Connective Tissue

Disorders
Irma A. Lee, MD, MHPEd
Department of Obstetrics and Gynecology
March 2, 2011
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
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
Autoantibodies
! Antibodies directed against self or normal
tissues
! Maybe stimulated by bacterial or viral injury of
susceptible tissues tissue destruction
VIA
1. 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
Systemic Lupus
Erythematosus
! Heterogenous syndrome with genetic
loci is on 1q and 6p
! Overactive ! lymphocytes
autoantibody production
! Prevalent in women; 1:500 during
child-bearing
Table 54-1
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.
Table 54-3
Table 54-2
Laboratory Findings
! Screening
- Antinuclear antibody (ANA) highly
sensitive but not specific
! Specific test for Lupus
- Double stranded DNA (dsDNA)
- Smith (Sm)

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
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 </= 1.5 mg/dl; proteinuria is <
3g/24hr and BP is controlled.
SLE Nephritis
! Proteinuria is the most common
presentation (75%),followed by hematuria
or aseptic pyuria (40%), and followed by
urinary cast (33%).
! Diffuse proliferative glomerulopnephritis
most common and most serious histologic
category.
! ! of women experienced renal deterioration
! 50% fetal loss rate if creatinine is >1.5mg/dl

Preeclampsia vs Lupus Nephritis
! It is difficult to differentiate SLE from
preeclampsia
! HPN and proteinuria common in all
women with SLE
! Superimposed preeclampsia is encountered
in those with nephropathy

Fetal Outcome
! Pregnancy loss
associated with APS , LAC
! Preterm delivery
HPN, renal compromise and PROM
! IUGR
! IUFD
APS, hx of fetal death, active disease at
the time of conception, lupus
nephropathy, HPN
Neonatal Outcome
! Congenital heart block
- anti SSA/Ro antibody
- anti SSB/La antibody
! Neonatal Cutaneous Lupus
! Hematologic
hemolytic anemia, leukopenia,
thrombocytopenia
- usually transient
Management
! Antepartum surveillance
- BPS, NST, CST, Doppler velocimetry
! !C3, C4 and CH50 associated with active
disease
! Hemolysis (+) Coombs test, anemia,
reticulocytosis, unconjugated hyperbilirubinemia
! Thrombocytopenia
! Leukopenia
! Urine test
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 SLE
ex. Nephritis, neurologic involvement,
thrombocytopenia, hemolytic anemia,
cutaneous manifestations
Pharmacologic Treatment
! Immunosuppression
- azathioprine
! Antimalarial
- interfere with normal phagocytic
function and antigen processing, inhibit
platelet aggregation and reduce serum
lipids
- hydroxychloroquine
SYSTEMIC SCLEROSIS
(SCLERODERMA)
! Multisystem disease with fibrosis and
thickening of the skin and visceral
organ due to accumulation of collagen

TYPES OF SYSTEMIC SCLEROSIS
1. Overlap Syndrome Systemic
Sclerosis with features of other
connective tissue disease
2. Mixed Connective Tissue Disease
Syndrome with Lupus, Systemic
Sclerosis, Polymyositis, Rheumatoid
Arthritis, high titers of Anti-RNP
antibodies
CLINICAL MANIFESTATIONS
! Reynauds Phenomenon
! Swelling of distal extremities and face
! Fullness & epigastric burning pain
! Dyspnea
! Renal
! CREST
MATERNAL COMPLICATIONS
1. Hypertension
2. Renal Failure
3. Cardio-pulmonary complications as a
result of pulmonary interstitial fibrosis
with vasculopathy " Pulmonary
hypertension
FETAL COMPLICATIONS
1. Preterm deliveries
2. Fetal growth restriction
3. Increase perinatal deaths
GOALS OF THERAPY
1. Improve organ function
2. Relieve symptoms
DRUG THERAPY
1. Corticosteroids myositis,
pericarditis, hemolytic anemia
2. ACE Inhibitors relief of hypertension
and renal failure
A P A S
Autoimmune disorder characterized by
circulating antibodies against
membrane phospholipid and one or
more specific clinical syndromes
Classification
! Primary APS
# occurs alone with associated thrombo-
embolic phenomena, thrombocytopenia,
adverse obstetrical outcome
! APS secondary to SLE, drugs, infections,
malignancies
-


