Clinical criteria
One or more episodes of arterial, venous, or small vessel thrombosis by validated criteria with no vessel wall inflammation
One or more unexplained fetal deaths later than 10 weeks’ gestation (morphologically normal fetus)
One or more premature births of morphologically normal neonate before 34 weeks’ gestation due to eclampsia or preeclampsia or recognized features of placental failure
Three or more unexplained consecutive spontaneous abortions before 10 weeks’ gestation, excluding hormonal or chromosomal causes
Laboratory criteria
Lupus anticoagulant in plasma on two or more occasions at least 12 weeks apart
IgG and/or IgM anticardiolipin antibodies in serum or plasma at medium or high titer on two or more occasions at least 12 weeks apart measured by a standardized ELISA
IgG and/or IgM anti-beta2glycoprotein I antibodies in serum or plasma at titer >99th percentile of healthy population on two or more occasions at least 12 weeks apart measured by a standardized ELISA
According to these recommendations, APS is defined by the presence of at least one clinical and one laboratory criterion (Table 19.1) [2, 3].
Patients with primary APS (PAPS) have no other autoimmune conditions, whereas secondary APS (SAPS ) is diagnosed where the criteria for APS are fulfilled in the presence of another condition – most commonly systemic lupus erythematosus (SLE ) [4]. The use of this term, however, does not imply that SLE causes APS to develop, and there are some cases where APS precedes SLE chronologically. Large cohort studies have found no differences in clinical features or consequences between PAPS and SAPS. Thus some experts suggested that the term SAPS should be abandoned in favor of terms such as SLE-associated APS, to document the coexistence of APS with other diseases [2].
The catastrophic APS (CAPS), a dramatic variant of APS, is characterized by acute widespread coagulopathy affecting small vessels leading to rapid multi-organ failure with high mortality rate [5].
The aPL can appear in different scenarios: asymptomatic carriers of aPL, “classical” APS with recurrent venous and/or arterial thrombosis with or without pregnancy morbidity, pure obstetric APS causing recurrent pregnancy loss with no thrombosis, aPL positivity with nonthrombotic manifestations (i.e., thrombocytopenia, hemolytic anemia, or livedo reticularis), or CAPS [6].
aPL have been reported in patients with:
Autoimmune rheumatic diseases
Infections
Malignancies
In association with certain drugs
But these aPL only seem to cause true APS in association with autoimmune rheumatic diseases and, rarely, with some infections . In this chapter, we will briefly discuss aPL found in infections and malignancies and in association with drugs and then concentrate on aPL and APS found in autoimmune rheumatic diseases, especially SLE .
19.2 Epidemiology of aPL and APS
Some evidence indicates that the incidence of the APS is around 5 new cases per 100,000 persons per year and the prevalence around 40–50 cases per 100,000 persons [6]. However, it is important to be aware that aPL can also occur in healthy people, in contrast to other autoantibodies , such as anti-dsDNA and anti-Sm, that are almost specific for patients with SLE [7].
Several studies evaluated the presence of aPL among healthy young people showing a prevalence range between 1 and 5 % for both aCL and LAC antibodies. Prevalence of anti-β2GPI and aCL (both IgM and IgG) antibodies in a large cohort of 510 healthy pregnant women studied prospectively at 15–18 weeks’ gestation was found to be 3.9 and 1.6 %, respectively. However, in most cases the antibodies were present at low titers, and only a minority of these individuals developed APS [8]. Prevalence of aPL antibodies (by all three standard assays) increases with age and, in particular, in elderly people with chronic diseases. However, in most cases these subjects do not develop APS clinical manifestations [9].
Recently, the APS ACTION group (AntiPhospholipid Syndrome Alliance For Clinical Trials and InternatiOnal Networking) published a literature review concerning the prevalence of aPL in the general population with pregnancy morbidity, stroke, myocardial infarction (MI), and deep vein thrombosis (DVT). Although 120 papers were included in the review, the authors noted a number of limitations in the evidence; the majority of studies were published several years ago, all three criteria aPL tests were performed in only 11 % of the papers, most studies used a low-titer aCL ELISA cutoff, the method of reporting the cutoff for anti-β2GPI ELISA was quite heterogeneous, confirmation tests for positive aPL were performed in only one-fifth of the papers, and the study design was retrospective in nearly half of the papers. The authors concluded the literature review by estimating that aPL are positive in approximately 13 % of patients with stroke, 11 % with MI, 9.5 % with DVT, and 6 % of patients with pregnancy morbidity [10].
