Autoimmune disease in pregnancy

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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.

• Categories of Autoimmune Disease

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.

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.

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.

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.

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.

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.

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

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

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

SLE

Clinical Manifestations of Systemic Lupus Erythematosus

Organ System Clinical Manifestations Percent

Systemic Fatigue, malaise, fever, weight loss 95

Musculoskeletal

Arthralgias, myalgias, polyarthritis, myopathy

95

Hematological

Anemia, hemolysis, leukopenia, thrombocytopenia, lupus anticoagulant, splenomegaly

85

Cutaneous

Malar (butterfly) rash, discoid rash, photosensitivity, oral ulcers, alopecia, skin rashes

80

Neurological

Cognitive dysfunction, mood disorder, headache, seizures

60

SLE

Clinical Manifestations of Systemic Lupus Erythematosus

Organ System Clinical Manifestations Percent

Cardiopulmonary Pleuritis, pericarditis, myocarditis, pneumonitis, Libman-Sacks endocarditis, pulmonary hypertension

60

Renal

Proteinuria, casts, nephrotic syndrome, renal failure

30–50

Gastrointestinal Anorexia, nausea, pain, diarrhea 40

Vascular Thrombosis: venous (10%), arterial (5%) 15

Ocular Conjunctivitis 15

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

SLE

• Some autoantibodies produced in patients with lupus

Antibody Prevalence (percent)

Clinical Associations

Antinuclear (ANA)

84–98 Best screening test, multiple antibodies; a second negative test makes SLE unlikely

Anti-double-stranded (ds)-DNA

62–70

High titers SLE-specific; may correlate with nephritis and vasculitis activity

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

SLE

• Some autoantibodies produced in patients with lupus

Anti-La (SS-B) Prevalence (percent)

Clinical Associations

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

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

SLE

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.

Criteria Comments

Renal disorder

Proteinuria greater than 0.5 g/day or > 3+ dipstick, or cellular casts

Neurological disorders

Seizures or psychosis without other cause

Hematological disorders

Hemolytic anemia, leukopenia, lymphopenia, or thrombocytopenia

Immunological disorders

Anti-dsDNA or anti-Sm antibodies, or false-positive VDRL, abnormal level of IgM or IgG anticardiolipin antibodies, or lupus anticoagulant

Antinuclear antibodies

Abnormal titer of ANAs

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.

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

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.

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)

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

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.

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

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.

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.

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.

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

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

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.

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

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 %.

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.

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.

SLE

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.

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.

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

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.

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

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.

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 antibodies

IgG or IgM isotypes in medium to high titers at least 6 weeks apart

Lupus anticoagulant

Identified twice, at least 6 weeks apart

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

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

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 .

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.

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

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.

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

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.

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.

APS

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.

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.

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

•

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.

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.

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.

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.

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.

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.

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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

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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

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• 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.

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• Contraception

– Combination oral contraceptives : logical choice

– effectiveness and the possibility that they might improve rheumatoid arthritis

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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

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.

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.

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

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

scleroderma

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.

Vasculitis Syndromes

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

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.

Polyarteritis Nodosa

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.

Wegener Granulomatosis

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.

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.

• 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.

• Symptoms of an autoimmune disease could improve, worsen,

or remain unchanged when a woman becomes pregnant

depending upon her specific autoimmune disease.

Effect of pregnancy on autoimmune disease

• 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

Effect of autoimmune disease on fetal outcome

• 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

Patient Education

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