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Venous thromboembolic disease in systemic autoimmune diseases: An association to keep in mind
Autoimmunity Reviews 12 (2012) 289–294
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Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev
Review
Venous thromboembolic disease in systemic autoimmune diseases: An association to keep in mind Ricardo Silvariño a, b, c, Álvaro Danza b, c, d, Valentina Mérola b, c, Adriana Bérez b, Enrique Méndez b, Gerard Espinosa e, Ricard Cervera e,⁎ a
Center of Nephrology and Department of Emergency, Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay Systemic Autoimmune Diseases Group, Society of Internal Medicine, Uruguay Clinical Department of Medicine, Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay d Autoimmune Diseases Research Unit, Department of Internal Medicine, Hospital Universitario Cruces, Barakaldo, Spain e Department of Autoimmune Diseases, Hospital Clinic, Barcelona, Catalonia, Spain b c
a r t i c l e
i n f o
Article history: Received 18 April 2012 Accepted 1 May 2012 Available online 7 May 2012
a b s t r a c t Systemic autoimmune diseases are conditions of unknown etiology, characterized by the simultaneous or successive involvement of most organs and systems, as well as the presence of autoantibodies as biological markers. Venous thromboembolic disease has a higher incidence in this population when compared to healthy individuals. This responds to the increase in congenital and acquired risk factors in this group. One of the main risk factors is linked to the presence of antiphospholipid antibodies, whose prevalence is increased among patients with such conditions. © 2012 Elsevier B.V. All rights reserved.
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . VTD in patients with SAD and aPL negativity 2.1. Systemic lupus erythematosus (SLE) 2.2. Systemic vasculitis . . . . . . . . 2.2.1. ANCA-associated vasculitis 2.2.2. Behçet's disease (BD) . . . 3. VTD in patients with aPL . . . . . . . . . 3.1. APS . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . Appendix A . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . .
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1. Introduction Systemic autoimmune diseases (SAD) are conditions of unknown etiology, characterized by the simultaneous or successive involvement of most organs and systems, as well as the presence of autoantibodies as biological markers.
⁎ Corresponding author at: Department of Autoimmune Diseases, Hospital Clínic, Villarroel, 170, 08036-Barcelona, Catalonia, Spain. Tel.: + 34 93 227 5774; fax: + 34 93 227 1707. E-mail address: [email protected] (R. Cervera). 1568-9972/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2012.05.002
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These diseases have a growing social and economic importance, since up to 8.5% of the population might be affected by some type of autoimmune (organ specific or non-specific) disease according to data from the National Institutes of Health (NIH) of the United States of America [1]. Venous thromboembolic disease (VTD) has a higher incidence in this population when compared to healthy individuals. This responds to the increase in congenital and acquired risk factors in this group. One of the main risk factors is linked to the presence of antiphospholipid antibodies (aPL), whose prevalence is increased among those with SAD. The objective of this review is to update the available information about the association between SAD and VTD. The main risk factors
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present in these patients will be discussed and recommendations for therapeutic management will be made according to the available evidence. 2. VTD in patients with SAD and aPL negativity 2.1. Systemic lupus erythematosus (SLE) SLE is the prototype of SAD, because of its rich clinical and immunologic expression, characterized by the production of multiple autoantibodies. It affects mostly women (female:male ratio 9:1). Its prevalence is variable, ranging from 159/100,000 among the Caribbean women, through 34/ 100,000 inhabitants in the Spanish population to 18/100,000 inhabitants in Japan [2]. VTD is more frequent in patients with SLE than in control groups [3]. In the Euro-lupus cohort, between 5 and 10% of the studied population presented thrombosis in a 10‐year follow-up period [4]. Together with exacerbations of the disease and infections, thrombosis is one of the main causes or morbidity and mortality in SLE [4–6]. The former are found mainly in the first 5 years of the disease, whereas thrombosis usually appears after this period [4]. This happens due to the increased presence of risk factors that are traditionally linked to VTD (age, overweight, sedentary life-style, and insulin resistance) [7–10], as well as other congenital and acquired risk factors that are more frequent in this population. The low prevalence of the disease and the low number of individuals included in the studies make the information available limited. Information is originated mainly from observational clinical studies. As a general practice, it is recommended to control all traditional VTD risk factors in this population, mainly those that have a proven link to the development of thromboembolic episodes: overweight, sedentary lifestyle and smoking [11,12]. Among those congenital risk factors, patients with SLE and absence of aPL present an increased prevalence of the homozygous mutation of the Methylene-tetra-hydrofolate-reductase gene (MTHFR) [13], factor V Leyden [14,15] and homozygous mutation of prothrombin G20210 [15]. The presence of these abnormalities results in an increased risk for VTD, which is higher than in the group without SLE [16–18]. Nevertheless, systematic testing for these prothrombotic genetic mutations is not recommended in patients with SLE unless there is family history of these mutations, thrombosis without a clear precipitating cause or thrombosis in an unusual location [15]. In relation to those acquired risk factors for VTD, it is worth mentioning that plasma levels of homocysteine are higher in patients with SLE than in the general population [13,19,20] and this quality determines an increased thromboembolic risk [21–23]. However, while there are no intervention studies in high risk patients, neither systemic quantification of total homocysteine nor its pharmacologic modification is justified except in specific situations. In the same line, there is an increased frequency of acquired resistance to C-reactive protein [20], which increases the risk of VTD [20,24]. There has been evidence of higher plasma fibrinogen levels in this group compared to healthy population, which was linked to a higher incidence of thrombotic episodes [13,25]. There has been evidence of abnormal platelet function, such as the increase of circulating microparticles derived from platelets [26] and persistent platelet activation [27,28] as another mechanism that increases the thrombotic risk in this group. Moreover, it has been found that in patients with SLE there are hemorheological abnormalities like increase in blood viscosity [29] that are associated with an increased risk of developing venous thrombosis [30]. Despite this, systematic testing for neither hemorheological abnormalities nor platelet function is justified. The presence of active disease measured by the Systemic Lupus Activity Index (SLAM) has also been associated to an increased risk of thrombotic episodes [11]. Other factors such as age at diagnosis, high
corticosteroid doses and poverty have also been associated to an increased risk and early development of thrombotic episodes [12]. Summarizing, as a general rule, the adequate control of the disease activity and the lowest corticosteroid dose use, tend to decrease thromboembolic risk. In terms of the therapeutic management of increased risk of VTD, there are no controlled randomized studies about the benefits of primary thromboprophylaxis in patients with SLE and absence of aPL. It may be beneficial to do primary thromboprophylaxis in those patients with SLE who present associated thromboembolic risk factors [31,32]. Antimalarials are widely used in the treatment of SLE and other SAD. Hydroxychloroquine (HCQ), mepacrine (MPC) and chloroquine (CQ) are part of this group of agents. HCQ decreases the risk of VTD in patients with SLE. This characteristic, along with other proven benefits of its use, justify the use of Hydroxychloroquine in every patient with SLE, unless there are specific contraindications for this [33,34]. 