Lupus Unlocked- Pregnancy and SLE Save

Hello, everyone. Welcome to Tuesday night rheumatology. It's lupus month. We have a lupus campaign called Lupus Unlocked. Tonight we're going to discuss lupus in pregnancy.

We've got a great panel. Joining us tonight is Megan Clouse from Duke University Medical Center, Jill Bouyen, who's coming from New York and NYU Medical Center, and Lisa Samaritano from Hospital for Special Surgery. These women have been the big leaders in the effort to educate all of us on pregnancy and its management in rheumatic disease and lupus. All three of them were very much involved in the reproductive guidelines. Lisa was recent author on the lupus nephritis guidelines.

Again, their contributions have been tremendous. So we have them tonight, we're going to discuss a lot of issues. Let me bring up our slides and we'll get right into our program. So here we go. This is again, part of our weekly Tuesday night rheumatology, the last in a series of four.

If you haven't seen the three prior ones, they're available on the YouTube channel on RheumNow as both videos and on our podcast channel that you can listen to them. They make for great education, share them with your friends. Tonight, we're going to be discussing pregnancy and lupus and APS beginning with basic principles of lupus pregnancy management. Next birth control, neonatal lupus and congenital heart block, the antiphospholipid syndrome and what to do. We're going to end with menopause.

I want to first thank the sponsor of this whole month, which is Aurinia Pharmaceuticals, and especially for sponsoring tonight's webinar. Second, I want to thank you the audience for participating and showing up and being one of 200 plus people who answered our survey questions. We want you to be involved in this program. You can do so by putting your questions and comments in the Q and A box, not the chat box, in the Q and A box and we'll get the answers from our expert panel. We did a survey, a one day survey yesterday.

We received two zero three responses as of just a few hours ago. This is almost ninety percent rheumatologists, a few about six or seven percent were nurse practitioners. There were other MDs in there about six percent. I think that it might have been a few OB GYNs even answering this. I didn't know we had OB followers.

Most of these answers today, they're usually fiftyfifty US and outside The US, about forty percent from The US, 60% from outside The US. I want to thank our panelists. Let's get right into our first question. The survey question that we begin with, when is the risk of SLE flares greatest with pregnancy in lupus? The lead answer was third trimester.

The next answer from thirty one percent down to twenty two percent was postpartum. But we're kind of all over the map on this. We're going to hold off and let Megan address this after she addresses the next question, which is which of these medicines is not pregnancy compatible in SLE? Mycophenolate is clearly the runaway answer because it is a clear cut teratogen, the most teratogen. That's the one thing I learned from working with Lisa and the team in the reproductive guidelines.

Lisa, what other drugs should they not be using that are choices here?

Well, the only one that they can use is tacrolimus.

Right.

The others really are not good options. Mycophenolate, lisinopril are contraindicated. Vocalosporin, the the data are not there and so, we do not recommend using it But tacrolimus has a lot of evidence behind it supporting safety and efficacy in pregnancy.

Maybe there's hope for voclosporin, but they got to do the work. They got to collect the data, they got to do the studies, and that takes time until then we do have other options. Let's get into other drugs. Megan, why don't you go over this?

Absolutely. So there's a lot of medicines that people can take in pregnancy when they have lupus. Hydroxychloroquine certainly leads the list. The ACR guidelines recommend that all women with lupus take it during pregnancy unless they have some major contraindication like an allergy, And that's because we know that it decreases lupus activity during pregnancy. So it's really important to take it.

Personally, I always prescribe four hundred milligrams a day in pregnancy because, you know, women get larger as pregnancy goes on. They get more blood volume. We've actually done PK studies showing that you really kind of need to be on four hundred milligrams to have therapeutic levels in pregnancy. Azathioprine is my number two go to. It's really what we use for women who have more significant inflammatory conditions with lupus and lupus nephritis and so on.

So in my cohort, twenty percent of our patients are taking azathioprine in pregnancy. And you can see other things there on the list as well. Prednisone, I have on the list because it certainly is considered pregnancy compatible, but I actually think of it as the most dangerous of anything in that pregnancy compatible box. It has been associated with early deliveries. It's been even if you control for disease activity.

So it's not my favorite drug, but I use it when people are really sick. You can see the list of things that cause major birth defects. Mycophenolate is certainly there. It causes one in four babies will have major birth defects. Methotrexate, cyclophosphamide, obviously thalidomide is on that list as well.

So there's a lot of drugs that are newer to lupus, right? Voclosporin is one, but especially medications like belimumab and anifrolumab that are biologic medications. And so this little picture kind of shows how biologic medications transfer across the placenta, and it's really how we think about their safety. In the first trimester, there's really limited to really probably no exposure that the baby has to a biologic. Second trimester, it kind of starts percolating up around sixteen weeks.

Third trimester, there's a lot of exposure, especially in the last month or so. Basically, the mother is just dumping all of her autoantibodies, her regular antibodies, and her biologic antibodies over to the baby so that the baby has an immune system. So the baby actually has 60% more drug than the mom does at delivery. So that's how we think about safety. If you have somebody who's doing great on like a belimumab medication, probably not a big problem early in pregnancy, but maybe there's some risks for infant immunosuppression if you were to continue it all the way to term.