The reported prevalence of aPL antibodies in children without any underlying disorder ranges from 3 to 28 % for aCL and from 3 to 7 % for anti-β2GPI. These figures are generally higher than those reported for adults. The reason for this is not yet understood but may be related to the frequent occurrence of infectious processes during childhood [11].
19.3 APS and Infection
19.3.1 aPL in Infectious Diseases
Wasserman described a complement fixation test for the serological diagnosis of syphilis (Wasserman test). This test can be falsely positive in the presence of aPL. This link between aPL and a false-positive test for syphilis was the first recognized association between APS and infectious diseases [12].
Since the association of aPL and syphilis was first described, many other viral, bacterial, and parasitic infections have been shown to induce the production of aPL. It is important, however, to emphasize that no particular infection or organism shows a high rate of association with aPL. Although molecular mimicry between infectious organisms and β2GPI has been suggested to play a possible key role in the pathogenesis of APS [13], this has not been ascribed convincingly to particular organisms. Although aPL have been reported in all the infections listed in Table 19.2, most patients who suffer these infections do NOT develop aPL.
Reports of aPL in infections have concentrated especially on viral illnesses. The prevalence of aPL in hepatitis C virus (HCV) infection has been reported to range from 3.3 to 46 % [8]. Sène and colleagues in a literature review published in 2008 estimated aCL prevalence of 18.6 % in HCV-infected patients compared with 1.78 % in control groups, while the anti-β2GPI prevalence was 1.65 % in the infected patients compared with 0.75 % in the controls [12]. In analogy, patients with hepatitis B virus (HBV) were found to be positive for aCL with a range between 18 and 42 %, while the figure for anti-β2GPI was lower (2–7.5 %) and no association has been demonstrated with APS-related phenomena [12, 14]. The reported prevalence of aCL and anti-β2GPI in patients with human immunodeficiency virus (HIV) ranges between 7–75 % and 3–20 %, respectively, but these antibodies are not significantly associated with thrombotic events or other APS manifestations [15].
aPL have been detected in patients with serology suggestive of other viral infections , including cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella-zoster virus (VZV), human T-cell lymphotropic virus type 1 (HTLV-1), adenoviruses, and parvovirus B19 with only anecdotal correlation with APS manifestations [16, 17]. In another study, a high prevalence of IgG aCL was found in patients with CMV infections after bone marrow transplantation, and a transient and high titer of aCL was found in pregnant women with primary parvovirus B19 infection [8, 12].
19.3.2 APS in Infectious Diseases
An important distinction in antigen-binding properties between infection-associated and APS-associated aPL has been recognized. Anti-CL antibodies detected in APS are thrombogenic and require the presence of serum cofactors, chiefly β2GPI, to bind CL. They are thus classified as “β2GPI dependent.” In contrast, aCL from patients with infections bind CL in the absence of serum cofactors and are described as “β2GPI independent” [18]. Moreover, aCL found in infections are more likely to be of IgM rather than IgG isotype [8]. The aPL occurring in infections may be transient and disappear within 2 or 3 months [19]. These largely IgM, often transient, β2GPI-independent aPL are rarely associated with clinical features of APS, and thus it is unusual for a positive aPL test in a patient suffering from infection to alter clinical management . However, it has been reported that certain infections, such as leprosy and parvovirus B19, are sometimes associated with anti-β2GPI or β2GPI-dependent aCL that are more likely to cause thrombotic events [16].
Rare cases of thrombosis with aPL occurring with HCV have been described: one venous thrombosis in a thalassemic patient with lupus anticoagulant and one lacunar cerebral infarction with high level of aCL [12].
Several isolated cases of thrombosis in patients with HIV were associated with the presence of aPL, including digital ischemia, deep vein thrombosis, arterial pulmonary embolism, portal vein thrombosis, cutaneous necrosis, testicular thrombosis, stroke, and bone avascular necrosis [8].
Ramos-Casals et al. reported a literature review of clinical features related to APS in patients with chronic viral infections , including HCV and HIV. They selected 82 patients (45 had chronic HCV infection, 32 had HIV infection, and 5 had HCV-HIV coinfection) and found that the main APS-related features in HCV-infected patients were intra-abdominal thrombosis and myocardial infarction, whereas, in HIV-infected patients, the main features were avascular bone and cutaneous necrosis. This evidence suggests that these viruses might act in some patients as chronic triggering agents inducing atypical presentation of APS [20].
