Antiphospholipid syndrome (APS) management: a 2023 update and practical algorithm-based approach

Abstract

Purpose of review:

Antiphospholipid syndrome (APS) is an acquired thrombo-inflammatory disease that has morbid and sometimes devastating effects on patients and their families. This review will discuss the most recent international societal treatment guidelines and propose practical management algorithms for various APS sub-types.

Recent findings:

APS represents a disease spectrum. While thrombosis and pregnancy morbidities are traditional hallmarks of APS, a variety of extra-criteria clinical phenotypes can often be seen, which makes clinical management more challenging. Primary APS thrombosis prophylaxis should take a risk-stratified approach. While vitamin k antagonists (VKAs) or heparin/low molecular weight heparin (LMWH) remain the preferred treatment for secondary APS thrombosis prophylaxis, some international society guidelines support the use of Direct Oral Anticoagulant (DOACs) in certain circumstances. Careful monitoring and individualized obstetric care with the use of aspirin and heparin/LMWH will improve pregnancy outcomes among pregnant individuals with APS. Treatment of microvascular and catastrophic APS remains challenging. While the addition of various immunosuppressive agents is often utilized, further systemic evaluations of their use are warranted before definitive recommendations can be made. Several new therapeutic strategies are on the horizon that might enable more personalized and targeted APS management in the near future.

Summary:

Although the knowledge of APS pathogenesis has grown in recent years, the management principles and strategies are largely unchanged. There is an unmet need for evaluating pharmacological agents, beyond anticoagulants, that target diverse thromboinflammatory pathways.

INTRODUCTION

Antiphospholipid syndrome (APS) is an acquired thrombo-inflammatory disease that has morbid and sometimes devastating effects on patients and their families. Clinically, APS represents a disease spectrum that makes management challenging. While thrombotic and pregnancy morbidities are traditional hallmarks of APS, various extra-criteria clinical manifestations can often be seen. Examples of such manifestations include hematologic derangements (thrombocytopenia, hemolytic anemia), cardiac valve thickening or vegetations, nephropathy, cognitive dysfunction, and livedo reticularis/racemosa (1). APS may exist in its primary form when it occurs in isolation or may be associated with other autoimmune diseases, particularly systemic lupus erythematosus (SLE) (2). Catastrophic antiphospholipid syndrome (CAPS), characterized by thrombi in multiple microvascular beds leading to multi-organ failure with high mortality, develops in a small subgroup of APS patients (3). A recent study estimated that the overall prevalence of APS is 50 per 100,000 people, and the incidence of APS is approximately two persons per 100,000 people per year (4). While the prevalence of persistently positive antiphospholipid antibodies (aPL, assessed by either ELISA or a functional assay) among the general population remains unknown, various cohort studies suggest that aPL might be present in 1–12% of healthy individuals (5–7). However, those studies are often limited by inconsistent testing methods and heterogeneity in the definition of positive aPL (7). This review will provide an update and a practical approach for managing aPL-positive and APS patients.

CLASSIFICATION CRITERIA

The current classification criteria for APS, devised in 1999 and revised in 2006, confirm the presence of disease when one or more aPL [lupus anticoagulant (LA), anticardiolipin antibodies (aCL, IgG, and/or IgM), and anti-beta-2 glycoprotein-I antibodies (aβ₂GPI, IgG and/or IgM)] are persistently positive in the setting of either vascular thrombosis (venous, arterial, or small vessel) or obstetric morbidity (fetal demise at or beyond ten weeks, recurrent early miscarriages before ten weeks, or premature delivery before 34 weeks due to severe preeclampsia or placental insufficiency) (8). These criteria are somewhat outdated, and their deficiency during real-world application has been widely recognized (9). Therefore, over the past few years, a joint effort by the American College of Rheumatology (ACR) and the European Alliance of Associations for Rheumatology (EULAR) is underway to develop and validate a new multi-criteria additive points system for APS classification, employing a balance of expert and data-driven methods (10). The first two phases of the clinical criteria-building process were published in 2021. They identified 27 APS candidate criteria in 6 clinical or laboratory domains utilizing data and consensus-driven methodology (10). Phases three and four focused on item reduction, weighting, threshold identification, and validation (9). The ACR and EULAR’s executive committee will review the draft criteria for final approval before publication.

