Antiphospholipid Syndrome

Chapter 44

Antiphospholipid Syndrome Vinicius Domingues1, Gustavo Guimarães Moreira Balbi2,3, Guilherme Ramires de Jesús4, Flavio Signorelli2,5, Roger Abramino Levy2,6 1Florida

State University, College of Medicine Daytona Beach, FL, United States; 2Department of Rheumatology, Hospital Universitário Pedro Ernesto, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil; 3Department of Rheumatology, Hospital Universitário, Universidade Federal de Juiz de Fora, Juiz de Fora, Brazil; 4Department of Obstetrics, Hospital Universitário Pedro Ernesto, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil; 5Department of Internal Medicine, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; 6Global Medical Expert, GSK, Upper Providence, PA, United States

INTRODUCTION Antiphospholipid syndrome (APS) is an acquired, immune-mediated thrombophilia. It is characterized by the occurrence of thrombosis in any vascular bed and gestational morbidity, associated with the identification of circulating antiphospholipid antibodies (aPL), namely lupus anticoagulant (LA), anticardiolipin (aCL) IgG and IgM, and anti-β2-glycoprotein I (aβ2GPI) IgG and IgM [1]. The aim of this chapter is to review the most relevant aspects of APS and provide evidence-based information for a better understanding and treatment of this complex disease.

PATHOGENESIS The etiopathogenesis of APS is not fully understood. Several different mechanisms of disease have been proposed, including triggering factors, molecular mimicry, direct participation of aPL, activation of endothelial cells, increased oxidative stress, impaired function of endothelial nitric oxide synthase, increased expression of Toll-like receptors (TLR) 4, antibody-mediated activation of complement C3 and C5, disruption of the annexin A5 shield, and many others [2]. Nonetheless, no single factor was identified as capable of causing APS and probably many of these are implied. In fact, neither the positivity of aPL alone was capable of inducing clot formation in animal models [3,4]. The presence of a “second hit” is required for the development of thrombosis, such as cigarette smoking, infections, and malignancies [5–7]. These two latter may also be involved in mechanisms of molecular mimicry in the pathogenesis of APS [8–12]. β2-glycoprotein I (β2GPI) is a cationic glycoprotein that binds to negatively charged phospholipids through its fifth domain. It has an important role as a natural circulating anticoagulant and is capable of interfering in the protein C/S system. LA because of the presence of aβ2GPI antibodies is more strongly associated with thrombosis than does LA due to antiprothrombin antibodies, and the domain I of the aβ2GPI confers the highest risk [2]. This indicates that β2GPI is probably the most relevant targeted antigen in the pathogenesis of APS. These autoantibodies bind directly to β2GPI and induce an NF-kB–dependent endothelial cells activation, with increased adhesion molecules expression (elevated levels of E-selectin, VCAM-1, and ICAM-1), cytokine secretion (elevated levels of IL-6), and arachidonic acid metabolism (elevated levels of 6-keto-PGF1-alpha, a metabolic of arachidonic acid) [13–15]. Consequently, it creates a prothrombotic state; it can also interact with von Willebrand factor receptor and cross-activate platelets, releasing thromboxane A2, which subsequently increases platelet adhesiveness [2]. Because both adaptive and innate immunity are involved in the pathogenesis of APS, it is probable that a predisposing genetic background exists. Several genetic HLA class II polymorphisms were associated with aPL production and the development of APS, such as HLA-DRB1*04, DRB1*07 (0701), DRB1*1302, DQB1*0301 (DQ7), DQB1*0302, and DQB1*0303. HLA-BDPB1 alleles, HLA-DM polymorphisms, and valine/leucine247 polymorphisms of β2GPI may also be involved [7,16,17]. In a recently published genome-wide association study, Sugiura-Ogasawara et al. found that the presence of TSHR and C1D genes were associated with obstetric APS (ObAPS) [18].

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TABLE 44.1  APS Classification Criteria Clinical Criteria

Laboratory Criteria

l

Vascular thrombosis One or more clinical episodes of arterial, venous, or small vessel thrombosis, in any tissue or organ, supported by unequivocal findings of appropriate imaging studies or histopathology. For histopathological support, it should be present without substantial evidence of inflammation in the vessel wall.