So I really think of those sort of limited data meds on a one on one basis. That's how I do it. I'd love to hear what Lisa and Jill do with these medications. If I think that the woman is going to get really sick without it, I continue it, but I'd love to hear what you guys do with those.

Lisa?

You're on mute.

Sorry, I'm getting over a cold and I keep clearing my throat. That's why I muted myself. Yes, I do the same. Know, I really think it's very much an individual patient focused decision. And it depends not only on the patient's clinical status, but on their, level of risk that they're willing to be comfortable with.

And if they are extremely risk averse and their disease is extremely stable, well, that makes it easy to stop earlier. But when it's not the case, you really need to have a good conversation regarding what we know, what we don't know, and explain it to them.

Yeah. Do you want to throw in a caveat about paternal exposures, Lisa? Everyone wants

Paternal to know about exposures, are of course not well studied. They're really, there are two things that one can consider. One is, does a drug impact fertility for a male? And the second is, does the drug impact the sperm and whether or not there would be abnormalities in the developing fetus? We think that continued use of a medication through pregnancy, it's very unusual for enough medication to be transmitted through semen that we worry about that being, having a significant effect on the developing fetus.

So cyclophosphamide is the big one. Of course, it causes or can cause infertility, and it can also cause DNA fragmentation, you know, in the sperm, which makes us worry about potential adverse outcomes. Thalidomide, you know, not that we use that very often, but in the reproductive health guideline, did recommend against men taking thalidomide while trying to conceive. And that was based on some very limited data about levels of thalidomide in semen, actually. Otherwise, other meds are fine, including methotrexate.

We don't know a lot about the newer meds, know, novel small molecules, but we do not have any data to suggest that any of the other meds cause a potential problem. Sulfasalazine can lower the sperm count. So that's something that people need to be aware of. If difficulty conceiving and the man is on sulfasalazine, you should have a semen analysis. And if it's low, stopping the med.

Do you have any comments on this?

Oh, no, I actually concur with everything that's said. Just to point out, in terms of pregnancy planning, there might be some issues with nonsteroidals and fertility that just like prior to that might be a consideration as well. And also to mention, because later on we might talk about different forms of steroids, and to keep in mind that at relatively low doses, prednisone in its form will not actually get into the fetal circulation, though there are obviously issues with regard to the mother. Whereas dexamethasone absolutely gets into the fetal circulation and you use it for that purpose. So there's some caveats there.

Okay. Do you have a question about rituximab during pregnancy in the mother?

Do I? I can take the rituximab question. I That's good question. There's really not a ton of data about rituximab in pregnancy, but there's some growing data actually, particularly out of the multiple sclerosis field where they've been using these anti B cell drugs for quite a while. So rituximab follows the same kind of trend that you see here on the graph, right?

So if you were to dose rituximab prior to or very early in pregnancy, the assumption is that it's really probably not going to cross the placenta much at all. It does have a pretty long half life, you know, so it might a little but not a lot. But if you were to dose it, you know, right there at like thirty five weeks, the baby is going to be born with a huge dose of rituximab, which could definitely cause and has been shown to cause basically absent B cells for months and months of the baby's life. So if I have somebody who is doing well on rituximab, also to be honest, if I have somebody who shows up suddenly pregnant with really active disease, I've been using rituximab and I'm actually going to switch over to obinutuzumab for this purpose if I can, I give them rituximab or anti B cell drug as early as possible in pregnancy, like they show up? A couple weeks later, I have them in the chair to get that drug so that it's in them for the rest of the pregnancy because the folks that fall pregnant when their lupus is really active, they haven't planned, they're not comfortable taking meds usually, and I have a really hard time getting them to take daily azathioprine and hydroxychloroquine and blood pressure medicine and prednisone.

So at least if I have an anti B cell drug in body, I think we have a better shot of having things go better. So I'm personally okay with Ritux prior to pregnancy and early in pregnancy.

So if you went over the reproductive guidelines like you should have, and it's a really useful reference to have handy. The one thing that you should walk away from is that planning and education is organically important in a successful management. Megan, do you want to address this in the next slide?

Absolutely. You know, I think, I mean, my biggest soapbox these days is pregnancy planning because we just don't know what to do when people fall pregnant when they're really sick. We just haven't figured that out, and I've been doing this for twenty years, and that's been my goal, and I still don't know what to really do when somebody is really sick and pregnant. And the best way to have them have successful outcomes is to help them not be pregnant when their lupus is really active, and we've been telling women that for a long time, right? We've been saying don't get pregnant when your lupus is active, but we really have to actually help them operationalize it by helping them get to birth control, which we're going to talk about in just a minute, but also helping them understand that they can actually impact the health of their baby forever.

So if you are at high risk for poor outcomes, if you're taking one of these teratogenic medicines like mycophenolate, you have very active lupus nephritis, you have uncontrolled hypertension, you have untreated antiphospholipid syndrome, we see for each of those, if you just have one, about forty percent pregnancy loss and about sixty to seventy percent preterm delivery. All of those things can be avoided in pregnancy, right? You can switch them off the teratogen. You can help them get good control of their lupus nephritis before they get pregnant. You can get them on pregnancy compatible hypertensives, and you can get their APS treated.

