SYSTEMIC
LUPUS
ERYTHEMATO
SUS
RUSHALIMATUN BINTI RUSLI
SUPERVISOR: DR RATNA WATI
Outline
• Definition
• History
• Epidemiology
• Types of Lupus
• Pathophysiology
• Clinical Manifestations
• Diagnosis
• Criteria
• Case Study
Definition
• SLE is a complex autoimmune disease with variable clinical
features
• SLE manifestations are associated with multiple autoantibodies,
ensuing immune complex formation and deposition, and other
immune processes
• Can affect any part of the body
◦ Often damages skin, joints, heart, kidneys, lungs, nervous
system
History
• ‘Lupus’ is the Latin word for wolf. ‘Erythematosus means’ red rashes. In
1851, Dr. Cazenave discovered red rashes on a patient’s face that
looked like wolf bites. He named the rash Discoid Lupus Erythematosus
(DLE).
• In 1885, Sir William Osler recognized that many people with lupus had
a disease involving not only the skin but many other organs or systems.
He named the disease Systemic Lupus Erythematosus (SLE).
Epidemiology
•More common in urban than
rural area.
•SLE tend to be milder in elderly.
10%
90%
African American and Latin American
• About 90% of SLE sufferers are women while are affected much more frequently
about 10% are men and children. than Caucasians.
• Women: childbearing years, within 15 - 50 y/o
Source: EULAR textbook of rheumatic diseases.
Epidemiology in Malaysia • In Malaysia, estimated that more than
10,000 people with SLE over 30 years
Race
• Chinese: 57/100 000
• Malay: 33/100 000
• India: 14/100 000
Survival :
• 1 year 93%
• 5 years 86%
• 10 years 70%
Causes of death :
• Active disease (19-95%),
• Infections (30-80%)
• Cardiovascular
Malaysia SLE Association
Types of Lupus
• Systemic Lupus Erythematosus (SLE)
• Discoid Lupus Erythematosus (DLE) is a chronic skin disorder in which a red,
raised rash appears on the face, scalp, or elsewhere
• Neonatal Lupus is a rare disorder that can occur in new born babies, caused
by auto-antibodies in the mother’s blood called anti-Ro (SSA) and anti-La
(SSB). At birth, the babies have a skin rash, liver problems, and low blood
counts. These symptoms gradually go away over several months, in rare
cases, babies with neonatal lupus may have a heart problem that slows
down the natural rhythm of the heart.
• Drug-induced Lupus most common drugs are as Isoniazid, hydralazine and
procainamides
Genetic factors:
•Higher incidence in monozygotic twins (>20%) as compared to
dizygotic twins (1-3%)
Etiology •Sibling risk for developing SLE is 8-29 fold higher than general
population.
•Klinefelter syndrome (XXY)
Genetic Immunological factors:
factors •Failure in self tolerance of B cells
•CD4+T helper cells escape tolerance
•Nuclear RNA and DNA activate B cells by TLRs
Hormonal
Immunological
factors Etiology
factors
Hormonal Factors
•Sex hormones – during reproductive years
Environmental Environmental factors:
factors •UV light exposure – induces apoptosis and alters DNA for
enhanced recognition of TLRs, promote IL1 production.
•Drugs- hydralazine, procainamide & isoniazid
•Virus / Bacteria – EBV, mycobacterial infection
Clinical
Manifestations
Clinical Manifestations
Mucocutaneous Manifestations
Constitutional Symptoms Musculoskeletal Manifestations
Acute cutaneous
lupus erythematosus
Fatigue (most common) (ACLE) (Malar rash) Arthritis/Arthropathy
Myositis
Fever Subacute cutaneous lupus (Generalized myalgia and muscle
erythematous (SCLE) tenderness)
(Annular/psoriasiform
10%) Osteonecrosis
Myalgia and weight loss (Develop after onset of
glucocorticosteroid therapy)
Chronic rashes (discoid lupus 25%)
Arthritis and arthralgia
(90% of patients) Photosensitivity
Mucous membrane
(depigmentation of lip, mouth ulcer)
Acute cutaneous lupus
erythematosus, ACLE (malar rash) Discoid Lupus Erythematosus ,DLE
-Erythematous, elevated lesion, pruritic -Discrete, erythematous, infiltrated plaque covered
and painful by well formed scale entend into hair follicles.
