Rheumatology JC084: Facial Rash And Painful Fingers: SLE Flashcards
***Salient features of SLE
- Young female
- Multi-system disease
- **Constitutional symptoms (malaise, fever, facial rash)
- **Inflammatory polyarthritis
- **Cutaneous manifestation (rash, purpuric petechiae)
- **Haemic involvement (pancytopenia, high ESR)
- ***Renal involvement (high creatinine, urine protein) - Possible triggering factor
- Autoimmunity
- **Positive AutoAb screen (ANA, Anti-dsDNA, Anti-ENA, ACA)
- **Coomb’s test (AIHA) - Immune complex disease (***Primary Pathology of SLE)
- ↓ complement levels
Spectrum of Autoimmune rheumatic diseases
SLE: part of spectrum of autoimmune rheumatic disease
1. SLE (overlapping features with all below diseases)
2. Sjögren’s syndrome
3. Rheumatoid arthritis (RA)
4. Systemic sclerosis (SSc)
5. Dermatomyositis (Dm)
6. Polymyositis (Pm)
7. Undifferentiated connective tissue disorder (uCTD)
8. Anti-phospholipid Ab syndrome (APS)
9. Primary biliary cirrhosis (PBC)
***Systemic Lupus Erythematosus (SLE)
**Chronic **Multisystem ***Autoimmune disorder
Loss of tolerance to nuclear self Ag —> AutoAb production —> IC deposition (SpC Revision)
Characterised by:
Profound immunological disturbances
—> excessive production of **AutoAb
—> some cause **direct tissue damage / others take part in immune complex (IC) formation
—> failure to remove ICs / accumulation of ICs (most important pathological mechanism of tissue damage in SLE)
—> **secondary inflammation
—> **Inflammatory + ***Thrombotic pathology (often Ab mediated)
(Self notes:
- IC formation —> Complement activation to clear IC —> Complement consumed during flare
- If born with Complement deficiency —> fail to clear IC —> more IC deposition —> prone to SLE flare)
(Web:
The complement system involves both the innate and the adaptive immune systems and has important roles in the pathogenesis of SLE. Complement deficiencies within the classical pathway (C1q, C4 and C2) of activation predispose for development of the autoimmune disease SLE. The association between complement deficiencies and SLE could be explained by several mechanisms, including impaired clearance of immune complexes and impaired handling of apoptotic cells, aberrant tolerance induction or changes in cytokine regulation. Also during SLE disease flares, the complement system is activated giving rise to partial deficiency or dysfunction due to consumption. On the other hand, complement also takes part in the inflammatory reaction in the disease that gives rise to the tissue and organ damage.)
Genome wide association studies (GWAS) in SLE
Genetic components play a large role:
1. T cell activation
- PTPN22
- TNFSF4
- HLA class 2
- B cell signaling
- BANK1
- BLK
- PRDMI - Immune complex + Ag clearance
- ITGAM
- TREX1
- FcRγ genes
- Complement genes - TLR-IFN pathways
- IRF5
- STAT4
- IRAK1
Epidemiology of SLE
- Wide racial differences in incidence, prevalence, clinical presentation, course of disease
—> ***Caribbean blacks (most prevalent, 1 in 250 + worst disease outcomes)
—> Orientals (~50-70 / 100,000)
—> Caucasians (~10-20 / 100,000 + best disease outcomes) - F:M = 9:1
- Affect women of child-bearing age (SpC Revision) - Genetic predisposition
- High concordance rate in identical twins (24-70%)
- 10% of 1st degree relatives have abnormal serology (not necessarily develop SLE)
- **Association with HLA B8, DR2, DR3 + Other HLA 3 + Non-HLA genes
- Genes that influence sex hormone status
- **Complement deficiency e.g. C4 deficiency occurs in ~5% of SLE patients - Some infections may be protective (e.g. ***malaria)
- SLE common in Afro-Americans but rare in Afro-Africans
