SLE Flashcards
What are risk factors associated with SLE?
The exact etiology is unknown, but several predisposing factors have been identified.
Genetic Predisposition
- HLA-DR2 and HLA-DR3 are commonly present in individuals with SLE.
- Genetic deficiency of classical pathway complement proteins (C1q, C2, C4) in approx. 10% of affected individuals
- Hormonal factors: Hyperestrogenic states (e.g., due to oral contraceptive use, postmenopausal hormonal therapy, endometriosis) are associated with an increased risk of SLE.
- Environmental factors
Cigarette smoking and silica exposure increase the risk of developing SLE.
UV light and EBV infection may trigger disease flares, but there is insufficient evidence on whether they cause SLE.
More common in FEMALES
Female: 10:1
Interestingly, patients with turner’s + klinefelters - less SLE
Clinical features of SLE
Non specific: fatigue > fever > weight loss
Joint:
- arthralgia + arthritis
- migratory, polyarticular and symmetrical. Normally affects knees, wrists, finger joints.
- Unlike RA, morning stiffness is less prominent and non-deforming/erosive
- Jaccoud’s arthropathy: tenosynovitis
- Rhupus: RA/SLE overlap
- Less common: myalgia, avascular necrosis
Mucocutaneous
- Acute (non-scarring): Malar rash
- Subacute: Photosenstivity: maculopapular rash
- Chronic: discoid rash, scarring can occur
- Non-scarring alopecia, usually diffused and related to disease activity. Lupus fizz (thin brittle hair around hairline).
- Oral ulcers (usually painless)
Vascular
- Raynauds
- Small vessel vasculitis: palpable purpura, livedo reticularis
Cardiovascular:
- Pericarditis most common
- Myocarditis
- Libmann sach’s endocarditis
- Valvular disease - mitral > aortic, regurgitation> stenosis
- Coronary artery disease, increased risk
Lung:
- pleuritis
- ILD
- Pneumonitis
Haem
- Anaemia
- Leukopenia
- Thrombocytopenia
- Evans syndrome: autoimmune haemolysis + ITP
Neuropsych
- Cognitive decline (lupus fog) > headache > mood disorder > CVA > myelitis
Lupus nephritis
Cause of drug induced SLE
Anti histone My Two HIPs - Methyldopa - TNF-a inhibitiors - Hydralazine - Isoniazid - Procainamide/Phenytoin - Sulfa drugs, eg: bactrim
Characteristics of lupus nephritis
- Most dangerous organ complication and common cause of death in SLE
- Can present as nephritic or nephrotic
- Mesangial or subendothelial deposition of immune complexes (anti-dsDNA, anti-sm) –> expansion and thickening of mesangium/capillary walls and GBM
- HTN, oedema, haematuria
- Proteinruia, haematuria, cellular casts
Tx: corticosteroids, immunosuppressants (mycophenolate, cyclophosphamide), ACEi
Autoantibodies involved in SLE
ANA > 1:80 (speckled)
ANA: 98%; Best screening test
- dsDNA ab: 70%: High titers are SLE-specific and in some patients correlate with disease activity, nephritis, vasculitis
- Anti-Sm (25%): SPECIFIC for SLE; no definite clinical correlations
- Anti-Ro (SSA): 30%; Not specific for SLE; associated with sicca syndrome, predisposes to subacute cutaneous lupus,neonatal lupus, photosensitivity, C2 deficiency. Also sjogrens.
- Anti-La (20%); a/w lower risk of nephritis . Also sjogrens
- Anti-histone antibodies (70%): Drug induced lupus
- Anti-phospholipid syndrome: Lupus anticoagulant >cardiolipin Ab> B2 glycoprotein Ab
- Ribosomal P ab: neurolupus
- U1RNP: mixed connective tissue disease (needs to be on its own for mixed)
Other: - Hypocomplementaemia, normally C4 Low C3/ complement levels (C3, C4) are low during active disease (formation of complexes leads to consumption of complement) - ESR>CRP - Positive RF
What are the SLE specific antibodies?