PRIMARY THROMBOSIS PROPHYLAXIS

Many patients can have clinically significant aPL profiles without a history of thrombosis or obstetric morbidity. A clinically significant aPL profile is defined by the persistent presence of aPL (LA test and/or moderate-to-high titer aCL/aβ2GPI, with cut off threshold of >40 GPL/MPL or above 99th percentile titer for the testing laboratory) at least 12 weeks apart (11). The exact risk of future thrombosis in these patients is difficult to ascertain, given that the process of thrombosis is multifactorial (11, 12). A 2018 study reviewed the existing literature and noted that the annual incident thrombotic risk among aPL-positive carriers was between 1.3–5.3% (12). Several studies evaluating the risk of first thrombosis among individuals with clinically significant aPL have noted the higher annual incidence of thrombosis in individuals who are double or triple-aPL positive or in those with positive LA (13–16). Notably, most of the aPL carriers in these studies also had other underlying systemic autoimmune diseases, such as lupus, which is an independent risk factor for thrombosis (13, 14, 17). It is noted that the thrombosis risk among patients with no underlying systemic autoimmune diseases is probably very low, less than 1% per year (12). When deciding on the optimal primary thrombosis prevention strategy, it is essential to consider individual patient characteristics such as cardiovascular disease, hypertension, smoking, diabetes, systemic autoimmune disease, and aPL profile.

ASPIRIN

Low-dose aspirin (LDA) has been utilized as primary thrombosis prophylaxis for persistently aPL-positive patients. However, its use remains controversial. Only one randomized controlled study to date evaluated the effect of aspirin in preventing first thrombotic events in individuals who were persistently aPL-positive but had no history of thrombosis (18). After a median follow-up of 2.3 years, daily LDA was not shown to prevent thrombosis when compared with placebo (hazard ratio [HR] 1.04, 95% CI 0.69, 1.56, P= 0.83). It is important to note that this study is limited by a small sample size and low incidence rate (2.75 per 100 patient-years in aspirin-treated subjects and 0 per 100 patient-years for the placebo-treated subjects) (18). Two subsequent meta-analyses suggested that LDA has a protective role in individuals with asymptomatic aPL and those with SLE (19, 20). The recent EULAR treatment guidelines for APS endorse the use of LDA for primary thrombosis prophylaxis in aPL-positive carriers with high thrombotic risk (21). The 16th International Congress on Antiphospholipid Antibodies also noted that LDA could be considered in patients with high-risk aPL profiles (such as persistently positive LA, double or triple positive aPL, or high titer aPL) while also considering individual risk for bleeding and gastroesophageal reflux. However, they also recognized that a randomized controlled trial is needed to understand better the appropriate use of LDA in primary thrombosis prophylaxis (1).

STATINS

Statins, also known as HMG-CoA reductase inhibitors, have been shown to protect against inflammation and thrombosis (22, 23). A 2018 single-center retrospective study found that statins were protective against thrombosis in the aPL-positive group (24). It is important to note that this study included individuals who were positive for non-criteria aPL (such as anti-phosphatidylserine/prothrombin antibodies). When the analysis was limited to patients with only criteria aPL, no statistically significant benefit was noted with statin use (24). Several mechanistic studies detail the effects of statins on various thrombo-inflammatory markers in aPL-positive patients. A 2011 study utilized 20 mg of daily fluvastatin taken for one month amongst APS patients and healthy donors. The study showed that baseline expression of tissue factor (TF), protease-activated receptor-1 (PAR1), and protease-activated receptor-1 (PAR2) were much higher in the APS group compared to the healthy donors. After fluvastatin treatment, monocytes from the APS group had significantly reduced TF, PAR1, and PAR2 expression (22). Similarly, a 2014 study showed that three months of treatment with 40 mg daily fluvastatin significantly decreased circulating prothrombotic and proinflammatory markers among aPL-positive and APS patients (25). While the definitive role of statins for primary thrombosis prevention among aPL-positive patients remains unclear, the 16^th International Congress on Antiphospholipid Antibodies suggested that statins may be considered in aPL-positive patients with additional cardiovascular risk factors (1). And recent EULAR recommendations for cardiovascular risk management in rheumatic diseases, including APS, also endorsed a similar approach (26).

