Jane Salmon, MD

Expert Perspective

Reproductive Health in Systemic Lupus Erythematosus

Headshot
Practice Community
New York, New York
Practice Niche
Lupus and Antiphospholipid Syndrome, Rheumatology
Hospital and Institute Affiliations
Director, Lupus and APS Center of Excellence, Hospital for Special Surgery
Co-Director, Mary Kirkland Center for Lupus Research, Hospital for Special Surgery

Question

What are the major clinical takeaways from systemic lupus erythematosus (SLE) studies in pregnancy presented at this year’s ACR/ARHP Annual Meeting in Chicago?

Answer

The key finding from our work is that women with systemic lupus erythematosus (SLE) whose disease is inactive can have safe and uncomplicated pregnancies.

During the last 30 years, it has been clear that some women with SLE do well in pregnancy and some women have difficulty. The challenge has been how to anticipate, before pregnancy, who is going to sail through and who is at high risk and should be watched carefully, and for whom preventative therapies need to be developed.

We used data from the PROMISSE study, a prospective, multicenter, multiethnic, multiracial observational study. Patients were followed every month of pregnancy beginning at 12 weeks with clinical exams, laboratory tests, and research biomarkers. Of the more than 700 patients we enrolled, 384 women met ≥4 American College of Rheumatology (ACR) criteria for SLE, and all had quiescent or mildly active disease at enrollment. PROMISSE also included women with primary antiphospholipid syndrome and healthy control patients. Flares during pregnancy and postpartum were assessed in all patients with SLE.

Of the patients with SLE, approximately 26% had a flare at any point during pregnancy, with most occurring during the second trimester. Only 6% of the flares were severe, and very few required treatment. Our data indicate that flares are uncommon during pregnancy if the pregnancy starts when the disease is quiescent.

The new data we are presenting at this conference describe postpartum flares, which we found to be similar to flares during pregnancy. In the postpartum period, we observed 23% of patients had mild/moderate flares and fewer than 2% had severe flares.

The independent predictors of experiencing any type of flare during pregnancy were age at screening (younger patients had more flares), ethnicity (non-Hispanic whites had fewer flares), low complement at baseline, and patient global assessment PGA score at baseline. Clinical features associated with adverse pregnancy outcome, including lupus anticoagulant, antihypertensive use, and platelet count, were not predictive of flares.

We considered the same baseline variables when analyzing postpartum flares and found that none was correlated with or independently associated with occurrence of any postpartum flares. We also evaluated laboratory values, disease activity, and medication use at the last visit during pregnancy and found that none was associated with postpartum flares. This lack of predictors could be because the mean time from the last visit during pregnancy to the postpartum visit was 20 weeks, ranging from 9 to 34 weeks.

Our new data extend our evidence to the postpartum period, indicating that pregnancies in patients with in SLE with quiescent disease are rarely associated with disease flares. When counseling patients, you can reassure them that if their disease is quiet at conception, they are unlikely to flare during pregnancy, and that flares postpartum are rare and mild.

From an economic standpoint, patients with SLE who have inactive disease who don’t have any of the important risk factors I mentioned may not require the monthly ultrasounds and intense monitoring that is now standard of care.

The key take-home message for clinicians is to advise patients before they become pregnant that they should wait to conceive until their SLE is quiescent. I think that’s the most important lesson we’ve learned.

Question

What are the research updates in regard to treating patients who are increased risk for pregnancy complications?

Answer

Although prospective observational studies have taught us a lot about risk stratification, we do not have preventative strategies for the more than 20% of pregnant patients with lupus who have the potential for serious complications.

Looking at biomarkers and at mouse models of lupus pregnancy, complement activation has been implicated as an important driver of disease activity. Presumably, if you can block complement activation, you can “rescue” poor pregnancies. But there are few complement inhibitor products on the market, and the ones that are available haven’t been used in many patients. In addition, the safety of these drugs in pregnancy is not yet clear.

An alternative approach is to prevent mediators downstream of complement activation. Complement drives inflammatory cells to release tumor necrosis factor (TNF) release. We used mouse models to ask: “Does TNF blockade rescue pregnancy complications?” And, in fact, it did. There are also data in humans, looking at the placenta, the amniotic fluid, and the blood, that suggest that TNF is associated with bad pregnancy outcomes.

