The document discusses autoimmune disease in pregnancy. It notes that autoimmune diseases involve the immune system attacking the body's own tissues. When autoimmune diseases occur during pregnancy, careful monitoring is needed as disease activity may be exacerbated or confused with normal pregnancy symptoms. For lupus specifically, outcomes are best if the disease is inactive prior to conception and complications like preeclampsia are avoided. Active management includes monitoring for signs of lupus flares or preeclampsia through laboratory tests and urine analysis.

1. Autoimmune disease in
pregnancy
주산기 김윤영

2. Autoimmune disease
• inappropriate immune response of the body against substances
and tissues normally present in the body
• In other words, the immune system mistakes some part of the
body as a pathogen and attacks its own cells
• The treatment of autoimmune diseases is typically with
immunosuppression medication which decreases the immune
response.

3. • Categories of Autoimmune Disease

7. Introduction
• Connective-tissue disorders, collagen-vascular disorders,
Immune-complex diseases, autoimmune disease
– generalized clinical findings
– autoantibody-mediated connective-tissue abnormalities
– sterile inflammation
– rheumatic diseases : skin, joints, blood vessels, kidneys
– primarily affect women
– disorders of bone, skin, cartilage, blood vessels, basement
membranes.
– Marfan syndrome, osteogenesis imperfecta, Ehlers-Danlos
syndrome.

8. Immune-Mediated Connective-Tissue Diseases
• pathogenesis has not been elucidated
• immune-mediated disorders
– associated with and those without autoantibody formation.
– rheumatoid factor
• autoantibody found in many autoimmune inflammatory
conditions.
• systemic lupus erythematosus(SLE), rheumatoid
arthritis(RA), systemic sclerosis (scleroderma), mixed
connective-tissue disease, dermatomyositis, polymyositis,
variety of vasculitis syndromes.

9. Immune-Mediated Connective-Tissue Diseases
• immune-mediated disorders can be separated into those clearly
– not display rheumatoid factor : seronegative
spondyloarthropathies
• strongly associated with the presence of the HLA-B27
antigen
• ankylosing spondylitis(AK), psoriatic arthritis, Reiter disease,
arthritis syndromes associated with ulcerative colitis and
Crohn disease.
• renal involvement is common and often adversely affects
pregnancy, a search for coexisting renal involvement is paramount.
• Hypertension likewise is common, and exacerbation during
pregnancy frequently forces early delivery
• In some of these immune-mediated diseases, antiphospholipid
antibodies are formed that can cause injury to maternal
vasculature and to the placenta.

10. Immunological Aspects
• The immune system
– protect cells, tissues, and organs perceived as self
– to attack and destroy foreign or nonself antigenic material by the
production of antibodies.
• This protection has two phases.
– innate phase : broad, rapid, mediated through neutrophils,
macrophages, and complement.
– adaptive phase : antigen-specific reactions through T and B
lymphocytes that result in memory for future exposures
• For some as yet unknown reason, the immune system may be
stimulated to begin producing antibodies directed against self or
normal tissues. These "misdirected" antibodies are called
autoantibodies.
• The stimulus responsible for their production is unknown, but
may be due to bacterial or viral injury to genetically susceptible
tissues.

11. Immunological Aspects 2
• Autoantibodies induce destruction by at least two mechanisms.
– The cytotoxic mechanism : antibody attachment to a specific
surface antigen→cell injury, destruction.
– The immune-complex mechanism : antigen-antibody complex
attaches to a susceptible tissue.
• incite a complement response or cascade, resulting in the
release of chemotactic substances that attract
polymorphonuclear cells.
• The major histocompatibility complex (MHC) :40 to 50 genes
located on the short arm of chr6
:human leukocyte antigen (HLA) complex.

12. Immunological Aspects 2
• These genetic loci code for distinct cell-surface glycoproteins,
including transplantation antigens, and are involved in self and
nonself recognition.
– Class I antigens include HLA-A, -B, and -C.
– Class II antigens include HLA-DR, -DQ, and -DP.
– Through complex interactions that include T- and B-cell
stimulation and interaction with immunoglobulins and the
complement system, nonself antigens or, in the abnormal
state, self antigens in normal tissue are destroyed.

13. Immune-Mediated Disease and Pregnancy
• Very few immune disorders arise only during pregnancy.
• Maternal isoimmunization from fetal red cell or platelet
antigens is the most common
– Some theories of the causes of preeclampsia-eclampsia and
recurrent abortion implicate an immunological basis.
• Some pregnancy-induced immune alterations may
modulate connective-tissue disorders
– the predominance of T2 helper cells over the cytokine-
producing T1 helper cells
– these immunological changes have negligible effects on
immune-mediated collagen-vascular disorders, the effects of
large amounts of estrogen, progesterone, and prolactin must
be considered.
– For example, estrogens upregulate and androgens
downregulate T-cell response, and a number of cytokines are
regulated by sex
– Progesterone is an immunosuppresive

14. SLE
Systemic Lupus Erythematosus (SLE)
• heterogeneous autoimmune disease
• complex pathogenesis
• interactions between susceptibility genes
and environmental factors that cause an
abnormal immune response
• include overactive B lymphocytes that are
responsible for autoantibody production.
• tissue and cellular damage when
autoantibodies or immune complexes are
directed at one or more cellular nuclear
components

