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SYSTEMIC LUPUS ERYTHEMATOSUS

Vincenzo Berghella

KEY POINTS

Diagnosis: 4/11 AmericanRheumatologic Association

criteria.

Preconception counseling: Feto-neonatal and maternal

complications are primarily seen in

systemic lupus erythematosus

(SLE) patients with active disease

periconception or patients with

hypertension, renal, heart, lungs orbrain disease, or antiphospholipid,

or SSA/SSB antibodies. Therefore,

it is recommended to screen for all

above, and to start pregnancy with

SLE in remission. Optimize

medical therapy preconception.

Laboratories: Complete bloodcount (CBC) with platelets,

transaminases, creatinine, BUN,

anti-Ro (SSA) and anti-La (SSB),anticardiolipin antibodies (ACA),

lupus anticoagulant (LA) or dilute

Russell's viper venom time

(DRVVT), anti beta-2

glycoprotein-I, antinuclear

antibodies (ANA), antids DNA,

C3, C4, urine sediment, 24-hour

urine for total protein and

creatinine clearance.

If stable with no recent flares onazathioprine and/orhydroxychloroquine (Plaquenil), it

is recommended to continue them

in pregnancy and postpartum. Keep

at lowest possible efficacious dose

of medications, including steroids.

For women with Antiphospholipidsyndrome, see chapter 26.

Women with antiSSA/Ro or antiSSB/La antibodies have a 2% to

5% risk of congenital heart block

(CHB); preventive screening andtherapy for CHB are not evidence

based. Women with fetuses with

CHB should be managed anddelivered at a tertiary care center

with the availability of immediate

neonatal pacing.

HISTORIC NOTES

In the 1950s, SLE 5-year survival:50%

In 1990s, 10-year survival: 95%.DIAGNOSIS

American Rheumatologic Association

(ARA) criteria: need 4 out of the

following 11 criteria to make diagnosis of

SLEeither serially or simultaneously (1).

1. Malar rash2. Discoid rash3. Photosensitivity4. Oral ulcerspainless5.

Arthritis (nonerosive, involvingtwo or more peripheral joints)

6. Serositis: pleuritis or pericarditis,conjunctivitis

7. Renal disorder: persistentproteinuria >0.5 g/day, or cellular

casts

8. Neurologic disorder: seizure orpsychosis

9. Hematologic disorder: hemolyticanemia with reticulocytosis, or

leukopenia 4000/mm3, orlymphopenia 1500/mm3, or

thrombocytopenia 100,000/mm3.

10.Immunologic disorder: positivelupus erythematosus cell

preparation, or antidoublestranded

(ds) DNA, or anti-Smith (SM)

antibody, or false-positive

serologic test for syphilis.

11.Antinuclear antibodies (ANA) inabnormal titers.

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SYMPTOMS

See the 11 diagnostic criteria. Also general

(fatigue, fever, malaise, weight loss); GI

(anorexia, ascites, vasculitis); thrombosis,

Raynaud's phenomenon, among others.

EPIDEMIOLOGY / INCIDENCE

1:700 to 2000 general population(1:200 in African Americans).

90% in women. 1/500 inchildbearing age.

ANA : positive in 95 % of SLEpatients, but not specific or

pathognomonic.

Anti ds DNA : positive in 70 % ofSLE Patiens, associated with

clinical activity/flare, renal disease.

Anti-SSA/Ro antibody : positive in30 % of SLE patients, associated

with congenital heart block (CHB)

( see below) neonatal lupus,

Sjogrens syndrome.

Anti-SSB/La antibody; positive in10 % of SLE patients; associated

with CHB, neonatal lupus,Sjogrens syndrome.

Anticardiolipin antibodies (ACA):positive in 50 % of SLE patients.

Associated with antiphospholipid

syndrome (APS) (see chapter 23),

thrombosis.

Lupus anticoagulant (LA) ;positive in 26 % of SLE patients,

associated with APS (Chapter 23),

fetal growth restriction (FGR), fetal

death and preeclampsia. 25 % of SLE patients meet criteria

for APS (see chapter 23)

Anti-SM : positive in 30 % of SLEpatients specific for SLE.

Anti RNP : positive in 40 % ofSLE patients, associated with

neonatal lupus, mixed connective

tissue (CT) disease.

Anti centromere : 90 % inCREST variant of scleroderma.

ETIOLOGY / BASIC

PATHOPHYSIOLOGY

Autoantibody (Ab) to fixed tissue antigen

(Ag) in vessel wall, nucleus, cytoplasmic

membranes, etc.; Ag-Ab complexes inserum.

COMPLICATIONS

Maternal

Hypertension and pre eclampsia

(20 50 %), preterm birth (PTB) 30 50

% (spontaneus premature preterm

rupture of membranes [PPROM] and

preterm labor [PTL] and indicated),gestational diabetes mellitus.