We have now embarked on an open-label interventional trial evaluating certolizumab, a TNF inhibitor that does not cross the placenta in measurable amounts. We used the risk factors identified in PROMISSE to select patients who are at increased risk for serious complications before 34 weeks of pregnancy. Women at <8 weeks of gestation who have antiphospholipid syndrome or lupus anticoagulant positivity on 2 or more occasions are eligible for enrollment in the trial. The National Institutes of Health is funding our study. Please contact me if you have such patients contemplating pregnancy.

Question

Do you have any concrete guidance for fellow rheumatologists on how to improve reproductive health guidance in patients with lupus?

Answer

There are data from patient surveys that show that physicians don’t discuss pregnancy with their patients with SLE, and I would like to encourage physicians to do so. Let’s discuss pregnancy before patients decide to become pregnant. Let’s start telling patients that if their disease is quiescent, they can absolutely start planning pregnancy. The process starts with patients telling their physicians about their reproductive plans, and the physician must encourage them to begin these discussions. I think these conversations should occur at least annually, and perhaps more often, depending on what the patient’s goals are.

An open-ended discussion can feed into a larger dialogue on overall reproductive health, which is another topic presented at this year’s ACR/ARHP Annual Meeting, held October 19 to 24, 2018, in Chicago, Illinois, and includes issues related to contraception. Is contraception safer than an ill-advised pregnancy when a patient’s disease is active? I think the guidelines will be extremely helpful because they discuss approaches to contraception, hormone replacement, and anticoagulation in patients with SLE and antiphospholipid syndrome. They will also cover drug safety, when to switch and what to switch to, and whether switching agents is necessary.

Another key take-home message from the guidelines relates to what was discovered in the PROMISSE study, which is that disease activity does have an effect on pregnancy. Patients are very concerned about drugs during pregnancy, and they reflexively may stop all medicines because they fear for the safety of their baby. But it may be worse for the pregnancy if the rheumatic disease flares. Patients should be counseled to continue medicines that are safe during pregnancy.

Question

What are the challenges you experience in treating lupus flares during pregnancy?

Answer

A major challenge for clinicians in management of pregnancy in patients with SLE is distinguishing preeclampsia from a SLE nephritis flare. It is extremely difficult, and the treatments for 1 may worsen the other. High-dose steroids may increase blood pressure and make preeclampsia worse, but they may be necessary to treat nephritis.

There are some nuanced differences between SLE nephritis flare and preeclampsia. Are there red cells in the urine? Is the complement low? This would suggest nephritis. However, interpreting changes in complement in pregnancy is difficult because complement normally goes up in pregnancy. What we showed in PROMISSE is that complement levels not increasing is a sign of increased risk for poor pregnancy outcomes. Hypocomplementemia isn’t required, but flat levels of complement should cause physicians to pay attention. Of note, we have been looking at some biomarkers that can actually be useful for diagnosing or predicting preeclampsia. There are rare situations in which a patient actually has both. So a clinician can eventually use the biomarker and think the patient has preeclampsia, but it may not be only preeclampsia.

Question

Should a patient with lupus be put on aspirin to prevent preeclampsia?

Answer

Patients with SLE are at increased risk of developing preeclampsia, so should we put every patient with SLE on aspirin therapy? The American College of Obstetricians and Gynecologists supports the use of low-dose aspirin prophylaxis in women at high risk for preeclampsia. Autoimmune diseases, including SLE and antiphospholipid syndrome, confer a high risk for preeclampsia.

Rheumatologists will have additional guidance on this issue when the new ACR reproductive health guidelines are approved and published. The guidelines will address whether aspirin should be started or continued during pregnancy, as well as issues related to the continuation of other disease-modifying antirheumatic medications. Although the evidence is not strong, it is reasonable to treat pregnant patients with SLE with low-dose aspirin to prevent preeclampsia.

In addition, rheumatologists should be aware that the American Heart Association recognizes that patients with preeclampsia are at increased risk for atherosclerotic cardiovascular disease. A fundamental question for clinicians is whether when they are doing a history and physical they are asking patients whether they ever had pregnancy complications. If patients have a history of preeclampsia, clinicians should be particularly vigilant about traditional cardiovascular risk factor reduction, including smoking, hypertension, and hypercholesterolemia. Patients with SLE are at increased risk for preeclampsia, and they are also at increased risk for heart disease.

Thus, it is imperative that rheumatologists obtain detailed pregnancy histories to be able to assess cardiovascular risk and to implement risk reduction strategies.

Disclosures/Conflicts of interest:

Dr Salmon has disclosed the following industry relationships:

Bristol-Myers Squibb – Consultant; Advisory Board

Exagen – Consultant

Ra Pharmaceuticals – Consultant

UCB – Research support; Consultant