Lupus anticoagulant present in plasma: l Two or more occasions l At least 12 weeks apart l Detected according to the guidelines of the International Society on Thrombosis and Hemostasis.

Gestacional morbidity One or more unexplained deaths of a morphologically healthy fetus at or beyond the 10th week of gestation, with healthy fetal morphology documented by ultrasound or by direct examination of the fetus. One or more premature births of a morphologically healthy newborn baby before the 34th week of gestation due to eclampsia, severe preeclampsia, or placental failure. Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomical or hormonal abnormalities and paternal and maternal chromosomal causes excluded.

Anticardiolipin antibody in serum or plasma: l IgG or IgM isotype, or both l Medium or high titers (i.e., >40 GPL or MPL, or greater than the 99th percentile) l Two or more occasions l At least 12 weeks apart l Measured by a standardized ELISA.

l

Anti-β2-glycoprotein 1 antibody in serum or plasma: l IgG or IgM isotype, or both l Titers greater than the 99th percentile l Two or more occasions l At least 12 weeks apart l Measured by a standardized ELISA, according to recommended procedures.

For the diagnosis of APS, at least one clinical and one laboratory criteria are required. Adapted from Miyakis S, Lockshin MD, Atsumi T, Derksen RHWM, de Groot PG, Koike T. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome. J Thromb Haemost 2006;4:295–306. (August 2005).

CLINICAL MANIFESTATIONS There is a wide array of clinical manifestations of APS and the hallmark of the syndrome is thrombosis [19]. However, in contrast with thromboses associated with congenital thrombophilias, those associated with APS might occur in any vascular bed [20]. Deep vein thrombosis is the most common venous thrombosis followed by pulmonary emboli [20]. In the arterial bed, the central nervous system (CNS) is the most affected with stroke and transient ischemic attacks; however, myocardial infarction is seen but less frequently [20]. Small vessel thrombosis can occur in the form of thrombotic microangiopathy (TMA). The current classification criteria for APS are outlined at Table 44.1 [1]. Recently, there has been a lot of attention on the noncriteria manifestations of APS, which resembles more of an inflammatory pathology than a thrombotic one per se [21]. CNS manifestations such as myelopathy, migraine, and epilepsy, which are refractory to standard treatment, have also been associated with aPL [22]. Mild cognitive impairment has been recorded in more than 40% of the patients with APS with a strong association with white matter lesions and multiple sclerosis–like CNS lesions and compatible clinical presentation [23–26]. aPL has been very closely associated with cardiac valvular disease with mitral most frequently affected followed by aortic valve [27]. Regurgitation is more common than stenosis and many patients remain asymptomatic for years until it is found by imaging a verrucous pattern lesion in the valve leaflets [27]. A recent metaanalysis also showed that the presence of aPL is strongly associated with pulmonary hypertension in systemic lupus erythematosus (SLE) patients [28]. Renal involvement in APS was first described in 1992 [29]. TMA is the most characteristic finding in APS nephropathy (APSN); however, fibrous intimal hyperplasia, focal cortical atrophy, and arterial occlusions have also been described [29]. Hypertension with proteinuria (often subnephrotic) and renal insufficiency are typical presentations of APSN [30]. Renal artery stenosis can also present as refractory hypertension [31]. Hematologic manifestations include thrombocytopenia that can be moderate to severe with bleeding and clotting and hemolytic anemia [21]. Livedo reticularis, a mottled reticulated vascular pattern that appears as a lace-like purplish discoloration of the skin, is present in about 25% of patients with APS and is associated with greater risk for arterial thrombosis [32]. Skin ulcers are frequently seen around and predominantly in lower extremities. Those ulcers are typically refractory to wound care and may take years to heal adequately [32]. Avascular necrosis, adrenal insufficiency, and diffuse alveolar hemorrhage are reported but seen less frequently [21].

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The most severe and fortunately infrequent form of APS is catastrophic APS (CAPS). This form is characterized by widespread small vessel thrombosis with multiorgan failure and carries a mortality of up to 50% [7].