***Trigger agent in SLE
- Infections
- e.g. EBV, parvovirus B19, rhabdovirus, HIV-1, adenovirus, salmonella - Chemical agents
- e.g. hydrazine, tartrazine, hair dyes, eosin, heavy metals (mercuric chloride, gold, cadmium) - Certain foods
- e.g. L-canavanine (alfafa seeds and sprouts) - ***UV lights (UVA,UVB)
-
**Drugs that may induce SLE
- Common: **Procainamide (anti-arrhythmic), ***Hydralazine
- Rare: β-blockers, D-penicillamine, Isoniazid, Phenytoin, Chlorpromazine, Quinidin, Reserpine -
**Drugs that may exacerbate SLE
- **Lovastatin
- ***Sulphonamide-containing drugs
- Estrogen OC pills (probably ok if disease is quiescent)
***Pathophysiology of SLE
Genetic background
—> ↑ Apoptosis rate
—> ***AutoAg (i.e. self Ag)
—> Recognised by T / B cells
—> T / B cell activation
Environmental Triggering factors
—> Activation of T cells
—> Activation of B cells
—> **AutoAb (Detectable but not pathogenic / Ab that cause Direct tissue damage / Ab that contribute to IC formation)
—> **IC trapped in microcirculation
—> ***Secondary inflammation
—> ↑ Adhesion molecule expression / endothelial damage
—> Failure to remove AutoAb / IC
—> Inflammatory-induced Tissue damage
***Classification criteria for SLE
NOT diagnostic criteria!
Allow comparison between cohort
- ACR 1982
- SLE: 4 out of 11 criteria
- Malar rash
- Discoid lupus erythematosus
- Photosensitivity
- Oral ulcers
- Arthritis
- Serositis
- Renal disorder
- Neurological disorder
- Haematological disorder
- Immunological disorders e.g. Anti-Sm, Anti-DNA, ACA
- ANA - SLICC 2012
- more features included
—> **Clinically related (e.g. cutaneous manifestation)
—> **Immunological features (e.g. ANA, Anti-dsDNA)
—> ***Evidence of IC formation (e.g. low complement, direct coombs test) - EULAR / ACR 2019
- **Scoring system based on
—> 1. **Clinical domains (Constitutional, Cutaneous, Arthritis, Neurologic, Serositis, Haematologic, Renal)
—> 2. **Immunologic domains (Antiphospholipid Ab, Complement proteins, Highly specific Ab)
- SLE:
—> **>=10 points
—> **ANA >=1/80
—> **At least 1 clinical domain
—> exclude other more likely disease
—> no double count within each domain, domain with highest point only
—> criteria can be serial / in parallel
—> higher the point, more specific the symptom is
***Clinical features of SLE
記: CRANCHS (Constitutional, Renal, Arthritis, Neurological, Cutaneous, Haematological, Serositis)
- Constitutional symptoms
- Fever
- Malaise
- Poor appetite
- Weight loss - Mucocutaneous
- Photosensitivity
- **Malar (butterfly) rash (may / may not associate with sun exposure, **nasolabial folds often spared)
- **Discoid lupus erythematosus (advancing inflammatory elevated edge, necrosis in centre with scarring even after treatment —> early treatment needed)
- **Subacute cutaneous lupus
- **Cutaneous vasculitis (nail edge / fold, splinter haemorrhages, palm, elbow, lower limb) (can lead to gangrene)
- **Livedo reticularis (non-specific rash)
- Hair loss (scarring / non-scarring)
- **Purpuric skin rash
—> thrombocytopenia
—> leukocytoclastic vasculitis (raised (∵ edema), papule, tender (∵ inflammation))
- Erythema nodosum
- Oral ulcers
- **Raynaud’s phenomenon - Musculoskeletal
- **Non-deforming polyarthritis / polyarthralgia —> RA distribution but **NO radiological erosions
- Avascular necrosis (secondary to vasculitic process / steroid use)
- Deforming arthropathy - **Jaccoud’s arthritis (uncommon, deforming but non-erosive)
- Erosive arthritis (rare)
- **Myopathy —> weakness, myalgia, myositis (low grade) (may be drug induced / SLE complications)
- Myasthenia gravis - Pulmonary
- **Pleurisy (∵ serositis)