Subacute cutaneous lupus erythematous, SCLE
-Symmetric, widespread, superficial and non scarring.
Arthritis/ Jacoud’s Arthropathy Mouth ulcer, lip ulcer
Cardiac manifestations
Pericarditis 25%
Pericardial Effusion
Endocarditis (libmann sacks)
VHD (regurgitation & stenosis)
Congenital heart block
(anti Ro, anti-La)
MI, heart failure, PE
Libman Sacks
Endocarditis
with valvular
vegitation
Source: EULAR textbook of rheumatic diseases.
Renal Manifestation
• They are usually asymptomatic.
• Occurs in 50% of SLE patient
Classification of Lupus Nephritis
• Acute or chronic renal failure : uremia,
fluid overload
• Nephritis : hypertension and hematuria
• Nephrotic: edema, weight
gain, hyperlipidaemia
Immune complex deposition results in
intraglomerular inflammation.
• RP
• Urinalysis should be advised for all
SLE patients.
1. Persistent proteinuria
>0.5g/day or >3+
2. Cellular casts: RBC, Hb, granular tubular,
mixed. International Society of Nephrology (ISN) and the Renal Pathology
• 24 hours urine pcr Society (RPS) in 2003
• Diagnosis is usually by renal biopsy
Lungs manifestations
Liver and GI Tracts
manifestations
Pleuritis (45-60%)
Dyspepsia (11-50%)
Pleural effusion (50%
Peptic ulcer (4-21%)
Acute Pneumonitis
Peritonitis
Interstitial Lungs disease(3-13%)
Mesenteric vasculitis
Bronchiolitis Obliterans
with Pancreatitis (2-8%)
pneumonia
Pulmonary hemorrhage (rare) Inflammatory bowel disease
Pulmonary hypertension (rare) Pulmonary hypertension
Pul. embolism/infarction
Pulmonary embolism/infarction
Lupoid hepatitis (12-25%)
Source: EULAR textbook of rheumatic diseases.
Vascular Features
Raynauds phenomenon
Vasculitis
Thromboembolic
Mesentric vasculitis, hepatic
vasculitis, retinal vasculitis
small vessel involvement: purpura,
petechiae, papulonodular lesions,
livedo reticularis, splinter
haemorrhages and ulceration.
Others Manifestations
Neuropsychiatic Hematological
Opthalmic Lymphadenopath
Features Features
Features y Splenomegaly
• Cognitive impairment, • Retinal artery
• Hemolytic anemia • LN usually soft, non
memory deficit, poor inflammation
• Leucopenia tender, discrete
concentration, difficulty • Retinal vessel
(<4000/mm3) (axillary, cervical and
in spoken • Lymphopenia infarction
• Retinal inguinal)
• Major psychosis (<1500/mm3)
vasculitis • Splenomegaly in 10-
• Seizure • Thrombocytopenia
• Uveitis 45% during disease
• CVA (<100000/mm3)
• Scleritis activity
• Cranial/peripheral • Optic Neuritis • Splenic atrophy and
neuropathy (rare) hypersplenism also
• Transverse been reported
myelitis
Source: EULAR textbook of rheumatic diseases.
Diagnosis
FBC, RP, UFEME/culture Antibody, ESR,
CRP, Complements level, LFT, CK, Direct
coombs test
CXR, CTPA to look for interstitial lungs disease,
pneumonitis, PE or aveolar hemorrhage.
MRI brain: ischaemia, vasculitis
Cardiac MRI : SLE myocarditis
.
ECHO: look for vavular heart disease,
vegetation, LVEF, emboli
Atherocentesis for joint effusion Lumbar
puncture : neurologic symptoms
Renal biopsy
Skin biopsy
Autoantibody test for SLE
Antibody Descriptions
ANA • Sensitivity (95%) but low specificity.
