8.6 - Lupus and related autoimmune connective tissue diseases Flashcards
What are the autoimmune connective tissue disorders? (4)
- systemic lupus erythematosus (SLE)
- autoimmune inflammatory muscle disease (myositis)
- systemic sclerosis (scleroderma)
- Sjogren’s syndrome
- (NB overlap syndromes can occur, especially in children)
Why is the term ‘connective tissue disorder’ not entirely accurate?
Often involvement of other organs - ‘multisystem autoimmune rheumatic diseases’ might be better
What is the main site of inflammation in rheumatoid arthritis?
Synovium
What autoantibodies is rheumatoid arthritis associated with? (2)
- rheumatoid factor (RF)
- anti-cyclic citrullinated peptide (CCP) antibodies
What can ankylosing spondylitis result in?
Chronic spinal inflammation that can result in spinal fusion and deformity (increased thoracic kyphosis and loss of normal lumbar lordosis)
What is the site of inflammation in ankylosing spondylitis?
Enthesis (bamboo spine - enthesitis)
Are there autoantibodies associated with ankylosing spondylitis?
No autoantibodies - seronegative
Does SLE have innate or adaptive immune system involvement?
Autoimmune disease involving disturbance of both innate and adaptive immune systems
What autoantibody is associated with SLE?
Antibodies to nuclear components (ANA)
What is the mechanism of chronic tissue inflammation in SLE?
Autoantibodies –> antibody-antigen (immune complexes) and other mechanisms –> circulate in blood and deposit in tissue–> chronic tissue inflammation
Where does inflammation affect the most in SLE?
Multi-site inflammation but particularly the joints, skin and kidney
How are arthralgia and arthritis different between RA and autoimmune connective tissue disorders (e.g. SLE)?
- arthralgia (joint pain) and arthritis (joint inflammation) are present in both but in SLE they are typically non-erosive (unlike in RA)
- this is because there is no underlying synovitis in SLE but there is in RA
- no obvious bedside inflammation of joints in SLE but there is in RA
How are serum antibodies important in diagnosing autoimmune connective tissue disorders (e.g. SLE)? (3)
- useful diagnostically - may aid diagnosis
- some correlate with disease activity
- may be directly pathogenic
Describe Raynaud’s phenomenon and the triphasic colour change seen in autoimmune connective tissue disorders (e.g. SLE).
- Raynaud’s phenomenon is common in these conditions
- intermittent vasospasm of digits
- usually triggered by cold exposure
- typically triphasic colour changes:
- WHITE - vasospasm leads to blanching of digit
- BLUE - cyanosis as static venous blood deoxygenates
- RED - reactive hyperaemia (painful)
- severe Raynaud’s –> tissue ischaemia, ulcers and necrosis
What usually triggers Raynaud’s phenomenon?
Cold exposure
What can severe Raynaud’s phenomenon lead to?
Tissue ischaemia, ulcers and necrosis
Describe the epidemiology of SLE.
- typical onset between 15-45 years
- F:M ~9:1
- prevalence and severity varies by ancestry: African > Asian > White European
What are the clinical manifestations of SLE like and how can this affect diagnosis?
- clinical manifestations are highly variable, which causes diagnostic difficulties
- disease may range from mild to life-threatening
What deformity may be seen in the digits of someone with SLE?
Swan neck deformity
What are some clinical features of SLE? (6 subtypes)
- skin and mucosa:
- malar rash - erythema that spares the nasolabial fold
- photosensitive rash
- mouth ulcers
- hair loss
- vascular: Raynaud’s phenomenon
- MSK: arthralgia and sometimes arthritis (non-erosive)
- internal organs:
- serositis (pericarditis - pain on leaning forward, pleuritis - pain on breathing in, less commonly peritonitis)
- renal disease - glomerulonephritis (lupus nephritis)
- cerebral disease - ‘cerebral lupus’ e.g. psychosis
- myocarditis
- haematological:
- autoimmune thrombocytopenia
- haemolytic anaemia
- lymphopenia
- other:
- lymphadenopathy
- fever in absence of infection
What are the main autoantibodies associated with SLE? (3)
- antinuclear antibodies (ANA)
- anti-double stranded DNA (anti-dsDNA)
- anti-phospholipid antibodies
How can antinuclear antibodies (ANA) be used in diagnosis of SLE?