Anti-dsDNA antibody
- Positive in 60-70% of patients and highly specific for SLE
- Levels correlate with disease activity
- Associated with lupus nephritis
- Associated with subacute cutaneous SLE
Anti-Sm Ab
- Positive in <30% of patients but highly specific for SLE
Diagnostic criteria
4 lab, 7 clinical 4/11
MDBRAINSOAP
4 Lab
- Bloods: haemolytic anaemia with reticulocytes, thrombocytopenia, leukopenia, lymphopenia
- Renal disorder: protein > 0.5h/day, cellular casts
- ANA
- Immunological manifestations
Antiphospholipid ab: lupus anticoagulant, anticardiolipin, anti B2 glycoprotein
Low C3/C4
Anti dsDNA, anti smith
7 clinical
- MUCOCUTANEOUS signs: malar rash (sparing nasolabial fold), discoid rash, photosensitive rash, oral/nasal ulcers (painless)
- SEROSITIS: pleuritis, pericarditis
- ARTHRITIS, non erosive small joint polyarthritis - Jaccoud’s arthritis
- Neurological disorders: seizures/
‘SOAP BRAIN MD’
Serositis: pleurisy or pericarditis
Oral ulcers
Arthritis
Photosensitivity
Blood: anaemia, leukopenia, lymphopenia and thrombocytopenia
Renal disorder: lupus nephritis - minimal mesangial, mesangial proliferative, focal, diffuse, membranous and advanced sclerosis
Antinuclear antibody
Immunology: anti-Smith, anti-ds DNA and antiphospholipid antibody
Neurologic disorder: seizures or psychosis
Malar rash
Discoid rash
Mixed connective tissue disease
SLE, systemic sclerosis (SSc), and polymyositis (PM)
High RNP Ab - infrequent development of diffuse proliferative glomerulonephritis, psychosis, or seizures; with the early development of Raynaud phenomenon in nearly all patients
Non-pharmacological management of SLE
Avoid triggers:
- Stress
- UV light (photoprotection)
- Oestrogens/OCP.
- Vitain D repletion
- Cease smoking, diet, exercise
- Immunisation
UV protection
Smoking cessation
Immunisation
Pharmacological management for SLE
Basic therapy: hydroxychlorquine, and addition of methotrexate or azathioprine if no response
Inductive Therapy
- Mild symptoms, no organs affected: glucocorticoids
- Severe symptoms, no vital organs: medium dose oral glucocorticoids
Immunosuppressive agents: mycophenolate, cyclophosphamide
Biologicals: belimumab (B cell inhibitor)
- Organ damage: IV steroids and above immunotherapy + biologicals
- Corticosteroids
- Methotrexate
- Azathioprine
- Leflunomide
- Mycophenolate - especially renal/pulmonary
- Cyclosporin
Benefits and side effects of hydroxychloroquine
- B/G therapy for all patients - indicate in all patients
BENEFITS:
- Decreased flares
- Decreased progression to renal nephritis + CNS lupus
- Decrease organ damage
- Doubles response to MMF
- CVS protection
- Decrease thrombosis
- Protect against CHB in SSA+ mothers
- Improved overall survival
- MOA
Increase lyosomal pH
Inhibits TLR9 on APC/dendritic cells and prevents the TH17 response by reducing IL-17 and IL-23
SE
- Immunomodulatory, not immunosuppressive
- RETINOPATHY - is cumulative dosing, “bull’s eye visual field loss”
- Haemolytic anaemia in G6PD
- Aggravates psoriasis
- Myelosuppression
MOA of belimumab
Monoclonal ab that binds to soluble BAFF/BLys (B cell activating factor/B lymphocyte stimulator) which is a critical factor in the regulation of B cell survival and differentiation
Treatment for Raynauds
Verapamil
Treatment for lupus nephritis
Class I, II, VI – no immunosuppression
Class III, IV (+/- V) – immunosuppression
Induce with IV methylpred for - 3 days and MMF/CYC
