Lupus Unlocked- Antiphospholipid Syndrome Save

Hi, everyone. Welcome to Tuesday Night Rheumatology, another webinar and panel discussion this week featuring the topic of antiphospholipid antibody. I want to thank you for joining us this week. We've got a great panel of experts in the field. First, Doctor.

Shruti Chatterveti, who's from Johns Hopkins. Second, Jason Knight, who's from University of Michigan. Thirdly, Katherine Sims, who's from Duke University Medical Center. Thank you very much for the three of you for being here on this Tuesday night Rheumatology Lupus Unlocked, where we're going to talk about anti phospholipid syndrome. Okay, so at the outset, I want to say a few things.

First, for the audience, really important that you ask us questions. We got a number of survey questions that we're going to review and discuss. But if you've got questions during this session, please put your comments and questions in the Q and A box, not the chat box. We're not going to be checking the chat box, we're going be doing just the Q and A box. That's really important so we can address your questions with the experts.

Second, I want to let everyone know that we always do survey questions ahead of these Tuesday night rheumatology sessions because they help inform and drive the discussion. I want you to know that survey questions that you're getting once a week now during lupus month are really for these Tuesday night rheumatology sessions. They're not dictated by any company. I come up with it with the help of our experts on the panel and our other guiding experts for this month. They're meant to be important academic and clinical practice questions.

These are not at all driven by any company at all. Although this session and this whole month has been sponsored thankfully by Aurinia and thanks to them for their support of educating everyone on lupus during the month of May. One last thing in this session on antiphospholipid syndrome, we are going to discuss the approach, which means the diagnostic approach, but also different treatment approaches to certain situations. We are not endorsing any therapy since we're working in an area that largely has no approved therapies other than anticoagulation. Everything you would be using would be theoretically off label, and you have to consider that when choosing your therapies.

I think that's where we want to begin. Again, this week, anti phospholipid, we're going to discuss the diagnosis of APS, how we use antiphospholipid autoantibody testing and interpretations, where guidelines come into play, and what's the treatment approach of APS and its complications. I want you to know that we sent out a time survey yesterday to everyone, and thankfully two forty of you responded, half being from The United States, ninety percent of you being rheumatologists, eight percent being nurse practitioners and physician assistants. Thank you for that because we're going to use those discussions in going forward. Panel, we're going to begin by talking about the diagnosis of antiphospholipid syndrome and the use of auto antibody testing.

Just asked a general question in the email, went out to everyone. If you're suspecting an antiphospholipid syndrome, what labs do you order most? Knowing that you have a lot of labs that you can choose from, And you can see that most of you, 75%, basically said I order a lot of labs, not just lupus anticoagulant or an RPR, but that I will order cardiolipin antibodies and beta-two glycoprotein antibodies. Even by saying all of these, were including AT3 and protein C and protein S, and I don't know that I would do that. But what do you think?

Jason, you want to start on this? Is this the right answer?

Sure, happy to jump in. Thanks for inviting me tonight. I mean, rheumatologists like to order a lot of labs, so I think that's a good default to go to. So I don't blame any respondent for wanting to order more, not less. I mean, for me, I would focus on three tests, all of which I see here, which is the cardiolipin antibodies, the anti beta-two glycoprotein antibodies, and then the one called lupus anticoagulant.

Know, RPR is a syphilis screen, which is kind of an old style way to detect anticardiolipin antibodies. So it's a good one to keep in mind because occasionally, like in the setting of a pregnancy, we might kind of get the first hint from that false positive syphilis test. But otherwise, I would not normally have that as part of my routine practice. So I think that's kind of straightforward. Those are the three classic tests.

Probably Shruti could talk to us about when the specialized anti thrombin three and protein CNS might be indicated. So yeah, I could pitch it to her.

Rudy, you're on mute.

I'm so sorry. Thanks, Jason, and thank you for having me. I agree with you completely. Those are the three tests that I would order as well. I actually do not think that there is substantial utility in ordering the anti thrombin three protein CRS in the type of setting where you're suspecting just antiphospholipid syndrome because they don't realistically change your management.

Even in the hematology world, we are starting to restrict ourselves to ordering tests that would change your management. And if you are testing because someone has had a blood clot and you think they may have a, you know, hypercoagulable state, protein CS and antithrombin, test in women of childbearing age, people who have relatives of childbearing age, because it might impact family, counseling, but it doesn't change our choice of anticoagulant. These are also quite rare and, tricky to interpret in the setting of anticoagulation with warfarin or in the setting of acute thrombosis. So at the risk of sounding dismissive, I would urge people to not order them unless we really know what we're going to do with the test and perhaps send it to a hematologist to test it at the right point of time.

Cassie, would your testing be different if this was, as we'll get into later, a case of recurrent fetal loss and what would your battery test look like?

Yeah, thank you for having me. And I agree with what's been said so far. So I frequently see recurrent pregnancy loss in our autoimmune pregnancy clinic. And our maternal fetal medicine physicians typically have already completed these tests, the three tests that have already been discussed before I see them in clinic. But these are the three original tests that I will run-in order to assess for any obstetric APS that could be playing a role in recurrent pregnancy loss.

And we can talk a little bit later about some of the less traditional tests that can be run. And it's a little bit more controversial to talk about a seronegative APS, which sometimes we get into conversations with hematology and MFM about. But my first initial tests are those three that have been listed so far.

Trudy, I think Hopkins recently published something on new testing or other ways of testing here. Is there anything that rheumatologists need to know about other ways of looking, especially if these tests proved negative, but we have recurrent thrombotic events?

