Prognosis in Antiphospholipid Syndrome

Chapter 19

Prognosis in Antiphospholipid Syndrome Rosa M. Serrano, Guillermo J. Pons-Estel, Gerard Espinosa and Ricard Cervera Department of Autoimmune Diseases, Hospital Clínic, Barcelona, Catalonia, Spain

19.1 INTRODUCTION Antiphospholipid syndrome (APS) is an acquired autoimmune disease defined by the persistent presence of moderate to high serum levels of antiphospholipid antibodies (aPL) in association with thrombotic events, pregnancy loss, or both [1]. This systemic autoimmune disease is characterized by a wide spectrum of clinical manifestations and may be primary or associated with other diseases, mainly systemic lupus erythematosus (SLE). The outcomes of patients can be variable with different degrees of severity and recurrence because of the heterogeneity of this syndrome. Although APS was described more than 30 years ago [2], specific publications about the prognosis [3,4] and natural history of this disease are scarce [5–7]. There is poor knowledge about what factors may influence the clinical evolution and what repercussions may have aPL positivity, even in healthy individuals [4]. Understanding the risk factors and predictors of disease and organ damage may assist clinicians in the management of APS. In this chapter, we will review existing information on the prognosis of APS. According to the heterogeneous condition of this disease, this topic will be discussed contextualizing in different situations and according to the clinical setting.

19.2  MORTALITY AND MORBIDITY IN PATIENTS WITH LONG-TERM FOLLOW-UP APS Most of the existing information about the outcome of APS is based on data from cohorts with long-term follow-up and a significant impact on morbidity and survival has been documented. Antiphospholipid Syndrome in Systemic Autoimmune Diseases. DOI: http://dx.doi.org/10.1016/B978-0-444-63655-3.00019-3 © 2016 Elsevier B.V. All rights reserved.

281

282  Antiphospholipid Syndrome in Systemic Autoimmune Diseases

The largest cohort of patients with APS that more clearly reflects an overview of the current status of APS is the ‘Euro-Phospholipid Project’. This is a European multicentre prospective study that included 1000 APS patients followed for 10 years. The analysis of epidemiological, clinical, laboratory, treatment, and mortality data at baseline, 5 and 10 years has provided important information on the outcome of the disease [5–7]. The impact of the APS in prognosis is high because it affects predominantly young people, it may occur as a severe form called catastrophic APS (CAPS) and accrue a significant rate of mobility and mortality despite treatment. In this study, 20% of patients presented recurrences during the 10 years of follow-up, 80% of them were thrombotic events and about half of these events occurred despite treatment. The frequency of CAPS was low and occurred in 0.9% (n = 9) of the patients. Of note, it was the presenting event of APS in six of them and five died. Patients with APS associated with SLE and primary APS showed similar clinical profiles.

19.2.1 Mortality Over the past years, efforts have been made focusing on the risk of mortality in patients with APS. In 2009, and most recently in 2015, the ‘Euro-Phospholipid Project’ reported the results of the 5- and 10-year follow-ups [6,7]. During the first 5 years [6], 53 patients died (21 in the first year, 12 in the second, 10 in the third, 5 in the fourth, and 5 in the fifth) and the most common causes of death were bacterial infections (20.8%) followed by thrombotic manifestations of APS, such as myocardial infarction (18.9%), stroke (13.2%), pulmonary embolism (9.4%), and CAPS (9.4%). Haemorrhagic events due to the anticoagulant therapy and malignancies were the cause of death in 11.3% of patients (each one). During the 10-year period [7], 93 (9.3%) patients died (72 females and 21 males) and the mean (SD) age at death was 59 (14) (range 19–94). The unadjusted standardized mortality ratio for the total cohort was 1.8 (95% confidence interval (CI) 1.5–2.1) in comparison with the general population of the area studied. Of them, 40 died during the second 5 years of follow-up, with a similar mortality rate between both periods. However, some differences were detected between both periods: fatal thrombotic events were higher during the initial period and the incidence of death because of malignancy became more frequent during the last period. In addition, infections and bleedings accounted for one-third of deaths during the long-term study, appearing in similar percentages during both periods. When the investigators tried to identify any clinical or immunological parameter with prognostic significance over mortality, no variable became significant. Interestingly, although survival probability decreased during the 10-year period, older age was not associated with increased mortality. This may be due to the fact that APS-related conditions dominated the causes of mortality in this cohort, but also because the population was not very old. When mortality rate from this cohort was matched with the 1000 patients from the ‘Euro-lupus cohort’ [8], it was 25% higher in APS patients than those with SLE.

