Systemic Lupus Erythematosus Definition • An inflammatory multi-system disease • Immunologic aberrations: excessive auto-antibody production • Tissue damage results from antibody and complement fixing immune complex deposition • wide spectrum of clinical presentations • characterized by remissions and exacerbations EPIDEMIOLOGY • SLE - recognized worldwide • Prevalence in USA: 15-50 \ 100,000 (1:2000) • Incidence in USA: 1.8-7.6 \ 100,000\ year • F:M 9:1 ( at age: 14-64 ) • Racial predisposition: x 3 more common in blacks: African-American; African-Caribbean; Hispanic; Asian EPIDEMIOLOGY in the young and elderly • Peak incidence is at age 15-40 But: Onset may be at any age • In pre- and post menopausal: female : male ratio 3:1 GENETIC EPIDEMIOLOGY- 1 • SLE is a multigenic disease • In < 5% of patients a single gene is responsible • Homozygous deficiencies of early components of complement (C1q, C1r, C1s, C4, C2) predispose to SLE • A null allele for C4A is the HLA-linked gene most consistently associated with susceptibility to SLE GENETIC EPIDEMIOLOGY- 2 • HLA class II genes are associated with production of certain auto-antibodies: anti-dsDNA; anti-Ro; anti-La; anti-Sm; anti-U1- RNP; anti-ribosomal P; antiphospholipid abs • TCR genes and Ig genes may contribute to susceptibility GENETIC EPIDEMIOLOGY -3 • relatives of SLE patients have increased incidence of: SLE, other auto-immune diseases and auto- antibodies (~ 10% of SLE patients have relatives with SLE) • family studies show no formal genetic linkage with HLA susceptibility genes • males need more susceptibility genes • concordance for monozygotic twins: 24-58% IMPORTANCE OF SEX HORMONES • Female predominance (9:1) • disease activity during menstrual period • increased disease activity in pregnancy • flares with oral contraceptive therapy • abnormally rapid testosterone metabolism • estrogenic metabolites persist longer ENVIRONMENTAL FACTORS • Ultraviolet light ( UVB ) alters location and \ or chemistry of: DNA , Ro, RNP antigens - increased immunogenicity • Drugs ( Septrin ) • Infections (parvovirus, CMV, HCV ) • Smoking ( DLE ) DEFECTIVE IMMUNE REGULATION • B cell and T cell hyperactivity leads to: T cell dependent autoAb production made in high quantity • subsets of autoAbs and the IC they form with Ag mediate tissue damage • defective clearance of IC • defects in immune tolerance and apoptosis • defects in T and natural killer regulatory cells Clinical Manifestations of SLE Constitutional non-specific but very common: - Fatigue - Fever - Weight Loss SKIN MANIFESTATIONS LE-specific lesions • Acute: - malar “butterfly rash” - generalized erythema - bullous LE • Subacute cutaneous lupus • Chronic lupus: - localized discoid - generalized discoid - lupus profundus Butterfly- malar rash Generalized, photosensitive erythema Bullous rash Subacute cutaneous rash psoriatiform annular Discoid rash SKIN MANIFESTATIONS LE-nonspecific lesions • Panniculitis • Urticarial lesions • Vasculitis • Livedo reticularis • Oral lesions • Nonscarring alopecia Vasculitis with finger tip ulcers Livedo reticularis Livedo reticularis with necrotic finger tips in Antiphospholipid syndrome Alopecia (diffuse or patchy) Nonscariing if part of SLE flare Scarring if results from discoid Skin biopsy: Lupus band test = immunofluorescent staining of IgG and complement deposits in dermoepidermal junction Skin biopsy-SLE dermatitis Thickened epidermal basement membrane (large arrows) Inflammatory infiltrates (small arrow) Skin biopsy-Discoid lesion Hyperkeratosis (small arrow) Lymphoid infiltrates (thick arrow) Deep dermis is fibrotic F MUSCULOSKELETAL FEATURES • Arthritis: - the most common manifestation of SLE - non-erosive, rarely deforming (Jaccoud’s) - synovial fluid- mild inflammation - tenosynovitis-may be early manifestation • Myositis: - true inflammation - myopathy 2nd to drugs: steroids, anti-malarials • Fibromyalgia Jaccoud arthropathy in a patient with systemic lupus erythematosus Boumpas, D. T. et. al. Ann Intern Med 1995;123:42-53 RENAL DISEASE in SLE • Proteinuria: 0.5 gr\ 24 hrs ( or > +3 ) • Urinary casts: RBC,granular,tubular,mixed • Hematuria: > 5 RBC / high power field • Pyuria: > 5 WBC / high power field • prevalence: 30-65% • in 3-6% renal disease is first manifestation WHO CLASSIFICATION of LUPUS NEPHRITIS • I - normal glomeruli • II- pure mesangial changes • III- focal proliferative glomerulonephritis • IV-diffuse proliferative glomerulonephritis • V-diffuse membranous glomerulonephritis • VI-advanced sclerosing glomerulonephritis WHO CLASSIFICATION of LUPUS NEPHRITIS (2003) • Class I - Minimal mesangial LN (mesangial immune deposits seen by IF) • Class II - Mesangial proliferative LN • Class III- Focal LN (<50% of glomeruli with focal subendothelial immune deposits) • Class IV - Diffuse segmental LN (IV-S) - Diffuse global LN (IV-G) (> 50% of glomeruli with subendothelial immune deposits) • Class V- Membranous LN (global or segmental subepithelial deposits) • Class VI- Advanced sclerosing LN (> 90% of glomeruli globally sclerosed) Assessment of Activity and Chronicity • Activity Indicators • Chronicity Indicators - cellular proliferation - glomerular sclerosis - necrosis, karryohexis - fibrous crescents - cellular crescents - interstitial fibrosis - wire loops, hyaline - tubular atrophy thrombi - leukocytic infitration - interstitial infiltration SEROSITIS in SLE • Pleuritis - occurs in 30-60% of patients • Pericarditis - occurs in 20-30% • Peritonitis CARDIAC INVOLVEMENT: • Pericarditis • Myocarditis • Endocarditis • Coronary heart disease PULMONARY INVOLVEMENT • Pleuritis • Pneumonitis - acute or chronic • Pulmonary hemorrhage - due to vasculitis • Pulmonary hypertension • Pulmonary embolism HEMATOLOGIC INVOLVEMENT • Anemia: - in acute SLE: hemolytic anemia - secondary to: chronic disease, CRF, blood loss, drugs. • Leukopenia / Lymphopenia: - in active disease - secondary to drugs, infection HEMATOLOGIC INVOLVEMENT Thrombocytopenia: - antiplatelet abs- common, not always associated with thrombocytopenia - occurs in active SLE - may be isolated finding ( < 50,000 without serious bleeding ) Neuropsychiatric syndromes in SLE Central nervous system Peripheral nervous system - Aseptic meningitis - Guillain –Barre’ syndrome - Cerebrovascular disease - Autonomic disorder - Demyelinating syndrome - Mononeuropathy, single/multiplex - Headache (migraine, benign - Myasthenia Gravis intracranial pressure) - Neuropathy, cranial - Movement disorder (chorea) - Plexopathyy - Myelopathy - Polyneuropathy - Seizure disorder - Acute confusional state - Anxiety disorder - Cognitive dysfunction The American College of Rheumatology - Mood disorder Nomenclature and case definitions for - Psychosis Neuropsychiatric lupus syndromes . Arthritis & Rheumatism 1999 NEUROLOGICAL LUPUS • Differential Diagnosis: - active Lupus - thromboembolic - atherosclerotic - infection - toxic\metabolic ANTI-NUCLEAR ANTIBODIES • ANA - abs directed