SLE - The British Society for Rheumatology

22/06/2011
SLE- Basics
Shahir Hamdulay
PhD, MRCP
Imperial College Healthcare NHS Trust
17.6.2011*
• Diagnosis
• Autoantibodies
• Management
1
22/06/2011
Connective Tissue Diseases
SLE
Myositis
Overlap
Scleroderma
Sjogrens
Rheumatoid
APLS
SLE- Hallmarks
• Multi-system
• Immune-mediated
• Polyclonal B-cell activation
• Antibodies directed against nuclear antigens
2
22/06/2011
Aetio-pathogenesis
Genetic
Environmental
Drugs
Procainamide
Hydralazine
Quinine
Twin studies
MZ- 25% v DZ- 2%
Epstein-Barr virus
Genetic complement
deficiency
C1q, C2, C4
UV light
Genome wide studies
HLA-A1, B8, DR3
C2, C4, CRP
Fc- receptors
PARP
TLR 5
PDCD1
Family studies
Interferon related genes
Defective clearance of apoptotic debris
‘”Waste disposal” hypothesis
Impaired immune complex clearance and phagocytosis
Exposure of nuclear antigens
Anti-nuclear antibodies
Rahman et al NEJM 2007
SLE - clinical features
• Musculoskeletal
– arthralgia in 90%
– Jaccoud’s arthropathy
– myalgia / myositis
• Skin
–
–
–
–
butterfly rash in 30%
photosensitivity
alopecia
mucosal ulceration
• Cardiovascular
– pericarditis
– myocarditis
– endocarditis (LibmanSachs)
• Pulmonary
– pleurisy in up to 60%
– pleural effusions
– interstitial fibrosis
• Renal
– proteinuria, nephrotic
– haematuria
– GN, any subtype
• Haematological
– anaemia
– leucopenia (lymphopenia)
– thrombocytopenia
• Neurological
– headaches
– seizures, psychosis
3
22/06/2011
Manifestations (%)
Onset
Ever
Constitutional
36
52
Arthritis
69
84
Skin
40
58
Mucous membrane
11
24
Pleurisy
17
36
Lung
3
7
Raynauds
18
34
Renal
16
39
CNS
12
27
Lymphadenopathy
7
12
Myositis
4
9
European cohort n= 1000
1997 Revised ACR criteria for classification of SLE
•
•
•
•
•
•
•
•
•
Malar rash
Discoid rash
Sicca symptoms
Raynauds
Photosensitivity
Oral ulcers
Arthritis
Serositis (pleurisy, pericarditis)
Renal disease (proteinuria, casts)
Neurological disease (seizures, psychosis)
Haematological disorder (anaemia, leukopenia,
thrombocytopenia)
• Immunological disorder (anti-dsDNA, anti-Sm etc)
• Anti-nuclear antibody
4/11 required, sens- 85% spec- 95%
4
22/06/2011
Autoantibodies in SLE
Homogenous
Speckled
Rodent liver/kidney v HEp-2 cells
Autoantibodies
Autoantibody Disease
dsDNA
Histone
Sm
SLE
Drug-ind LE
SLE
La
Ro
Sjogren’s
Sjogren’s
SLE
Scleroderma
lcSSc
Polymyositis
APS
MCTD
Vasculitis
Scl-70
Centromere
Jo-1
Cardiolipin
U1 RNP
ANCA
Prevalence
40-90%
30-80%
4% Caucasian
40% Afro-Caribb
50%
80%
50%
27%
70%
25%
40%
90%
Variable
Specificity
High
High
High
High
Low
High
Moderate
High
High
High
Variable
5
22/06/2011
Autoantibodies in SLE
• Lucile crithidia- ‘gold standard’
• dsDNA ELISA
Predictors of disease
Autoantibody
Prevalence
Specificity