Cervera et al. described the clinical and serological characteristics of 100 patients with APS related to infections (68 had primary APS, 27 had SLE , 2 had LLD, 2 had inflammatory bowel diseases, and 1 had RA). The main clinical manifestations of APS included pulmonary involvement (39 %), skin involvement (36 %), and renal involvement (35 %). The main associated infections and agents included skin infection (18 %), HIV (17 %), pneumonia (14 %), hepatitis C (13 %), and urinary tract infection (10 %) [21]. Of particular note, APS presented as a catastrophic syndrome in 40 % of these infection-related cases, whereas CAPS constitutes fewer than 2 % of all APS cases. CAPS is an exception to the rule that infection and APS are rarely linked. CAPS develops after a specific precipitating event in 60 % of cases, and 25 % of these events are infections [22].
19.4 APS and Malignancy
Isolated case reports and some retrospective studies showed the association of aCL with vascular events in patients with a variety of malignant conditions, including solid tumors and lymphoproliferative malignancies, compared with the general population. Since malignancy is also a hypercoagulable state, it is controversial whether the aPL have a pathogenic role in the thrombosis or are just an epiphenomenon in cancer patients [23]. From the literature, the incidence of aPL positivity in cancer varies with few reports on the persistence of aPL positivity.
Yoon et al. observed an incidence of aPL antibodies in up to 60 % of cancer patients in a small cohort of 33 Asian subjects, although the most prevalent antibody was anti-β2GPI IgA [24]. Additionally, Miesbach et al. performed a retrospective study in which a history of malignancy was found in 58 of 425 aPL-positive patients [25]. Armas et al. found a significantly higher aCL IgG levels in cancer patients compared with general population, although no differences in the incidence of thrombotic events were observed between aCL-positive and aCL-negative patients with cancer [26]. In contrast, another study demonstrated a higher prevalence of aCL IgM in patients with malignancies but without thrombosis compared with healthy controls [27]. Additionally, a prospective study evaluated the occurrence of malignancy in patients with aPL antibodies and found that 19 % developed cancer. None of these patients with malignancy and aPL antibodies were noted to develop any thromboembolism [28].
In another study the prevalence of aCL was compared between cancer patients with positive or negative history for acute thrombosis and healthy controls. No differences in mean value of aCL IgG were found, whereas a higher prevalence of aCL IgM was observed in patients with thrombotic events than without [29].
Pusterla and colleagues demonstrated an increased rate of thrombosis among patients with lymphoma and aPL compared with aPL-negative patients. In contrast, Genvresse reported a prevalence of 26.6 % of aPL in patients with non-Hodgkin lymphoma, but none of these patients presented clinical manifestations suggestive for APS [30].
Zuckerman et al. found a higher prevalence of aCL in a study of 216 patients with solid and nonsolid tumors compared with 88 healthy controls (22 % vs. 3 %), and, moreover, only those patients with high level of aCL had a higher rate of thromboembolic events [31]. Bazzan et al. found a higher prevalence of low titers of aPL in a series of 137 cancer patients compared with healthy controls. No significant difference was found between rates of thromboembolic events between aPL-positive and aPL-negative patients [32]. Font et al. found a low prevalence and transience of aPL positivity in patients with solid malignancies who developed venous thromboembolism [23]. In contrast, De Meis and colleagues found a strong correlation between thrombosis and LAC positivity in a cohort of patients with lung adenocarcinoma [33].
In conclusion, conflicting data are available regarding the role of aPL in patients with cancer. The reported aPL prevalences varied widely between studies, probably related to different clinical characteristics of the study populations and different ELISA techniques for aPL detection. However, there is no clear evidence that the aPL are necessarily associated with an increased thrombophilic risk. Conversely, presence of aPL may be a risk for hematological malignancies [34] (Table 19.3).
Table 19.3
Studies on aPL and malignancies
Study | No. of cancer patients/healthy controls | No. of cancer patients with aPL | aPL antibodies | No. of patients with aPL, malignancy , and thrombosis |
|---|---|---|---|---|
Zuckerman et al. | 216/88 | 47 | aCL IgG, IgM | 13 |
Ozguroglu et al. | 61/20 | NA | aCL IgG, IgM | NA |
Yook et al. | 33/0 | 20 | aCL IgG, IgM | NA |
anti-β2GPI IgG, IgM, IgA | ||||
Miesbach et al. | 58/0 | 58 | LAC | 24 |
aCL IgG, IgM | ||||
Pusterla et al. | 100/100 | 27 | LAC | 6 |
aCL IgG, IgM | ||||
Bazzan et al. | 137/137 | 33 | aCL IgG, IgM | 1 |
anti-β2GPI IgG, IgM | ||||
Font et al. | 258/142 | 23 | LAC | 21 |
aCL IgG, IgM | ||||
anti-β2GPI IgG, IgM | ||||
Genvresse et al. | 90/0 | 24 | aCL IgG, IgM | 0 |
anti-β2GPI IgG, IgM |
19.5 APS and Drugs
Several drugs may induce generation of aPL with a low prevalence and no clear association with APS clinical manifestations. Some reports include phenothiazines (chlorpromazine), phenytoin, hydralazine, procainamide, quinidine, quinine, Dilantin, ethosuximide, interferon-alfa, amoxicillin, chlorothiazide, oral contraceptives, and propranolol [4].