OBSTETRIC MANIFESTATIONS Besides vascular thrombosis, APS can also present with obstetric morbidity, which some authors call “ObAPS.” Recurrent miscarriages, fetal loss, placental insufficiency, or preeclampsia has been related to aPL and is part of International Consensus Statement on classification criteria for APS [1]. Those obstetric complications can occur in patients with previous vascular thrombotic events, precede thrombotic events, or be the only type of manifestation of the disease. The first obstetric criteria described in International Consensus is “One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, with normal fetal morphology documented by ultrasound or by direct examination of the fetus” and is considered the most specific criterion for ObAPS [1]. Two recently published multicenter studies support this association, with the first one reporting that elevated levels of aCL and anti-β2-glycoprotein-I antibodies were associated with a three- to fivefold increased odds of stillbirth [33], while the other one described LA as the primary predictor of adverse pregnancy outcome after 12 weeks, including fetal death [34]. Another criterion related to pregnancy loss is associated with early miscarriage: Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and/or paternal and maternal chromosomal causes excluded. Recurrent early abortion has been classified by some authors and also by International Consensus [1] as the most sensitive obstetric criterion, although not very specific. In the same way that occurs with fetal death, it is important to exclude other causes that may be related to the miscarriage. Recent studies [34] reported that abnormal embryonic karyotype is the most frequent cause of recurrent miscarriage, in a similar frequency that occurs in single spontaneous abortions, but this investigation is not frequent in clinical practice considering the high cost of the procedure. This inability to adequately exclude other causes of recurrent abortion, combined with different inclusion criteria, may explain the conflicting results in observational studies and clinical trials performed in this group of patients [35]. Additionally, well-designed studies following strictly the International Consensus are lacking, and some authors are questioning the association between recurrent early miscarriage and aPL [36]. Patients with APS develop preeclampsia more frequently than general population, which occurs in 5%–10% of pregnancies. The real frequency of aPL in patients with preeclampsia is still unknown, but most of the studies reported a significant association with early-onset and severe cases [37]. Considering that both preeclampsia and placental insufficiency can have the same underlying mechanism, i.e., abnormal trophoblastic invasion, it is not surprising that both complications can affect the same pregnancy. Some authors have described between 15 and up to almost 40% [38,39] of small for gestational age neonates (below the 10th percentile) in pregnant patients with APS. The exclusion of other justifiable causes of placental insufficiency should be pursued to confirm its relationship to aPL, but sometimes it may be impossible in the clinical or even in the research settings as more than one confounding factor can be present. This prevents an adequate estimate of aPL frequency among patients with placental failure. To improve the specificity, the International Consensus recommends including only cases that required delivery before 34 weeks of pregnancy, usually more severe than those that develop close to term. However, the criteria’s authors report that this criterion may be relatively insensitive or nonspecific. It is also important to notice that delivery usually occurs by medical intervention because of those obstetric complications because spontaneous preterm delivery is not usual in patients with ObAPS [35]. Other pregnancy morbidities not present in International Consensus have been associated to aPL, but there is lack of consensus in this topic. HELLP syndrome, an acronym for hemolysis, elevated liver enzymes, and low platelet count, usually occurs as a severe form of preeclampsia. The substantial increase in the incidence of preeclampsia in patients with APS may result in an increased frequency of cases of HELLP syndrome, but sometimes differential diagnosis between APS and HELLP syndrome can be difficult, as overlapping clinical findings can develop [40]. Placental abruption is also related to hypertensive disorders of pregnancy, which is clearly a confounding factor to associate this disease with aPL. To date, there is no described underlying mechanism that can justify an increased incidence of placental abruption related to aPL. Infertility is a common gynecologic condition and has been tentatively linked to aPL for decades. In vitro studies have proposed some pathophysiological mechanisms [41], but clinical studies in this topic failed to prove such an effect. Although some authors identified more aPL in patients than controls, the results are arguable considering heterogeneity of clinical and methodological aspects, such as definition of positivity different from International Consensus or small number of participants. In addition, several studies included noncriteria aPL tests, which have controversial clinical significance [42]. A recent review of the subject reported a lack of association between aPL and assisted reproductive therapy (ART) outcome and no benefit on ART outcome when treating aPL-positive women [41], conclusions that are supported by the American Society of Reproductive Medicine [43].