• Positive in: scleroderma, polymyositis,
dermatomyositis, RA, autoimmune thyroiditis,
autoimmune hepatitis, infection, neoplasm, drugs
• Negative ANA doesn’t exclude diagnosis.
ds-DNA • Sensitivity 70% and specificity 95%
• LN, progression of ESRF and poor survival
Anti-Sm: Most specific but 30-40% sensitive
Anti Ro (SS-A) & Anti La (SSB) Neonatal lupus, congenital heart block,
Sjogren syndrome
Anti-histone Drug induced ANA abs (procainamide,
hydralazine)
Anti-ribosomal P CNS disease, psychosis
Antiphospholipid abs: aPS, venous thrombosis, fetal loss,
thrombocytopenia, CNS involvement,
severe LN
EULAR Recommendation 2019
American College of Rheumatology,
ACR Criteria (1997)
• Presence of 4 out of
11 criteria is
considered as SLE
• Sensitivity 82.8%
• Specificity 93.4%
EULAR Recommendation 2019
Systemic Lupus International
Collaborating Classification,
SLICC Criteria 2012
• Presence of 4 out of
17 criteria, including
at least 1 clinical
criteria and 1
immunologic criteria
OR biopsy proven
lupus nephritis
European League Against
Rheumatism, EULAR /
American College of
Rheumatology, ACR
Classification of SLE 2019
• Score of 10 or more
with at least one clinical
criteria OR 7 clinical
criteria and 3
immunologic criteria
• Sensitivity 96.1%
• Specificity 93.4%
Management of SLE
Multidisplinary approach:
• Rheumato
• Neuro
1. Pharmacological treatment • Respi
• Cardio
2. Management of specific manifestations • Gastro
• Nephro
3. Comorbidities • Derma
• Hemato
• O&G
EULAR Recommendation 2019
Goals of treatment
Remission of disease Prevent flares/ Minimize drugs Improvement
organ damage dose and side Quality of life
effects
Source: EULAR textbook of rheumatic diseases.
1. Pharmacological treatment
01 Antimalaria
Hydroxychloroquine (HCQ), Quinacrine
02 Glucocorticoids
Oral Prednisolone, IV Methylprednisolone (short term)
03 Immunosuppressive/Cytotoxic Drugs
Methotrexate, Azathioprine, Mycophenolate, Cyclophosphamide
04 Biological Agents
Belimumab, Rituximab, IVIG
05 Calcineurin inhibitors
(CNIs)
Tacrolimus, Cyclosporine
Antimalaria,
Hydroxycloroquine
Side Effects:
• HCQ is recommended in all • Retinal toxicity 10% after 20
1 patient with SLE 3 years of continuos use.
• Its an alkalinizing • Skin rash
lysosomatic • cardiomyopathy
drugs Contraindication:
• Retinal disease
• Prevent thrombotics events
• CKD
2 • Acts as antiplatelet, inhibit
aPL induced GPIIb/IIIa 4 • Eye Screening baseline after
• Prevent flares and disease
5 years then yearly.
progression
• Dose: 200-400mg OD
• Down regulates
• Stable: 200mg OD
inflammation
• Alternative: Coroquine,
• Lower glycemic and lipid
Quinacrine
EULAR Recommendation 2019
• IV Methylprednisolone 250-1000mg/day
for 1-3 days
Glucocorticoids • Prednisolone dose :
- low: 0.1-0.2mg/kg
- moderate: 0.2-0.5mg/kg
- high: 0.5-0.1mg/kg
MOA: decrease inflammation by
reduce capillary pemeability
and suppress neutrophil activity 3
For maintanence therapy:
2 4 minimize to <7.5mg/day
or withdrawn .
Dose and route depends
on the severity of organ 5 Side effect for long term use:
1 infections, muskuloskeletal
involvement
and metabolic disorder
Immunosuppresive / Cytotoxic drugs
Immunosuppressive agents can
be used in initial therapy of
organ threatening disease. Cyclophosphamide used for
Methotrexate
severe lifethreatening SLE or
Azathioprine 3
rescue therapy in patient not
Mycophenolate
4 respond to other
Cyclophosphamide 2
immunosuppressive
medications
• If not responding to HCQ or
GC.
