The impact of antiphospholipid antibodies/antiphospholipid syndrome on systemic lupus erythematosus

Abstract

aPLs are a major determinant of the increased cardiovascular risk in patients with SLE. They adversely affect clinical manifestations, damage accrual and prognosis. Apart from the antibodies included in the 2006 revised classification criteria for APS, other non-classical aPLs might help in identifying SLE patients at increased risk of thrombotic events. The best studied are IgA anti-β2-glycoprotein I, anti-domain I β2-glycoprotein I and aPS-PT. Major organ involvement includes kidney and neuropsychiatric systems. aPL/APS severely impacts pregnancy outcomes. Due to increased thrombotic risk, these patients require aggressive cardiovascular risk factor control. Primary prophylaxis is based on low-dose aspirin in high-risk patients. Warfarin is the gold-standard drug for secondary prophylaxis.

Introduction

SLE is an autoimmune rheumatic disease predominantly affecting women of childbearing age. Its clinical manifestations range from mild skin rashes to severe renal and neuropsychiatric involvement [1]. Despite improvement in survival rates in the last 70 years [2], the prognosis remains highly impacted by infections and cardiovascular events, which are major causes of mortality [3]. Apart from the traditional risk factors, steroids and aPLs increase the adverse cardiovascular profile in SLE [4–6]. APLs are present in 30–40% of SLE patients [7], of whom about one-third develop the clinical features, notably increased risk of blood clots and miscarriages typical of the clinically overt APS [8, 9]. Patients tend to have either the clotting or obstetric clinical features rather than both [10, 11]. Patients with thrombotic events receive long-term anticoagulation, whereas low-dosage aspirin (LDA) with/without low molecular weight heparin (LMWH) is recommended for women with obstetric complications [12]. The classification of APS requires at least one clinical feature [thrombotic event or adverse pregnancy outcome (APO)] together with persistent positivity of at least one aPLs: an LA, IgG or IgM aCL, and IgG or IgM anti-β2-glycoprotein I (aβ2GPI) [13]. In addition, several non-criteria antibodies and manifestations have been associated with APS [14]. In 2013, the aPLs Task Force recommended that the criteria include some of these manifestations, namely APS nephropathy, valve heart lesions, livedo reticularis, chorea and longitudinal myelitis, because of their relationship with classical aPLs, thrombosis and APOs [15]. New classification criteria are being developed [16]. The term ‘seronegative APS’ identifies patients fulfilling the clinical criteria, but without classical aPLs. Some studies reported that >50% of sera from patients with seronegative APS can have positive extra-criteria antibodies, of which the most studied are aPS-PT, anti-domain I of β2GPI (anti-DI β2GPI) and IgA aβ2GPI [17, 18].

APS can be primary (PAPS) or secondary (SAPS), when it occurs in the context of other autoimmune disorders. Some authors have reported that the presence of aPLs increases the risk of developing organ damage [7] and that the pattern of aPLs positivity could predict the risk of thrombosis in SLE patients [19], suggesting that the aPLs profile might provide useful information for the management of these patients. Here, we review the emerging evidence on the impact of aPLs and APS on SLE patients (SLE-APS).

What effect does a positive aPL test have on prognosis and outcome in an SLE patient?

IgM antibodies

The role of IgM aCL and IgM aβ2GPI in SLE patients is controversial. Swadźba et al. [20] found that, in SLE-APS patients, an elevated titre of IgM aCL, but not IgM aβ2GPI, was associated with an increased risk of arterial thrombosis (AT).

Another small retrospective study in 157 patients with APS (35 PAPS, 122 SLE-APS) showed that patients with elevated titre of IgM aCL antibodies were at higher risk of venous thrombosis (VT), while IgM aβ2GPI antibodies were associated with neither thrombosis nor recurrent fetal loss [21]. The potential bias derived from analysing the outcomes of PAPS patients together with SLE-APS patients must be considered [22].

The association between IgM aCL and aβ2GPI with thrombotic events was insignificant in two large cohorts of lupus patients [23, 24], while two meta-analyses showed that the IgM isotype was significantly associated with haematological manifestation [25, 26].