Are we talking about the complement focused testing?

Yeah.

All right. So absolutely, we do have what we call functional testing for complement activation. And this really speaks to the fact that we all have complement and complement is activated in the fluid phase, but also on cell surfaces. And what's happening in the fluid phase doesn't always reflect what's happening on the cell surface, and that's what we're interested in disorders like APS that are disorders of endothelial injury and cellular activation at the end of the day. So this is taking a cell line that is very susceptible to complement.

It's been engineered to be that way, and we pour serum on top of it. And if there is too much activated complement in that, in the serum, the cells die down. And you can detect that with a cell viability assay, or you can make these cells autonomously bioluminescent so the light dies out. And that tells you that there's enough complement activation to be causing cellular damage. And if this is happening in a patient who is having recurrent thrombosis despite anticoagulation, we have good data that the complement activation in this setting is likely driving that thrombosis and completely off label, I have to say.

We've added on complement inhibition with C5 inhibitors, which appears to effectively mitigate the thrombosis. I don't think this is a diagnostic test for APS, but maybe a test that helps screen for people at risk of worse outcomes, like either catastrophic APS or recurrence despite anticoagulation. And we hope that in the future it may help guide treatment for people who may benefit from adding on C5 inhibition, but I don't recommend it as standard of care quite yet.

That's really helpful.

It's available commercially should anyone want to send it. Like you can send the test to a lab in California that will now run these tests for you.

Okay. You brought up catastrophic APS, which most of us don't want to see, but is there anything by lab profiling that would help us to maybe identify those people earlier?

I'll go first, but I'm going to hand it over to Jason as well after this. The literature would suggest that anecdotally, it seems to be a triple positive patients who are at greater risk. That said, in my clinical experience, we've had people that are single positive with catastrophic APS as well. With my hematologist lens on, it appears that, you know, having thrombocytopenia, either at the onset of that acute episode or chronically may be a predictor of someone who has got the CAPS phenotype. But in our research experience, identifying the patients with complement activation at baseline seems to be the best predictor.

It's hard to tell who's going to develop CAHPS, our standard prediction models like the, you know, global APS severity score or even triple positivity are not great predictors who which that one percent is. But moving on to maybe Jason has a different experience here.

No. I mean, that resonates with me, and I think the first two things you mentioned were things I was thinking about. I mean, it tends to be people with strong antibody profiles. I mean, yeah, on average, that's what you would expect to see in that rare patient. And then often someone that's had some other either microvascular manifestations of their APS or something like hematologic manifestations like thrombocytopenia.

I think it's often that flavor of APS that goes on to develop it. I am though Yeah, I followed Shruti's work closely and her collaborators there at Hopkins, and I do like the idea that maybe the antiphospholipid antibodies are one of the hits, but then there's this second hit that for some reason, folks are bad at putting the brakes on the complement system. And so it's the kind of work that gives you hope that there could be a future in which we're more proactive. We can kind of identify these folks early on and either get them on preemptive treatment or get them excellent education in terms of things to look out for. So great question.

I like the next question on the right there because the audience was split, which means that there's a good need for the right answer here. Meaning to establish the diagnosis of antiphospholipid syndrome, obviously one has to have the clinical scenario that a thrombotic event or fetal loss or whatever. But as far as the auto antibody testing, is one test enough or do they have to be multiple tests? Who wants to tackle that?

So I can start. Typically when I am suspicious of APS in a non pregnant patient, if I'm working up recurrent fetal loss, I will first screen with lack, anticardiolipin, and anti beta-two glycoprotein. And if there is a single positive above 40 for IgM and IgG, anticardiolipin or anti beta-two glycoprotein, I will then wait twelve weeks and retest again to see if it's a persistently moderate to high elevated titer. I've also read, and Trudy and Jason, you can correct me if I'm wrong, that you can have a lupus anticoagulant alone that's persistently positive and you can still meet criteria for APS. Something that I've heard, Jason, you talk about before is this triple positivity and persistent lack.

I tend to be much more proactive with patients who want to get pregnant in terms of higher dose aspirin, low molecular weight heparin when they have this higher risk profile, because I'm much more concerned about placental insufficiency, preeclampsia, stillbirth, and preterm delivery. And I'm kind of curious if my co panelists also tend to be a little bit more aggressive upfront with a higher risk profile in APS.

When you say persistent lack, you're talking about lupus anticoagulant.

Yes, that's what I mean.

Jason?

Yeah, and I think it's interesting even a little bit how you framed the question, Jack, in terms of, because I kind of believe these people always, well, maybe not always had APS, but it's not like they did not have APS one day and then they have a pregnancy loss and now they suddenly have APS. For confidence of diagnosis, events increases your confidence for sure. And more positive tests increases your confidence as well. But yeah, I definitely agree with Cassie's point. I mean, those folks that come in triple positive the first time, I mean, yes, we should nominally repeat that after twelve weeks to kind of follow the rules.

But it's very rare that that individual would have those antibodies disappear. You can be pretty confident that that's the real deal. I wouldn't a mistake I sometimes see is someone potentially withholds treatment because they know they have to wait for twelve weeks to repeat. And I mean, I think a lot of times you can make a decision sooner than that. I wonder if this was split because some people were kind of thinking about it like, do we need to get a repeat test or not?

And some were maybe thinking like, at the time of first testing, but

think it's a good question because I think it caught them off guard. Like they don't think in these terms, they just do the test and I don't think they think in terms of should I be doing it again? Trudy, in RA, rheumatoid arthritis is this tremendous importance of double positivity for ACCO and rheumatoid factor and the strength of the autoantibody. It looks like that holds true in antiphospholipid testing.

