Autoimmunity Reviews 13 (2014) 699–707

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Review

14th International Congress on Antiphospholipid Antibodies Task Force Report on Catastrophic Antiphospholipid Syndrome Ricard Cervera a,⁎, Ignasi Rodríguez-Pintó a, Serena Colafrancesco b, Fabrizio Conti b, Guido Valesini b, Cristina Rosário c, Nancy Agmon-Levin d,e, Yehuda Shoenfeld d,f, Claudia Ferrão g, Raquel Faria g, Carlos Vasconcelos g, Flavio Signorelli h, Gerard Espinosa a a

Department of Autoimmune Diseases, Hospital Clínic, Barcelona, Catalonia, Spain Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Rome, Italy c Internal Medicine Department, Hospital de Pedro Hispano, Matosinhos, Portugal d The Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Israel e Sackler Faculty of Medicine, Tel-Aviv University, Israel f Incumbent of the Laura Schwarz-Kipp Chair for Research of Autoimmune Diseases, Tel-Aviv University, Israel g Unidade de Imunologia Clínica, Hospital Santo António, Centro Hospitalar do Porto, ICBAS, Instituto Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal h Hospital Universitário Pedro Ernesto, Universidade do Estado do Rio de Janeiro, Brazil b

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a b s t r a c t

Article history: Received 15 February 2014 Accepted 28 February 2014 Available online 20 March 2014

The 'Task Force on Catastrophic Antiphospholipid Syndrome (CAPS)' was developed on the occasion of the 14th International Congress on Antiphospholipid Antibodies. The objectives of this Task Force were to assess the current knowledge on pathogenesis, clinical and laboratory features, diagnosis and classification, precipitating factors and treatment of this condition in order to address recommendations for future research. This article summarizes the studies analyzed by the Task Force, its recommendations and the future research agenda. © 2014 Elsevier B.V. All rights reserved.

Contents 1. Introduction . . . . . . . . . 2. Pathogenesis . . . . . . . . 3. Clinical and laboratory features 4. Diagnosis and classification . . 5. Precipitating factors . . . . . 6. Treatment . . . . . . . . . . 7. Recommendations . . . . . . 8. Further research . . . . . . . Take-home messages . . . . . . . References . . . . . . . . . . . .

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1. Introduction The ‘Task Force on Catastrophic Antiphospholipid Syndrome (CAPS)’ was developed on the occasion of the 14th International Congress on Antiphospholipid (aPL) Antibodies. The objectives of this Task Force were to assess the current knowledge on pathogenesis, clinical and ⁎ Corresponding author at: Servei de Malalties Autoimmunes, Hospital Clínic, Villarroel, 170, 08036 Barcelona, Catalonia, Spain. Tel.: +34 93 227 5774; fax: +34 93 2271707. E-mail address: [email protected] (R. Cervera).

http://dx.doi.org/10.1016/j.autrev.2014.03.002 1568-9972/© 2014 Elsevier B.V. All rights reserved.

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laboratory features, diagnosis and classification, precipitating factors and treatment of this condition in order to address recommendations for future research. The members of the Task Force included all the authors of this paper. During a pre-congress workshop in Rio de Janeiro, Brazil, on 18 September 2013, the members presented the current evidence in their area of expertise and provided relevant literature on it. An open discussion followed (both during the pre-congress workshop and during the elaboration of the manuscript), to reach consensus. Where data was limited or incongruent, expert opinion supplements

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the recommendations. This article summarizes the studies analyzed by the Task Force. 2. Pathogenesis Although clinical findings are well defined, the pathological mechanisms of CAPS are less understood. Nonetheless, the close association between CAPS and classic antiphospholipid syndrome (APS) suggests the presence of possible overlapping mechanisms. However, it is still unclear why some patients will develop recurrent thrombosis mainly affecting large vessels (classic APS), while others develop rapidly recurrent vascular occlusions, predominantly affecting small vessels (CAPS). In 1998, Kitchens introduced the new concept of “thrombotic storm” to describe a peculiar event in the course of CAPS referred to the possible ability of vascular occlusion to trigger itself additional thrombosis [1]. According to such hypothesis, the author proposed that while clots continue to generate thrombin, fibrinolysis is decreased by an increase in plasminogen activator inhibitor (PAI) type-1 determining a consumption of the natural anticoagulant proteins such as protein C and antithrombin. APS is considered to have a multifactorial etiopathogenesis and the involvement of both adaptive immunity and innate immunity, supported by the presence of a predisposing genetic background, is required [2]. An association between HLA class II genes and aPL production has been already described. Specifically, an association with several polymorphisms [HLA-DRB1*04, DRB1*07 (0701), DRB1*1302, DR53, DQB1*0301 (DQ7), *0302, and *0303] shows not only a predisposition to aPL production, but also a possible binding of peptides useful for T cells recognition mediated by HLA class II molecules [3,4]. Later on, other possible associations including HLA-DPB1 alleles [5], HLA-DM polymorphisms [6] or valine/leucine247 polymorphism of β2-glycoprotein I (β2GPI) [7] have been identified. In association with the presence of a predisposing genetic background able to determine aPL production, the existence of a genetic thrombophilia may represent another possible predisposing risk factor for CAPS development. Specifically, this kind of predisposition includes a depression of the natural anticoagulant system, endogenous hypofibrinolysis (i.e. PAI-1 4G/5G, t-PA I/D), prothrombin G20210A mutation or a MTHFR C677T mutation [8]. In such condition, the presence of aPL may represent the “first hit” leading to an increase in the thrombophilic risk. Nonetheless, the positivity of such antibodies is not sufficient to trigger the clot and the presence of an inflammatory hit, named the “second hit”, is required. In fact, the presence of environmental trigger factors seems to be essential in CAPS development [9]. These trigger factors have been recognized in more than half of CAPS cases, mostly represented by infections (viral or bacterial) [9]. The presence of aPL has been identified in several infections confirming a potential relationship with APS pathogenesis [10]. During microvessels thrombosis an excessive release of different cytokines (especially interleukin IL-1, IL-6 and TNF) is commonly observed, a phenomenon that can occur during CAPS and that has been referred to as the “cytokine storm”. This event is responsible for the development of a dramatic systemic inflammatory response syndrome (SIRS). Cytokines are small secreted extra-cellular signaling proteins/ peptides which regulate cell-mediated immune responses [11]. These molecules include interleukins, interferons, hematopoietic stimulating factors and tumor necrosis factors [12]. They are the key components of effector phase immunity. There are no studies on cytokine involvement in CAPS because due to its rarity it is difficult to collect blood and serum samples during an episode of CAPS. Additionally, there is a lack of knowledge of physicians in intensive care units where most of these patients are admitted. However, there is indirect evidence that cytokines play a major role in CAPS. There are two theoretical explanations for the clinical manifestations in CAPS: 1) manifestations dependent on the organs that are affected by