HYDROXYCHLOROQUINE

Hydroxychloroquine (HCQ) is an essential disease-modifying agent that is routinely utilized in the treatment of SLE. In APS mouse models, HCQ was shown to reduce thrombus size and persistence (27). HCQ has also been shown to prevent the formation of aPL- β₂GPI complexes, protect the endothelial annexin-A5 matrix and rescue in-vitro aPL-mediated endothelial dysfunction (28–30). A prospective observational study suggested that HCQ use was protective against thrombosis in SLE patients with and without aPL (31). The HAQ trial was the only prospective randomized controlled trial (RCT) to evaluate HCQ for primary thrombosis prevention in persistently aPL-positive patients with no prior history of thrombosis. Unfortunately, it was terminated early due to the low recruitment rate and high cost (32). A more recent open label, randomized, prospective study evaluated the efficacy and safety of HCQ for thrombosis prevention in patients with APS. The study followed 50 primary APS patients and 15 asymptomatic aPL carriers over an average of 2.6 years. HCQ was safe among primary APS patients and aPL-positive carriers. Primary APS patients who received HCQ plus standard care (anticoagulation plus or minus an antiplatelet agent) had a marginally lower incidence of thrombosis after adjusting known thrombosis risk factors than those who received standard care alone (HR 0.09, 95% CI 0.01, 1.26, P= 0.074). The study also found that long-term HCQ use was associated with decreased aPL titers in the asymptomatic aPL carriers (33). While the result of this study is encouraging, further dedicated RCT to evaluate the role of HCQ as a primary thrombosis prophylaxis agent among asymptomatic aPL carriers is warranted before making a more definitive recommendation. The 16th International Congress on Antiphospholipid Antibodies suggested HCQ should be considered as primary thrombosis prophylaxis among aPL-positive patients with underlying systemic autoimmune diseases such as lupus (1).

WARFARIN / VITAMIN K ANTAGONISTS

Warfarin is an essential treatment for APS secondary thrombosis prophylaxis. However, its role in primary thrombosis prophylaxis was not explored until a prospective, randomized controlled trial in 2014 (34). The study examined the efficacy of a low-intensity warfarin regimen (INR of 1.5) plus LDA in comparison with LDA alone as primary thrombosis prophylaxis in aPL-positive patients. No difference was found between the number of thrombotic events in the group treated with LDA plus low-dose warfarin compared to the group treated with LDA alone. It is important to note that 11 individuals in the LDA plus low-dose warfarin group developed bleeding side effects (34). Available data do not support long-term low-intensity warfarin for primary thrombosis prevention in aPL-positive carriers.

Here we propose a practical approach for primary thrombosis prophylaxis based on available data and current guidelines (Figure 1).

Figure 1.

Practical treatment algorithm for primary thrombosis prophylaxis of antiphospholipid lipid antibodies positive individuals.

SECONDARY THROMBOSIS PROPHYLAXIS

WARFARIN / VITAMIN K ANTAGONISTS

Vitamin K antagonists (VKAs), such as warfarin, remain one of the mainstays for secondary thrombosis prevention in patients with both primary and secondary thrombotic APS. Debate exists regarding the optimal intensity of warfarin therapy in APS patients. Two randomized controlled trials investigated the optimal anticoagulation intensity of warfarin in preventing thrombosis among APS patients (35, 36). Both studies found that high-intensity warfarin therapy (INR of 3.0 – 4.5, or 3.1 – 4.0) was not more effective at preventing recurrent thrombotic events than standard intensity (INR of 2.0 – 3.0) therapy in APS patients (35, 36). Some experts in the field argue that the proportion of participants who persistently achieved the higher INR target was low, and a very limited number of APS patients with arterial thrombosis were enrolled. They, therefore, continue to endorse high-intensity warfarin or the combination of LDA and standard-intensity warfarin among high-risk APS patients with a history of arterial thrombosis, citing older systemic reviews and observational studies (37, 38). There is also very limited high-quality evidence guiding the management of patients who have recurrent venous thrombotic events despite being treated with standard-intensity warfarin. For these patients, current EULAR recommendations (assuming they adhere to warfarin) suggest either adding LDA, aiming for a higher INR target of 3–4, or transitioning to LMWH (21).