2.2. Systemic vasculitis They represent a clinical pathological process characterized by inflammation of blood vessels, generally accompanied by necrosis of the vascular wall that causes occlusion and ischemia of affected tissues and organs. Their etiology is unknown, and multiple pathologic mechanisms are responsible for the endothelial cells’ injury. Until today, the classification proposed by the Chapel Hill consensus is still used, which groups them in terms of size of vessels mostly compromised (large, medium and small) [35]. Within this group, we will focus on the systemic vasculitis of smallsize vessels associated to antineutrophil cytoplasmic antibodies (ANCA) and Behçet's disease, since they have an increased prevalence of VTD. 2.2.1. ANCA-associated vasculitis Among the small-size vessel pauci-immune vasculitis, the most outstanding ones because of their link with thrombotic episodes are granulomatosis with polyangiitis (Wegener's granulomatosis (WG)), microscopic polyangiitis (MPA) and Churg–Strauss syndrome (CSS). All of them are associated to the presence of ANCA in 80 to 90% of the cases [35]. A higher prevalence of VTD has been evidenced in patients with cANCA-associated vasculitis and seropositivity for antiproteinase-3 (PR3) antibodies, determined by ELISA. Thromboembolic complications are mainly observed during active phase of the disease [36]. Specific changes in the venous system like venulitis, as well as the systemic inflammatory state with proinflammatory cytokine release may trigger the thrombotic process. The presence of apoptotic cells, consequence of PR3 activity among others, functions as procoagulant and proadhesive for platelets [36,37]. An increased prevalence has not been found, in comparison with the general population, in terms of the presence of prothrombotic congenital factors (factor V Leyden, prothrombin G20210, mutation of MTHFR gene) in patients with ANCA-associated vasculitis [37]. In relation to acquired risk factors, an increased prevalence of anticardiolipin antibodies (aCL) in low levels has been found in patients with ANCA-associated vasculitis. This finding, as well as the presence of anti-β2-glycoprotein I antibodies (aβ2GPI), was not correlated to increase in thrombotic episodes [37]. Such as what happens in SLE, activity of the disease constitutes a risk factor for VTD [36]. Based on the evidence, unless special circumstances are present, a systematic testing for thrombotic congenital and acquired risk factors is not recommended in patients with ANCA-associated vasculitis [36,37]. There are no controlled randomized studies about the benefit of primary thromboprophylaxis in patients with ANCA-associated vasculitis [36]. It may be beneficial to apply primary thromboprophylaxis in those patients with ANCA-associated PR3 positive vasculitis that
R. Silvariño et al. / Autoimmunity Reviews 12 (2012) 289–294
present associated thromboembolic risk factors [36,37]. Adequate immunosuppressive therapy during the active phase of the disease decreases the risk of VTD [36,37]. 2.2.2. Behçet's disease (BD) BD is a systemic vasculitis whose minimum diagnostic criterion, oral and genital ulcers, is frequently followed by a spectrum of clinical manifestations that include uveitis, vein thrombosis, erythema nodosum, arthritis, gastrointestinal involvement, neurologic involvement and pulmonary involvement. Vascular involvement is frequent and contributes considerably to morbidity and mortality in this group. It appears as vein thrombosis, arterial thrombosis and aneurysms. This condition is associated with a characteristic prothrombotic state as a consequence of vein and arterial inflammatory involvement [38]. There is an increase in the risk of thromboembolism in patients with BD when compared to the general population. Venous thrombosis occurs earlier during the course of the disease than arterial involvement [39]. Venous involvement includes large-size vessels (inferior and superior vena cava, hepatic veins) as well as lower-caliber veins, determining deep venous thrombosis in the lower limbs or superficial venous thrombosis [39,40]. A discrete increase in procoagulant factors (Von Willebrand Factor, thrombomodulin and prostacyclin) has been found in patients with BD. The presence of these factors has been associated mainly to the development of ocular thrombotic involvement and not to other thromboembolic manifestations [39]. Mutation of Factor V Leyden has been found with higher prevalence among patients with BD of Turkish and Arabic origin, unlike among those of Italian and British origin, which depicts relevant differences in geo-epidemiology [38,39,42]. A higher frequency in the mutation of the G20210A gene was found in the subgroup of patients with BD and posterior uveitis or retinal vasculitis [40]. Primary pathogenesis of VTD in BD is the inflammation of the vascular wall, which is why the presence of active disease is a risk factor to develop this complication [36]. Except for special situations, systematic testing for congenital and acquired thromboembolic risk factors is not recommended in patients with BD [38–41]. There are no randomized controlled studies about the benefit of primary thromboprophylaxis in BD. Immunosuppressive treatment has been associated with a lower incidence of thromboembolic disease in this population [43]. The use of immunosuppressive drugs in patients with recurrent or progressive thrombosis has been linked to a decrease in the incidence of new thrombotic episodes [39,41]. Clinical trials have shown the benefit of intense anticoagulation with heparin or warfarin associated to antiaggregation in the group of patients that present thrombotic manifestations under immunosuppressive treatment and standard anticoagulation [43]. According to what was previously stated, it may be beneficial to implement primary thromboprophylaxis in those patients with BD that present associated thromboembolic risk factors [43]. The use of immunosuppressive drugs such as corticosteroids, azathioprine, cyclophosphamide or cyclosporine is recommended for treatment of VTD in patients with BD [43], mainly among those with recurrent or progressive thrombosis [39,41]. In those patients that present new thromboembolic episodes under standard anticoagulation and immunosuppressive therapy, it is recommended to implement intense anticoagulation with heparin or warfarin associated to antiaggregation [43,44]. 3. VTD in patients with aPL The aPL are autoantibodies directed against plasma proteins that bind to anionic phospholipids. Even though a wide variety of aPL has been detected, there is general consensus in that autoantibodies directed against β2GPI are the clinically relevant ones. In clinical
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practice, systematic testing is done to find the presence of anticardiolipin antibodies (aCL) in their IgM and IgG isotopes, aβ2GPI and lupus anticoagulant (LA). The presence of aPL is associated to a marked increase in the risk of arterial and venous thrombosis [45– 47] which has been estimated to be near 3.8% annually [48]. On the other hand, antiphospholipid syndrome (APS) is an acquired thrombophilia which can account for approximately 20% of the thromboembolic events in young adults [49]. Some risk factors increase the risk of VTD in patients with aPL: 1Profile and levels of aPL: The presence of LA determines an increase in risk of 5 to 16 times for developing thromboembolic episodes and obstetric morbidity. This risk is higher than the one determined by aCL and aβ2GPI [50–52]. Intermediate or high levels of IgG aCL represent a risk factor for the presence of the first thrombotic episode in asymptomatic aPL carriers [53]. Among asymptomatic aCL carriers, the risk of VTD is raised by the increase in their levels [54]. 2—Persistence of aPL over time: Patients with persistently positive testing for aPL over time present an increased thrombotic risk compared to those with transiently positive testing [55]. 3—Presence of aPL in the context of SLE: The presence of aPL in the context of SLE determines a higher risk than in patients without SLE [52,56]. The presence of LA increases the risk for developing VTD six times, representing the risk factor that is most linked to its development in this population [57,58]. The presence of aCL duplicates the risk of presenting VTD in patients with SLE [58]. 4—“Triple positivity” for aPL: “Triple positive” patients, named as such for presenting positivity for the three aPL, present a higher risk of developing thrombotic events. Recently, 104 patients with this condition were followed through a mean of 4.5 years. Accumulated incidence of a first thrombotic event in 10 years was estimated in 37.1% (CI 95% 19.9% – 54.3%). The appearance of thromboembolic events in this population was more frequent in men and patients that present other risk factors for developing VTD. Impressively, primary prophylaxis with Aspirin did not reduce the risk of thrombosis in this population [59]. 5—Surgery and prolonged immobilization: These are factors that were present in an important percentage of asymptomatic aPL carriers at the time of the first thrombotic episode [60]. 6—Presence of prothrombotic congenital factors: Association with congenital risk factors increases substantially the risk of VTD in patients with aPL [61,62]. It is necessary to keep in mind that the presence of aPL is not “all or none”. Its presence contributes to global thrombotic risk of a determined patient in a context and in the presence of other risk factors for VTD. Furthermore, aPL carriers have a higher risk of presenting thrombosis when hypertension, hypercholesterolemia, sedentary life-style, smoking, diabetes, or use of contraceptive drugs with estrogens are present [53]. Recently, the recommendations of the 13th International Congress on Antiphospholipid Antibodies have been published [63]. Data about the benefit of primary thromboprophylaxis are contradictory [48,64,65], and the only prospective study implemented has important methodological limitations [66]. Experts recommend that asymptomatic aPL carriers, particularly those with high thrombotic risk either because of the presence of a high risk antibody profile or because of coexistence of other vascular risk factors, receive low‐dose aspirin [63]. On the other hand, aPL carriers must receive primary thromboprophylaxis with low-molecular-weight heparin (LMWH) in high risk situations such as surgery, prolonged immobilization or puerperium. Simultaneously, HCQ has been proven to decrease thrombotic risk in patients with SLE and aPL [34]. Consequently, patients with SLE and LA or aCL at persistently high levels must receive primary thromboprophylaxis with HCQ and low‐dose aspirin.
