Systemic Lupus Erythematosus

Question 1

SLE is an autoimmune disease caused by autoantibodies and complement deposition, causing manifestation on skin, joint, multiorgan dysfunction

Question 2

Epidemiology of SLE

Answer 2

1. Female > male (10-15 times)
2. Age 15-45 years old
3. 3-4 times higher in non-Caucasian (African-American, Asian, Hispanic)

Question 3

Laboratory hallmark of SLE

Answer 3

1. Elevated ANA (very sensitive but not specific)
   - Most specific: Peripheral or rim pattern
   - Commonest but least specific: speckled pattern
   - Nucleolar pattern -> scleroderma
2. dsDNA - highly specific, correlates with lupus nephritis activity
3. Histones (H1, H2A, H2B, H3, H4)
4. anti-Sm - highly specific, no activity correlation
5. Ribosomal P proteins - highly specific
6. Low C3 and low C4

Others:
1. U1-RNP - MCTD
2. Ro/SSA - scleroderma, neonatal lupus
3. La/SSB - scleroderma, neonatal lupus
4. Antiphospholipids

Question 4

Memorising characteristic manifestations of SLE (ACR 1997 Criteria for SLE)
(SOAP-BRAIN-MD)

Answer 4

S: serositis - pleuritis, pericarditis
O: oral or nasal ulcers
A: arthritis (non-erosive)
P: photosensitivity rashes

B: blood disorders - haemolytic anaemia, leukopenia, lymphopenia, thrombocytopenia
R: renal involvement: proteinuria, cellular casts
A: ANA
I: immunologic - dsDNA, anti-Sm, APLAs
N: neurologic - seizures, psychosis

M: malar rashes
D: discoid rashes

Question 5

ACR/EULAR Classification of SLE (2017)

Answer 5

Highly sensitive (96%), specific (93%)
Mandatory ANA + at least 10 point criteria

Mandatory criteria:
1. ANA titre > 1:80

Points criteria (at least 10 points):
- Do not count if due to other cause than SLE
- at least 1 clinical criterion

Clinical
1. Renal involvement
- Class 3/4 nephritis - 10
- Class 2/5 nephritis - 8
- Proteinuria >0.5g/day - 4

2. Arthritis - 6
3. Serosal
   - Pericarditis - 6
   - Pleural or pericardial effusion - 5
4. Mucocutaneous
   - Cutaneous lupus - 6
   - Subacute cutaneous or discoid lupus - 4
   - Oral ulcers - 2
   - Non-scarring alopecia - 2
5. Neuropsychiatry
   - Seizure - 5
   - Psychosis - 3
   - Delirium - 2
6. Haematologic
   - AIHA - 4
   - Thrombocytopenia - 4
   - Leukopenia - 3
7. Constitutional - Fever - 2

Laboratory
1. SLE-specific antibodies
- anti-dsDNA or anti-Smith - 6

2. Complement proteins
   - Low C3 and C4 - 4
   - Low C3 or C4 - 3
3. Any APLAs - 2

Question 6

Describe the different types of lupus

Answer 6

A. SLE
- Multiple organs can be involved
- ANA and SLE specific antibodies
- Variable prognosis

B. Subacute cutaneous SLE
- Skin only involvement
- ANA negative, SSA or SSB positive
- 5-10% eventual progress to SLE

C. Drug-induced lupus
- Systemic but without CNS or renal
- Anti-histone antibodies
- Improves when drug stopped

D. Discoid lupus
- Skin only involvement
- ANA negative
- Rarely progresses to SLE unless ANA turns positive

Question 7

ANA-negative SLE

Answer 7

Rare

1. Must have excluded less sensitive test
   (must run ANA using HEp-2 assay)
2. Positive cytoplasmic antigens - antibodies to SSA/Ro-52kD (TRIM-21) or ribosomal P
3. Severe proteinuria (loss of Igs and unable to bind to HEp-2)
   -> ANA turns positive with treatment
4. Post-cytotoxic therapy in remission