DIRECT ORAL ANTICOAGULANTS

Direct oral anticoagulants (DOACs) are routinely used to treat deep vein thrombosis, pulmonary embolism, and atrial fibrillation. They have several benefits compared to VKAs, such as a lack of routine lab monitoring, fixed dosing, minimal drug-drug interactions, and a lack of need for dietary modifications. Given these practical benefits over VKAs, DOACs have been investigated recently as secondary thrombosis prophylaxis among thrombotic APS patients. Four randomized controlled trials have evaluated the effectiveness and safety of DOACs for secondary thrombosis prevention among APS patients (39–42). We have summarized the findings of these trials in Table 1. Overall, these randomized controlled trials failed to demonstrate the non-inferiority (in terms of safety and efficacy) of DOACs compared to warfarin among thrombotic APS patients.

Table 1.

Summary of all randomized controlled trials evaluated DOACs as secondary thrombosis prophylaxis agent for APS.

Year	Authors	Study Description	Results
2016	Cohen, et al. (RAPS) [39]	-116 patients with APS −54 randomized to the rivaroxaban group (20 mg daily) −56 randomized to the warfarin group (continuation of previous therapy) -Primary outcome was a percentage change of endogenous thrombin potential (ETP) from randomization to day 42	-ETP was higher at day 42 in the rivaroxaban group (geometric mean of 1086 nmol/L/min, 95% CI 957, 1233 vs. 548, 95% CI 484, 621) -ETP for rivaroxaban did not reach the non-inferiority threshold, and the primary endpoint of the study was not met
2018	Pengo, et al. (TRAPS) [40]	-120 high-risk patients (triple positive for aCL, aβ2GPI, and LA of the same isotype) −59 randomized to the rivaroxaban group (20 mg daily) −61 to the warfarin group (target INR 2.5) -Mean follow-up of 569 days -Composite primary outcome was thromboembolic events, major bleeding, and vascular death	-The composite primary outcome occurred in 11 patients in the rivaroxaban group and 2 patients in the warfarin group -Study terminated prematurely due to an excess of events in the rivaroxaban group
2019	Ordi-Ros, et al. [41]	-190 patients with APS −95 randomized to the rivaroxaban group (20 mg daily) −95 were randomized to the vitamin K antagonist (VKA) group [target INR of 2.0 – 3.0 or 3.1 – 4.0 (if there was history of recurrent thrombosis)] -Follow-up of 36 months -Primary efficacy outcome was the proportion of patients with new thrombotic events	-The rivaroxaban group had 9 recurrent thrombotic events while the VKA group had zero (RR: 19.00, 95% CI 1.12, 321.90) -Rivaroxaban did not show non-inferiority to dose-adjusted VKAs in thrombotic APS
2022	Woller, et al. (ASTRO-APS) [42]	-48 patients with APS −25 randomized to the warfarin group (target INR of 2.0 – 3.0) −23 randomized to the apixaban group (2.5 mg twice daily) -Follow-up of 12 months -Primary efficacy outcome was clinically overt thrombosis and vascular death -Study protocol was modified twice, which included increasing apixaban to 5 mg twice daily, and pre-screening participants with brain MRI to confirm absence of prior stroke or white matter changes	-The study was ended prematurely when 6 out of the 23 patients randomized to the apixaban group had a stroke, whereas none of the 25 patients randomized to the warfarin group had a stroke -Suggested that apixaban should not be routinely substituted for warfarin to prevent recurrent thrombosis in APS patients, particularly in those patients with a history of arterial thrombosis

