Systemic Lupus

Erythematosus
Systemic Lupus Erythematosus
Aetiology
Pathogenesis
Clinical features
Investigations
Diagnostic criteria
Treatment
An autoimmune disease characterized by
immune responses against endogenous
nuclear antigens, due to impaired tolerance to
them.

Spectrum of Antibodies in SLE

Non-Specific
a) Ab against nuclear components
b) Ab against cell components
Specific
a) Ab against surface antigens of blood cells
b)Ab against proteins in complex with
phospholipids
Anti-nuclear antibodies
1)Ab to DNA
2)Ab to histones
3)Ab to Non-Histones bound to RNA
4)Ab to nucleolar antigens

 Immunofluorescence assay (IFA) is widely used to identify

antinuclear antibodies. This test is 95% sensitive.
 There are 4 staining patterns.
1)Homogenous/Diffuse
2)Rim/Peripheral
3)Speckled
4)Nucleolar
 Prevalence- In USA- 51/100000
 Incidence has tripled over the last 40 years
 More common in urban areas than in rural areas
 65% of patients present between 16 to 55 yrs
 20% present before 16 yrs
 Men- have less photosensitivity, more serositis
 present later in life
 higher 1 year mortality
 Elderly- Milder disease
 greater prevalence of serositis, Pulmonary
involvement,sicca syndrome, musculoskeletal involvement
Natural History
 Starts with a pre-clinical phase characterized by auto
antibodies
 Proceeds to clinically overt autoimmune disease specific
phase
 Periods of flares and remissions are present
 Culminating disease and treatment related damage.
Genetic factors-
 Familial association- increased risk for family members
- 20% of clinically unaffected first
degree relatives may have the disease
- Monozygotic twins- 25% concordance
- Dizygotic twins- 1% concordance
 HLA Association- if both HLA DR2 and DR3 are present,risk
increases by 5 fold
 Genetic deficiencies of C1q, C2 or C4 complement
deficiencies cause defective clearance of immune
complexes and apoptotic cells
 Fc receptor polymorphism- inadequate control of B cell
activation
 Post translational methylation of histone
Environmental factors-
 UV radiation- causes apoptosis of host cells leading to an
increases burden of nuclear of nuclear fragments and
inflammation responses to the products of dead cells.
 Cigarette smoking- tobacco may modulate the production
of auto antibodies
 Sex hormones- reproductive ages – F:M 9:1
Childhood, after 65 yrs- F:M 3:1
 Drugs- procanamide, hydralazine can induce SLE-like
disease.
 Post translational methylation of histones
 Pathogenesis
1)Nucleic acids
The target in lupus.
In healthy people, their recognition as antigens is
prohibited by many barriers
2)Apoptosis
A source of autoantibodies and molecules with cytokine
(IFN-alpha) inducer activities.
Apoptotic cell blebs rich in lupus auto antigens.
Rate of apoptosis is increased by UV light.
3)T and B cells
Interaction between them contributes to B cell
differenciation to Ab producing plasma cells.
Chromatin containing immune complexes are 100 fold
more efficacious in stimulating B cells.
 Pathogenesis
4)Immune complexes
In healthy people, they are cleared by FcR and
complement receptors.
In lupus, genetic variances occur in these receptors,
and clearance of immune complexes is impaired.
They then get deposited in tissues, causing tissue
damage.
5)Toll-like receptors
They are located in cell membranes, endosomal
compartments and cytosol.
They survey extracellular and intracellular space.
Toll-like receptor recognizing nucleic acids are
endosomal.
These receptors activate dendritic cells to produce INF-
alpha and B cells to become plasma cells.
 Pathogenesis
6)Dendritic cells
Two types-1)Plasmacytoid dendritic cells-produce INF-
alpha
2)Myeloid dendritic cells- immature cells are
involved in antigen presentation and promote
tolerance.
- Mature cells- maturation of myeloid
dendritic cells is promoted by INF alpha and immune
complexes. These mature cells lead to autoreactivity.