Question 8

Risk factors for SLE

Answer 8

1. Environmental
   - Smoking, viral (EBV, CMV), silica, UV light, pesticides, gut microbiome, demyelinating drugs
2. Genetics
   - First degree relatives with SLE
   - Identical twins
   - MHC - HLA DR2, DR3
   - Complement deficiency
3. Gender and hormone
   - Women of childbearing age
   - Klinefelter (14 fold risk)
   - Rare in Turner’s syndrome

Question 9

Pathogenesis of CNS manifestation of SLE

Answer 9

Diffuse manifestation - transient, reversible with therapy
Focal manifestation - permanent, pathological lesions on autopsy

Possible endothelial dysfunction
- Complement activation during acute lupus
- Progoagulant factors (APLAs)
- Thrombosis and emboli
- Microvasculoparhy and disruption of BBB
- Influx of cells, autoantibodies and cytokines into CNS

Associated autoantibodies:
1. Antiphospholipids
2. Antineuronal
2. Ribosomal P
4. NMDA receptor
5. AQP4/NMO

Question 10

What are the neuropsychiatric manifestations of SLE?
- Diffuse
- Focal

Answer 10

Diffuse
1. Acute confusional state and coma
2. Cognitive dysfunction and dementia
3. Psychosis, depression, anxiety
4. Intractable headache (pseudotumour cerebri)
5. Aseptic meningitis

Focal
1. Stroke syndromes
2. Seizures
3. Chorea, ataxia, hemiballismus
4. Demyelinating syndromes
5. Transverse myelitis

Question 11

Approach to SLE patient presenting with neuropsychiatry changes

Answer 11

Differential diagnoses:
1. Neuropsychiatric SLE
2. Prednisolone incuded psychosis
3. Delirium - infection
4. Metabolic abnormalities
5. Primary mental illness not due any secondary causes

Evaluation:
1. Signs and symptoms for SLE, localise infections
2. Examination for focal neurological deficits
3. Labs and imaging to exclude infection
4. Check SLE labs: C3/C4, anti-dsDNA levels
5. Consider specific NPSLE serologies: anti-ribosomal P, anti-NMO
6. Lumbar puncture, OP, CSF testing
7. MRI brain +/- spinal cord +/- angiogram/venogram
8. EEG

Question 12

Respiratory manifestation of SLE

Answer 12

1. Pleuritis (commonest)
   - Bilateral involvement. Elevated CRP. Consider infection
2. Acute lupus pneumonitis with/without pulmonary haemorhage
   - Ground glass changes. Associated with APLAs
   - Progressive to ILD
   - Broncoscopy: DAH +/- infection
3. ILD/fibrosis
   - Rare in non-overlap SLE, common in MCTD or prior lupus pneumonitis
   - Medication effect (nitrofurantoin) or overlap with anti-synthetase antibody syndrome
4. Pulmonary hypertension
5. Shrinking lung syndrome - reduced lung volume
   - A/w phrenic neuropathy, myopathy, pleural fibrosis
6. Crytogenic organisign pneumonia
   - Responsive to steroids
   - Overlap with anti-synthetase antibody syndrome
7. Infections, especially atypicals
   - Tree in bud appearance

Question 13

Cardiac manifestations in SLE

Answer 13

1. Pericarditis +/- left pleural effusion
   - Treat with colchicine
2. Myocarditis (rare)
   - Presents as heart failure, tachycardia. Elevated trops
   - Consider myocardial biopsy
3. Coronary vasculitis (rare)
4. Secondary atherosclerotic CAD and MI (commonest)
5. Secondary hypertensive disease - kidney failure, chronic steroids use
6. Medication induced cardiomyopathy - hydroxycholoquine
7. Valvular disease in APS
8. Libman-Sacks endocarditis/verrucae
   - Posterior leaflet of mitral valve or aortic valve
   - Leads to embolic stroke
   - high concomitant subacute bacterial endocarditis
   - TEE more sensitive than TTE

Question 14

Gastrointestinal manifestations of SLE

Answer 14

Usually rare, and unlikely due to SLE
UNLESS patient has active SLE in other organs and abnormal serologies

1. Oesophageal dysmotility
   - Upper 1/3 involvement, esp in SLE myositis, overlap syndromes
2. Pancreatitis - usually non SLE related (gallstones, alcohol, hyperTG)
   - Medication (azathioprine)
   - Diffusely active if due to SLE
3. Serositis
4. Mesenteric vasculitis, bowel oedema, fat stranding
   - Associated with active SLE
5. Hepatitis - from mediaction, or non-lupus
   - Must not have anti-smooth muscle and anti-LKM if due to SLE
6. Intestinal pseudo-obstruction
7. Protein losing enteropathy
   - Low albumin without proteinuria
   - Chronic diarrhoea, generalised oedema
   - Diagnosed with fecal alpha-1 antitrypsin or transferrin

Question 15

What are the indications for renal biopsy in SLE patient?