15. SLE
Clinical Findings
• notoriously variable in its presentation, course, and
outcome
• Clinical manifestations may be confined initially to one
organ system, with others becoming involved as the disease
progresses
• Alternatively, lupus may initially manifest by multisystem
involvement.
• Common findings are malaise, fever, arthritis, rash,
pleuropericarditis, photosensitivity, anemia, cognitive
dysfunction.
• At least half of patients have renal involvement.
• These valvular lesions may cause thromboembolic seeding
but uncommonly lead to hemodynamic dysfunction
• There is also evidence that lupus is associated with decline
in attention, memory

16. SLE
Clinical Manifestations of Systemic Lupus Erythematosus
Organ System Clinical Manifestations Percent
Systemic Fatigue, malaise, fever, weight loss 95
Musculoskeletal Arthralgias, myalgias, polyarthritis, 95
myopathy
Hematological Anemia, hemolysis, leukopenia, 85
thrombocytopenia, lupus anticoagulant,
splenomegaly
Cutaneous Malar (butterfly) rash, discoid rash, 80
photosensitivity, oral ulcers, alopecia,
skin rashes
Neurological Cognitive dysfunction, mood disorder, 60
headache, seizures

17. SLE
Clinical Manifestations of Systemic Lupus Erythematosus
Organ System Clinical Manifestations Percent
Cardiopulmonary Pleuritis, pericarditis, myocarditis, 60
pneumonitis, Libman-Sacks
endocarditis, pulmonary hypertension
Renal Proteinuria, casts, nephrotic syndrome, 30–50
renal failure
Gastrointestinal Anorexia, nausea, pain, diarrhea 40
Vascular Thrombosis: venous (10%), arterial (5%) 15
Ocular Conjunctivitis 15

18. SLE
Laboratory Findings
• antinuclear antibodies(ANA):best screening test, not specific for lupus.
• Antibodies to double-stranded DNA (dsDNA) and to Smith (Sm)
antigens are relatively specific for lupus, whereas other antibodies are
not
• Anemia is common, and there may be leukopenia and
thrombocytopenia.
• Proteinuria and casts are found in the half of patients with glomerular
lesions, and there may be renal insufficiency.
• Nephropathy is more common when antiphospholipid antibodies are
found
• Other laboratory findings : false-positive syphilis serology, prolonged
partial thromboplastin time, positive serum rheumatoid factor assay.
• Elevated serum D-dimer levels commonly follow a flare or infection,
but unexplained persistent elevations are associated with a high risk for
thrombosis

19. SLE
• Some autoantibodies produced in patients with lupus
Antibody Prevalence Clinical Associations
(percent)
Antinuclear 84–98 Best screening test, multiple antibodies; a
(ANA) second negative test makes SLE unlikely
Anti-double- 62–70 High titers SLE-specific; may correlate with
stranded (ds)- nephritis and vasculitis activity
DNA
Anti-S 30–38 Specific for SLE
Anti-RNP 33–40 Not SLE specific, correlates with myositis,
esophageal dysmotility; a defining antibody for
mixed-connective tissue disease
Anti-Ro (SS-A) 30–49 Not SLE specific; associated with Sjögren
syndrome, cutaneous lupus, ANA-negative lupus,
neonatal lupus with heart block

20. SLE
• Some autoantibodies produced in patients with lupus
Anti-La (SS-B) Prevalence Clinical Associations
(percent)
Anti-La (SS-B) 10–35 Present in SLE—possibly decreased
risk of nephritis; Sjögren syndrome,
neonatal lupus with heart block
Antihistone 70 Common in drug-induced lupus (95%)
Antiphospholipid 21–50 Lupus anticoagulant and
anticardiolipin antibodies associated
with thrombosis, fetal loss,
thrombocytopenia, valvular heart
disease; false-positive test for syphilis
Antierythrocyte 60 Overt hemolysis uncommon
Antiplatelet 30 Thrombocytopenia in 15%; poor
clinical test

21. SLE
Diagnosis
Criteria Comments
Malar rash Malar erythema
Discoid rash Erythematous patches, scaling, follicular plugging
Photosensitivity Exposure to UV light causes rash
Oral ulcers Usually painless oral and nasopharyngeal ulcers
Arthritis Nonerosive involving two or more peripheral joints
Serositis Pleuritis or pericarditis
aIf
four or more criteria are present at any time during disease course, SLE can
be diagnosed with 75-percent specificity and 95-percent sensitivity.

22. SLE
Criteria Comments
Renal disorder Proteinuria greater than 0.5 g/day or > 3+ dipstick, or
cellular casts
Neurological Seizures or psychosis without other cause
disorders
Hematological Hemolytic anemia, leukopenia, lymphopenia, or
disorders thrombocytopenia
Immunological Anti-dsDNA or anti-Sm antibodies, or false-positive VDRL,
disorders abnormal level of IgM or IgG anticardiolipin antibodies, or
lupus anticoagulant
Antinuclear Abnormal titer of ANAs
antibodies
aIf
four or more criteria are present at any time during disease course, SLE can
be diagnosed with 75-percent specificity and 95-percent sensitivity.

23. SLE
Drug-Induced Lupus
• Numerous drugs have been reported to
induce a lupus-like syndrome.
• procainamide, quinidine, hydralazine, -
methyldopa, phenytoin, phenobarbital.
• rarely associated with glomerulonephritis
• usually regresses when the medication is
discontinued

24. SLE
Lupus and Pregnancy
• an incidence of approximately 1 in 1250 pregnancies
: nearly 16.7 million pregnancies in the United States from 2000
to 2003, 13,555 were complicated by lupus
• Over the past several decades, pregnancy outcomes in women
with SLE have improved remarkably.
• Important factors for pregnancy outcome include whether
antibodies are detected disease is active at the beginning of
pregnancy, age and parity, coexistence of other medical or
obstetrical disorders, and whether antiphospholipid
• During pregnancy, lupus improves in a third of women, remains
unchanged in a third, and worsens in the remaining third.
• It is certain that lupus can be life threatening to both the
mother and her fetus-infant.

