Diagnosis and management of antiphospholipid syndrome

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Today on the Australian Prescriber Podcast, we are talking about a rare multisystem autoimmune disorder, antiphospholipid syndrome. I'm Dr Laura Beaton, your GP host for this episode. Now, unless you're a healthcare professional who works in a tertiary rheumatology or obstetric or fetal medicine setting, like me it might've actually been a really long time since you’ve thought about antiphospholipid syndrome. Dr Paul Kubler is the Director of Rheumatology at the Royal Brisbane and Women's Hospital, and along with colleagues, has written an article for Australian Prescriber that covers the diagnosis and management of antiphospholipid syndrome. Paul, thanks so much for coming on the show today to refresh us all.

Thanks very much for having me along.

Antiphospholipid syndrome is very rare, and so let's start with the kinds of clinical presentations that might make us think could this be antiphospholipid syndrome, or APS for short.

For a clinician, the 2 main ways that you'll see it is both thrombotic manifestations, and typically the most common one is a DVT [deep vein thrombosis] or a pulmonary embolism, but other things that you can see as a thrombotic manifestation are a central venous thrombosis or an unexplained acute arterial event, such as a myocardial infarct in a person who's relatively young, who's got a paucity of the traditional cardiovascular risk factors, and they're the most common sort of thrombotic manifestations. Occasionally, you do see some other manifestations such as someone who has a thickening on a heart valve that's unexplained. The other one you should think about too is stroke. So not just heart attacks but strokes in an otherwise young person.

Now the second type of manifestation is the obstetric manifestations. So typically, this is in a young to middle-aged woman, who has recurrent miscarriages or an unexplained loss of pregnancy either in the late first trimester or at any point thereafter in the pregnancy.

So we find that that's become an increasingly recognised testing modality where a lot of women having 2 or more miscarriages [are] having testing done and it's identified. Now, probably an easy way to think about obstetric APS, it's akin to gestational diabetes. It means that person probably has an increased risk of developing thrombotic manifestations down the track [in] 7 to 10 years. And it's a little bit unclear how many of those people with obstetric manifestations will go on to develop thrombotic [manifestations], but it's probably more than half [who] will develop an event. And as a general practitioner, if you see someone who's had a history of an obstetric event, then it's probably worthwhile to really address the traditional cardiovascular risk factors and be quite aggressive about it, like blood pressure, lipid profile, smoking cessation, optimal weight, to try and reduce their risk of future thrombotic events.

That's a really helpful practice point because as you said, this is really rare, but in general practice, we will come across these people and be thinking about their holistic care around their antiphospholipid syndrome. And so we've gone through those major clinical manifestations. Once we suspect that maybe antiphospholipid syndrome might be what's going on, what's the actual diagnostic pathway that gets followed?

So then we would do some testing. There's 2 antibody tests, an anticardiolipin test and an anti-beta2-glycoprotein, and then a non-antibody test called lupus anticoagulant. So they're the 3 tests. They should be really done together as a trifecta. And then you also look to see is it related to an underlying problem? So typically, you would do a full blood count, so sometimes people with primary antiphospholipid syndrome will have mild to moderate thrombocytopenia, which is unexplained. They may have some other haematological abnormalities. And then you've got to think, is there an underlying connective tissue disease associated with it? The most common being lupus, but it can appear in other conditions such as Sjögren's and scleroderma. So you think about is there an associated autoimmune connective tissue disease. And then to make the diagnosis, usually you like to see the persistence of the antibody. So we would usually do the antibody testing on 2 occasions separated by a period of around 12 weeks. So you want to know that it's a persistent phenomenon.

Sometimes when it's tested on a singular setting, you can get a false positive at a low level as a transient phenomenon. So we sometimes see that after someone who's had this significant infection, which can be either viral or bacterial. So you want to see the persistence of the antibody. But mind you, if someone presents acutely with a DVT and has a high level of an anticardiolipin antibody or equivalent, they've probably got the real deal and they're going to have a persistent antibody. So you shouldn't delay treatment based on waiting for the second test, but we nonetheless do the second test more than 12 weeks apart just to confirm that it is persistent.

And your article does go through some of the pitfalls that we need to consider with antibody testing, and you've mentioned non-persistence of these antibodies, some false negatives. Any others that we need to keep in mind?

