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:
– Genetic factors– Immunologic factors– Hormonal factors– Environmental factors
EBV?
Genetic predisposition
InfectionAbnormal (control of) immune responses
Hormonal factors
Baseline immunological abnormalities
SLE
GENETIC SUSCEPTIBILITYConcordance 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*1501HLA class III genesC1q deficiency results in high likelihood of developing SLEComplement C4A deficiency: 80% of people with SLE have at least one null alleleC1r/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 90% develop SLE
C3 deficiency 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: 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 FACTORSENVIRONMENTAL 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
The fundamental abnormality in SLE is selective loss of tolerance and self/non-self recognition and the development of auto-
antibodies
SOURCE OF THE AUTO-ANTIGENS IN LUPUS
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
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• 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
Pleuritis (pleuritic chest pain )
Pleural effusion (Dyspnea )
Pneumonitis
Pulmonary hemorrhage
Interstitial lung fibrosis
Cardiovascular
Pericarditis
Pericardial effusion
Myocarditis
Pulmonary hypertension
Libman-Sacks endocarditis
RESPIRATORY/CARDIOVASCULAR
Kidney
Lupus Glomerulonephritis
Proteinuria > 0.5 gm/ day
Hematuria
Cellular cast
Liver /Gastrointestinal
Hematological involvement :
Hemolytic Anemia
Thrombocytopenia <100,000 /
Neutropenia < 4000/
Lymphopenia < 1500/
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-beta2-glycoprotein [GP] I)
●C3 and C4 or CH50 complement levels
Clinical Course of SLE: Disease activity and Damage
TIMETIME
PRE-CLINICAL CLINICAL Co-morbidities
GENES Environment
AutoantibodiesGeneral- specific
AutoantibodiesGeneral- specific
•Inflammatory•Involvement of first organ
•Inflammatory•Involvement of first organ
•Flares•Involvement of additional organs•Damage (SLICC)
•Flares•Involvement of additional organs•Damage (SLICC)
•Infections•Atheroscherosis•Malignancies
•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
AutoantibodiesANA: 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 proteinsRNA-protein complex
………
POSITIVE ANA– 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 is unique to SLE patients
It bind to conserved nucleic acidAnti ds-DNA titer vary over time and disease activity:
Can correlate with nephritisImmune complexes with anti-DNA ab/DNA can increase the expression of IFN-α via plamacytoid dendritic cells
ANTI DS-DNA
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 dermal-epidermal 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 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/lupus-diagnosis#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 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
Benlysta
Biological Therapies
• Proteins that affect cells or signals in the immune system
• Usually need to be injected or infused (IV)
IFN-α
Apoptotic Material
Apoptotic Material APC T Cell B Cell
Antibodies
CD 22IL6R
CD 20
Bly S
Immune complexes containing nucleic acids
pDC
Immune Stimulation
RontalizumabSifalimumab
IPP 201101
Fostamatinib
Belimumab Atacicept
RituximabOcrelizumabVeltuzumab
Abatacept Tocilizumab
epratuzumababAbetimus
Biological Therapies
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, end-stage 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 anti-nuclear 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.
26-y old femaleInflammatory polyarthritis
malar rash proteinuria
Summary:
Arthritis in a female 25-50 years of age:
1. Systemic lupus erythematosus2. Rheumatoid arthritis3. Other CT diseases: SS; DM; MCTD4. Viral infection5. ……….
Inflammatory:
RA, SLE, DM/PM, SS, MCTD, seronegativesInfectious: Viral ,Some bacterial agents ( gonorrhea, brucellosis)
Neoplastic:
Leukemia, metastasis
COMMONEST CAUSES OF POLYARTHRITIS
Causes of erythematous rash over cheeks:
Systemic lupus erythematosus
Dermatomyositis
See more at:
- http://www.lupus.org
- http://www.lupus.com
- Davidson's Principles and Practice of Medicine, 22nd Edition
QUESTION