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R. Silvariño et al. / Autoimmunity Reviews 12 (2012) 289–294 (continued) Appendix A (continued)
3.1. APS
Absence of antiphospholipid antibodies
According to Sydney's criteria [66], APS is defined by the association of a clinical manifestation (arterial thrombosis, venous thrombosis, obstetric morbidity) and the presence of intermediate-to-high levels of aPL (aCL, LA, aβ2GPI) persistently positive and in two or more observations separated at least 12 weeks. Associated APS refers to its appearance in the context of another systemic autoimmune disease (usually SLE) and primary APS refers to its appearance in their absence [67]. Deep venous thrombosis and pulmonary embolism are its most frequent thromboembolic manifestations. Even when appropriate treatment is applied, patients with APS present significant morbidity and mortality [46], caused mainly by deep venous thrombosis and stroke [68]. At the time of the first venous thrombotic episode, nearly 50% of the patients with APS present as an associated additional risk factor the presence of prior surgery or prolonged immobilization [60]. Prior history of VTD represents a strong risk factor for the development of a new thromboembolic episode [3,32]. Consequently, in patients with APS and a first venous thromboembolic episode, it is recommended to apply undefined therapy with warfarin with a target INR between 2 and 3 [69,70]. However, in those cases in which thrombosis occurs with a predisposing factor and there is a low-risk antibody profile, treatment for a period of 3 to 6 months has been proposed [63]. There is debate in terms of the treatment to apply in patients with recurrent venous thrombosis or arterial thrombosis. The main agreement consists of a prolonged treatment with warfarin with a target INR between 3 and 4 [63,71]. In cases of recurrent thrombosis in spite of appropriate anticoagulation (INR between 3 and 4), complementary treatments can be resorted to, such as anticoagulation for an undetermined period of time with LMWH or addition of low‐dose aspirin, HCQ or statins [71–74].
Clinical condition
ANCA-associated vasculitis
Behçet disease
Take-home messages • In SAD, except for special situations, systematic testing for congenital or acquired thromboembolic risk factors is not recommended. • In all situations, an integral assessment of all thromboembolic risk factors must be taken. • Primary thromboprophylaxis is not recommended in SAD with the absence of aPL except in special circumstances. • Hydroxychloroquine decreases thromboembolic risk in patients with SLE. • A good control of disease activity decreases the risk for thromboembolic events. • In all cases, seropositivity for aPL increases thromboembolic risk and requires a different therapeutic approach. Appendix A
Absence of antiphospholipid antibodies Clinical condition
Recommendation
Reference
Systemic lupus erythematosus
Control classic risk factors for VTD: overweight, sedentary life-style, smoking Systematic testing for prothrombotic genetic mutations is not recommended unless there is family history of mutations, thrombosis without a clear precipitating factor or thrombosis in unusual location Neither systemic quantification of total homocysteine nor its pharmacological modification is recommended except for specific situations. Neither systematic testing for hemorheological abnormalities nor platelet function testing are recommended
[11,12] [15]
[19]
Recommendation
Reference
Activity control is recommended in order to decrease thromboembolic risk. Primary thromboprophylaxis may be beneficial in patients with associated thromboembolic risk factors Administering hydroxychloroquine is recommended because of its antithrombotic effect, among others Systematic testing for congenital or acquired thromboembolic risk factors is not recommended Primary thromboprophylaxis may be beneficial in patients with ANCA-PR3+ associated vasculitis that present associated thromboembolic risk factors Activity control is recommended in order to decrease thromboembolic risk. Systematic testing for congenital or acquired thromboembolic risk factors is not recommended Primary thromboprophylaxis may be beneficial in patients that present associated thromboembolic risk factors Immunosuppressive drugs such as corticosteroids, azathioprine, cyclophosphamide, or cyclosporine are recommended for the treatment of VTD mainly in patients with recurrent or progressive thrombosis Intense anticoagulation with heparin or warfarin associated to platelet antiaggregation is recommended in patients with new thromboembolic events under standard anticoagulation and immunosuppressive therapy
[11] [31,32]
[33,34]
[36,37]
[36,37]
[36,37] [38–41]
[43]
[43,39,41]
[43]
Presence of antiphospholipid antibodies Clinical condition
Recommendation
Asymptomatic APL Control additional thrombotic risk factors are antibodies carriers’ recommended. Low-dose aspirin treatment is recommended in all patients with LA or with persistently positive ACL antibodies, especially if these are IgG and in medium-to-high levels when there are other vascular risk factors present Primary thromboprophylaxis with lowmolecular-weight heparin is recommended in risk situations such as surgery, prolonged immobilization or puerperium Antiphospholipid Prolonged therapy with warfarin is syndrome recommended to reach a target INR between 2 and 3 in patients with the first venous thromboembolic episode Prolonged therapy with warfarin is recommended to reach a target INR between 3 and 4 in patients with recurrent venous thromboembolic events or arterial thrombosis In cases of recurrent thrombosis despite adequate anticoagulation (INR between 3 and 4), alternative therapies such as undetermined-length anticoagulation with low-molecular-weight heparin, addition of low-dose aspirin, hydroxycholoroquine or statins may be resorted to Systemic lupus Primary thromboprophylaxis with low-dose erythematosus aspirin is recommended Primary thromboprophylaxis with hydroxychloroquine is recommended
Reference [53] [63]
[63]
[69,70]
[63,71]
[71]
[63] [34]
References [26–28] [1] Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol 1997;84(3):223–43.
R. Silvariño et al. / Autoimmunity Reviews 12 (2012) 289–294 [2] Cervera R, Pallarés L. Epidemiología y clasificación del lupus eritematoso sistémico. In: Cervera R, Jimenez-Alonso J, editors. Avances en Lupus Eritematoso Sistémico; 2008. p. 41. Ed Marge. Barcelona. Cap 2. [3] Cogo A, Bernardi E, Prandoni P, Girolami B, Noventa F, Simioni P, et al. Acquired risk factors for deep-vein thrombosis in symptomatic outpatients. Arch Intern Med 1994;154(2):164–8. [4] Cervera R, Khamashta MA, Font J, Sebastiani GD, Gil A, Lavilla P, et al. European Working Party on Systemic Lupus Erythematosus. 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 2003;82(5):299–308. [5] Abu-Shakra M, Urowitz MB, Gladman DD, Gough J. Mortality studies in systemic lupus erythematosus. Results from a single center. I. Causes of death. J Rheumatol 1995;22:1259–64. [6] Manger K, Manger B, Repp R, Geisselbrecht M, Geiger A, Pfahlberg A, et al. Definition of risk factors for death, end stage renal disease, and thromboembolic events in a monocentric cohort of 338 patients with systemic lupus erythematosus. Ann Rheum Dis 2002;61:1065–70. [7] Mok CC, Poon WL, Lai JP, Wong CK, Chiu SM, Wong CK, et al. Metabolic syndrome, endothelial injury, and subclinical atherosclerosis in patients with systemic lupus erythematosus. Scand J Rheumatol 2010;39(1):42–9. [8] Calvo-Alén J, Toloza S, Fernández M, Bastian H, Fessler B, Roseman J, et al, for the LUMINA Study Group. Systemic Lupus Erythematosus in a Multiethnic US Cohort (LUMINA) XXV. Smoking, older age, disease activity, lupus anticoagulant, and glucocorticoid dose as risk factors for the occurrence of venous thrombosis in lupus patients. Arthritis Rheum 2005;52(7):2060–8. [9] Telles R, Lanna C, Ferreira G, Ribeiro A. Metabolic syndrome in patients with systemic lupus erythematosus: association with traditional risk factors for coronary heart disease and lupus characteristics. Lupus 2010;19(7):803–9. [10] Bellomio V, Spindler A, Lucero E, Berman A, Sueldo R, Berman H, et al. Metabolic syndrome in Argentinean patients with systemic lupus erythematosus. Lupus 2009;18(11):1019–25. [11] Ho KT, Ahn CW, Alarcón GS, Baethge BA, Tan FK, Roseman J, et al. Systemic lupus erythematosus in a multiethnic cohort (LUMINA): XXVIII. Factors predictive of thrombotic events. Rheumatology (Oxford) 2005;44(10):1303–7. [12] Burgos PI, McGwin Jr G, Reveille JD, Vilá LM, Alarcón GS. Factors predictive of thrombotic events in LUMINA, a multi-ethnic cohort of SLE patients (LXXII). Rheumatology (Oxford) 2010;49(9):1720–5. [13] Afeltra A, Vadacca M, Conti L, Galluzo S, Mitherhoffer A, Ferri