7) INF-alpha
A cytokine produced mainly by plasmacytoid dendritic
cells with potent biological activity on B cells, T cells,
endothelial cells, neuronal cells and renal cells,
causing tissue damage.
 Pathogenesis
8)Complement
Activation of complement facilitates clearance of
apoptotic material in healthy people.
In lupus, due to genetic variations, complement levels
are low.

9)Neutrophils
In lupus there is a distinct subset of proinflammatory
neutrophils.They induce vascular damage and
produce INF-alpha.

10)Endothelial cells
Impaired DNA degradation as a result of a defect in
repair endonucleases.
SLE of the skin is characterized by deposition of complement and
IgG antibodies and influx of neutrophils and lymphocytes.
 Biopsies of other tissues can show vasculitis affecting capillaries,
arterioles and venules.
 CNS lesions due to-vascular lesions
- multi-focal cerebral micro-infarcts
-Small vessel angiopathy with intimal
proliferation
-Antiphospholipid antibodies
-premature atherosclerosis
 Spleen- moderately enlarged
- capsular fibrous thickening
- follicular hyperplasia
- central peniciliary arteries show thickening and perivascular
fibrosis, producing onion-skin lesions.
Heart- libman sacks endocarditis- non-bacterial warty deposit
Kidney-
Class I -minimal mesangial lupus nephritis- rare
- immune complexes present in the mesangium
- no structural alteration seen in LM

Class II nephritis-immune complexes deposited in mesangium, with

a mild to moderate increase in mesangial matrix and cellularity

Class III-Focal Lupus Nephritis- 20-35%

-Lesions seen in <50% glomeruli- segmentally or globally
distributed in each glomerulus
- Proliferation of endothelial and mesangial cells
- Infiltration by neutrophils
- Fibribnoid deposits with capillary thrombi
Class IV- Diffuse Lupus Nephritis- 35-60%
-most serious and most common
- more than 50% glomeruli involved
-Endothelial and mesangial proliferation, epithelial crescents
- Subendothelial immune complexes cause thickening of
capillary walls, resembling rigid wire loops in LM
- EM shows prominent electron dense subendothelial
complexes between endothelium and basement membrane
- later, glomerulosclerosis results

Class V- Membranous Lupus Nephritis -10-15%

- Subepithelial immune complexes cause widespread
thickening of capillary walls
-Increased deposition of basement membrane-like material

Class VI- Advanced Sclerosing Lupus Nephritis

- Complete sclerosis of >90% of glomeruli
 Malar rash: This is a
"butterfly-shaped" red
rash over the cheeks below
the eyes and across the
bridge of the nose. It may
be a flat or a raised rash.
The rashes are made
worse by sun exposure.
Discoid lupus
These are red, raised
patches with scaling of
the overlying skin.
 Vasculitic skin lesion

 Livedo reticularis
 Raynaud’s
phenomenon
(a triphasic reaction of distal
digits to cold or emotion,
in which the skin colour
changes from white to
blue to red)
 Oral ulcer: Painless
sores in the nose or
mouth need to be
observed and
documented by a
doctor.
Renal Manifestations
Class I-MMLN- no clinical manifestations

Class II-MPLN- mild clinical symptoms

Class III-FLN- mild microscopic haematuria and

proteinuria ranging to more active urinary sediment
with RBC casts and AKI

Class IV- DLN- Haematuria, moderate to severe

proteinuria, Hypertension, CRF

Class V-MLN- Severe proteinuria leading to

nephrotic syndrome

Class VI- End Stage Renal Disease

 CNS lupus (Neuropsychiatric)
– headache
– mood disorders, psychosis
– seizures
– TIA/ stroke
– Aseptic meningitis
– Transverse myelitis

