Systemic Lupus Erythematosus, Part II: Treatment

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So how do we manage lupus in pregnancy? 

  • Medications 

    • Hydroxychloroquine

      • Can decrease disease activity, prednisone use, and adverse pregnancy outcomes.

      • SMFM: We recommend that all patients with SLE, other than those with quiescent disease, either continue or initiate HCQ in pregnancy. 

      • ACR: conditionally recommends starting HCQ in pregnant patients with SLE who are not on it.

      • Some investigators recommend that patients with quiescent disease who have anti-SSA, anti-SSB, or APLS to consider starting HCQ because some studies suggest improved maternal and fetal outcomes in this specific population.  

    • Corticosteroids 

      • Recommended where SLE is not controlled simply with HCQ 

      • Un-fluorinated corticosteroids are largely inactivated by the placenta and preferred:

        • Prednisone, hydrocortisone, prednisolone.

      • Recent evidence suggests corticosteroids are not associated with fetal malformations 

      • However, steroids use can increase risk of gestational diabetes, preeclampsia, FGR, PPROM and PTB 

    • Other immunosuppressive agents 

      • Azathioprine - ok to use, not usually associated with fetal teratogenicity 

      • Cyclosporine - can also be used for refractory lupus flares 

      • Tacrolimus - calcineurin inhibitor - can be used, and has been reported to be more effective than cyclosporine 

    • What should I avoid? 

      • Prolonged use of NSAIDs - can lead to oligohydramnios, increased risk of NEC, premature closure of ductus arteriosus, and pulmonary hypertension 

      • Methotrexate discontinue 1-3 months prior to pregnancy due to teratogenicity 

      • Mycophenolate discontinue at least 6 weeks before attempting pregnancy 

      • Leflunomide - teratogen, and pregnancy should be delayed 2 years after use because of its long half-life and enterohepatic circulation 

    • Biologics 

      • There have been a lot used recently, including TNF-alpha inhibitors (ie. certolizumab, infliximab, adalimumab, golimumab) and other biologics 

      • Certolizumab can be safely used throughout pregnancy 

      • Decision to initiate or continue biologics should be made in collaboration with rheumatology and also be individualized for each patient

What about antenatal considerations? 

  • APLS 

    • If someone has met clinical and laboratory criteria for APLS, goal is to improve maternal, fetal, and neonatal outcomes.

    • For those who have not had previous thrombotic event: recommend prophylactic anticoagulation during pregnancy + 6 weeks postpartum 

    • For those with history of thrombotic event: recommend therapeutic anticoagulation throughout pregnancy + 6 weeks postpartum 

  • Antiphospholipid antibodies without APLS 

    • Patients with antibodies, especially lupus anticoagulant, who don’t meet clinical criteria for APLS remain at risk for preeclampsia

      • The risk of other adverse pregnancy outcomes and optimal management remains unclear 

    • Meta-analysis of those with asymptomatic APL antibodies with or without SLE found no difference in adverse pregnancy outcomes in those who had prophylactic treatment (aspirin) and those who did not 

    • SMFM recommend treatment with low-dose aspirin alone (i.e., no prophylactic anticoagulation)

  • SSA, SSB antibodies 

    • Given risk of neonatal lupus syndrome with or without SLE in those with these antibodies, recommendation is to treat 

    • Treatment with HCQ throughout pregnancy has been proposed to decrease the occurrence of congenital heart block in at-risk fetuses 

      • However, data is still lacking due to adequately powered clinical trials 

    • Another method proposed is to screen for 1st and 2nd degree heart block with echocardiograms, and then use steroids to try and prevent 3rd degree heart block 

      • However, in the PR Interval and Dexamethasone Evaluation (PRIDE) study, they showed that treatment with dexamethasone in some women did reverse first degree heart block 

        • However, some first degree heart block resolved on its own 

        • Several cases of complete heart block occurred without a graded progression through 1st and 2nd degree heart block 

      • There is some retrospective data as well to look at this, but overall, the utility of screening for or treating early heart block remains unproven 

