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Systemic Lupus Erythematosus (SLE)
Dr.hanan alrayes,md Consultant Rheumatology
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Systemic Lupus Erythematosus (SLE)
Epidemiology Pathogenesis of Lupus Clinical manifestation Discuss the clinical Course of SLE Diagnostic criteria Management
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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
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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
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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
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Abnormal (control of) immune responses
SLE - Etiology The etiology of SLE remains unknown Yet, SLE is clearly multifactorial: Genetic factors Immunologic factors Hormonal factors Environmental factors EBV? Genetic predisposition Baseline immunological abnormalities Infection Hormonal factors Abnormal (control of) immune responses SLE
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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 SNR signle-nucleotide polymorphisms
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Risk factors The Complement Paradox
Deficiencies in C1,C2,C4 and CR1 predispose to the development of SLE Complete lack of C1q or C % develop SLE C3 deficiency % lupus like disease Trouw, L.A. et al., Mol Immunology (2008) 45:
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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
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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
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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 11
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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
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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.
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Clinical Manifestations
Oral /Nasopharyngeal ulcers Alopecia Raynaud's phenomena
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Musculoskeletal Arthritis/Arthralgia
Symmetrical inflammatory polyarthritis Non erosive Swan neck like deformities called Jaccoud's arthritis Myositis/ myalgia
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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
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Respiratory/cardiovascular
Pleuritis (pleuritic chest pain ) Pleural effusion (Dyspnea ) Pneumonitis Pulmonary hemorrhage Interstitial lung fibrosis Cardiovascular Pericarditis Pericardial effusion Myocarditis Pulmonary hypertension Libman-Sacks endocarditis
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Liver /Gastrointestinal
Kidney Lupus Glomerulonephritis Proteinuria > 0.5 gm/ day Hematuria Cellular cast Liver /Gastrointestinal
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Hematological involvement : Hemolytic Anemia Thrombocytopenia <100,000 / 𝑚𝑚 3 Neutropenia < 4000/ 𝑚𝑚 3 Lymphopenia < 1500/ 𝑚𝑚 3
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The clinical spectrum of SLE is very broad
It make SLE both fascinating but potentially difficult to diagnose and manage 21 21 21
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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
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Clinical Course of SLE: Disease activity and Damage
GENES Environment PRE-CLINICAL CLINICAL Co-morbidities TIME Flares Involvement of additional organs Damage (SLICC) Infections Atheroscherosis Malignancies Autoantibodies General- specific Inflammatory Involvement of first organ 23 23 23 23
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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
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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 ……… THE central immunological disturbance in SLE is autoantibodies production
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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) 26
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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 27 27
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Autoantibodies SSA/Ro and SSB/La: detect ribonucleoproteins, associated with SICCA syndrome and photosensitivity Anti-Sm: detects ribonucleoproteins involved in processing of mRNA RNP
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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
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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 30
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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 NMDA (N methyl- D- Aspartate) 31
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1997 Acr Classification CRITERIA
Malar rash: butterfly-shaped rash across cheeks and nose Discoid (skin) rash: raised red patches Photosensitivity: skin rash as result of unusual reaction to sunlight Mouth or nose ulcers: usually painless Arthritis (nonerosive) in two or more joints, along with tenderness, swelling, or effusion. With nonerosive arthritis, the bones around joints don’t get destroyed. Cardio-pulmonary involvement: inflammation of the lining around the heart (pericarditis) and/or lungs (pleuritis) Neurologic disorder: seizures and/or psychosis Renal (kidney) disorder: excessive protein in the urine, or cellular casts in the urine Hematologic (blood) disorder: hemolytic anemia, low white blood cell count, or low platelet count Immunologic disorder: antibodies to double stranded DNA, antibodies to Sm, or antibodies to cardiolipin Antinuclear antibodies (ANA): a positive test in the absence of drugs known to induce it. - See more at: diagnosis#sthash.9vPrenyo.dpuf
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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
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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
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The ‘traditional treatment armamentarium’
Benlysta
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Biological Therapies Proteins that affect cells or signals in the immune system Usually need to be injected or infused (IV)
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Biological Therapies APC Immune Stimulation IFN-α Rituximab
Rontalizumab Sifalimumab Immune Stimulation IFN-α pDC Belimumab Atacicept Rituximab Ocrelizumab Veltuzumab Immune complexes containing nucleic acids IPP CD 20 Fostamatinib Bly S Apoptotic Material T Cell B Cell APC Antibodies CD 22 IL6R epratuzumabab Abatacept Tocilizumab Abetimus 39
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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
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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)
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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.
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Inflammatory polyarthritis malar rash proteinuria
Summary: 26-y old female Inflammatory polyarthritis malar rash proteinuria
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Arthritis in a female 25-50 years of age:
Systemic lupus erythematosus Rheumatoid arthritis Other CT diseases: SS; DM; MCTD Viral infection ……….
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COMMONEST CAUSES OF POLYARTHRITIS
Inflammatory: RA, SLE, DM/PM, SS, MCTD, seronegatives Infectious: Viral ,Some bacterial agents ( gonorrhea, brucellosis) Neoplastic: Leukemia, metastasis
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Causes of erythematous rash over cheeks:
Systemic lupus erythematosus Dermatomyositis
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See more at: - Davidson's Principles and Practice of Medicine, 22nd Edition
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QUESTION
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