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DIAGNOSIS AND CLASSIFICATION There are three criteria antibodies in APS classification: LA, aCL, and aβ2GPI. LA should be detected according to the guidelines of the International Society on Thrombosis and Hemostasis. aCL of IgG and/or IgM isotype in serum or plasma should be present in medium or high titer (>40 GPL or MPL [IgG and IgM phospholipid units], or >the 99th percentile), measured by a standardized ELISA. Finally, aβ2GPI of IgG and/or IgM isotype should be present in serum or plasma (in titer >the 99th percentile), measured by a standardized ELISA. They should be detected in plasma on two or more occasions at least 12 weeks apart. Additionally, classification of APS should be avoided if the positive aPL test and the clinical manifestation are separated for more than 5 years [1]. Accordingly to the presence of one or more laboratory criteria, APS patients can be further classified into one of the following categories: I—more than one laboratory criteria present (any combination); IIa—LA present alone; IIb—aCL antibody present alone; IIc—aβ2GPI present alone [1].

LABORATORY PITFALLS LA detection is technically laborious, envisaging screening, mixing, and confirming tests [44]. A weak LA should be considered a positive test [42], but there is still some concern about the clinical relevance of this result [45]. Another critical point is the equivocal laboratory results in patients under anticoagulation. LA can be falsely positive in patients treated with heparin, vitamin K antagonists (VKA), and direct oral anticoagulants (DOACs) [46]. When international normalized ratio (INR) is >3.5, the LA testing is unworkable [1]. Likewise, pregnancy and oral contraceptive pills can lead to aCL and aβ2GPI transiently positive [46]. Interpretation and confirmation of aPL is another challenge. When both aCL and aβ2GPI ELISAs are positive in the same patient, they should be both positive for the same isotype (IgG or IgM). Triple positivity (LA+; aCL+; and aβ2GPI+, same isotype) is the most reliable profile and always confirmed after 12 weeks. On the other hand, single positivity is confirmed after 12 weeks in less than 50% [45].

Noncriteria Antiphospholipid Antibody Tests Current APS classification criteria identify a homogeneous group of APS patients but exclude patients with clinical manifestations highly suggestive of APS. Therefore, “noncriteria” aPL that target other plasma proteins or phospholipid-bound proteins complexes may help to classify additional APS patients recognized as “seronegative” [47]. Using 11 noncriteria markers, including aCL IgA e aβ2GPTN I IgA; aβ2GPI DI; antibodies to phosphatidylserine (aPS) IgM, IgG and IgA; antibodies to the phosphatidylserine–prothrombin complex (aPS/PT) IgG and IgM; antiphosphatidylethanolamine (aPE) IgG and IgM; aCL/vimentin antibodies IgG, a recent study could reclassify combining the results, 25 out of 68 seronegative patients into seropositive (36.8%). Conversely, seropositive patients were positive for at least one non–antibody criteria in 83.2% of cases [47]. We will discuss below the most relevant noncriteria aPL.

IgA Isotypes (aCL IgA e aβ2GPTN I IgA) The heterogeneity in different study designs and the use of various nonstandardized assays is troublesome to make a recommendation. Besides, positive IgA aPL are usually associated with other isotypes in the presence of the major manifestations of APS, making it difficult to understand the role of IgA alone [48]. IgA aPL is the dominant isotype in Afro-Caribbeans and in Afro-Americans. However, they are probably not associated with clinical manifestations in these ethnic groups, besides being usually transient and present at low or moderate titers [49]. The SLICC classification criteria for SLE included as a new aPL criterion both IgA aCL and IgA aβ2GPI [48]. It seems that IgA aβ2GPI is highly prevalent in SLE patients and associated particularly with arterial thrombosis, making them a relevant test in this group of patients [42]. IgA aPL antibodies are also linked to skin ulcers, Raynaud’s phenomenon, livedo, or cutaneous vasculitis. Furthermore, in pretransplant patients, IgA aβ2GPI was correlated with lower graft and patient survival at 6 months and may be an early transplant failure biomarker [49]. In summary, testing for IgA aPL could contribute to the assessment of risk for thrombosis and/or pregnancy morbidity, especially in SLE patients, when there is a strong suspicion of APS but other aPL tests are negative [42].