- Maintain: AZA/MMF/CYC
- If refractory: Rituximab / Tacrolimus
Serological monitoring – rising dsDNA can predict clinical relapse
ACEi, aim LDL<2.6, BP <130/75
Novel therapies for SLE management
- Rituximab: chimeric anti-CD20 monoclonal antibody that binds to CD20 on B lymphocytes and starts an immune response that lyses normal and malignant B cells. Apoptosis is also induced. Regeneration of normal B lymphocytes occurs
Infusion reaction: Occur 30–120 minutes after starting infusion and include fever, chills and/or rigors, nausea, vomiting, urticaria, itch, headache, bronchospasm, dyspnoea, angioedema, rhinitis, hypotension
Lymphopaenia, recovery starts at 6 months post cessation - Belimumab: Human mAb that binds to soluble BAFF/BLyS, which regulates B cell proliferation and differentiation
SE: infections, hypersensitivity and infusion-related effects (below), diarrhoea, nausea, leucopenia, depression, anxiety
Anifrolumab: Anti-IFN receptor mAb -IFN therapies
Causes of death in SLE
- Renal disease
- Infections: disease related factors and immunosuppressive therapy
Cardiovacular complications: most common cause of death of SLE
““Redness in Cheeks”
Pregnancy and SLE
- Avoid pregnancy in active disease as it worsens disease and increases risk of maternal and foetal adverse outcomes; cardiac/renal insufficiency; pulmonary hypertension
- Aim pregnancy when disease stable >6 months
- Avoid OCP in women of childbearing age
- Anti Ro60 and La antibodies - risk of neonatal lupus –> CONGENITAL HEART BLOCK, go across the placenta and ab against AV node
Risk increases with subsequent pregnancies - Most manifestations (e.g. rash, hematologic, hepatic) resolve with clearance of maternal Ab by 6-8mo
- CHB most serious manifestation – occurs in 2% (recurrence rates 16-20%), mostly b/w 16-26 wks gestation, thought to be irreversible once established
- Consider fluorinated steroids in 2nd degree HB (+ possibly 1st degree HB) to prevent progression
- Hydroxychloroquine prevents cardiac neonatal lupus in future pregnancies
- Use azathioprine for lupus flares in pregnancy; avoid CYC, MMF, MTX
- Avoid NSIADs in 3rd trimester due to risk of premature ductus arteriosus closure
Increased risk of CS, preeclampsia, HTN, spontaneous abortion, VTE, post partum infection
What does anti Ro and La indicate in SLE
Sign of neonatal SLE
Impact of lupus on pregnancy
- Does not affect fertility
- Higher rates of maternal + fetal complications
- Maternal mortality 20x higher
- 2-4x risk of obstetrical complications: pre term delivery, pre-eclampsia, thrombosis
Antiphospholipid syndrome
Asymptomatic: low dose aspirin
- Prior obstetrical morbidity: low dose aspirin, prophylactic LMWH
- Prior thrombosis: therapeutic LMWH, continue 6/12 post partum
Characteristics of neonatal lupus syndrome
- Occurs due to transfer of maternal ab (anti-Ro, anti-la)
- Causes heart block, perioribtal/diffuse rash, cytopenia, hepatitis
- Diagnosis (requires 2 criteria)
1. Anti Ro, Anti La
2. Heart block, rash, hepatitis/cytopenia
Most manifestations (e.g. rash, hematologic, hepatic) resolve with clearance of maternal Ab by 6-8mo
Strongly associated with anti ro
What is Jaccoud’s arthropathy?
NON EROSIVE small joint polyarthritis most commonly caused by SLE and characterised by reducible subluxation of the digits, swan neck deformities and ulnar deviation of fingers due to attenuation of the joint supporting structures.