 PNS
Mononeuritis multiplex
Peripheral neuropathy
 Joint involvement is the most common clinical
feature (>90%).
 Symmetrical small joint arthralgia.
 Erosions and deformities rare.
 Jaccoud’s arthropathy
 Avascular necrosis affecting the
hip or knee
Haematological – lymphocytopenia, Anaemia,
Leucopenia, Warm antibody AIHA and
thrombocytopenia
 Pulmonary – Pleuritis, pleural effusions
Fibrosing alveolitis
 Gastrointestinal – Abdominal pain (mesenteric
vasculitis)
 Cardiac – Pericarditis-25%
myocarditis
Libman-Sacks endocarditis- May cause
acute thrombosis
 FBC : Leucopenia,
lymphopenia,thrombocytopenia
Anaemia(ACD, AIHA)
 ESR: High
 CRP: usually normal
 UFR : proteinuria, active sediments
 Serum creatinine
 Serum compliment: Low C3 C4
 Autoantibodies
 ANA – screening test (95% sensitivity, 80%
specificity)
 Anti-dsDNA (sensitivity 70% specificity 95%)
 Anti-Sm ( 30% sensitivity, specificity 99%)
 Anti-Ro/anti-La
 Anti-ribosomal P
 Anti-RNP
 Anti-histone (drug-induced lupus)
 Anticardiolipin antibodies
 Joint x-rays: no erosions, periarticular osteopenia
and soft tissue swelling may be present

 CXR/CT chest: interstitial lung disease,

pneumonitis, pulmonary emboli, alveolar
hemorrhage

 CT Brain or Brain MR angiography: lupus white

matter changes, vasculitis or stroke

 Echo: pericardial effusion, pulmonary

hypertension or Libman-Sacks endocarditis
American College of Rheumatology

4/11 criteria (sensitivity 85%, specificity 95%)

“SOAP BRAIN MD”

Serositis – pleurisy, pericarditis

Oral ulcers – oronasal ulceration,painless,
specifically in the palate
Arthritis – non-erosive, 2 or more joints
Photosensitivity
 Blood disorders –
leucopenia,lymphopenia(<1500),
thrombocytopenia, haemolytic anaemia
 Renal involvement – proteinuria >0.5g per day,
and cellular casts
 ANA – titer > 1:160
 Immunologic phenomena – LE cells, anti-dsDNA
Ab, anti-Sm Ab, antiphospholipid Ab, false WR +
 Neurological disorders – seizures/ psychosis
 Malar rash – fixed erythema on cheeks + nasal
bridge, flat or raised
 Discoid rash – rimmed with scaling, follicular
plugging and scarring
 Drug induced lupus erythematosus
 Small vessel vasculitis
 Other autoimmune diseases: SSc, RA
 Leukemia
 HIV
 Multiple sclerosis
 Depends on disease severity
 Fever, skin, musculoskeletal and serositis =
milder disease
 CNS and renal involvement – aggressive Rx
 Emergencies: - severe CNS involvement
- systemic vasculitis
- profound thrombocytopenia
(TTP-like syndrome)
- rapidly progressive nephritis
- diffuse alveolar hemorrhage
 Mild disease:
NSAIDs, Hydroxychloroquine

 Severe disease:
High dose steroids +/-Cyclophosphamide +/-
Mycophenolate mofetil (MMF)

Azathioprine
Rituximab
Plasma exchange/ IVIG
 Medication-related (steroid) complications (Ca,
vit D, bisphosphonates)
 Aggressive BP and lipid control
 Immunization (complement deficient)
 Stress-dose steroid protocols for patients on
maintenance corticosteroids (surgery/ infection)
 Avoid UV exposure
 Avoid estrogen therapies
 Avoid sulfa-containing medications
 Pregnancy planning
 Fertility is usually normal except in severe disease
 Recurrent miscarriages can occur, especially in
women with antiphospholipid antibodies.
 Exacerbations can occur during pregnancy with
frequent exacerbations of the disease
postpartum.
 The patient’s medications should be reviewed
 Benign to rapidly progressive
 10 year survival rate – 90%; lower if major organ
involvement
 Major cause of early mortality due to renal,
cerebral, infectious disease.
 Increased risk of CAD, stroke
 Increased risk of cancers (lymphoma)
 Arterial or venous thrombosis and/or
 Recurrent miscarriages (1st trimester) AND
 Positive anti phospholipid antibodies
(persistently positive at least 12 weeks apart)
 Primary APLS
 Secondary APLS : associated with other
conditions. Eg SLE
 Treatment: Anticoagulation + treat underlying
condition if secondary