      • Current studies ongoing = STOP BLOQ (Surveillance and Treatment to Prevent Fetal AV Block Likely to Occur Quickly)

    • Current recommendation: steroids should not be used routinely for treatment of fetal heart block due to anti-SSA/SSB antibodies given their unproven benefits nad known risks 

    • Serial fetal echos for assessment of PR interval not be routinely performed in patients with anti-SSA or SSB antibodies outside of clinical trial settings 

    • Doppler assessment of fetal heart rate during routine prenatal visits can be used to screen for fetal complete heart block 

  • Mild lupus flares 

    • Clinical and lab evaluation of possible SLE flare 

      • Physical exam, CBC, anti-dsDNA, complement levels 

      • Start HCQ 200 mg BID, if not already on it 

      • If already on it, can increase to 400 mg 2x/day 

      • If not responding, then can start 15-20 mg of prednisone a day.

  • Severe lupus flares 

    • Same clinical and lab evaluation 

    • Can also look for preeclampsia 

    • Start glucocorticoid dosage 1.0-1.5 mg/kg, then tapered per improvement 

    • Hospitalization may be needed 

    • Rheumatology consultation 

Other recommendations in pregnancy and labor

  • Pre-pregnancy counseling 

    • Patients with SLE should get prepregnancy counseling with MFM and rheumatology - discuss risks for both mom and fetus 

    • In those with severe maternal risk, pregnancy should be discouraged 

      • Active nephritis

      • Severe pulmonary, cardiac, renal, or neurologic disease

      • Recent stroke

      • Pulmonary hypertension 

  • Antenatal Testing

    • Antenatal testing and serial growth scans recommended in patients with SLE due to increased risk of FGR and stillbirth 

      • Currently no evidence to support optimal approach 

      • Usually, will start interval growths at 28 and assess every 4 weeks 

      • Fetal surveillance may start at around 32 weeks 

  • Delivery considerations 

    • Timing, mode, and management of delivery should be individualized 

    • If uncomplicated, early delivery is not recommended, but can be considered at term - ie. at 39 weeks 

    • If other complications, should manage per complication

    • Stress dose steroids in those with prolonged use of steroids 

  • Postpartum management 

    • Incidence of relapse or flare will increase in SLE - as with other autoimmune disease 

    • Can discuss with rheumatology regarding treatment postpartum - not all patients will need prophylactic treatment 

    • NSAIDs can be used for joint pain  

    • Can breastfeed if desired (NSAIDs, HCQ, and corticosteroids are considered compatible by AAP) 

  • Contraception 

    • LARCs such as IUD (with or without levonorgestrel) and etonogestrel implants are good options for patients with SLE 

    • Estrogen-containing oral contraceptives pose a theoretical risk for SLE flares 

      • Can be used in patients with SLE 

      • However, patients with history of active and severe SLE were excluded from randomized trials proving estrogen safety in those with SLE 

      • Contraindicated in those with previous thrombosis or those with APLS  

    • Progesterone only contraception is also safe

Systemic Lupus Erythematosus, Part I: Diagnosis and Risks

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Reading: SMFM Consult Series #64: SLE in Pregnancy

What is systemic lupus erythematosus?

  • Definition

    • Chronic, multisystem, inflammatory autoimmune disease characterized by relapses and remission

    • Many organs can be involved and manifestations are variable between individuals

  • Why do we care about SLE in pregnancy?

    • The prevalence of SLE is about 28-150/100,000 individuals

    • More prevalent in females than males; often affects young adults, so it is a condition that can be encountered in pregnant individuals – currently 3300 deliveries per year are in people with SLE

How do we diagnose lupus?