A recent systematic review highlighted various international societies’ recommendations regarding the use of DOACs in APS (43). We note that the 2019 European Society of Cardiology (ESC) and American Society of Hematology (ASH) guidelines recommended against the use of DOACs in all APS patients (44, 45). Whereas the European League Against Rheumatism (EULAR), British Society for Hematology (BSH), and International Society on Thrombosis and Hemostasis (ISTH) had more nuanced recommendations which stated that while warfarin should remain the first-choice agent, DOACs could be considered for non-triple-positive patients who are already stable on a DOAC, unwilling to undergo INR monitoring, have low adherence to VKAs, or who have a history of serious adverse events or contraindications to VKAs (21, 43, 46, 47). Based on current guidelines, we proposed a practical approach for secondary thrombosis prophylaxis (Figure 2).

Figure 2.

Practical treatment algorithm for secondary thrombosis prophylaxis of APS patients.

OBSTETRIC MANAGEMENT

The absolute adverse pregnancy outcome risk associated with aPL is challenging to assess and often confounded by aPL profiles, maternal age, obesity, and other chronic conditions predisposing individuals to adverse pregnancy outcomes such as hypertension, kidney disease, and systemic autoimmune diseases (48, 49). Various studies suggest that the persistent presence of LA is likely the single most powerful predictor of obstetric complications. For example, a prospective observation of 44 aPL-positive patients found that LA was present in 69% of patients with adverse pregnancy outcomes compared with 27% of patients without adverse pregnancy outcomes (50). A meta-analysis of case-control studies found LA significantly associated with preeclampsia (OR 2.34, 95% CI 1.18–4.64), intrauterine fetal growth restriction (OR 4.65, 95% CI 1.29–16.71), and fetal death (OR 4.73, 95% CI 1.08–20.81) (51). Furthermore, aPL-positive women with a history of thrombosis, SLE, or prior pregnancy morbidities have a heightened risk for future adverse pregnancy outcomes (52–55).

The goal of obstetric management of aPL-positive or APS patients is to reduce the risk of adverse maternal and fetal outcomes. Current recommendations are primarily derived from small trials, observational studies, or expert consensus. Here we will summarize pertinent evidence and updated treatment recommendations for three clinical APS-related obstetric scenarios (Figure 3).

Figure 3.

Practical treatment algorithm for obstetric aPL positive or APS patients.

ASYMPTOMATIC aPL CARRIERS

Early studies of pregnant women with positive aPL but lacking a history of SLE or traditional APS showed no difference in the live birth rate with the use of LDA (56–58). Patients enrolled in these studies did not meet the criteria for APS and had no prior history of thrombosis. Therefore, the overall low obstetric risk of enrolled participants may have affected the detection power of these studies. A recent randomized controlled trial of 1176 individuals with general high-risk pregnancy (advanced maternal age, smoking, hypertension, diabetes, low-level pregnancy-related plasma protein A, and a small number of patients with APS) found that aspirin led to a significantly lower incidence of preterm preeclampsia (59). Current ACR guidelines for the management of reproductive health support the use of LDA (81 to 100 mg daily) before 16 weeks gestation among pregnant individuals with positive aPL (60). In contrast, EULAR guidelines only recommend aspirin for women with high-risk aPL profiles, such as persistently positive LA or double/triple positive aPL (21).

APS WITH HISTORY OF OBSTETRIC APS CLINICAL MANIFESTATIONS (NO HISTORY OF THROMBOSIS)

The best treatment strategy for this clinical scenario continues to be debated due to conflicting trial data. Four RCTs found a significantly higher live birth rate when utilizing a combination of LDA and either prophylactic low molecular weight heparin (LMWH) or prophylactic heparin (61–64). However, two other RCTs found no significant difference in the live birth rate between participants treated with LDA alone and those treated with heparin and LDA together (65, 66). A systematic review of all completed trials in 2014 favored the use of LDA with heparin/LMWH but also noted several limitations to the existing literature (67). A more recent 2020 Cochrane review found that a combination of heparin plus LDA may increase the number of live births in women with a history of obstetric APS compared to aspirin alone (RR 1.27, 95% CI 1.09 to 1.49 from 5 studies with 1295 women) (68). However, it is essential to note that adverse events were not uniformly reported in many of the included studies. Current ACR guidelines for the management of reproductive health and expert consensus favor combining LDA and prophylactic heparin/LMWH for aPL-positive women with prior obstetric APS complications (60, 69).