I agree it holds true, but I'd say for the most part, at least in my world, the patient usually comes to attention because they've already had an event. And if you've already had a major clotting event and you're single positive, for example, for lupus anticoagulant, that in itself has declared someone having a thrombotic phenotype. What I'd really caution everyone against is that, you know, traditional teaching is that we need to repeat the testing to confirm the diagnosis, to Jason's point. But particularly if someone has high titer positivity on the first testing or multiple antibodies positive, we know that they are less likely to turn negative at the twelve week point. And in my clinical practice, I document this and I call this presumptive APS so that we treat them as APS at that point and not three months later, giving them a chance to fail a DOAC in that period of time.

Okay, that's really, really helpful. All right, so I'm going to move on. I want to encourage the audience, if you have questions at any time, please put them in the Q and A box, we'll address them as we go along. Staying on this topic, I think associations with antiphospholipid antibodies, I'm just going to throw out this question of if someone has anti phospholipid syndrome? What's the importance of ANA or is it not important?

You can see the audience was fairly split on that. A lot of patients with APL might be ANA negative. There's no importance that they're ANA positive, that ANA positive people have more miscarriages, ANA positive people will not necessarily have more thrombosis. I'm all over the map on this one, right? If you were the policeman, you'd be pulling me over and saying, What are you doing?

Shruti, why don't you take a stab at at least ANA and what it means in a situation?

Don't make the hematologist talk about ANAs. All I know about this is that my rheumatology friends tell me, Do not send the ANA.

Yeah, see Shruti was doing the same to us when we had the hematology tests and now we see the other side of the coin. She's out there sending ANAs left and right probably.

Never send an ANA.

Room referral.

I

just call my friendly neighborhood rheumatologist to ask them what to do.

So Jason, do the ANAs confound the situation or help?

More

information always helps. Send any testing you want and we'll figure it out. I mean, I think if someone has APS, they could be ANA positive or ANA negative. Certainly if they have both lupus and APS, they're likely to fall into that ANA positive group, right? But I mean, I have some folks in my practice that I feel they have primary APS.

They certainly don't have a lupus syndrome that I'm used to noticing, but they still do have that positive ANA. It's something I take note of. I think that's a person I'm more likely to get on hydroxychloroquine kind of out of the gates, although that's not necessarily evidence based. There's some data for this, that that's someone we should watch to see if they are going to develop more of a lupus picture over time. I think in the short term, it doesn't change so much with decision making, but I do think it can maybe give you some things to look out for in the future.

I don't know, as a rheumatologist, what Cassie's experience has been with this scenario.

Yeah, typically when I see patients with their current pregnancy loss, they've already had a screening ANA. And part of the question is also if they're Ro positive and that's leading to their recurrent fetal loss as well or contributing to pregnancy complications. So normally they either come to me with an ANA positivity or they're asking for a full autoimmune workup. And so while we get the APS serologies in that same visit, I am likely screening for things like Rho positivity and lupus as well to look for an overlap syndrome. Because if they are Rho positive, obviously we would be starting hydroxychloroquine doing fetal echo, so it would drastically change our management and could be an alternative explanation to recurrent fetal loss.

We got a question on lupus anticoagulant testing. There are a number of tests that we can do there. Obviously, the one to one correction of Doctor. VVT, the platelet neutralization test, hexagonal testing. Do all these qualify, Shruti, or is there one that we really should be pushing for?

I think all of them are valid assays for detecting a lupus anticoagulant. The ISTH, which is the International Society of Thrombosis and Hemostasis, has specific guidelines about how this testing should be performed and interpreted. The hexagonal phase of assay, in my experience, is not the most popular. Know, the DRVVT tends to be slightly more popular, but the hexagonal phase is a fairly straightforward assay where you use a PTT reagent that is sensitive to lupus anticoagulant, and you use hexagonal phase phospholipids as a source of phospholipid for correction. The interpretation is slightly different than the DRVVT ratio, but there's actually like the delta between the times is what's calculated usually.

Shruti, is it correct that ISTH says that centers doing this testing professionally should probably run two tests as part of a lupus anticoagulant panel? So it'd be common to see like a DRVT test sent as well as a hexagonal hexagonal neutralization assay sent in parallel. And I think the rationale is that, I mean, is kind of a screwy thing we're doing using this kind of accident of history and now trying to use it as a lab test, and maybe no single test is gonna pick up all lupus anticoagulants. So I'd be surprised to see that test, in isolation, right? It would often be part of the panel?

It usually is. I have seen that in the ISTH testing guidelines at some point of time, in the reasonably recent past. I know that they are being updated. And clinically, like our center runs these, but they only run the DRVVT. They do not run the hexagonal phase or platelet utilization test.

Does your center run more than one?

Yeah, we run the two. So someone gets a DRVVT and, they also get the hexagonal phase test done in parallel. Then the pathologist tries to put that whole combo together and give kind of a yes or no readout, based on what they're seeing.

How do you deal with the discrepancy? Like if one is positive and one is negative, who wins?

Yeah, it's interesting. I think the strongest patients tend to have everything positive. So, it's the kind of test I think, we're not taught to score it as like this is a high risk lupus anticoagulant versus maybe a slightly lower risk, but I think there's probably something to that. If you see everything turning positive, that's a strong patient beyond the alert is how I think of it.

This reminds me of other situations in diagnosis, latent TB, a positive TST followed up by an IGRA. And basically you keep ordering tests until you get the result you want. You didn't believe one, order the other. And then it's the same thing with ANA testing. I didn't believe it was negative.

