lupus and relted autoimmune disease Flashcards
what are autoimmune connective tissue disorders
SLE
sjogrens syndrome
systemic sclerosis
autoimmune inflammatory muscle disease
rheumatoid arthritis
Chronic joint inflammation that can result in joint damage
Main site of inflammation is the synovium
Associated with autoantibodies:
Rheumatoid factor
Anti-cyclic citrullinated peptide (CCP) antibodies
ankylosing spondylitis
Chronic spinal inflammation that can result in spinal fusion and deformity
Site of inflammation includes the enthesis
No autoantibodies (‘seronegative’)
seronegative inflammatory arthritis
Ankylosing spondylitis
Reactive Arthritis
Arthritis associated with psoriasis (psoriatic arthritis)
Arthritis associated with gastrointestinal inflammation (enteropathic arthritis)
SLE
Autoimmune disease involving disturbance of both innate and adaptive immune systems
Autoantibodies (antibodies directed against self antigens)
-antibodies to nuclear components
Antibody-antigen (immune complexes) & other mechanisms -> chronic tissue inflammation:
Multi-site inflammation but particularly the joints, skin and kidney
autoimmune connective tissue disorders
1) Arthralgia and arthritis is typically non-erosive (unlike rheumatoid)
2) Serum autoantibodies are characteristic and…
Useful diagnostically
Some correlate with disease activity
May be directly pathogenic
3) Raynaud’s phenomenon is common in these conditions
Intermittent vasospasm of digits
Usually triggered by cold exposure
Typical triphasic colour changes
WHITE -> Vasospasm leads to blanching of digit
BLUE -> Cyanosis as static venous blood deoxygenates
RED -> Reactive hyperaemia
Severe Raynaud’s -> tissue ischaemia, ulcers and necrosis
sle epidemiology
Typical onset between 15 – 45 years
F:M ~9:1
Prevalence and severity varies by ancestry
African > Asian > White European
Clinical manifestations highly variable:
causes diagnostic difficulties
Disease may range from mild to life-threatening
sle clinical features
Clinical features:
Skin and mucosa:
Malar rash – erythema that spares the nasolabial fold
Photosensitive rash
Mouth ulcers
Hair loss
Vascular:
Raynaud’s
MSK:
Arthralgia and sometimes arthritis (usually non-erosive)
Internal organs:
Serositis (pericarditis, pleuritis, less commonly peritonitis)
Renal disease – glomerulonephritis (‘lupus nephritis’)
Cerebral disease – ‘cerebral lupus’ e.g. psychosis
Myocarditis
Haematological:
autoimmune thrombocytopenia (low platelets)
haemolytic anaemia
Lymphopenia
Other
Lymphadenopathy
Fever in absence of infection
Arthritis and deformity of fingers,
Including swan neck deformity.
X-rays showed no bony erosions i.e. deformity due to soft tissue damage
ANA
A hallmark of SLE is the presence of ANA
Found in all SLE patients
Negative ANA effectively rules out SLE
However, ANA is not specific for lupus;
may be seen in other autoimmune diseases, infection or even healthy people
further autoab tests do identify what ana is reacting to
Anti-ds-DNA antibodies
Anti-Ro
Anti-La
Anti-centromere
Anti-Smith (Sm)
Anti-RNP
Anti-Scl-70
antiphospholipid anitbodies
As well as ANA, some SLE patients have antibodies directed to phospholipids on cell membrane
APL are associated with ↑ risk of:
1) Thrombosis
arterial (e.g. stroke)
venous (e.g. deep vein thrombosis, DVT)
2) Pregnancy loss (miscarriage)
APL we measure in clinical lab: anticardiolipin antibodies, anti-beta2glycoprotein 1 antibodies
Persistent presence of APL + a clinical event = “anti-phospholipid antibody syndrome”
Anti-phospholipid antibody syndrome can also occur in absence of SLE
(‘primary anti-phospholipid antibody syndrome’ )
main autoantibodies in sle
ANA-seen in all sle cases but not specific for sle
anti double stranded dna antibodies are specific for sle . serum level antibody correlates with disease severity
anti phospholipid-associated with risk of arterial and venous thrombosis in SLE may also occur in absence of sle in primary anti phospholipid antibody syndrome
anti sm antibodies (antigen is a ribonucleoprotein)- specific for sle,serum levels dont correlate with disease severity
anti ro antibodies (antigen is a ribonucleoprotein) and anti La antibodies- secondary sjogrens syndrome and neonatal lupus syndrome where transient rash occurs and can lead to permanent heart block
sle immunopathogenesis
innate immunity
Overactivity of type 1 interferon pathway
Complement pathway abnormalities
adaptive immunity
Autoreactive B and T cells
type 1 ifn
Type 1 interferons are proteins normally produced in response to viral infections
Type 1 interferons include several different proteins, including interferon-alpha
Gene expression studies comparing the blood of lupus patients to healthy controls revealed overexpression of genes that are activated downstream of binding of the type 1 interferon receptor. This is sometimes called the “interferon gene signature”. A high interferon gene signature is associated with worse disease.
