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Systemic Lupus Erythematosus Definition

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					     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.

				
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