Transcript Systemic Lupus Erythematosus (SLE)

SYSTEMIC LUPUS
ERYTHEMATOSUS (SLE)
DR.HANAN ALRAYES,MD
CONSULTANT RHEUMATOLOGY
SYSTEMIC LUPUS ERYTHEMATOSUS
(SLE)
Epidemiology
Pathogenesis of Lupus
Clinical manifestation
Discuss the clinical Course of SLE
Diagnostic criteria
Management
SYSTEMIC LUPUS ERYTHEMATOSUS
(SLE)
 SLE is a chronic multisystem
autoimmune inflammatory disease that is
commonly diagnosed in women of
childbearing age and it can affect any age
group.
 Symptoms for each patient will be
different, and this makes the disease difficult
to diagnose
WHAT IS AUTOIMMUNITY?
 Diseases in which the pathology is caused by adaptive immune
responses to self-antigens are called autoimmune disease
 Basically, in autoimmune diseases, the human immune system
recognizes parts of the body as harmful antigens and so builds a
response, targeting self-cells.
 Autoimmunity is very complex. There are many different
autoimmune diseases, each affecting the body in vastly different
ways.
 Even patients with the same autoimmune disease may show
different symptoms.
 Autoimmune disease affect mostly women of childbearing age.
 While there is clear evidence of a genetic factor, environment,
hormones, aging and chronic stress are also thought to play a role.
 Generally, autoimmune diseases are lifelong conditions, although
medication and treatment can make quality of life better for the
patient
EPIDEMIOLOGY
 The incidence and prevalence of SLE varies across the world by race
and ethnicity as well as geography
 Incidence is 1.8 to 7.6/100,000 per year
 Prevalence reporting
 average of 20/100,000 per year in the U.S
 19.28 per 100,000 population in Qaseem region(Saudi Arabia)
 AGE :
 In female 80% present during childbearing years (20-45 years)
 SLE can occur in all age groups, but it is uncommon before 8 years
of age
 Female: male 9:1 (in adults)
 In prepubertal children as low as 2:1
SLE - Etiology
• The etiology of SLE remains unknown
• Yet, SLE is clearly multifactorial:
EBV?
– Genetic factors
– Immunologic factors
– Hormonal factors
– Environmental factors
Genetic predisposition
Baseline immunological abnormalities
Infection
Hormonal factors
Abnormal (control of) immune responses
SLE
GENETIC SUSCEPTIBILITY
Concordance of SLE is 25% among monozygotic twins but
only 2% among dizygotic twins
It is estimated that at least 4 susceptibility genes are needed
for the development of SLE:
HLA-DR2 and HLA-DR3 confer relative risk of 2-5. DRB1*0301 and
DRB1*1501
HLA class III genes
C1q deficiency results in high likelihood of developing SLE
Complement C4A deficiency: 80% of people with SLE have at least
one null allele
C1r/s and C2 deficiency.
Mocc et al, J clininal pathology; Jul 2003
RISK FACTORS
THE COMPLEMENT PARADOX
Deficiencies in C1,C2,C4 and CR1 predispose to the development of SLE
Complete lack of C1q or C4
C3 deficiency
90% develop SLE
23% lupus like disease
Trouw, L.A. et al., Mol Immunology (2008) 45:1199-1207.
RISK FACTORS
SEX, HORMONES AND HPA AXIS
 F:M ratio 9:1
 Both physiological and supra physiological concentration
of estrogen facilitate humoral responses , leading to
increased B cell proliferation and antibodies production
 The HPA axis is the chief component of the stress system:
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Defective HPA axis ass with decrease in CRH mRNA expression
Increase in oestrogen metabolism to more potent metabolites
Low androgen values, as it correlate inversely with disease activity
Hyprprolactinaemia
Ulff et al ,J Rheumatol 2009;36:1903
RISK FACTORS
ENVIRONMENTAL FACTORS
 Environmental factors such as ultraviolet light and sunlight, it
can precipitate SLE flares, particularly skin disease
 Infectious agents are thought to possibly induce
autoimmune responses by molecular mimicry or another
unknown mechanism
 Silica dust, found in materials such as soil, cement and
cigarette smoke, may increase the risk of SLE
 Smoking is associated with a higher prevalence and
greater severity of SLE
SOURCE OF THE AUTO-ANTIGENS IN LUPUS
The fundamental abnormality in SLE is selective loss of
tolerance and self/non-self recognition and the development
of auto-antibodies
CLINICAL MANIFESTATIONS
 Ranges from a relatively mild disorder to rapidly progressing,
affecting many body systems
 Most commonly affects the skin, joints, muscles, lining of lungs,
heart, nervous tissue, and kidney.
 Constitutional symptoms
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Fever
Fatigue: mild to extreme fatigue
Lymphadenopathy
weight loss
WHAT ARE THE SYMPTOMS OF SLE?
 Skin rashes :
 Acute Butterfly rashes :Raised or flat
malar rashes that occur across the
bridge of the nose and on the
cheeks.
 Suacute
 Chronic Raised discoid rashes occur
on the face, hand or other body parts.