Prognosis in Antiphospholipid Syndrome  Chapter | 19  283

More information on this topic comes from a systematic review by RuizIrastorza et al. [9], which focused on the efficacy of secondary thromboprophylaxis for APS. Of the 660 patients with APS or the presence of aPL, 44 (7%) died, and 28 (62%) of the deaths were directly related to thrombotic events. Malignancy was the cause of death in six (21%) patients, and sepsis and multiorgan failure in one patient each. Fatal bleeding (massive haemoptysis in a patient with bronchiectasis) secondary to anticoagulant treatment was the main cause of death in only one patient. In the remaining eight cases, the cause of death was not specifically reported and was attributed to associated or coincident diseases. Interestingly, in 24 (54.5%) patients, death was related to a recurrent thrombosis during follow-up (17 arterial, 6 venous, and 1 case of widespread thrombosis). Moreover, only one study included in this systematic review attempted to identify the risk factors associated with the mortality. However, the proportions of the variables analysed (sex, age, the presence of diabetes, hypertension, or hyperlipidaemia, platelet counts, and positive IgG or IgM isotype of anticardiolipin antibodies (aCL) or lupus anticoagulant (LA)), were similar between patients who died and those who survived [10].

19.2.2 Morbidity 19.2.2.1  Organ Damage The morbidity and organ dysfunction are secondary to cumulative irreversible damage. Although more prospective studies of large cohorts are needed, recent observations provide some information about predictors of organ damage and prognostic factors. Grika et al. [11] assessed the accumulated organ damage in a retrospective study of 135 APS patients (89 primary APS and 46 with APS associated with SLE) followed 10 years from disease onset by using the Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) damage index. Patients were clustered according to the initial event: arterial thrombosis, venous thrombosis, or pregnancy morbidity. They observed that the type of initial presentation was preserved with regard to a second event and, therefore, arterial events are followed by arterial and venous by venous thrombotic events, while pregnancy morbidity recurs more frequently with pregnancy morbidity. One-fourth of the patients progressed to organ damage and the SLICC/ACR, which increased over time, was associated with increased mortality. The highest morbidity was attributed to neurologic damage, which was significantly more common in patients with arterial thrombosis as an initial manifestation compared with the venous thrombosis group. Pregnancy morbidity was found to be associated with less damage compared with thrombosis at presentation. In addition to the type of initial event, CAPS and coexistent SLE were significant moderators of damage. Tektonidou et al. [12] confirmed the association between the type of initial clinical presentation and subsequent rate and type of serious clinical outcomes. They also concluded that a first presentation with two clinical events (arterial, venous

284  Antiphospholipid Syndrome in Systemic Autoimmune Diseases

thrombosis, and recurrent abortions) or haemolytic anaemia and the presence of anti-β2-glycoprotein I antibodies (anti-β2GPI) carried a worse overall prognosis. Instead, therapy with warfarin or aspirin showed a beneficial effect on overall prognosis. In a longitudinal study of SLE patients followed for 9.7 years, Ruiz-Irastorza et al. [13] observed that APS with thrombotic manifestations was a major predictor of irreversible organ damage and death in patients with SLE. All patients with APS experienced thrombosis, mostly in the arterial territory. Damage was more severe in patients with APS and cumulative survival at 15 years was also lower in patients with APS than in those without APS. Regarding primary APS, Dall’Ara et al. [14] also found similar results in a retrospective study of 35 patients monitored for 15 years. Organ damage was present in 20% of patients at the end of the follow-up (17% neurological and 3% renal) and was significantly associated with the occurrence of thrombotic events, particularly arterial. Neither the aPL profile nor the presence of other autoantibodies or disease duration and, above all, the type of pharmacological treatment were significantly associated with organ damage. Finally, Erkan et al. [15] showed in a retrospective study of 39 patients with primary APS, that after 10 years of disease, one-third had organ damage and one-fifth of them were functionally impaired. Over the years, organ damage in APS patients has been evaluated using the SLICC/ACR damage index [16] validated only for SLE. Although it includes damage caused by APS and can provide a crude estimate of APS-related organ damage, it has limitations. In persistently aPL-positive patients with SLE, it should be interpreted cautiously because it can overestimate SLE-related damage and underestimate aPL-related damage [17]. It was thus imperative to quantify organ damage in APS to better assess prognosis and treatment. A damage index for patients with thrombotic APS (DIAPS) was proposed by Amigo et al. [18]. This is a 37-item instrument considered by an expert panel agreement to reflect damage in thrombotic APS. Although it is not intended to evaluate the obstetrical impact of chronic damage, infertility was included. The DIAPS has an initial validation and also recently has shown a significant correlation with the EuroQoL, a generic, standardized measurement of health to determine the quality of life that has shown a significant association with chronic damage [18].

19.2.2.2  Quality of Life There is scare information about the long-term impact on quality of life in patients with APS. According to the previously mentioned study by Erkan et al. [15], the functional outcome was affected in 20.5% of young surviving patients with prolonged primary APS. They were unable to perform everyday activities important to their quality of life and the main causes of this functional impairment were cognitive dysfunction, cardiovascular disease, aphasia, and locked-in syndrome. A recent study published by Georgopoulou et al. [19] investigated health-related quality of life (HRQoL) in 270 APS patients using the Short Form-36 (SF-36) Health Survey. This instrument assesses disease influence on patients’ physical condition, psychological, and social well-being.

