Immune-Mediated Connective Tissue Diseases

8/10/2019 Immune-Mediated Connective Tissue Diseases

1/68

Irma A. Lee, MD, MHPhEd

Department of Obstetrics and Gynecology

Faculty of Medicine and SurgerySeptember 30, 2011


2/68


3/68

Autoantibodies

- Antibodies directed against self or normal tissues

- Maybe stimulated by bacterial or viral injury ofsusceptible 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


4/68

Human Leukocyte Antigen (HLA) Genetic loci code for cell-surface glycoprotein for

self and non-self recognition

!

Class I HLA-A, HLA-B, HLA-C! Class II HLA-DR, HLA-DQ, HLA-DP


5/68

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


6/68

Table 54-1


7/68

Table 54-2


8/68

Table 54-3


9/68

Laboratory Tests:1. Antinuclear antibody (ANA) best screening

but not specific

2. Double-stranded DNA (dsDNA) antibodies

Smith (Sm) antigen specific for SLE3. CBC anemia, leukopenia, thrombocytopenia

4. Proteinuria, casts

5. APTT

6. Rheumatoid factor assay


10/68

Table 54-4


11/68


12/68


13/68


14/68


15/68

Goals During Pregnancy1. 6 months remission prior to conception

2. No renal involvement

3. Prevent superimposed pre-eclampsia

4. No APA activity


16/68

Major Complications1. Infection

2. Lupus flares

3. End-organ failure

4. Cardiovascular disease


17/68

DRUG-INDUCED LUPUS- Lupus-like syndrome

- Procainamide

- Quinidine

- Hydralazine- Alpha-methyldopa

- Phenytoin

- Phenobarbital


18/68

SLE Nephritis- Proteinuriais the most common presentation

(75%),followed by hematuriaor aseptic pyuria(40%), and followed by urinary cast (33%)

- Diffuse proliferative glomerulopnephritis mostcommon and most serious histologic category

- "of women experienced renal deterioration

- 50% fetal lossrate if creatinine is >1.5mg/dl


19/68

Preeclampsia vs Lupus Nephritis

- It is difficult to differentiate SLE frompreeclampsia

- HPN and proteinuria common in all womenwith SLE

- Superimposed preeclampsia is encountered inthose with nephropathy


20/68

Fetal Outcome- Pregnancy loss

Associated with APS , LAC

- Preterm delivery

HPN, renal compromise and PROM

- IUGR

- IUFDAPS, hx of fetal death, active disease at the

time of conception, lupus nephropathy, HPN


21/68

Neonatal Outcome- Congenital heart block

anti SSA/Ro antibody

anti SSB/La antibody

- Neonatal Cutaneous Lupus

- Hematologic - usually transient

hemolytic anemia, leukopenia,

thrombocytopenia


22/68

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


23/68

Pharmacologic TreatmentAnalgesics

arthralgia, serositis, arthritis, fever- acetaminophen, NSAIDs, aspirin

Corticosteroid therapy- for life threatening manifestations of SLE ex.Nephritis, neurologic involvement,thrombocytopenia, hemolytic anemia, cutaneousmanifestations- Prednisone 1-2mg/kg/day 10-15mg/day


24/68

Pharmacologic TreatmentImmunosuppression

- azathioprine

Antimalarial- interfere with normal phagocytic function andantigen processing, inhibit platelet aggregationand reduce serum lipids

- hydroxychloroquine


25/68


26/68

A P A SAutoimmune disorder characterized by circulating

antibodies against membrane phospholipid andone or more specific clinical syndromes


27/68

Classification

Primary APS

occurs alone with associated

thrombo-embolic phenomena,

thrombocytopenia,

adverse obstetrical outcome


28/68

Classification

APS secondary to:

SLE

Drugs

Infections

Malignancies


29/68

Clinical Manifestations

- Pregnancy wastage due to decidual/placentalthrombosis 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%


30/68

Clinical Criteria for Definite APS

1. Vascular Criteria confirmed by imaging,Doppler, or histopathology

2. Pregnancy Morbiditya. > 1 unexplained death of a normal fetus > 10 weeks

b. > 1 premature births < 34 weeks due to pre-eclampsiaor placental insufficiency

c. > 3 consecutive spontaneous abortions < 10 weeks

International Consensus Statement on

Preliminary Criteria for

Classification of APS

Wilson, Arthritis Rheuma 1999


31/68

Laboratory Criteria for Definite APS

1. Lupus Anticoagulant (LAC)

! > 2 6 weeks apart

! Prolonged phospholipid-dependent coagulation

(aPTT, DRVVT, KCT, DPTT, Textarin Time)


Preliminary Criteria for the




32/68

Laboratory Criteria for Definite APS

2. Anticardiolipin Antibodies (ACA)

! > 2 6 weeks apart

! Medium to high titer IgG or IgM by ELISA


Preliminary Criteria for the




33/68

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 ofthrombosis


34/68

Prevalence of ACA

- 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


35/68


36/68

2. Syndrome of low levels of IgG or IgM ACL antibodiesassociated with fetal death or recurrent, pre embryonic orembryonic pregnancy loss

3. Syndrome of APL other than LA and ACL antibodies

associated with fetal death or recurrent pre embryonic orembryonic pregnancy loss