What is the importance of biopsy?

Answer 15

Indications
1. Increasing creatinine without alternative cause
2. Proteinuria > 1g/day
3. Proteinuria >0.5g/day wtih haematuria or cellular casts

Importance of biopsy
1. Histologic changes of chronicity - scarring, fibrosis indicates less likely responsive to therapy
2. Evaluate for microthrombotic disease in APS
3. Calculated scoring on disease activity (mixed predictive value, no longer universally use)

Question 16

SLE Glomerulonephritis Classification Sytem (2004)

Answer 16

Class I - minimal mesangial
- No clinical manifestation
- Histology: mesangial immune deposits on IF / EM

Class II - mesangial proliferative
- Microscopic haematuria, proteinruia, rare HTN
- Histology: mesangial hypercellularity or matrix expansion, few subepithelial/subendothelial deposit

Class III - focal (A: active; C: chronic)
- Haematuria, proteinuria, HTN
- Reduced GFR or nephrotic syndrome
- Histology: < 50% glomeruli affected; almost uniformly involved. EM - immune deposits, some mesangial and some subedothelial space

Class IV - diffuse (S: segmental; G: global; A and C)
- Haematuria, nephrotic range proteinuria
- Cellular casts, reduced GFR, HTN
- Hypocomplementaemia, elevated dsDNA
- Histology: > 50% glomeruli involvement; generalised hypercellularity of mesangial and endothelial cells; extensive deposition. EM immune complxes in both subendothelial and subepithelial

Class V - membranous
- Extensive proteinuria, minimal haematuria
- Minimal renal function abnormalities
- Histology: granular global or segmental subepithelial immune deposits

Class VI - advanced sclerosing
- CKD
- Histology > 90% global glomerulosclerosis without residual activity

Question 17

Serologic tests for lupus nephritis follow up

Answer 17

1. dsDNA - elevates with disease flare
2. Complement levels - decrease with active disease
   (Some patients have chronic partial C4 deficiency, thus C3 might be more useful for follow up)
3. ANCA - perinuclear (PR3)
   (MPO not useful)

Caveats:
Some patients can develop GN even with normal complements and no dsDNA

Question 18

What are risk factors for SLE nephritis progression to ESRF?

Answer 18

1. African american, Hispanics, especially males
2. Low SES
3. Poor medication compliance
4. Pooly controlled comorbids: DM, HTN
5. persistent elevatec creatinine or failure to normalise on therapy
6. Persistent proteinuria > 6 months of treatment
7. Renal biopsy - crescent (high disease activity) or interstitial fibrosis (chronic)

Question 19

Pathologic scoring of lupus nephritis

Answer 19

Based on chronicity and activity

Chronicity
1. Glomerular sclerosis
2. Fibrous crescent
3. Fibrous adhesions
4. Interstitial fibrosis

Activity
1. Cellular proliferation
2. Fibrinoid necrosis
3. Cellular crescents
4. Hyaline thrombi

Question 20

Treatment for severe lupus nephritis
- To note: different for SLE without severe nephritis
- Class III/IV treatment differs from class V

Answer 20

Class III and IV lupus nephritis - induction and maintenance

Induction therapy
1. IV methylprednisolone 500mg-1g OM for 3 days
2. Followed by prednisolone 1mg/kg/day (crescent) or 0.5mg/kg/day (no crescent)
- Taper after a few weeks to lowest effective dose
3. Immunosuppressives: choice of
A. MMF 2-3g/day for 6 months (better in Hispanics, African)
B. IV cyclophosphamide
(NIH high dose regime: 500-1000 mg/m2 monthly x6)
(Eurolupus low dose regime: 500mg every 2 weeks x6)