Prognosis in Antiphospholipid Syndrome  Chapter | 19  285

They concluded that APS has a significant impact on patients’ HRQoL. In primary APS, it appears to be generally better than APS associated with SLE in physical domains, but poorer in mental domains. The major APS-related issues exerting significant impact on illness management and daily living were pain, fatigue, lack of health care professional/public awareness, and medication unpredictability. Another multicentre French study showed similar findings and also observed significant impairment of HRQoL in APS patients with history of arterial thrombosis [20].

19.2.3  Thrombosis and Rethrombosis Thrombosis is the main feature of APS and frequently recurs during the followup. In the Euro-Phospholipid Project, thrombotic events appeared in 16.6% of this cohort during the first 5-year period of the study and in 15.3% during the second 5-year period of follow-up. The most common thrombotic events were strokes (5.3% of the total cohort), transient ischaemic attacks (4.7%), deep vein thrombosis (4.3%), and pulmonary embolism (3.5%) [6,7]. The long-term prognosis in patients with APS was primarily influenced by the risk of recurrent thrombosis, especially arterial thrombosis [11,14]. Over the years, several contributions have been made in order to identify the risk factors of thrombosis in APS and the influence of aPL. 1. The positivity of aPL have shown to be predictor factors of thrombosis. Ginsburg et al. [21] reported in a prospective study, that a high level of aCL was a risk factor for deep venous thrombosis or pulmonary embolisms, but not for ischaemic stroke in healthy men, independent of age and smoking status. In addition, Vaarala [22], in a prospective cohort of healthy middle-aged men, showed that the presence of a high aCL level was an independent risk factor for myocardial infarction or cardiac death. In a large prospective study, Finazzi et al. [23] showed that a high level of IgG aCL was a significant predictor for thrombosis in unselected LA and/or aCL-positive patients. A metaanalysis by Reynaud et al. [24] quantified the association between aPL and the risk of venous and arterial thrombosis in asymptomatic carriers: LA and aCL were associated with an increased risk of venous thrombosis, contrary to antiβ2GPI. Classical (LA, aCL, and anti-β2GPI) antibodies and others, such as antiprothrombin and antiphosphatidylserine autoantibodies, were predictive of arterial thrombosis. Moreover, in patients with APS, positive IgG aCL, livedo reticularis, hypertension, and hypercholesterolaemia have been identified as risk factors for arterial thrombosis [25]. 2. Patients with high titres of aCL are more likely to develop thrombosis than those with low titres of aCL. Galli et  al. [26] found that the risk of both venous and arterial thrombosis and/or thromboembolism was increased in individuals with positive tests for LA activity or with medium or high levels of aCL. Shah et al. [27] studied 52 patients with raised levels of aCL. After a 10-year follow-up, 29% of APS patients had new thrombotic events and

286  Antiphospholipid Syndrome in Systemic Autoimmune Diseases

52% of patients with aCL, but lacking the clinical features of APS, developed the syndrome. 3. Multiple positivity of aPL shows a marked association with thromboembolic events [28,29]. Pengo et al. [30] concluded after studying a large retrospective analysis that APS patients with triple positivity for aPL (LA, aCL, and anti-β2GPI) are at high risk of developing future thromboembolic events. Recurrence remains frequent despite the use of oral anticoagulants, which significantly reduces the risk of thromboembolism. 4. Finally, the presence of aCL is a risk factor for recurrences. A large prospective study performed by Schulman et al. [31] on over 412 patients presenting with a first episode of venous thromboembolism who were treated with 6 months of anticoagulation with warfarin found that the risk of recurrence within the first 6 months after stopping anticoagulation was twice as high among patients with aCL compared with those without such antibodies. In addition, the risk of recurrence increased with the aCL titre. Significant advances have been recently made in order to develop scores that may predict the occurrence of thrombosis. Oku et al. [32] introduced the antiphospholipid score, a quantitative marker that represents aPL profile. They have validated its efficacy for the diagnosis of APS and predictive value for thrombosis. This score is a useful quantitative index for diagnosing APS, but it does not take into account associated conventional risk factors for thrombosis in addition to the aPL profile or evaluate the risk for PL. Another score was developed by Sciascia et al. [33] This Global APS Score (GAPSS) for primary APS was derived from the combination of independent risk factors for thrombosis and pregnancy loss, taking into account the aPL profile (criteria and noncriteria aPL), the conventional cardiovascular risk factors and the autoimmune antibody profile. GAPSS proved to be a valid tool for a substantial improvement in risk stratification for thrombosis in primary APS. The prognosis of APS may also vary according to the site of the thrombotic event, its complications, recurrences, and severity. Deep venous thrombosis is the most frequent thrombosis and may be multiple, bilateral, associated with superficial thrombophlebitis, and also may be complicated by chronic venous stasis ulcers affecting medial malleolus. These ulcers should be differentiated from those caused by multiple small-vessel occlusions on the laterals of the lower limbs. Medium- or large-artery occlusion of the extremities can also produce gangrene and even amputation. In addition, one-third of APS patients with deep venous thrombosis are complicated by pulmonary embolism. Recurrent pulmonary embolism may lead to pulmonary hypertension and clinical manifestations of right-heart disease with worse prognosis despite treatment [34]. Central nervous system (CNS) thrombosis is another important cause of morbidity and mortality. Stroke and transient ischaemic attacks are the most common arterial thrombotic manifestation in APS, and often may progress to vascular dementia [11]. Recently, cognitive deficits have been often found among patients with APS, usually associated with livedo reticularis and the

