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Connective TissueDisorders
Irma A. Lee, MD, MHPEdDepartment of Obstetrics and Gynecology
March 2, 2011
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Systemic Lupus
Erythematosus
! Multisystemic autoimmune rheumatic
diseases with protean and often
complex manifestations
! Chronic or of a relapsing or remitting
form
! Has serious muskuloskeletal, renal
and cardiovascular effects
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Pathogenesis
! SLE occurs when a patient develops
persistent pathogenic autoantibodies
and immune complexes
! These alter the normal anatomy and
function of target tissues and organs
! These gives rise to a constellation of
signs and symptoms
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Autoantibodies
! Antibodies directed against self or normal
tissues
! Maybe stimulated by bacterial or viral injury of
susceptible tissues tissue destruction
VIA1. CYTOTOXIC MECHANISM antibody attachment
to specific surface antigen CELL INJURY
2. IMMUNE COMPLEX MECHANISM antigen-
antibody complex attaches to susceptible tissues
CASCADE OF CHEMOTACTIC RELEASE
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Table 54-1
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Clinical Findings
! May be confined initially to one organ
system, with others being involved as the
disease progresses.
! Alternatively, the disease may initially
manifest by multisystem involvement.
! Common findings are malaise, fever,
arthritis, rash, pleuropericarditis,
photosensitivity, anemia, and cognitive
dysfunction.
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Table 54-3
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Table 54-2
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Laboratory Findings
! Screening
- Antinuclear antibody (ANA) highly
sensitive but not specific
! Specific test for Lupus
- Double stranded DNA (dsDNA)
- Smith (Sm)
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Effect of SLE on Pregnancy
! If no HPN, renal impairment or APS ---
pregnancy outcome is better
! Renal disease HPN developed and
proteinuria worsened! Increase incidence of preeclampsia
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SLE Nephritis
! Require intense fetal and maternal
surveillance
! Pregnancy outcome is better if lupus activity
has been quiescent for at least 6 months
before pregnancy
! Pregnancy outcome is better if at conception
creatinine
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SLE Nephritis
! Proteinuriais the most commonpresentation (75%),followed by hematuriaor aseptic pyuria (40%), and followed byurinary cast (33%).
!
Diffuse proliferative glomerulopnephritismost common and most serious histologiccategory.
! !of women experienced renal deterioration
! 50% fetal lossrate if creatinine is >1.5mg/dl
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Fetal Outcome
! Pregnancy loss
associated with APS , LAC
! Preterm delivery
HPN, renal compromise and PROM
! IUGR
! IUFD
APS, hx of fetal death, active disease atthe time of conception, lupusnephropathy, HPN
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Management
! Antepartum surveillance
- BPS, NST, CST, Doppler velocimetry
! !C3, C4 and CH50 associated with activedisease
!
Hemolysis (+) Coombs test, anemia,reticulocytosis, unconjugated hyperbilirubinemia
! Thrombocytopenia
! Leukopenia
! Urine test
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Pharmacologic Treatment
! Analgesics arthralgia, serositis, arthritis, fever
- acetaminophen, NSAIDs, aspirin
!
Corticosteroid therapy- Prednisone 1-2mg/kg/day 10-15mg/day
- for life threatening manifestations of SLEex. Nephritis, neurologic involvement,thrombocytopenia, hemolytic anemia,cutaneous manifestations
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Pharmacologic Treatment
! Immunosuppression
- azathioprine
!
Antimalarial
- interfere with normal phagocyticfunction and antigen processing, inhibit
platelet aggregation and reduce serum
lipids
- hydroxychloroquine
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SYSTEMIC SCLEROSIS
(SCLERODERMA)
! Multisystem disease with fibrosis and
thickening of the skin and visceral
organ due to accumulation of collagen
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CLINICAL MANIFESTATIONS
! Reynauds Phenomenon
! Swelling of distal extremities and face
!
Fullness & epigastric burning pain
! Dyspnea! Renal
!
CREST
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MATERNAL COMPLICATIONS
1. Hypertension
2. Renal Failure
3.
Cardio-pulmonary complications as a
result of pulmonary interstitial fibrosiswith vasculopathy"Pulmonary
hypertension
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FETAL COMPLICATIONS
1. Preterm deliveries
2. Fetal growth restriction
3.
Increase perinatal deaths
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GOALS OF THERAPY
1. Improve organ function
2. Relieve symptoms
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DRUG THERAPY
1. Corticosteroids myositis,
pericarditis, hemolytic anemia
2.
ACE Inhibitors relief of hypertension
and renal failure
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A P A S
Autoimmune disorder characterized by
circulating antibodies against
membrane phospholipid and one or
more specific clinical syndromes
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Classification
! Primary APS
# occurs alone with associated thrombo-
embolic phenomena, thrombocytopenia,
adverse obstetrical outcome
! APS secondary to SLE, drugs, infections,
malignancies
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Proposed mechanisms in pregnancy loss inAPS
TARGET
! Eicosanoids
! Antithrombin III
! Protein C & S
! Endothelial cells
and platelets
! Annexin V
MECHANISM
Decrease prostacyclin & increase inthromboxane production by endothelial
cells
Inhibition of heparan sulfate heparin-
dependent activation of antithrombin III
Inhibition of the activation of Protein C-Protein S- pathway
Activation of endothelial cells & platelets;
expression of adhesion molecules
Reduce annexin V production, inhibition of
its function in placenta by APLantibodies
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Clinical Manifestations
! Pregnancy wastage due to decidual/placental
thrombosis or immune complex deposition! Pre-eclampsia in 20-30%
! IUGR (50%), associated with moderate to high titerACA IgG, history of fetal demise, prednisonetherapy
!