- Infections
- Recurrent atelectasis (shrunken lungs)
- **Diffuse lung infiltration + fibrosis
- Pulmonary hypertension
- Pulmonary infarct - Cardiac
- **Pericarditis —> Pericardial effusion
- Cardiomyopathy
- Pulmonary hypertension
- **Libman-Sacks endocarditis (aseptic endocarditis) - Glomerulonephritis (often asymptomatic) (need renal biopsy to diagnose)
- **Proteinuria (must check urine dipstick for protein + RBC)
- Urine sediments
- Urine RBC + casts
- HT
- Acute / Chronic renal failure
- **WHO class 1-6
—> Normal
—> Mesangial
—> **Focal proliferative (of inflammatory cells within glomeruli) (most severe) —> need immunosuppressant
—> **Diffuse proliferative (most severe) —> need immunosuppressant
—> Membranous (Secondary membranous GN) (BM thickened —> proteinuria but less likely to develop renal failure —> better prognosis than class 3, 4)
—> Sclerotic (dead glomeruli, not salvageable) - Neurological
Unknown patho-etiology
- Depression / Psychosis
—> not always related to disease activity
—> considerable variability
—> usually reversible
—> somatic treatment may help
- Migranous headache
—> peri-menstrual
—> may be associated with disease activity
—> poor response to treatment
Known patho-etiology: Vasculitis, Thrombosis, AutoAb mediated, Infection related, Unknown
- **Cerebral ischaemia (microinfarct / TIA / stroke)
- Retinopathy (cotton wool spot)
- Cranial / **Peripheral neuropathy
- Myelitis
- Chorea
- Cerebellar ataxia
- Meningitis + Cerebral abscesses
- Haematological features
- Lymphadenopathy (25% patient)
- Pancytopenia
- Leukopenia (Anti-leukocyte Ab)
- Anaemia (Haemolytic anaemia, Normochromic normocytic)
- Thrombocytopenia (Anti-platelet Ab, Anti-phospholipid syndrome)
- **Thrombosis
—> **Secondary Anti-phospholipid syndrome
—> Vasculitis
—> Use of corticosteroid
- Splenomegaly (onion-skin lesions) - Susceptibility to infection (**most important cause of death in SLE!!!)
Intrinsic factors
- **Low complements
- ***Anti-WBC Ab (Low WBC)
- Impaired cell mediated immunity
- Defective phagocytosis
- Poor Ab response to certain Ag
- Hyposplenism
Extrinsic factors
- **Steroid
- Other immunosuppressive drugs
- **Nephrotic syndrome
- Uraemia
Lupus band test for Cutaneous lupus
Lupus band:
- Deposition of immune complexes (shown by Immunofluorescence stain in dermal-epidermal junction)
***Screening tests for suspected SLE
-
**ANA (Anti-nuclear Ab”s”)
- usually suffices
- **very high sensitivity but very low specificity (non-specific) + non-diagnostic
—> negative ANA to **rule out SLE except when typical features are present (SpC Revision)
—> higher titre —> more specific
—> pattern of ANA —> determine target of AutoAb
- a group of AutoAb against nuclear component of cell (e.g. DNA, ribosome)
- collectively detected by a single assay
—> Anti-ssDNA
—> Anti-histone
—> **Anti-dsDNA
—> **Anti-ENA (Anti-Sm, Anti-Ro, Anti-RNP, Anti-La, Anti-P)
- Anti-dsDNA, Anti-ENA, **APA only if ANA +ve / SLE strongly suspected
- staining pattern has no prognostic values (e.g. homogeneous, speckled, nucleolar etc.)
- serum titre does ***NOT correlate with disease severity / activity (∵ non-specific)
- may become negative if there is severe proteinuria - ***Complement levels
- depressed during active disease —> indicate IC formation - Rheumatoid factor
- exclude possible RA / Sjogren’s - Ig pattern (only if strong degree of suspicion)
- CBC + D/C
- RFT including **urine examination including protein, cells, **casts
- Albumin + Globulin level in serum
(8. Dense fine speckle pattern (DFS) (SpC Medicine)
- IF stain
- 越低越positive)
When should a positive ANA test be taken seriously?