25. SLE
Complications in 13,555 Pregnancies in Women with
Systemic Lupus Erythematosus
Complications (%)
Comorbid illness
Pregestational diabetes (5.6)
Thrombophilia (4.0)
Hypertension (3.9)
Renal failure (0.2)
Pulmonary hypertension (0.2)
Pregnancy complications
Preeclampsia (22.5)
Preterm labor (20.8)
Fetal-growth restriction (5.6)
Eclampsia (0.5)

26. SLE
Complications in 13,555 Pregnancies in Women with
Systemic Lupus Erythematosus
Complications (%)
Medical complications
Anemia (12.6)
Thrombocytopenia (4.3)
Thrombotic—stroke, pulmonary embolism, deep-vein thrombosis (1.7)
Infections—pneumonia, sepsis syndrome (2.2)
Maternal morbidity-mortality rate 325/100,000

27. SLE
• In general, pregnancy outcome is better if:
– Lupus activity has been quiescent for at least 6
months before conception
– There is no active renal involvement manifest by
proteinuria or renal dysfunction
– Superimposed preeclampsia does not develop
– There is no evidence of antiphospholipid antibody
activity.

28. SLE
Lupus versus Preeclampsia-Eclampsia
• Chronic hypertension complicates up to 30% of pregnancies in
women with SLE
• preeclampsia is common, and superimposed preeclampsia is
encountered even more often in those with nephropathy and in
women with antiphospholipid antibodies
• difficult, if not impossible, to differentiate lupus nephropathy
from severe preeclampsia if organs other than the kidney are
not involved
• ↓complement values, ↑ anti-DNA titers : not useful to identify
worsening lupus activity
• diagnosis of a reactivation of lupus nephritis, termed renal flare.
• Central nervous system involvement with lupus may culminate in
convulsions similar to those of eclampsia.
• Thrombocytopenia, with or without hemolysis, may further
confuse the diagnosis because of its similarity to the hemolysis,
elevated liver enzymes, low platelet count (HELLP) syndrome

29. SLE
Management during Pregnancy
• monitoring the maternal clinical and laboratory conditions as well
as fetal well-being.
• Pregnancy-induced thrombocytopenia and proteinuria resemble
lupus disease activity,
• identification of a lupus flare is confounded by the increase in
facial and palmar erythema of normal pregnancy
• Monitoring of lupus activity and identification of pending lupus
flares
– The sedimentation rate may be misleading because of pregnancy-
induced hyperfibrinogenemia.
– Serum complement levels are also normally increased in pregnancy
– Falling or low levels of complement components C3, C4, and CH50 are
more likely to be associated with active disease, higher levels provide
no assurance against disease activation.
– no correlation between clinical manifestations of disease and
complement levels.

30. SLE
• Serial hematological studies may detect changes in disease
activity.
– Hemolysis : positive Coombs test, anemia, reticulocytosis,
unconjugated hyperbilirubinemia.
– Thrombocytopenia, leukopenia, or both may develop.
– chronic thrombocytopenia in early pregnancy may be due to
antiphospholipid antibodies.
– Later, thrombocytopenia may indicate the onset of
preeclampsia.
– Serum transaminase activity reflects hepatic involvement, as
does a rise in serum bilirubin.
– Azathioprine therapy also may induce enzyme elevations
– Urine is tested frequently to detect new-onset or worsening
proteinuria.
– Overt proteinuria that persists is an ominous sign, even more
so if accompanied by other evidence of the nephrotic
syndrome or abnormal serum creatinine levels.

31. SLE
• The fetus should be closely observed for adverse effects. Fetal
growth is monitored, and careful attention is given to the
development of hypertension.
– screening for anti-SS-A and anti-SS-B antibodies, and if found,
fetal cardiac function should be evaluated.
– Although we routinely evaluate the fetus for arrhythmias, we
do not screen for these antibodies.
– Unless hypertension develops or there is evidence of fetal
compromise or growth restriction, pregnancy is allowed to
progress to term.
– Peripartum corticosteroids in "stress doses" are given to
women who are taking these drugs or who recently have
done so.

32. SLE
Pharmacological Treatment
• no cure, complete remissions are rare
• Approximately ¼ of patients : mild disease-not life threatening, but may
be disabling because of pain and fatigue.
– Arthralgia, serositis are managed by NSAID including aspirin.
– the risk of premature closure of the fetal ductus arteriosus, therapeutic doses
probably should not be used after 24 weeks
– Low-dose aspirin throughout gestation.
• Severe disease -corticosteroids such as prednisone, 1 to 2 mg/kg per day.
– After the disease is controlled, this dose is tapered to a daily dose of 10 to 15 mg
each morning.
– Corticosteroid therapy can result in the development of gestational or even type 1
diabetes.
• Long-term antibody-based immunoadsorption : in pregnancy for removal
of autoantibodies and lipoproteins in women with serious complications
who did not respond to conventional therapy

33. SLE
• Immunosuppressive agents(azathioprine): beneficial in controlling
active disease
– nonpregnant patients: reserved for lupus nephritis or disease
that is steroid resistant.
– Azathioprine has a good safety record during pregnancy
– daily oral dose is 2 to 3 mg/kg.
– cyclophosphamide : teratogenic,
• not usually recommended during pregnancy
• severe disease may be treated after 12 weeks.
– Antineoplastic Agents and Immunosuppressants, other
medications to be avoided include mycophenolate mofetil and
methotrexate

34. SLE
• Antimalarials
– help control skin disease.
– cross the placenta, hydroxychloroquine has not been
associated with congenital malformations.
– long half life
• When severe disease supervenes—usually a lupus flare—high-
dose glucocorticoid therapy is given.
– methylprednisolone, 1000 mg given intravenously over 90
minutes daily for 3 days, then a return to maintenance doses
if possible.