And that actually, if you hit the little button, the animation will show you that with planning, the ladies move and they move down to the lower risk category, and that is really important. So helping women understand that if they work with you to do some planning and it might take six to twelve months, but they can have a much higher success rate, which will be a huge impact on their own personal lives but also the lives of their children. So helping women understand that I think is really important, and that means talking about this really early, like when you first meet them, but even just periodically asking, Are you thinking about getting pregnant? Oh, good. Well, I'd have you stay on your hydroxychloroquine, right?

Just that kind of thing helps women take the right steps when they finally get there.

Megan, do you want to go back and address the who's more likely to flare during pregnancy? Obviously, a patient is uncontrolled.

This is a discussion. I personally think, and I'd like to hear what everybody else thinks, I don't think women flare in pregnancy anymore now that we actually use medicines in pregnancy. There were tons of studies back in the 1980s about do people flare more, do people flare less, I think. And we actually looked at Michele Petrie's data. Amanda Udi did this, my PhD epidemiologist for her dissertation and found that if you were taking hydroxychloroquine in pregnancy versus outside of pregnancy, same exact flare rate in pregnancy, same exact flare rate postpartum if you were taking hydroxychloroquine.

If you were not taking hydroxychloroquine, then you had a higher flare rate in pregnancy and a higher flare rate postpartum. So I think in modern times, we actually don't see flares much. And if you look at the PROMISE data, Jill, your data showed that you really don't see a lot of flares.

Bill, do you agree?

I absolutely agree. And I was actually going to ask her the answer to that first question because I don't think you could pick a trimester or postpartum. And for God's sakes, please do not give glucocorticoids to prevent postpartum flares. Very old fashioned. Probably people don't think about that anymore, but it was in the literature in the old days.

Absolutely. And we could just stop telling women that they're gonna have a postpartum flare.

Yeah. I think stop. Absolutely.

Yeah, comes in, Well, I'm really worried about my postpartum flare. I'm like, That doesn't really happen. I mean, you're tired. Yeah, it's hard, but we don't really see a lot of flares.

Wow. This is an eye opening. Lisa, you agree?

Well, I do with the caveat that when we talk about this, we're talking about the patients that we plan with who have stable, quiet disease and they're on their pregnancy compatible meds. But, you know, that isn't always the case. And I think that's the reason if you look back over those studies that Megan was mentioning through the 80s and 90s, the flare rates in different populations range from thirteen percent to sixty five percent. Why is that? Because some groups of patients were counseled and had quiet disease and you know, were planning and starting a pregnancy at an appropriate time.

Other groups were not. I mean, we try as hard as we can to counsel our patients, but some patients don't understand or don't accept that kind of information and get pregnant without planning. And when they have active disease within the few months before pregnancy, much higher chance that they'll flare. When they stop their Plaquenil because they don't wanna take anything during pregnancy, that's when they'll flare. So I agree completely.

The risk of flare is low throughout in the patient population that we have described where we've done our best to counsel them and get them into a good place for a safe pregnancy.

So the two pillars I think of planning pregnancies have to be education and contraception. So we ask the question, what is the preferred contraceptive to use for lupus patients who are of childbearing potential but don't want to, shouldn't get pregnant just yet? The audience answered 60% IUDs, 36% progestin implants, and a smattering of applause for estrogen progestin pills. Lisa, what say you?

I am so impressed with those answers because we have been trying to educate our colleagues in terms of the safety and efficacy of these various contraceptives. So first I will say that, you know, our ACR guideline recommends either an IUD, whether progestin or copper, usually progestin because it has a better side effect profile, or a progestin implant because any patient is able to use those unless they have some gynecology contraindication. So there's no estrogen involved in either of those options. We don't have to worry about thrombosis or perhaps FLAIR. They can be used in any age range.

Young women, teenagers who are nulliparous can have an IUD placed. So they really are highly effective, and that term means the risk of pregnancy over the course of a year is less than one in one hundred. That is actually even a little bit more effective than so called permanent contraception with vasectomy or tying tubes. So they are effective and safe. There is a good amount of data, not in our transplant patients and also HIV patients, that women who are immunosuppressed can safely have IUDs placed.

That was a concern early on because of the earliest IUDs that did predispose to development of pelvic inflammatory disease. But today's IUDs do not do that. So when I say here, the effectiveness varies, the effectiveness varies dramatically. So for implant and IUD, it's less than one in one hundred. For birth control pills and some other related types of contraceptives, those are moderately effective.

And that means the risk of pregnancy is one in ten to one in twenty. And for condoms, which are least effective, the risk of pregnancy is one in five. So there's a huge difference and it makes a difference because of what we just talked about. What is the best way to ensure a safe and successful pregnancy? Have that pregnancy at the right time on the right medicines.

And so birth control is the way to do that. So LARC stands for long acting reversible contraception, and that is IUD or implant. Not all methods are safe for all women with lupus. There's concern for risk of FLAIR and or thrombosis with estrogen in patients with lupus. And as Doctor.

Bayan knows well from the Selena study, that study showed that for women with lupus who had quiet or mild disease activity, who did not have high titer anaphospholipid antibodies, they could safely take birth control pills without an increase in risk of FLAIR. There are a couple of caveats there. One is they really should not have significant APL antibodies and they should have mild or stable disease activity. We don't know what the risk of flare is in someone with active lupus nephritis. That's not something that we were willing to study.