the thrombotic events and extent of the thrombosis; and 2) manifestations related to the SIRS [13]. Cytokines seem to play a role in both the thrombotic manifestations and those relate to the SIRS. Certainly, some nonthrombotic manifestations, particularly ARDS, are frequently encountered in both CAPS and sepsis. ARDS is known to be induced by pro-inflammatory cytokines including TNF-α, IL-1, IL-6, IL-18 and macrophage-migration inhibitory factor [14]. Moreover, in the sepsis model, proinflammatory cytokines are important in inducing a procoagulant effect. Coagulation pathways are initiated by lipopolysaccharide (LPS), inducing expression of tissue factor on mononuclear and endothelial cells [15]. There is some evidence that in CAPS, anti-β2GPI antibodies trigger an endothelialsignaling cascade comparable to that activated by LPS in sepsis [16]. The thrombophilic state in APS has been attributed to the induction of a proinflammatory and procoagulant endothelial cell phenotype resulting from anti-β2GPI binding to β2-GPI expressed on the endothelial cells. Anti-β2GPI binding has been shown to induce NF-κB translocation, leading to a proinflammatory endothelial cell phenotype (similar to that elicited by microbial products such as LPS in sepsis) and the production of proinflammatory cytokines [17]. The accelerated activation of this mechanism could possibly contribute to SIRS and thrombosis seen in CAPS patients. As mentioned above, both adaptive immunity and innate immunity are involved in APS pathogenesis suggesting their participation in CAPS as well. Anti-β2GPI antibodies are the expression of the adaptive immune response and have a pro-thrombotic role through several mechanisms, including interference with natural anticoagulants (such as protein C and annexin V), inhibition of fibrinolysis, interference with cells of the coagulation cascade (such as endothelial cell perturbation, circulating monocytes and platelet activation), and by triggering complement activation [2]. Recently, other possible autoantigens have been supposed to take part to the pathogenic mechanisms of APS. Specifically, anti-vimentin/ cardiolipin antibodies have been identified in patients with APS and a new possible role for vimentin, as a cofactor for aPL antibodies has been proposed [18]. On the other side, massive complement activation in the course of APS is the expression of the innate immune system involvement. Currently, we know that complement cascade, induced by aPL, is linked with pregnancy loss, fetal growth restriction and thrombosis. Complement C1q protein is significantly activated in patients with APS inducing the cascade onset with a further release of active fragments of the complement system leading to the amplification of the activation of monocytes, platelets or endothelial cells [19]. These fragments, such as C5a, were found to induce tissue factor expression on neutrophils, resulting in a modified prothrombin time [20]. These findings brought to the usage of targeted therapy against complement as a novel approach in the treatment of APS [21]. Tissue factor is another key initiator of the clotting cascade and aPLs were found to be able to induce its expression on monocytes, endothelial cells and platelets [22]. It has been demonstrated that patients with APS may have an increased β2GPI exposure on cell surface which leads to persistently high monocyte tissue factor expression [23]. Another key mechanism in classic APS as well as in CAPS is endothelial cell activation. There is strong evidence that, in the absence of other detectable traditional risk factors for atherosclerosis, aPLs perturb the endothelium by inducing vasculopathy and an endothelial proinflammatory/coagulant phenotype [24]. It has been recently demonstrated that receptors of innate immunity, such as TLR-4, are involved in endothelial cell activation following the binding of anti-β2GPI antibodies [25]. Such activation of TLR4 triggers IL-1 receptor-associated kinase phosphorylation and NF-κB translocation, promoting VCAM expression on endothelial cells and TNF-α release by monocytes [26]. In addition to the above-mentioned mechanisms, recent reports suggest a possible pathogenic role for oxidative stress. In fact, an increased oxidative stress in the course of APS has been observed. The oxidation determines the exposition of the critical epitope domain I

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on β2-GPI, which is recognized by B-cells. Moreover, in a murine model, anti-β2GPI antibodies seem to be able to decrease bioavailable nitric oxide by antagonizing the activity of endothelial nitric oxide synthase [27]. Oxidative stress seems to be involved also in aPL production supporting the possible clinical value of antioxidant treatment [28]. Other histopathologic and clinical features of CAPS are the occurrence of thrombotic microangiopathy, which is the hallmark of thrombotic thrombocytopenic purpura (TTP) and the onset of a SIRS. CAPS is one of the most frequent clinical presentations in patients with microangiopathic hemolytic anemia (MHA) associated with aPL [29]. In light of such finding, since MHA in patients with TTP is due to a secondary deficiency of ADAMTS13, this can be responsible for the development of microthrombosis also in CAPS [30]. Recently, a possible pathogenic implication of ferritin and a plausible role as a marker of ensuing CAPS have been theorized. In more detail, CAPS has been included in a new group of syndromes characterized by the presence of similar clinical and laboratory features including as the common hallmark the presence of a severe hyperferritinemia: the “hyperferritinemic syndrome” [31]. In these conditions, ferritin besides being a marker of inflammation may be pivotal in thrombosis since high levels of ferritin are associated with the presence of thrombocytopenia, lupus anticoagulant (LA), and anticardiolipin (aCL) antibodies in patients with systemic lupus erythematosus (SLE) [32]. Further studies confirmed the relationship between hyperferritinemia and APS clinical manifestations and a straight link to the development of the catastrophic variant has been recognized [33]. Unveiling the winding roads of CAPS pathogenesis is a major task that research must achieve in the next years to improve the management and treatment of these patients suffering from such harmful and dramatic condition. 3. Clinical and laboratory features Up to September 2013, the “CAPS Registry” (https://ontocrf.costaisa. com/en/web/caps/) included 433 patients corresponding to 469 episodes of CAPS. Overall, 69% are females, with a mean age of 38.5 ± 17.0 (range, 0 to 85 years). The majority of patients suffered from primary APS (59%), 26.9% from SLE, 3.4% from lupus-like disease, and the remaining from other autoimmune diseases. In 49.1% of patients, CAPS was the first manifestation of APS. A precipitating factor was reported in 65.4% of the catastrophic episodes. The most common precipitating factors were infections (46.7%), followed by neoplasms (17.6%), surgical procedures (16.8%), and anticoagulation withdrawal or low international normalized ratio (INR) (10.9%). Regarding the main organs involved, the kidneys were the most frequently affected (73.0% of episodes), followed by the lungs in 58.9%, the brain in 55.9%, the heart in 49.7%, and the skin in 45.4%. Other organs affected were the peripheral vessels (36.2%), the intestine (24.0%), the spleen (16.7%), the adrenal glands (10.6%), the pancreas (7.2%), the retina (5.8%), and the bone marrow (3.1%). Other organs may be occasionally affected, including testicular/ovarian infarction, necrosis of the prostate, and acalculous cholecystitis. The majority of patients with renal disease had renal insufficiency (74.5%); hypertension was present in 22.2%, proteinuria at variable degrees in 25.0%, and hematuria in 12.7% of them. Pulmonary complications, with acute respiratory distress syndrome (ARDS) (37.1%) and pulmonary emboli (24.9%) accounted for the majority of these patients, while pulmonary hemorrhage (10.5%) occurred in the minority of patients. Cerebral manifestations presented in the form of encephalopathy in 40.2% of episodes, stroke in 35.2%, seizures in 14.6%, headache in 8.5%, and coma in 6.1%. Cardiac problems occurred frequently in the form of heart failure in 42.1% of episodes of CAPS, often with myocardial infarction (27.8%), and valvular defects (mitral, aortic) (28.0%). Skin complications were present in form of livedo reticularis in 42.3% of episodes, skin necrosis in 25.2%, ulcers in 23.5%, and digital ischemia in 10.0% of

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them. Considering peripheral vessels, venous involvement was present in 69.2% whereas arterial vessels presented with thrombosis in 47.8%, respectively. Interestingly, demographic and clinical manifestations of the first 50 patients with CAPS were similar with these most recent data. Thrombocytopenia was detected in 65% of cases. LA was present in 81.7% of episodes. IgG isotype of aCL was positive in 81.5%, whereas IgM aCL positivity being less frequent (48.1%). Information from antiβ2GPI antibodies is scarce but, overall, IgM anti-β2GPI antibodies were present in 3.2% of patients and IgG anti-β2GPI in 11.1%. Schistocytes, markers of thrombotic MHA, were present in 21.7%. The current descriptive analysis had some limitations. First, as all registry studies, the accuracy of the data recorded and the final clinical diagnosis was considered according to the criteria of the attending physician and in some cases it could not be verified. Second, and very important, the correct attribution of some clinical manifestations, such as heart failure or encephalopathy, to CAPS has not been monitored. Finally, it is important to keep in mind possible differences in laboratory methods to detect. For the upcoming future, it would be interesting to analyze specific subsets of patients with CAPS such as those with relapsing episodes of CAPS or patients with thrombotic MHA, to analyze some precipitating factors, such as infections or neoplasia, and to improve the quality of the data recorded in the “CAPS Registry”. 4. Diagnosis and classification The first preliminary classification criteria on CAPS were published in 2002 by Asherson et al. [34] and, later, accepted on a presymposium workshop on occasion of the 10th International Congress on aPL. In this consensus, the participants agreed that patients with a debatable diagnosis or with less severe disease would be classified separately from those with a “definite” CAPS diagnosis. One year later, these first international consensus classification criteria were published [35]. These criteria have been used since then without any change. In these criteria (Table 1), a definitive CAPS was considered present in a given patient when all four criteria were met. They require the involvement of three or more organs, systems and/or tissues, the presence of aPL and a biopsy showing microthrombosis. However, when only two organs are affected, small vessel occlusion cannot be pathologically confirmed, the third event develops in more than a week but less than a month despite anticoagulation or the aPL positivity cannot be confirmed six weeks apart due to early death the cases are considered to be probable. These criteria were accepted for classification purposes and were not created to be used as strict diagnostic criteria in a given patient. Two years later these criteria were validated. According to the findings published, the sensitivity of these criteria for the classification of CAPS is 90.3%, the specificity 99.4%, the positive predictive value 99.4%, and the negative predictive value 91.1% [36].