35. SLE
Perinatal Mortality and Morbidity
• Adverse perinatal outcomes are increased significantly in
pregnancies complicated by lupus.
– preterm delivery, fetal-growth restriction, stillbirths, and neonatal
lupus.
– Outcomes are worse with a lupus flare; significant proteinuria; renal
impairment; and with chronic hypertension, development of
preeclampsia, or both
– In a mouse SLE model, they showed that autoantibodies directed
against the N-methyl-D-aspartate neuroreceptor caused fetal
neurotoxicity and speculate that this might account for the high
incidence of learning disorders in children of affected mothers.
• The reasons at least partially responsible for adverse fetal
consequences include decidual vasculopathy with placental
infarction and decreased perfusion
• Anti-SS-A (Ro) and anti-SS-B (La) antibodies may damage the
fetal heart and conduction system, causing neonatal death

36. SLE
Neonatal Lupus
• unusual syndrome
• skin lesions, or lupus dermatitis; a variable number of hematological and
systemic derangements; and occasionally congenital heart block
• usually associated with anti-SS-A and -SS-B antibodies
– affected infant in whom only anti-RNP antibodies were found.
• Thrombocytopenia and hepatic involvement is seen in 5-10 %.
• neonatal lupus may appear up to 4 weeks after birth
• prospectively followed 91 infants born to women with lupus. Four had
definite neonatal lupus and four had possible disease.
• Clinical manifestations:cutaneous lupus, thrombocytopenia, autoimmune
hemolysis, are transient and clear within a few months
• The recurrence risk in subsequent offspring for neonatal lupus is 25 %.

37. SLE
Congenital Heart Block
• This fetal complication results from diffuse myocarditis and
fibrosis in the region between the atrioventricular (AV) node and
bundle of His.
• congenital heart block occurred almost exclusively in fetuses of
women with antibodies to the SS-A or SS-B antigens.
• cause otherwise unexplained stillbirths
• the presence of such antibodies, the incidence of arrhythmia is
only 3 percent.
• The cardiac lesion is permanent, and a pacemaker is generally
necessary.
• Long-term prognosis : poor, 1/3 affected infants die within 3
years
• The risk of recurrence in subsequent offspring is 10-15 %
• Maternal corticosteroid administration to treat fetal heart block is
controversial.

38. SLE
Long-Term Prognosis and Contraception
• women with lupus and chronic vascular or renal disease
should limit family size because of morbidity associated
with the disease as well as increased adverse perinatal
outcomes.
– combination oral contraceptives (COCs) did not increase the
incidence of lupus flares
– COC use be avoided in women who have nephritis,
antiphospholipid antibodies, or a vascular disease.
– Progestin-only implants and injections also provide effective
contraception with no known effects on lupus flares.
– Concerns that intrauterine device (IUD) use and
immunosuppressive therapy lead to increased infection rates
in these patients are not evidenced based.
– Tubal sterilization may be advantageous and is performed with
greatest safety postpartum or whenever the disease is
quiescent.

39. APS
Antiphospholipid Antibodies
• Phospholipids are the main lipid constituents of
cell and organelle membranes.
• Several antibodies directed against these various
phospholipids and to proteins bound to
phospholipids have been described.
• These antibodies include lupus anticoagulant
(LAC) and anticardiolipin antibodies (ACAs). They
may be of IgG, IgM, and IgA classes, alone or in
combination.
• Cardiolipin is but one of many phospholipids
and is found in mitochondrial membranes and
platelets.

40. APS
Antiphospholipid Antibodies
• Phospholipids are the main lipid constituents of cell and organelle
membranes.
• Several antibodies directed against these various phospholipids
and to proteins bound to phospholipids have been described.
• antibodies
– lupus anticoagulant (LAC) anticardiolipin antibodies (ACAs).
– IgG, IgM, and IgA classes, alone or in combination.

41. APS
Clinical Features
• Antiphospholipid antibodies
– may be found in asymptomatic patients with or without lupus,
– associated with the antiphospholipid antibody syndrome (APS).
– recurrent arterial or venous thromboses, thrombocytopenia,
and fetal losses—especially stillbirths—during the second half
of pregnancy
• may develop alone or in association with lupus or other
autoimmune disorders.
• Central nervous system involvement is one of the most
prominent clinical manifestations and includes
– arterial and venous thrombotic events,
– psychiatric features, and other
– nonthrombotic neurological syndromes

42. APS
Clinical Features
• Renovascular involvement may lead to renal failure, and it may be
difficult to differentiate from lupus nephitis
• may mimic the presentation of multiple sclerosis.
• reported a woman who developed spontaneous cecal perforation
postpartum presumably from antibody induced infarction.