G, et al. Thrombosis in systemic lupus erythematosus: congenital and acquired risk factors. Arthritis Care Res 2005;53(3):452–9. [14] Topaloglu R, Akierli C, Bakkaloglu A, Aydintug O, Ozen S, Besbas N, et al. Survey of factor V leiden and prothrombin gene mutations in systemic lupus erythematosus. Clin Rheumatol 2001;20(4):259–61. [15] Brouwer J, Bijl M, Veeger N, Kluin-Nelemans H, Van der Meer J. The contribution of inherited and acquired Thrombophilic defects, alone or combined with antiphospholipid antibodies,to venous and arterial Thromboembolism in patients with systemic lupus erythematosus. Blood 2004;104:143–8. [16] Kaiser R, Barton J, Chang M, Catanese J, Li Y, Begovich A, et al. Factor V Leiden and thrombosis in patients with systemic lupus erythematosus (SLE): a meta-analysis. Genes Immun 2009;10(5):495–502. [17] Regéczy N, Lakos G, Balogh I, Ajzner E, Kiss E, Szegedi G. The Leiden mutation of coagulation factor V in Hungarian SLE patients. Clin Appl Thromb Hemost 2000;6(1): 41–5. [18] Galli M, Finazzi G, Duca F, Norbis F, Moia M. The G1691→A mutation of factor V, but not the G20210→A mutation of factor II or the C677→T mutation of methylenetetrahydrofolate reductase genes, is associated with venous thrombosis in patients with lupus anticoagulants. Br J Haematol 2000;108:865–70. [19] Martínez-Berriotxoa A, Ruiz-Irastorza G, Egurbide MV, Rueda M, Aguirre C. Homocisteína plasmática en pacientes con lupus eritematoso sistémico. Medicina clínica 2003;120(18):681–5. [20] Oh D, Kim SH, Kang MS, Kim NK, Chang NS, Na BW, et al. Acquired activated protein C resistance, high tissue factor expression, and hyper-homocysteinemia in systemic lupus erythematosus. Am J Hematol 2003;72(2):103–8. [21] Petri M, Roubenoff R, Dallal GE, Nadeau MR, Selhub J, Rosenberg IH. Plasma homocysteine as a risk factor for atherothrombotic events in systemic lupus erythematosus. Lancet 1996;348(9035):1120–4. [22] Refai TM, Al-Salem IH, Nkansa-Dwamena D, Al-Salem MH. Hyperhomocysteinaemia and risk of thrombosis in systemic lupus erythematosus patients. Clin Rheumatol 2002;21(6):457–61. [23] Fijnheer R, Roest M, Haas FJ, De Groot PG, Derksen RH. Homocysteine, methylenetetrahydrofolate reductase polymorphism, antiphospholipid antibodies, and thromboembolic events in systemic lupus erythematosus: a retrospective cohort study. J Rheumatol 1998;25(9):1737–42. [24] Male C, Mitchell L, Julian J, Vegh P, Joshua P, Adams M, et al. Acquired activated protein C resistance is associated with lupus anticoagulants and thrombotic events in pediatric patients with systemic lupus erythematosus. Blood 2001;15:844–9. [25] Ames PR, Alves J, Pap AF, Ramos P, Khamashta MA, Hughes GR. Fibrinogen in systemic lupus erythematosus: more than an acute phase reactant? J Rheumatol 2000 May;27(5):1190–5. [26] Pereira J, Alfaro G, Goycoolea M, Quiroga T, Ocqueteau M, Massardo L, et al. Circulating platelet-derived microparticles in systemic lupus erythematosus. Association with increased thrombin generation and procoagulant state. Thromb Haemost 2006;95(1):94–9. [27] Ekdahl KN, Bengtsson AA, Andersson J, Elgue G, Rönnblom L, Sturfelt G, et al. Thrombotic disease in systemic lupus erythematosus is associated with a maintained systemic platelet activation. Br J Haematol 2004;125(1):74–8.
293
[28] Tam LS, Fan B, Li EK, Thomas GN, Yim SF, Haines CJ, et al. Patients with systemic lupus erythematosus show increased platelet activation and endothelial dysfunction induced by acute hyperhomocysteinemia. J Rheumatol 2003 Jul;30(7):1479–84. [29] Booth S, Chohan S, Curran J, Karrison T, Schmitz A, Utset T. Whole blood viscosity and arterial thrombotic events in patients with systemic lupus erythematosus. Arthritis Care Res 2007;57(5):845–50. [30] Banyai S, Banyai M, Koppensteiner R. Blood rheology in deep venous thrombosis: relation to persistent and transient risk factors. Thromb Res 2002;107: 101–7. [31] Rocha A, Paiva E, Lichtenstein A, Milani R, Cavalheiro-Filho C, Maffei F. Risk-assessment algorithm and recommendations for venous thromboembolism prophylaxis in medical patients. Vasc Health Risk Manag 2007;3(4):533–53. [32] Hill J, Treasure T. National Clinical Guideline Centre for Acute and Chronic Conditions. Reducing the risk of venous thromboembolism in patients admitted to hospital: summary of NICE guidance. BMJ 2010;27:340. [33] Ruiz-Irastorza G, Egurbide MV, Pijoan JI, Garmendia M, Villar I, Martinez-Berriotxoa A, et al. Effect of antimalarials on thrombosis and survival in patients with systemic lupus erythematosus. Lupus 2006;15(9):577–83. [34] Ruiz-Irastorza G, Ramos Casals M, Brito-Zeron P, Kamashta M. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann Rheum Dis 2010;69:20–8. [35] Jennette C, Falk R. Small vessel vasculitis. N Engl J Med 1997;337:1512–23. [36] Weidner S, Hafezi- Rachti S. Thromboembolic events as a complication of antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 2006;55:146–9. [37] Merkel P. Brief communication: high incidence o venous thrombotic events among patients with Wegener granulomatosis: the Wegener´s clinical occurrence of thrombosis (weCLOT) study. Ann Intern Med 2005;142:620–6. [38] Ames P, Steuer A. Thrombosis in Behçet disease: a retrospective survey from a single UK centre. Rheumatology 2001;40:652–5. [39] Kural-Seyahi E, Fresko I. The long term mortality and morbidity of Behçet syndrome. A 2 decade outcome survey of 387 patients followed at a dedicated center. Medicine 2003;82(6):60–76. [40] Calamia KT, Schirmer M, Melikoglu M. Major vessel involvement in Behçet disease. Curr Opin Rheumatol 2005;17(1):1–8. [41] La Regina M, Gasparyan A, Orlandini F, Prisco D. Behçet disease as a model of venous thrombosis. Open Cardiovasc Med J 2010;4:71–7. [42] Kiraz S, Ertenli I, Oztürk MA, Haznedaroğlu IC, Celik I, Calgüneri M. Pathological haemostasis and prothrombotic state in Behçet’s disease. Thromb Res 2002;105(2):125–33. [43] Hatemi G, Silman A, Bang D, Bodaghi B, Chamberlain C, Gul A, et al. EULAR recommendations for the management of Behcet disease. Ann Rheum Dis 2008;67:1656–62. [44] Mendoza-Pinto C, García-Carrasco M, Jiménez-Hernández M, Jiménez Hernández C, Riebeling-Navarro C, Nava Zavala A, et al. Etiopathogenesis of Behcet's disease. Autoimmun Rev 2010;9:241–5. [45] Cervera R. Lessons from the ‘Euro-phospholipid’ project. Autoimmun Rev 2008;7: 174–8. [46] Cervera R, Khamashta MA, Shoenfeld Y, Camps MT, Jacobsen S, Kiss E, et al. Euro-Phospholipid Project Group (European Forum on Antiphospholipid Antibodies). Morbidity and mortality in the antiphospholipid syndrome during a 5-year period: a multicenter prospective study of 1000 patients. Ann Rheum Dis 2009;68(9):1428–32. [47] Alessandri C, Conti F, Pendolino M, Mancini R, Valesini G. New autoantigens in the antiphospholipid syndrome. Autoimmun Rev 2011;10:609–16. [48] Erkan D, Harrison MJ, Levy R, Peterson M, Petri M, Sammaritano L, et al. Aspirin for Primary Thrombosis Prevention in the Antiphospholipid Syndrome. A randomized, double-blind, placebo-controlled trial in asymptomatic antiphospholipid antibody‐ positive individuals. Arthritis Rheum 2007;56(7):2382–91. [49] Roldan V, Lecumberri R, Muñoz-Torrero JF, Vicente V, Rocha E, Brenner B, et al. Thrombophilia testing in patients with venous thromboembolism. Findings from the RIETE registry. Thromb Res 2009;124(2):174–7. [50] 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;101:1827–32. [51] 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;33:2214–21. [52] Tarr T, Lakos G, Bhattoa H, Shoenfeld Y, Szegedi G, Kiss E. Analysis of risk factors for the development of thrombotic complications in antiphospholipid antibody positive lupus patients. Lupus 2007;16:39–45. [53] Ruffatti A, Del Ross T, Ciprian M, Nuzzo M, Rampudda M, Bertero M, et al. Risk factors for a first thrombotic event in antiphospholipid antibody carriers. A multicentre, retrospective follow-up study. Ann Rheum Dis 2009;68:397–9. [54] Harris EN, Chan JKH, Asherson RA, Aber VA, Gharavi AE, Hughes GRV. Thrombosis, recurrent fetal loss, thrombocytopenia: predictive value of IgG anticardiolipin antibodies. Arch Intern Med 1986;146:2153–6. [55] Martinez-Berriotxoa A, Ruiz-Irastorza G, Egurbide M, Garmendia M, Erdozain J, Villar I, et al. Transiently positive anticardiolipin antibodies and risk of thrombosis in patients with systemic lupus erythematosus. Lupus 2007;16:810–6. [56] Soltész P, Veres K, Lakos G, Kiss E, Muszbek L, Szegedi G. Evaluation of clinical and laboratory features of antiphospholipid syndrome: a retrospective study of 637 patients. Lupus 2003;12:302–7. [57] Wahl DG, Guillemin F, de ME, Perret-Guillaume C, Lecompte T, Thibaut G. Meta-analysis of the risk of venous thrombosis in individuals with antiphospholipid antibodies without underlying autoimmune disease or previous thrombosis. Lupus 1998;7:15–22.