Table 1 Diagnostic criteria for CAPS. 1. Evidence of involvement of 3 organs, systems, and/or tissues. 2. Development of manifestations simultaneously or in less than 1 week. 3. Laboratory confirmation of the presence of aPL (LAC and/or aCL and/or anti-2GPI antibodies) in titers higher than 40 UI/l. 4. Exclude other diagnosis. Definite CAPS: • All 4 criteria. Probable CAPS • All 4 criteria, except for involvement of only 2 organs, system, and/or tissues. • All 4 criteria, except for the absence of laboratory confirmation at least 6 weeks apart associable to the early death of a patient never tested for aPL before onset of CAPS. • 1, 2, and 4. • 1, 3, and 4, and the development of a third event in N1 week but b1 month, despite anticoagulation treatment.

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On occasion of the 13th International Congress on aPL, the Task Force on CAPS proposed the delineation of a diagnostic algorithm to help clinicians facing patients with multiorgan thrombosis [37]. The revalidation of current classification criteria using a control group that includes conditions with MHA was proposed. However, CAPS is a rare disease, and thus at best, only case–control studies can be used to validate the criteria. Since pathological confirmation of small vessel involvement is not normally performed in patients with the main differential diagnosis disease, this study cannot be easily performed. Further, the biopsy is very often missing in patients with CAPS decreasing the eligible number of patients [36]. Most cases of CAPS present as microangiopathic storms rather than large vessel occlusion [29]. However, the presence of multiple large vessel occlusion should always rise the suspicion of CAPS, although the possibility of a combination of thrombophilic factors playing together should be kept in mind and, therefore, testing for other thrombophilic diseases is warranted. The differential diagnosis in a patient with MHA includes disseminated intravascular coagulation (DIC), heparin induced thrombocytopenia (HIT), HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome, TTP, hemolytic uremic syndrome and scleroderma renal crisis when kidney is the main organ involved [38] (Table 2). The presence of widespread hemorrhage should lead to suspect a DIC and the determination of fibrinogen levels. One may think that the presence of aPL in a patient with multiple thromboses should give the clue for the differential diagnosis of CAPS. However, on the one side, the presence of aPL might not imply that they are in fact pathogenic and, on the other side, the negative results of aPL tests do not rule out the diagnosis because classic APS manifestations with negative aPL at the time of thrombosis have been reported [39]. Systemic infections may mimic clinical features of CAPS. Specially, when sepsis is associated with DIC, the development of thrombocytopenia and microthrombosis may remind the clinical picture of CAPS [29]. Furthermore, infections are the most frequently reported trigger of CAPS [40]. Both viral and bacterial infections may induce synthesis of aPL without a significant pathological role [41]. Even when long standing post infectious aPL in patients with thrombosis have been reported [42], transient positivity without a clinical significance is the rule. When aPL tests in association with an infection are positive, they are usually at low aCL titer. The presence of aCL in viral infections is mainly non-β2GPI dependent. Some authors have suggested the assessment of cofactor dependency to distinguish patients most likely to experience aPLrelated clinical features, but this distinction is not absolute and this test is not broadly available [43]. Needless to say, retesting subjects for aPL persistence 12 weeks apart of the acute event is highly recommended. HIT is a severe complication which usually occurs within 4 to 10 days of heparin treatment [44]. The severe form (Type II) is an immune mediated disorder characterized by the formation of antibodies against the heparin-platelet factor 4 (PF4) complex that binds into platelets leading to cell activation and aggregation and can lead to thrombosis. However, aCLs have been found to be present in about one third of the patients with HIT [45]. They are mainly of the IgG isotype. Furthermore, antiheparin-PF4 antibodies have been found in heparin-naïve lupus with and without aPL [46]. Thus, the history of previous exposure to heparin, the low titer of aPL and the test for the presence of anti-heparin-PF4

antibodies should be taken into account when facing the differential diagnosis between CAPS and HIT. HELLP syndrome is an endothelium-based disease, predominantly affecting small vessels in the hepatic circulation. During pregnancy, clinical signs of CAPS can be confused with those of HELLP syndrome and, indeed, HELLP syndrome may be considered an expression of CAPS in some cases or a precipitant factor for the CAPS [47,48]. The relatively small number of patients with CAPS during the obstetric period makes it difficult to definitely conclude whether this group corresponds to a different subset of patients with CAPS or are different diseases. The most difficult differential diagnosis in patients with CAPS is TTP. The presence of renal and neurological dysfunction and schistocytes can be found both in TTP and in CAPS. Some authors support the idea that TTP is defined by severe ADAMTS-13 deficiency. However, others consider TTP as an appropriate diagnosis for all patients in the presence of MHA without an apparent alterative etiology, regardless of ADAMTS13 activity [49]. However, even when not pathognomonic, the severe decrease on ADAMTS-13 activity should strongly suggest the diagnosis of TTP, while the presence of high titer of aPL should point to the diagnosis of CAPS. As ADAMTS-13 activity measurement is not available in every institution, through times, some CAPS cases may have been misdiagnosed as TTP in patients with SLE or APS. This Task Force would like to remark that it is not our intention to classify these diseases in thigh compartments but, probably, a continuum of interrelations exists between them. In CAPS, the positivity of aPL is almost always shown. Even when some cases with positive aPL have been reported in other microangiopathies, they are normally present in low titers. Thus, the high levels of aPL should be taken as a high specific finding for the diagnosis of CAPS patients but the final diagnosis should be done taking into account of the full clinical picture. Additionally, the presence of other clinical manifestations and the presence of antibodies against anti-heparin-PF4 and anti-ADAMTS-13 may help in its differential diagnosis. The clinical picture with the presence of aPL confirmed 12 weeks apart and the exclusion of its main differential diagnosis conditions has probably a sensitivity good enough to perform the diagnosis. The performance of a biopsy is not always needed in order to diagnose a patient as CAPS, although it is stressfully recommended. However, there is a continuum between different microangiopathic syndromes and, in some patients, different etiologic pathways might be working together in the development of a clinical picture. 5. Precipitating factors Several precipitating factors have been identified in more than 50% of CAPS patients [37]. In an early description of the “CAPS Registry”, Cervera et al. [40] described that the most common precipitating factor were infections, followed by surgery, withdrawal or improper use of anticoagulants, obstetric complications, neoplasia and the flare of concomitant SLE. Recently, new hastening factors were suggested, namely thrombocytopenia, elevated levels of ferritin and, possibly, low levels of vitamin-D. Infectious diseases were found to trigger CAPS in a high percentage of cases. The most common infectious agents linked with this devastating form of APS are bacteria such as Escherichia coli, Shigella, Salmonella, Streptococcus, Staphylococcus (MRSA), Klebsiella and viruses, mainly of

Table 2 Differential diagnosis.

Previous history Thrombosis Typical antibodies Schistocytes Fibrinogen

CAPS

TTP

HELLP

Sepsis

DIC

HIT

Previous APS/SLE/malignancy/pregnancy Large/small vessels aPL Present Normal/high