5 Side effects
• Unable to reduce GC 1
- Cyclophosphamide: risk of
below dose of chronic use.
infections, malignancy
Methotrexate: moderate to severe; Oral: Initial 7.5 mg once weekly; may increase by
2.5 mg increments weekly (maximum: 20 mg once weekly), in combination with
prednisone.
Azathioprine: 2–3 mg/kg per day PO for induction; 1–2 mg/kg per day for
maintenance; decrease frequency of dose if CrCl <50 mL/min
Mycophenolate mofetil: MMF: 1–3 g/d PO total given BD for induction therapy, 1-2 g/d
total given BD for maintenance therapy; max 1 g BD if CrCl <25 mL/min. Begin with low
dose and increase every 1–2 weeks to minimize GI side effects. Start treatment at 0.5 g
BD
Cyclophosphamide: Low dose (500mg every 2 weeks for 6 doses, then begin
maintenance with MMF or AZA after 3 months. High dose: 7–25 mg/kg/ month × 6
Calcineurine Inhibitors
Tacrolimus
•: Trough blood level should
not exceed 5.5 ng/mL to
minimise toxicity. Cyclosporine:
• Begin dose at 2 mg bid. • Inhibits T-cell activation
• S/E infection, of transcript. It is used
nephrotoxicity, neural in refractory skin
toxicity. involvement, lupus
Nephropathy, bone
marrow hypoplasia.
• Dose: 4-5 mg/kg/day
in 2 divided doses.
EULAR Recommendation 2019
Biologicals Agents
Residual disease activity 2 In organ threatening disease,refractory or
not allowing tapering of GC
and/frequent relapses, add- with intolerance to standard IS agents,
on treatment with consider Rituximab.
Belimumab.
3
In patients with inadequate 1
response to standard-of-
care (combinations of HCQ,
GC, other IS agents)
Belimumab vs Rituximab
Human monoclonal antibody
inhibits soluble form of B cell Chimeric B cell depleting
monoclonal antibody.
Used in : Resistant cases of
cutaneous and used in severe disease
musculoskeletal disease. burden: lupus nephritis
as a last resort
Contraindicated in: Lupus
nephritis and active CNS
Off label use
involvement.
Side effects : infusion reactions,
• Initial: 10 mg/kg every 2 weeks Hep B reactivation, PML,
for 3 doses; mucocutaneous reaction.
• Maintenance: 10
mg/kg every 4 weeks
• SubQ: 200 mg once weekly
.
Source: up-to-
date
Severity of SLE
Mild Moderate Severe
MAJOR ORGAN THREATENING
DISEASE (nephritis, celebrities,
myelitis, pneumonitis,
mesentric vasculitis
thrombocytopenia with platelets
<20 x 103/mm3
TTP like disease or
Acute
hemophagocytic
syndrome
SLEDAI >12
Source: Fanouriakis A, et al. Ann Rheum Dis 2019
Treatment for SLE
2. Management of Specific Manifestations
Haematological Neuropsychiatric
Skin Manifestations manifestations Manifestations
First-line treatment of Acute treatment Related neuropsychiatric
skin disease: of lupus thrombocytopenia: manifestations, can be facilitated
1. Topical agents 1. High-dose by neuroimaging, investigation of
(glucocorticoids, glucocorticoids ( IV cerebrospinal fluid, consideration
calcineurin Methylprednisolone) of Risk factors :
inhibitors) (2b/B) and/or IVIG (4/C) 1. Type and timing of the
2. Antimalarials (HCQ, Maintenance of response: manifestation
quinacrine) (1a/A) 1. IS/GC-sparing agents 2. Age
3. Systemic Mycophenolate, 3. Non-neurological
glucocorticoids (4/C) Azathioprine lupus activity
In non resposive case (2b/C) 4. Antiphospholipid
requiring high dose 2. Cyclosporine antibodies (aPL)
Treatment
GC (4/C) 1. Glucocorticoids or
1. Methotrexate Refractory Immunosuppressive agents
(3a/B) 1. Rituximab (3a/C)
cases: 2. Antiplatelet/anticoagulants
2. Retinoids, Dapsone, 2. cyclophosphamide.(4/C) for atherothrombotic/aPL-related
or Mycophenolate manifestations.
can be added (4/C)
EULAR Recommendation
2019
American Journal of KidneyDisease
Lupus Nephritis
Protective measures:
• ACE Inhibitor or ARB
• Blood pressure
<130/80mmhg
• Minimize GC
• Education on adherence
• Partial Remission: reduction proteinuria >50%, creat
within 10% from baseline
• Complete Remission: Proteinuria <500mg/24H, scr 10%
from basline
3.