4. Consider switching if fail to improve on MMF -> Cyc and vice versa. And if fail, consider rituximab or CNI

Class V lupus nephritis
1. Oral prednisolone 0.5mg/kg/day for 6 months
2. MMF 2-3g/day for 6 months
3. Add on CNI (tacrolimus, cyclosporin) if needed
4. IV cyclosporin if treatment fails

Maintenance post-induction - adjucts
1. Hydroxycloroquine, azathioprine
2. ACEi or ARBs if proteinuria > 0.5g/day, control BP < 130/80
3. Statin
4. Stop smoking
5. Counsel against pregnancy while in active nephritis or teratotoxic drugs
6. Rituximab

Question 21

Considerations for high dose vs low dose cyclophosphamide (NIH high dose vs Eurolupus low dose)

Answer 21

Low dose
Pros: fewer serious infections, lesser infertility (premature ovarian failure), lesser bladder toxicity
Cons: higher rate of fail to respond

Premature ovrian failure and bladder cancer correlates with cumulative dose (>10-15g total) and age (>30 years)

Emerging studies:
CALIBRATE study - rituximab 1g + cyc 500-750mg + belimumab (not promising)

Question 22

Cyclophosphamide infusion protocol

Answer 22

A. Pre-medications
1. +/- Dexamethasone or hydrocortisone
2. Anti-emetics: metoclopramide or ondansetron

B. Adjuncts
1. Mesna - pre-dose as IV, post-dose as oral x2
- Reduces risk of haemorrhagic cystitis
2. Premature gonadal failure prevention
- IM Gonadotropin-releasing hormon (Lupron) 3.75mg, 10 days prior to CYC … or
- IM testosterone 200mg 2 weekly

Question 23

1. Progression of lupus nephritis to ESRF
2. Survivability of ESRF lupus nephritis on dialysis
3. Lupus nephritis recurence post-transplantation

Answer 23

25% lupus nephritis progress to ESRF over 10 years
(1-2% of all ESRF cases)

Clinical course and survival on dialysis favourable (80-90% 5 year survival)

Excellent candidate for transplantation
- Living donor better than cadaveric

Recurrence: 2-11%
- And recurrence unlikely lead to allograft loss
- Retroanaluysis - similar incidence of graft survival rates as non-lupus patient, except in APS (thrombosis)

Question 24

Haematologic manifestations of SLE

Answer 24

1. AIHA
2. Leukopenia (lymphopenia, neutropenia)
3. Thrombocytopenia
4. APS
5. Anaemia of chronic disease
6. Thrombotic thrombocytopenia purpura (TTP)
7. Macrophage activation syndrome (MAS)

Question 25

What is macrophage activation syndrome (MAS)

Answer 25

Can be triggered by EBV or CMV infection Fatal condition - inability of liver to synthesise proteins such as fibrinogen, high TG, high ferritin, high IL-2 receptor (CD25) Resulting in fever, cytopenias, organ dysfunction, splenomegaly, low ESR Criteria: 1. High ferritin 2. Thrombocytopenia <181 3. AST >48 4. Hypertriglyceridaemia 5. Low fibrinogen

Question 26

Haemolytic anaemia workup

Answer 26

1. FBC 2. PBF - spherocytes vs schistocytes 3. LDH - raised 4. Haptoglobin - low 5. Bilirubin - total and direct 6. Reticulocytes 7. Direct Coombs test

Question 27

When and how would you treat thrombocytopenia in SLE

Answer 27

Treat if platelet < 30 or with significant bleeding 1. Steroids, consider pulse if severe 2. IVIG: 2g/kg (0.4g/kg/day for 5 days) 3. Anti-D in Rh-positive non splenectomised pt 4. IV rituximab - response > 1 year 18-35% 5. Splenectomy Second line agents - AZA, MMF, CNIs, Danazol, Cyclophosphamide, fostamatinib, dapsone, vincristine Novel agents - Thrombopoietin receptor agonist (romiplostim, elterombopag, avatrombopag) > Very expensive (85k per year) > Tends to recur when drug is stopped