Preterm delivery (25-40%) secondary to PPROM inpatients on steroids
! Thrombosis (20-60%)
Venous lower limb 55%
Arterial involves the brain in 50%, heart 25%,renal 25%
Vascular occlusion from mitral or aortic valve 49%
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Clinical Criteria for Definite APS
1. Vascular Criteria confirmed by imaging,
Doppler, or histopathology
2. Pregnancy Morbidity
a. > 1 unexplained death of a normal fetus > 10 weeks
b. > 1 premature births < 34 weeks due to pre-eclampsia
or placental insufficiencyc. > 3 consecutive spontaneous abortions < 10 weeks
International Consensus Statement on
Preliminary Criteria for
Classification of APS
Wilson, Arthritis Rheuma 1999
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Classification Criteria for the
Antiphospholipid Antibody Syndrome
Clinical! Thrombosis
# Unexplained venous arterial, or small vesselthrombosis in any organ or tissue
! Pregnancy#
One or more unexplained fetal losses after 10weeks
# 3 or more consecutive abortions before 10weeks
# Preterm delivery for severe preeclampsia
# Placental insufficiency before 34 weeks
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Classification Criteria for the
Antiphospholipid Antibody Syndrome
Laboratory
! Anticardiolipin antibodies
# IgG or IgM isotypes in medium to high titers at
least 6 weeks apart
! Lupus anticoagulant#
Partial thromboplastin time, dilute Russel viper
venom test (dRVVT) and the plateletneutralization procedure
# Identified twice at least 6 weeks apart
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RESULT IgM (MPL) IgG (GPL)
Negative < 10 < 8
Low Positive 10-19 8-19*Mid Positive 20-50 20-80
*High Positive > 50 > 80
ACA (ELISA) : 10-30% of ACA (+) will be LAC (+)
--- predictive of adverse fetal outcome
LAC: 70-80% LAC (+) will be ACA (+)
--- predictive of thrombosis
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! Low titer ACA IgG
0-3% non-pregnant women
2-4% of pregnant women
4-5% with single unexplained early pregnancyloss
! Moderate to High titer ACA IgG
5 20% > 3 spontaneous pregnancy losses
Prevalence of ACA
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Indications to Identify Lupus Anticoagulant andAntiphospholipid Antibodies
! Recurrent pregnancy loss! Unexplained 2ndor 3rdtrimester loss
! Early onset severe preeclampsia
! Venous or arterial thrombosis! Unexplained fetal growth restriction
! Autoimmune or connective tissue disease
! False positive serological test for syphilis
! Prolonged coagulation studies
! Positive autoantibody test
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Management of Classical APS
# Risks of fetal loss
# Thrombosis or stroke
# Preeclampsia
# IUGR
# Preterm delivery
1.
Preconception Counseling
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Management of Classical APS
# Prevention of pregnancy loss
# Thromboprophylaxis
# Prevention of complications of placental
insufficiency
# Postpartum treatment
2. Treatment Regimens
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Treatment Guidelines
! Low dose aspirin, 80mg daily
- blocks the conversion of arachidonic acid tothromboxane A2 while sparing prostacyclin
! Heparin, 5000-10,000 units SC q 12 hours
- prevent venous and arterial thromboticepisodes
! Glucocorticoids use only if with connective
tissue disorder
! Immunoglobulin therapy 0.4 g/kg daily for 5days
- use when 1stline therapies have failed
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Treatment Guidelines
! Calcium and Vitamin D
- prevent osteoporosis
!
Fetal antepartum surveillance
- fetal growth monitoring- Biophysical profile scoring
- NST, CST
- Doppler velocimetry
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Recurrent Pregnancy Loss with Antiphospholipid
Antibody:
A Systematic Review of Therapeutic Trials
! Combination therapy with Aspirin and Heparin may reduce
pregnancy loss in women with antiphospholipid antibodies
by 54%. Further large, randomized controlled trials with
adequate allocation are necessary to exclude significantadverse events
Empson et al
ACOG January 2002
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Rheumatoid Arthritis
! Chronic inflammatory/autoimmune disease
! Characterized by symmetrical polyarthritis of
the small joints of hands and feet
! Cardinal feature is inflammatory synovitis
that usually involves the peripheral joints.! The disease has a propensity for cartilage
destruction, bony erosions, and joint
deformities.
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Rheumatoid Arthritis
! Genetic predisposition
!
Cigarette smoking increase the
risk
! Protective effect of pregnancy
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Clinical Manifestations
! Prodromal phase malaise, weight
loss, arthralgias, or joint stiffness
! The onset is insidous with pain and
swelling in one or more joints in the
upper extremities
! Progression is usually centripetal (from
small joints to large joints)
!
Clinical improvement during pregnancy
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Management
! Pain relief
! Reduction of inflammation
! Protection of articular
structures
! Preservation of function
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Management
! Systemic and articular rest
! Use of heat and cold modalities
! Physical and occupational therapy
! Aspirin or NSAIDs
! COX-2 inhibitors
! Disease modifying antirheumatic drugs
(DMARDs)
! Glucocorticoid therapy
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Thank You