Antibodies Against Specific Domains of aβ2GPI β2GPI is a glycoprotein with five domains (DI–DV) and the most relevant epitope is located in DI in patients with autoimmune diseases. Domain I is responsible for binding with the aPL, and DV in turn is responsible for binding the complex

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β2GPI-aPL with the phospholipid on the cell surface. aβ2GPI DI antibodies carry at high specificity and low sensitivity, putting their clinical utility doubtful. A large cohort of patients demonstrated that IgG targeting DI represents the prevalent aβ2GPI antibody subpopulation among patients with APS and with autoimmune conditions without any clinical feature suggestive of APS. On the other hand, anti-DIV/V antibodies were in asymptomatic aPL carriers or those without any underlying autoimmune disease. It means that the ratio between antibodies to DI and DIV/V may be a predictor for systemic autoimmunity [49].

Antibodies to the Phosphatidylserine–Prothrombin Complex Antiprothrombin antibodies are a heterogeneous population including antibodies against prothrombin alone (aPT-A) and antibodies to the phosphatidylserine–prothrombin complex (aPS/PT) detected by ELISA [1]. There is a strong association between aPS/PT and the LA. In fact, up to 86.7% of patients with aPS/PT are also LA positive [47], suggesting that aPS/PT can serve as a confirmatory assay for LA [1] or to replace it when clotting test cannot be performed because of technical limitations [50]. Still, aPS/PT has been shown to be useful in establishing the thrombotic risk, irrespective of the site and type of thrombosis, in patients with previous thrombotic events and/or systemic autoimmune diseases [49]. Measurement of the three criteria aPL, in conjunction with IgG aPS/PT, might contribute to a better and more complete identification of patients at risk of thrombotic complications [50]. The aPS/PT inclusion as a laboratory criterion for the APS should be strongly considered [49].

Antibodies as Prognostic Biomarkers The aPL most strongly related to thrombosis is LA. In addition, multiple positive aPL or high-titer aPL correlate to thrombotic events [51]. Ruiz-Irastorza et al. defined three high-risk serological features in patients with APS: LA positivity, triple positivity, and isolated persistently positive aCL at medium–high titers (the last only studied in patients with SLE) [51]. The need of thrombotic risk stratification in APS patients has led to the emergence of two important scores: the Antiphospholipid Score (aPL-S) and the Global Antiphospholipid Syndrome Score (GAPSS). Both have shown a degree of accuracy in identifying high-risk APS patients, especially those at a high risk of thrombosis [52]. GAPSS includes the testing for aPS/PT, an assay that is not commercially available and consequently not routinely performed. Therefore, an adjusted score was created, excluding the aPS/PT, the aGAPSS; it is calculated by adding the points corresponding to the risk factors, based on a linear transformation derived from the β-regression coefficient as follows: 3 for hyperlipidemia, 1 for arterial hypertension, 5 for aCL IgG/IgM, 4 for aβ2GPI IgG/IgM, and 4 for LA [53]. Radin et al. demonstrated that higher aGAPSS values were observed in patients with acute myocardial infarction and this finding could aid to the risk stratification of APS patients younger than 50 years old for the likelihood of developing coronary thrombotic events [53]. In the field of pregnancy morbidity, the PROMISSE study (Predictors of Pregnancy Outcome: Biomarkers in APL Syndrome and SLE) independently confirmed in a group of aPL-positive patients that LA is the only aPL predictor of poor pregnancy outcomes after the first trimester of pregnancy [54].

TREATMENT Thrombotic Antiphospholipid Syndrome The current recommendation for thrombotic APS is lifelong treatment oral anticoagulation with VKA. There is much controversy related to the INR range to target, especially in those with recurrent venous events in spite of treatment and those with arterial thrombosis, low-intensity anticoagulation (INR 2–3) against high-intensity anticoagulation (INR 3–4). Against the high intensity, there are difficulties in keeping a stable INR over 3 and there is also a possibility for interference by aPL on the thromboplastins used for INR measurement. Additionally, bleeding is a major concern, although studies are not concordant in reporting an increased risk of bleeding when high-intensity regimen is compared with the low-intensity group [55]. Moreover, INR equal or over 3.0 dramatically reduced recurrent thrombosis [56]. In summary, for practical issues, venous thrombosis is treated with anticoagulation targeting INR 2–3. When there are arterial thromboses or venous recurrent thrombosis with a target INR between 2 and 3, we recommend that the treatment should aim an INR of 3–4 or LDA (low-dose aspirin) plus VKA. These recommendations are based on two randomized controlled trials (RCTs) of limited quality and a systematic review (observational studies) for venous thrombosis and on observational studies and one RCT of low quality for arterial thrombosis. There are no studies available regarding triple aPL positivity and anticoagulation should follow according to the type of thrombosis (venous or arterial) as mentioned or may be based on clinical judgment [57].