43. APS
Association of Antiphospholipid Antibodies with
Lupus
• lupus anticoagulant(LAC) or antiphospholipid antibodies, or
both
• LAC have higher levels of antiphospholipid antibodies
• 1/3 biological false-positive tests for syphilis have ACAs
• Only about 20% of patients with identifiable ACAs also have
LAC.
• in patients with lupus, documentation of either ACA or LAC is a
risk factor for thrombosis, neurological disorders, and
thrombocytopenia
• Autoimmune Factors, these antibodies have also been
associated with excessive pregnancy loss

44. APS
Antiphospholipid Antibodies and Normal
Pregnancy
• 5 % of all healthy nonpregnant : nonspecific antiphospholipid
antibodies in low titers.
– 0.3%(2/ 737)- lupus anticoagulant
– 2.2%(16/737)–↑ concentrations of either IgM- or IgG-ACAs.
– 1.8%(26/1449) consecutive pregnant women and found
– 1.8 % were positive for IgG-ACAs and
– 4.3 % for IgM-ACAs.
– 0.1%(1/933) -ACAs,
– 11–1.2 %–with LACs
– 0.2%(2/933)- ACAs, LACs
– 7 %o860 pregnant Japanese women had ACAs.
• Taken together, these studies totalling almost 4000 normal
pregnancies reported an
average prevalence of 4.7 %—the same as normal nonpregnant
individuals.

45. APS
Diagnosis of Antiphospholipid Antibody
Syndrome (APS)
Clinical
Thrombosis Unexplained venous, arterial, or small vessel thrombosis
in any organ or tissue
Pregnancy One or more unexplained fetal losses after 10 weeks;
three or more consecutive miscarriages before 10 weeks;
or preterm delivery for severe preeclampsia or placental
insufficiency before 34 completed weeks
Laboratory
Anticardiolipin IgG or IgM isotypes in medium to high titers at least 6
antibodies weeks apart
Lupus Identified twice, at least 6 weeks apart
anticoagulant

46. APS
Pathophysiology of Antiphospholipid
Antibodies in Pregnancy
• The combination of lupus anticoagulant
and high levels of ACAs : decidual
vasculopathy, placental infarction, fetal-
growth restriction, early-onset preeclampsia,
and recurrent fetal death.
• high incidence of venous and arterial
thromboses, cerebral thrombosis, hemolytic
anemia, thrombocytopenia, and pulmonary
hypertension

47. APS
Mechanism of Action
• It is not precisely known how these antibodies cause damage,
• actions are multifactorial.
– platelets may be damaged directly by antiphospholipid antibody or indirectly
by binding 2-glycoprotein I, which causes platelets to be susceptible to
aggregation.
– phospholipid-containing endothelial cell or syncytiotrophoblast membranes
may be damaged directly by the antiphospholipid antibody or indirectly by
antibody binding to either 2-glycoprotein I or annexin V
– This prevents the cell membranes from protecting the syncytiotrophoblast
and endothelium and results in exposure of basement membrane.
– It is known that damaged platelets adhere to exposed basement membrane
of endothelium and syncytiotrophoblast and result in thrombus formation
– antiphospholipid antibodies decreased decidual production of the
vasodilating prostaglandin E2.
– Decreased protein C or S activity and increased prothrombin
– presented evidence that thrombosis with APS is due to activation of the tissue
factor pathway.
– uncontrolled placental complement activation by antiphospholipid antibodies
may play a role in fetal loss and growth restriction

48. APS
Adverse Pregnancy Outcomes
• antiphospholipid antibodies are associated with increased rates of
fetal wastage
• data currently are too limited to draw precise conclusions
concerning the impact of these antibodies on adverse pregnancy
outcomes.
• women with higher antibody titers have worse outcomes
compared with those with low titers
• unexplained fetal deaths are examined, ACAs do not appear to
play a significant role.
• history of recurrent pregnancy loss, those with antiphospholipid
antibodies had a higher rate of preterm delivery
• Despite a worse pregnancy outcome, there was no evidence of
greater endothelial cell activation during pregnancy in women
who were receiving treatment for APS .

49. APS
Treatment Guidelines
• current treatment recommendations may be confusing to the clinician).
• The schema discussed in Diagnosis of Antiphospholipid Antibody
Syndrome (APS) is used to semiquantify antibody levels that bind
immunoglobulins G, M, and A.
• GPL, MPL, and APL binding units are expressed as negative, low-positive,
medium-positive, or high-positive
• Low-positive titers of GPL or MPL anticardiolipin antibodies are of
questionable clinical significance.
• And any titer of APL antibodies has no known relevance at this time.
• Antiphospholipid Antibodies, women with prior thromboembolic events
who have antiphospholipid antibodies are at risk for recurrence in
subsequent pregnancies.

50. APS
Treatment Guidelines
• close antepartum observation with or without prophylactic- or
intermediate-dose heparin, and some form of postpartum
anticoagulation for 4 to 6 weeks.
• women with medium- or high-positive ACA titers or those with LAC
activity and a previous second- or third-trimester fetal death not
attributable to other causes should also be treated
• Similarly, Immunological Factors , some report that women with recurrent
early pregnancy loss and medium- or high-positive titers of antibodies
may benefit from therapy

51. APS
• Aspirin
– 60 to 80 mg daily,
– blocks arachidonic acid → thromboxane A2
– reduced thromboxane A2 : platelet aggregation and vasoconstriction,
– no major side effects from low-dose aspirin other than a slight risk of small-vessel
bleeding during surgical procedures.
• Heparin
– Unfractionated heparin, subcutaneously, 5000 to 10,000 units every 12 hours.
– measurement of heparin levels because clotting tests may be altered by LAC
– to prevent venous and arterial thrombotic episodes
– To prevents thrombosis in the microcirculation, including the decidual-trophoblastic
interface
– binds to 2-glycoprotein I : prevents binding of anticardiolipin and anti-2-
glycoprotein I antibodies to their surfaces, which likely prevents cellular damage
– complications : bleeding, thrombocytopenia, osteopenia, osteoporosis.