Question 28

TTP in SLE - Manifestations - Important lab findings - Treatment

Answer 28

_Manifestations_ 1. Fever 2. Altered mental status 3. Worsening renal function 4. Haemolytic anaemia 5. Thrombocytopenia _Important lab findings_ 1. PBF: schistocytes, microangiopathic HA (MAHA) 2. LDH very high 3. Possible Coombs positive AIHA and spherocytes 4. ADAMTS13 activity/inhibitor profile - low (Ab against it) _Treatment_ 1. Plasma exchange with FFP replacement (plasmapheresis) - removes autoAb and vWF multimers 2. Second line - antiplatelets, steroids, IST 3. Maintenance with steroids and ISTs 4. Eculizumab (C5 monoclonal antibody) in refractory cases

Question 29

Joint manifestations of SLE

Answer 29

Pain and tenderness more severe than degree of swelling, but rarely destruction of bones 1. Tenosynovitis 2. Jaccoud arthritis (non-erosive) in 10-35% - MCPJ subluxation, ulnar deviation, swan neck from lax joint capsules, tendons, ligaments 3. Reversible deformities early, fixed at late stage 4. Erosive, symmetric polyarthritis (Rhupus) - RA resembling fixed deformity with radiographic erosions and possible positive RF / CCP

Question 30

Treatment of SLE with arthritis without end organ involvement

Answer 30

1. NSAIDs and COX2i - Beware of APLAs and APS - Avoid ibuprofen - risk of aseptic meningitis 2. Celecoxib may cause rashes (sulphur based) 3. Meloxicam, etodolac 4. Antimalarial drugs 5. Others: MTX, leflunomide, AZA, MMF

Question 31

Mucocutaneous lesions in SLE

Answer 31

_Common rashes_ 1. Malar rash 2. Oral ulcers 3. Discoid rash and scarring alopecia 4. Subacute rash _Uncommon rashes_ 1. Bullous lesions 2. Palpable purpura - small vessel vasculitis 3. Urticaria - anti-C1q Ab 4. Panniculitis and subcutaneous nodules (lupus profundus) 5. Livedo reticularis - in APLAs 6. Perniosis (distal vasculopathy _Pathology_ 1. Interface dermatitis or dermatomyositis 2. Immunoglobulin deposition at dermal epidermal junction (lupus band test on IF) 3. Drug induced in > 50 years old with SCLE _Treatment_ 1. Avoid sunlight - apply sunblock 2. Control SLE activity 3. Hydroxychloroquine 4. Dapsone - vesicular lupus skin lesions 5. Thalidomine - mouth ulcer (must avoid pregnancy) 6. Belimumab - recalcitrant discoid or subacute rashes 7. Others: MTX, MMF, AZA, rituximab

Question 32

Differentiating SLE hand rash vs dermatomyositis

Answer 32

SLE - erythematous over dorsum of hands and fingers, affecting skin between joints Dermatomyositis - lesion over MCPJ and PIPJ (Gottron's papules) --- Insert picture for comparison

Question 33

How may a patient with SLE present with alopecia?

Answer 33

1. Active disease - diffuse stress alopecia (telogen effluvium) - 2-4 months after severe flare, massive hair shedding - Reversible once disease is controlled 2. Discoid lupus - patchy hair loss - Permanent -> hair follicle inflammation and damage 3. Drug induced (cyclophosphamide) - diffuse hair loss - Reversible after therapy discontinued 4. Vasculitis or Ab against hair follicles - focal alopecia areata-like with patchy hair loss

Question 34

Topical steroids and alternatives for skin lesions in SLE

Answer 34

Facial - low to medium potency non-fluorinated (hydrocortisone, desonide) Trunk/arm - medium potency, fluorinated (betamethasone valerate, triamcinolone acetonide) Hypertrophic - high potency, fluorinated (betamethasone diproprionate, clobetasol) _Alternatives_ Topical tacrolimus BD for 3 weeks

Question 35

Management of resistant SCLE

Answer 35

1. Stop smoking - affects HCQ effect 2. Hydroxychloroquine: LE > SCLE > DLE 3. Steroids < 30mg/day 4. Belimumab 5. Bullous: dapsone 6. SCLE: MMF, metinoids, cyclosporine, dapsone 7. DLE: HCQ +/- quinacrine, thalidomide, cyclosporin 8. Lupus profundus: dapsone 9. > 50% chronic lesions: tacrolimus, MMF, belimumab 10. Vasculitis: systemic ISTs 11. Hyperkeratotic: oral retinoids 12. Trial drugs: apremilast, ustekinumab, JAK inhibitors

