1.SYSTEMIC LUPUS ERYTHEMATOSUS- AN OVERVIEW- Dr. Parvez Khan - Dr. Deepak KapoorAssistant Professors, M - 1 Department of Internal MedicineDeccan College of Medical Sciences

2. Systemic Lupus ErythematosusDefinition 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 3. Epidemiology SLE - recognized worldwide Prevalence in USA: 15-50100,000 (1:2000) Incidence in USA: 1.8-7.6100,000 year F:M 9:1 ( at age: 14-64 ) Racial predisposition:x 3 more common in blacks 4. Epidemiology in the young and elderly Peak incidence is at age 15-40But: Onset may be at any age In pre-pubertal and post menopausal:female : male ratio 3:1 5. Genetic Epidemiology SLE is a multi-genic 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 6. Genetic Epidemiology HLA class II genes are associated with production of auto-antibodies TCR genes and Ig genes may contribute to susceptibility FC RIIA, FC RIIIA predispose to SLE in someethnic groups (possibly responsible for impaired IC clearing) 7. Genetic Epidemiology concordance for monozygotic twins: 24-58% relatives of SLE patients have increased incidence of: - SLE - other auto-immune diseases - auto-antibodies ~ 10% of SLE patients have relatives with SLE males need more susceptibility genes 8. 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 9. Environmental Factors Ultraviolet light ( UVB ) Alfalfa sprouts, chemicals ( hydrazines) ? Drugs (Resprim = Trimethoprim + sulphamethoxazole) Infections (parvovirus, CMV, HCV ) Smoking ( Discoid LE ) 10. Defective Immune Regulation B cell and T cell hyperactivity leads to: T cell dependent auto-Ab production made in high quantity Subsets of auto-Abs and the ImmuneComplexes they form with Ag mediate tissuedamage Defective clearance of Immune Complexes Defects in immune tolerance and apoptosis Defects in T and natural killer regulatory cells 11. Pathogenic auto-antibodiesMechanisms of damage Direct binding to tissue via charge or cross-reactivity ( anti-DNA) Production of Immune Complexes leads to complement mediated damage Direct binding to cell membranes ( RBCs, Platelets) 12. Clinical Manifestations of SLE Constitutional non-specific but very common:- Fatigue- Fever- Weight Loss 13. Skin ManifestationsLE-specific lesions Acute: - malar butterfly rash - generalized erythema - bullous LE Subacute cutaneous lupus Chronic lupus: - localized discoid - generalized discoid - lupus profundus 14. Butterfly- malar rash 15. Generalized, photosensitive erythema 16. Bullous rash 17. Subacute cutaneous rashpsoriatiformannular 18. Discoid rash 19. Skin ManifestationsLE-nonspecific lesions Panniculitis Urticarial lesions Vasculitis Livedo reticularis Oral lesions Non-scarring alopecia 20. Panniculitis 21. Vasculitis with finger tip ulcers 22. Livedo reticularis 23. Alopecia (diffuse or patchy)Non-scarring if part of SLE flareScarring if results from discoid 24. Skin biopsy:Lupus band test = immunofluorescent staining ofIgG and complement deposits in dermo-epidermal junction 25. Skin biopsy - SLE dermatitisThickened epidermal basement membrane (large arrows)Inflammatory infiltrates (small arrow) 26. Skin biopsy - Discoid lesionHyperkeratosis (small arrow)Lymphoid infiltrates (thick arrow)Fibrosis of deep dermis F 27. Musculoskeletal Manifestations Arthritis:- the most common manifestation of SLE- non-erosive, rarely deforming (Jaccouds deformity)- synovial fluid- mild inflammation- tenosynovitis-may be early manifestation Myopathy:- myositis = true inflammation- myopathy 2nd to drugs: steroids, anti-malarials 28. Jaccouds arthropathy 29. 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 30. WHO Classification of Lupus NephritisJ Am Soc Nephrol 15: 241-250, 2004 Class I - Minimal mesangial LN(mesangial immune deposits seen by IF) Class II - Mesangial proliferative LN Class III- Focal proliferative LN( 50% of glomeruli with subendothelial immune deposits) Class V - Membranous LN(global or segmental subepithelial deposits) Activity index Chronicity Index Class VI - Advanced sclerosing LN(> 90% of glomeruli globally sclerosed) 31. Renal disease in SLE Mild disease -Class II Serious disease - Class III, IV, V Clinical course:- Class II:hematuria, sub-nephrotic proteinuria, preserved GFR- Class III and IV:edema, HTNnephritic sediment, mild-mod proteinuria, acute GFR- Class V:features of nephrotic syndrome, preserved/ gradual GFR 32. Serositis in SLE Pleuritis - occurs in 30-60% of patients Pericarditis - occurs in 20-30% Peritonitis 33. Cardiac Manifestations Pericarditis Myocarditis Endocarditis (Libman -Sacks endocarditis) Coronary heart disease 34. Pulmonary Manifestations Pleuritis Pneumonitis - acute or chronic Pulmonary hemorrhage - due to vasculitis Pulmonary hypertension Pulmonary embolism 35. Hematologic Manifestations Anemia:- in acute SLE:coombs positive hemolytic anemia- secondary to:chronic disease, CRF, blood loss, drugs. Leukopenia / Lymphopenia:- in active disease- secondary to drugs, infection 36. Hematologic Manifestations