52. APS
<<Immunotherapy>>
• Glucocorticoids :
– should not be used with primary APS
– secondary APS seen with lupus, the dose of prednisone should be maintained at the lowest
effective level to prevent flares.
– adverse effects : osteopenia, osteoporosis, and pathological fractures. impede wound healing,
and they induce gestational and overt diabetes
• Immunoglobulin therapy :overt disease, heparin-induced thrombocytopenia, or both.
• when other first-line therapies have failed, especially in the setting of preeclampsia and
fetal-growth restriction
• IV, 0.4 g/kg daily for 5 days—total dose of 2 g/kg. repeated monthly, or it is given as a
single dose of 1 g/kg each month.
• not been well evaluated,
• Azathioprine, cyclosporine do not appear to improve standard therapies
• methotrexate, cyclophosphamide, mycophenolate mofetil : contraindicated because of
teratogenic potential

53. APS
• Low-Dose Aspirin Plus Heparin
– the most efficacious therapy
– low-dose heparin—7500 to 10,000 units
subcutaneously, twice daily
– concurrently with low-dose aspirin, 60 to 80
mg once daily
– If active lupus coexists, then prednisone is
usually also given.

54. APS
Effect of Treatment on Perinatal Loss
• recurrent fetal loss is still 20-30% even with treatments described above.
•
• 23/32 women with a prior fetal death and antiphospholipid antibody
levels greater than 40 IgG units had a recurrent fetal death despite
treatment with prednisone, aspirin, or both.
• with lupus and antiphospholipid antibodies have normal pregnancy
outcomes without treatment.
• women with LAC and prior bad pregnancy outcomes have had liveborns
without treatment
• 30 percent of neonates demonstrate passively acquired antiphospholipid
antibodies, there is concern for any adverse effects.
– suggest possible increased learning disabilities.
– reported a fourfold increased risk for perinatal strokes in these infants.
– More data are needed before firm conclusions can be drawn.

55. RA
Rheumatoid Arthritis
• chronic multisystem disease of unknown cause
• immunologically mediated pathogenesis
• Infiltrating T cells secrete cytokines that mediate
inflammation and systemic symptoms.
• prevalence is about 0.8%
• women : three times more often than men
• inflammatory synovitis, the peripheral joints.
• cartilage destruction, bony erosions, and joint
deformities.
• Onset is generally between 35 and 50 years.

56. RA
Diagnostic criteria
American College of Rheumatology Revised 1987 Criteria for
Classification of Rheumatoid Arthritis
1. Morning joint stiffness
2. Arthritis of three or more joint areas
3. Arthritis of wrist, metacarpophalangeal joint, or proximal interphalangeal
joint
4. Symmetrical arthritis
5. Rheumatoid nodules
6. Serum rheumatoid factor
7. Radiographic changes
Four of seven criteria required for
diagnosis.
Criteria 1-4 must be present for at least 6
weeks.
Criteria 2-5 must be observed by a
physician.

57. RA
• association with the class II major
histocompatibility complex molecule
HLA-DR4 and HLA-DRB1 alleles
• Cigarette smoking also appears to
increase the risk of rheumatoid arthritis
in women
•

58. RA
• Clinical Manifestations
– chronic polyarthritis
– synovitis, fatigue, anorexia, weakness, weight
loss, depression, vague musculoskeletal
symptoms.
– hands, wrists, knees, and feet are commonly
involved.
– Pain: aggravated by movement+ swelling,
tenderness.
– Extra-articular manifestations: rheumatoid
nodules, vasculitis, pleuropulmonary symptoms.

59. RA
Management
• pain relief, reduction of inflammation
• protection of articular structures, preservation of function.
• Physical and occupational therapy and self-management instructions are
essential.
• Aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs)
– symptomatic therapy
– not retard progression of disease.
– inhibit cyclooxygenase-1 (COX-1)—an enzyme critical to normal platelet function
– Inhibit COX-2—an enzyme which mediates inflammatory response mechanisms.
• Side effect: Gastritis with acute bleeding
• Specific COX-2 inhibitors have been used to avert this complication
• long-term use of COX-2 inhibitors is associated with increased
myocardial infarction, stroke, and heart failure
• risks versus benefits of these medications must be considered.

60. RA
• Glucocorticoid therapy may be added to NSAIDs : 7.5 mg of prednisone daily for the
first 2 years of active disease substantively reduces progressive joint erosions
• NSAIDs and glucocorticoids : primarily for symptomatic relief,
• recommends disease-modifying antirheumatic drugs (DMARDs).
– the potential to reduce or prevent joint damage
– within 3 months of diagnosis
– variety of DMARDs, and many have considerable toxicity: hydroxychloroquine, sulfasalazine,
leflunomide, and methotrexate, tumor necrosis factor alpha (TNF-) inhibitors, etanercept (Enbrel),
adalimumab (Humira), and infliximab (Remicade),
• 300 reported cases in their review with no fetal effects.
• interleukin-1 receptor antagonist, anakinra (Kineret), and the antagonist to the B-cell
CD20 antigen, rituximab (Rituxan), are now available.
• azathioprine, penicillamine, gold salts, minocycline, and cyclosporine.
• Orthopedic surgery for joint deformities, including replacement, is commonly performed.