- When presents with ***Connective tissue disease features
- When other AutoAb e.g. **APA (Anti-phospholipid Ab), **Positive direct coombs test (Haemolytic anaemia) are present
- Where there is evidence of IC disease
***Common AutoAb in SLE
- Anti-dsDNA Ab (60-70%)
- Anti-ENA Ab
- Anti-Ro (40-50%) +/- Anti-La (30-40%)
- Anti-Sm (10-20%)
- Anti-RNP (30-40%) - Antiphospholipid Ab (not part of ANA family)
- Anti-cardiolipin Ab (IgG + IgM)
- Anti-β2 glycoprotein 1 Ab
- Lupus anticoagulant (coagulation assay)
Anti-dsDNA
- ~60% of SLE patients
- ***Highly specific for SLE —> One of classification criteria for SLE
- Titre ***correlate with disease activity
- may be associated with ***Lupus nephritis
Anti-ENA
- A group of different AutoAb
—> Anti-Ro (40-50%) +/- Anti-La (30-40%)
—> Anti-Sm (10-20%)
—> Anti-RNP (30-40%) - Most, except ***Anti-Sm, are not diagnostic of SLE
- Probably ***no correlation with disease activity
- Found in many ***connective tissue disorders
- May **predict clinical manifestations —> may have **prognostic value
- Anti-Sm:
- **highly specific (~10-20%)
- 1 of classification criteria
- **neurological involvement - Anti-Ro
- not sensitive / specific (~60%)
- usually associated with Anti-La
- **cutaneous manifestations (e.g. photosensitivity)
- **Secondary Sjogren’s features
- ***congenital heart block + neonatal LE - Anti-RNP
- not sensitive / specific (~30%)
- ***sclerodermatous skin lesions, Raynaud’s phenomenon, low grade myositis - Anti-P (Anti-ribosomal P Ab) (~40%)
- ***neurological disease
Antiphospholipid syndrome (APLS)
Anti-phospholipid Ab:
3 members
1. Anti-cardiolipin Ab (IgG + IgM)
2. Anti-β2 glycoprotein 1 Ab
3. Lupus anticoagulant (coagulation assay)
Anti-phospholipid syndrome:
- +ve **Anti-cardiolipin Ab or **Lupus anticoagulant
Clinical presentation:
1. Arterial / Venous **thrombosis
2. Superficial thrombophlebitis and **Livedo reticularis (wiki: caused by reduction in blood flow through arterioles, resulting in deoxygenated blood showing as blue discolouration)
3. Transverse myelitis
4. **Recurrent abortions
5. Mild / Moderate **thrombocytopenia
Primary vs Secondary APLS:
Primary APLS:
- Anti-PL Ab
- All above clinical presentations
- but NO underlying conditions
Secondary APLS
- Anti-PL Ab
- All above clinical presentations
- ***HAVE underlying conditions
—> SLE
—> Other connective tissue disorders (RA, Sjogren’s)
NB: patients with other conditions may have Anti-PL but not clinical presentations —> do NOT have APLS
Antibodies in SLE (SpC Revision)
ANA:
- Very good sensitivity for SLE (>90%)
- Low specificity
- Good for excluding SLE (but if typical features present still cannot rule out diagnosis)
Anti-dsDNA:
- Renal involvement
- CNS involvement
- Titre correlate with SLE disease activity
Anti-Sm:
- Renal involvement
- CNS involvement
- Specific for SLE
Anti-RNP:
- Raynaud’s phenomenon
- mCTD associated
Anti-Ro:
- Photosensitivity
- Subacute cutaneous lupus
- Neonatal lupus
- Sjogren syndrome
Anti-La:
- Neonatal lupus
- Sjogren syndrome
Anti-phospholipid Ab:
- Thrombotic complications
- Pregnancy complications
Anti-globulin test (Coomb’s test):
- AIHA