The whole reason for the Selena study, which Doctor. Bayan put together many years ago now, and I was lucky enough to work on it with her, was that for years, patients were told they couldn't take birth control pills at all, ever. And this study showed that in a subset of patients with lupus, it does seem to be safe and not increase the risk for FLAIR. And although it wasn't designed to look at risk of thrombosis, there wasn't a significant difference in the rate of thrombosis in the treatment group versus the control group. Again, these patients could not have significant APL antibodies.

So for those who do not want an IUD, do not want an implant, the progestin only pill is moderately effective and it's safe for everybody. It does not, the current progestin only pills, do not increase risk of thrombosis. There's no evidence that progestins increase risk for lupus flare. And then I mentioned that condoms are less effective, but remember, they're more effective than no birth control, right? The risk of becoming pregnant over the course of a year is eighty to eighty five percent with no effort at birth control.

And importantly, they can prevent sexually transmitted diseases. So that may be another reason to incorporate that. But I think there are a lot of caveats, but the message obviously has gotten across to our respondents that IUDs and implants are safe and effective. And that is because they are removed from the time of intercourse. The patients don't have to think about it.

They can't miss their pill. I will say there are some contraceptives that are out now that we need to be a little bit careful about. There are fourth generation progestins, Drospirenone is the name of it. That is a progestin only pill, but it has a spironolactone like effect and it can cause hyperkalemia in women with kidney disease. So that I think is important to be aware of.

And then I would say my last point is just that don't forget to tell your patients ahead of time that morning after pills or emergency contraception is safe for them, whether or not they have antiphospholipid antibodies or active disease, that needs to be taken within seventy two hours. It's available over the counter and any of our patients can use that if they wish.

Jill, Lisa brought up the Salina study often talked about, can you give us a few caveats from that that you want the audience to know about? Because it is a

I very think the most important caveat from that is that people were thinking no way can a lupus patient ever take an estrogen containing pill. And we unequivocally proved that that was not true. And I do wanna make a point about the progestin only pill. People bleed at irregular times. Patients hate it.

And so one of the things that I would say is I probably would never give a progestin only pill if somebody had no antiphospholipid antibodies and never had a clot. I would unequivocally prefer the oral contraceptive. There really are a lot of patients who are very shy about IUDs. And I'm pretty encouraging about estrogen containing birth control, to be honest. And as well, as long as you've tested them for APL, I'm really pretty good with that.

And that's why you went through the trouble of doing that study. I'm pro that myself.

Can I jump in and just say that my answer to which is the best birth control is the one that they will use?

Because I

think we all get a lot of pushback from women about various birth control. There's actually a lot on social media these days about, you know, how hormones aren't natural and you need to use natural birth control. It's this whole movement. If you're getting this in your clinic and you're like, what are these people talking about? It's a social media whatever thing.

And so I really struggle to get people to get LARC these days often unless they are more educated and and or really don't wanna get pregnant. So it's kind of like what whatever they'll use. I've even now started talking about multiple verse multiple less effective things, condoms plus spermicide plus tracking on your phone with your you know, on one of those apps that tells you when you're fertile or not. Those are much better probably than what other people, you know, were using, or people can get the Oura Ring, which is like a ring they wear and they're ovulating. So things that, like, that people count as natural are better than nothing.

There's something called Phexxy, P H E X X Y, which is a new it changes the it's like a spermicide kind of gel that you put in your vagina, and it changes the pH of your vagina, which sounds terrible. But, anyway, I think it it makes it makes it so it's really it's a good birth control form, actually. It's not as great as birth control pills and that sort of thing, but in combination with other things, you can at least get people closer to contraceptive when they're really at high risk for bad things happening to them.

We have a question about progestin use and I guess hormonal use and maybe worsening osteoporosis or are we dealing with wrong end of the spectrum here, and this is sort of a non issue?

Well, you know, the only, there is one progestin which does increase risk of osteoporosis and that's Depo Medroxyprogesterone acetate, DMPA. That's the injection that they use either every month or every three months. That is a high dose of progesterone that is given. And it's a high enough dose that it inhibits ovulation, but there's no estrogen to replace the estrogen that's not being made naturally. And for that reason, it causes a drop in bone density.

I think it's seven percent over two years in the one study that tracked it. But the other thing about DMPA is that it is the only progestin that may increase risk of thrombosis, and it may also be related to the large dose that they use. So the implant, the IUD, the progestin only pill, no issue with blood clots, but DMPA has about double the risk compared to second generation progestins.

You went to osteoporosis, you didn't mean blood clot.

No, I'm saying both. Sorry. I mean that it can contribute to osteoporosis. And of course, our patients are already at such great risk, right, with their steroids. But also there is this additional risk of, increased risk of blood clots.

I do wanna just go on the other side of that, however, and say, if what the patient will do is depo and she has active lupus nephritis, like, I would give her depo. I would give her depo for more than two years. I would if that's what we can get in the patient and that's what they're comfortable with, I'm personally okay with that. Often when you actually look at the osteoporosis data, it does they do have bone loss while they're on the depot, but at least it hasn't been studied in lupus patients, but when they come off of it, their bone density goes back up because their estrogen levels come back, And the risk of osteoporotic fractures is undoubtedly much higher from the prednisone that we are giving them than from the depo. So it's like there's always caveats, and for some of our patients falling pregnant unintentionally is worse though.