  • Lupus = a syndrome and diagnosis requires presence of characteristic clinical features + confirmatory laboratory studies

    • Unfortunately, there are broad clinical manifestations, lack of pathognomic features or lab tests

    • Usually, you won’t have to diagnose lupus and someone will come into pregnancy already with the diagnosis

    • However, knowing the diagnostic criteria can be helpful in recognizing individuals who may have lupus

    • Can help the patient have faster recognition + referral to rheumatology

  • Diagnostic criteria – will include 2

    • From The European Alliance of Associations for Rheumatology (EULAR) – sensitivity of 96%, specificity is 93%

    • From the Systemic Lupus International Collaborating Clinics (SLICC) – sensitivity is 97%, specificity is 84%

smfm sTATEMENT ON sle; eular cRITERIA FOR sle

smfm; slicc criteria for sle

smfm; aplas criteria

Pregnancy and lupus

  • Increased maternal morbidity and mortality

    • Complications include nephritis, hematologic complications, neurologic abnormalities

    • Several fold increased risk of thrombosis, thrombocytopenia, infection, multiorgan disease

    • Pregnancy can also increase risk of disease flare, and 15-30% of flares are severe, and some can be life-threatening  

  • Lupus nephritis

    • Active renal disease is defined as >1g/day of proteinuria or GFR <60 in non-pregnant state

    • There is increased risk of permanent renal damage if GFR going into pregnancy is <40 or creatinine is >/= 1.5 mg/dL

    • One issue: difficult to differentiate lupus nephritis from preeclampsia

      • We discussed this in our episode “Imitators of Pre-eclampsia”

      • Features more common with lupus flare and less likely to be preeclampsia: increased anti-dsDNA ab, decreased levels of complements, usually will not have thrombocytopenia or elevated LFTs

      • Also, kidney biopsy that showed glomerulendotheliosis can yield a definitive diagnosis

      • Important to differentiate because the treatment for lupus nephritis can be medical, while severe preeclampsia may require delivery à if we don’t differentiate, could deliver extremely premature infant with no need

  • Hematologic Complications

  • Central Nervous System and Neurologic Complications

    • Can include headache, seizures, neuropathy, chorea, cerebritis, and even psychosis

    • CNS vasculitis is the most serious CNS disorder  

  • Other organ manifestation:

    • Cutaneous lupus erythematousus

    • Can also affect bones, joints, lungs, heart

  • So… how does all this affect pregnancy?

    • Obstetric outcomes:

      • 3x increased risk of pregnancy loss; however, if well controlled, risk ranges from 8-32%, which may not be substantially different from rates reported in the general obstetrical population for early pregnancy loss

      • Increased risk of preeclampsia: 15-35%

        • Risk is highest in those with active disease at time of conception, renal disease, chronic hypertension, those on high-dose prednisone, or those with APLS antibodies  

        • Prevention: low dose aspirin beginning at 12 weeks of gestation until delivery to decrease risk of preeclampsia

    • Fetal outcomes:

      • Risk of fetal growth restriction is 6-35% depending on the study

      • Increased risk of preterm birth, ranging from 19%-49%

        • The risk of preterm birth is associated with increased disease activity at time of conception, nephritis, chronic hypertension, and APLS antibodies

    • Neonatal complications 

      • Occurs in 1/20,000 live births, so it is rare but it is a serious complication

      • Caused by antibodies that can cross the placenta, usually anti-SSA, though anti-SSB antibodies can also cause this

      • Manifestations include skin lesions, congenital heart block, anemia, hepatitis, and thrombocytopenia

        • Skin lesions occur in approximately 50% of affected infants

      • Recurrence risk in patients with history of neonatal lupus and positive antibodies is 15-20% 

      • Because it is due to antibodies, skin, hematologic manifestations, and hepatitis usually resolves 3-6 months after birth; however, congenital heart block will not resolve as SSA antibodies lead to fibrosis of myocardial tissue and conduction system 

Imitators of Pre-Eclampsia

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Each of the conditions we’ll discuss today could be an episode all its own, so this will be way too brief to cover these topics in detail! But it’s important to keep a broad diagnostic mind open, especially if you feel the picture doesn’t totally add up. 

Reading: Sibai: Imitators of Severe Pre-Eclampsia (2007)

Previous podcasts: Hypertension and Pregnancy Trio (3/2019)

Diagnosing Pre-Eclampsia:

  • Pre-eclampsia is a syndrome - a recognizable complex of symptoms and physical findings that indicate a specific condition, but for which a cause isn’t necessarily understood. 

  • We need to think about the symptoms and signs of pre-eclampsia and determine how they overlap with other diseases!