Anticardiolipin antibody testing in Australia, it's not standardised, and that creates some difficulty. There's a significant number of pathology providers through Australia, and they use a variety of different assays with also different cut-off thresholds for what is a positive and negative test. So sometimes they're not always interchangeable. One of the key points, particularly for an anticardiolipin or an anti-beta2-glycoprotein, is the level of the titre. The higher it is, the more likely it is to be real. So if you're unsure because it's a low-level titre, that's probably where it requires a little bit more specialist interpretation. But if it's a high-level titre, it's probably a real result.

And that's a principle that rings true for a lot of antibody testing we're doing in other fields of medicine where low titre [is] really quite common [and] reasonably likely to be a false negative.

It's the same for us like a rheumatoid factor, a really high rheumatoid factor is probably rheumatoid arthritis or another connective tissue disease, or a very high ANA (antinuclear antibody) result particularly in a younger person is probably a real result, and a low titre is often not necessarily clinically significant.

I will recommend that everybody, if you're really interested in nerding out on the immunology, check out Table 1 in the article which goes through what each antibody does.

Lupus anticoagulant, that's probably the most significant one to identify. It has the most significance for developing a clinical thrombotic event. So that's the highest risk of developing a future thrombotic manifestation. That automatically puts someone in a moderate risk of recurrence if they're presented with one clot and have a positive lupus anticoagulant.

Your article also goes through the fact that a diagnosis has both clinical and lab criteria, and that's been updated 2023, I believe.

Yes, correct. Yep.

And in general practice, we're probably not making this diagnosis, but for your reference, everybody, Table 3 has all of the lab and clinical criteria to make a diagnosis.

I find these classification criteria actually quite helpful. I don't tend to use it meticulously in clinical practice, but the principles of what it's sort of telling you is how you interpret the results. For instance, say you've got a venous thrombosis or an arterial thrombosis, if you've got [a] high cardiovascular risk profile, it's scored lower than if you've got no cardiovascular risk profile. So it sort of makes sense that it's scoring it based on is there an alternative explanation or not.

That sounds very helpful clinically. So it sounds like diagnosis is probably case finding after clinical manifestation, and there is certainly not a recommendation for general screening for antiphospholipid syndrome, but there is a certain cohort of patients that really should get screened. Who are these?

Well, I think the screening patients are anyone who's got an autoimmune connective tissue disease, in particular lupus, they should probably have these done, and that's typically in young women. So that's often important to know that at baseline, because often future pregnancy is being considered. In terms of the obstetric manifestations, as I said, I think I'd stick more to recurrent miscarriage. That's probably the most common scenario, or an unexplained loss of pregnancy after about 10 weeks for any reason. So if they haven't identified a chromosome or abnormality on fetal analysis, that was where you'd probably test upfront.

Let's move on now from diagnosis to treatment. What are the medications that we use?

So if you've developed a thrombotic manifestation and you test positive on the antibodies, most patients are going to require warfarin. And warfarin is probably required indefinitely, lifelong. The main reason is depending a little bit on their antibody profile and other cardiovascular risk factors, they've got a pretty substantial risk of developing a second thrombotic event in their lifetime. And when I say substantial, at least 40 to 50% chance. So that's usually what I say to a patient as in, this is the reason why you need long-term anticoagulation because there's close to a 1 in 2 chance you are going to develop another significant blood clot at some point in the future. Most people will find that an unacceptably high risk. Often patients will want to ask you about can I use a direct acting oral anticoagulant? That is used in some selected scenarios, but there was a study done just prior to COVID comparing warfarin with a direct acting oral anticoagulant in patients who are at moderate to high risk of a recurrent [thrombotic event], and determined that direct acting oral anticoagulants were inferior. So for most patients, warfarin is the desired long-term anticoagulation.

There is some question mark still about whether people who are at the lower risk profile, and when I mean a lower risk profile, they don't have a lupus anticoagulant and they only test positive for one of either lupus [anticoagulant], anticardiolipin antibody, or anti-beta2-glycoprotein. That's where you may consider a direct acting oral anticoagulant. And of course, sometimes patients have got unstable INR control on warfarin, or they just had an allergy to warfarin, which is pretty uncommon, or they're just unable to achieve a target INR. Again, that's a very unusual or select scenario. So most patients with a thrombotic manifestation will end up being on warfarin, and that's the best treatment for them with moderate to high risk of recurrence.