Malignancy/non Small vessels Anti-ADAMS-13 Present Normal/high

Pregnancy Small vessels None Scanty Normal/high

Infection Large/small vessels None Scanty Normal/low

Infection/malignancy Small vessels None Scanty Normal/low

Heparin exposure Large/small vessels Anti-HP4 Scanty Normal/high

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the herpes viruses' family. The most common infected organs described are the lungs, brain, kidney, heart and multi-organs involvement during sepsis [30,37,50]. The links between infections and the induction of CAPS are frequently attributed to molecular mimicry between infectious constituents and β2GPI and other auto-antigens of the aPL [51,52]. Pregnancy and postpartum are periods of high risk of CAPS. This was largely reported, among pregnant women who presented with the HELLP syndrome in which the risk is assumed the highest. In a recent study, 12/13 women with CAPS were first diagnosed with HELLP. Preeclampsia and eclampsia were diagnosed in 6 and 3 of them respectively [48]. In the same study, no correlations between low complement levels or ovarian vein thrombosis and CAPS were documented. Surgery and trauma has been documented as triggers of CAPS. Invasive procedures may induce the catastrophic cascade via stress related changes in the hormonal milieu, cytokines and chemokine levels and exposed tissue factor. Furthermore, excess hypercoagulability such as the one related to malignancy (i.e. as the cause for surgery) and the abbreviation of anti-coagulation therapy, required for most surgical procedures, were both identified as independent risk factors for CAPS [40,53]. Warfarin withdrawal or under treatment (e.g. low levels INR) may be followed by recurrent thrombosis within several days to weeks [54, 55]. Thus, although APS is considered a high risk thrombophilia, one may suggest that considering low risk surgical procedure warfarin treatment may be continued [56]. Other measurements to minimize the risk of re-thrombosis and the potential risk of initiating CAPS perioperatively are: optimizing the bridging therapy, delaying surgical or other invasive procedures for 3 months following a thrombotic event and a proper reassessment of the need to perform non-vital procedures [56]. Last but not the least, adding pre-operative preventive measurement, such as reducing levels of aPL (e.g. plasma exchange), has been proposed and requires further studies. In the same line of thought, ischemia may initiate a vicious cycle that includes cytokine and chemokines expression followed by newly formed clots and disruption of the thrombogenesis–fibrinolysis equilibrium. The latter will lead to accelerate thrombin generation, while excessive concentrations of plasminogen overwhelm the fibrinolytic capacity. In other words, vascular occlusion itself may trigger additional thrombosis and the appearance of CAPS. In some of these devastating scenarios, amputation of the ischemic limb may be the only plausible way to cease the thrombotic storm. Thus unlike other conditions in which ischemia may be treated medically and “conservatively”, among APS patients, especially those at high risk of a CAPS, early amputation of the ischemic limb should be considered [1,55,57]. Additional elements were linked with CAPS explicitly, i.e. thrombocytopenia and MHA, elevated levels of ferritin and, perhaps, vitamin-D deficiency. Thrombocytopenia is present in 20–30% of APS patients versus 65% of those diagnosed with CAPS. CAPS related thrombocytopenia is characterized by severe and abrupt onset as well as concomitant increased schistocytes (usually ≥20%). This contrasts with the milder form (i.e. platelets of 50,000/μL to 140,000/μL), typically seen in APS. The aggressive form of thrombocytopenia in CAPS may reflect widespread thrombosis and platelet consumption, sepsis with DIC, HELLP, platelet consumption in a necrotic organ or the effect of drugs (e.g. heparin, antibiotics) [50,57]. Parallel to thrombocytopenia and the presence of schistocytes on blood smear in CAPS patients, laboratory features of MHA are not rare. Moreover, in the “CAPS Registry”, MHA was recorded in 13/18 (72%) of patients with recurrent CAPS episodes. Thus, a conceivable association between MHA and relapsing CAPS was put forward [30]. Ferritin is a key player in the metabolism of iron and an acute phase reactant. It also exhibits different immunological activities such as suppression of T cell activity, antibody production, phagocytosis and regulating granulocytopoiesis. Besides, ferritin was found to be a stimulator of vascular endothelium and a direct inducer of ischemic and non-ischemic neuronal damage [31]. In recent years, elevated levels

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of ferritin were allied with several autoimmune and inflammatory diseases [32,58,59]. Lately, elevated levels of ferritin were suggested to be the common denominator of a new syndrome, the “hyperferritinemic syndrome”, which comprises the adult's Still disease, macrophage activation syndrome, sepsis and other conditions [31]. In a study that evaluated serum ferritin levels among 176 APS patients and 98 healthy controls, high ferritin levels were observed in 9% vs. 0% of APS patients and controls, respectively (p b 0.001). These higher ferritin levels were linked with thrombosis, and cardiac and neurological manifestations of APS. Additionally, in the same report, 14 patients with CAPS were evaluated of which 71% had elevated levels of ferritin. Moreover, very high levels of ferritin (i.e. ≥1000 ng/mL) were documented in 36% of CAPS patients vs. less than 1% among non-CAPS–APS ones. Taking it all together, one may suggest that elevated levels and, particularly, very high levels of ferritin may serve as a marker of CAPS. Further studies regarding the plausible role of ferritin in these inflammatory conditions are warranted. Another environmental factor linked with autoimmunity and, particularly, APS is vitamin-D [60]. Deficiency of vitamin-D was found to be common among APS patients and correlated with increased thrombosis. Moreover, in an in-vitro model of anti-ß2GPI-mediated thrombosis, the addition of vitamin-D diminished endothelial activation and tissue factor expression, alluding to a role of vitamin D in APS-mediated thrombosis [61]. Remarkably, similar but more aggressive endothelial activation was observed in CAPS patients [62] and vitamin-D deficiency has been coupled with thrombosis, cardiac damage and poor outcome of critically ill patients [63,64]. Hence, vitamin-D was suggested to be at least a marker of poor outcome among these groups of patients. Lastly, during a catastrophe early intervention may determine outcome. The concept of a double hit, namely the presence of aPL and another risk factor (i.e. infection), was established for APS associated thrombosis. For CAPS patients, it seems that multiple hits may be linked with each event, as several precipitating factors may be operating simultaneously. Early assessment of these factors and aggressive intervention may ameliorate the course of CAPS and save lives. 6. Treatment In fact, the treatment of CAPS is directed at two different points: the thrombotic events and the suppression of the cytokine cascade [14]. Anticoagulation with heparin is the mainstay of treatment in patients with catastrophic APS. Anticoagulation with heparin dose not only inhibits clot generation by thrombin inhibition but also promotes clot fibrinolysis [65]. Antithrombin acceleration leads to thrombin, factor Xa and other activation factors' inhibition resulting in clot formation impairment and lysis of existing ones. Moreover, the administration of heparin seems to inhibit aPL binding to their target on the cell surface and inhibit complement activation [66]. While the patient is in the intensive care unit, intravenous anticoagulation is normally chosen. This form of anticoagulation enables to rapidly throw back its effect in case of necessity either because of bleeding or electively to perform invasive procedures often needed in the ICU. Once the patient is stabilized, oral anticoagulation with warfarin is started and intravenous anticoagulation discontinued once the therapeutic INR is achieved. Immunosupressors (IS) and intravenous immunoglobulins (IVIG) act mostly in the inflammation control. Glucocorticosteroids (GC) and cyclophosphamide are the most widely used IS in CAPS. GC inhibit nuclear factor (NF)-κB, a mediator of SIRS [67]. Antiβ2GPI antibodies induce pro-coagulation/inflammation via NF-κB. There are no evidence-based recommendations for the route, optimal dose and duration of GC. Usual dosage is 1000 mg of methylprednisolone for 3 to 5 days. GC alone did not improve the outcome data from “CAPS Registry”. Cyclophosphamide blocks the production of the deoxyribonucleic acid (DNA) in immune cells, preventing them from dividing and leading to cell death. Different doses might have different effects; generally, it

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Table 3 All treatment modalities for the 342 patients reported. Modalities of treatment

No. of patients

No treatment AC AC

1 127 37

14 50 14

100.0% 39.4% 37.8%

26 32

5 11

19.2% 34.4%

22 24 38 8 7 3 1 1 1 1 342

5 8 10 5 1 1 1 1 0 0 126

22.7% 33.3% 26.3% 62.5% 14.3% 33.3% 100.0% 100.0% 0% 0% 36.8%

AC AC

GC GC

DMARDs:

GC GC

- 35 CYC - 3 AZA CYC DMARDs:

Plasm IVIG

Mortality

- 30 CYC - 1 AZA, 2 CsA, 1 MMF AC AC AC AC AC AC AC

GC GC GC GC GC GC GC

Plasm Plasm Plasm Plasm Plasm Plasm Plasm Plasm

IVIG IVIG IVIG IVIG IVIG

DMARDs CYC

RTX RTX/ECU

MTX RTX

Global mortality

AC — anticoagulation; GC — glucocorticosteroids; Plasm — plasmapheresis; IVIG — intravenous immunoglobulin; DMARDs — disease modifying anti-rheumatic drugs; CYC — cyclophosphamide; AZA — azathioprine; CsA — cyclosporine A; MMF — mofetil mycophenolate; MTX — methotrexate; RTX — rituximab; ECU — eculizumab.