Prognosis in Antiphospholipid Syndrome  Chapter | 19  287

presence of white matter lesions on brain magnetic resonance, independent of any history of CNS involvement [35]. Cardiac involvement takes several forms (ie, myocardial infarction, cardiomyopathy, and thrombotic valve lesions), all having a high impact on the outcome of the disease [36]. A relationship between aPL and premature atherosclerosis has been established [37]. Peripheral arterial disease with aCL also was associated with overall mortality and cardiovascular mortality [38]. Nephropathy is also associated with poor outcome. Although thrombosis may develop at any location within renal vessels, the characteristic renal injury of APS is the thrombotic microangiopathy. This lesion may vary in severity and extent. The clinical consequences include severe renovascular hypertension and renal failure. At end-stage renal disease, these patients are at high rate of thrombosis of haemodialysis access, arteriovenous grafts, and post-transplant renal thrombosis. The possible beneficial effects of immunosuppressive treatment need further study [39–43].

19.2.4  Haemorrhagic Complications Apart from thrombotic recurrences, the most frequent complications that occurred during the follow-up are haemorrhages. The most common cause is the antithrombotic treatment. During the 10-year follow-up of the EuroPhospholipid Project, 61 major bleeding episodes developed. All of them were in patients on antithrombotic treatments, 33% at a target international normalized ratio (INR) >3 (50.8% mucocutaneous, 24.6% cerebral, 16.4% gastrointestinal, and 8.2% intra-abdominal) and 16.4% were fatal [7]. Dall’Ara et al. [14] recorded haemorrhages in 34% of patients on treatment. No significant difference in bleeding risk was found between patients receiving oral anticoagulant and those receiving antiplatelet therapy. They could be classified as mild events (ecchymosis, epistaxis, gingival bleeding, mild metrorrhagia) in 26% of patients, while 8% of patients, all on oral anticoagulants, experienced a severe haemorrhagic complication (subdural haematoma, severe metrorrhagia, oesophageal varices bleeding). In terms of safety, the administered treatments seem to be acceptable; few major bleeding events have been registered, apparently independent of the intensity of therapy [44]. Thrombocytopenia is a common manifestation associated with APS, but severe thrombocytopenia is not a frequent finding and usually does not require therapeutic intervention because it infrequently causes major bleeding. In patients with APS associated with SLE, however, thrombocytopenia has been associated with an increased risk of mortality [45].

19.3  OBSTETRIC APS The prognosis of pregnancies in patients with APS has greatly improved over the past two decades due to the effect of multidisciplinary management (obstetricians, internists, rheumatologists, haematologists, etc.), an appropriate

288  Antiphospholipid Syndrome in Systemic Autoimmune Diseases

preconception assessment, and counselling, including information on the potential maternal and obstetric problems [46]. Different clinical and immunological profiles have clear prognostic significance and are an extremely important tool for guiding clinical decisions. Maternal risk factors in the PROMISSE study (Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus study), an ongoing multicentre, National Institutes of Health (NIH)–funded prospective observational study of pregnancies in women with aPL, SLE, or both included prior thrombosis, young maternal age, and the coexistence of clinically evident SLE or other systemic autoimmune diseases. Surprisingly, the number of prior losses was not predictive. When patients were stratified according to presence or absence of LA, either low molecular weight or unfractionated heparin (initiated at pregnancy confirmation) did not influence outcome, whereas aspirin (all but one patient received 81 mg/day) was associated with fewer adverse events. Neither hydroxychloroquine nor corticosteroid therapy influenced outcome, but few patients took either of these drugs [47]. Within the immunological profile, the presence of a positive LA was found to be the most powerful predictor of recurrent foetal losses before 24 weeks of gestation in women without autoimmune disease. While in this same group, IgG aCL were associated with early and late recurrent foetal losses and moderate to high titres increased the rate of this association. Meanwhile, IgM aCL were associated with late recurrent foetal losses. Finally, no relationship was found between anti-β2GPI and recurrent miscarriages [48]. Similar results have been observed in primary APS, in a study performed by Ruffatti et al. [49] where LA was the aPL that most strongly influenced pregnancy outcome. Moreover, those women with more than one positive test for aPL had poorer outcomes; those women who were positive for all three tests, called ‘triple positive’, had a significantly higher incidence of pregnancy loss compared with women who had one or two positive tests for aPL. Simchen et al. [50] also demonstrated a risk of adverse foetal/neonatal outcomes, 5.7 times higher for pregnant women with antibody titres greater than four times the upper limit of normal. Finally, Lockshin et al. [47] studied pregnancies of patients with APS, SLE, or both, and reported that 35% of women with LA and low-titre (<40 GPL units) IgG aCL had adverse pregnancy outcomes, mostly live infants, as did 43% with LA and high-titre aCL (the difference between low- and high-titre aCL was not significant). By contrast, no women with low titre and only 8% of women with high-titre aCL who did not have LA had adverse outcomes, a rate not different from normal. If a woman had SLE and LA, she had a 55% risk, and if she had LA, but did not have SLE, she had a 35% risk. IgM anti-β2GPI and triple positivity added no information not given by LA alone. Test at first pregnancy visit predicted outcome; subsequent tests during pregnancy did not change their conclusions. Other prognostic indexes of poor pregnancy outcome in APS include the uterine velocimetry Doppler that provides a non-invasive measure of the uteroplacental blood flow, which was able to detect a condition of impaired placental