    • What else might tie together: 

      • Hypertension

      • Neurologic changes

      • Pulmonary edema

      • LFT abnormalities and RUQ pain

      • Thrombocytopenia

      • Acute kidney injury

  • Some potential examples:

    • Acute hepatitis or cirrhotic liver disease

    • Lupus

    • Meningitis

    • TTP / HUS

    • Drug reactions or overdoses

    • Malignant hypertension (i.e., pheochromocytoma, renal artery stenosis)

    • Heart failure or heart attack

      • You can probably think of more if you try!

  • Let’s focus this broad differential on three primary significant culprits today: Acute Fatty Liver of Pregnancy (AFLP); Thrombotic Thrombocytopenic Purpura (TTP) / Hemolytic Uremic Syndrome (HUS); and a Lupus (SLE) Flare

Acute Fatty Liver of Pregnancy

  • Exactly what it sounds like -- acute fatty infiltration of the liver, typically in the 3rd trimester, leading to fulminant hepatic failure.

    • Appears to be related to defects in fatty acid metabolism -- 20% of AFLP associated with long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD) deficiency of the fetus. 

  • Incidence: 1 in 7k-20k pregnancies.

  • Risk factors:

    • Fetal LCHAD deficiency: fetal homozygosity renders it incapable of processing fatty acids, and mother (typically heterozygous) has decreased function to keep up -- thus the infiltration.

    • Prior history of AFLP

    • Multiple gestation

    • Preeclampsia / HELLP syndrome (so they can even be co-existent!)

    • Male fetal sex

    • Low BMI (<20)

    • Nulliparity

  • Typical presentation:

    • 3rd trimester: most common after 30 weeks

    • Often nonspecific symptoms: nausea/vomiting, abdominal pain, malaise, headache, anorexia

    • Frequently with hypertension +/- proteinuria 

      • Reported co-existent HELLP in 20-40% of cases

    • Hypoglycemia is frequent on laboratories - from impaired hepatic gluconeogenesis

      • Additionally can see signs of acute liver failure -- jaundice, ascites, encephalopathy, DIC. 

    • Renal failure upwards of 90% of cases.

  • Diagnosis:

    • Typically a clinical diagnosis -- biopsy can be performed to demonstrate fatty infiltration, but rarely performed.

    • Swansea criteria:

      • Ranges pending on reading from 6-9 positive signs. 

        • Most typically need 6 (in my experience)

      • Supposed to be done in patients without HELLP syndrome/preeclampsia, limiting utility.

    • Imaging can be performed, but is also of limited utility in diagnosis

Swansea Criteria (UpToDate)

  • Treatment of AFLP:

  • Supportive with critical care expertise! 

  • Have ongoing monitoring for:

    • MELD score (Model for End-Stage Liver Disease) - high MELD > 30 associated with increased risk of maternal complications

    • Hypoglycemia: typically need infusion of dextrose-containing fluids

    • Coagulopathy

  • Delivery!

    • Labor induction is reasonable if can be reasonable accomplished within 24 hours, and disease not rapidly progressing.

    • Cesarean delivery outright should be considered otherwise.

    • Betamethasone administration for FLM given, but shouldn’t delay delivery.

    • Magnesium as indicated for suspected preeclampsia and/or for CP prophylaxis. 

  • Postpartum:

    • Mortality in AFLP is attributable to hemorrhage, liver failure, and kidney injury.

    • AFLP will often resolve within 7-10 days after delivery

    • Hemorrhagic pancreatitis is a potential and fatal complication known to be associated with AFLP - follow lipase

    • Liver transplantation may need to be considered in those with persistent fulminant hepatic failure (though this is rare). 

    • LCHAD deficiency testing should be pursued in infants.

      • LCHAD deficiency in newborns can be life-threatening!

Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic Uremic Syndrome (HUS)

  • Related but different diseases characterized by microangiopathic hemolysis, thrombocytopenia, acute renal failure, neurologic abnormalities, and fever.

  • TTP - caused by deficiency in ADAMST13, a protein involved in regulating blood-clotting by cleaving von Willebrand factor from endothelial surfaces, and at the sites of vascular injury.