against nuclear antigens • may occur in other systemic rheumatic diseases • most frequent and highest in titer in SLE • Positive in 98% of SLE patients ( on human tissue cultures ) ANTI-NUCLEAR ANTIBODIES • SLE: many ANA’s with simultaneous appearance • Systemic Rheumatic diseases: - fewer types of ANA’s in each individual - have antibodies of other specificities • Normal population: ANA seen at low frequency and low titer, frequency increases with age. ANAs ANA’s can be divided into: • those directed against dsDNA • those directed against ssDNA • those directed against histones • those directed against non-histone nuclear proteins : nucleic acid-protein complexes ANA testing • ANA’s are detected by indirect immunofluorescence or immunoenzyme assays • Substrate: - Cryopreserved tissue such as mouse kidney - Tissue culture cell lines: HEp-2 . Sensitivity increased with active dividing cells Immunofluorescent staining of ANAs Patterns of IF staining Four patterns of staining are seen: 1. Homogenous (diffuse) dsDNA, histone seen in SLE, drug induced SLE, RA 2. Speckled seen in MCTD, SLE, Sjogren, Systemic Sclerosis 3. Nucleolar seen in Systemic Sclerosis, Sjogren, SLE 4. Rim (peripheral) dsDNA, histones characteristic of SLE Show IFA slide ANAs in SLE Autoantibody Prevalence • anti ds DNA • 50% • anti ss-DNA • 60-70% • anti- Histones • 70% • anti- Sm ( Smith) • 30% • anti- RNP • 35% • anti- Ro ( SSA) • 30% • anti-La ( SSB) • 15% Anti DNA antibodies • Anti ss- DNA: nonspecific and not in clinical use • Anti-ds DNA: specific for SLE Clinical use important: - levels correlate with disease activity - presence and level associated with risk for renal disease - pathogenic effect mediated through direct binding to glomeruli or immune-complex mechanisms. CLINICAL ASSOCIATIONS of AUTOANTIBODIES in SLE ANTIBODY FREQUENCY % SPECIFICITY CLINICAL SUBSET dsDNA 50-60 ++ Nephritis ssDNA 60-70 - Histones 70 + Drug-induced LE Ro 30 + Subactue La 15 + cutaneous Lupus, Heart block Sm 30 ++ Nephritis,CNS RNP 10 + MCTD Diagnosis of SLE • Based on a combination of clinical manifestations and laboratory findings which may occur simultaneously or serially • Classification criteria are used for research Classification criteria of SLE (1982 ACR revised criteria) Criterion Definition 1. Malar Rash 1. Fixed erythema, malar distribution 2. Discoid rash 2. Erythematous raised patches with scaling, atrophy, scarring 3. Photosensitivity 3. Skin rash as result of sunlight 4. Oral ulcers 4. Oral\ nasopharyngeal, usually painless 5. Arthritis 5. Nonerosive, 2 or more joints 6. Serositis 6. Pleuritis OR Pericarditis 7. Renal disorder 7. Proteinuria > 0.5gr or >+3 OR cellular casts 8. Neurologic disorder 8. Seizures OR Psychosis 9. Hematologic disorder 9. Hemolytic anemia with reticulocytosis OR Leukopenia < 4000/ mm3 OR Lymphopenia <1500/mm3 OR Thrombocytopenia < 100.000/mm3 Classification criteria of SLE (1982 ACR revised criteria) Criterion Definition 10. Immunologic disorder 10. - anti-dsDNA OR - anti- Sm OR - false positive VDRL or antiphospholipid antibody 11. Anti-nuclear antibody 11. Abnormal titer of ANA in absence of drugs known to cause DIL For diagnosis: any 4 of 11 criteria Drug Induced Lupus • Clinical manifestations of SLE appear while taking a drug improve on discontinuation of the drug • 10% of the incidence of SLE • Clinical features are less severe than SLE. • Common clinical features: fatigue, weight loss, fever, arthritis, serositis, cytopenias. • Uncommon: CNS and renal involvement Drug Induced Lupus • ANA-positive • Anti-Histone - positive in > 90% but nonspecific ( found in SLE as well) • Anti-DNA- negative, complement usually normal • serology resolves slowly on drug discontinuation Immunology in Drug Induced Lupus COMMON LESS COMMON ANA RF Anti Histone antibodies CIC Anti- ss DNA ANCA Coombs Antiphospholipid antibodies hypergammaglobulinemia Drugs associated with Drug Induced Lupus • Definite: Hydralazine (5-10%) , Procainamide (15-20%), Chlorpromazine, Methyldopa, Isoniazid • Possible association: Phenytoin, Penicillamine, Quinidine • Questionable association: Gold salts, Griseofulvin Management of SLE THE CHALLENGE • Treat Active Lupus • Prevent Damage from: - Active lupus - Corticosteroids - Immunosuppressive agents TREATMENT of ACTIVE SLE Organ System Approach • Use the drug with the: - LEAST side effects - LOWEST dose to control disease - LONG TERM damage prevention Mild disease: AVOID Steroids Severe disease: Aggressive treatment Available treatments for SLE • NSAIDs • Corticosteroids • Hydroxychloroquine (Plaqeunil) • Chloroquine (Aralen) Antimalarials • Quinacrine ( Mepacrine; Atabrine) • Methotrexate • Azathioprine • Cyclophosphamide • Cyclosporine • Mycophenolate Mofetil (Cellcept) • IVIG • Thalidomide Corticosteroids • Effective for the suppression of all SLE manifestations • NOT justified for Arthritis • Moderate doses (20-30mg\d) sufficient for: pleuritis\ pericarditis • High doses (1mg\kg) required for: Nephritis, CNS disease, Severe hemolytic anemia or thrombocytopenia • IV pulse 1gr methylprednisone sometimes used for refractory nephritis or life threatening disease Anti-malarials Hydroxychloroquine, Chloroquine, Quinacrine • Effective for the treatment of : Fatigue, Arthritis, Skin disease • Prevents SLE flares • Lowers cholesterol levels • Anti-aggregant effect Methotrexate • May be effective as a steroid sparing agent in the treatment of: - arthritis - skin disease Immunosuppressive agents Azathioprine, Cyclophosphamide, Cyclosporine, Cellcept • Used mainly for nephritis • May be used for major organ involvement - Azathioprine: P.O. 2-3mg\kg - Cyclophosphamide : IV pulses of 0.5-1.0gr/m2 once a month to once every 3 months for up to 2 yrs - Cyclosporine: P.O. 1-3mg\kg\d - Cellcept: P.O. 0.75-3gr\d Treatment of Lupus Nephritis • Induction: - Corticosteroids - IV Cyclophosphamide \ q month - Mycophenalte Mofetil ( Cellcept ) ? • Maintenance: - IV Cyclophosphamide \ q 3 mo - Azathioprine - Mycophenalte Mofetil - Cyclosporine Corticosteroids- the price: • Avascular Necrosis of Bone • Osteoporosis with Fracture • Premature Atherosclerosis • Quality of life: Weight, Cushingoid Habitus, Mood changes Cyclophosphamide side effects • Infection: - frequency - 45% - risk factors: - sequential infusions - WBC<3000 • Premature ovarian failure - risk factors: age: < 25 - 6% >31 - 67% - cumulative dose • Malignancy : leukemia, gynecologic malignancies, bladder DISTRIBUTION of DAMAGE Johns Hopkins Cohort • 25.2% musculoskeletal • 6.1% diabetes • 15.0% neuropsychiatric • 2.5% malignancy • 12.6% ocular • 1.2% premature gonadal • 11.7% renal failure • 10.4% pulmonary • 10.1% cardiovascular • 7.4% gastrointestinal • 7.4% skin DAMAGE in SLE : CORONARY ARTERY DISEASE • Major cause of morbidity • Bimodal pattern of mortality in SLE: early - due to disease and infection late - due to Cardiovascular disease • prevalence: 8% • Hydroxychloroquine- may be protective: reduces