promotes the proliferation of effector T cells, suppression of helper Th1 activity, and enhancement of helper Th2 responses and abrogates the function of regulatory T cells (Tregs). As it may take several weeks for improvement, GC should always be first administered. Other IS have been described in case reports of CAPS: 4 with azathioprine, 2 with cyclosporine and 1 with mycophenolate mofetil. IVIG have been used in the treatment of CAPS and their benefic effects could be related to direct effects, through the Fc receptor, blocking pathological antibodies, increasing its clearance, and indirect effects as immunomodulation through idiotype–anti-idiotype network and modulating/suppressing cytokines, inhibiting CD8, increasing Tregs (high doses) and inhibiting complement system activation. IVIG are used in a dose of 0.4 g/d/kg for 5 days and should be administered after the last day of plasma exchange to prevent their removal. IVIG are well tolerated, but we should be cautious with thrombosis, particularly in those cases where anticoagulation (AC) has to be stopped because of bleeding. Elderly patients with diabetes, hypertension or hypercholesterolemia should also be infused with care, with a reduced rate of IVIG infusion. Besides its efficacy in patients with severe thrombocytopenia refractory to high dose steroid therapy, a special recommendation for its use in CAPS is when associated to infection because of its immunomodulator effects rather than it being an immunosuppressor [68]. Two recent studies about the use of IVIG in APS patients that can also be important to its use in CAPS were published. One study used 0.4 g/kg/day every month to 3 primary and 4 SLE-associated APS patients for two years, in addition to conventional therapy (anticoagulants or antiplatelets). When compared with 6 primary and 1 SLE-associated APS patients treated only with conventional therapy the first group had less thromboembolic events, pointing to the efficacy of IVIG in preventing its occurrence [69]. The other study was a long-term (N 5 years) open study with 5 highrisk primary APS patients. Three consecutive intravenous daily infusions of IVIG were given at a dose of 0.4 g/kg/day every month for 3 months, followed by a single monthly infusion for 9 months combined with hydroxychloroquine and, in patients with cerebral strokes, acetylsalicylic acid. The authors found it to be effective in preventing recurrent thrombosis [70]. A PubMed search was performed, from inception through August 2013, applying the terms ‘antiphospholipid syndrome’, ‘catastrophic

antiphospholipid syndrome’, ‘IVIg’, ‘immunosupression’, ‘glucocorticosteroids’ and combinations of these. As there were no meta-analyses or randomized controlled trials, most of the reviewed papers were case reports and some case series. Only papers written in English, French, Spanish or Portuguese were included. Exclusion criteria were: papers not about CAPS, only mentioning it; laboratory studies non-patient based papers; review articles; and case reports in which there were diagnostic doubts. The online available “CAPS Registry” was consulted (the first 282 patients) and data was crossed with the PubMed reported cases to avoid duplication. At the end, 342 cases of CAPS with available treatment were analyzed. The treatment modalities of all patients are shown in Table 3 and the non-parametric Mann–Whitney test was used for comparison of results. 14 patients had no treatment since diagnosis was made in autopsy. The double therapy strategy (AC + GC) when used alone did not change global mortality compared to the other strategies but when used as a “backbone of therapy” changes mortality (p b 0.001). This result must be interpreted with caution since very few patients were not treated with AC + GC. The triple therapy strategy – AC + GC + either plasma exchange, IVIG or both – changed mortality compared to other strategies that did not use plasma exchange, IVIG or both (p = 0.04). Although there are very few patients having been treated with IS (any of them), they did not change mortality significantly (p = 0.33). Cyclophosphamide, in the usual dose of a pulse of 0.5 to 1 g/m2, was associated to less survival in primary CAPS, but these patients had a higher mean number of organs involved [71,72]. It may be used in SLECAPS patients, as SLE is a poor prognostic factor, especially if active [71, 72]. Some authors consider also its use in patients with high titers of aPL to avoid a rebound after plasma exchange or IVIG use [73]. Several mechanisms could be targeted with the use of biologic agents in the context of CAPS. Current therapies for APS do not target antibodies and B cells are responsible for the generation of those pathogenic antibodies [74]. A subset of B cell can express CD5 associated with aPL; they also can act as antigen presenting cells and can differentiate into B cell effectors and regulates helper T cells [75]. Besides, B cells release pro-inflammatory cytokines [76]. So it seems very reasonable to modulate or deplete B cells in CAPS. Abatacept and belimumab were studied only in murine models of APS, but not in the catastrophic presentation form. The blockage of CTLA4Ig showed efficacy before aPL appearance in mice, reduced thrombosis and prolonged survival. After the aPL production, the

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Table 4 Critical appraisal of rituximab studies in CAPS [91]. Study

Outcomes

Design

Limitations Indirectness Inconsistency Imprecision Publication bias Quality

Kumar et al. [78] Khattri et al. [75] Berman et al. [77] Erkan et al. [79]

Effect on aPL profile effect on clinical CAPS survival Effect on aPL profile effect on clinical CAPS survival Effect on clinical CAPS survival relapse Survival safety

Systematic review Systematic review Systematic review Prospective

Serious Serious Serious Serious

disease was not prevented, although the co-stimulatory signal blocker showed a modest increase in survival. On the other hand, the BLyS/ BAFF inhibitor belimumab action was not dependent of aPL appearance and prolonged survival. When both were administered, there was no advantage of this association over BLyS/BAFF blockade alone [75]. In humans, only two biologics were studied for CAPS, rituximab and eculizumab. Unfortunately in small series and there is still little information about them. The most studied biologic agent in APS is rituximab and we are aware only of 20 cases reported. Therefore, we selected five main outcomes concerning rituximab in order to review the strength of recommendation of each one. The outcomes chosen were safety, effect on clinical CAPS, survival, effect on aPL profile and the potential of preventing relapses. At least 14 studies were conducted with rituximab, but most of them are included in the last review of the “CAPS Registry” [77]. Therefore, we can reduce the real number of important studies to four, three of them being systematic reviews [75,77,78] and only one a prospective study named the RITAPS (RITuximab AntiphosPholipid Syndrome) trial [79] (Table 4). RITAPS was designed for non-criteria manifestations of APS, not for CAPS. Nevertheless, it was the only study that gave information about safety of this drug in APS. This outcome in APS patients is consistent with the known safety profile of rituximab in other diseases [79]. These studies were rated according to GRADE system (Grading of Recommendations Assessment, Development and Evaluation) [91] (Table 4). Final rating of evidence quality can be increased as warranted. Besides all the appraisal points being the same for all of them, RITAPS was the only interventional study. Plausible confounding factors could have reduced a demonstrated effect on the other outcomes. Therefore, it can be upgraded to a MODERATE grade of quality. The “CAPS Registry” is an important tool in our understanding of such a rare manifestation of APS. All outcomes but safety were reported. The last time it was published only 20 were treated with rituximab, of those, ten were published and ten were personal communications. Thirty percent had the catastrophic presentation as first event and primary APS was diagnosed in 55%. Treatment prescribed was AC (100%), GC (85%), IVIG (80%), plasma exchange (65%) and cyclophosphamide (20%). Those who received rituximab were prescribed as first line therapy in 40%, the main reasons being the severity or associated lymphoma. The other 60% were prescribed as second line therapy based on poor response of the initial regimen or relapse. Different regimens were used, but the most common was 1 g fortnightly twice. Four patients died (20%) and half of them received as first line regimen [77]. The effect of the anti-CD20 on aPL profile is controversial. In the “CAPS Registry” only eight patients had their aPL profile reported and four of them became negative (two for LA, one for triple positivity and one for anti-β2GPI antibodies) [77]. In contrast, in the RITAPS trial, all nineteen patients enrolled remained with aPL profile positive [79]. A specific review of the effect of rituximab in aPL showed that eight of twelve patients normalized or had reduction on aPL titers [80]. Conflicting results may be partially explained by the lack of uniformity of documentation with incomplete profiles, as well as different positivity thresholds and, possibly, the negativation of autoantibodies due to IS [77]. Another question yet to be solved is if the negativation on aPL profile is really necessary for clinical rituximab benefit. Arguments supporting this may be partially exemplified by the RITAPS trial results. The absence of substantial change in autoantibodies also had a limited clinical response and it is well known that rituximab has no