    • Can be familial or acquired

    • Characterized by marked thrombocytopenia - platelets frequently <20k

  • HUS - can be caused by a variety of insults, but commonly Shiga-toxin from certain bacterial organisms as well as with abnormalities in complement system regulation. 

    • Renal failure is the dominating feature of HUS and tends to be particularly severe. 

  • Presentation:

    • Also tends to be vague: abdominal pain, nausea/vomiting, headache, vision changes, confusion, fever

    • May also include bleeding: epistaxis, GI bleeding, petechia/purpura, hematuria (particularly in HUS)

    • Can present with or without hypertension

  • Diagnosis:

    • Involve your hematology colleagues if there’s suspicion!

    • Early-onset preeclampsia may raise suspicion: 20-26ish week range, but can occur at any point

  • Treatment:

    • Plasma exchange: helps to remove large multimers of von Willebrand factor and autoantibodies against ADAMST13. 

    • Steroids - help to calm autoimmune response

    • Splenectomy - helps to avoid sequestration of platelets 

    • Platelet transfusion should be avoided - may contribute to increased microvascular thrombus formation

  • Delivery:

    • Not indicated immediately! PLEX and other therapies can be given opportunity to work

    • However, serial / frequent therapy is often indicated to continue pregnancy and prevent relapse

Systemic Lupus Erythematosus / Antiphospholipid Antibody Syndrome

  • SLE is an autoimmune disorder with varying symptomatology but can result in significant end-organ damage

    • 30-40% of SLE patients have antiphospholipid antibodies

    • Only 1% of patients will have antiphospholipid antibody syndrome - a disorder that is characterized by microangiopathy affecting multiple organ systems, and with particularly high pregnancy risks

  • Diagnosis:

    • Classically SLE diagnosis requires at least 4 / 11 American College of Rheumatology criteria;

    • However, in 2019 the ACR and European League Against Rheumatism came up with a combined criteria based on a points system:

ACR / ELAR Combined Diagnostic Criteria for SLE (2019)

  • APLAS diagnostic criteria we’ve previously reviewed in our RPL episode:

  • One of two clinical criteria:

    • a) Vascular thrombosis 

    • b) Pregnancy morbidity, defined as:

      • One or more unexplained deaths of morphologically normal fetus after 10 weeks of gestation by ultrasound or direct examination of fetus.

      • One or more premature births of morphologically normal neonate before 34 weeks because eclampsia or severe pre-eclampsia or recognized features of placental insufficiency.

      • Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation with maternal anatomic or hormonal abnormlaities and paternal and maternal chromosomal causes excluded.

  • And one of the following laboratory criteria 

    • a) Lupus anticoagulant present in plasma on 2 or more occasions at least 12 weeks apart or 

    • b) Anticardiolipin antibody IgG or IgM isotype in serum or plasma present in medium or high titer on 2 or more occasions at least 12 weeks apart, or  

    • c) Anti-B2 glycoprotein-I antibody of IgG and/or IgM isotype in serum or plasma (in titer >99th%ile), present on two or more occasions at least 12 weeks apart 

  • Fortunately, many patients with SLE will come into pregnancy with an established diagnosis.

    • To determine if they’re having a flare to distinguish from preeclampsia, you’ll often use a serum marker for rheumatologic disease, such as:

      • Hypocomplementemia (C3 / C4 levels)

      • Anti ds-DNA antibody levels

  • Symptoms are vague, as previously described with the clinical criteria for SLE diagnosis, and have overlap with preeclampsia! 

  • Treatment:

    • If known from outset of pregnancy -- these patients should definitely be on aspirin for preeclampsia prevention!

    • Steroids are often used in acute flares - prednisone

    • DMARDs - safe medications for pregnancy can include azathioprine, hydroxychloroquine, and encouraging data exists for immunomodulating antibodies (i.e., adalimumab / Humira)

    • APLAS - low molecular weight heparin for prevention of VTE and pregnancy morbidity

SIBAI 2009 (ref above)

SIBAI 2009 (ref above)