Thrombocytopenia:- anti-platelet abs- common, not alwaysassociated with thrombocytopenia- occurs in active SLE- may be isolated finding( ~ 50,000 without serious bleeding ) 37. Neuropsychiatric SLECentral nervous system Peripheral nervous system- Aseptic meningitis - Guillain - Barre syndrome- Cerebrovascular disease- Autonomic disorder- Demyelinating syndrome - Mononeuropathy, single/multi- Headache (migraine, benign plexintracranial pressure) - Myasthenia Gravis- Movement disorder (chorea) - Neuropathy, cranial- Myelopathy - Plexopathyy- Seizure disorder - Polyneuropathy- Acute confusional state- Anxiety disorder- Cognitive dysfunction- Mood disorderThe American College of Rheumatology- PsychosisNomenclature and case definitions for Neuropsychiatric lupus syndromes . Arthritis & Rheumatism 1999 38. Anti-Nuclear Antibodies (ANA) 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 detected by indirect immuno-fluorescence 39. Patterns of IF ANA staining Homogenous (diffuse) - dsDNA, histoneSLE, drug induced SLE, RA SpeckledMCTD, SLE, Sjogren, Systemic Sclerosis NucleolarSystemic Sclerosis, Sjogren, SLE Rim (peripheral) - dsDNA histonescharacteristic of SLE 40. Patterns of Immuno-fluorescence ANAstaining 41. ANAsANAs 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 42. AUTOANTIBODIES IN SLE: AutoantibodyPrevalence anti- ds DNA 50-60% anti- ss DNA 60-70% anti- Histones 70% anti- Sm ( Smith) 30% anti- RNP 35% anti- Ro ( SSA) 30% anti- La ( SSB) 15% 43. Anti DNA antibodies in SLE 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. 44. Clinical Associations of Auto-antibodies in SLEANTIBODYFREQUENCY % SPECIFICITY CLINICALSUBSETdsDNA 50-60 ++NephritisssDNA 60-70 -Histones70+ Drug-induced LERo30+ Subactue La 15+ cutaneous Lupus,Heart blockSm30++Nephritis,CNSRNP 10+ MCTDAntiphospholipid 30-40ThrombosisantibodiesRecurrent fetalloss 45. 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 46. Classification criteria of SLECriterion Definition1. Malar Rash - Fixed erythema, malar distribution- Erythematous raised patches with2. Discoid rashscaling, atrophy, scarring- Skin rash as result of sunlight3. Photosensitivity - Oral nasopharyngeal, usually painless4. Oral ulcers- Nonerosive, 2 or more joints5. Arthritis- Pleuritis OR Pericarditis6. Serositis -Proteinuria > 0.5gr or >+3 ORcellular casts7. Renal disorder - Seizures OR Psychosis8. Neurologic - Hemolytic anemiaOR disorder Leukopenia < 4000/ mm3 OR9. HematologicLymphopenia 31 yrs - 67% Malignancyleukemia, gynecologic malignancies, bladder 59. Mycophenolate Mofetil ( MMF = Cellcept) Immunosuppressive for:kidney, liver and heart transplant Inhibitor of : Inosine Monophosphate (IMP) dehydrogenase- key enzyme in de novo purine synthesis- glycosylation of adhesion molecules in T and B cells Inhibits:- proliferation of T and B lymphocytes- production of abs- generation of cytotoxic T cells- recruitment of leukocytes to sites of inflammation 60. MMF or IV Cyclophosphamide for Lupus NephritisGinzler et al. NEJM 2005 140 pts class III, IV, V (24 week trial) MMF (71 pts) CTX (69 pts)At 12 weeks:- Complete remission 164- Partial remission: 21 17- Death 03- Severe infections 16- Diarrhea 152Conclusion:- MMF more effective than CTX in inducing remission- severe infections : less with MMF 61. Sequential Therapies for proliferative LNContreras G et al. NEJM 2004 59 patients: class: III-12; IV-46; Vb-1 Induction: IV CYC (0.5-1gr/m2) q mo for up to 7 pulses + steroids Maintenance (1-3 yrs): - IV CYC q 3 months - AZA 1-3 mg/kg/d - MMF 0.5-3 gr/d 62. Future possible treatments for SLETreatments designed to effect specific processes LJP 394:B cell toleragen: cross links anti-DNA receptors on B cells Anti IL-10: IL-10 is increased on correlates with disease activity Anti-CD40 ligand: prevents T cell activation CTLA4Ig: blocks CTLA4 on activated T cells from binding to B7 on Bcells Anti C5 complement C1q immunoadsorption: removes immune complexes Anti CD 20 (Rituximab):CD20 is B cells restricted ag- leads to B celldepletion Anti-BLyS: anti B Lymphocyte Stimulator protein which is elevated in SLE 63. PrognosisSurvival: 90-95% at 2 years 82-90% at 5 years 71-80% at 10 years 63-75% at 20 yearsPoor prognostic factors:- creatinine, nephrotic syndrome- hypertension- thrombocytopenia- African- American race- low socioeconomic status 64. Pregnancy and SLE 1950s:- in SLE: pregnancy is not advised- termination should be offered 1990s:- 10-30% flare during pregnancy / postpartum- most flares are minor 65. Pregnancy Outcomes in SLEJohns Hopkins Cohort Fertility rates: normal 2-2.4 pregnanciespatient Preterm< 37 weeks40.5%< 36 weeks32.1% Pregnancy loss 10-30%1st trimester6.0%2nd trimester7.1% 66. The Mother in SLE 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 Severe exacerbations: in 20% of pregnancies 67. Management of SLE flares in pregnancy Prednisone IV Pulse methylprednisolone NSAIDs ( during 1st trimester ) Plaquenil Azathioprine Cyclosporine 68. THANK YOU