SYSTEMIC LUPUS ERYTHEMATOSUS Vincenzo Berghella

KEY POINTS Diagnosis: 4/11 American Rheumatologic Association criteria. Preconception counseling: Fetoneonatal and maternal complications are primarily seen in systemic lupus erythematosus (SLE) patients with active disease periconception or patients with hypertension, renal, heart, lungs or brain 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 blood count (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 on azathioprine and/or hydroxychloroquine (Plaquenil), it is recommended to continue them in pregnancy and postpartum. Keep at lowest possible efficacious dose of medications, including steroids. For women with Antiphospholipid syndrome, see chapter 26. Women with anti SSA/Ro or anti SSB/La antibodies have a 2% to 5% risk of congenital heart block (CHB); preventive screening and therapy for CHB are not evidence

based. Women with fetuses with CHB should be managed and delivered 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 rash 2. Discoid rash 3. Photosensitivity 4. Oral ulcerspainless 5. Arthritis (nonerosive, involving two or more peripheral joints) 6. Serositis: pleuritis or pericarditis, conjunctivitis 7. Renal disorder: persistent proteinuria >0.5 g/day, or cellular casts 8. Neurologic disorder: seizure or psychosis 9. Hematologic disorder: hemolytic anemia with reticulocytosis, or leukopenia 4000/mm3, or lymphopenia 1500/mm3, or thrombocytopenia 100,000/mm3. 10. Immunologic disorder: positive lupus erythematosus cell preparation, or antidoublestranded (ds) DNA, or anti-Smith (SM) antibody, or false-positive serologic test for syphilis. 11. Antinuclear antibodies (ANA) in abnormal titers.

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

ETIOLOGY / PATHOPHYSIOLOGY

BASIC

Autoantibody (Ab) to fixed tissue antigen (Ag) in vessel wall, nucleus, cytoplasmic membranes, etc.; Ag-Ab complexes in serum. COMPLICATIONS

1:700 to 2000 general population (1:200 in African Americans). 90% in women. 1/500 in childbearing age. ANA : positive in 95 % of SLE patients, but not specific or pathognomonic. Anti ds DNA : positive in 70 % of SLE Patiens, associated with clinical activity/flare, renal disease. Anti-SSA/Ro antibody : positive in 30 % of SLE patients, associated with congenital heart block (CHB) ( see below) neonatal lupus, Sjogrens syndrome. Anti-SSB/La antibody; positive in 10 % 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 pre eclampsia. 25 % of SLE patients meet criteria for APS (see chapter 23) Anti-SM : positive in 30 % of SLE patients specific for SLE. Anti RNP : positive in 40 % of SLE patients, associated with neonatal lupus, mixed connective tissue (CT) disease. Anti centromere : 90 % in CREST variant of scleroderma.

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 firsttrimester spontaneous pregnancy loss (10 20%), fetal death (130 %), FGR (10 20%), CHB (see below), neonatal lupus (see below). These adverse outcomes are primarily 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 more frequently 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% of patients will have measurable lupus

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 usually required 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 hour preconceptionally, there is small risk of irreversible renal deterioration. MANAGEMENT Principles Over 90% of women without endorgan 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. Work Up Baseline prenatal laboratory tests should 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 cells and 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 laboratory tests. 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 and manage 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.

Therapy NSAIDs (nonsteroidal inflammatory drugs) anti

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 firsttrimester 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 antiSSB/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 SLE therapies.

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 maintenance doses 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 or divided 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 (Plaquenil) sulfate

Antimalarian drug. 400 to 600 mg orally daily, then 200 to 400 mg daily. Probably safe in pregnancy. If stopped, 2.5

Prenatal Care CONGENITAL HEART BLOCK Incidence About 2% - 5% of SSA/SSB positive women. Etiology Therapy 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 15 33 % 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 is measured 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 antiSSA/Ro and/or anti-SSB/La antibodies and is not evidence based. A complete (third degree) CHB, this is considered to be irreversible. The effectiveness of steroids,betamimetics,digoxin or intravenous immunoglobulin (IVIG) or any other therapy to normalize conduction or improve 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%. Fetal echocardiography: 10 20 % of CHB have a congenital heart detect (CHD) and not anti-SSA/Ro dan/or antiSSB/La antibodies, but 95% of CHB without CHD have anti-SSA/Ro and/or anti-SSB/La antibodies.