Prognosis in Antiphospholipid Syndrome  Chapter | 19  289

perfusion due to the presence of circulating aPL [51,52]. This is a useful tool to identify APS pregnancies at higher risk of adverse pregnancy outcome [53]. The presence of a false-positive IgM for toxoplasmosis, others, rubella, cytomegalovirus, herpes viruses (TORCH) complex could also be associated with a worse pregnancy outcome because it reflects a dysregulation of the immune system, which may amplify placental autoimmune damage. In addition, low levels of complement components are related to an increased incidence of obstetrical complications, suggesting that placental deposition of immune complexes and activation of complement cascade may contribute to APS-related placental failure [54]. The presence of aPL is considered a risk factor for preeclampsia. In a metaanalyses, do Prado et  al. [55] found an association between aCL and preeclampsia (odds ratio (OR) 2.86, 95% CI 1.37–5.98) and between aCL and severe preeclampsia (OR 11.15, 95% CI 2.66–46.75). When nonsevere preeclampsia was evaluated, there was no association with aCL. Another meta-analysis by Abou-Nassar et al. [56] included studies evaluating LA, aCL, and anti-β2GPI in association with the adverse pregnancy outcomes of preeclampsia, late foetal loss, foetal growth restriction, and placental abruption. There was an increased probability of LA in preeclampsia in 10 case-control studies (OR 2.34, 95% CI 1.18–4.64), but not in the three cohort studies (OR 5.17, 95% CI 0.6–44.56). There was a higher probability of aCL in preeclampsia in 19 case-control studies (OR 1.52, 95% CI 1.05–2.2), but not in cohort studies. In addition, antiβ2GPI was more common in preeclampsia patients in cohort studies (OR 19.14, 95% CI 6.34–57.77), but not more commonly detected in case-control studies. Interestingly, these associations were inconsistent when analysed by study type. In addition, in this second meta-analysis, titre levels of 5 GPL/MPL were considered positive, which is a significantly lower level than defined by the international criteria. In the Euro-Phospholipid Project during the 10-year follow-up period, 127 (15.5%) women became pregnant (range 1–4). A total of 188 pregnancies occurred and 72.9% of pregnancies succeeded in having one or more live births (range 1–3; total number of live births, 137). The most common obstetric complication was early pregnancy loss (less than 10 weeks) that appeared in 16.5% of pregnancies. The obstetric morbidity rate was lower during the last 5 years of the study, so that no women developed preeclampsia/eclampsia. Regarding foetal morbidity, the most frequent manifestations were birth prematurity (48.2% of the total live births) and intrauterine growth restriction (26.3%) [7]. The long-term thrombotic prognosis of obstetric patients is far from positive. Erkan et al. [57] reported for the first time a thrombosis rate of 1.3 of 100 patients/year for 31 obstetric women who had been taking aspirin for 49 ± 37 months and 7.4 of 100 patients/year for 34 patients without aspirin followed for 35 ± 33 months. The rate of thrombosis may also be affected by the antibody profile of the pregnant women. In 2011, Lefèvre et al. [58] reported in 32 obstetric APS patients a thrombotic rate of 3.3 of 100 patients/year and 4.6, 4.5, and 10 of 100 patients/year when they considered at least two aPL antibody

290  Antiphospholipid Syndrome in Systemic Autoimmune Diseases

positivities (among LA, aCL, and anti-β2GPI), antinuclear antibody positivity, or SLE-associated APS patients, respectively. Additional risk factors, such as oestrogen-containing contraceptives and situations in which preventive anticoagulation should be considered, such as prolonged immobilization, need to be taken into account in obstetric APS.