PREGNANCY WITH HISTORY OF THROMBOTIC APS

A small observational study evaluated 20 pregnant women with a history of thrombotic APS who received daily aspirin (100 mg) and therapeutic LMWH and found the live birth rate amongst this group to be 91.3% (70). It is important to note that despite treatment with aspirin and LMWH, a high incidence of obstetric complications such as preeclampsia and premature delivery was still observed. The current consensus treatment guidelines from ACR and EULAR favor a combination of LDA and therapeutic dose of heparin/LMWH during pregnancy for women with a history of thrombotic APS (21, 60).

POSTPARTUM MANAGEMENT

Pregnant individuals during the postpartum period have more than a 6-fold higher risk of venous thrombosis than non-pregnant individuals (71). This risk is further exacerbated with other pre-existing prothrombotic risks, such as prior thrombosis history or aPL (72). Both recent EULAR and ACR guidelines recommended that obstetric APS patients receive at least six weeks of prophylactic heparin after delivery. Pregnant individuals with thrombotic APS should resume therapeutic anticoagulation immediately to prevent postpartum thrombosis (21, 60).

MICROVASCULAR APS / CATASTROPHIC APS TREATMENT

In addition to thrombosis and obstetric complications, many APS patients also have small vessel or microvascular disease. Some examples of microvascular manifestations include aPL-nephropathy, diffuse alveolar hemorrhage (DAH), livedoid vasculopathy, and cardiac micro-thrombosis. An international clinical database for patients with APS estimated that roughly 10% of aPL-positive patients develop microvascular disease (73). Many of these microvascular manifestations can be difficult to define clinically as they require invasive testing (such as biopsy or bronchoscopy) to confirm, leading to delays in treatment. Microvascular APS (MAPS) management remains challenging due to heterogeneous clinical manifestations and organ involvement. Systemic studies of MAPS treatments are lacking. Currently, treatment strategies are primarily based on anecdotal reports and expert opinions. A recent expert perspective included a practical algorithm to navigate the clinical management of patients with microvascular APS (74). Expert opinion encourages an individualized approach to treatment based on organ involvement, the severity of clinical presentation, and the patient’s response to intervention. Examples of treatments that can potentially be employed for the various manifestations of microvascular APS include anticoagulation, antiplatelet agents, glucocorticoids, mycophenolate, and/or rituximab (74).

Another notable area of microvascular involvement in APS is the cardiovascular system, specifically heart valve disease (defined as valve lesions or thickening, non-bacterial valvular vegetations also known as Libman-Sacks endocarditis, or moderate to severe dysfunction in the absence of rheumatic fever or infective endocarditis) (8). A recent review of cardiac manifestations of APS noted that valvular disease could be found in up to one-third of primary APS patients (75). Management recommendations for APS-related valvular disease were based on expert opinion and a 2003 consensus report on APS cardiac disease. Screening transthoracic echocardiogram is recommended for all APS patients. Prophylactic LDA alone is recommended for asymptomatic patients without prior history of thrombosis or echogenic evidence of valvular vegetation or dysfunction. For symptomatic patients with valvular vegetations and/or systemic embolization secondary to heart valve disease, anticoagulation with warfarin (target INR of 2.0 – 3.0) is recommended. Surgical intervention must be considered for patients with severe heart valve disease, such as severe valvular dysfunction and recurrent embolism despite anticoagulation (75–77).