Question 36

What are the lupus conditions that warrant high dose corticosteroids (>1mg/kg/day)

Answer 36

1. Severe lupus nephritis 2. CNS lupus, transverse myelitis 3. Autoimmune thrombocytopenia with Plt < 30 4. AIHA 5. Acute pneumonitis 6. Diffuse alveolar haemorrhage (DAH) 7. Severe vasculitis with visceral organ involvement 8. Pleuritis, pericarditis, peritonitis 9. MAS

Question 37

Osteonecrosis and avascular necrosis risk in SLE

Answer 37

In patient with SLE presenting with progressive hip pain in the groin _Higher Risks_ 1. High dose prednisolone > 20mg/day over 1 month 2. Other end organ damage from steroid use 3. Antiphospholipid antibodies 4. Raynaud's phenomenon _Considerations and Management_ 1. Consider septic arthritis as differential 2. MRI of bilateral hip (50% involvement of contralateral side) 3. Core decompression if >25% femoral head involved, and without bony collapse

Question 38

How does ESR, CRP , WBC count, complements help in identifying disease activity or infection in SLE?

Answer 38

1. ESR - might remain elevated even when disease is controlled (persistent polyclonal gammopathy) 2. CRP < 6 times ULN during disease flare - > 6 times suggestive of infection, systemic vasculitis, significant serositis - Fever + raised CRP - must rule out infection 3. WBC - Leukopenia in SLE flare, or due to infection - Deceiving normal SLE in low WBC SLE in acute infection - Left shifting - infection 4. Procalcitonin and lactate - bacterial infection 5. Complements - Drop in SLE flare - Rise in infection

Question 39

Serology test for SLE disease activity and prediction of disease flare

Answer 39

1. Low C3 (C4 may be chronically low) 2. High dsDNA Patients usually are serologically active and flare, but certain caveats: 1. Serologically active, never flare 2. Flare with no change to serology Important to establish serology patterns of each patient To adjust immunosuppression only in those who demonstrates serologically activity correlating with flare

Question 40

Overall review in management of SLE

Answer 40

1. Explore other causes than SLE - infection, thrombosis, drug side effect, hypothyroidism, fibromyalgia, sleep apnoea Mild disease - fatigue, arthritis, rash, serositis 1. NSAIDs - watch renal function, photosensitivity, aseptic meningitis 2. Hydroxychloroquine 3. Low dose prednisolone, taper to lowest effective dose 4. Methorexate or leflunomide Moderate disease - unresponsive severe minor symptoms 1. MMF or AZA 2. Belimumab 3. Prednisolone 20-40mg/day 4. Calcineurin inhibitors (CyA or tacrolimus) Severe disease - nephritis, CNS, pneumonitis, vasculitis, severe cytopenias 1. High dose prednisolone or pulse methylpred 2. Cytotoxic induction: CYC (or biologics: rituximab - limited data) 3. Manitenance with AZA, MMF, CNI 4. Additional therapies might be needed - Plasma exchange - IVIg - Stem cell transplant

Question 41

Emerging biologics and small molecule therapies in SLE

Answer 41

1. Belimumab 2. Rituximab TNF-inhibitors - mixed or negative results 1. Abatacept 2. Epratuzumab 3. Tabalumab 4. Ocrelizumab 5. Tocilizumab Oral JAK inhibitors - atacicept Low dose IL-2 apremilast Ustekinumab

Question 42

Commonest morbidities and mortalities in SLE

Answer 42

_Morbidities_ 1. Renal failure 2. AVN 3. Neuropsychiatric deficits 4. Cardiovascular disease 5. Disfiguring skin lesion 6. Osteoporosis _Mortalities_ 1. Infection - each increase of pred by 10mg/day incrases risk 11 fold 2. Active SLE - lupus nephritis, CNS lupus, vasculitis, pneumonitis 3. Cardiovascular disease 4. Malignancy Overall 5-year survival rate improved to 95%, 10-year 90% from early diagnosis and aggressive treatment