloroquine and steroids (higher dose then in mild)
Non-pharmacological treatment of SLE
Vaccinations - flu, Pneumococcal, HZV, Gardazil Sun protection Nutrition Exercise Smoking Treat co-morbid conditions (CVS, pul HTN, osteoporosis, anti phospholipid) Reproductive considerations
Also important to consider bone protection
What drugs should be avoided in SLE
Sulphonamide antibiotics and high dose estrogen as can exacerbate flares
What are some other therapies that can be considered in severe SLE with failure of primary treatment?
Belimumab
- human mAB against soluble B lymphocyte stimulator (BLyS).
- BLyS is a critical factor in the regulation of B cell survival and differentiation
- works best in those with dsDNA or low C3/C4
Rituximab - anti CD20, only in refractory cases but ??? does it work
Cyclosporin
What are poor prognostic factors in SLE
Renal dysfunction Hypertension Male Young or old age at presentation Poor socioeconomic status African American Overall high disease activity Presence of anti-phospholipid antibodies
What is the incidence of SLE?
In Caucasian population ~ 1/2500 but increased in African Americans, Indians and Aboriginal populations
What is the key inflammatory mediator in SLE?
IFN alpha
What are the most recent criteria for the diagnosis of SLE?
- 4+ criteria of which 1 must be clinical and 1 must be immunological
- biopsy proven nephritis with positive ANA or dsDNA
What are the clinical criteria for SLE?
Acute or subacute cutaneous lupus • Chronic cutaneous lupus • Oral/nasal ulcers • Non scarring alopecia • Inflammatory synovitis • Serositis • Renal: proteinuria 500mg/24hr or red cell casts • Neurologic: seizures, mono neuritis multiplex, myelitis, peripheral or cranial neuropathy, cerebritis (acute confusion) • Haemolytic anaemia • Leucopenia
What are the different types of cutaneous lupus?
Acute cutaneous lupus - malar rash, psoriaform - associated with anti-Ro (SSA) - heals well Chronic cutaneous rash - discoid rash - scars
What is Jaccoud’s arthritis?
deformities as you would see with RA but absence of erosions on x-ray
- 4% of SLE
What is the definition of renal lupus?
renal biopsy suggestive
positive ANA
proteinuria > 0.5g/24 hours
red cell casts
What are the WHO grades of lupus nephritis?
I - minimal mesangial II - Mesangial III - focal proliferative IV - diffuse proliferative V - Membranous V1 - advancing sclerosis
caused by sub endothelial immune complexes
- without treatment 5 year survival is ~ 20%
What is the treatment for lupus nephritis?
Induction
- pulse steroids
- MMF (preferred in African Americans and Hispanics) or Cyclophosphamide
Maintenance
- Prednisone
- AZA or MMF
What are the contraindications to pregnancy in SLE?
- Active disease: Diffuse proliferative GN
- Nephrotic syndrome
- Moderate/severe HTN
- Creatinine>140umol/L
- Poor cardiopulmonary reserve
Pre-pregnancy counselling important
Pregnancy can flare SLE
What are some pregnancy related complications of SLE?
Pre-eclampsia Fetal loss Pre-term delivery Congenital heart block (anti-Ro/La) Congenital Lupus (anti Ro/La) Increased rates of maternal death
Must check antiphospholipid Abs pre-conception even if no suggestion of Antiphospholipis syndrome
What are favourable features for pregnancy in SLE?
- Inactive disease for at least 6 months
- Serum cr60ml/min
- Proteinuria
What is the female: male ratio for SLE?
10:1
What are some genetic associations with SLE?
increased risk with FH of autoimmunity
~4% assoc. with FH of SLE
90% of patients homozygous for C1q deficiency develop SLE
What are the 5 most common symptoms/signs of SLE?
Arthralgia Constitutional symptoms Skin manifestations Renal Raynauds
What are the 3 important features when assessing a renal biopsy for SLE?
WHO class
activity score
chronicity score
What defines mild/mod/severe SLE?
Mild - athralgias, arthritis, fatigue, rash
Mod - pleuritis, pericarditis
Severe - lupus nephritis, CNS lupus
What is the leading cause of death in SLE?
Cardiovascular disease
- manage RFs
- statins, ACE-i, BP management
- minimise steroids
- Hydroxychloroquine lowers cholesterol
What are the proposed mechanisms behind the pathogenesis of anti-phospholipid syndrome?
- antibodies to beta2 glycoprotein 1 form leading to activation of cell endothelial cell surface markers which induces inflammation and a pro-thrombotic phenotype
- Production of antibodies against coagulation factors, including prothrombin, protein C, protein S, and annexin
- Activation of platelets to enhance endothelial adherence
- Reaction of antibodies to oxidized low-density lipoprotein, thus predisposing to atherosclerosis and myocardial infarction
can be primary form or secondary form - most commonly associated with SLE
What are the Modified Sapporo Criteria for Anti-phospholipid syndrome?
- vascular thrombosis (arterial or venous)
- Pregnancy morbidity
- 3 + consecutive miscarriages at 10/40 (placental damage)
- placental insufficiency or pre-eclampsia with delivery 12 weeks apart
- lupus anticoagulant on 2 occasionna > 12 weeks apart
Pregnancy complications are due to aPL-induced inhibition of trophoblast differentiation
Why is it of utmost importance to bridge with Clexane on initiating Warfarin therapy in anti-phospholipid syndrome?
To prevent Warfarin induced skin necrosis
What is the management of anti-phospholipid syndrome?
Secondary thromboprophylaxis
- Warfarin with bridging Clexane
In pregnancy
- low dose Aspirin + Clexane
- improves conception as well as reducing pregnancy related complications
What tests should be performed if you suspect APL?
Anti-cardiolipin antibodies (IgG, IgM)
Anti–beta-2 glycoprotein I antibodies (IgG, IgM)
lupus anticoagulant
APTT
Serologic test for syphilis (false-positive result)
CBC count (thrombocytopenia, hemolytic anemia)
Dilute Russel Viper Venom Time (dRVVT)
What is the Dilute Russell Viper Venom Time and why is it useful in APL syndrome?
In vivo antiphospholipid Abs promote clotting, in vitro they inhibit clot and therefore prolong the APTT
- this principle is utilised in the dRVVT test to distinguish between an inhibitor and a factor deficiency
- venom activates clotting factors which are blocked by APL Abs
mixing test is performed with patients plasma and normal plasma:
- patient plasma with APL - prolonged APTT
- Russell Viper venom added - delayed coagulation
- normal serum added - delayed coagulation (not factor deficiency as this would correct at this point)
- phospholipid added to supersaturate the APL Abs -> coagulation and APTT corrects
the ratio of the two times are calculated
a ratio > 1.2 suggests the presence of anti-phospholipid antibodies
What test is used to monitor heparin in APL syndrome?
Factor 10a levels
- cannot used APTT as APL Abs prolong the APTT in most tests
- there are sensitive APTT tests