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The cessation of anticoagulation in APS patients who became aPL negative has been questioned. Khamashta et al. showed that the rate of thrombosis recurrence was highest (1.30 per patient year) during the first 6 months after the cessation of warfarin therapy [56]. A retrospective study was conducted in 44 APS patients who interrupted oral anticoagulation for various reasons, including prolonged disappearance of aPL. Results demonstrated that 11 (25%) patients developed a recurrent thrombotic event after oral anticoagulation cessation. Three had CAPS and one died because of lower limb ischemia [58]. Another study showed that 11 out of 24 (45.8%) patients still developed recurrent thrombosis despite oral anticoagulation with a follow-up of 60 months since aPL disappearance [59]. The current recommendation is lifelong oral anticoagulation unless contraindicated. Regarding the DOACs, only one trial is completed. RAPS (Rivaroxaban in APS) was a prospective, randomized, controlled, noninferiority, phase 2/3 clinical trial of rivaroxaban versus warfarin in APS patients (primary APS or with SLE) with venous thrombosis. The primary outcome was not clinical focused in the percentage change in endogenous thrombin potential assessed using thrombin generation testing. Rivaroxaban failed to reach the noninferiority threshold [60]. To date, there are four other DOACs trials ongoing, being three with rivaroxaban and one with apixaban. TRAPS (Trial on Rivaroxaban in Antiphospholipid Syndrome) was designed to evaluate the efficacy and safety of rivaroxaban in high-risk APS patients with triple-positive thrombotic APS patients regardless of the presence of arterial events [61]. ASTRO-APS (Apixaban for the Secondary Prevention of Thrombosis Among Patients With Antiphospholipid Syndrome) is a pilot phase 3 trial, which will analyze secondary prevention of thrombosis as a secondary outcome in patients with venous thrombosis [62]. Hydroxychloroquine (HCQ) has been controversial but a promising adjuvant therapy in APS. A prospective nonrandomized trial compared oral anticoagulation plus HCQ (400 mg daily) versus oral anticoagulation alone in primary APS patients. All patients were off antiplatelet aggregation therapy. Six patients (30%) in the monotherapy group (N = 20) had venous events despite therapeutic range INR in contrast to none in the HCQ group (N = 20) during the 6 month and 36 month follow-up, respectively. HCQ should be prescribed in all aPL-positive SLE patients. There are no strong data to recommend HCQ in persistently aPL-positive patients without other autoimmune diseases [63].

Gestational Antiphospholipid Syndrome Current treatment for recurrent abortions or fetal loss in patients with APS is based on RCTs developed in the late 90s and in the early years of this century. The results are conflicting and this can be attributed to different inclusion criteria, especially concerning aPL profile [64]: LDA alone was found to be inferior to LDA plus heparin in two studies [65,66], whereas other studies reported similar results when those treatment groups were compared [67,68]. Due to this discrepancy, there is no consensus on a treatment recommendation for recurrent abortion before 10 weeks of pregnancy, when LDA alone or LDA plus heparin can be used for recurrent miscarriage related to APS, with the latter usually being preferred by specialists. In the same fashion, most of authors recommend LDA plus prophylactic dose heparin in patients with fetal loss (after 10 weeks of pregnancy) throughout pregnancy until 6 weeks postpartum [69], although trials with this specific group of patients are lacking. There is, however, a significant increase in live birth rates from as low as 4% [70] before the diagnosis and treatment of ObAPS to up to 85% after treatment [38,70]. If pregnancy failure occurs despite recommended medications, there is no study to support the use of any different drug and suggested treatments rely on expert’s opinion. Prednisone, intravenous immunoglobulin (IVIG), HCQ, and anti-TNF drugs have been proposed to be used in patients with APS and pregnancy losses, but there are no evidences to support the use of any of them [71]. Actually, few drugs, such as prednisone, have been associated with more adverse pregnancy results [72] and should be used with caution. Considering patients with definite APS, there are no RCTs that included patients with exclusively severe preeclampsia or eclampsia and premature birth before the 34th week, as stated by the classification criteria [64]. Therefore, recommended treatment for this group of patients (LDA plus heparin) is the same as for the patients with pregnancy loss; however, the real efficacy is unknown. The main question is if the treatment can prevent the development of preeclampsia and intrauterine growth restriction in aPL-positive patients, as some authors have reported a high incidence of these complications despite appropriate treatment for APS [37]. High prevalence of preeclampsia in APS patients despite treatment may represent a different pathway of non-aPL– related hypertensive disorder of pregnancy. For example, LDA, used in all recommended protocols for APS, reduced the occurrence of preeclampsia in 53% of non-APS high-risk patients when started before 16 weeks of pregnancy, with a reduction of almost 80% of the severe cases [73]. Although studies in APS patients are still lacking, we do not seem to be closer to those numbers with the current treatment. In addition to preeclampsia, IUGR is commonly found in pregnant women with APS before and after treatment. A publication evaluating the efficacy of prophylaxis using LDA and unfractionated heparin (UFH) in the prevention of IUGR