A drug blocking the type 1 interferon receptor (anifrolumab) has recently shown success in randomized clinical trials in SLE; it’s not yet available in the UK
sle waste disposal hypothesis
Apoptosis leads to translocation of nuclear antigens to membrane surface
Impaired clearance of apoptotic cells results in enhanced presentation of nuclear antigens to immune cells
b cell autoimmunity
Tissue damage by antibody effector mechanisms e.g. complement activation and Fc receptor engagement
why are manifestations so varied for lupus
organ specific autoimmunity
systemic autoimmunity
sle ivx
Inflammation:
high ESR but usually normal C-reactive protein unless infection or serositis/arthritis
Haematology:
Haemolytic anaemia, Lymphopenia, Thrombocytopenia
Renal:
very important to measure urine protein (urinalysis + quantify with urine protein:creatinine ratio [uPCR])
Creatinine (part of “U&E”, measure of renal function)
look at albumin
Kidney biopsy if persistent proteinuria
Immunological
Antinuclear antibodies
Anti-double-stranded DNA antibodies - highly specific, correlate with disease activity
Complement consumption – e.g. low C4 and C3
antiphospholipid antibodies
In treated patients SOME changes may reflect ADVERSE REACTIONS TO MEDICATION
e.g. abnormal liver function tests (‘transaminitis’) or fall in neutrophil count (neutropenia)
measuring disease activity in sle
Combination of:
-Clinical symptoms and signs
-Investigations
Unwell Patient with active lupus typically has:
Low complement C3 and C4 levels
High anti-dsDNA antibodies
sle management
1.Treatment in SLE aims at remission or low disease activity and prevention of flares
- Balance of controlling disease vs avoiding iatrogenic harm (especially steroids)
NB steroid side effects (see RA lecture), especially:
Infection
Osteoporosis
Avascular necrosis (AVN) - often affects hips: higher incidence in lupus, especially in presence of APL Abs
Appropriate initiation of immunomodulatory agents can expedite the tapering/discontinuation of glucocorticoids
- Specific choice of treatment will depend on disease severity and organ manifestations
meds for sle
Hydroxychloroquine is recommended in all patients with lupus
Steroids for acute flare but aim to withdraw as soon as safe to do so
Mild disease: Hydroxychloroquine alone may be sufficient
If more serious disease, immunomodulatory agents (mycophenolate, methotrexate, azathioprine)
Mycophenolate +/- rituximab usually used for renal disease
In persistently active disease: B cell targeted therapies
Rituximab = anti-CD20 monoclonal antibody: depletes B cells
Belimumab = anti-BAFF antibody (BAFF = a B cell survival factor/cytokine)
Severe or life-threatening disease (e.g. myocarditis) : iv steroids + iv cyclophosphamide (+/- rituximab)
Patients with SLE and antiphospholipid antibody syndrome (i.e. episode of clot + antiphospholipid antibody positive) should be treated with anticoagulation (warfarin)
Emerging therapies: anifrolumab (interferon receptor blockade)
sle and pregancy
SLE affects typically affects women during reproductive years
Consider both risk of disease & drugs to both mother and to fetus
Best outcomes with pre-pregnancy planning and getting SLE into remission first
Specific considerations
1) Antiphospholipid antibodies associated with miscarriage.
Can reduce risk with aspirin or heparin
2) Pregnancy increases haemodynamic demands – will worsen renal dysfunction
3) Ro antibodies: can cause fetal heartblock
4) Drug considerations:
MMF, cyclophosphamide, methotrexate, warfarin are teratogenic.
Hydroxychloroquine, azathioprine, low molecular weight heparin (LMWH) safe
Other autoimmune connective tissue disorders
Sjögren’s syndrome
Autoimmune inflammatory muscle disease (‘myositis’)
Polymyositis
Dermatomyositis
Systemic sclerosis (scleroderma)
Diffuse cutaneous
Limited cutaneous
Systemic sclerosis (scleroderma)
Thickened skin with Raynaud’s phenomenon
dermal fibrosis
cutaneous calcinosis
telangiectasia
Skin changes may be limited or diffuse
Limited systemic sclerosis*
Fibrotic skin limited to hands, forearms, feet, neck and face
Anti-centromere antibodies
Pulmonary hypertension
Long history of Raynaud’s phenomenon
Diffuse systemic sclerosis
Fibrotic skin proximal to elbows or knees (excluding face and neck)
Anti-Scl-70 antibodies
Pulmonary fibrosis, renal (thrombotic microangiopathy) involvement
Short history of Raynaud’s phenomenon