- a hallmark feature of SLE is the presence of ANA
- found in all SLE patients
- negative ANA effectively rules out SLE
- however, ANA is not specific for SLE - may be seen in other autoimmune diseases, infection or even healthy people
- if ANA +ve, the laboratory will report strength
The laboratory does further specific autoAb tests to see what ANA are reacting to - what can these autoAb be? (7 - bold indicates may be positive in SLE)
- anti-ds-DNA antibodies
- anti-Ro
- anti-La
- anti-centromere
- anti-Smith (Sm)
- anti-RNP
- anti-Scl-70
What are antiphospholipid (APL) antibodies?
As well as ANA, some SLE patients have antibodies directed to phospholipids on cell surfaces
What are antiphospholipid (APL) antibodies associated with increased risk of? (2)
- thrombosis - arterial (e.g. stroke), venous (e.g. DVT)
- pregnancy loss (miscarriage)
What is anti-phospholipid antibody syndrome?
- persistent presence of APL + a clinical event
- can also occur in the absence of SLE (‘primary anti-phospholipid antibody syndrome’ i.e. ANA will be negative)
Describe the significance of antinuclear antibodies (ANA).
- seen in all SLE cases
- not specific for SLE
Describe the significance of anti-double stranded DNA antibodies (anti-dsDNA).
- specific for SLE
- serum level of antibody correlates with disease activity
Describe the significance of anti-phospholipid antibodies.
- associated with risk of arterial and venous thrombosis in SLE
- may also occur in absence of SLE in what is termed the ‘primary anti-phospholipid antibody syndrome’
Describe the significance of anti-Sm antibodies.
- antigen is a ribonucleoprotein
- specific for SLE
- serum level of antibody does NOT correlate with disease activity
Describe the significance of anti-Ro and anti-La antibodies. (Not tested)
- antigen = ribonucleoprotein
- secondary Sjogren’s syndrome
- neonatal lupus syndrome (transient rash in neonate, permanent heart block)
What are the key autoantibodies associated with rheumatoid arthritis? (2)
- rheumatoid factor
- anti-cyclic citrullinated peptide antibody (AKA antibodies to citrullinated peptide antigens - ACPA)
What are the key autoantibodies associated with SLE? (7)
- antinuclear antibodies (ANA)
- anti-double stranded DNA antibodies (anti-dsDNA)
- anti-phospholipid antibodies (APL)
- anti-Smith
- anti-Ro
- anti-La
- anti-RNP
What are the key autoantibodies associated with osteoarthritis?
None
What are the key autoantibodies associated with reactive arthritis?
None
What are the key autoantibodies associated with gout?
None
What are the key autoantibodies associated with ankylosing spondylitis?
None
What are the key autoantibodies associated with systemic vasculitis? (Not tested)
Anti-neutrophil cytoplasmic antibodies (ANCA)
What is the immunopathogenesis of SLE? (3)
- overactivity of type 1 interferon pathway (innate immunity, normally IRT viral infection)
- complement pathway abnormalities (innate immunity)
- autoreactive B and T cells (adaptive immunity)
How is the immune system generating a response to nuclear antigens in SLE (should be hidden inside the cell) - the ‘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
What types of investigation do we do for SLE? (5)
- inflammation: high ESR but normal CRP (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&Es, measure renal function)
- look at albumin (can be low due to proteinuria)
- kidney biopsy if persistent proteinuria
- immunological: ANA, anti-dsDNA, complement consumption (low C3 and C4), anti-phospholipid antibodies
- in treated patients SOME changes may reflect adverse reactions to medication e.g. abnormal LFTs (transaminitis) or neutropenia
What adverse effects can occur from SLE medication? (2)
- abnormal LFTs - transaminitis
- neutropenia
How do we measure disease activity in SLE? (2)
Combination of:
- clinical symptoms and signs
- investigations e.g. measuring complement levels (C3&C4) and anti-dsDNA antibodies
What does an unwell patient with SLE typically have? (2)
- low complement C3 and C4 levels
- high anti-dsDNA antibodies
What is the aim of SLE treatment?
Remission or low disease activity and prevention of flares
What do we need to balance when considering SLE treatment?
Balance between controlling disease vs avoiding iatrogenic harm (especially steroids)
What are some side effects of steroids for treating SLE? (3)
- infection
- osteoporosis
- avascular necrosis - often affects hips, higher incidence in lupus especially in presence of APL antibodies
What can speed up the tapering/discontinuation of glucocorticoids for SLE?