Association
dsDNA
Sm
Ro
La
Ribosomal P
C1q
Nucleosome
U1 RNP
70%
30-50%
40%
15%
15%
50%
60-90%
30%
high
high
low
low
high
high
high
low
nephritis, skin
nephritis, CNS
skin, neonatal lupus
skin, neonatal lupus
CNS
nephritis
nephritis, skin
overlap
NMDA receptor
Phospholipid
a-actinin
33-50%
30%
20%
high
high
high
CNS
thrombosis, fetal loss
nephritis
6
22/06/2011
Autoantibodies in SLE
• ANA+ in 99%
• Unclear if antibodies are ‘directly’ pathogenic
• Specific antibody profiles may predict disease
expression
• Accrual of antibodies at disease onset
Therapies
Organ / Life
threatening
disease
Minor
disease
Hydroxychloroquine
Prednisolone
Methylprednisolone
Azathioprine
Methotrexate
Mycophenolate
Cyclophosphamide
Rituximab
Plasma exchange
IVIG
7
22/06/2011
8
22/06/2011
Therapies
Drug
N
Disease
Outcome
Cyclophos
(LD v’s HD)
90
Nephritis
No difference
Eurolupus
MMF v’s Cyclo
370
Nephritis
No difference
Appel et al
MMF v’s Aza
105
Nephritis
No difference 5
years
MAINTAIN
MMF v’s Aza
227
Nephritis
MMF superior to
aza
ALMS
Belimumab
819
Non-renal
Superior to
placebo
BLISS 52 and 76
Rituximab
257
Non- renal
No difference
Merril et al
Rituximab
144
Nephritis
No difference
LUNAR
• Diagnosis - is it SLE ?
• How severe is it ? – complications
• How are you going to treat it ?
9
22/06/2011
Case 1
•
A 28 year old lady is referred with multiple joint pains and a skin
rash affecting her face, hands and feet.
•
No oral ulcers, alopecia, Raynauds phenomenon or chest pains
•
Hb- 12.5g/dl, Plt- 180 WBC-7.5 Neut.- 4.8 Lymph- 1.5
•
ESR 12mm/hr
CRP<5
•
ANA negative
RhF negative
•
C3 1.2g/l
C4 0.24g/l
10
22/06/2011
11
22/06/2011
Necrotic keratinocytes
Mononuclear and
perivascular infiltrate
Linear C3 and IgM
deposition
12
22/06/2011
13
22/06/2011
SLE – treatment (1)
Cutaneous disease
High factor sun block
Topical steroids
Topical tacrolimus
Oral low dose steroids
Hydroxychloroquine
Mepacrine
Dapsone
Azathioprine
ANA negative
14
22/06/2011
Case 2
•
•
•
A 21 year old asian lady is referred with joint pains and describes
hands which change colour in the cold weather.
She has no oral ulcers or alopecia.
No other symptoms
•
•
•
•
ESR 12mm/Hr, CRP<5
Hb 13.5g/dl, WBC 8.4, Neut. 6.5, Plt 180
C4 - 0.22 g/dl, C3- 1.28g/dl
ANA+ (>1:640), ENA negative, dsDNA negative
• What is the diagnosis?
15
22/06/2011
•
5 years later she is admitted with a 1 week history of shortness of
breath and haemoptysis
•
Over the last four weeks she has become increasingly tired and noticed blood
in her urine
•
She has painful wrists and several swollen joints
•
2 years ago she developed mouth ulcers, joint pains, pleuritic chest pains and
Raynauds phenomenon
•
•
•
•
Urine dipstick- 3+ blood, 3+ protein
ESR- 90mm/Hr, CRP- <5mg/ml.