Regarding obstetric APS, a multicentre, prospective observational study (PROMISSE, Predictors of pRegnancy Outcome: bioMarkerIn antiphospholipid antibody Syndrome and Systemic lupus Erythematosus) [27] of 385 SLE pregnant women reported that aCL and aβ2GPI antibodies were not associated with the occurrence of APOs.

Recently, a systematic review reported that the presence of concomitant autoimmune disease did not adversely affect the obstetric outcomes in APS patients [28]. Thus, patients with/without SLE were considered comparable.

IgG antibodies

IgG aPLs are more strongly associated with thrombotic events than IgM in various diseases, including SLE [29, 30]. Domingues et al. [23] reported the rate ratios (RRs) of thromboses in IgG aCL-positive compared with -negative groups. The RRs were 1.8 (P = 0.0052) for any thromboses, 1.9 (P = 0.015) for VT and non-significant for AT.

In contrast, Swadźba et al. [20] observed that single IgG aCL and single IgG aβ2GPI positivity were predictors of AT, but not VT in SLE patients. The odds ratios (ORs) were 5.67 for IgG aCL and 4.69 for IgG aβ2GPI, suggesting that patients with raised levels of IgG aPL antibodies were more likely to develop clinical APS complications than those with elevated IgM aCL or aβ2GPI. Moreover, the authors noted that in SLE patients the ORs for arterial thrombosis were higher than in patients without SLE.

It is hard to compare these discrepant studies because some authors distinguished patients with isolated positivity from those with multiple positivity [20, 24, 31], whereas others did not analyse the links to concomitant positivities [23].

The PROMISSE study and a subsequent meta-analysis did not find statistically significant associations between IgG aPL antibodies and APOs [27, 28].

LA

Amongst the aPLs, the LA carries the strongest risk of increased rates of clinical complications. A meta-analysis showed that LA positivity was associated with an increased risk of VT in SLE patients, with an OR of 4.92 [32]. Demir et al. [24] observed an RR of 4.89 (P < 0.0001) for VT and 3.14 (P = 0.005) for AT in a cohort of 821 lupus patients. LA was also significantly associated with valvular heart disease [33] and thrombocytopenia [26].

Regarding obstetric APS, a prospective multicentre study found that women with LA positivity in the first trimester were significantly more likely to experience an APO compared with their counterparts without LA [34].

Petri et al. [35] noted that more patients were defined as having persistent LA positivity defined by frequently repeated LA testing compared with considering only two LA assessments. These two groups had a similar thrombotic rate.

IgA isotype

In a prospective cohort of SLE patients, IgA aβ2GPI antibodies were significantly associated with VT, stroke and thrombocytopenia [30]. The ORs were generally lower than those observed for IgG. It is unclear whether the analysis only considered patients with an isolated IgA aPL elevation or factored in the concomitant presence of other positive aPLs.

The pooled analysis of data from the LUMINA (LUpus in MInorities, NAture versus nurture) and Hopkins SLE cohorts showed that patients with elevated IgA aβ2GPI antibodies were more at risk of having arterial clots than those without them (17.0% vs 10.4%, P = 0.021). The presence of IgA aβ2GPI on its own carried an increased risk of all types of thrombosis (P = 0.0003) and AT (P = 0.0003) [36]. In another prospective cohort study of 821 SLE patients, IgA aβ2GPI antibodies were significantly associated with VT after adjusting for LA status (P = 0.0218) [24].

A subgroup analysis of 145 patients with SLE showed that IgA aCL positivity was not linked to a significant hazard ratio for APS, while IgA aβ2GPI had the second highest hazard ratio for APS among the nine antibody isotypes analysed [37]. Another study [23] found no significant association between IgA aCL antibodies and VT or AT, whereas in a Hopkins Lupus Cohort study, IgA aCL antibodies were significantly associated with VT (P = 0.023) [38]. Neither study provided information about the association between increased clotting risk with other aPLs. This is a major limitation and a likely cause of the inconsistency in the results.