19.4  CATASTROPHIC APS CAPS is infrequent (less than 1% of patients with APS develop this complication). Nevertheless, it is potentially lethal, with a mortality rate close to 35%. Investigators from the CAPS Registry studied the main precipitating factors in 280 patients and the most common were infections and surgical procedures. Other less common causes were anticoagulation withdrawal or low INR, use of medications, obstetric complications, neoplasia, and SLE flares [59]. The prognosis of patients who survived the initial catastrophic event was evaluated by Erkan et al. [60] who demonstrated that 66% of them remain free of thrombosis and 17% develop further APS-related manifestation during a follow-up of approximately 6 years. In this cohort, no patient had relapses of CAPS. Secondary analysis about the functional outcome found that 15% were significantly functionally impaired due to the initial CAPS event. Finally, recurrent or relapsing CAPS is a distinctly uncommon complication in patients with CAPS. In the CAPS Registry, the relapse rate was 3% of all patients. The presence of schistocytes and microangiopathic haemolytic anaemia has been associated with the development of relapses [61]. In patients with CAPS, mortality rates are higher in the CAPS Registry among the 280 patients, 123 (44%) died at the time of the CAPS event [59]. Different groups have evaluated the predictors of mortality in CAPS. Bucciarelli et al. [62] in a study with 250 patients found that the presence of SLE and positive antinuclear antibody titre were associated with a higher risk of mortality. Conversely, sex, mean age, the presence of a precipitating factor at the time of the CAPS event, and the number of organs affected were not associated with a worse prognosis. Confirmation of this association comes from a study published by Bayraktar et  al. [63], which showed that at the time of CAPS diagnosis, after adjusting for age, sex, the presence of organ involvement, and treatment, patients with SLE had a higher risk of mortality than patients without SLE.

REFERENCES [1] Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4(2):295–306. [2] Hughes GR. Thrombosis, abortion, cerebral disease, and the lupus anticoagulant. Br Med J (Clin Res Ed) 1983;287(6399):1088–9. [3] Alarcon-Segovia D, Perez-Ruiz A, Villa AR. Long-term prognosis of antiphospholipid syndrome in patients with systemic lupus erythematosus. J Autoimmun 2000;15(2):157–61.

Prognosis in Antiphospholipid Syndrome  Chapter | 19  291 [4] Amigo MC. Prognosis in antiphospholipid syndrome. Rheum Dis Clin North Am 2001;27(3):661–9. [5] Cervera R, Piette JC, Font J, et  al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum 2002;46(4):1019–27. [6] Cervera R, Khamashta MA, Shoenfeld Y, et al. Morbidity and mortality in the antiphospholipid syndrome during a 5-year period: a multicentre prospective study of 1000 patients. Ann Rheum Dis 2009;68(9):1428–32. [7] Cervera R, Serrano R, Pons-Estel GJ, et al. Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients. Ann Rheum Dis 2015;74(6):1011–18. [8] Cervera R, Khamashta MA, Font J, et al. Morbidity and mortality in systemic lupus erythematosus during a 10-year period. A comparison of early and late manifestations in a cohort of 1,000 patients. Medicine (Baltimore) 2003;82:299–308. [9] Ruiz-Irastorza G, Hunt BJ, Khamashta MA. A systematic review of secondary thromboprophylaxis in patients with antiphospholipid antibodies. Arthritis Rheum 2007;57(8):1487–95. [10] Giron-Gonzalez JA, Garcia del Rio E, Rodriguez C, Rodriguez-Martorell J, Serrano A. Antiphospholipid syndrome and asymptomatic carriers of antiphospholipid antibody: prospective analysis of 404 individuals. J Rheumatol 2004;31(8):1560–7. [11] Grika EP, Ziakas PD, Zintzaras E, Moutsopoulos HM, Vlachoyiannopoulos PG. Morbidity, mortality, and organ damage in patients with antiphospholipid syndrome. J Rheumatol 2012;39(3):516–23. [12] Tektonidou MG, Ioannidis JP, Boki KA, Vlachoyiannopoulos PG, Moutsopoulos HM. Prognostic factors and clustering of serious clinical outcomes in antiphospholipid syndrome. QJM 2000;93(8):523–30. [13] Ruiz-Irastorza G, Egurbide MV, Ugalde J, Aguirre C. High impact of antiphospholipid syndrome on irreversible organ damage and survival of patients with systemic lupus erythematosus. Arch Intern Med 2004;164(1):77–82. [14] Dall’Ara F, Reggia R, Taraborelli M, et al. Patients with longstanding primary antiphospholipid syndrome: retrospective analysis of organ damage and mortality. Lupus 2014;23(12): 1255–8. [15] Erkan D, Yazici Y, Sobel R, Lockshin MD. Primary antiphospholipid syndrome: functional outcome after 10 years. J Rheumatol 2000;27(12):2817–21. [16] Stoll T, Seifert B, Isenberg DA. SLICC/ACR Damage Index is valid, and renal and pulmonary organ scores are predictors of severe outcome in patients with systemic lupus erythematosus. Br J Rheumatol 1996;35(3):248–54. [17] Barbhaiya M, Erkan D. The optimal tool for assessment of organ damage in antiphospholipid syndrome. J Rheumatol 2013;40(1):89. [18] Amigo MC, Goycochea-Robles MV, Espinosa-Cuervo G, et al. Development and initial validation of a damage index (DIAPS) in patients with thrombotic antiphospholipid syndrome (APS). Lupus 2015;24(9):927–34. [19] Georgopoulou S, Efraimidou S, MacLennan SJ, Ibrahim F, Cox T. Antiphospholipid (Hughes) syndrome: description of population and health-related quality of life (HRQoL) using the SF-36. Lupus 2015;24(2):174–9. [20] Zuily S, Rat AC, Regnault V, et al. Impairment of quality of life in patients with antiphospholipid syndrome. Lupus 2015;24(11):1161–8. [21] Ginsburg KS, Liang MH, Newcomer L, et al. Anticardiolipin antibodies and the risk for ischemic stroke and venous thrombosis. Ann Intern Med 1992;117(12):997–1002.