It's a hard balance, but

Let's go into APS and heart block. So The question that we asked the audience was, what's the strongest risk factor for fetal congenital heart block? The number one answer was high titer SSA antibodies, which we're going to find out is a good risk factor, but not the biggest. The second answer was thirty three percent with a prior child with AV block. True false, the detection of heart block is most common between weeks eighteen and twenty five gestation.

Eighty four percent said that's true. Another true false, the risk of heart block is seen with both low and high titer SSA antibodies. Two thirds of you said that that's true. Jill, control yourself and try to address it.

I can control myself, don't worry, Jack. Okay, so let me just say that the highest risk for having a child with heart block is having had a prior child with heart block. That risk is about eighteen percent, where the risk with high titer is probably still under ten percent, more like four percent. You got the detection time right, and that's really very precise and helps guide when is the best time to actually monitor for the problem. I think we've come to realize that low titer anti Ro antibodies are probably not even associated with risk at all.

But the big question is what constitutes low titer? And right now with all the commercial laboratories that we have, that is not the most obvious of answers. And you really have to take that on an individual basis. But just to say, probably the most common way most of you get your anti RoTE tested is by the BioPlex assay. That's done commercially by LabCorp, by Quest and many university labs.

And in that case, you get an answer of less than one, negative, one to eight, or greater than eight. And by and large, people who are between one and eight, particularly those that are like two, three, and four, are probably not at any risk for having a child with heart block, which then translates to less surveillance need. So that's a point. So just to remind everybody, what is this neonatal lupus? The mother doesn't have to have lupus, though this is a lupus conversation.

And keep in mind that any of the rheumatic diseases are associated in part with anti Ro antibodies. So anyone who even has any semblance of an autoimmune thing, I would even say thyroid disease, I think anti roentibodies should be checked. But it's not about whether the mother has lupus or Sjogren's, she could be totally asymptomatic, she just has to make the antibodies. And these cross the placenta and that placenta transport we've already discussed. It's operative starting around fifteen, sixteen weeks, and just gets more and more as the pregnancy progresses.

And the two problems are congenital heart block. When it's third degree, there's no going back. And the reason it's called neonatal lupus is this rash that you see can look like the rash a person with lupus can have that can be at birth, or it's actually most common about six weeks postpartum and watch out for sunlight if you have antibodies and taking your little baby out in the sun. Slide.

Jill, is the neonatal lupus rash, is it related to the C deficiency or to the Rho antibody?

I think it's related to the Rho antibodies. Absolutely. Yes. So these are just some little facts. If you happen to be called about somebody who has bradycardia, the cardiologist tells you it's heart block, almost all of these women will turn out to have anti Rho antibodies.

If we've discussed already the risk, if you've never had a child affected and you have substantial titers of Rho antibodies, you're talking about a four percent risk. If had you a previous child, that's about eighteen percent. That goes down by half if you prescribe hydroxychloroquine. And I was really interested in hearing Megan say that she actually puts all her pregnant patients on four hundred of Plaquenil. That's interesting, we should discuss that.

Now, this is not a benign disease. Overall, it's about a seventeen percent mortality. And beyond block, there can also be what we call extranodal disease. That's the dangerous aspect of this. Despite the fact that you may not have that, or even only second degree, almost all these children eventually require permanent pacing.

And what's fascinating is that as we talk about monitoring, which we won't go into today, one can go from a normal sinus rhythm to block within twelve hours. And it's fascinating how that may happen, which has implications to surveillance and the new kid on the block, which is a fetal heart rate monitor, which again is perhaps part of another discussion. That's what I have here, Jack. You took out all the other stuff. So I would say again, consider checking anti roe antibodies.

I shouldn't say consider, I say check. Refer to a pediatric cardiologist for surveillance. And for those with a previous child with heart block who might not have lupus, I would absolutely start hydroxychloroquine at four hundred milligrams before ten weeks of gestation. We could spend the whole two hours talking about this.

These cases and in the others, there was this belief by most people that patients with lupus or APS or CHP being detected or suspected, that they be managed by multiple specialists. What is your recommendations as to how you manage your pregnancies or these individual cases? Is it always with maternal fetal health? Is it with a select high risk pregnancy OB? Or is there a right way here?

Well, I think in all of our discussion today, I think a patient with a rheumatic disease should be followed by a paternal fetal medicine. I do think the experience of a quote, MFM versus a traditional OB really is important, and I hope my panelists agree with that. And I always ask the patient, has your obstetrician ever had a patient with lupus or Sjogren's or anti Ro antibodies? And if the answer is, I don't know, I say check. And if then the answer is no, I actually advise if it's possible to find a more experienced person.

And for the Roe business, I generally do refer to pediatric cardiology.

I do the same thing. Like for all my lupus patients, for sure, I want them all to have seen maternal fetal medicine. Some of my like rheumatoid arthritis patients who are really stable, don't necessarily, but definitely my lupus patients, I always want them to see maternal fetal medicine, but it really varies based on where they live, what's available. So I have a lot of patients, for example, who live multiple hours away where there's not a lot of maternal fetal medicine doctors. So they actually often follow with a local OB who does, like, all of the scans and stuff and all the usual kind of tests, but I always have them see one of my MFMs or in MFM, and the MFM tells the OB what to do.