294
R. Silvariño et al. / Autoimmunity Reviews 12 (2012) 289–294
[58] Horbach DA, Oort EV, Donders RCJM, Derksen RHWM, De Groot PG. Lupus anticoagulant in the strongest risk factor for both venous and arterial thrombosis in patients with systemic lupus erythematosus: comparison between different assays for the detection of antiphospholipid antibodies. Thromb Haemost 1996;76:916–24. [59] Pengo V, Ruffatti A, Legnani C, Testa S, Fierro T, Marongiu F, et al. Incidence of a first thromboembolic event in asymptomatic carriers of high-risk antiphospholipid antibody profile: a multicenter prospective study. Blood 2011;118(17):4714–8. [60] Girón-González JA, García del Río E, Rodríguez C, Rodríguez-Martorell J, Serrano A. Antiphospholipid syndrome and asymptomatic carriers of antiphospholipid antibody: prospective analysis of 404 individuals. J Rheumatol 2004;8:1560–7. [61] Brouwer JL, Bijl M, Veeger NJ, Kluin-Nelemans HC, van der MJ. The contribution of inherited and acquired thrombophilic defects, alone or combined with antiphospholipid antibodies, to venous and arterial thromboembolism in patients with systemic lupus erythematosus. Blood 2004;104:143–8. [62] Hudson M, Herr AL, Rauch J, Neville C, Chang E, Ibrahim R, et al. The presence of multiple prothrombotic risk factors is associated with a higher risk of thrombosis in individuals with anticardiolipin antibodies. J Rheumatol 2003;30: 2385–91. [63] Ruiz-Irastorza G, Cuadrado MJ, Ruiz-Arruza I, Brey R, Crowther M, Derksen R, et al. Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid antibody-positive patients: report of a task force at the 13th International Congress on antiphospholipid antibodies. Lupus 2011;20(2):206–18. [64] 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;44:1466–7.
[65] Erkan D, Yazici Y, Peterson MG, Sammaritano L, Lockshin MD. A crosssectional study of clinical thrombotic risk factors and preventive treatments in antiphospholipid syndrome. Rheumatology (Oxford) 2002;41:924–9. [66] Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey KL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295–306. [67] Asherson RA, Cervera R. Unusual manifestations of the antiphospholipid syndrome. Clin Rev Allergy Immunol 2003;25:61–78. [68] Cervera R, Piette JC, Font J, Khamashta MA, Shoenfeld Y, Camps MT, et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum 2002;46:1019–27. [69] Ruiz-Irastorza G, Hunt B, Khamashta M. A systematic review of secondary thromboprophylaxis in patients with antiphospholipid antibodies. Arthritis Rheum 2007;57(8):1487–95. [70] Cervera R. Estrategias terapéuticas en el sindrome antifosfolipídico. Reumatol Clin 2010;6(1):37–42. [71] Ruiz-Irastorza G, Crowther M, Branch W, Khamashta M. Antiphospholipid syndrome. Lancet 2010;376(9751):1498–509. [72] Espinosa G, Berman H, Cervera R. Management of refractory cases of catastrophic antiphospholipid syndrome. Autoimmun Rev 2011;10:664–8. [73] Scoble T, Wijetilleka S, Khamashta MA. Management of refractory anti-phospholipid syndrome. Autoimmun Rev 2011;10:669–73. [74] Tincani A, Taraborelli M, Cattaneo R. Antiphospholipid antibodies and malignancies. Autoimmun Rev 2010;9:200–2.
Cyclic nucleotide phosphodiesterase 4 (PDE4) inhibitors are effective in the treatment of nephropathy in lupus-prone mice Cyclic nucleotide phosphodiesterases (PDE) belong to an enzyme superfamily which modulates cyclic AMP/GMP intracellular metabolism, thus regulating inflammatory cell response. In particular, the PDE4 family hydrolyses cAMP in peripheral leucocytes and macrophages and essentially modulates TNFα production by these inflammatory cells. In order to investigate whether specific inhibition of PDE4 activity could be a potential therapeutic strategy for systemic lupus erythematosus (SLE), Keravis et al. (Plos ONE 2012;7:e28899) have recently evaluated the effects of in vivo treatment with different kidney PDE4 inhibitors on the disease progression in MRL/lpr lupus-prone female mice. PDE4 activity and protein expression, determined using a radioenzymatic assay and immunoblotting in kidney extracts, significantly increased during the course of the disease in lupus-prone mice compared with age-matched controls. The treatment of MRL/lpr mice with NCS 613, a selective PDE4C subtype inhibitor, was the most effective and potent in decreasing proteinuria and delaying disease progression, as demostrated by the significant increase of survival rate in NCS-treated mice compared to the untreated mice as well as the mice treated with other non-selective PDE inhibitors. Furthermore, NCS 613 treatment was effective either in vivo or ex vivo in significantly reducing LPS-induced TNFα secretion by peripheral blood leucocytes from NCS-treated lupus-prone mice and from three SLE patients. In conclusion, the anti-inflammatory potential of PDE4 inhibitors could be beneficial in the treament of SLE nephropathy. Anna Ghirardello
Contents lists available at SciVerse ScienceDirect
Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev
Review
Venous thromboembolic disease in systemic autoimmune diseases: An association to keep in mind Ricardo Silvariño a, b, c, Álvaro Danza b, c, d, Valentina Mérola b, c, Adriana Bérez b, Enrique Méndez b, Gerard Espinosa e, Ricard Cervera e,⁎ a
Center of Nephrology and Department of Emergency, Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay Systemic Autoimmune Diseases Group, Society of Internal Medicine, Uruguay Clinical Department of Medicine, Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay d Autoimmune Diseases Research Unit, Department of Internal Medicine, Hospital Universitario Cruces, Barakaldo, Spain e Department of Autoimmune Diseases, Hospital Clinic, Barcelona, Catalonia, Spain b c
a r t i c l e
i n f o
Article history: Received 18 April 2012 Accepted 1 May 2012 Available online 7 May 2012
a b s t r a c t Systemic autoimmune diseases are conditions of unknown etiology, characterized by the simultaneous or successive involvement of most organs and systems, as well as the presence of autoantibodies as biological markers. Venous thromboembolic disease has a higher incidence in this population when compared to healthy individuals. This responds to the increase in congenital and acquired risk factors in this group. One of the main risk factors is linked to the presence of antiphospholipid antibodies, whose prevalence is increased among patients with such conditions. © 2012 Elsevier B.V. All rights reserved.