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in patients with APS provided negative results. Of the study group, 32.3% had low birth weight newborns (below 10th percentile) compared with 2.5% of the control group. The mean birth weight of the newborn babies of the study group was also smaller than controls (2798 vs. 3124 g, respectively) [74]. Patients with previous thrombosis using long-term anticoagulants should change warfarin to full-dose heparin (preferably low molecular weight heparin) and LDA during pregnancy, which can be switched back after delivery. Warfarin during pregnancy has been associated with congenital malformations (warfarin embryopathy) and fetal bleeding, so it should be avoided [37].

Noncriteria Manifestations Different noncriteria manifestations have been described in APS. Their treatments are mainly based on case series and open-label studies, and some of them are extrapolated from SLE patients’ data [57]. Steroids, IVIG (in cases refractory to steroids), azathioprine, and rituximab are the most common medications used for the treatment of APS-related thrombocytopenia and autoimmune hemolytic anemia. In patients with aPL-related thrombocytopenia, primary thromboprophylaxis with LDA and/or HCQ should be considered [57]. When there are neurological manifestations, such as chorea, myelitis, and multiple sclerosis–like disease, steroids and immunosuppressive agents (i.e., cyclophosphamide), in addition to anticoagulation therapy, may be considered, especially in cases associated with SLE [57]. The treatment of aPL-associated nephropathy includes antiplatelet and/or anticoagulation therapy, with variable results. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers should be prescribed for controlling hypertension and proteinuria [57]. Patients with symptomatic heart disease must undergo anticoagulation therapy, as they are at high risk of thromboembolic events. Asymptomatic disease is treated with LDA. Infective endocarditis prophylaxis is not currently recommended [57].

Catastrophic Antiphospholipid Syndrome Treatment of CAPS is directed to the two most important mechanisms of disease: controlling the thrombotic events and suppressing the inflammation/cytokine cascade [7]. According to the 14th International Congress on Antiphospholipid Antibodies Task Force Report on CAPS, glucocorticoids (GC) and anticoagulation are the “backbone of therapy” for CAPS. In addition to the combination of GC plus anticoagulation, IVIG and/or plasma exchange (PE) should always be considered, especially in life-threatening disease because it was associated with reduction in mortality, when compared with strategies that not included IVIG and/or PE (P = .04) [7]. In the last CAPS Registry analysis, triple therapy was associated with a mortality rate of 27.9% (vs. 40.6% with other combination and 75% with no treatment) [75]. Anticoagulation remains the most important therapeutic intervention in CAPS. Although no difference between unfractionated heparin and low molecular weight heparin has been reported, intravenous unfractionated heparin is the therapy of choice because of its reversibility [76]. There is no data supporting the use of DOACs, fibrinolytics, or antiplatelet therapy in CAPS [76,77]. GC are usually prescribed in pulse therapy (p.e. methylprednisolone 500–1000 mg, 1–3 days) or at doses of 1–2 mg/kg per day of prednisone or equivalent [75]. IVIG is used in a dose of 2 g/kg, given in 5 days (i.e., 0.4 g/kg per day for 5 days). PE is used to remove aPL, proinflammatory cytokines (such as TNF-alpha), and complement components. In the majority of cases reported, the replacement fluid used was fresh frozen plasma, which contains natural anticoagulants (p.e. antithrombin III) and procoagulant factors. It is unclear if the use of albumin as replacement fluid results in different outcomes [78]. Immunosuppressive drugs (IS) are reserved for patients with SLE or other autoimmune diseases. Cyclophosphamide is the most common IS prescribed (65 patients), followed by azathioprine (4 patients), cyclosporine (2 patients), and mycophenolate mofetil (1 patient). Nonetheless, no evidence-based data support the choice of one over another. The use of IS in CAPS because of primary APS is not established [7]. Rituximab and eculizumab have been used with success in refractory CAPS cases [7,76,79–81].