Obstetric antiphospholipid syndrome is a different scenario. Most of that is trying to manage that person through a successful pregnancy with a healthy baby outcome. And so typically that involves low-molecular-weight heparins with aspirin in the preconception phase throughout the pregnancy and then for up to 6 to 12 weeks thereafter.

Of course, one of the risks though with using extended periods of low-molecular-weight heparin, particularly in young women, is that it increases their bone loss, so it puts them at an increased risk of osteoporosis when they're on extended courses that go for such a long period of time. But that is generally the treatment of it. For most people, you'd be thinking prophylactic low-molecular-weight heparin with low-dose aspirin to achieve a pregnancy, and then to make sure that pregnancy progresses to term with minimal complications. One of the risks of untreated antiphospholipid [syndrome] is that you get placental insufficiency, so you'll have premature birth, a small birthweight baby. So the idea is to try and get someone pregnant and then also to get them through to term with a normal healthy baby.

It does sound like these are high-risk pregnancies that are going to be co-managed by their rheumatologist, but also an obstetric or maternal fetal medicine specialist as well.

Yeah, definitely. And then of course, we're worried in the postpartum phase that they're at increased risk of developing a thrombotic manifestation, so that's why we extend the anticoagulation beyond the delivery for 6 to 12 weeks depending on the scenario.

So to round out our conversation today, treating the 2 extreme ends of clinical presentations, one is catastrophic antiphospholipid syndrome and also those asymptomatic people who have persistent antiphospholipid antibodies. So we actually didn't talk about catastrophic antiphospholipid syndrome earlier, but this is going to be treated in ICU. If it is catastrophic APS, what do we specifically use to treat it?

It's a really difficult scenario, which happens uncommonly, but involves basically anticoagulation. Typically, we will put someone onto full doses of heparin. It often involves high-dose steroids and then is often followed by either plasma exchange or rituximab. From a general perspective, with catastrophic antiphospholipid [syndrome], it's most important to try and recognise it early. Often people get delayed presentations. I think the most important thing is to be aware of when it can occur, and it's basically at a juncture, as in a switch of anticoagulation, sometimes in an elective, but sometimes in an acute unwell state. So typically we see someone ceasing warfarin to go onto a prophylactic heparin, usually to have an elective procedure such as a colonoscopy, or they've come in to have some elective surgery. The other time when they might get it is they present with an acute abdomen and require cessation of warfarin because they're going to surgery and they're already got an active infection and dehydrated.

Now, the asymptomatic people, again, a lot of uncertainty. So in someone who's got a connective tissue disease, it informs you that you may want to treat them if they're planning a pregnancy, so you might want to follow the obstetric care pathway in terms of preconception and obstetric care. One of the common questions that arises is about what should I do for thromboprophylaxis if I'm going on a long-haul flight or travel? I don't think there's any clear answer, but I would probably assess the patient's overall cardiovascular risk factor profile and look at things like their traditional cardiovascular risk factors, smoking cessation and all the other mechanisms, talk to the person about what risk they're prepared to accept or not accept, and then tailor the treatment based on their concerns about the risk, because there's no clear answer to be honest.

And don't worry, in general practice, we are really used to working with no clear answers and tailoring our approaches for each individual person because it is tricky. We often do have people who, for whatever reason have had this test done and it is a persistent presence of this antibody, and they haven't had a manifestation. People who have had serious consequences are often really motivated to have treatment so that they don't have it happen again. So it's good to know that this is an area that requires patient-centred management according to their individual risk factors. Thanks so much, Paul, and also to your colleagues for this article and your time today to go through the discussion of the key points around antiphospholipid syndrome.

Thanks very much.

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The views of the hosts and the guests on the podcast are their own and may not represent Australian Prescriber or Therapeutic Guidelines. Paul Kubler has received funding from AbbVie for trials of upadacitinib for systemic lupus erythematosus. Paul was a member of the expert group for Therapeutic Guidelines Rheumatology version 4. Paul has received funding from AstraZeneca for educational content related to anifrolumab.