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . VTD in patients with SAD and aPL negativity 2.1. Systemic lupus erythematosus (SLE) 2.2. Systemic vasculitis . . . . . . . . 2.2.1. ANCA-associated vasculitis 2.2.2. Behçet's disease (BD) . . . 3. VTD in patients with aPL . . . . . . . . . 3.1. APS . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . Appendix A . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . .
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1. Introduction Systemic autoimmune diseases (SAD) are conditions of unknown etiology, characterized by the simultaneous or successive involvement of most organs and systems, as well as the presence of autoantibodies as biological markers.
⁎ Corresponding author at: Department of Autoimmune Diseases, Hospital Clínic, Villarroel, 170, 08036-Barcelona, Catalonia, Spain. Tel.: + 34 93 227 5774; fax: + 34 93 227 1707. E-mail address: [email protected] (R. Cervera). 1568-9972/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2012.05.002
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These diseases have a growing social and economic importance, since up to 8.5% of the population might be affected by some type of autoimmune (organ specific or non-specific) disease according to data from the National Institutes of Health (NIH) of the United States of America [1]. Venous thromboembolic disease (VTD) has a higher incidence in this population when compared to healthy individuals. This responds to the increase in congenital and acquired risk factors in this group. One of the main risk factors is linked to the presence of antiphospholipid antibodies (aPL), whose prevalence is increased among those with SAD. The objective of this review is to update the available information about the association between SAD and VTD. The main risk factors
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present in these patients will be discussed and recommendations for therapeutic management will be made according to the available evidence. 2. VTD in patients with SAD and aPL negativity 2.1. Systemic lupus erythematosus (SLE) SLE is the prototype of SAD, because of its rich clinical and immunologic expression, characterized by the production of multiple autoantibodies. It affects mostly women (female:male ratio 9:1). Its prevalence is variable, ranging from 159/100,000 among the Caribbean women, through 34/ 100,000 inhabitants in the Spanish population to 18/100,000 inhabitants in Japan [2]. VTD is more frequent in patients with SLE than in control groups [3]. In the Euro-lupus cohort, between 5 and 10% of the studied population presented thrombosis in a 10‐year follow-up period [4]. Together with exacerbations of the disease and infections, thrombosis is one of the main causes or morbidity and mortality in SLE [4–6]. The former are found mainly in the first 5 years of the disease, whereas thrombosis usually appears after this period [4]. This happens due to the increased presence of risk factors that are traditionally linked to VTD (age, overweight, sedentary life-style, and insulin resistance) [7–10], as well as other congenital and acquired risk factors that are more frequent in this population. The low prevalence of the disease and the low number of individuals included in the studies make the information available limited. Information is originated mainly from observational clinical studies. As a general practice, it is recommended to control all traditional VTD risk factors in this population, mainly those that have a proven link to the development of thromboembolic episodes: overweight, sedentary lifestyle and smoking [11,12]. Among those congenital risk factors, patients with SLE and absence of aPL present an increased prevalence of the homozygous mutation of the Methylene-tetra-hydrofolate-reductase gene (MTHFR) [13], factor V Leyden [14,15] and homozygous mutation of prothrombin G20210 [15]. The presence of these abnormalities results in an increased risk for VTD, which is higher than in the group without SLE [16–18]. Nevertheless, systematic testing for these prothrombotic genetic mutations is not recommended in patients with SLE unless there is family history of these mutations, thrombosis without a clear precipitating cause or thrombosis in an unusual location [15]. In relation to those acquired risk factors for VTD, it is worth mentioning that plasma levels of homocysteine are higher in patients with SLE than in the general population [13,19,20] and this quality determines an increased thromboembolic risk [21–23]. However, while there are no intervention studies in high risk patients, neither systemic quantification of total homocysteine nor its pharmacologic modification is justified except in specific situations. In the same line, there is an increased frequency of acquired resistance to C-reactive protein [20], which increases the risk of VTD [20,24]. There has been evidence of higher plasma fibrinogen levels in this group compared to healthy population, which was linked to a higher incidence of thrombotic episodes [13,25]. There has been evidence of abnormal platelet function, such as the increase of circulating microparticles derived from platelets [26] and persistent platelet activation [27,28] as another mechanism that increases the thrombotic risk in this group. Moreover, it has been found that in patients with SLE there are hemorheological abnormalities like increase in blood viscosity [29] that are associated with an increased risk of developing venous thrombosis [30]. Despite this, systematic testing for neither hemorheological abnormalities nor platelet function is justified. The presence of active disease measured by the Systemic Lupus Activity Index (SLAM) has also been associated to an increased risk of thrombotic episodes [11]. Other factors such as age at diagnosis, high
corticosteroid doses and poverty have also been associated to an increased risk and early development of thrombotic episodes [12]. Summarizing, as a general rule, the adequate control of the disease activity and the lowest corticosteroid dose use, tend to decrease thromboembolic risk. In terms of the therapeutic management of increased risk of VTD, there are no controlled randomized studies about the benefits of primary thromboprophylaxis in patients with SLE and absence of aPL. It may be beneficial to do primary thromboprophylaxis in those patients with SLE who present associated thromboembolic risk factors [31,32]. Antimalarials are widely used in the treatment of SLE and other SAD. Hydroxychloroquine (HCQ), mepacrine (MPC) and chloroquine (CQ) are part of this group of agents. HCQ decreases the risk of VTD in patients with SLE. This characteristic, along with other proven benefits of its use, justify the use of Hydroxychloroquine in every patient with SLE, unless there are specific contraindications for this [33,34]. 2.2. Systemic vasculitis They represent a clinical pathological process characterized by inflammation of blood vessels, generally accompanied by necrosis of the vascular wall that causes occlusion and ischemia of affected tissues and organs. Their etiology is unknown, and multiple pathologic mechanisms are responsible for the endothelial cells’ injury. Until today, the classification proposed by the Chapel Hill consensus is still used, which groups them in terms of size of vessels mostly compromised (large, medium and small) [35]. Within this group, we will focus on the systemic vasculitis of smallsize vessels associated to antineutrophil cytoplasmic antibodies (ANCA) and Behçet's disease, since they have an increased prevalence of VTD. 2.2.1. ANCA-associated vasculitis Among the small-size vessel pauci-immune vasculitis, the most outstanding ones because of their link with thrombotic episodes are granulomatosis with polyangiitis (Wegener's granulomatosis (WG)), microscopic polyangiitis (MPA) and Churg–Strauss syndrome (CSS). All of them are associated to the presence of ANCA in 80 to 90% of the cases [35]. A higher prevalence of VTD has been evidenced in patients with cANCA-associated vasculitis and seropositivity for antiproteinase-3 (PR3) antibodies, determined by ELISA. Thromboembolic complications are mainly observed during active phase of the disease [36]. Specific changes in the venous system like venulitis, as well as the systemic inflammatory state with proinflammatory cytokine release may trigger the thrombotic process. The presence of apoptotic cells, consequence of PR3 activity among others, functions as procoagulant and proadhesive for platelets [36,37]. An increased prevalence has not been found, in comparison with the general population, in terms of the presence of prothrombotic congenital factors (factor V Leyden, prothrombin G20210, mutation of MTHFR gene) in patients with ANCA-associated vasculitis [37]. In relation to acquired risk factors, an increased prevalence of anticardiolipin antibodies (aCL) in low levels has been found in patients with ANCA-associated vasculitis. This finding, as well as the presence of anti-β2-glycoprotein I antibodies (aβ2GPI), was not correlated to increase in thrombotic episodes [37]. Such as what happens in SLE, activity of the disease constitutes a risk factor for VTD [36]. Based on the evidence, unless special circumstances are present, a systematic testing for thrombotic congenital and acquired risk factors is not recommended in patients with ANCA-associated vasculitis [36,37]. There are no controlled randomized studies about the benefit of primary thromboprophylaxis in patients with ANCA-associated vasculitis [36]. It may be beneficial to apply primary thromboprophylaxis in those patients with ANCA-associated PR3 positive vasculitis that