Data on pregnancy outcomes in SLE patients with positive IgA aPL antibodies are lacking as most studies enrolled mixed populations of PAPS and SLE-APS without separate results. A significant association between IgA aCL antibodies and pregnancy loss in a cohort of patients with SLE-APS and with PAPS (P = 0.035) was reported [21]. A single-centre study of 187 patients, with 59 SLE-APS and 63 SLE without clinical features of APS, did not find a significant association between IgA aβ2GPI and APOs [39].

aPS-PT

Two different assays can detect the presence of antibodies directed against prothrombin. One uses ELISA plates coated with prothrombin (anti-prothrombin antibodies, aPT), the other uses the complex phosphatidylserine/prothrombin and detects aPS-PT [40]. Some authors have suggested that the two assays might identify different populations of antibodies [41]. Most of the data available describe aPS-PT antibodies.

A meta-analysis including 1775 patients (1170 with SLE) concluded that testing for aPS-PT, but not for aPT, might be useful in patients with previous thrombosis and/or SLE. aPS-PT positivity was linked to an increased risk of thrombosis, with ORs ranging from 3 to 18, while the evidence linking aPT antibodies and thrombotic events was less strong [42].

A retrospective cohort study suggested that aPS-PT antibodies might be stronger predictors of thrombosis than LA in SLE [43]. IgG and IgM aPS-PT were associated with VT, while IgA was associated with AT. The significant association between LA and thrombosis was lost after adjusting for aPS-PT positivity. A significant correlation between pathogenic LA and aPS-PT antibodies was noted.

Another study found that a high percentage of LA-positive patients with autoimmune disease were also positive for aPS-PT (82%) [44]. This observation, if confirmed in prospective and more representative populations, could have practical implications as aPS-PT antibodies might provide a further diagnostic tool in patients on anticoagulants, where the results of LA testing may not be reliable [45].

Evidence of the impact of aPS-PT antibodies on pregnancy outcomes of women with SLE is lacking. A prospective study of 55 APS patients (11 had SLE) reported that aPS-PT antibodies were significantly associated with intrauterine growth restriction and preeclampsia [46]. However, the low number of patients enrolled and the population heterogeneity necessitates cautious interpretation of the data.

Anti-DI β2GPI

Antibodies against β2GPI can recognize different epitopes of the glycoprotein. The pathogenic antibodies bind to the N-terminal portion of β2GPI (domain I, DI) [47]. Most studies exploring the predictive value of anti-DI antibodies were conducted on heterogeneous populations of patients with PAPS and SAPS [48, 49]. A meta-analysis including 1218 and 318 patients with APS and SLE, respectively, reported an overall OR for thrombosis of 1.99 considering the pooled data in those positive for anti-DI antibodies (P < 0.0001) [50].

IgA, IgM and IgG anti-DI antibodies were evaluated in 111 patients with APS (26 with SLE), 119 with SLE alone and 200 healthy controls [37]. In SLE patients, IgA, IgM and IgG anti-DI antibodies were all significantly associated with thrombosis.

The risk of vascular events was reviewed in 400 patients with SLE in whom IgG aCL, aβ2GPI and anti-DI were measured in samples taken within the first 2 years of diagnosis [51]. None of these antibodies alone had a significant effect on risk of vascular events.

Studies exploring the role of anti-DI antibodies in obstetric APS included heterogeneous populations and reported conflicting results. In a retrospective study of 477 patients, 93 with SLE, an increased rate of APOs was noted in those with positive anti-DI antibodies, especially for the APOs occurring after the 10th week of pregnancy. Patients with anti-DI antibodies had a 2-fold increase in the risk of fetal death after 10 weeks of gestation and premature birth before 34 weeks due to preeclampsia or placental insufficiency [52]. In contrast, other authors did not find any difference in the rate of pregnancy loss between patients with and without anti-DI antibodies. However, the proportion of SLE patients in the population studied is not always specified [48]. Further studies with a more homogeneous population are needed.

Multiple positivity

Double or triple criteria aPLs positivity has been recognized as a high-risk profile for APS-related events in a heterogeneous population of patients with PAPS and SAPS [53, 54]. The role of multiple aPLs positivity in selected cohorts of SLE patients was analysed. Demir et al. [24] found that the combination of LA with any isotype (IgA/IgM/IgG) of aβ2GPI or of aCL did not carry an increased risk of thrombotic events in lupus patients.

Among 23 combinations of aPLs, the triple positivity of LA, aβ2GPI (IgG/IgM) and aPS-PT (IgG/IgM) was the strongest predictor for thrombosis and/or APOs [55].