Catastrophic APS (CAPS) is a life-threatening variant of APS that occurs in approximately 1% of APS patients (78). Clinically it is manifested by microvascular thrombosis in multiple organs and cytokine-driven systemic inflammatory response syndrome (SIRS) — that lead to rapid organ failure with high mortality (3, 74). Due to CAPS being relatively rare, the majority of our knowledge about CAPS is derived from the “CAPS Registry,” which, as of September 2019, included 571 cases describing episodes of CAPS (78). In 2018, the McMaster RARE-Bestpractices project formed a panel of international experts who employed the GIN-McMaster Guideline Development checklist and GRADE methodology to develop guideline recommendations for CAPS (79). The guidelines conditionally recommended that first-line treatment of patients with CAPS include a combination of glucocorticoids, heparin, and plasmapheresis or IVIG over a single agent or other therapies. The only strong recommendation mentioned was first-line treatment using therapeutic-dose anticoagulation. They also recommended avoiding first-line treatment of CAPS patients with rituximab (79). The 16^th International Congress on Antiphospholipid Antibodies Task Force Report on CAPS endorsed these recommendations (78). It is important to note that there is a lack of robust primary evidence, such as clinical trials for CAPS. Some experts favor the addition of cyclophosphamide for CAPS patients with a history of SLE (3). This practice was based on a multivariate analysis of the CAPS Registry that showed cyclophosphamide use was associated with decreased mortality in CAPS patients with SLE (80). While often utilized in refractory and resistant cases, the role of additional immunosuppression, particularly among primary CAPS patients, warrants further systematic evaluation. Here we proposed a practical approach for the management of CAPS (Figure 4).

Figure 4.

Practical treatment algorithm for CAPS patients.

TREATMENTS ON THE HORIZON

While current APS management primarily focuses on prothrombotic risk modification and anticoagulation, advances in understanding APS pathogenesis have shed light on various new therapeutic targets within the innate and adaptive immune systems. Recent exploration of agents that target autoreactive B cells, plasma cells, complement activation, and mitigation of NETosis provide promising new avenues for further research into the treatment of APS.

CHIMERIC ANTIGEN RECEPTOR T-CELL THERAPY

Chimeric antigen receptor (CAR) T-cell therapy is a form of immunotherapy wherein autologous T-cells are modified to express a receptor that can direct the patient’s own lymphocytes against pathogenic cell populations (81). A case study from 2019 detailed the use of CD19-targeting CAR T-cell therapy in a 67-year-old patient with a longstanding history of refractory APS on warfarin and diffuse large B-cell lymphoma (DLBCL). Interestingly, the aCL IgM level was significantly reduced in this patient after CAR T-cell therapy, which suggested that CAR T-cell therapy could be beneficial in treating APS. However, the study failed to evaluate other aPL, such as LA and aβ₂GPI, and the results are difficult to interpret given the many different immunosuppressive agents the patient received as part of DLBCL therapy (82). A recent abstract presented at the 2022 ACR Convergence meeting detailed the development of T-cells engineered to express domain I of β₂GPI, which selectively targeted and depleted anti-β₂GPI-expressing B-cells. This study provided promising preclinical data for the future development of precision cellular immunotherapy to target various autoimmune conditions, including APS (83).

TNF INHIBITORS FOR OBSTETRIC APS

Prior work has suggested that increased TNF-α is involved in aPL-related placental injury and increased risk of recurrent fetal loss, gestational diabetes mellitus, hypertensive syndromes, and fetal growth restriction (84, 85). A 2019 study assessed the effectiveness of TNF-α blockers on aPL-positive women with a history of recurrent pregnancy complications despite therapy with LMWH, LDA, and HCQ (86). The study was a prospective case series that included 12 women who met the criteria for obstetric APS and 6 women who had obstetric morbidity thought to be related to aPL. Sixteen patients were started on adalimumab, 2 were started on certolizumab, 9 women completed gestation at term, and 3 were pre-term. Overall, good obstetric results were observed in 70% of women who were previously refractory to LMWH, LDA, and HCQ (86). Another ongoing clinical trial is poised to evaluate the effect of certolizumab in addition to the usual treatment (heparin and LDA) in pregnant individuals with APS and persistently positive LA (87).