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present associated thromboembolic risk factors [36,37]. Adequate immunosuppressive therapy during the active phase of the disease decreases the risk of VTD [36,37]. 2.2.2. Behçet's disease (BD) BD is a systemic vasculitis whose minimum diagnostic criterion, oral and genital ulcers, is frequently followed by a spectrum of clinical manifestations that include uveitis, vein thrombosis, erythema nodosum, arthritis, gastrointestinal involvement, neurologic involvement and pulmonary involvement. Vascular involvement is frequent and contributes considerably to morbidity and mortality in this group. It appears as vein thrombosis, arterial thrombosis and aneurysms. This condition is associated with a characteristic prothrombotic state as a consequence of vein and arterial inflammatory involvement [38]. There is an increase in the risk of thromboembolism in patients with BD when compared to the general population. Venous thrombosis occurs earlier during the course of the disease than arterial involvement [39]. Venous involvement includes large-size vessels (inferior and superior vena cava, hepatic veins) as well as lower-caliber veins, determining deep venous thrombosis in the lower limbs or superficial venous thrombosis [39,40]. A discrete increase in procoagulant factors (Von Willebrand Factor, thrombomodulin and prostacyclin) has been found in patients with BD. The presence of these factors has been associated mainly to the development of ocular thrombotic involvement and not to other thromboembolic manifestations [39]. Mutation of Factor V Leyden has been found with higher prevalence among patients with BD of Turkish and Arabic origin, unlike among those of Italian and British origin, which depicts relevant differences in geo-epidemiology [38,39,42]. A higher frequency in the mutation of the G20210A gene was found in the subgroup of patients with BD and posterior uveitis or retinal vasculitis [40]. Primary pathogenesis of VTD in BD is the inflammation of the vascular wall, which is why the presence of active disease is a risk factor to develop this complication [36]. Except for special situations, systematic testing for congenital and acquired thromboembolic risk factors is not recommended in patients with BD [38–41]. There are no randomized controlled studies about the benefit of primary thromboprophylaxis in BD. Immunosuppressive treatment has been associated with a lower incidence of thromboembolic disease in this population [43]. The use of immunosuppressive drugs in patients with recurrent or progressive thrombosis has been linked to a decrease in the incidence of new thrombotic episodes [39,41]. Clinical trials have shown the benefit of intense anticoagulation with heparin or warfarin associated to antiaggregation in the group of patients that present thrombotic manifestations under immunosuppressive treatment and standard anticoagulation [43]. According to what was previously stated, it may be beneficial to implement primary thromboprophylaxis in those patients with BD that present associated thromboembolic risk factors [43]. The use of immunosuppressive drugs such as corticosteroids, azathioprine, cyclophosphamide or cyclosporine is recommended for treatment of VTD in patients with BD [43], mainly among those with recurrent or progressive thrombosis [39,41]. In those patients that present new thromboembolic episodes under standard anticoagulation and immunosuppressive therapy, it is recommended to implement intense anticoagulation with heparin or warfarin associated to antiaggregation [43,44]. 3. VTD in patients with aPL The aPL are autoantibodies directed against plasma proteins that bind to anionic phospholipids. Even though a wide variety of aPL has been detected, there is general consensus in that autoantibodies directed against β2GPI are the clinically relevant ones. In clinical
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practice, systematic testing is done to find the presence of anticardiolipin antibodies (aCL) in their IgM and IgG isotopes, aβ2GPI and lupus anticoagulant (LA). The presence of aPL is associated to a marked increase in the risk of arterial and venous thrombosis [45– 47] which has been estimated to be near 3.8% annually [48]. On the other hand, antiphospholipid syndrome (APS) is an acquired thrombophilia which can account for approximately 20% of the thromboembolic events in young adults [49]. Some risk factors increase the risk of VTD in patients with aPL: 1Profile and levels of aPL: The presence of LA determines an increase in risk of 5 to 16 times for developing thromboembolic episodes and obstetric morbidity. This risk is higher than the one determined by aCL and aβ2GPI [50–52]. Intermediate or high levels of IgG aCL represent a risk factor for the presence of the first thrombotic episode in asymptomatic aPL carriers [53]. Among asymptomatic aCL carriers, the risk of VTD is raised by the increase in their levels [54]. 2—Persistence of aPL over time: Patients with persistently positive testing for aPL over time present an increased thrombotic risk compared to those with transiently positive testing [55]. 3—Presence of aPL in the context of SLE: The presence of aPL in the context of SLE determines a higher risk than in patients without SLE [52,56]. The presence of LA increases the risk for developing VTD six times, representing the risk factor that is most linked to its development in this population [57,58]. The presence of aCL duplicates the risk of presenting VTD in patients with SLE [58]. 4—“Triple positivity” for aPL: “Triple positive” patients, named as such for presenting positivity for the three aPL, present a higher risk of developing thrombotic events. Recently, 104 patients with this condition were followed through a mean of 4.5 years. Accumulated incidence of a first thrombotic event in 10 years was estimated in 37.1% (CI 95% 19.9% – 54.3%). The appearance of thromboembolic events in this population was more frequent in men and patients that present other risk factors for developing VTD. Impressively, primary prophylaxis with Aspirin did not reduce the risk of thrombosis in this population [59]. 5—Surgery and prolonged immobilization: These are factors that were present in an important percentage of asymptomatic aPL carriers at the time of the first thrombotic episode [60]. 6—Presence of prothrombotic congenital factors: Association with congenital risk factors increases substantially the risk of VTD in patients with aPL [61,62]. It is necessary to keep in mind that the presence of aPL is not “all or none”. Its presence contributes to global thrombotic risk of a determined patient in a context and in the presence of other risk factors for VTD. Furthermore, aPL carriers have a higher risk of presenting thrombosis when hypertension, hypercholesterolemia, sedentary life-style, smoking, diabetes, or use of contraceptive drugs with estrogens are present [53]. Recently, the recommendations of the 13th International Congress on Antiphospholipid Antibodies have been published [63]. Data about the benefit of primary thromboprophylaxis are contradictory [48,64,65], and the only prospective study implemented has important methodological limitations [66]. Experts recommend that asymptomatic aPL carriers, particularly those with high thrombotic risk either because of the presence of a high risk antibody profile or because of coexistence of other vascular risk factors, receive low‐dose aspirin [63]. On the other hand, aPL carriers must receive primary thromboprophylaxis with low-molecular-weight heparin (LMWH) in high risk situations such as surgery, prolonged immobilization or puerperium. Simultaneously, HCQ has been proven to decrease thrombotic risk in patients with SLE and aPL [34]. Consequently, patients with SLE and LA or aCL at persistently high levels must receive primary thromboprophylaxis with HCQ and low‐dose aspirin.
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R. Silvariño et al. / Autoimmunity Reviews 12 (2012) 289–294 (continued) Appendix A (continued)
3.1. APS
Absence of antiphospholipid antibodies
According to Sydney's criteria [66], APS is defined by the association of a clinical manifestation (arterial thrombosis, venous thrombosis, obstetric morbidity) and the presence of intermediate-to-high levels of aPL (aCL, LA, aβ2GPI) persistently positive and in two or more observations separated at least 12 weeks. Associated APS refers to its appearance in the context of another systemic autoimmune disease (usually SLE) and primary APS refers to its appearance in their absence [67]. Deep venous thrombosis and pulmonary embolism are its most frequent thromboembolic manifestations. Even when appropriate treatment is applied, patients with APS present significant morbidity and mortality [46], caused mainly by deep venous thrombosis and stroke [68]. At the time of the first venous thrombotic episode, nearly 50% of the patients with APS present as an associated additional risk factor the presence of prior surgery or prolonged immobilization [60]. Prior history of VTD represents a strong risk factor for the development of a new thromboembolic episode [3,32]. Consequently, in patients with APS and a first venous thromboembolic episode, it is recommended to apply undefined therapy with warfarin with a target INR between 2 and 3 [69,70]. However, in those cases in which thrombosis occurs with a predisposing factor and there is a low-risk antibody profile, treatment for a period of 3 to 6 months has been proposed [63]. There is debate in terms of the treatment to apply in patients with recurrent venous thrombosis or arterial thrombosis. The main agreement consists of a prolonged treatment with warfarin with a target INR between 3 and 4 [63,71]. In cases of recurrent thrombosis in spite of appropriate anticoagulation (INR between 3 and 4), complementary treatments can be resorted to, such as anticoagulation for an undetermined period of time with LMWH or addition of low‐dose aspirin, HCQ or statins [71–74].