Double positivity for aβ2GPI and aPS-PT antibodies carried a higher risk of VT than triple-criteria aPL positivity [43]. The triple positivity for aβ2GPI, aPS-PT and LA was associated with an 8.1-fold increase in the risk of VT, confirming an earlier study [55].

Triple positivity for IgG anti-DI, IgG aCL and IgG aβ2GPI detected in the first 2 years after the diagnosis of SLE [51] identified a subgroup at increased risk of experiencing vascular events compared with single positive or negative patients (P = 0.0057). The association of any aCL and/or aβ2GPI isotype with anti-DI antibodies is associated with a 3- to 5-fold increase in the risk of APS compared with the double positivity of aCL and aβ2GPI [37].

Multiple IgG aPLs have also been reported as an independent risk factor for recurrent thrombosis in lupus patients [56]. See Tables 1 and 2 for detailed data.

Which major organs can be involved in both SLE-APS and PAPS and to what extent do the clinical features differ?

Kidney involvement

Kidney involvement occurs in both SLE and APS [57]. It is present in 30–50% of SLE patients, classically with lupus glomerulonephritis (LN) [58], although it may affect other kidney components [59]. Most patients with LN have proteinuria, including nephrotic syndrome. Other features include microscopic haematuria with/without red cell casts, hypertension and kidney function impairment [60].

The most common renal manifestations of APS are thrombotic microangiopathy, renal vein thrombosis, renal infarction and renal artery stenosis [61, 62]. These patients may present with nephritic or nephrotic syndrome, acute or chronic kidney injury, hypertension, haematuria and mild proteinuria [63]. Histologically, microthrombi and chronic vascular lesions, notably intimal hyperplasia, focal atrophy and repermeabilization of occlusive lesions, occur [64]. The diagnosis is established by kidney biopsy to distinguish it from LN [65].

Some authors reported that aPLs-positive patients with LN had worse survival rates, mainly because of vascular events, and worse renal outcomes compared with those without aPLs, while having better long-term renal survival than APS-LN patients [66]. However, the prevalence of these antibodies is identical in patients with/without LN [67]. Approximately 25% of SLE patients with diffuse proliferative glomerulonephritis have microthrombi, conferring a higher risk of glomerular sclerosis and an adverse renal prognosis [68, 69]. Glomerular microthrombi were related to LA and aβ2GPI positivity and decreased C3 levels but not to aCL positivity [68].

aPLs were also implicated in obstetric and vascular complications in LN patients [70]. Similar renal function was observed in patients with LN regardless of the presence of aPLs [67].

About two-thirds of SLE-APS patients have APS nephropathy (APSN) [62]. This prevalence was increased in aPLs patients (40% vs 2.1%), suggesting a pathogenic role in APSN. APSN represents a significant risk factor for hypertension, interstitial fibrosis and renal function deterioration, leading to end-stage kidney disease [71, 72].

The main adverse event in kidney transplant APS patients is graft thrombosis [73, 74]. APS was also correlated with graft loss but not transplant rejection. Recent evidence has shown that LN and APS patients undergoing kidney transplantation have a worse prognosis compared with patients with only LN, with a higher risk of graft loss, acute rejection and delayed graft function [75]. Even in APS-negative patients with aPLs, deterioration in renal function occurs after renal transplantation [76]. The presence of IgA anti-β2GPI antibodies, more frequent in patients with SLE-APS than in patients with PAPS, has been associated with thrombosis and graft loss [77–79].

CNS involvement

The CNS may be affected in SLE and APS. Clinical manifestations range from mild forms (e.g. depression, anxiety, headaches and cognitive dysfunction) to severe with psychosis, seizures, stroke and vasculitis [80, 81]. These manifestations occur in 46–80% of SLE patients [81]. APS patients may present with central thrombotic events, notably stroke or transient ischaemic attack or non-thrombotic events, namely cognitive dysfunction and seizures [82].