Appears very similar to rheumatoid arthritis (affects MCP, PIP, swan neck/boutonniere deformity)
However, when they use their fingers, it is complete reducible as inflammation affects the connective tissue rather than joint, non-erosive
Pathophysiology of SLE
- autoimmune disease: SLE a type 3 hypersensitivity reaction
- associated with HLA B8, DR2, DR3
- thought to be caused by immune system dysregulation leading to immune complex formation
- immune complex deposition can affect any organ including the skin, joints, kidneys and brain
Discoid SLE
Discoid lupus erythematosus is a benign disorder generally seen in younger females. It very rarely progresses to systemic lupus erythematosus (in less than 5% of cases). Discoid lupus erythematosus is characterised by follicular keratin plugs and is thought to be autoimmune in aetiology
Features
erythematous, raised rash, sometimes scaly
may be photosensitive
more common on face, neck, ears and scalp
lesions heal with atrophy, scarring (may cause scarring alopecia), and pigmentation
Management
topical steroid cream
oral antimalarials may be used second-line e.g. hydroxychloroquine
avoid sun exposure
Antiphospholipid Syndrome
Antiphospholipid syndrome is an acquired disorder characterised by a predisposition to both venous and arterial thromboses, recurrent fetal loss and thrombocytopenia. It may occur as a primary disorder or secondary to other conditions, most commonly systemic lupus erythematosus (SLE)
A key point for the exam is to appreciate that antiphospholipid syndrome causes a paradoxical rise in the APTT. This is due to an ex-vivo reaction of the lupus anticoagulant autoantibodies with phospholipids involved in the coagulation cascade
Features venous/arterial thrombosis recurrent fetal loss livedo reticularis thrombocytopenia prolonged APTT other features: pre-eclampsia, pulmonary hypertension
Associations other than SLE
other autoimmune disorders
lymphoproliferative disorders
phenothiazines (rare)
Management - based on EULAR guidelines
primary thromboprophylaxis
low-dose aspirin
secondary thromboprophylaxis
initial venous thromboembolic events: lifelong warfarin with a target INR of 2-3
recurrent venous thromboembolic events: lifelong warfarin; if occurred whilst taking warfarin then consider adding low-dose aspirin, increase target INR to 3-4
arterial thrombosis should be treated with lifelong warfarin with target INR 2-3
Mixed Connective Tissue Disease
Mixed connective tissue disease (MCTD, Sharp’s syndrome) is a rare, heterogeneous, multi-system autoimmune disorder. It is a distinct clinical entity, but features of systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and myositis may all be present. It is associated with anti-U1 ribonucleoprotein (RNP) antibodies.* It is not to be confused with ‘undifferentiated connective tissue disease’.**
Epidemiology
• Male:female ratio 1:3
• Average age of presentation 30-40, may present in children
• Rare - incidence in adult population is estimated to be 2.1/million/year in one Norwegian study
Presentation: • Raynaud's phenomenon often precedes other symptoms and occurs in 90% of cases • Polyarthralgia/arthritis • Myalgia • 'Sausage fingers'(dactylitis)
Other clinically important features:
• Dermatological: photosensitive rash, scleroderma-like changes, alopecia
• Oesophageal dysfunction
• Respiratory: pleuritis, pulmonary hypertension, interstitial lung disease
• Haematological: anaemia, lymphadenopathy, splenomegaly, rarely TTP
• Cardiac: pericarditis, pericardial effusion, accelerated coronary artery disease
• Renal: glomerulonephritis (tends to be milder than SLE)
• Neuropsychiatric: seizures, mood disturbance
Investigations:
• Exclude other connective tissue disease/vasculitis
• Bloods FBC: anaemia, leucopenia, thrombocytopenia, U+E: renal impairment, CRP/ESR raised
• ANA (usually) positive, anti Ds-DNA and scleroderma-specific antibodies (e.g. Anti-Scl70) are negative
• Anti-U1 RNP (an extractable nuclear antigen, ENA), must be positive*.