cholesterol, anti-aggregation properties Prevalence of cardiovascular disease in SLE • Hospitaliztion of young SLE women compared to non SLE: - 2-3 times more likely to have MI - 3.8 times more likely to have CHF - 2.1 times more likely to have CVA • SLE women age 35-44: 50 times more likely to have MI compared to women of similar age (Framingham offspring study) Atherosclerosis in SLE Disease related ? • Circulating immune complexes increase cholesterol uptake by smooth muscle cells • antiphospholipid antibodies • anticardiolipin increases uptake of oxidized LDL • anti- endothelial abs Risk factors for cardiovascular disease in SLE • Hypertension • Hyperlipidemia • Diabetes Mellitus • Obesity • Chronic steroid treatment • Active SLE: - chronic inflammation leads to endothelial damage - anti-endothelial abs, anti-phospholipid antibodies Prognosis Survival: • 90-95% at 2 years • 82-90% at 5 years • 71-80% at 10 years • 63-75% at 20 years Poor prognostic factors: • increased creatinine • nephrotic syndrome • hypertension • thrombocytopenia • African- American race • low socioeconomic status THE CHALLENGE • Treat Active Lupus • Prevent Damage from: - Active lupus - Corticosteroids - Immunosuppressive agents Pregnancy and SLE • 1950s: in SLE pregnancy is not advised, termination should be offered • 1990s: 40-50% flare during pregnancy and postpartum - most are minor Pregnancy Outcomes in SLE Johns Hopkins Cohort • Fertility rates: normal 2-2.4 pregnancies\patient • Preterm < 37 weeks 40.5% < 36 weeks 32.1% • Pregnancy loss 10-30% 1st trimester 6.0% 2nd trimester 7.1% The Mother in SLE • Severe exacerbations: in 20% of pregnancies • Risk factors for exacerbation: - active disease 3-6 months before conception - pre-existing renal disease • Conception during remission: 10-30% risk of flare. • Mild lupus rarely exacerbates in pregnancy Management of SLE flares in pregnancy • Prednisone • IV Pulse methylprednisolone • NSAIDs ( during 1st trimester ) • Plaquenil • Azathioprine • Cyclosporine Neonatal Lupus 1. Neonatal cutaneous lupus 2. Congenital heart block • Occurs in women with: - anti Ro\SSA - anti La\SSB - anti U1 RNP • Due to placental transmission of maternal IgG abs • The mother may be : asymptomatic, have SLE, Sjogren syn, other rheumatic disease. Prevalence of neonatal lupus • Prevalence of auto-abs in women with SLE: - anti Ro: 25-40% of patients - anti- La: 10-15% of patients • Proportion of children with neonatal lupus in mothers with the auto-abs: 2-5% (up to 8.8%) • of reported neonatal lupus cases: - 37% are cutaneous - 54.4% are congenital heart block - 7.1% have both Cutaneous neonatal lupus • 70-75% of affected babies are female • transient skin rash: erythematous, annular (2-6 months) • occurs on: face, scalp, trunk, extremities • rash appears shortly after birth, is photosensitive • resolves without a scar Congenital heart block (CHB) • Prevalence: 1:20,000 births ( 0.005%) • clinically detected at 18- 25 wks gestation • fetuses of all women with anti Ro\anti La should have weekly echocardiographies (between wks 18-25) • the block is complete in 90% of reported cases • 60% of babies require pacemakers, 30% - die • recurrence of CHB low - 13% Management of congenital heart block • Prophylactic treatment of the high risk mother is not helpful. • Treatment of identified block: T. Dexamethasone 4mg\d • Rationale for treatment of identified block: - reduce generalized inflammatory insult - lower titer of maternal autoabs.