I'm gonna order all the sub auto antibodies under ANA to try to prove the point. Think it's, you're getting further from the truth when you start looking because the system's likely to give you one positive, one negative, and ultimately say, okay, time to put on your diagnostic pants and make a real diagnosis here, not based on a lab, but based on the clinical scenario. These are hard situations. I know if we really have a great answer. Someone writes in the comments that according to the Hopkins cohort, Michelle published that fifty percent of APS patients, I assume that don't have lupus and it will eventually go on to develop lupus over time.

I was not aware of that high percentage. Do you think that's true, Doctor. Chattergood?

I think there is something there, but I do think that number maybe, it's a little higher than I would expect. I wonder wonder if there is some component of selection bias there because these are the patients that were seen in the rheumatology clinic or the lupus clinic who also have antiphospholipid antibodies versus, you know, a mixed hematology rheumatology clinic where I tend to see only primary APS for the most part. And I'd say about ten, fifteen percent of my patients over the last five to eight years have developed lupus. It may also be a function of how long you follow these patients.

All right. For those asking great questions, if I don't answer and get into it right away, that means I'm going to get into it in subsequent questions. So just hold tight. Another survey true false was SLE patients who test positive for anti phospholipid antibodies are higher risk for diffuse alveolar hemorrhage. These are lupus patients who have a positive APL autoantibody, and two thirds of you said yes, that according to a recent report is true as the right answer.

I guess the question is, if you're a lupus patient and you have an anti phospholipid antibody, what else are you at risk for? I'll just throw out obviously thrombotic events, fetal loss, myocardial infarction is on that list, CVA is on that list, even transverse myelitis and valvulitis. Anybody want to add further to the list of risks associated with being APL positive with lupus, but not yet had one of those events? What they might be interested for? Go ahead.

You could have libido.

Yes.

And, you know, libidoide vasculopathy in the skin, which can be quite debilitating. We've had patients with, cognitive impairment that and when you do MRIs, you see tiny ditzels that look like silatone forks or white matter changes. And then you're at risk for thrombocytopenia. And sometimes thrombocytopenia is just thrombocytopenia, and sometimes it's severe ITP that needs treatment.

Okay. Anyone want to add to that, Cassie?

Yeah. Was just gonna say nephropathy. I mean, when these patients are pregnant, it's really, really tough. Sure, there's added risk of preterm delivery, preeclampsia, fetal loss, but also we get into this spot of, is this active lupus? Is this preeclampsia?

Is this lupus nephritis? Is this the APS? And it becomes almost impossible to differentiate between a pregnancy complication versus a lupus versus APS. And so it does complicate our ability to decipher what the etiology is, and that's huge because the treatments can be vastly different. It complicates the pregnancy picture as well.

We're going to go on with a few more questions from yesterday's survey. Who usually manages patients with antiphospholipid syndrome and the need for anticoagulation? I gave single choice answers and the rheumatologists, fifty six percent said hematology is basically managing that. Thirty seven percent said the room is managing it and only a minority of others. You guys are the experts who should be managing these patients.

Someone who meets criteria, has the syndrome, has had events, needs anticoagulation, who should be managing them? Let's start with the hematology side of things.

I am always happy to manage them. I enjoy doing this and we are used to managing anticoagulation and clots. That said, I trust my rheumatology colleagues completely, particularly when lupus is also involved and they have an interest and experience in this. I'm also going to put a little caveat there. There are hematologists and there are hematologists and oncologists, and the hematologists would love to help you out with this.

But there are a lot of people who treat primarily cancer and are not very comfortable with this. So in those situations, the patient may be in better hands with a rheumatologist.

Cassie, what's your experience?

I realize that I have a very niche experience in the pregnancy clinic. Actually, maternal fetal medicine tends to take over Lovenox injections during pregnancy. I will say that there's a little bit of tension sometimes between rheumatology, heme, and MFM about when to start the Lovenox. So typically it's at conception, but there's a concern that if there's an ectopic or tubal pregnancy or the patient goes forward with an abortion or a termination, obviously you don't want them to have an increased risk for bleeding. So sometimes there's a little bit of tension on when to start either right at the home pregnancy test or after there's been an ultrasound confirming the location of the pregnancy.

Jason, how do you feel?

Yeah, I I see a lot of APS patients at my clinic, including some with primary APS, and I'm pretty comfortable. And what does managed warfarin mean? Don't have to actually tell them how to adjust the INR because we're lucky to have a team of very excellent nurses that do that. But I'm happy for a lot of them to be the prescriber. I have a rule of thumb that I tell our junior faculty, which is, however, if the patient ever has both bleeding and clotting as part of their story, then we for sure need a hematologist on board.

We don't want to be trying to weigh those decisions. Many of my patients have a hematologist that I kind of co manage with, but sometimes I feel comfortable on my own.

All right, that's the first quotable quote from this session. Bleeding and clotting, call him. Definitely very smart. I like that. The question is in patients who have antiphospholipid syndrome, they've had an event, how do you monitor them?

Obviously, you bring them back to your clinic. Most of the audience, a little more than half said it's mainly a history and exam part. But that says I'm preferring that over lab testing. What would you do as far as monitoring? Obviously, you're going do a history and exam, but people are kind of split on whether you do selective testing for what was abnormal previously, or whether you repeat all those tests again to increase the cost of healthcare and make us less efficient than we already are.

Jason, what would you do?