Appropriate initiation of immunomodulatory agents
e.g. methotrexate, mycophenolate, azathioprine
What does specific choice of treatment for SLE depend on?
Disease severity and organ manifestations
What drug do we recommend to all patients with lupus?
Hydroxychloroquine
What drug type do we use for acute flares of lupus?
Steroids for acute flare but aim to withdraw as soon as safe to do so (appropriate initiation of immunomodulatory agents e.g. mycophenolate, methotrexate, azathioprine to speed up withdrawal)
What do we use to manage mild lupus?
Hydroxychloroquine alone may be sufficient
What do we use to manage more serious lupus?
Immunomodulatory agents (mycophenolate, methotrexate, azathioprine)
What do we use to manage renal disease in lupus?
Mycophenolate +/- rituximab
What do we use to manage persistently active lupus?
- B cell targeted therapies:
- rituximab = anti-CD20 monoclonal antibody, depletes B cells
- belimumab = anti-BAFF antibody (BAFF = B cell survival factor/cytokine)
What do we use to manage severe/life-threatening disease (e.g. myocarditis) in lupus?
IV steroids + IV cyclophosphamide (+/- rituximab)
What do we use to manage patients with SLE and antiphospholipid antibody syndrome (i.e. episode of clot + APL positive)?
Anticoagulation e.g. warfarin
What is an emerging therapy for SLE?
Anifrolumab (interferon receptor blockade)
What is the link between SLE and pregnancy?
- SLE typically affects women during reproductive years
- consider both risk of disease and drugs to both mother and foetus
- best outcomes with pre-pregnancy planning and getting SLE into remission first
e.g. APL antibodies can increase miscarriage risk
What are some specific considerations you need to take into account when looking at SLE and pregnancy? (4)
- antiphospholipid antibodies associated with miscarriage (can reduce risk with aspirin or heparin)
- pregnancy increases haemodynamic demands - will worsen renal dysfunction
- Ro antibodies (SLE) can cause foetal heart block
- drug considerations:
- MMF, cyclophosphamide, methotrexate and warfarin are teratogenic
- hydroxychloroquine, azathioprine and LMWH are safe
What are the two types of autoimmune inflammatory muscle disease (myositis)?
- polymyositis
- dermatomyositis
What are the two types of systemic sclerosis (scleroderma)?
- diffuse cutaneous
- limited cutaneous
Describe Sjogren’s syndrome (NOT TESTED)
- autoimmune exocrinopathy - lymphocytic infiltration of exocrine glands
- exocrine gland pathology results in dry eyes (xerophthalmia), dry mouth (xerostomia) and parotid gland enlargement
- sometimes extra-glandular manifestations: non-erosive arthritis, Raynaud’s phenomenon, pleural effusion, autoimmune hepatitis
- autoantibodies: Ro+, La+, RF often +, CCP -
- termed ‘secondary Sjogren’s syndrome’ if occurs in context of another CTD e.g. SLE
Describe inflammatory muscle disease. (NOT TESTED)
- autoimmune-mediated inflammation of muscle
- causes proximal muscle weakness and sometimes pain
- dermatomyositis = muscle and skin inflammation
- polymyositis = muscle only, no rash
- investigations:
- bloods: elevated CK
- electromyography
- muscle biopsy (polymyositis = CD8 T cell infiltrate; dermatomyositis = CD4 T cell in addition to B cells)
- NB associated with malignancy (10-15%) and pulmonary fibrosis
What are the skin changes in dermatomyositis? (2)
- lilac-coloured (heliotrope) rash on eyelids, malar region and naso-labial folds
- red/purple flat or raised lesions on knuckles (Gottron’s papules)
What is systemic sclerosis? (NOT TESTED)
Thickened skin with Raynaud’s phenomenon:
- dermal fibrosis
- cutaneous calcinosis
- telangiectasia
What are the features of limited systemic sclerosis? (4)
- fibrotic skin limited to hands, forearms, feet, neck and face
- anti-centromere antibodies
- pulmonary hypertension
- long history of Raynaud’s phenomenon
What are the features of diffuse systemic sclerosis? (4)
- 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
What is CREST syndrome? (Type of limited systemic sclerosis)
- Calcinosis
- Raynaud’s phenomenon
- Esophageal dysmotility
- Sclerodactyly
- Telangiectasia