ANA > 1:640, Ro+, La+, Sm+, dsDNA>180
C3 0.42 g/l, C4 0.04 g/l
•
Protein: Cr ratio = 180mg/mmol
16
22/06/2011
• SLE
– Pulmonary alveolitis with haemorrhage
– Class IV lupus nephritis
• Treatment
– Pulse methylprednislolone (1g X 3)
– Iv cyclophosphamide followed by MMF
– Plasma exchange
17
22/06/2011
Accrual of antibodies precede diagnosis
Arbuckle et al., NEJM 2003
Lupus nephritis
• Kidney involvement common
– Up to 50% have abnormalities of urine or renal function early in
disease course
– Up to 60% will develop renal abnormalities
• Monitor patients with urine dipstick and protein: Cr ratios
• Refer early for renal biopsy
– Diagnosis, activity/chronicity, class and prognosis
18
22/06/2011
International society of Nephrology
Renal pathology society 2003
Class I
Minimal mesangial
Normal light microscopy;
abnormal electron microscopy
Class II
Mesangial
proliferative
Hypercellular on light
microscopy
Class III
Focal proliferative
<50% glomeruli involved
Class IV
Diffuse proliferative
>50% glomeruli involved;
segmental/global
Class V
Membranous
Predominantly nephrotic
disease
Class VI
Advanced
sclerosing
Chronic lesions and sclerosis
A 32 year old lady is admitted via A&E with increasing stiffness and
several swollen joints. Symptoms started 6 months ago and progressively
deteriorated. She has also noticed that her hands change colour in the
cold weather and she is losing hair.
Examination reveals a swollen left elbow with a flexion deformity, swollen
wrists, ankles and MCPs, PIPs and MTP’s.
Urine dipstick negative
Blood tests show :
ESR 93mm/hr, CRP 15mg/ml, WBC 2.4,Lymph 0.5, Hb 10.4. RhF positive,
ANA positive (1:1280), anti-Ro positive, anti-La negative, dsDNA negative.
X-rays of her hands and feet are normal.
19
22/06/2011
A 17 year old lady presents to casualty with multiple joint pains, stiffness and
fatigue which has deteriorated over the last 6 weeks.
Examination reveals no swollen joints but she is tender over her shoulders,
neck, behind the knees, buttocks and lower spine.
X-rays of her hands are normal.
Blood tests: ESR 8, CRP< 5, Hb-12.3, Plts- 220, WBC 7.0,
RhF positive, Anti-CCP ab positive, ANA positive, ENA negative
•
•
•
A 38 year old lady presents with increasing malar rash, headache,
neck stiffness and nausea but no photophobia
She has a past diagnosis of SLE and a glioma
Prednisolone 10mg od, Kepra
•
She wants to become pregnant
•
•
•
•
Hb 12.3, WBC 3.7, Lymph 0.7, Plt 102, ESR 28,
Ur 5.3, Cr 64, Na 138, K 4.1
C4 < 0.08, C3 0.35
ANA> 1:640, ENA negative, dsDNA – 735!
•
What will you do next?
20
22/06/2011
21
22/06/2011
•
•
•
•
•
•
Lumbar puncture
Opening pressure 12cm H20
Protein 0.04g/l
Microscopy and gram stain- acellular
Culture negative
Viral PCR negative
•
Treatment
• Oral prednisolone 60mg od
• Azathioprine 100mg od
Markers of impending flare/
disease activity markers
• Clinical – symptoms, signs
• Laboratory
–
–
–
–
Hb, Neutrophils, lymphocytes, platelets (all may decrease)
ESR (not CRP)
Complement (decrease C4>C3)
dsDNA
22
22/06/2011
Complement
Immune complexes
Mannose on bacteria
Endotoxin
classical pathway
lectin pathway
alternative pathway
MBL
MASPs
C3
C1q
C1r
C1s
C4
C2
C4
C2
C1 inhibitor
opsonin, anaphylatoxin,
leucocyte activation
C3
anaphylatoxin
C9
C5
C8
C7
C6
MAC
membrane damage or lysis
Presentation
Case TT
1.25
C3
1.00
0.75
0.50
0.25
0.00
0.30
ESR 14
WBC 7.0
Plt 206
Hb 13.3
Lym 0.6
0.20
0.10
0.00
800
700
600
dsDNA
ESR 28
WBC 3.7
Plt102
Hb 12.3
Lym 0.7
C4
0.40
500
400
300
200
100
0
0
10
20
30
40
Time/ months
23
22/06/2011
Lupus and Pregnancy
• Use steroids, azathioprine, hydroxychloroquine,
tacrolimus
• Don’t use cyclophosphamide or MMF
• Rituximab?