Biologic medications and in particular tumor necrosis factor-alpha (TNF-α) inhibitors (adalimumab, etanercept, infliximab) induce the production of autoantibodies including aCL . One possible explanation for the induction of aPL positivity in patients treated with anti-TNF-α is that downregulation of TNF-α leads to upregulation of interleukin-10 (IL-10), which in turn activates autoreactive B cells and thus induces autoantibody production [36]. Ferraccioli et al. observed the induction of aCL in 5 of 8 RA patients treated with etanercept and followed for 85 weeks. The authors showed that the appearance of these autoantibodies correlated with infections including urinary or upper respiratory tract infections and that antibiotic treatment restored normal aCL antibody levels [37]. Another study evaluated 39 RA patients treated with infliximab and followed over 78 weeks. Among these a significant increase level of aCL was observed, starting at 30 weeks for IgM antibodies but not till the final time point (78 weeks) for IgG antibodies. However, the levels were low and none of the patients exhibited any clinical features related to APS [38]. Two case reports provide evidence of APS related to anti-TNF-α treatment. Hemmati et al. described a 67-year-old woman who developed APS and vasculitis associated with de novo positive aCL antibody following the third dose of adalimumab therapy for the treatment of spondyloarthropathy [39]. Vereckei and colleagues reported a case of infliximab-induced APS with manifestation as necrotizing vasculitis of toes and fingers in a patient with RA [40].
19.6 APS Associated with Autoimmune Rheumatic Diseases
In 1983 Graham Hughes identified a group of patients with SLE , who suffered from obstetric morbidity and/or recurrent thromboses and with serum IgG aCL positivity [41]. Since then, the majority of publications related to APS in the setting of another autoimmune rheumatic disease have continued to relate to SLE, as this is by far the most commonly associated condition. In this section, therefore, we will concentrate on SLE-associated APS before covering the relatively sparse literature on APS in association with other autoimmune rheumatic diseases .
19.6.1 APS Developing in Patients with Preexisting SLE
The prevalence of aPL among patients with SLE ranges from 12 to 44 % for aCL , from 15 to 34 % for LAC, and from 10 to 19 % for anti-β2GPI [34]. Interestingly, a meta-analysis of the published studies was performed by Avcin and colleagues showing a global prevalence of 44 % for aCL, 40 % for anti-beta2GPI, and 22 % for LAC among the SLE pediatric population [42]. It is possible that the real frequency of aPL in patients with SLE is underestimated, especially if patients develop these antibodies intermittently or if levels are altered by treatment [43].
APS may develop in 30–70 % of aPL-positive patients with SLE within 20 years of follow-up [8]. Alarcon-Segovia et al. showed that up to 30 % of patients with SLE and positive aCL have no clinical manifestation of APS during an average follow-up of 7 years. Conversely, in the Hopkins lupus cohort the risk of developing thrombosis in SLE patients with LAC positivity was about 50 % at 20 years of follow-up [43, 44].
19.6.2 SLE Developing in Patients with Preexisting APS
Progression from primary APS to a full-blown SLE is rare event. To date, there are several reported cases of patients whose PAPS evolved to SLE or LLD. Moreover, some large studies have addressed this issue in detail.
In a retrospective study, Gomez-Puerta et al. followed up for about 9 years 128 patients with PAPS of whom 11 (8 %) patients developed SLE , 6 (5 %) developed lupus-like disease, and 1 (1 %) developed myasthenia gravis. The remaining 110 patients (86 %) continued to have primary APS. In this study a positive Coombs test was a clinically significant predictor of progression to SLE [45].
Recently, Freire PV et al. retrospectively analyzed a cohort of 80 patients with primary APS. Among these 14 (17.5 %) patients who were significantly younger at the time of diagnosis, with a longer disease duration, progressed within 5.2+/-4 years to SLE -related APS. All these patients were ANA positive before the diagnosis of SLE, compared to 51 % of the 66 patients who did not develop SLE [46].
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