Sunlight usually aggravates these
rashes.
CLINICAL MANIFESTATIONS
Oral /Nasopharyngeal ulcers
Alopecia
Raynaud's phenomena
MUSCULOSKELETAL
Arthritis/Arthralgia
 Symmetrical inflammatory polyarthritis
 Non erosive
 Swan neck like deformities called
Jaccoud's arthritis
Myositis/ myalgia
Neuropsychiatric symptoms
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Seizures
Psychosis
Cognitive dysfunctions
Cranial nerves
Lupus headache
Transverse myelitis
Cerebrovascular accident ( CVA)
Neuropathy (mononeuritis multiplex, peripheral neuropathy)
Neurological manifestations are most likely due to the affect of
autoantibodies on the central nervous system.
Eye involvement :
Retinal hemorrhage
Optic neuritis
RESPIRATORY/CARDIOVASCULAR
Respiratory
Pleuritis (pleuritic chest pain )
Pleural effusion (Dyspnea )
Pneumonitis
Pulmonary hemorrhage
Interstitial lung fibrosis
Cardiovascular
Pericarditis
Pericardial effusion
Myocarditis
Pulmonary hypertension
Libman-Sacks endocarditis
Kidney
Lupus Glomerulonephritis
Proteinuria > 0.5 gm/ day
Hematuria
Cellular cast
Liver /Gastrointestinal
Hematological involvement :
Hemolytic Anemia
Thrombocytopenia <100,000 /𝑚𝑚3
Neutropenia < 4000/𝑚𝑚3
Lymphopenia < 1500/𝑚𝑚3
LABORATORY TESTING
●Complete blood count and differential may reveal leukopenia,
mild anemia, and/or thrombocytopenia
●Elevated serum creatinine may be suggestive of renal dysfunction
●Urinalysis with urine sediment may reveal hematuria, pyuria,
proteinuria, and/or cellular casts
●Erythrocyte sedimentation rate (ESR) and/or C-reactive protein
(CRP) levels
●Urine protein-to-creatinine ratio
SEROLOG
● ANA, Anti ds DNA , Anti Sm , anti SSA , anti SSB, Anti-U1 RNP
antibodies
●Antiphospholipid antibodies: (lupus anticoagulant [LA], IgG and IgM
anticardiolipin [aCL] antibodies; and IgG and IgM anti-beta2glycoprotein [GP] I)
●C3 and C4 or CH50 complement levels
Clinical Course of SLE:
Disease activity and Damage
GENES
Environment
PRECLINICAL
CLINICAL
Co-morbidities
TIME
Autoantibodies
General- specific
•Inflammatory
•Involvement of first
organ
•Flares
•Involvement of
additional organs
•Damage (SLICC)
•Infections
•Atheroscherosis
•Malignancies
DIAGNOSIS
 The diagnosis of SLE is generally based on clinical judgment,
after excluding alternative diagnoses.
 Serological findings
ANA are important to suggesting the possibility of SLE
Anti-double-stranded DNA [dsDNA] and anti-Smith [Sm])
highly associated with SLE.
 SLE classification criteria
Autoantibodies
ANA:
 Against targets in the nucleus
 The different types of ANAs are
defined by their target antigen,
including
 double-stranded DNA,
 individual nuclear histones,
other nuclear proteins
RNA-protein complex ………
POSITIVE ANA
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–
–
SLE
Other CTD (RA, SS, PSS, CREST, DM/PM)
DRUG-INDUCED
NORMAL (FALSE POSTIVE) 5-20% of population
LYMPHOPROLIFERATIVE DISORDER
– CHRONIC INFECTION (HIV, Leprosy)
Autoantibodies
ANTI DS-DNA
 Anti ds-DNA is unique to SLE patients
 It bind to conserved nucleic acid
 Anti ds-DNA titer vary over time and disease
activity:
Can correlate with nephritis
Immune complexes with anti-DNA ab/DNA can
increase the expression of IFN-α via plamacytoid
dendritic cells
AUTOANTIBODIES
 SSA/Ro and SSB/La: detect ribonucleoproteins,
associated with SICCA syndrome and
photosensitivity
 Anti-Sm: detects ribonucleoproteins involved in
processing of mRNA
 RNP
WHY ARE AUTOANTIBODIES SO BAD?
Skin disease
 Inflammation and breakdown of the dermalepidermal junction.
 UV exposure can worsen because it promotes
apoptosis in the skin resulting in autoantibody
binding and tissue injury via complement
activation or inflammatory cell activation
 Anti-Ro antibodies are associated with skin
flares
Renal disease
IgA, IgM, IgG and complement deposition in the
mesangium and subendothelial and subepithelial of the
GBM that results in complement activation and
recruitment of inflammatory cells that result in tissue
destruction.
 Cross reactivity of anti-DS DNA antibodies with actinin may also result in a direct focusing of
complement activation

Why are autoantibodies so bad?
