Systemic lupus erythematosus overview

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Systemic lupus erythematosus overview

  1. 1. SYSTEMIC LUPUS ERYTHEMATOSUS - AN OVERVIEW - Dr. Parvez Khan - Dr. Deepak Kapoor Assistant Professors, M - 1 Department of Internal Medicine Deccan College of Medical Sciences
  2. 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. 3. 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
  4. 4. Epidemiology in the young and elderly Peak incidence is at age 15-40 But: Onset may be at any age In pre-pubertal and post menopausal: female : male ratio 3:1
  5. 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. 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 some ethnic groups (possibly responsible for impaired IC clearing)
  7. 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. 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. 9. Environmental Factors Ultraviolet light ( UVB ) Alfalfa sprouts, chemicals ( hydrazines) ? Drugs (Resprim = Trimethoprim + sulphamethoxazole) Infections (parvovirus, CMV, HCV ) Smoking ( Discoid LE )
  10. 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 Immune Complexes they form with Ag mediate tissue damage Defective clearance of Immune Complexes Defects in immune tolerance and apoptosis Defects in T and natural killer regulatory cells
  11. 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. 12. Clinical Manifestations of SLE Constitutional non-specific but very common: - Fatigue - Fever - Weight Loss
  13. 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. 14. Butterfly- malar rash
  15. 15. Generalized, photosensitive erythema
  16. 16. Bullous rash
  17. 17. Subacute cutaneous rashpsoriatiform annular
  18. 18. Discoid rash
  19. 19. Skin ManifestationsLE-nonspecific lesions  Panniculitis  Urticarial lesions  Vasculitis  Livedo reticularis  Oral lesions  Non-scarring alopecia
  20. 20. Panniculitis
  21. 21. Vasculitis with finger tip ulcers
  22. 22. Livedo reticularis
  23. 23. Alopecia (diffuse or patchy)Non-scarring if part of SLE flareScarring if results from discoid
  24. 24. Skin biopsy:Lupus band test = immunofluorescent staining ofIgG and complement deposits in dermo-epidermal junction
  25. 25. Skin biopsy - SLE dermatitisThickened epidermal basement membrane (large arrows)Inflammatory infiltrates (small arrow)
  26. 26. Skin biopsy - Discoid lesionHyperkeratosis (small arrow)Lymphoid infiltrates (thick arrow)Fibrosis of deep dermis F
  27. 27. Musculoskeletal Manifestations Arthritis: - the most common manifestation of SLE - non-erosive, rarely deforming (Jaccoud’s deformity) - synovial fluid- mild inflammation - tenosynovitis-may be early manifestation Myopathy: - myositis = true inflammation - myopathy 2nd to drugs: steroids, anti-malarials
  28. 28. Jaccoud’s arthropathy
  29. 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. 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 focal subendothelial immune deposits)  Class IV - Diffuse proliferative segmental LN (IV-S) - Diffuse proliferative global LN (IV-G) (> 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. 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, HTN nephritic sediment, mild-mod proteinuria, acute GFR - Class V: features of nephrotic syndrome, preserved/ gradual GFR
  32. 32. Serositis in SLE  Pleuritis - occurs in 30-60% of patients  Pericarditis - occurs in 20-30%  Peritonitis
  33. 33. Cardiac Manifestations Pericarditis Myocarditis Endocarditis (Libman -Sacks endocarditis) Coronary heart disease
  34. 34. Pulmonary Manifestations Pleuritis Pneumonitis - acute or chronic Pulmonary hemorrhage - due to vasculitis Pulmonary hypertension Pulmonary embolism
  35. 35. Hematologic Manifestations Anemia: - in acute SLE: coomb’s positive hemolytic anemia - secondary to: chronic disease, CRF, blood loss, drugs. Leukopenia / Lymphopenia: - in active disease - secondary to drugs, infection
  36. 36. Hematologic Manifestations Thrombocytopenia: - anti-platelet abs- common, not always associated with thrombocytopenia - occurs in active SLE - may be isolated finding ( ~ 50,000 without serious bleeding )
  37. 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 plex intracranial pressure) - Myasthenia Gravis- Movement disorder (chorea) - Neuropathy, cranial- Myelopathy - Plexopathyy- Seizure disorder - Polyneuropathy- Acute confusional state- Anxiety disorder- Cognitive dysfunction- Mood disorder The American College of Rheumatology- Psychosis Nomenclature and case definitions for Neuropsychiatric lupus syndromes . Arthritis & Rheumatism 1999