Because I'm a rheumatologist, I do sometimes repeat the test because I'm a little bit interested. Though I agree with you, it's a little bit like repeating the ANA, not something that we should really be advocating to be done routinely. Though often patients are interested, and so sometimes you wonder after multiple years, might I manage the patient different if those antibody levels are decreasing or even if they have surprisingly gone away completely. I mean, history and exam, and certainly the basic organ function labs, right? Like if we teach lupus to the med students, we tell them you have to test kidney function if you can only do one thing, versus sending a fancy autoantibody.

So I think that should always be kept in mind. I mean, these are patients that can have new issues with thrombocytopenia over time, new issues with their kidney function. I mean, that type of testing, I think, is really important. And then for me, I test inflammatory markers often. I mean, this can also help me think about the patient that might need hydroxychloroquine added.

So yeah, that's how I think of it. I don't know, Shruti, from a hematology perspective, like what the heck happens when the patient comes back to your clinic? You regale them with knowledge about your fancy complement studies, then you must do something else as well.

No, I do. So, I actually do not repeat testing a ton in routine clinical practice because I have the conversation with the patient about if this comes back negative, what will we do differently? And the answer is usually nothing. And I'm a bit of a purist about clinical testing. We do have people repeat labs as research assays, but that is completely besides the point.

One thing that I might be doing differently from you all is, you know, we do clinical exam and history for sure, and the INR is very critical to their monitoring, as you know. But about once a year at the very least, particularly for my patients who have high tidal lupus anticoagulants, I will get a chromogenic factor ten activity along with the INR just to make sure that the INR is truly accurate in this individual. The disclaimer here is that very often to end up in my clinic, you may have failed anticoagulation at least once anyway. That is one additional thing that I do that I believe changes management.

The only thing I would add from a fertility reproductive health perspective is if a patient is experiencing infertility and wants to undergo assisted reproductive technology, I will retest their lupus anticoagulant, Beta-two, and cardiolipin, because if they're persistently positive, then we likely will not advise to move forward with assisted reproductive technology.

Jack, can I follow-up on the pearl that Shruti mentioned? Because I do think it's a really good one and something I learned that I think has helped me help some patients. The idea of the chromogenic factor 10, which is instead of using a functional assay, which can potentially be distorted by the lupus anticoagulant, as Shruti was implying, we can kind of directly assay factor X levels, two, seven, nine, and ten. These are the factors that are affected by warfarin. So it's a different way.

It's a way to kind of spot check that you set the right INR goal for your patient. Because I've seen patients, I'm sure Shruti has because she's one of the people that taught me about this, where the INR is 2.2, but from the chromogenic factor 10, you can tell those factors are just not depleted enough. You've got false confidence in how thin the patient's blood is, if you will. And so for me, that's a time that

anticoagulant in about seven percent of patients interferes with clot based assays. It prolongs them. So the INR you're measuring is not real. It's falsely inflated. Well, if the clot based assay doesn't work, use a color based assay like the chromogenic factor ten.

And you can either do what Jason said, that you can reestablish your INR range. And I have patients who are running at, you know, five to seven INR, but their chromogenic suggests that they're at the equivalent of two to three. It's just that it's a measurement issue. Or in some centers, and even with commercial labs now, you can actually just use a chromogenic to test and monitor, they come back pretty quickly. The other pearl perhaps is that, a venipuncture INR when you do a blood draw is not the same as a fingerstick INR in some patients with APS.

And they may not correlate. The finger stick may overestimate the INR in a very small fraction.

We have two questions from the audience. One, is there a value, to the anti phosphatidylserine to PT prothrombin ratio as a predictor of thrombosis in SLE or in APS patients? Does anybody have experience with this?

I could say something. These are good questions. I do like that test, and I could see it as a test that eventually ends up in the criteria, actually. So we're testing for antibodies against prothrombin, which you've heard of, but the test becomes a lot more specific for APS if you coat that prothrombin onto a phosphatidylserine surface. So that's where the PS part of it comes in.

But this is a test that I like to use it to A lot of your isolated lupus anticoagulant patients, this may antibody behind the scenes that's driving that phenotype. And so in scenarios where you can't trust the lupus anticoagulants quite as well, perhaps the patient's already on an anticoagulant, I think it can be a useful test double check. I commonly see it being strongly positive in folks that are, you know, I was on the fence about whether they were truly leucine anticoagulant positive, and it kind of pushes me over. So That's been my experience. I think it's a good test and it is commercially available.

For me, it's the one non criteria test that I do send routinely. I didn't mention it at the front, but I like this test.

Shruti, there are batteries of anti phosphatidyl blah, blah, blah, and really extensive batteries. Roger Bicke used to run these when I was working with him and pontificate on their importance. But clinically, I wasn't sure of their importance. Should an extended anti phospholipid panel be chosen ever?

I think, I am of the opinion that you should do this extended testing only if you know that it's going to help you in some way. I have sent these in the past, but they have never changed my decision about what to do with the patient so far. I So struggle with that a little bit. Now Jason's point about really teasing out the real lupus anticoagulant positive versus the, you know, false positive maybe because they were on apixaban is a valid one. And it may be helpful in that kind of setting.

What I found somewhat more helpful is actually to use this different test called the DOAC Stop, which is now available commercially at many, many places where they really use activated charcoal to take the anticoagulant out of the system and test again. It kind of takes care of the false positives.

That's called a DOAC stop?

That's the commercial name of it and I'm not paid by them, I don't even know who makes this. But we have it available to us at our lab and many other labs in the area. It's not just a Hopkins thing.