The monitoring, the more intensive monitoring that we do for these patients in pregnancy is actually the same as what it's very normal to the OB to like do the same remember those non stress tests that you've got when you did gynecology, you know, back in medical school, right? So it's the same test, it's the same ultrasound, It's just that the lupus patients get them a lot more often in the third trimester. So I always have somebody see maternal fetal medicine, and if they live really far away, I will let them be monitored by a local OB if things are stable.

How do you feel about midwives? I think it's a popular topic. What do you think about midwives?

What do you think, Lisa?

You know, honestly, practice in Manhattan. I don't have a lot of experience with my patients wanting to deliver with a midwife. And I know it may be more common elsewhere, but it's not something that I would be comfortable with. I wouldn't be comfortable with my patient delivering at home or in a pool. I mean, I really think that our patients are at greater risk for complications and I really want to know that we're doing everything we can to monitor them and be ready for anything that might go wrong.

Yeah.

Think that's a really important point, Jack, and I had to mention that, and I'm glad that we all seem to feel the same way about it.

I mean, it's actually at Duke. Maternal fetal medicine has a ton of nurse midwives that manage patients and sort of under the auspices of the attendings, and I think they do a fine job for the routine stuff. Certainly nobody should only see a nurse midwife as their OB, but they can do the regular follow-up and the, like, how's it going and doing the tests. But, right, I agree that, like, nobody should deliver at home who has lupus. That's for darn sure.

Can I ask two practical issues? One, how often should your lupus or APS patient be seeing you, the rheumatologist, during their pregnancy? And two, do you have any unique advice about exercise activity or diet during pregnancies that you don't want to pass on? Let's start with Lisa and then Jill and then Megan.

So I would say the bare minimum is once a trimester for the patient with mild lupus on hydroxychloroquine alone, never internal organ involvement. And then depending on how active they have been in the past, depending on their clinical history, whether or not they've had nephritis, whether they have APL, you know, I will see them about once a month or once every six weeks if all is stable, more often if needed. And it is interesting that even the MFMs don't often do labs on their patients other than the ones that are needed for management of the pregnancy. And I find it very reassuring to be able to do the labs periodically because we do see platelet counts dropping down. Obviously, they're they're great at looking for proteinuria.

But some of the other things, they're not as tuned into. So I feel more comfortable when I do that myself. Jill?

That's something horrifying to tell you. So it turns out, I don't know if you're aware, but the new MFM guidelines are not to check protein during pregnancy because they're not sure how to interpret it. So I think there are a lot of things that we take on as almost their primary pregnancy caregivers. So I go to you. I see them each trimester.

I've actually called all the MFM and said, please, you must do a urine. I found this out because I asked my patient, oh, of course, you give urine every time you go. And she said, no, never. And it's really shocked me that I talked to the head of MFM at NYU who said, oh, we don't really do that anymore because we don't know what to do about it. Fascinating.

But I agree with you. I see patients every trimester. But if I feel there's active disease, whatever else makes me nervous, I'll try to see them every month, honestly.

Megan?

I do the same thing. I sort of see people on every six to ten week kind of cadence in pregnancy usually, and then I usually try to see people about six weeks after delivery as well. I just set that up sort of at their third, you know, mid third trimester visit. I usually don't see people right there at end the of pregnancy, to be honest, because there's not much I'm going to do. They're going come in at seven weeks and be really uncomfortable and I'll be like, Yes, just almost there.

So I usually sort of miss that last window, and I will second what Jill says. Like they are not checking urine proteins like they used to, and you cannot rely on them to be checking that. And so making sure that your patients are getting urine proteins, I think that's actually the most important lab test, in fact, almost the only one that matters that much in the vast majority of our pregnancies, especially in terms of who's going to have a poor outcome. Urine protein, the urine protein to creatinine ratio is reliable enough in pregnancy. The people who are above 500 and certainly above 1,000 with a history of lupus nephritis have very high risk for poor outcomes, and so that needs to be followed throughout pregnancy and before pregnancy as well.

What about monitoring hydroxychloroquine levels during pregnancy?

Well, I do that. I do it for I

don't even do it when they're not pregnant, how about that? Do it all Of the course, they don't. I mean, I'm a rebel about that. And until I really I have to have patients have complete diaries, explain what they do every hour and how they take it before I'll get a level. And I'm really not kidding.

Oh, really? You don't get levels? Is that what you said, Jill?

And the reason I don't get levels is I basically have to talk to the patients about how they're taking their medications before I will even begin to interpret it. And I think the idea that you're gonna raise it when somebody has told you, oh, well, I've skipped it for three days. I mean, actually reading some of the articles you've written have made me more and more not wanna get levels. They stop it for a day. Some people give it four days a week and then stop on the weekend.

Do you take it on the day before, the two hundred or the four hundred? It's not so clear cut the relationship, in my opinion, based on the work that you and Stephen have done.

All right. Let's move

on. I'm a rebel about that.

I check hydroxychloroquine levels often.

All right. So getting into management, again, who manages these patients? We have said that we do combination management in at least three quarters of us and nine percent just MFMs. Then do you agree with this that lupus and APS, Jill said this all rheumatic patients basically, but certainly SLE and APS patients should be considered high risk pregnancies and appropriately managed that way. Right?