Novel and Upcoming Treatments Different new treatments are being developed for APS, as the current ones do not meet all the patients’ needs. HCQ, statins, rituximab, belimumab, eculizumab, antiplatelets glycoprotein receptor inhibitors, protease-activated receptor (PAR) antagonists, peptide therapies, coenzyme Q10, TLR-4 inhibitors, tissue factor inhibitors, mTOR inhibitors, intracellular signaling blockade, and others are under investigation. The various aspects of these medications will be discussed elsewhere [82].

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[29] Amigo M, Garcia-Torres R, Robles M, Bochicchio T, Reyes P. Renal involvement in primary antiphospholipid syndrome. J Rheumatol 1992;9:181–5. [30] Tektonidou M, Sotisou F, Nakapoulou L, Vlachoyiannopoulos P, Moutsopoulos H. Antiphospholipid syndrome nephropathy in patients with systemic lupus erythematosus and antiphospholipid antibodies: prevalence, clinical associations and long-term outcome. Arthritis Rheum 2004;50:2569–79. [31] Paul S, Sangle S, Bennett A, El-Hachmi M, Hangartner R, Hughes G, et al. Vasculitis, antiphospholipid antibodies, and renal artery stenosis. Ann Rheum Dis 2005;62:1800–2. [32] Francès C, Niang S, Laffitte E, Pelletier F, Costedoat N, Piette J. Dermatologic manifestations of the antiphospholipid syndrome: two hundred consecutive cases. Arthritis Rheum 2005;52:1785–93. [33] Lockshin M, Kim M, Laskin C, Guerra M, Branch D, Merrill J, et al. 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How to identify high-risk APS patients: clinical utility and predictive values of validated scores. Curr Rheumatol Rep 2017;19:51. [53] Radin M, Schreiber K, Costanzo P, Cecchi I, Roccatello D, Baldovino S, et al. The adjusted Global AntiphosPholipid Syndrome Score (aGAPSS) for risk stratification in young APS patients with acute myocardial infarction. Int J Cardiol 2017;240:72–7. [Internet]. Elsevier B.V. Available from: https://doi.org/10.1016/j.ijcard.2017.02.155. [54] Yelnik C, Laskin C, Porter T, Branch D, Buyon J, Guerra M, et al. Lupus anticoagulant is the main predictor of adverse pregnancy outcomes in aPLpositive patients: validation of PROMISSE study results. Lupus Sci Med 2016;3:e000131. [55] Pengo V, Ruiz-Irastorza G, Denas G, Andreoli L, Khamashta M, Tincani A. High intensity anticoagulation in the prevention of the recurrence of arterial thrombosis in antiphospholipid syndrome: “PROS” and “CONS”. Autoimmun Rev 2012;11:577–80. 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[60] Cohen H, Hunt BJ, Efthymiou M, Arachchillage DRJ, Mackie IJ, Clawson S, et al. Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial. Lancet Haematol 2016;3:e426–36. [Internet]. The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license, Available from: https://doi.org/10.1016/S2352-3026(16)30079-5. [61] Pengo V, Banzato A, Bison E, Zoppellaro G, Jose SP, Denas G. Efficacy and safety of rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome: rationale and design of the Trial on Rivaroxaban in AntiPhospholipid Syndrome (TRAPS) trial. Lupus 2016;25:301–6. [62] Woller SC, Stevens SM, Kaplan DA, Branch DW, Aston VT, Wilson EL, et al. 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