That's really interesting. I'm going to move on. Our next question is, what's your preferred first line therapy in a newly diagnosed APS patient? Half are choosing warfarin and the other half are split between aspirin, antimalarial and a low molecular weight heparin, no one choosing a DOAC. Cassie, what's your approach with a new newly diagnosed APL?

Well, if they want to get pregnant or they are pregnant, I cannot use warfarin. I'm typically going with Lovenox And if they have this SLE overlap, sometimes I will reach for Plaquenil as well and aspirin. I'm typically, again, depending on their profile and overlapping autoimmune diseases like lupus, I'm being pretty aggressive upfront, but Coumadin or warfarin is not safe in pregnancy.

Shorty, what do you think?

I'm going to say it depends. It depends on where they're clotted, arterial or venous, and it also kind of depends on what the antiphospholipid antibody profile is. So if they have, if they have venous thrombosis, I go with warfarin for the most part. If they have arterial thrombosis, I lean towards the warfarin plus low dose aspirin rather than the warfarin with higher INR. That that that's an alternative.

And this is what I talk with every patient, you know, upfront. That said, sometimes you see patients who are like single positive, their IgM only single positive, they're like an IgG cardiolipin, but it's, you know, a titer of 45 and it's one test. And they really, really don't want to be on warfarin. In those situations, I will have the risk benefit discussion with the patient about the fact that warfarin is, at least by the textbook and by clinical trials, the preferred agent, but that single positive and low risk patients were underrepresented. And if they really want to do a direct oral anticoagulant, I will be okay with that.

And the third category is the patient who had a clot a year and a half ago and has been on a direct oral anticoagulant since then. And you diagnose them with APS like a year or two after the event, they have already declared that they do fine on a DOAC. I give them the option to stay on if they really want to because the trials were not perfect.

Right. Jason, what's your view?

Yeah, that was so well stated. I agree with all of that. I do think we've gotten a little overly negative on DOACs. We know the high risk patients, the arterial patients don't do well on those agents, but there's surely a subset of people with APS that would do okay. So you're on safest ground if you go with warfarin, I think the way Shruti framed the conversation is a good one, but there is some nuance there, and I think there's select patients that can do okay on DOAC.

Okay. I'm glad we got into that because I was going to ask about the DOACs. What about hydroxychloroquine's role? Obviously, has tremendous benefits in lupus, including an anti thrombotic event. It has tremendous benefits in pregnancy as far as fetal loss.

I'm just now going to say across the board, patients who have APL antibodies that are high risk or high titer triple positivity, should everybody be on hydroxychloroquine? It's not the only drug, obviously, on the clinical scenario, you might have to use anticoagulation as well. But should this be, as Michelle Petrie says, it's vitamin H for everyone with lupus. Could you use vitamin H for everyone who's at risk for thrombotic events with APL antibodies? Cassie, it's easy Yeah, for

it's easy for me. It's a very different scenario when pregnancy is in the mix.

Yeah, I think it's attractive. Getting the data to prove that this is an agent and there are there's some work underway in Europe right now, both in the setting of pregnancy and thrombosis is my understanding to try to show for those heart events that it makes a difference. But I mean, treating an autoimmune condition with blood thinners just is not appealing to either doctor or patient in terms of being the only thing we're doing. So I do kind of feel this gets us a little closer to the source of the problem. And I don't do it in everyone.

If someone has a simple venous thrombosis, it just seems to be otherwise healthy and totally fine, ANA negative. I mean, I'm not saying everyone should be on it, but when I have high risk patients, they're invariably on this, including those that are going for pregnancy. I can't imagine, well, and Cassie, I guess maybe now or later can tell us what she does, but I mean, all of my patients are nowadays on hydroxychloroquine just because I want to bring everything I can to bear.

Yeah, absolutely. Everybody, all of mine are on four hundred milligrams of Plaquenil daily during the pregnancy and at least six weeks postpartum, just to gain whatever benefit we can improve pregnancy outcomes. But it's not all patients. So if I'm seeing a non pregnant patient or somebody planning for pregnancy, I don't have them on it at that time. It's just during the pregnancy period and then the immediate postpartum.

Trudy, is there any of your colleagues in hematology who would strongly advocate for wider use of hydroxychloroquine?

I think I'm probably the only one, but I would restrict it to our high risk patients or patients failing anticoagulation. I struggle with the idea of doing it for primary prophylaxis and people who've not had an APL related event because a vast majority will never have an event. And we really would need well powered trials to make a strong recommendation in favor.

Okay, that's very helpful.

Do you prescribe it yourself, Shruti? Are you terrified of this specialized drug and could never do that?

I mean, considering that I also prescribe chemotherapy, hydroxychloroquine isn't that bad.

You're willing to do it? Okay.

She's held in high regard by the rooms over there at Hopkins.

Well, I will say it's amongst the least toxic drugs that I use, just putting it out there.

Absolutely. Here's a clinical scenario, an APS case recurrent thrombosis despite a therapeutic range with the use of warfarin with a PT of two to three. What's your next best step? The audience was kind of split the leading one third said add low dose aspirin to warfarin. The next choice was confirm the accuracy with a chromogenic factor ten assay as was spoken about, and the next was to switch to low molecular weight heparin.

Jason, you and Shruti were discussing this quite a bit. Jason, what's your approach here?

Yeah, and this is kind of what I thought might happen as we crafted this perfect perfect question is that we might get kind of a equal distribution amongst those three. I think those three choices are all things that could happen. The easy one is to do what Trudy suggested, which is confirm the INR because maybe that person was just being undertreated, Optimize the medication they're on before adding others. But I see both switching patients to low molecular weight heparin, that's sometimes something we do, versus adding an aspirin to the warfarin, especially in the Yeah, my practice is similar to Shruti's that I would often have a patient with an arterial history on an aspirin already. But certainly, if that's part of the mix, then aspirin becomes an obvious thing to add.