Can I actually say one more thing about sort of what the role of the rheumatologist is in pregnancy? Because I think people are really nervous that like we will see patients who said, My rheumatologist said, Don't come back until I'm not pregnant anymore, like, and don't really want to be involved. And what I want to encourage is that rheumatologists, your role in pregnancy is just to assess their lupus and help guide the lupus meds. You don't have to do the rest. And lupus in pregnancy looks basically exactly the same as lupus outside of pregnancy, so you can use all of your skills of assessing lupus activity outside of pregnancy.

Just use the same ones in pregnancy and just do your sort of usual rheumatology thing with them, and you'll make a huge difference because just like you don't deliver babies, you certainly don't want me delivering a baby, maternal fetal medicine doctors cannot assess lupus activity at all, at all, and so leaving it to them is just terrible.

Fraught with danger. Okay. Here's a case, and lupus anticoagulant positive on multiple occasions, woman of 35 is now eight weeks pregnant. She had two prior pregnancies that were problematic with miscarriages that occurred early in the pregnancy. How would you treat this?

We actually showed this question last week. I want to get our input from our experts on whether they agree with what rheumatologists chose fifty five percent of the time, which is both low dose aspirin and low molecular weight heparin or Lobanox. Do you agree?

I think this is actually exceptionally controversial. I think that emotionally, we all would probably treat this with low dose aspirin and low molecular weight heparin, but it sounds like it's actually not super clear that early miscarriages, even recurrent ones, are due to antiphospholipid syndrome, and the patient doesn't meet APS criteria, so we actually don't really have data to tell us what the right thing is to do. And so I think actually aspirin alone would be acceptable. I think both low dose aspirin and Lovenox would be acceptable. I think doing nothing would be acceptable.

I would not give low Benox alone. That's the only one I wouldn't do. What do you guys think? What would you what do you guys think?

I would only make sure they were aspirin because I think there's a preeclampsia issue here too. I mean, aspirin Sure. I put a lot so I I think about aspirin not necessarily as anticoagulant, but I think about it more as a prevention for preeclampsia and other kind of vascular effect that way. So just to clear up that issue, aspirin is for sure for me here. I guess for me, I don't know what you mean by early miscarriages.

And I have this sort of ridiculous notion that once a heartbeat is heard, I'm kind of moving into a different category and that something has been going on, there's placentation, things are growing, and then something bad happens. And for me, once you've got a heartbeat, now all those anatomical things, those hormonal things are out of the way, and now I'm worried. So I suppose that if there were two miscarriages after a heartbeat, I probably would go for the anticoagulation.

Think it's important to point out that, you know, the OBGYN, has to do their due diligence, right, and make sure it isn't, inadequate progesterone, that there isn't some structural issue. I mean, this is assuming there's nothing else going on. And it's important for us to remember that because as rheumatologists, we don't do that workup. We have to rely on the OBGYNs to do it. And I think the other, there are a couple of other sort of subtle issues.

One thing that would push you towards, low molecular weight heparin would be the fact that it's lupus anticoagulant positive and not an isolated anti cardiolipin IgM of 56. However, another thing that might push me towards low molecular red heparin would be that this woman has undergone six IVF cycles. And for her to pregnant again is going to mean a seventh or an eighth. So all of these other things, I think play into this kind of decision. I would say there is no right answer for this as it is written.

And of course, it depends in part on the patient and what their feelings are, and their understanding of the low but real risk of being treated with low molecular weight heparin. So I think there is no one correct answer. It has to be a physician patient discussion. Clearly, as written, this patient should not be treated with low molecular weight heparin because does not meet criteria for obstetric APS.

Okay, so let's get into APS and some new developments on APS. Megan, do you want to go over the criteria?

Absolutely, So I'm gonna use this as a moment to say that there are new ULAR ACR, APS criteria that have been created. When I read through them, you know, it's really clear to me that they're really basically designed to figure out who should be in trials for antiphospholipid syndrome. They are not diagnostic criteria, and I would say less diagnostic criteria than any criteria I've ever seen. So I personally am not using them when I'm deciding who to treat at this point because they actually make it much harder to meet APS obstetric APS criteria. They actually have moved the pregnancy loss requirement up to three before sixteen weeks.

And the instead of just one loss after ten weeks, which is how a lot of people meet the criteria, it's actually just one loss after sixteen weeks. So actually about a third of women with obstetric antiphospholipid syndrome move out of the diagnosis with the new criteria, but there hasn't been a study of those patients to see what we should do with them, right? Those women were all in the original trials with low molecular weight heparin. So I personally am sticking with what I know. It's easier.

I also can follow it. Women can also tell you these things for the most part. So I'm sticking with the old criteria for now, and then I have how I treat it down there at the bottom. Well, to be honest, I give everybody with lupus gets aspirin eighty one milligrams a day. We're actually sometimes using one hundred and sixty two for people who are very high risk for preeclampsia.

So everybody gets aspirin whether or not they have APS antibodies. And then if they've had a prior history of a blood clot, then they get therapeutic dosed low molecular weight heparin. And if they've never had a blood clot, so they just have obstetric APS, they get prophylactic low molecular weight heparin. And in my experience, the OBs, especially maternal fetal medicine, usually manage the low molecular weight heparin. They give a lot of heparin in pregnancy.

They're very comfortable with it. You should be able to allow the the OB to manage the low molecular weight heparin in my experience.