Stroke

Strokes occur in 1% of SLE patients, especially at a younger age, with a higher risk in the first year post-diagnosis [83–86]. Blood–brain barrier inflammation, complement deposition and cardiovascular risk factors contribute to these manifestations [87]. In patients with a first stroke episode, about 11% are aCL positive [88], and it seems to correlate with aCL IgM [89]. These cases tend to present with large-vessel disease, namely carotid artery stenoses [90, 91]. aβ2GPI are associated with stroke and cerebral venous thrombosis [92, 93]. Persistent IgG aβ2GPI titres increase stroke recurrence risk [94]. IgG aPS-PT and IgA aβ2GPI may be associated with stroke, although further studies are needed [87]. Rare intracerebral haemorrhagic events have also been described [95, 96].

Other CNS manifestations

Cognitive dysfunction may be present in APS patients [97]. Mechanisms involved include thrombotic, immune-mediated and inflammatory phenomena [98]. In aPL patients, cognitive dysfunction is described in 19–40% [99, 100]. In PAPS, it is up to 80% [101]. In SLE patients, cognitive decline is described in 7–75% [102, 103]. Affected areas in SLE-APS are identical to those of PAPS [100]. Advanced age, positive aCL and persistence of positive IgM aCL titres were identified as risk factors [104]. Hypertension and stroke history were identified as additional risk factors [102]. A relationship is evident with aCL and LA [105], mainly due to thrombotic mechanisms [103, 106].

Transverse myelitis occurs in <1.5% of SLE patients and in up to 4% of APS patients [81, 99, 107]. Potential causes include ischaemia and immune-mediated phenomena [80]. Distinguishing multiple sclerosis is essential [108]. In 15 SLE patients with transverse myelitis as the inaugural manifestation, 73% had positive aPLs [109].

Chorea occurs in 1–3% of SLE and PAPS patients [99] either due to a vascular process or through binding of aPL antibodies to the basal nuclei [110]. IgM aβ2GPI antibodies, young age and female gender are the most frequent clinical features in these patients [111, 112].

Seizures are described in PAPS patients in 3.2–10%, especially in refractory cases, probably based on immune-mediated phenomena [111, 113, 114]. Seizures occur in 8% of SLE patients and are associated with moderate to high aPL titres, particularly IgM and IgG aCL [80, 81, 115]. Risk factors include ischaemia, smoking, livedo reticularis and valvular heart disease [111, 116].

Headache is common in SLE patients, described in 5.6–68% [117]. In APS, it can be present in 20–40% [118, 119]. Cytokines, neuronal damage and vascular injury are thought to be implicated [97]. There are contradictory data regarding the association between aPLs and headaches [120]. Risk factors for headaches in PAPS include stroke or transient ischaemic attack history and aCL positivity [121].

To what extent does the presence of aPL/APS affect the damage accrual and the prognosis in SLE patients?

The coexistence of APS in SLE patients increases damage and mortality [5, 12]. A retrospective analysis described an 8-year survival rate in SLE patients of 98% compared with 75% in patients with SLE-APS and 83% in PAPS. Arterial thrombosis, disease activity at the onset, thrombocytopenia, capillaritis, digital ischaemia, nephritis and valvular heart disease were risk factors for mortality [122]. Notably, criteria aPLs, especially IgG aCL and LA, were significantly associated with valvular heart disease in SLE patients [33, 123]. In the Euro-phospholipid project, 7.1% PAPS patients died, similar to the SLE-APS group (6.8%). The main causes of death were from thrombotic phenomena [124]. SLE-APS patients experienced an increase in damage in the long term, while in PAPS, the damage derived mainly from early events [125]. The persistence of high titres of aPLs also promotes higher damage accrual (2- to 3-fold) in SLE patients [126]. SLE-APS patients have a quality-of-life decrease, mainly due to stroke, compared with SLE without APS [127].

How should SLE patients be managed in the presence of aPL/APS?

The control of cardiovascular risk factors is essential in SLE-aPL [128, 129]. These patients should stop smoking and avoid estrogen-based oral contraceptives [128]. Progesterone-based contraceptives are an alternative. However, copper or levonorgestrel-based intrauterine devices are the preferred methods [130]. Moderate physical exercise is recommended [131].

Risk stratification should be performed in all patients to determine cardiovascular risk and aPL profile [132].

HCQ is a well-tolerated and safe drug used in autoimmune diseases and may have some antithrombotic effect. It improves the lipid profile and inhibits platelet aggregation and activation. It has been shown to increase survival, reduce damage, minimize flares and reduce the persistence of aPL positivity in SLE patients. It should be considered in all SLE patients [133].