Shruti, what do you think? You took my simple question and made it more complicated for the audience.

Thank you.

Well, I would start with making sure the INR works. Because warfarin is infinitely easier than adding on an adipater agent, which also increases bleeding risk or going on low monoclavate heparin, which really does hurt. But, if I'm certain that my INR is accurate and they are adequately therapeutic on warfarin, if it was a venous clot, I would probably switch to low molecular weight heparin. And if it was arterial, on aspirin or go to a high dose of aspirin. But I have a pretty low threshold to add on something else at this point, that something else is either hydroxychloroquine and or off label anticompliment therapy.

If it's truly bad thrombo life threatening thrombosis, microvascular thrombosis that's happening despite anticoagulation, we'll have the doc, particularly microvascular type manifestations.

I have a few case questions. The patient has positive APL antibodies, whatever ones we do, but no history of any events, should they be on, aspirin routinely? Or is it only people with high risk APL profiles? Shruti, what do you think?

I think only high risk and the data supporting that also is not the most robust.

Cassie, in pregnancy, no history of events, including fetal events, but there's APL antibodies on board. Do you give everybody aspirin?

I would in this case. The big discussion is whether it's 81 or 162. As the audience knows, it's not just antiplatelet, but it's also a prophylaxis against preeclampsia. If this patient potentially is higher risk for a poor pregnancy outcome, we view the risk of adding on aspirin is quite low compared to the potential benefit of avoiding preeclampsia.

Yeah, Ben Lechner gives a case of a 70 year old man with an MI in 2004, a cerebellar stroke in 2017, who's on Plavix, has subsequent cerebral emboli, Eliquis was added, LAC was negative, APL and Beta two were moderately elevated. Should that be treated?

Well, it sounds like the patient needs some type of treatment. I mean, as you get into older individuals and more like borderline anti phospholipid antibody profiles, I think it becomes a little hard to disentangle whether it's kind of yeah, normal risk factors that are driving the thrombotic phenotype or the anti phospholipid antibodies.

No, I just want to add one thing for this particular type of story. This person needs a cardiac workup yesterday because you're seeing multiple emboli. This is screaming either PFO or a fib or some thrombus showering from somewhere.

That's very helpful. Our next question is one regarding pregnancy. A woman who's eight weeks pregnant and she's lupus anticoagulant positive since she's 35, a prior history of two miscarriages occurred early in pregnancy. How would you then anticoagulate this patient as they come to see you or would you anticoagulate? The choices, as you can see there are across the board.

Most of you chose both low dose aspirin and low molecular weight heparin. The next choice was just low molecular weight heparin. No one was brave enough to say no anticoagulation is needed. Cassie, what's your approach in this situation?

Yeah, this is what I was getting at at the beginning where you have somebody with a lupus anticoagulant and she has two early miscarriages, may not meet the technical criteria of obstetric APS because she needs one more early miscarriage. But I think this is a case where I would, of course, talk with maternal fetal medicine about potentially being more aggressive in doing both aspirin and low molecular weight heparin. And I understand that that is a conversation with the patient, it's risk benefit, but I am very concerned that this patient will have another miscarriage without intervention early on in the pregnancy. And as we know, this placental insufficiency that occurs, I mean, can occur very early on in the pregnancy, which is why you can have recurrent early miscarriages. So in order for us to be the most efficacious, it's really acting early on in the pregnancy.

I actually think that really speaks to your previous point about the timing of starting these therapies, both Lovenox and aspirin, because when we are waiting for a particular point of time to make sure there's not going be an ectopic or a loss or an abortion, you may be missing that window to prevent miscarriages as well. So I really lean towards when the line is pink on the pregnancy test, you start right that day.

Yeah. I'll just make one more point. Knight was on the impact study, congratulations, that was just recently published. Looking at TNF inhibitor use in obstetric APS. But the reason they dose a TNF inhibitor so early on in that clinical trial is because that's where they think the etiology of placental insufficiency starts is eight weeks of pregnancy.

So we really have to have a high clinical suspicion and be aggressive as early as possible.

Jason, could you summarize that study? I'm not familiar with it, and I think the audience would not be either. Is the IMPACT study?

Yeah, it was published in Annals of Rheumatic Diseases, but I think it's still in the kind of online only style, so it hasn't maybe gotten the full rollout. But this is the study that was led by Jane Salmon at HSS Cornell and Ware Branch, who's an obstetrician, famous in the APS world in Utah. And they added SertilizumabCimzia to normal standard of care. I guess selected that one because of its pegylation is felt to be the very optimal one for not exposing the fetus. And it was rationale based on the inflammatory aspects of APS going back to work Jane Salmon had done in mice, kind of, I mean, really approaching twenty years ago now.

So I think a labor of love from her. But it was not a randomized study, and so I don't think it's going to have the juice to acquire an approval. But I do think it provides useful information for that refractory patient where all the right things have been done. And we'll see what the future holds. Maybe it will become something we just do automatically.

But I think for now it's probably thinking about it as something you could bring to bear in someone who's not getting good outcomes despite standard treatment.

Again, the cerdulizumab had a protective effect?

Yeah, so it was a good outcome and that compared to historical control. So that's a caveat to the study as they went with historical controls, filling the randomizing this population wasn't going to be easy. But compared to historical controls, these folks seem to do better. Everyone was on Lovenox and aspirin and most were also on hydroxychloroquine in addition to the sartilizumab.