292  Antiphospholipid Syndrome in Systemic Autoimmune Diseases [22] Vaarala O. Antiphospholipid antibodies and myocardial infarction. Lupus 1998;7(Suppl. 2):S132–4. [23] Finazzi G, Brancaccio V, Moia M, et al. Natural history and risk factors for thrombosis in 360 patients with antiphospholipid antibodies: a four-year prospective study from the Italian Registry. Am J Med 1996;100(5):530–6. [24] Reynaud Q, Lega JC, Mismetti P, et al. Risk of venous and arterial thrombosis according to type of antiphospholipid antibodies in adults without systemic lupus erythematosus: a systematic review and meta-analysis. Autoimmun Rev 2014;13(6):595–608. [25] Matyja-Bednarczyk A, Swadzba J, Iwaniec T, et al. Risk factors for arterial thrombosis in antiphospholipid syndrome. Thromb Res 2014;133(2):173–6. [26] Galli M, Luciani D, Bertolini G, Barbui T. Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood 2003;101(5):1827–32. [27] Shah NM, Khamashta MA, Atsumi T, Hughes GR. Outcome of patients with anticardiolipin antibodies: a 10 year follow-up of 52 patients. Lupus 1998;7(1):3–6. [28] Pengo V, Biasiolo A, Pegoraro C, Cucchini U, Noventa F, Iliceto S. Antibody profiles for the diagnosis of antiphospholipid syndrome. Thromb Haemost 2005;93(6):1147–52. [29] Lee EY, Lee CK, Lee TH, et al. Does the anti-beta2-glycoprotein I antibody provide additional information in patients with thrombosis? Thromb Res 2003;111(1-2):29–32. [30] Pengo V, Ruffatti A, Legnani C, et al. Clinical course of high-risk patients diagnosed with antiphospholipid syndrome. J Thromb Haemost 2010;8(2):237–42. [31] Schulman S, Svenungsson E, Granqvist S. Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Duration of Anticoagulation Study Group. Am J Med 1998;104(4):332–8. [32] Oku K, Amengual O, Atsumi T. Antiphospholipid scoring: significance in diagnosis and prognosis. Lupus 2014;23(12):1269–72. [33] Sciascia S, Sanna G, Murru V, Roccatello D, Khamashta MA, Bertolaccini ML. The global antiphospholipid syndrome score in primary APS. Rheumatology (Oxford) 2015;54(1):134–8. [34] Sandoval J, Amigo MC, Barragan R, et al. Primary antiphospholipid syndrome presenting as chronic thromboembolic pulmonary hypertension. Treatment with thromboendarterectomy. J Rheumatol 1996;23(4):772–5. [35] Tektonidou MG, Varsou N, Kotoulas G, Antoniou A, Moutsopoulos HM. Cognitive deficits in patients with antiphospholipid syndrome: association with clinical, laboratory, and brain magnetic resonance imaging findings. Arch Intern Med 2006;166(20):2278–84. [36] Asherson RA, Cervera R. Cardiac manifestations of the antiphospholipid syndrome. Coron Artery Dis 1993;4(12):1137–43. [37] Vaarala O. Antiphospholipid antibodies and atherosclerosis. Lupus 1996;5(5):442–7. [38] Puisieux F, de Groote P, Masy E, et al. Association between anticardiolipin antibodies and mortality in patients with peripheral arterial disease. Am J Med 2000;109(8):635–41. [39] Hernandez-Molina G, Garcia-Trejo LP, Uribe N, Cabral AR. Thrombotic microangiopathy and poor renal outcome in lupus patients with or without antiphospholipid syndrome. Clin Exp Rheumatol 2015;33(4):503–8. [40] Amigo MC, Garcia-Torres R, Robles M, Bochicchio T, Reyes PA. Renal involvement in primary antiphospholipid syndrome. J Rheumatol 1992;19(8):1181–5. [41] Korkmaz C, Kabukcuoglu S, Isiksoy S, Yalcin AU. Renal involvement in primary antiphospholipid syndrome and its response to immunosuppressive therapy. Lupus 2003;12(10):760–5. [42] Mondragon-Ramirez G, Bochicchio T, Garcia-Torres R, et  al. Recurrent renal thrombotic angiopathy after kidney transplantation in two patients with primary antiphospholipid syndrome (PAPS). Clin Transplant 1994;8(2 Pt 1):93–6.