Yes Yes Yes Yes

Yes Yes Yes Yes

Yes Yes Yes Yes

Probable Probable Probable Probable

Very low Very low Very low Moderate

effect on memory B cells or plasma cells. An argument against is that we must consider that B cells have effector functions independent of antibody production [77]. Finally, the potential of preventing relapses must be discussed. First, it is necessary to differentiate the definition of refractoriness and relapse. In the first one, the patient did not respond to triple standard therapy with AC, GC and plasma exchange or IVIG and died [81]. Relapsing episodes of CAPS are clinical and hematological manifestations recurring after 30 days of apparent remission [82]. Several prognostic factors were identified in relapsing cases, such as the concomitance of SLE, age higher than 36 years old, pulmonary and renal involvement, as well the presence of antinuclear antibodies and the presence of lupus anticoagulant [82]. A strong consideration must be done with MHA. MHA was more frequent in the “CAPS Registry” in relapsing cases (72% versus 7%, p b 0.0001, 95% CI 0.459–0.841) [77]. Asherson et al. had previously demonstrated five relapses out of seven patients with MHA [83]. Eculizumab was also studied to prevent relapses. Eculizumab is a monoclonal antibody against C5 that blocks complement at the level of end-organ parenchymal microvasculature. It is approved for paroxysmal nocturnal hemoglobinuria (PNH). Until now, there are five studies (three case reports and two case series) using as prophylactic regimen to relapsing APS/CAPS in patients submitted to renal transplantation [84–88] and there is also an ongoing trial, a phase 2 study of the use of eculizumab to prevent thrombosis after renal transplantation in patients with a history of CAPS (NCT01029587). These studies are very limited, leading to a very low strength of evidence. There are many opened questions yet to be elucidated. We do not know if rituximab should be used as a first or second line therapy. Maybe identifying patients with increased risk factors would be reasonable as initial adjuvant therapy, especially for those with MHA. In addition, rituximab seems to be an important tool for relapsing cases. Another doubt is if rituximab response may be clinical manifestation dependent. The RITAPS trial identified good clinical response for skin ulcer and not for cardiac valve disease, for instance [79]. We have rare cases with hemorrhagic manifestations (i.e. diffuse alveolar hemorrhage) in which AC is a contraindication. We have evidence that rituximab works in this context and could be a good indication for its use [89]. Still, we do not know the best dosage regimen or if other treatments mask the real effect of this drug. Besides, there is a probable anecdotal case report of APS development after rituximab use [90]. We may conclude that rituximab is safe in APS and CAPS patients, with a variable effect on aPL profile. Rituximab may have a role in the treatment of CAPS, especially in refractory and relapsing cases. Due to the very low prevalence of CAPS, a randomized study in this setting is unlikely and there is limited information concerning other biologics in CAPS. 7. Recommendations • Think on CAPS in front of a patient with severe multiorgan involvement with thrombotic MHA findings. • The possible interplay in different pathogenic pathways between the different microangiopathic syndromes should be kept in mind. • High titers of aPL may be used as a useful hallmark for the differential diagnosis but the full clinical picture may be taken into account. • Testing for antibodies against HP4, fibrinogen, ADAMTS-13 activity and ADAMTS-13 autoantibody is encouraged.

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• The performance of a biopsy is not required for diagnostic purposes although it is highly recommended. • Regarding treatment for CAPS, the following levels of evidence and grades of recommendations were found: - Cumulative case series analysis: Level of evidence II - CAPS should not be left untreated: Grade of recommendation B - AC or GC should not be used alone: Grade of recommendation B - AC + GC should be the backbone of therapy: Grade of recommendation B - Triple therapy (AC + GC + plasma exchange and/or IVIG): Grade of recommendation B - Expert opinion: Level of evidence V - If infection is ongoing with CAPS, IVIG should be used: Grade of recommendation D - Tetra therapy (AC + GC + plasma exchange and/or IVIG + cyclophosphamide) to patients with SLE or other autoimmune disease that could benefit from extra immunosuppression: Grade of recommendation D - Although cyclophosphamide is the more used DMARD, there are no sufficient data to choose between one and another: Grade of recommendation D • Rituximab may have a role as an initial adjuvant therapy in risk factor patients, especially for those with MHA, a potential marker for relapsing cases. • Rituximab may have a role as a second line therapy in patients refractory to standard triple therapy. • Rituximab may be an alternative adjuvant therapy in CAPS patients in which anticoagulation is a contraindication. 8. Further research It is imperative to collect blood and serum during acute episodes. These samples should be centralized in a core laboratory. It should be done in parallel with the “CAPS Registry” asking physicians who contact the CAPS Registry to collect blood and send it to the core lab. Take-home messages • Catastrophic antiphospholipid syndrome (CAPS) should be suspected in front of a patient with severe multiorgan involvement with thrombotic microangiopathic findings. • Triple therapy (anticoagulants + glucocorticoids + plasma exchange and/or intravenous immunoglobulins) is recommended for the management of patients with CAPS (grade of recommendation B). • Rituximab may have a role as initial adjuvant therapy in risk factor patients, especially for those with microangiopathic hemolytic anemia, a potential marker for relapsing cases. It may also have a role as a second line therapy in patients refractory to standard triple therapy and may be an alternative adjuvant therapy in CAPS patients in which anticoagulation is a contraindication. • Although the clinical findings of CAPS are well defined, its pathological mechanisms are less understood. Therefore, it is imperative to collect blood and serum during acute episodes for mechanistic studies.

[6]

[7]

[8]

[9] [10] [11]

[12] [13]

[14] [15] [16] [17]

[18]

[19]

[20]

[21] [22]

[23]

[24]

[25]

[26]

[27] [28]

[29]

[30]

References [31] [1] Kitchens CS. Thrombotic storm: when thrombosis begets thrombosis. Am J Med 1998;104:381–5. [2] Meroni PL. Pathogenesis of the antiphospholipid syndrome: an additional example of the mosaic of autoimmunity. J Autoimmun 2008;30:99–103. [3] Asherson RA, Doherty DG, Vergani D, Khamashta MA, Hughes GR. Major histocompatibility complex associations with primary antiphospholipid syndrome. Arthritis Rheum 1992;35:124–5. [4] Caliz R, Atsumi T, Kondeatis E, Amengual O, Khamashta MA, Vaughan RW, et al. HLA class II gene polymorphisms in antiphospholipid syndrome: haplotype analysis in 83 Caucasoid patients. Rheumatology (Oxford) 2001;40:31–6. [5] Sebastiani GD, Galeazzi M, Tincani A, Scorza R, Mathieu A, Passiu G, et al. HLADPB1 alleles association of anticardiolipin and anti-beta2GPI antibodies in a

[32]

[33]

[34]