Comorbidities
01 All SLE patients should be screened at diagnosis for aPL
Evaluate risk factors: estrogen used, smoker,
Antiphospholipid immobility, previous surgery and spesis.
antibody 02 High-risk aPL profile/atherosclerotic/thrombophilic factor
+
syndrome Prophylaxis with antiplatelet agents
Secondary prevention of thrombosis in nonpregnant
03 patients with SLE/thrombosis associted with APS
Long term anticoagulants treatment
04 In pregnant patient with SLE and APS
Unfractioned of low molecular weight heparin and
aspirin - reduce risk of pregnancy loss.
EULAR Recommendation 2019
Comorbidities
SLE patients should be assessed for general and
1 disease-related risk factors
Advanced age/frailty, renal involvement,
Immunosuppressive/ biologic therapy and
high-dose glucocorticoids
Infection
2 General preventative measures
Patients with SLE need regular assessment for traditional
Immunizations, early
recognition and treatment of
1 and disease-related risk factors for CVD
infection/sepsis.
Persistently active disease, increased disease duration,
medium/high titres of aPL abs, renal involvement, persistent
proteinuria and/or GFR <60 ml/min) and chronic use of
Cardiovascular glucocorticoids - high risk of CVD
2 High cardiovascular risk profile
• Low-dose aspirin and/or lipid-lowering agents.
(Atorvastatin or fluvastatin)
EULAR Recommendation
• GC (low dose) + HCQ (reduce lipid and
antihrombotic)
SLE in Pregnancy
Investigations:
• AntiSSA/anti SSB abs for
CHB (16-24 weeks POG)
• APA, anti dsDNA
• RP, albumin, uric acid, anti
dsDNA, C3 /C4, TFT
Management:
• HCQ have to maintain, can
reduced risks of CHB
• Low dose for GC
• Other drugs: AZA, Aspirin or
LMWH
• Containdicated for : MMF,
CYC, MTX
Preconception
• Ensure lupus inactive for at
least 6 months
• Monitor BP and proteinuria • Discourage pregnancy if
• Differentiate between preeclampsia and LN creatinine >177umol/L
• Presence of generalized lupus activity, • Contraception, preferabbly
active urine sediments, low complement POP
favours LN
(SLEDAI)
• Strong predictors of damage
and mortality
• SLEDAI are use for daily
practice.
• SLEDAI Score:
0: no activity
1-5: mild activities
6-10: mod activities
11-19: high activity
>20 very high
• Specificity 93.4%
Prevention
Avoid sun
exposure
Vitamin D Exercise to avoid
Low fat diet
supplement rapi mascle loss
sunscreen
>50SPF
Vaccinations:
Contraceptio
Avoid sulpha menigococcal,
Stop smoking n and Family
based
planning
medications pneumococcal
Child: Hib
Source: EULAR textbook of rheumatic diseases.
Follow up and Prognosis
Follow Up:
Prognosis:
• Quarterly visit
• Milder and high
• FBC, RP,
survival rate :
Urinalysis,
Isolated skin and
complement,
MSK involvement
dsDNA
• Monitor sign &
symptoms • Poor and decrease
• Response and survival rate: Renal,
adverse effects of CVS and CNS disease
therapy
EULAR recommendation 2019 .
REFERENCES
• EULAR Recommendation
2019
• EULAR textbook of
rheumatic diseases
• American College of
Rheumatology
• American College of
Rheumatology
• British Medical
Journal
• www.medscape.com
• Malaysia SLE
Association