Prognosis in Antiphospholipid Syndrome  Chapter | 19  293 [43] Prieto LN, Suki WN. Frequent hemodialysis graft thrombosis: association with antiphospholipid antibodies. Am J Kidney Dis 1994;23(4):587–90. [44] Espinosa G, Cervera R. Current treatment of antiphospholipid syndrome: lights and shadows. Nat Rev Rheumatol 2015;11(10):586–96. [45] Uthman I, Godeau B, Taher A, Khamashta M. The hematologic manifestations of the antiphospholipid syndrome. Blood Rev 2008;22(4):187–94. [46] Nalli C, Iodice A, Andreoli L, et al. The effects of lupus and antiphospholipid antibody syndrome on foetal outcomes. Lupus 2014;23(6):507–17. [47] Lockshin MD, Kim M, Laskin CA, et al. Prediction of adverse pregnancy outcome by the presence of lupus anticoagulant, but not anticardiolipin antibody, in patients with antiphospholipid antibodies. Arthritis Rheum 2012;64(7):2311–18. [48] Opatrny L, David M, Kahn SR, Shrier I, Rey E. Association between antiphospholipid antibodies and recurrent fetal loss in women without autoimmune disease: a metaanalysis. J Rheumatol 2006;33(11):2214–21. [49] Ruffatti A, Tonello M, Cavazzana A, Bagatella P, Pengo V. Laboratory classification categories and pregnancy outcome in patients with primary antiphospholipid syndrome prescribed antithrombotic therapy. Thromb Res 2009;123(3):482–7. [50] Simchen MJ, Dulitzki M, Rofe G, et  al. High positive antibody titers and adverse pregnancy outcome in women with antiphospholipid syndrome. Acta Obstet Gynecol Scand 2011;90(12):1428–33. [51] Holers VM, Girardi G, Mo L, et al. Complement C3 activation is required for antiphospholipid antibody-induced fetal loss. J Exp Med 2002;195(2):211–20. [52] Tincani A, Rebaioli CB, Andreoli L, Lojacono A, Motta M. Neonatal effects of maternal antiphospholipid syndrome. Curr Rheumatol Rep 2009;11(1):70–6. [53] De Carolis S, Botta A, Garofalo S, et al. Uterine artery velocity waveforms as predictors of pregnancy outcome in patients with antiphospholipid syndrome: a review. Ann NY Acad Sci 2007;1108:530–9. [54] De Carolis S, Botta A, Santucci S, et al. Predictors of pregnancy outcome in antiphospholipid syndrome: a review. Clin Rev Allergy Immunol 2010;38(2–3):116–24. [55] do Prado AD, Piovesan DM, Staub HL, Horta BL. Association of anticardiolipin antibodies with preeclampsia: a systematic review and meta-analysis. Obstet Gynecol 2010;116(6):1433–43. [56] Abou-Nassar K, Carrier M, Ramsay T, Rodger MA. The association between antiphospholipid antibodies and placenta mediated complications: a systematic review and meta-analysis. Thromb Res 2011;128(1):77–85. [57] Erkan D, Merrill JT, Yazici Y, Sammaritano L, Buyon JP, Lockshin MD. High thrombosis rate after fetal loss in antiphospholipid syndrome: effective prophylaxis with aspirin. Arthritis Rheum 2001;44(6):1466–7. [58] Lefèvre G, Lambert M, Bacri JL, et  al. Thrombotic events during long-term follow-up of obstetric antiphospholipid syndrome patients. Lupus 2011;20(8):861–5. [59] Cervera R, Bucciarelli S, Plasin MA, et al. Catastrophic antiphospholipid syndrome (CAPS): descriptive analysis of a series of 280 patients from the ‘CAPS Registry’. J Autoimmun 2009;32(3–4):240–5. [60] Erkan D, Asherson RA, Espinosa G, et al. Long term outcome of catastrophic antiphospholipid syndrome survivors. Ann Rheum Dis 2003;62(6):530–3. [61] Espinosa G, Rodriguez-Pinto I, Gomez-Puerta JA, Pons-Estel G, Cervera R, Catastrophic Antiphospholipid Syndrome Registry Project Group. Relapsing catastrophic antiphospholipid syndrome potential role of microangiopathic hemolytic anemia in disease relapses. Semin Arthritis Rheum 2013;42(4):417–23.

294  Antiphospholipid Syndrome in Systemic Autoimmune Diseases [62] Bucciarelli S, Espinosa G, Cervera R, et al. Mortality in the catastrophic antiphospholipid syndrome: causes of death and prognostic factors in a series of 250 patients. Arthritis Rheum 2006;54(8):2568–76. [63] Bayraktar UD, Erkan D, Bucciarelli S, Espinosa G, Asherson R, Catastrophic Antiphospholipid Syndrome Project G The clinical spectrum of catastrophic antiphospholipid syndrome in the absence and presence of lupus. J Rheumatol 2007;34(2):346–52.