large series of European patients with systemic lupus erythematosus. Lupus 2003;12:560–3. Sanchez ML, Katsumata K, Atsumi T, Romero FI, Bertolaccini ML, Funke A, et al. Association of HLA-DM polymorphism with the production of antiphospholipid antibodies. Ann Rheum Dis 2004;63:1645–8. Yasuda S, Atsumi T, Matsuura E, Kaihara K, Yamamoto D, Ichikawa K, et al. Significance of valine/leucine247 polymorphism of beta2-glycoprotein I in antiphospholipid syndrome: increased reactivity of anti-beta2-glycoprotein I autoantibodies to the valine247 beta2-glycoprotein I variant. Arthritis Rheum 2005;52:212–8. Ortega-Hernandez O-D, Agmon-Levin N, Blank M, Asherson Ra, Shoenfeld Y. The physiopathology of the catastrophic antiphospholipid (Asherson's) syndrome: compelling evidence. J Autoimmun 2009;32:1–6. Asherson RA. The catastrophic antiphospholipid (Asherson's) syndrome in 2004—a review. Autoimmun Rev 2005;4:48–54. Levy Y, Almog O, Gorshtein A, Shoenfeld Y. The environment and antiphospholipid syndrome. Lupus 2006;15:784–90. De Jager W, Bourcier K, Rijkers GT, Prakken BJ, Seyfert-Margolis V. Prerequisites for cytokine measurements in clinical trials with multiplex immunoassays. BMC Immunol 2009;10:52. Meager A. Measurement of cytokines by bioassays: theory and application. Methods 2006;38:237–52. Espinosa G, Bucciarelli S, Cervera R, Gómez-Puerta JA, Font J. Laboratory studies on pathophysiology of the catastrophic antiphospholipid syndrome. Autoimmun Rev 2006;6:68–71. Cervera R. Update on the diagnosis, treatment, and prognosis of the catastrophic antiphospholipid syndrome. Curr Rheumatol Rep 2010;12:70–6. Cohen J. The immunopathogenesis of sepsis. Nature 2002;420:885–91. Espinosa G, Cervera R, Asherson RA. Catastrophic antiphospholipid syndrome and sepsis. A common link? J Rheumatol 2007;34:923–6. Meroni PL, Raschi E, Testoni C, Parisio A, Borghi MO. Innate immunity in the antiphospholipid syndrome: role of toll-like receptors in endothelial cell activation by antiphospholipid antibodies. Autoimmun Rev 2004;3:510–5. Ortona E, Capozzi A, Colasanti T, Conti F, Alessandri C, Longo A, et al. Vimentin/ cardiolipin complex as a new antigenic target of the antiphospholipid syndrome. Blood 2010;116:2960–7. Oku K, Amengual O, Atsumi T. Pathophysiology of thrombosis and pregnancy morbidity in the antiphospholipid syndrome. Eur J Clin Invest 2012;42:1126–35. Ritis K, Doumas M, Mastellos D, Micheli A, Giaglis S, Magotti P, et al. A novel C5a receptor-tissue factor cross-talk in neutrophils links innate immunity to coagulation pathways. J Immunol 2006;177:4794–802. Lim W. Complement and the antiphospholipid syndrome. Curr Opin Hematol 2011;18:361–5. Pierangeli SS, Vega-Ostertag M, Harris EN. Intracellular signaling triggered by antiphospholipid antibodies in platelets and endothelial cells: a pathway to targeted therapies. Thromb Res 2004;114:467–76. Conti F, Sorice M, Circella A, Alessandri C, Pittoni V, Caronti B, et al. Beta-2glycoprotein I expression on monocytes is increased in anti-phospholipid antibody syndrome and correlates with tissue factor expression. Clin Exp Immunol 2003;132:509–16. Cugno M, Borghi MO, Lonati LM, Ghiadoni L, Gerosa M, Grossi C, et al. Patients with antiphospholipid syndrome display endothelial perturbation. J Autoimmun 2010;34:105–10. Raschi E, Borghi MO, Grossi C, Broggini V, Pierangeli S, Meroni PL. Toll-like receptors: another player in the pathogenesis of the anti-phospholipid syndrome. Lupus 2008;17:937–42. Colasanti T, Alessandri C, Capozzi A, Sorice M, Delunardo F, Longo A, et al. Autoantibodies specific to a peptide of β2-glycoprotein I cross-react with TLR4, inducing a proinflammatory phenotype in endothelial cells and monocytes. Blood 2012;120:3360–70. Giannakopoulos B, Krilis Sa. The pathogenesis of the antiphospholipid syndrome. N Engl J Med 2013;368:1033–44. Ferro D, Iuliano L, Violi F, Valesini G, Conti F. Antioxidant treatment decreases the titer of circulating anticardiolipin antibodies: comment on the article by Sambo et al. Arthritis Rheum 2002;46:3110–2. Espinosa G, Bucciarelli S, Cervera R, Lozano M, Reverter JC, de la Red G, et al. Thrombotic microangiopathic haemolytic anaemia and antiphospholipid antibodies. Ann Rheum Dis 2004;63:730–6. Espinosa G, Rodríguez-Pintó I, Gomez-Puerta JA, Pons-Estel G, Cervera R. Relapsing catastrophic antiphospholipid syndrome potential role of microangiopathic hemolytic anemia in disease relapses(1). Semin Arthritis Rheum 2012;42:417–23. Rosário C, Zandman-Goddard G, Meyron-Holtz EG, D'Cruz DP, Shoenfeld Y. The hyperferritinemic syndrome: macrophage activation syndrome, Still's disease, septic shock and catastrophic antiphospholipid syndrome. BMC Med 2013;11:185. Zandman-Goddard G, Orbach H, Agmon-Levin N, Boaz M, Amital H, Szekanecz Z, et al. Hyperferritinemia is associated with serologic antiphospholipid syndrome in SLE patients. Clin Rev Allergy Immunol 2013;44:23–30. Agmon-Levin N, Rosário C, Katz BS, Zandman-Goddard G, Meroni P, Cervera R, et al. Ferritin in the antiphospholipid syndrome and its catastrophic variant (cAPS). Lupus 2013;22:1327–35. Asherson RA, Espinosa G, Cervera R, Font J, Reverter JC. Catastrophic antiphospholipid syndrome: proposed guidelines for diagnosis and treatment. J Clin Rheumatol 2002;8:157–65.

R. Cervera et al. / Autoimmunity Reviews 13 (2014) 699–707 [35] Asherson RA, Cervera R, de Groot PG, Erkan D, Boffa MC, Piette JC, et al. Catastrophic antiphospholipid syndrome: international consensus statement on classification criteria and treatment guidelines. Lupus 2003;12:530–4. [36] Cervera R, Font J, Gómez-Puerta Ja, Espinosa G, Cucho M, Bucciarelli S, et al. Validation of the preliminary criteria for the classification of catastrophic antiphospholipid syndrome. Ann Rheum Dis 2005;64:1205–9. [37] Cervera R, Tektonidou MG, Espinosa G, Cabral AR, González EB, Erkan D, et al. Task Force on Catastrophic Antiphospholipid Syndrome (APS) and non-criteria APS manifestations (I): catastrophic APS, APS nephropathy and heart valve lesions. Lupus 2011;20:165–73. [38] Ortel TL, Kitchens CS, Erkan D, Brandão LR, Hahn S, James AH, et al. Clinical causes and treatment of the thrombotic storm. Expert Rev Hematol 2012;5:653–9. [39] Nayfe R, Uthman I, Aoun J, Saad Aldin E, Merashli M, Khamashta MA. Seronegative antiphospholipid syndrome. Rheumatology (Oxford) 2013;52:1358–67. [40] Cervera R, Bucciarelli S, Plasín MA, Gómez-Puerta JA, Plaza J, Pons-Estel G, et al. Catastrophic antiphospholipid syndrome (CAPS): descriptive analysis of a series of 280 patients from the “CAPS Registry”. J Autoimmun 2009;32:240–5. [41] Cervera R, Asherson Ra, Acevedo ML, Gómez-Puerta JA, Espinosa G, De La Red G, et al. Antiphospholipid syndrome associated with infections: clinical and microbiological characteristics of 100 patients. Ann Rheum Dis 2004;63:1312–7. [42] Avcin T, Toplak N. Antiphospholipid antibodies in response to infection. Curr Rheumatol Rep 2007;9:212–8. [43] McNally T, Purdy G, Mackie IJ, Machin SJ, Isenberg DA. The use of an anti-beta 2glycoprotein-I assay for discrimination between anticardiolipin antibodies associated with infection and increased risk of thrombosis. Br J Haematol 1995;91:471–3. [44] Arepally GM, Ortel TL. Clinical practice. Heparin-induced thrombocytopenia. N Engl J Med 2006;355:809–17. [45] Gruel Y, Rupin A, Watier H, Vigier S, Bardos P, Leroy J. Anticardiolipin antibodies in heparin-associated thrombocytopenia. Thromb Res 1992;67:601–6. [46] Alpert D, Mandl La, Erkan D, Yin W, Peerschke EI, Salmon JE. Anti-heparin platelet factor 4 antibodies in systemic lupus erythematosus are associated with IgM antiphospholipid antibodies and the antiphospholipid syndrome. Ann Rheum Dis 2008;67:395–401. [47] Gómez-Puerta JA, Cervera R, Espinosa G, Asherson RA, García-Carrasco M, da Costa IP, et al. Catastrophic antiphospholipid syndrome during pregnancy and puerperium: maternal and fetal characteristics of 15 cases. Ann Rheum Dis 2007;66:740–6. [48] Hanouna G, Morel N, Le Thi Huong D, Josselin L, Vauthier-Brouzes D, Saadoun D, et al. Catastrophic antiphospholipid syndrome and pregnancy: an experience of 13 cases. Rheumatology (Oxford) 2013;52:1635–41. [49] George JN, Charania RS. Evaluation of patients with microangiopathic hemolytic anemia and thrombocytopenia. Semin Thromb Hemost 2013;39:153–60. [50] Kim S, Moskowitz NK, DiCarlo EF, Bass AR, Erkan D, Lockshin MD. Catastrophic antiphospholipid syndrome triggered by sepsis. HSS J 2009;5:67–72. [51] Blank M, Asherson RA, Cervera R, Shoenfeld Y. Antiphospholipid syndrome infectious origin. J Clin Immunol 2004;24:12–23. [52] Shoenfeld Y, Blank M, Cervera R, Font J, Raschi E, Meroni P-L. Infectious origin of the antiphospholipid syndrome. Ann Rheum Dis 2006;65:2–6. [53] De Runz A, Zuily S, Gosset J, Wahl D, Simon E. Particular catastrophic antiphospholipid syndrome, on the sole surgical site after breast reduction. J Plast Reconstr Aesthet Surg 2013;66:e321–4. [54] Katikireddi VS, Kandiah DA. Progression of antiphospholipid antibody syndrome to catastrophic antiphospholipid antibody syndrome acutely with cessation of antithrombotic therapy. Intern Med J 2012;42:585–91. [55] Amital H, Levy Y, Davidson C, Lundberg I, Harju A, Kosach Y, et al. Catastrophic antiphospholipid syndrome: remission following leg amputation in 2 cases. Semin Arthritis Rheum 2001;31:127–32. [56] Baron TH, Kamath PS, McBane RD. Management of antithrombotic therapy in patients undergoing invasive procedures. N Engl J Med 2013;368:2113–24. [57] Sacks S, Finn J, Sanna G, Khamashta MA, Chowdhury F, Hunt BJ, et al. N2010 adultonset Still's disease complicated by hemophagocytic syndrome and catastrophic antiphospholipid syndrome resulting in four limb amputation. Isr Med Assoc J 2013;15:192–4. [58] Sousa GM, Oliveira RC, Pereira MM, Paraná R, Sousa-Atta MLB, Atta AM. Autoimmunity in hepatitis C virus carriers: involvement of ferritin and prolactin. Autoimmun Rev 2011;10:210–3. [59] Da Costa R, Szyper-Kravitz M, Szekanecz Z, Csépány T, Dankó K, Shapira Y, et al. Ferritin and prolactin levels in multiple sclerosis. Isr Med Assoc J 2011;13:91–5. [60] Agmon-Levin N, Theodor E, Segal RM, Shoenfeld Y. Vitamin D in systemic and organspecific autoimmune diseases. Clin Rev Allergy Immunol 2013;45:256–66. [61] Agmon-Levin N, Blank M, Zandman-Goddard G, Orbach H, Meroni PL, Tincani A, et al. Vitamin D: an instrumental factor in the anti-phospholipid syndrome by inhibition of tissue factor expression. Ann Rheum Dis 2011;70:145–50. [62] Bontadi A, Ruffatti A, Falcinelli E, Giannini S, Marturano A, Tonello M, et al. Platelet and endothelial activation in catastrophic and quiescent antiphospholipid syndrome. Thromb Haemost 2013;109:901–8. [63] Brenner ZR, Miller AB, Ayers LC, Roberts A. The role of vitamin D in critical illness. Crit Care Nurs Clin North Am 2012;24:527–40.