In SLE and high-risk aPL profile, LDA should be initiated in order to reduce the thrombotic risk [134]. These patients need prophylactic LMWH during surgery, prolonged immobilization and puerperium [135].

Adequate management of pregnant SLE-APL patients reduces morbidity and mortality in these patients and in the fetus, allowing for a successful pregnancy rate of up to 80% [136]. All these pregnant women should take LDA, including in the preconception period [130, 137]. Aspirin inhibits platelet activation and stimulates IL-3 responsible for placental implantation and growth [138]. It reduces the risk of pre-eclampsia and preterm delivery [137]. In high-risk cases, namely advanced maternal age, high-risk aPL profile and medically assisted reproduction, prophylactic LMWH dose is recommended [139]. Patients on steroids or heparin or with hypovitaminosis D in the first trimester should be supplemented with calcium, vitamin D and folic acid [130].

After the first thrombotic event in APS, long-term coagulation with vitamin K antagonist (VKA) is recommended [target international normalized ratio (INR) of 2.0–3.0 for venous clots, 3.0–4.0 for arterial]. Alternatively, the combination of VKA (INR 2.0–3.0) and LDA can be used after AT or recurrence of VT [135, 140], balancing thrombotic and haemorrhagic risk [141].

In SLE-obstetric APS patients, a combined regimen of LDA and LMWH is used. In patients without previous thrombotic events, a prophylactic LMWH dose should be administered and maintained in the first 6 weeks of puerperium [139], as the postpartum period represents a hypercoagulability state [142]. If there is a history of thrombotic events, therapeutic LMWH dose should be given [143] (Table 3). Warfarin is compatible with breastfeeding and can replace LMWH after delivery [144]. Gestational loss refractory to conventional therapy may necessitate additional therapy with prednisolone in the first trimester [145], plasmapheresis [146] and IVIG [147].

Although the European and British guidelines stated that direct oral anticoagulants (DOACs) could be considered in APS patients with previous VT without triple-positive aPLs [12, 148], a meta-analysis reported an increased risk of AT during treatment with DOACs at standard doses regardless of the previous history of AT and the number of positive aPLs [149]. However, the authors also concluded that DOACs were not associated with an increased risk of VT or major bleeding. Statins may be used given their anti-inflammatory and antithrombotic effects, reduction of low-density lipoprotein cholesterol, and inhibition of endothelial activation induced by aPL [150].

Conclusion

The aPL profile is essential to estimate the thrombotic risk and the prognosis in patients with SLE. The guidelines recommend testing for criteria aPLs. While LA is the best predictor of thrombosis and APOs in SLE, IgG aPLs have better predictive value than IgM aPL. IgA β2GPI, aPS-PT and anti-DI β2GPI antibodies are also able to predict APS-related events in lupus. The available evidence supports more frequent testing of LA and the detection of anti-DI β2GPI antibodies in newly diagnosed SLE patients. These measures might identify patients at increased risk of thrombotic events. aPS-PT antibodies might act as a surrogate of LA in anticoagulated SLE patients.

Few studies have only included patients with lupus, and additional data are required to provide further evidence about the role of criteria and non-criteria aPLs in increasing the risk of AT and VT in SLE patients. More studies on the optimal timing and frequency of testing for aPLs are necessary.

SLE-APS patients with renal involvement have a worse prognosis, mainly due to microthrombotic events. This phenomenon is also responsible for graft thrombosis and loss in transplanted patients. Neuropsychiatric manifestations include mild and severe forms. aPL/APS play a major role in these features.

SLE-APS patients have a decreased quality of life, increased damage accrual, reduced survival rate and worse prognosis when compared with SLE. Thrombotic events are the main causes of death. Thus, stratification and regular assessment of cardiovascular risk factors are essential. HCQ should be prescribed to them all. Aspirin is helpful for primary prophylaxis for SLE patients with high-risk aPL profile, during pregnancy and in selected cases as an adjuvant for secondary prophylaxis. Warfarin is the gold standard for secondary prophylaxis. Pregnant women with prior obstetric or thrombotic events should be managed with LMWH in this period.

Data availability

No new data were generated in support of this article.

Funding

No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article.

Disclosure statement: The authors have declared no conflicts of interest.

References