Classification System for Women with APS

d h l


37/68

Proposed mechanisms in pregnancy lossin APS

TARGET

Eicosanoids

Antithrombin III

Protein C & S

Endothelial cells andplatelets

Annexin V

MECHANISM

Decrease prostacyclin & increase inthromboxane production by endothelial cells

Inhibition of heparan sulfateheparin-dependent activation of antithrombin III

Inhibition of the activation of Protein C-Protein

S- pathwayActivation of endothelial cells & platelets;

expression of adhesion molecules

Reduction of annexin V production, inhibitionof its function in placenta by APL antibodies


38/68

Therapeutic approach to APAS inpregnancy

Objectives:

1. Improve maternal and fetal-neonatal outcomeby preventing pregnancy loss, pre-eclampsia,placental insufficiency and preterm birth

2. Reduce or eliminate maternal thrombotic risk


39/68

Management of Classical APS

! Risks of fetal loss

!Thrombosis or stroke

! Preeclampsia

! IUGR

! Preterm delivery

1.

Preconception Counseling


40/68

Management of Classical APS

! Prevention of pregnancy loss

!Thromboprophylaxis

! Prevention of complications of placentalinsufficiency

! Postpartum treatment

2. Treatment Regimens


41/68

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 tissuedisorder

- Immunoglobulin therapy 0.4 g/kg daily for 5 days- use when 1stline therapies have failed


42/68

Treatment Guidelines

- Calcium and Vitamin D

- Prevent osteoporosis

- Fetal antepartum surveillance

- Fetal growth monitoring

- Biophysical profile scoring

- NST, CST

- Doppler velocimetry


43/68

Thromboprophylaxis


44/68


45/68

Postpartum Treatment

Sodium warfarin for 6 weeks postpartum

Lifelong Anticoagulation 2.5 to 3.0

International Normalized Ratio (INR)

Woman Diagnosed w/APS d i


46/68

APS desires pregnancy

Preconception consultation w/Obstetrician & rheumatologist;

Inititate low dose aspirin

TVS to confirm liveembryo at 5.5-6.5 wks AOG

Initiate heparin treatment

DIAGNOSTIC TESTSCLINICALCARE

Prenatal visit q 2-4 wksuntil 20-24 wks then q

1-2 wks, thereafter

Monitor for fetal death,Preeclampsia & IUGR

Rheumatology visit q 2-4 wks

Obstetric ultrasound q 3-4weeks from 17-20 wks ofgestation

Assess fetal growth and AFI

Fetal surveillance weekly fr30-32 wks earlier if placental

Insufficiency is suspected


47/68


48/68

SYSTEMIC SCLEROSIS (SCLERODERMA)

Multisystem disease with fibrosis and

thickening of the skin and visceral organ

due to accumulation of collagen


49/68

TYPES OF SYSTEMIC SCLEROSIS

1. Overlap Syndrome Systemic Sclerosis withfeatures of other connective tissue disease

2. Mixed Connective Tissue Disease Syndrome

with Lupus, Systemic Sclerosis, Polymyositis,Rheumatoid Arthritis, high titers of Anti-RNPantibodies


50/68

CLINICAL MANIFESTATIONS

- Reynauds Phenomenon

- Swelling of distal extremities and face

- Fullness & epigastric burning pain

- Dyspnea- Renal

- CREST


51/68


52/68

FETAL COMPLICATIONS

1. Preterm deliveries

2. Fetal growth restriction

3. Increase perinatal deaths


53/68

GOALS OF THERAPY

1. Improve organ function

2. Relieve symptoms


54/68


55/68


56/68

TABLE 5-3 page 137


57/68

URINARY TRACT INFECTIONS

1. Asymptomatic bacteriuria

2. Cystitis/Urethritis

3. Pyelonephritis


58/68


59/68


60/68

CYSTITIS AND URETHRITIS

- Dysuria, urgency and frequency

- Pyuria, bacteriuria, hematuria

- 3 day regimen

- Chlamydia Trachomatis!cause of urethritis w/o growth on culture


61/68

ACUTE PYELONEPHRITIS

- Occurs at the 2ndtrimester unilaterally and right-sided

- Characterized by fever, chills, and lumbar pain"CVA tenderness

- Organisms! E.Coli 75-80%! Klebsiella 10%! Enterobacter 10%! Proteus 10%


62/68

ACUTE PYELONEPHRITIS

- Bacteremia!Sepsis syndrome

- Ampicillin + Gentamicin, Cefazolin orCeftriaxone


63/68

FIGURE 42-4 page 994


64/68


65/68

NEPHROLITHIASIS DURING PREGNANCY

- Pregnancy does not increase risk for stoneformation

- Presents with gross hematuria

- Sonography confirms suspected stone

- Intravenous Hydration & Analgesics- Lithotripsy


66/68


67/68

ACUTE NEPHRITIC SYNDROME

- Characterized by hematuria and proteinuria withrenal insufficiency and salt-water retention!edema, hypertension and circulatory congestion

-

Acute poststreptococcal glomerulonephritis

- Membranous IgA and mesangial glomerulonephritisare seen on renal biopsy

- Associated with fetal loss and perinatal mortality,

preterm delivery and growth restriction


68/68

Immune-Mediated Connective Tissue Diseases

Documents