• Refer to specialist units
•
A 35 year old woman has had Raynaud’s phenomenon for 7 years. This
is a photograph of her new born son. This was her second pregnancy,
the first ended in the stillbirth of a hydropic fetus.
24
22/06/2011
Neonatal lupus
•
features include:
– congenital complete heart block
– transient rash in neonatal period
•
associated with maternal anti-Ro antibodies
•
risk of child developing neonatal lupus if anti-Ro present is ~4-5%
•
•
•
•
A lady of 78 years with grade 4 lupus nephritis, presents to A&E with
confusion and fatigue.
Prednisolone 10mg od, Mycophenolate 1g bd.
Pyrexia (39) with tachycardia
Remainder physical examination normal
•
Urine dipstick- 2+ blood, 3+ leucocytes, nitrites negative, ketones +
•
•
Hb-7.5g/dl, MCV 75, platelets 85, WBC 12.5, ESR 85
CRP 180, Ur 20, Cr 400, K 5.4, Na 130
Key investigations?
Likely diagnosis?
Treatment?
Outcomes?
25
22/06/2011
Mortality
Cardiovascular
disease
Death
Bimodal pattern
SLE
Infection
Time from diagnosis
M Urowitz et al 1976
Rubin et al 1985
Mortality
Cause of Death
1990-2000 (n = 68)
No (%)
Active SLE
18 (27)
Infection
Bacterial
Fungal
Viral
17 (25)
15 (22)
1 (1.5)
1 (1.5)
Thrombosis
18 (26.5)
Malignancy
4 (5.9)
Total cohort = 1000
 Infection accounts for 25% of mortality
 Highest prevalence within first 5 years after diagnosis
Cervera et al. 2003
26
22/06/2011
Summary
• Diagnosis
– Apply ARC criteria
– If diagnosis in doubt- biopsy
• Beware of infection
• Treatment tailored to severity of disease
• Evolving biologic therapies
27
22/06/2011
SLE
•
•
•
•
•
Prevalence varies: 4 - 250 /100000
UK prevalence 1 / 3000
More common and more severe in Afro-Caribbeans and Asians than
caucasians
Female : Male approx 9 : 1
Usually presents age 16-55Genetic factors
– concordance 24 % MZ twins, 2% DZ twins
– HLA-DR2 and DR3 increase susceptibility
•
Environmental factors
– sex hormones
– drugs (e.g. hydralazine)
– UV light
•
High-titres of autoantibodies found
– e.g. anti-dsDNA, anti-Ro, anti-La
•
Immune complex formation important
SLE - prognosis
• Overall 5-year survival 90%
• 15 year survival
– with renal disease 60%
– without renal disease 85%
• Death from
– cardiovascular disease
– renal disease
– infection (N.B. SLE itself causes immune paresis)
28
22/06/2011
What is shown on the CXR:
A Pulmonary infarction
B Pulmonary oedema
C Pulmonary haemorrhage
D Pulmonary fibrosis
E Bilateral hilar lymphadenopathy
Which of the following is likely to be positive:
A Anti-GBM antibodies
B Anti-nuclear antibody
C Renal tract ultrasound
D dsDNA antibodies
E ANCA antibodies
What is the most likely diagnosis:
A Goodpastures disease
B SLE
C Tuberculosis
D Legionnaires disease
E Pulmonary embolism
SLE - treatment
•
•
•
•
Hydroxychloroquine treats rash
High factor sun protection
NSAIDs for joint problems
organ- or life-threatening flares:
– Steroids- pulse methylpred, oral pred
– immunosuppressive agents