So the new big thing we published on RheumNow yesterday that I learned about from you all was this impact study. Megan, do you want to just tell the audience about that? It was published with Jane Salmon as a lead author from HSS.

Yeah. I'll give the short version, and Jill, you add. How about that? So, this was a new study that Jane just has, just very recently published. Its inclusion criteria is basically anybody with antiphospholipid syndrome, though almost all of them had obstetric APS in particular with a history of pretty terrible outcomes when you look at them as a population, persistently positive lupus anticoagulant because that's really in her study has been shown to be the most problematic.

And actually, they decided it was okay to have some mild lupus in the study. The reason that it's important to know that people were allowed to have mild lupus is because they were given cerdulizumab. All of these, which is a TNF inhibitor, right, that it was pegylated, so we don't think it crosses the placenta as much as the others. So everybody, it was an open label study, everybody got the usual aspirin, everybody got the usual low molecular weight heparin, and everybody got cerdulizumab. They did loading dose for three doses, and then they did two hundred milligrams every other week, weeks eight through twenty eight.

And the outcomes really look great in the sense that they met their primary outcome. If you hit enter again, it'll show up, Jack.

Oh, sorry.

I'm sorry. I really like animation. Keep going. There were fifty one pregnancies in it. You can see the composite outcome of fetal death greater than ten weeks or delivery due to preeclampsia or placental insufficiency before thirty four weeks was seventeen point six percent.

When they looked at the PROMISE study data, which is really the historic data, that risk was forty four percent, and all those patients were on aspirin and low molecular weight. And if you hit the button one more time, these were the patients, their prior pregnancies, many of whom had been on aspirin and low molecular weight heparin, and you can see they had a much higher rate of adverse outcomes. So this met their primary outcome, and I think it's fascinating and I think really an opportunity for us to offer, particularly our patients with poor outcomes in the past, a new approach to treatment.

So when they excluded the genetic abnormalities and others and the denominator changed here, it got no higher than twenty percent, This is clearly still half or much less than what we had with the other one. Very important study, not controlled, but uses historic controls. Will this change the management of such patients?

Does for me. Absolutely. Yes.

I mean, I think one thing is really funny.

The only challenge is how you get the insurer to pay for it. And because unfortunately, and we won't get into the detail of how the study was designed to consents and information for the labeling, it's not allowed to be in the labeling even as a concept at the moment. So it's our challenge in how we actually get it approved for an individual patient. But this paper, you just clip it to your bag and hope for the best, best, right? But it's not like it's in the package insert.

Yeah, well, won't be an indication, but it will be included in the PLLR data, right?

They have to do that.

Megan, no?

I don't think they're going to, Jack. I think the last they'd heard from the FDA was that they weren't gonna let them put it in the pregnancy and lactation section either. No. I think I don't know why they put

No. There there is a caveat to it about how the consents were done and information that was allowed to go back to the company. It's a complicated situation for which I'm trying to avoid in dealing with the FCRN. But there is a little bit of a wrinkle there. There's a little wrinkle.

It's not about science, it's about technical.

We've got three minutes left.

Let's

close with the discussion of menopause and lupus. Lisa.

Yes. Okay. Well, I will not give you the whole history then of HRT, but as you know, HRT was promoted in the 60s and 70s, and then everyone stopped taking it in 2002 when the Women's Health Initiative study report came out. And now we have reached, I think, an equilibrium where we know that if someone has really debilitating vasomotor symptoms, many women can successfully take HRT if they take it soon after menopause less than ten years from menopause onset and they're under the age of 60 because those women are not at the same risk for cardiovascular disease and breast cancer. What does this mean for our lupus patients?

Well, we know from the Selena study looking at HRT that again, while there was a small increase in mild moderate flares, no increase in severe flares. So for women who are APL negative and who have mild or stable disease, they can absolutely use HRT. I would recommend transdermal estrogen first, because if you look at the hematology literature, transdermal estrogen likely doesn't increase risk of thrombosis in the way that oral estrogen hormone replacement does. So, that seems to be a no brainer. There are non hormonal therapies for vasomotor symptoms for APL positive patients or women with a history of thrombosis.

And that's been SSRIs, etcetera. Not terribly helpful, but there is a new FDA approved centrally acting drug called fezulinitant, which is quite effective. And it's a centrally acting agent. It is not a hormone and that is something APL positive women should be aware of. And then finally, even women with positive APL can use intravaginal estrogen tablets for local genitourinary symptoms, and that can be quite effective.

The systemic absorption is very limited and we feel like that is okay for those patients. So that's sort of the rundown on menopause.

A question from Helen Cooley, two equivocal LAC tests but no clots. Okay to use transdermal estrogen? Equivocal, that's not answer, isn't it?

Yeah. You know, again, LAC to me conveys greater risk. Two tests conveys greater risk. I would not recommend it. Have I had patients with indeterminate APLs go on and use transdermal estrogen against my recommendation?

Yes, I have. And they have been fine, just a handful of women. But I think we just don't have enough data to say that we recommend it to our patients. We just don't know, even though in theory we think it might be fine.

Okay. It's at the top of the hour. I want to end this session, which was a fabulous session. Thanks to Jill Byan and Megan Clouse and Lisa Samaritano. Can't thank you enough for your expertise here, a great discussion.

We'll see you in our next lupus meeting.

Thank you. Thanks.

Bye, everyone.