61. RA
Pregnancy and Rheumatoid Arthritis
• improves in up to 90% of affected women during pregnancy
• some women develop disease during pregnancy
• others become worse
• postpartum exacerbation is common
• flare was more common if women were breast feeding.
– prospective study in the United Kingdom, and 140 women recruited
during the last trimester were seen at 1 and 6 months postpartum.
There was only a modest fall in objective disease activity.
– Only 16 percent: complete remission.
– At least 25 percent : substantive levels of disability.
– although overall disease actually did not exacerbate postpartum, the
mean number of inflamed joints increased significantly.

62. RA
• protective effect of pregnancy for women developing subsequent
new-onset rheumatoid arthritis.
• protective effect of pregnancy in the long term, the likelihood of
new-onset rheumatoid arthritis was increased sixfold during the
first 3 postpartum months.
• significant reduction in the risk of subsequent arthritis in women
who breastfed longer than 12 months
• developed rheumatoid arthritis—a prevalence of 0.7%(619/87,000)
• twofold increased risk for its development in women with infants
born weighing more than 4540 g.

63. RA
Juvenile Rheumatoid Arthritis
• the most common cause of chronic arthritis in
children.
• They persist into adulthood
• Pregnancy had no effects on presentation of
disease
• disease activity became quiescent or remained
so during pregnancy.
• Postpartum flares were common
• Joint deformities were common: 15 of 20
cesarean deliveries were done for contracted
pelvis or joint prostheses.

64. RA
Perinatal Outcome
• no obvious adverse effects of rheumatoid
arthritis on pregnancy outcome, including
preterm labor
• women with rheumatic disease with two
previous poor pregnancy outcomes were at
high risk for recurrent adverse outcomes.
• later develop the disease have had a
higher-than-expected incidence of
spontaneous abortion

65. RA
Management during Pregnancy
• Treatment of symptomatic women during
pregnancy :aspirin and NSAIDs
• concerns for impaired hemostasis, prolonged
gestation, premature closure of the ductus arteriosus
• Low-dose corticosteroids
• Gold compounds : 14 women experiencing 20
pregnancies on gold therapy, 75 percent delivered
healthy liveborns

66. RA
• Immunosuppressive therapy
– azathioprine, cyclophosphamide, methotrexate
– not routinely used during pregnancy.
• only azathioprine should be considered during early pregnancy
– because the other agents are teratogenic as discussed previously
• TNF- drugs are considered category B for pregnancy, although data with
regard to safety for a developing human fetus are limited
• Leflunomide is a pyrimidine synthesis inhibitor used for rheumatoid
arthritis in nonpregnant patients. It is teratogenic in animals, and it is
detectable up to 2 years in plasma after discontinuation
• not been shown to be teratogenic for humans, but it should be avoided.

67. RA
• Contraception
– Combination oral contraceptives : logical
choice
– effectiveness and the possibility that they
might improve rheumatoid arthritis

68. scleroderma
Systemic Sclerosis (Scleroderma)
• chronic multisystem disorder of unknown
etiology
– microvascular damage
– immune system activation leading to inflammation
– excessive deposition of collagen in the skin and
often in the lungs, heart, gastrointestinal tract, and
kidneys.
• typically affects those aged 30 to 50 years

69. scleroderma
Clinical Course
• overproduction of normal collagen
• limited cutaneous systemic sclerosis—progression is slow.
• diffuse cutaneoussystemic sclerosis
• skin thickening progresses rapidly
• skin fibrosis is followed by gastrointestinal tract fibrosis : especially the distal esophagus
– esophageal involvement, especially fullness and epigastric burning pain
• Pulmonary interstitial fibrosis along with vascular changes may cause pulmonary
hypertension.
– Pulmonary involvement is common and causes dyspnea.
• Antinuclear antibodies are found in 95% patients, and immunoincompetence is common.
• Raynaud phenomenon : in 95%, as well as swelling of the distal extremities and face.
• Mortality rates are high with renal or pulmonary involvement
• 10-year survival rate is less than 50 percent.

70. scleroderma
Pregnancy and Systemic Sclerosis
• prevalence of about 1 in 22,000 pregnancies : 504/11.2 million
• stable disease during gestation if their baseline function is good.
• dysphagia and reflux esophagitis are aggravated by pregnancy
• Symptomatic treatment
• renal insufficiency, malignant hypertension have an increased incidence of superimposed
preeclampsia. In the presence of rapidly worsening renal or cardiac disease, pregnancy
termination should be considered.
• Pulmonary hypertension usually contraindicates pregnancy
• Vaginal delivery may be anticipated, unless the soft tissue thickening wrought by
scleroderma produces dystocia requiring abdominal delivery.
• Tracheal intubation for general anesthesia has special concerns because of limited ability
of these women to open their mouths widely
• Because of esophageal dysfunction, aspiration is also more likely, and epidural analgesia
is preferable.

71. scleroderma
Pregnancy Outcomes
• Maternal and fetal outcomes: related to the severity of underlying
disease.
• 1/3 women had exacerbations of symptoms during pregnancy
• The maternal mortality rate :15 %
– due to hypertension, renal failure, or cardiopulmonary complications.
• The fetal mortality rate : 20 %
– Steen and colleagues (1989, 1999) reported more optimistic outcomes in 214
women with systemic sclerosis, 45 percent of whom had had diffuse disease.
– Major complications included renal crisis in three women.
– increased rates of preterm birth.
– Chung and colleagues (2006) also reported
– increased rates of preterm delivery, fetal-growth restriction, perinatal mortality.
– related to placental abnormalities that include decidual vasculopathy, acute
atherosis, and infarcts.
– These reduce placental blood flow and are found in many cases

72. scleroderma
• Contraception
– Scleroderma may be associated with subfertility
– several reversible contraceptive methods are
acceptable.
– hormonal agents, especially combination oral
contraceptives should not be used, especially in
women with pulmonary, cardiac, or renal
involvement.
– Due to the progressive and often unrelenting
nature of progressive systemic sclerosis,
permanent sterilization should also be
considered

73. Vasculitis
Syndromes
Vasculitis Syndromes
• Inflammation and damage to blood vessels may be primary
or due to another disease.
• immunopathogenic mechanisms, specifically, immune-
complex deposition
• difficult to classify because of overlap.
• Primary causes
– polyarteritis nodosa
– Wegener granulomatosis
– Churg-Strauss syndrome
– temporal or giant cell arteritis
– Takayasu arteritis
– Henoch-Schönlein purpura
– Behçet syndrome
– cutaneous or hypersensitivity arteritis.