• Azathioprine, mycophenolate mofetil
• Cyclophsphamide, Rituximab (anti-CD20 antibody)
29
22/06/2011
Case 1 pulmonary haemorrhage
12.7 g/dl
Haemoglobin
12
9.5 g/dl
7
4
Hb (g/dl)
Eosinophils
3.6
3
Eosinophils
2
1
0
0
1
2
3
4
5
6
7
8
Days of admission
Lung function tests
FEV 1 2.19L (52%), FVC 1.77L (48%), TLCO 130%, KCO 292%
CXR, HRCT
Lung function tests with gas transfer
Bronchoscopy, BAL, Biopsy
Patient 3 glomerulonephritis
Ur- 5.0 Cr- 53 eGFR 95
Blood pressure 110/83
Urine dipstick: 3+ blood 3+ protein
Urinary protein: Cr ratio 65g/dl
30
22/06/2011
A 58 year old married lady presents to A&E with a 2 week history of a febrile
Illness with multiple joint pains, pleuritic chest pains, fatigue and hair loss. There is
a past history of Raynauds phenomenon and Graves disease.
Examination- pale, tachycardia 120/minute, BP 130/70, JVP not visible, soft heart
sounds, chest clear
Hb-12.5g/dl, WBC 2.5, neut. 1.2, lymph. 0.4, Platelets 238, ESR 80, CRP 20.
How will you investigate this patient?
31
22/06/2011
CXR and ECG
Key investigations?
Likely diagnosis?
Treatment?
Outcomes?
•
•
A lady of 48 years presents to a A&E with acute shortness of breath. She has a 2
week history of increasing peripheral oedema. There is a past history of
Raynauds phenomenon.
Tachypnoeic, crackles at the lung bases
BP 210/130, normal heart sounds
Urine dipstick: protein 1+ protein, 1+ blood
•
•
•
•
Ur 24, Cr 250, K 5.1, Na 142,
Hb- 7.7g/dl, plt- 105, WBC 12.2,
Blood film- fragmented red cells, LDH 350
ANA +, ENA pending
•
Which test is likely to be positive:
A
B
C
D
E
Coombs test
Anti-Ro
Anti-centromere
Scl-70
PM-Scl
What is the most likely diagnosis:
A
B
C
D
E
Limited cutaneous systemic sclerosis
Diffuse cutaneous systemic sclerosis
Micro-angiopathic hemolytic anaemia
SLE with nephritis
Malignant hypertension
32
22/06/2011
•
•
A lady of 48 years presents to a A&E with acute shortness of breath. She has a 2
week history of increasing peripheral oedema. There is a past history of
Raynauds phenomenon.
Tachypnoeic, crackles at the lung bases
BP 210/130, normal heart sounds
Urine dipstick: protein 1+ protein, 1+ blood
•
•
•
•
Ur 24, Cr 250, K 5.1, Na 142,
Hb- 7.7g/dl, plt- 105, WBC 12.2,
Blood film- fragmented red cells, LDH 350
ANA +, ENA pending
•
What is the best treatment:
A
B
C
D
E
IV GTN and CPAP
Captopril
Ramipril and GTN
Iloprost
Iloprost and captopril
•
A 37 year old woman with SLE presents to A&E with a 2 day history
of fever - 38oC - sweats and a cough. She is on prednisolone 7.5mg
daily and hydroxychloroquine 200mg twice daily.
•
Investigations reveal: ESR 80 mm in first hour, CRP 46 mg/l, WCC
5.4 (neutrophils 4.5, lymphocytes 0.7), platelets 115.
•
What is your management?
A
B
C
D
E
stop hydroxychloroquine
increase prednisolone
antibiotics
antibiotics and increase prednisolone
stop hydroxychloroquine and give antibiotics
33
22/06/2011
B-cell biology
34