• Organ-specific investigations, e.g. ECG, echo, CT chest, MRI brain
Management:
• No large-scale trials - patients have been included in trials for SLE/SSc and show similar levels of response to immunosuppression/DMARDs
• Calcium channel blockers may be used for the treatment of Raynaud’s
• Proton pump inhibitors for reflux disease
• Endothelin receptor antagonists/prostacyclin analogues in pulmonary hypertension
• Smoking cessation, moderate exercise
Prognosis:
• 1/3 long-term remission, 1/3 have chronic symptoms, 1/3 develop severe systemic involvement and premature death.
- Note that anti-U1 RNP antibodies are not completely specific and may also be seen in definite SSc and SLE
- *Undifferentiated connective tissue disease refers to syndromes in which features of one or more ‘classical’ connective tissue disease may be present, but do not meet diagnostic criteria. Anti-U1 RNP is absent.
Signs of drug induced lupus
In drug-induced lupus not all the typical features of systemic lupus erythematosus are seen, with renal and nervous system involvement being unusual. It usually resolves on stopping the drug.
Features
arthralgia
myalgia
skin (e.g. malar rash) and pulmonary involvement (e.g. pleurisy) are common
In SLE, what should you think of if someone has high CRP
- In SLE, the CRP is not always elevated
- If CRP is elevated, think serositis (pleuritis, pericarditis)
- Think of other differentials, eg: infection
Pulmonary manifestations of SLE
- Acute pneumonitis
- Other ILD: organising pneumonia, NSIP
- Pulmonary embolism - think ANTIPHOSPHOLIPID SYNDROME
- Pulmonary HTN
- Pulmonary haemorrhage
- “Shrinking” lung syndrome
Cardiovascular manifestations of SLE
- Premature CV disease is the most likely
- Vasculitis
- Libman sacks endocarditis
- Lupus myocarditis
- Pericarditis
Haematological manifestations of SLE
- Anaemia: often multifactorial iron deficiency anaemia, chronic disease, autoimmune (AIHA, DAT+), aplastic, anti EPO Ab
- Leukopenia: peripheral destruction and suppressed production
- Thrombocytopenia: common overlap with ITP
- MAHA (TTP)
- Myelofibrosis
Neurological manifestations of SLE
- Brain fog is universal
- CNS: headache, mood disorder, seizure, cognitive dysfunction, CVA, myelitis
- PNS: present in up to 20%, sensorimotor axonal polyneuropathy is the most common
- Consider catastrophic APLS - seizure, encephalopathy
- Ribosomal P Abs = neurolupus
Mechanism of action of mycophenolate
Mycophenolate mofetil is a prodrug of mycophenolic acid (MPA), an inhibitor of inosine-5’-monophosphate dehydrogenase. MPA depletes guanosine nucleotides preferentially in T and B lymphocytes and inhibits their proliferation, thereby suppressing cell-mediated immune responses and antibody formation.
Biologics in SLE
Belimumab: against BAFF (B cell activating factor)
Tibulizumab: against BAFF and IL17
Rituzimab, Veltuzumab: against B cells
Anifrolumab in SLE
Monoclonal ab directed at the subunit of the IFN-a receptor (Type 1 IFN)
Antiphospholipid Syndrome in SLE
- Primary or secondary
- Thrombosis +/- obstetric complications
- Also thrombocytopenia, cardiac valve abnormalities, livedo reticularis, renal microangiopathy, chorea, myelitis
- Associated conditions: HELLP, pre-eclampsia, MAHA
- “triple positive” at highest risk of thrombosis - lupus anticoagulant (most important), anticardiolipin IgG , B2 glycoprotein
- Look out for prolonged APTT
Antiphospholipid syndrome treatment
- Asymptomatic/Primary Prevention (contentious): no treatment/low dose aspirin, HCQ
- Secondary Prevention: WARFARIN
DOACs are not recommended
May require higher INR if recurrent/arterial
Management in Pregnancy
- Prior Thrombosis: therapeutic LMWH + aspirin
- Prior Pregnancy Loss: low dose LMWH + aspirin
Which medications are safe in pregnancy
PASH
- Prednisone
- Azathioprine
- Sulfasalazine
- Hydroxychloroquine