74. Polyarteritis Nodosa
Polyarteritis Nodosa
• uncommon disease with protean manifestations.
• necrotizing vasculitis of small and medium-sized arteries.
• Myalgia, Neuropathy, gastrointestinal disorders, hypertension, renal
disease.
• 1/3 cases are associated with hepatitis B antigenemia
• Symptoms are nonspecific and vague.
– Fever, weight loss, malaise
– Renal failure, hypertension, arthralgias
• Diagnosis is made by biopsy
• treatment consists of high-dose prednisone plus cyclophosphamide.
• Vasculitis due to hepatitis B antigenemia responds to lamivudine

75. Polyarteritis Nodosa
Pregnancy
• Only a few documented cases of polyarteritis nodosa in
association with pregnancy have been reported.
• Although definitive conclusions are unclear, certainly if
active arteritis is identified during pregnancy, mortality rates
are high.
•
– Owen and Hauth (1989) reviewed the courses of
– 12 such pregnant women.
• 7 : polyarteritis first manifested during pregnancy, and it was rapidly
fatal by 6 weeks postpartum.
- The diagnosis was not made until autopsy in six of the seven women.
• 4 : continued pregnancy, resulting in one stillborn and three
successful outcomes.

76. Wegener Granulomatosis
Wegener Granulomatosis
• necrotizing granulomatous vasculitis of the upper and lower respiratory tract and kidney.
• Common lesions
– sinusitis and nasal disease—90 %
– pulmonary infiltrates or nodules—85 %
– glomerulonephritis—75 %
– musculoskeletal lesions—65 percent.
• It is uncommon and usually encountered after 50 years of age.
• The few cases reported in association with pregnancy
• Corticosteroids are the standard treatment.
• For moderate and severe cases in the late second or third trimester, the use of
cyclophosphamide in combination with prednisolone is acceptable.
• Azathioprine, cyclosporine, and intravenous immunoglobulin can also be used.

77. Marfan Syndrome
• common autosomal dominant connective-tissue disorder
• prevalence of 1 in 3000 to 5000
• It affects both sexes equally.
• mutation of the fibrillin-1 (FBN1) gene on the long arm of
chromosome 15
• The FBN1 gene has a high mutation rate, and there are
many mild, subclinical cases.
• In severe disease, degeneration of the elastic lamina in the
media of the aorta.
• This weakness predisposes to aortic dilatation or dissecting
aneurysm that appears more likely in pregnancy
• Aortic dissection may occur after elective cesarean delivery.

78. Ehlers–Danlos Syndrome
• variety of changes in connective tissue, including hyperelasticity of the
skin.
• more severe types, there is a strong tendency for rupture of any of
several arteries to cause either strokes or bleeding.
– Rupture of the colon or uterus has been described.
• several types of disease based on skin, joint, or other tissue involvement.
• Some are autosomal dominant, some recessive, and some X-linked.
• Their aggregate prevalence is about 1 in 5000
• Types I, II, and III are autosomally dominant, and each accounts for about
30 percent of cases.
• Type IV is uncommon, but is known to predispose to preterm delivery,
maternal great-vessel rupture, postpartum bleeding, and uterine rupture
• In most, the underlying molecular defect is that of collagen or
procollagen.

79. • increased frequency of preterm rupture of membranes, preterm delivery,
and antepartum and postpartum hemorrhage
• Tissue fragility makes episiotomy repair and cesarean delivery difficult.
– Sorokin and colleagues (1994) surveyed female members of the Ehlers-Danlos
National Foundation. They reported a
– stillbirth rate of 3 percent,
– preterm delivery rate of 23 percent,
– cesarean delivery rate of 8 percent,
– problematic postpartum bleeding in 15 percent.
• number of cases of spontaneous uterine rupture have been described
• maternal and fetal death from spontaneous rupture of the right iliac
artery was described)
• described a newborn with multiple congenital skull fractures and
intracranial hemorrhage caused by Ehlers-Danlos type VIIC.

80. Effect of pregnancy on autoimmune disease
• Symptoms of an autoimmune disease could improve, worsen,
or remain unchanged when a woman becomes pregnant
depending upon her specific autoimmune disease.

81. Effect of autoimmune disease on fetal outcome
• Premature delivery in lupus and APS
• Fetal loss in lupus, APS and inflammatory arthritis
• Fetal loss and premature delivery in systemic sclerosis
• Fetal loss and premature delivery in the vasculitides

82. Patient Education
• Patients with autoimmune diseases should avoid
pregnancy when the disease is active, especially if it is
of recent onset
• Pregnancy is more likely to be successful, with less
maternal and fetal morbidity and mortality, if the
mother has been in remission for over 6 months in
lupus, the vasculitides and systemic sclerosis

83. 감사합니다.