DEFIBROTIDE AND DIPYRIDAMOLE

Neutrophil extracellular traps (NETs) have recently received increasing attention as drivers of thromboinflammation in APS (88). Two medications with anti-neutrophil properties, defibrotide and dipyridamole, demonstrated mechanistic potential as new therapies for APS thromboinflammation. Defibrotide is a collection of single-stranded oligonucleotides purified from the intestinal mucosal cells of pigs. Defibrotide has been found to have anti-neutrophilic properties and a protective effect against endothelial activation by agonism of the adenosine A1 and A2 receptors (89, 90). A 2022 study utilized a mouse model of antiphospholipid-accelerated thrombosis to show that defibrotide inhibited NET formation and venous thrombosis in an adenosine A_2A receptor-dependent pathway (91). Notably, a 2002 case report details the successful use of defibrotide in a patient with refractory CAPS (92). A more recent mechanistic study found that defibrotide counteracted NET-mediated endothelial cell activation and protected against histone-accelerated inferior vena cava thrombosis, likely through the exertion of an electrostatic effect directly on histones (93).

Dipyridamole is an anti-thrombotic medication that has been shown to act as an indirect adenosine A_2A receptor agonist by blocking adenosine re-uptake and maintaining levels of extracellular adenosine. One proposed regulatory mechanism of NETosis involves surface adenosine A_2A receptors, which are abundant on the surface of neutrophils and act as a brake on inflammation. A 2019 mechanistic study utilized a mouse model of aPL-mediated thrombosis to show that dipyridamole suppressed aPL-mediated NETosis via the A_2A receptor, which in turn mitigated venous thrombosis (94).

DARATUMUMAB (ANTI-CD38)

Daratumumab is a human monoclonal antibody that targets CD38 IgG-kappa, which targets and depletes plasma cells in the bone marrow (95). The drug was initially approved for use in multiple myeloma (96). A recent case report described the use of daratumumab in an attempt to reset humoral immunity in an APS patient with refractory thromboembolic events despite appropriate treatment with anticoagulation (97). A notable decline in aCL IgG and aβ2GPI IgG persisted for 108 days after the first dose of medication. Significant clinical improvement was noted after 4 weeks of treatment (97). Notably, the Daratumumab in Primary Antiphospholipid Syndrome (DARE-APS) trial was recently launched. It is a phase 1b open-label study aimed at determining the safety and efficacy of daratumumab in primary APS patients. The trial will assess the dose-limiting toxicities of daratumumab, any post-treatment changes in aCL and aβ₂GPI levels, and LA positivity (98).

CONCLUSION

Although knowledge of APS pathogenesis has been augmented in recent years, the principles and strategies for the clinical management of APS have yet to be revolutionized. Primary thrombosis prophylaxis for patients with positive aPL but no definitive clinical findings of thrombosis or pregnancy morbidity should take a risk-stratified approach. VKAs or heparin/LMWH remain the recommended secondary thrombosis prophylaxis for patients with definitive thrombotic APS. Some international society guidelines suggested that DOACs may be considered in certain circumstances for patients with non-triple-positive APS who lack a history of arterial thrombosis. Careful monitoring and individualized obstetric care with the use of aspirin and heparin/LMWH will improve pregnancy outcomes among pregnant individuals with aPL or obstetric APS. Treatment of microvascular APS and CAPS remains challenging. While various immunosuppressive agents are being explored, further systematic evaluations are warranted before definitive recommendations can be made. As we gain more knowledge of the pathogenesis and molecular mechanisms that drive APS, several new therapeutic strategies are on the horizon, which could enable a more personalized and targeted approach to APS management in the near future.

KEY POINTS.

• Primary thrombosis prophylaxis for patients with positive aPL but no history of thrombosis should take a risk-stratified approach.

• While vitamin k antagonists or heparin/low molecular weight heparin (LMWH) remain the preferred treatment for secondary APS thrombosis prophylaxis, some international society guidelines support the use of Direct Oral Anticoagulant in certain circumstances.

• Careful monitoring and individualized obstetric care with the use of aspirin and heparin/LMWH will improve pregnancy outcomes among pregnant individuals with APS.

• New therapeutics that target autoreactive B cells, plasma cells, complement activation, and NETosis provide promising new avenues for further research into the treatment of APS.