Excellent. All right, very helpful.

Sorry, buried the lead there, the high level outcome. No,

that's okay. I want to end with each of our panelists giving us important take home messages from this session that you have a captive rheumatology audience, what's the thing they really need to focus on? I just suggest, are there mistakes in testing, mistakes in management, or what should we be doing in pregnancy with APL? Let me begin with Doctor. Chatterveti.

Thank you, Jack. I think we've gone through a lot of these, but, you know, very briefly, mistakes in testing, I'd say would be no timing of testing, testing while on anticoagulants, so, which makes the testing the interpretation of the lupus anticoagulant test itself unreliable. And sometimes I think for the highest risk patients, the patients coming in with, you know, I'm not catastrophic APS, but life threatening thrombosis, large organ threatening thrombosis, waiting three months before before putting them on warfarin versus another agent may be a mistake just to just to confirm testing. Something, else I'd like to add in here is that, you know, we should not forget to evaluate reversible risk factors or transient risk factors even in patients with antiphospholipid antibodies because they do plague the risk of thrombosis is multifactorial, and sometimes it's not the antibody itself. And that speaks to things like, you know, maybe the person was on oral contraceptive pills.

Maybe that's not such a great idea if they can, contain estrogen. There may be other reversible risk factors that should be addressed, whether it's smoking or hypertension, etcetera. The antibodies don't operate in a vacuum. It's a multi hit disease, and we owe it to our patients to deal with each and every one of those. And finally, something that I didn't run into very early in my career, but I'm starting to run into it now that I've been following patients for well over five years, is that it's worth doing a, you know, bleeding risk assessment on these patients as well, at least every year or two, because having APS doesn't mean that you cannot bleed.

And the worst thing, I've had to deal with is someone with real deal APS and who's also bleeding. So if we can prevent the bleeding, that's better.

Excellent advice. Jason. Yeah, those were

all brilliant pearls. Mistakes in testing, it's beta-two glycoprotein, not beta-two microglobulin. If you find the house officer who knows that as an intern especially, peg that person for rheumatology. But I think we covered other things I see on that front, so I think we did a good job during this session. And mistakes in management, I think just a general concept, which maybe won't be the specificity people want, but I just get tired of being reactive, and I think I just look for areas where I can be more proactive with making adjustments.

Think that's why I try to do a good set of labs once a year and just kind of re risk stratify this patient and look for opportunities to be proactive with your patients. Of course, no one ever messages you, Thanks for being proactive. I didn't get a clot today. You only get the bad news. That's the challenge of managing this condition.

Jason, you want to address the issue of long term management. Once they qualify with an event and a high risk antibody profile, are they forever on anticoagulation or can they go off? Like Trudy was saying, sometimes their risk factors for clotting will change and maybe you can stop therapy, but is it basically long term management, long term anticoagulation?

Nobody knows if you can stop. I try to write a provocative editorial for ANR that went online today, though it's still not formatted and I guess won't be for a few months. But I think we may be entering an era where we have immunomodulatory treatments, some of these fancy newer ones that actually allow us to make the antibodies go away. And so what are we going to do in those scenarios? I mean, I think we are gonna have to tackle this question in the coming years as we get smarter with some of our therapies.

I would posit that these antibodies are pathogenic, not just markers of disease, and if we can cure the antibodies, then maybe we've cured the patient. But it's going to be a complicated topic that's going to take some hard work to figure out.

Cassie, why don't you close with your advice when pregnancy is in play as regards these antiphospholipid antibodies and the syndrome?

Yeah. I think the one thing is cautiously interpreting APS serologies during pregnancy. Things like ESR and CRP, they can be impacted by a physical pregnancy state and so can APS serology. So just keeping that in mind, but also being aggressive upfront with treatment like we were talking about before. And the last thing I'll say is that APS serologies impact a lot of major reproductive milestones in patients' lives.

So it affects your contraceptive options. So should women just have IUDs or progesterone only pills they're higher risk than they have thrombotic or obstetric APS? Can they undergo reproductive technology, which uses a ton of exogenous hormones? And can they do hormonal therapy during perimenopausal phases? So this truly affects the lifelong opportunities of women who have APS and potentially overlapping lupus.

I am constantly collaborating with maternal fetal medicine, but also hematology when making these decisions because it can be very complicated and most things are off label, as Shruti said. Just keeping that in mind and giving patients the options and allowing them to be empowered to make the decisions for themselves as well.

Can you make a concluding statement on how rheumatologists should be using maternal fetal medicine specialists?

Early and often, especially about reproductive health conversations. But the biggest thing that, you know, I tell patients when they are concerned about getting pregnant, planning your pregnancy with all the right subspecialists plugged in, which in this case would be hematology, maternal fetal medicine, is probably one of the biggest ways that we can mitigate complications and reduce the risk for adverse pregnancy outcomes. So, we see patients who have experienced multiple fetal losses, and that is physically exhausting, but it also takes a massive mental toll on these patients. And so everything we can do upfront with maternal fetal medicine, and that is APS testing, discussing who's gonna prescribe the Lovenox, when to start it, and adding aspirin and Plavix, and seeing the patient every six to eight weeks throughout the pregnancy is key in order to monitor them closely and optimize pregnancy outcomes.

Excellent. I want to remind our audience that next week we'll be discussing pregnancy and lupus with Drs. Megan Clouse, Lisa Samaritano and Jill Bullion. It too will be another lively session here on Tuesday at Rheumatology. My thanks to Shruti, Jason, and Cassie for a great session.

Tune in next week.