Fetal / neonatal

Increased incidence of first-

trimester spontaneous pregnancy loss (10

20%), fetal death (130 %), FGR (10

20%), CHB (see below), neonatal lupus

(see below).

These adverse outcomes areprimarily seen in SLE patients with active

disease periconceptionally, or in patients

with hypertension, renal, cardiac,

pulmonary or neurologic

disease, or antiphospholipid antibodies.

APS is associated with most fetal deaths in

SLE. Renal disease is present in 50% of

SLE patients. Lupus nephritis and APS are

associated with higher incidence of PTL

and hypertensive disorders. Above

complications may also be seen morefrequently in multiple pregnancies with

SLE.

PREGNANCY CONSIDERATIONS

Effect of pregnancy on SLE

Pregnancy usually does not affect

long-term prognosis of SLE. Incidence of

flares varies widely, depending on the

definition of flare, patient selection, and

clinical status at conception. About 50% ofpatients will have measurable lupus

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activity during pregnancy. Flares can occur

in any trimester, but are most common in

late pregnancy and postpartum. Most flares

in pregnancy are mild (90%),

musculoskeletal, and hematologic.

Prednisone 20 mg only is usuallyrequired for severe flares.

Effect of SLE on pregnancy

Increased incidence of

complications (see above). If renal SLE,

50% have hypertension, 10% to 30%

worsening but usually reversible renal

disease. If creatinine 1.3 mg/dL, and/or

creatinine clearance 50 mL/min, and/or

proteinuria >3 g in 24 hourpreconceptionally, there is small risk of

irreversible renal deterioration.

MANAGEMENT

Principles

Over 90% of women without end-

organ disease or antiphospholipid

antibodies (APAs) do well, and take home

babies. Goal: pregnancy with SLE in

remission. Start pregnancy with SLE in

remission. To achieve this, usually need to

optimize medical therapy

preconceptionally. Most drugs are safe

(see below), and should be continued

throughout pregnancy.

WorkUp

Baseline prenatal laboratory testsshould include the following (Table 25.1) :

CBC with platelets, transaminases,

creatinine, blood urea nitrogen (BUN),

anti-Ro (SSA), anti-La (SSB), ACA, LA,

anti-beta 2-glycoprotein-I, ANA, antids

DNA, C3, C4, urine sediment, 24-hour

urine for total protein and creatinine

clearance.

Differential Diagnosis

Distinguish SLE flare from

preeclampsia includes the following: C3,

C4 ( in SLE), and antids DNA ( in

SLE), urine sediment (red and white cellsand cellular casts seen in SLE).

Gestational age (GA) at onset of

symptoms is also helpful, with

preeclampsia usually only after 24 weeks.

Preconception Counseling

Review all of above with patient

and family, especially diagnosis, risks and

complications, and management. Evaluate

by history, physical exam, and laboratorytests. Obtain records. Discuss current

medications. To insure pregnancy is

conceived with SLE quiescent, encourage

patient to wait at least six months without

flares/active disease before attempting

conception. If stable with no recent flares

on azathioprine and/or

hydroxychloroquine, it is recommended to

continue them in pregnancy and

postpartum. Keep at lowest possible

efficacious dose of steroids. Discuss

contraception. Consider multidisciplinary

management with a rheumatologist.

Prenatal Care

For women with positive

antiphospholipid antibody, see chapter 26.

Treatment decisions are based on the past

obstetric history and any history of prior

thromboembolic events. Identify andmanage risk factors for early pregnancy

loss. The use of medications to treat or

suppress SLE flares will need to be

evaluated on an individual basis. If

patients have been maintained on

medication(s) throughout the pregnancy,

these should be continued through the

postpartum period. Counsel regarding

avoiding excessive sun exposure or

fatigue.

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Therapy

NSAIDs (non- steroidal anti

inflammatory drugs)

Safe up to 28 to 30 weeks. Side

effects: fetal ductal closure and

oligohydramnios, especially after 30

weeks.

Corticosteroids

Mechanism of action: increase

antibody levels. Prednisone: 5 - 80 mg

usual daily dose. Try to keep maintenancedoses 20 mg/day. For treatment of flares,

usually need 60 mg/day for three weeks.

Safe in pregnancy (metabolized by

placenta, does not cross it). Animal studies

report facial clefts. Safe for breast-feeding.

High doses: risk of diabetes (perform early

glucola),and of PPROM. Taper if used

more than seven days. Stress steroids in

active labor up to one dose post delivery (

hydrocortisone 100 mg IV q8h) are

indicated only if steroid therapy in

pregnancy for > 14 days (to prevent

Addisonian collapse [very rare] general

malaise, nausea/vomiting, skin changes).