Proposed mechanisms in pregnancy loss in
APS
TARGET
! Eicosanoids
! Antithrombin III
! Protein C & S
! Endothelial cells
and platelets
! Annexin V
MECHANISM
Decrease prostacyclin & increase in
thromboxane 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 APL
antibodies
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 titer
ACA IgG, history of fetal demise, prednisone
therapy
! Preterm delivery (25-40%) secondary to PPROM in
patients 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%

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 insufficiency
c. > 3 consecutive spontaneous abortions < 10 weeks

International Consensus Statement on
Preliminary Criteria for
Classification of APS
Wilson, Arthritis Rheuma 1999
Classification Criteria for the
Antiphospholipid Antibody Syndrome
Clinical
! Thrombosis
# Unexplained venous arterial, or small vessel
thrombosis in any organ or tissue
! Pregnancy
# One or more unexplained fetal losses after 10
weeks
# 3 or more consecutive abortions before 10
weeks
# Preterm delivery for severe preeclampsia
# Placental insufficiency before 34 weeks
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 platelet
neutralization procedure
# Identified twice at least 6 weeks apart
Laboratory Criteria for Definite APS
1. Lupus Anticoagulant (LAC)
# > 2 6 weeks apart
# Prolonged phospholipid-dependent coagulation
(aPTT, DRVVT, KCT, DPTT, Textarin Time)

2. Anticardiolipin Antibodies (ACA)
# > 2 6 weeks apart
# Medium to high titer IgG or IgM by ELISA






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

! Low titer ACA IgG
0-3% non-pregnant women
2-4% of pregnant women
4-5% with single unexplained early pregnancy
loss
! Moderate to High titer ACA IgG
5 20% > 3 spontaneous pregnancy losses
Prevalence of ACA

Indications to Identify Lupus Anticoagulant and
Antiphospholipid Antibodies
! Recurrent pregnancy loss
! Unexplained 2
nd
or 3
rd
trimester 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
Adverse Effects
! Arterial and venous thrombosis
! Autoimmune thrombocytopenia
! Fetal loss
! Preeclampsia
! IUGR
! Placental insufficiency
! Preterm delivery
Management of Classical APS

# Risks of fetal loss
# Thrombosis or stroke
# Preeclampsia
# IUGR
# Preterm delivery
1. Preconception Counseling

Management of Classical APS

# Prevention of pregnancy loss
# Thromboprophylaxis
# Prevention of complications of placental
insufficiency
# Postpartum treatment


2. Treatment Regimens

Treatment Guidelines
! Low dose aspirin, 80mg daily
- blocks the conversion of arachidonic acid to
thromboxane A2 while sparing prostacyclin
! Heparin, 5000-10,000 units SC q 12 hours
- prevent venous and arterial thrombotic
episodes
! Glucocorticoids use only if with connective
tissue disorder
! Immunoglobulin therapy 0.4 g/kg daily for 5
days
- use when 1
st
line therapies have failed
Treatment Guidelines
! Calcium and Vitamin D
- prevent osteoporosis
! Fetal antepartum surveillance
- fetal growth monitoring
- Biophysical profile scoring
- NST, CST
- Doppler velocimetry
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 significant
adverse events


Empson et al
ACOG January 2002
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.
Rheumatoid Arthritis
! Genetic predisposition
! Cigarette smoking increase the
risk
! Protective effect of pregnancy
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
American College of Rheumatology Revised 1987
Criteria for Classification of Rheumatoid Arhtritis
1. Morning joint stiffness
2. Arthritis of 3 or more joints
3. Arthritis of wrist, metacarpophalangeal joint
or proximal interphalangeal joint
4. Symmetrical arthritis
5. Rheumatoid nodules
6. Serum rheumatoid factor
7. Radiographic changes
Management
! Pain relief
! Reduction of inflammation
! Protection of articular
structures
! Preservation of function


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
Thank You