 In the CNS, vasculitis is rare
 Anti-NMDA receptor antibodies may contribute to cerebral
lupus phenotypes
 Microinfarcts and degeneration or proliferative changes in
blood vessels, thought to be related to IC deposition
 Antiphospholipid abs may contribute to thrombotic
events anywhere in the body
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aPLs bind to endothelial cells, monocytes, neutrophils and
platelets causing inflammation and procoagulant release
This process is dependent on complement activation
1997 ACR CLASSIFICATION CRITERIA
1.
Malar rash: butterfly-shaped rash across cheeks and nose
2.
Discoid (skin) rash: raised red patches
3.
Photosensitivity: skin rash as result of unusual reaction to sunlight
4.
Mouth or nose ulcers: usually painless
5.
Arthritis (nonerosive) in two or more joints, along with tenderness, swelling, or effusion.
With nonerosive arthritis, the bones around joints don’t get destroyed.
6.
Cardio-pulmonary involvement: inflammation of the lining around the heart (pericarditis)
and/or lungs (pleuritis)
7.
Neurologic disorder: seizures and/or psychosis
8.
Renal (kidney) disorder: excessive protein in the urine, or cellular casts in the urine
9.
Hematologic (blood) disorder: hemolytic anemia, low white blood cell count, or low
platelet count
10.
Immunologic disorder: antibodies to double stranded DNA, antibodies to Sm, or
antibodies to cardiolipin
11.
Antinuclear antibodies (ANA): a positive test in the absence of drugs known to induce it.
- See more at: http://www.lupusresearchinstitute.org/lupus-facts/lupusdiagnosis#sthash.9vPrenyo.dpuf
DIFFERENTIAL DIAGNOSIS
 Rheumatoid arthritis
 Mixed connective tissue disease
 Drug induced lupus
 Undifferentiated connective tissue disease
 Dermatomyositis
 Sjögren’s syndrome
 Vasculitis
 Adult Still’s disease (ASD)
 Kikuchi’s disease
 Multiple sclerosis (MS)
 Infection
 malignancy
MANAGEMENT
 General measure
 Sun protection
 Diet and vitamin D
 Exercise
 Immunization
 Medications and/or therapies are often used to suppress the
response of the immune system according to the severity and
organ involved.
 Treating comorbid conditions
The ‘traditional treatment armamentarium’
FDA Approved drugs
 glucocorticoids
Benlysta
 hydroxychloroquine
 low dose ASA
‘Off-label’ but standard of care
 azathioprine
 cyclophosphamide
 NSAIDs
Immunosuppressives developed for other diseases
 mycophenolate mofetil
methotrexate
 cyclosporin
leflunomide
 tacrolimus
fludarabine
Biological Therapies
• Proteins that affect cells or signals in the
immune system
• Usually need to be injected or infused (IV)
Biological Therapies
Rontalizumab
Sifalimumab
IFN-α
Immune
Stimulation
pDC
Belimumab
Atacicept
Immune
complexes
containing
nucleic acids
Ocrelizumab
Veltuzumab
IPP 201101
Bly S
Fostamatinib
Apoptotic
Material
Rituximab
APC
T Cell
CD 20
B Cell
Antibodies
IL6R
CD 22
epratuzumabab
Abatacept
Tocilizumab
Abetimus
PROGNOSIS
 Prognosis is variable, depending on the systems involved.
 Mortality in the first 5 years tends to be from active SLE or
infection.
 Thereafter, mortality results from coronary heart disease, endstage renal failure, or severe infection without active SLE
KEY POINTS
 Systemic lupus erythematosus is a chronic multisystem
autoimmune disease that predominantly affects the skin and
joints, although any body system can be involved
 The most common presentation is a butterfly rash on the face,
low-grade fever, and non-deforming arthritis
 The diagnosis is made on clinical grounds and based on the
presence of antibodies to nuclear antigens such as antinuclear antibodies (ANA) and related serology, such as anti–
double-stranded DNA (anti-dsDNA)
Case 1
A 26-year old female presented with generalized fatigue and
pain and swelling of her hands, knees and feet with a MS of
60 minutes of 5 weeks duration. Associated with
photosensitive skin rash
Examination:
Arthritis of small joints of hands,Knees
Facial rash.
Labs: ESR 70; Hb 11.5; WBC 4.2;lyhphocyte 1, plat 221;
urine: proteinuria with casts on microscopy.
Summary:
26-y old female
Inflammatory polyarthritis
malar rash
proteinuria
Arthritis in a female 25-50 years of
age:
1.
2.
3.
4.
5.
Systemic lupus erythematosus
Rheumatoid arthritis
Other CT diseases: SS; DM; MCTD
Viral infection
……….
COMMONEST CAUSES OF POLYARTHRITIS
Inflammatory:
RA, SLE, DM/PM, SS, MCTD, seronegatives
Infectious:
Viral ,Some bacterial agents ( gonorrhea, brucellosis)
Neoplastic:
Leukemia, metastasis
Causes of erythematous rash over cheeks:
Systemic lupus erythematosus
Dermatomyositis
See more at:
-
http://www.lupus.org
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http://www.lupus.com
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Davidson's Principles and Practice of Medicine, 22nd Edition