Side effects: increased bone loss,

especially together with heparin (give

calcium).

Azathioprine ( Azasan,Imuran)

Daily 50 to 100 mg orally ordivided bid. Increase after six to eight

weeks. Safe in pregnancy. FGR

association is probably due to SLE, not

azathioprine. It induces chromosomal

breaks, which disappear as infant grows.

Hydroxycholoroquine sulfate

(Plaquenil)

Antimalarian drug. 400 to 600 mg orally

daily, then 200 to 400 mg daily.Probably safe in pregnancy. If stopped, 2.5

times risk of flare compared to placebo.

Important not to stop drug

periconceptionally. No long-term effects.

Safe in breast-feeding.

Other Agents

Acethaminophen (paracetamol):

safe throughout pregnancy, but usually not

as effective as other therapies. Avoid

cyclophosphamide, methotrexate,

penicillamine, and mycophenolate mofetil,

which are not safe in pregnancy.

Plasmapheresis is a last resort, consult

rheumatologist.

Antepartum testing

Accurate gestational age

assessment is important; therefore, a first-

trimester ultrasound examination is

indicated.

Fetal growth can be evaluated

throughout the pregnancy with ultrasound

examinations every 46 weeks. For

women with anti SSA/Ro, and/or anti-

SSB/La antibodies, see CHB below. A

fetal echocardiogram is indicated if CHB,

arrhythmia or hydropic signs are detected.

Patients in whom disease activity is

quiescent, and there is no evidence of

hypertension, renal disease, FGR, or

preeclampsia, can begin weekly fetal

testing at 34 to 36 weeks' gestation.

Patients with active disease,

antiphospholipid antibodies, renal disease,

hypertension, or FGR can begin

antepartum testing earlier, for example, 30

to 32 weeks.

Delivery

Stress dose steroids are indicated

only if steroid use > 14 days during

pregnancy ( see corticosteroids above).

Postpartum/breastfeeding

Flares are more common.

Continue, and consider increasing SLEtherapies.

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CONGENITAL HEART BLOCK

Incidence

About 2% - 5% of SSA/SSB positivewomen.

Etiology

Anti-SSA/Ro and anti-SSB/La

antibodies cause myocarditis and fibrosis

in the atrioventricular (AV) node and

bundle of His regions.

Counseling

Usually permanent, with

pacemaker needed. One-third of untreated

CHB infants die within three years

(sudden death). There is about a 1533 %

recurrence in future siblings.

Complications: congestive heart failure

(hydrops).

MANAGEMENT

Prevention

If at high CHB risk given presence of anti

SSA/Ro dan/or anti-SSB/La

antibodies,consider following with serial

echocardiography about every 2 weeks

from about 16 to 32 weeks to look for

prolonged PR (AV) interval and any

dysrhythmia, especially looking for

incomplete ( first or second) degree block.

The fetal mechanical PR interval ismeasured from simultaneous mitral and

aortic Doppler waveforms. If incomplete

block is detected, consider therapy with

dexamethasone (4 mg orally) to prevent

progression to complete (third) degree

block. This screening may not be cost

effective, given CHB is uncommon in

prospective series even with positive anti-

SSA/Ro and/or anti-SSB/La antibodies

and is not evidence based.

Prenatal Care

Fetal echocardiography: 1020 %

of CHB have a congenital heart detect

(CHD) and not anti-SSA/Ro dan/or anti-

SSB/La antibodies, but 95% of CHBwithout CHD have anti-SSA/Ro and/or

anti-SSB/La antibodies.

Therapy

A complete (third degree) CHB,

this is considered to be irreversible. The

effectiveness of steroids,beta-

mimetics,digoxin or intravenous

immunoglobulin (IVIG) or any other

therapy to normalize conduction orimprove outcome has not been confirmed

in any trial. Women with fetuses with

CHB should be managed and delivered at

a tertiary care center with the availability

of immediate neonatal pacing.

Delivery

While trial of labor (TOL) by

repeated scalp sampling to assure fetal

well-being can be attempted, TOL is often

difficult to manage clinically.

NEONATAL LUPUS

Transient neonatal SLE, that results from

maternal immunoglobulin G (IgG) passing

through the placenta. Usually, neonatal

lupus occurs in 10% of ati SSA/Ro

and/or anti-SSB/La positive pregnancies.

Thus, prophylaxis is not indicated.Female:Male ratio = 14:1. Not always

mother has diagnosis of SLE. Most cases

are cutaneous (transient rash) and have

thrombocytopenia. Can also have other

hematological,CHB,etc., complications.

Can last for 14 to 16 weeks. The Neonatal

death rate is 1% to 2%.