707

[64] Braun AB, Gibbons FK, Litonjua AA, Giovannucci E, Christopher KB. Low serum 25hydroxyvitamin D at critical care initiation is associated with increased mortality. Crit Care Med 2012;40:63–72. [65] Weitz J, Hirsh J, Samama M. New anticoagulant drugs: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:265S–86S. [66] Girardi G, Redecha P, Salmon JE. Heparin prevents antiphospholipid antibodyinduced fetal loss by inhibiting complement activation. Nat Med 2004;10:1222–6. [67] Auphan N, DiDonato JA, Rosette C, Helmberg A, Karin M. Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis. Science 1995;270:286–90. [68] Hartung H-P, Mouthon L, Ahmed R, Jordan S, Laupland KB, Jolles S. Clinical applications of intravenous immunoglobulins (IVIg)—beyond immunodeficiencies and neurology. Clin Exp Immunol 2009(158 Suppl.):23–33. [69] Tenti S, Guidelli GM, Bellisai F, Galeazzi M, Fioravanti A. Long-term treatment of antiphospholipid syndrome with intravenous immunoglobulin in addition to conventional therapy. Clin Exp Rheumatol 2013;31:877–82. [70] Sciascia S, Giachino O, Roccatello D. Prevention of thrombosis relapse in antiphospholipid syndrome patients refractory to conventional therapy using intravenous immunoglobulin. Clin Exp Rheumatol 2012;30:409–13. [71] Asherson RA, Cervera R, Piette JC, Shoenfeld Y, Espinosa G, Petri MA, et al. Catastrophic antiphospholipid syndrome: clues to the pathogenesis from a series of 80 patients. Medicine (Baltimore) 2001;80:355–77. [72] Bayraktar UD, Erkan D, Bucciarelli S, Espinosa G, Asherson R. The clinical spectrum of catastrophic antiphospholipid syndrome in the absence and presence of lupus. J Rheumatol 2007;34:346–52. [73] Asherson RA, Cervera R. The catastrophic antiphospholipid syndrome: a review of pathogenesis, clinical features and treatment. Isr Med Assoc J 2000;2:268–73. [74] Bakshi J, Stevens R. Rituximab therapy for recurrent thromboembolic disease in antiphospholipid syndrome. Lupus 2013;22:865–7. [75] Khattri S, Zandman-Goddard G, Peeva E. B-cell directed therapies in antiphospholipid antibody syndrome—new directions based on murine and human data. Autoimmun Rev 2012;11:717–22. [76] Costa R, Fazal S, Kaplan RB, Spero J, Costa R. Successful plasma exchange combined with rituximab therapy in aggressive APS-related cutaneous necrosis. Clin Rheumatol 2013;32(Suppl. 1):S79–82. [77] Berman H, Rodríguez-Pintó I, Cervera R, Morel N, Costedoat-Chalumeau N, Erkan D, et al. Rituximab use in the catastrophic antiphospholipid syndrome: descriptive analysis of the CAPS registry patients receiving rituximab. Autoimmun Rev 2013;12:1985–90. [78] Kumar D, Roubey RAS. Use of rituximab in the antiphospholipid syndrome. Curr Rheumatol Rep 2010;12:40–4. [79] Erkan D, Vega J, Ramon G, Kozora E, Lockshin MD. A pilot open label phase II trial of rituximab for non-criteria manifestations of antiphospholipid syndrome. Arthritis Rheum 2013;65:464–71. [80] Erre GL, Pardini S, Faedda R, Passiu G. Effect of rituximab on clinical and laboratory features of antiphospholipid syndrome: a case report and a review of literature. Lupus 2008;17:50–5. [81] Espinosa G, Berman H, Cervera R. Management of refractory cases of catastrophic antiphospholipid syndrome. Autoimmun Rev 2011;10:664–8. [82] Bucciarelli S, Erkan D, Espinosa G, Cervera R. Catastrophic antiphospholipid syndrome: treatment, prognosis, and the risk of relapse. Clin Rev Allergy Immunol 2009;36:80–4. [83] Asherson Ra, Espinosa G, Menahem S, Yinh J, Bucciarelli S, Bosch X, et al. Relapsing catastrophic antiphospholipid syndrome: report of three cases. Semin Arthritis Rheum 2008;37:366–72. [84] Lonze BE, Singer AL, Montgomery R. Eculizumab and renal transplantation in a patient with CAPS. N Engl J Med 2010;362:1744–5. [85] Hadaya K, Ferrari-Lacraz S, Fumeaux D, Boehlen F, Toso C, Moll S, et al. Eculizumab in acute recurrence of thrombotic microangiopathy after renal transplantation. Am J Transplant 2011;11:2523–7. [86] Velik-Salchner C, Lederer W, Wiedermann F. Eculizumab and renal transplantation in a patient with catastrophic antiphospholipid syndrome: effect of heparin on complement activation. Lupus 2011;20:772. [87] Canaud G, Kamar N, Anglicheau D, Esposito L, Rabant M, Noël LH, et al. Eculizumab improves posttransplant thrombotic microangiopathy due to antiphospholipid syndrome recurrence but fails to prevent chronic vascular changes. Am J Transplant 2013;13:2179–85. [88] Lonze BE, Zachary AA, Magro CM, Desai NM, Orandi BJ, Dagher NN, et al. Eculizumab prevents recurrent antiphospholipid antibody syndrome and enables successful renal transplantation. Am J Transplant 2014;14:459–65. [89] Scheiman Elazary A, Klahr PP, Hershko AY, Dranitzki Z, Rubinow A, Naparstek Y. Rituximab induces resolution of recurrent diffuse alveolar hemorrhage in a patient with primary antiphospholipid antibody syndrome. Lupus 2012;21:438–40. [90] Faillace C, de Carvalho JF. Antiphospholipid syndrome development after rituximab treatment. Joint Bone Spine 2012;79:200–1. [91] Guyatt GH, Oxman AD, Schünemann HJ, Tugwell P, Knottnerus A. GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology. J Clin Epidemiol 2011;64:380–2.