  38. 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. 39. Patterns of IF ANA staining Homogenous (diffuse) - dsDNA, histone SLE, drug induced SLE, RA Speckled MCTD, SLE, Sjogren, Systemic Sclerosis Nucleolar Systemic Sclerosis, Sjogren, SLE Rim (peripheral) - dsDNA histones characteristic of SLE
  40. 40. Patterns of Immuno-fluorescence ANAstaining
  41. 41. ANAsANA’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
  42. 42. AUTOANTIBODIES IN SLE: Autoantibody Prevalence  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. 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. 44. Clinical Associations of Auto-antibodies 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 Antiphospholipid 30-40 Thrombosis antibodies Recurrent fetal loss
  45. 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. 46. Classification criteria of SLECriterion Definition1. Malar Rash - Fixed erythema, malar distribution - Erythematous raised patches with2. Discoid rash scaling, 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 OR cellular casts7. Renal disorder - Seizures OR Psychosis8. Neurologic - Hemolytic anemia OR disorder Leukopenia < 4000/ mm3 OR9. Hematologic Lymphopenia <1500/mm3 OR disorder Thrombocytopenia < 100.000/mm3
  47. 47. Classification criteria of SLECriterion Definition10. Immunologic disorder - anti-dsDNA OR - anti- Sm OR - false positive VDRL / anti-phospholipid antibody11. Anti-nuclear antibody Abnormal titer of ANA in absence of drugs known to cause DIL For diagnosis: any 4 of 11 criteria
  48. 48. MANAGEMENT OF SLE
  49. 49. The Challenge  Treat Active Lupus  Prevent Damage from: - Active lupus - Corticosteroids - Immunosuppressive agents
  50. 50. Treatment of active SLEOrgan 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
  51. 51. Treatments for SLE  NSAIDs  Corticosteroids  Hydroxychloroquine (Plaquenil)  Chloroquine (Aralen) Antimalarials  Quinacrine ( Mepacrine; Atabrine)  Methotrexate  Azathioprine  Cyclophosphamide  Cyclosporine  Mycophenolate Mofetil (Cellcept)  IVIG  Thalidomide
  52. 52. 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 1g methylprednisolone sometimes used for refractory nephritis or life threatening disease
  53. 53. Corticosteroids- the price: Avascular Necrosis of Bone Osteoporosis with Fracture Hypertension, Hyperglycemia Premature Atherosclerosis Quality of life: Weight, Cushingoid Habitus, Mood changes
  54. 54. Anti-MalarialsHydroxychloroquine, Chloroquine, Quinacrine Effective for the treatment of : Fatigue, Arthritis, Skin disease Prevents SLE flares Lowers cholesterol levels Anti-aggregant effect
  55. 55. Methotrexate  May be effective as a steroid sparing agent in the treatment of: - arthritis - skin disease
  56. 56. Immunosuppressive agentsAzathioprine, Cyclophosphamide, Cyclosporine, Cellcept Used mainly for nephritis May be used for major organ involvement - Azathioprine: P.O. 2-3mgkg - Cyclophosphamide : IV pulses 0.5-1.0gr/m2 q month than q3 months for 2-3 yrs- Cyclosporine: P.O. 1-3mgkgd- Mycophenolate Mofetil (Cellcept) : P.O. 1-3grd
  57. 57. Treatment of Lupus Nephritis Induction: - Corticosteroids - IV Cyclophosphamide q month - Mycophenolate Mofetil (Cellcept) ? Maintenance: - IV Cyclophosphamide q 3 mo - Azathioprine - Mycophenolate Mofetil ( Cellcept ) - Cyclosporine
  58. 58. Cyclophosphamide side effects Infection - frequency - 45% - sequential infusions - WBC < 3000 Premature ovarian failure - cumulative dose - age: < 25 yrs - 6% > 31 yrs - 67% Malignancy leukemia, gynecologic malignancies, bladder
  59. 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. 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 16 4- Partial remission: 21 17- Death 0 3- Severe infections 1 6- Diarrhea 15 2Conclusion:- MMF more effective than CTX in inducing remission- severe infections : less with MMF
  61. 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. 62. Future possible treatments for SLE Treatments 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 B cells Anti C5 complement C1q immunoadsorption: removes immune complexes Anti CD 20 (Rituximab):CD20 is B cells restricted ag- leads to B cell depletion Anti-BLyS: anti B Lymphocyte Stimulator protein which is elevated in SLE
  63. 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. 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. 65. Pregnancy Outcomes in SLEJohns Hopkins Cohort Fertility rates: normal 2-2.4 pregnanciespatient Preterm < 37 weeks 40.5% < 36 weeks 32.1% Pregnancy loss 10-30% 1st trimester 6.0% 2nd trimester 7.1%
  66. 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. 67. Management of SLE flares in pregnancy Prednisone IV Pulse methylprednisolone NSAIDs ( during 1st trimester ) Plaquenil Azathioprine Cyclosporine
  68. 68. THANK YOU

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