Clinical condition
ANCA-associated vasculitis
Behçet disease
Take-home messages • In SAD, except for special situations, systematic testing for congenital or acquired thromboembolic risk factors is not recommended. • In all situations, an integral assessment of all thromboembolic risk factors must be taken. • Primary thromboprophylaxis is not recommended in SAD with the absence of aPL except in special circumstances. • Hydroxychloroquine decreases thromboembolic risk in patients with SLE. • A good control of disease activity decreases the risk for thromboembolic events. • In all cases, seropositivity for aPL increases thromboembolic risk and requires a different therapeutic approach. Appendix A
Absence of antiphospholipid antibodies Clinical condition
Recommendation
Reference
Systemic lupus erythematosus
Control classic risk factors for VTD: overweight, sedentary life-style, smoking Systematic testing for prothrombotic genetic mutations is not recommended unless there is family history of mutations, thrombosis without a clear precipitating factor or thrombosis in unusual location Neither systemic quantification of total homocysteine nor its pharmacological modification is recommended except for specific situations. Neither systematic testing for hemorheological abnormalities nor platelet function testing are recommended
[11,12] [15]
[19]
Recommendation
Reference
Activity control is recommended in order to decrease thromboembolic risk. Primary thromboprophylaxis may be beneficial in patients with associated thromboembolic risk factors Administering hydroxychloroquine is recommended because of its antithrombotic effect, among others Systematic testing for congenital or acquired thromboembolic risk factors is not recommended Primary thromboprophylaxis may be beneficial in patients with ANCA-PR3+ associated vasculitis that present associated thromboembolic risk factors Activity control is recommended in order to decrease thromboembolic risk. Systematic testing for congenital or acquired thromboembolic risk factors is not recommended Primary thromboprophylaxis may be beneficial in patients that present associated thromboembolic risk factors Immunosuppressive drugs such as corticosteroids, azathioprine, cyclophosphamide, or cyclosporine are recommended for the treatment of VTD mainly in patients with recurrent or progressive thrombosis Intense anticoagulation with heparin or warfarin associated to platelet antiaggregation is recommended in patients with new thromboembolic events under standard anticoagulation and immunosuppressive therapy
[11] [31,32]
[33,34]
[36,37]
[36,37]
[36,37] [38–41]
[43]
[43,39,41]
[43]
Presence of antiphospholipid antibodies Clinical condition
Recommendation
Asymptomatic APL Control additional thrombotic risk factors are antibodies carriers’ recommended. Low-dose aspirin treatment is recommended in all patients with LA or with persistently positive ACL antibodies, especially if these are IgG and in medium-to-high levels when there are other vascular risk factors present Primary thromboprophylaxis with lowmolecular-weight heparin is recommended in risk situations such as surgery, prolonged immobilization or puerperium Antiphospholipid Prolonged therapy with warfarin is syndrome recommended to reach a target INR between 2 and 3 in patients with the first venous thromboembolic episode Prolonged therapy with warfarin is recommended to reach a target INR between 3 and 4 in patients with recurrent venous thromboembolic events or arterial thrombosis In cases of recurrent thrombosis despite adequate anticoagulation (INR between 3 and 4), alternative therapies such as undetermined-length anticoagulation with low-molecular-weight heparin, addition of low-dose aspirin, hydroxycholoroquine or statins may be resorted to Systemic lupus Primary thromboprophylaxis with low-dose erythematosus aspirin is recommended Primary thromboprophylaxis with hydroxychloroquine is recommended
Reference [53] [63]
[63]
[69,70]
[63,71]
[71]
[63] [34]
References [26–28] [1] Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol 1997;84(3):223–43.
R. Silvariño et al. / Autoimmunity Reviews 12 (2012) 289–294 [2] Cervera R, Pallarés L. Epidemiología y clasificación del lupus eritematoso sistémico. In: Cervera R, Jimenez-Alonso J, editors. Avances en Lupus Eritematoso Sistémico; 2008. p. 41. Ed Marge. Barcelona. Cap 2. [3] Cogo A, Bernardi E, Prandoni P, Girolami B, Noventa F, Simioni P, et al. Acquired risk factors for deep-vein thrombosis in symptomatic outpatients. Arch Intern Med 1994;154(2):164–8. [4] Cervera R, Khamashta MA, Font J, Sebastiani GD, Gil A, Lavilla P, et al. European Working Party on Systemic Lupus Erythematosus. 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 2003;82(5):299–308. [5] Abu-Shakra M, Urowitz MB, Gladman DD, Gough J. Mortality studies in systemic lupus erythematosus. Results from a single center. I. Causes of death. J Rheumatol 1995;22:1259–64. [6] Manger K, Manger B, Repp R, Geisselbrecht M, Geiger A, Pfahlberg A, et al. Definition of risk factors for death, end stage renal disease, and thromboembolic events in a monocentric cohort of 338 patients with systemic lupus erythematosus. Ann Rheum Dis 2002;61:1065–70. [7] Mok CC, Poon WL, Lai JP, Wong CK, Chiu SM, Wong CK, et al. Metabolic syndrome, endothelial injury, and subclinical atherosclerosis in patients with systemic lupus erythematosus. Scand J Rheumatol 2010;39(1):42–9. [8] Calvo-Alén J, Toloza S, Fernández M, Bastian H, Fessler B, Roseman J, et al, for the LUMINA Study Group. Systemic Lupus Erythematosus in a Multiethnic US Cohort (LUMINA) XXV. Smoking, older age, disease activity, lupus anticoagulant, and glucocorticoid dose as risk factors for the occurrence of venous thrombosis in lupus patients. Arthritis Rheum 2005;52(7):2060–8. [9] Telles R, Lanna C, Ferreira G, Ribeiro A. Metabolic syndrome in patients with systemic lupus erythematosus: association with traditional risk factors for coronary heart disease and lupus characteristics. Lupus 2010;19(7):803–9. [10] Bellomio V, Spindler A, Lucero E, Berman A, Sueldo R, Berman H, et al. Metabolic syndrome in Argentinean patients with systemic lupus erythematosus. Lupus 2009;18(11):1019–25. [11] Ho KT, Ahn CW, Alarcón GS, Baethge BA, Tan FK, Roseman J, et al. Systemic lupus erythematosus in a multiethnic cohort (LUMINA): XXVIII. Factors predictive of thrombotic events. Rheumatology (Oxford) 2005;44(10):1303–7. [12] Burgos PI, McGwin Jr G, Reveille JD, Vilá LM, Alarcón GS. Factors predictive of thrombotic events in LUMINA, a multi-ethnic cohort of SLE patients (LXXII). Rheumatology (Oxford) 2010;49(9):1720–5. [13] Afeltra A, Vadacca M, Conti L, Galluzo S, Mitherhoffer A, Ferri G, et al. Thrombosis in systemic lupus erythematosus: congenital and acquired risk factors. Arthritis Care Res 2005;53(3):452–9. [14] Topaloglu R, Akierli C, Bakkaloglu A, Aydintug O, Ozen S, Besbas N, et al. Survey of factor V leiden and prothrombin gene mutations in systemic lupus erythematosus. Clin Rheumatol 2001;20(4):259–61. [15] Brouwer J, Bijl M, Veeger N, Kluin-Nelemans H, Van der Meer J. The contribution of inherited and acquired Thrombophilic defects, alone or combined with antiphospholipid antibodies,to venous and arterial Thromboembolism in patients with systemic lupus erythematosus. Blood 2004;104:143–8. [16] Kaiser R, Barton J, Chang M, Catanese J, Li Y, Begovich A, et al. Factor V Leiden and thrombosis in patients with systemic lupus erythematosus (SLE): a meta-analysis. Genes Immun 2009;10(5):495–502. [17] Regéczy N, Lakos G, Balogh I, Ajzner E, Kiss E, Szegedi G. The Leiden mutation of coagulation factor V in Hungarian SLE patients. Clin Appl Thromb Hemost 2000;6(1): 41–5. [18] Galli M, Finazzi G, Duca F, Norbis F, Moia M. The G1691→A mutation of factor V, but not the G20210→A mutation of factor II or the C677→T mutation of methylenetetrahydrofolate reductase genes, is associated with venous thrombosis in patients with lupus anticoagulants. Br J Haematol 2000;108:865–70. [19] Martínez-Berriotxoa A, Ruiz-Irastorza G, Egurbide MV, Rueda M, Aguirre C. Homocisteína plasmática en pacientes con lupus eritematoso sistémico. Medicina clínica 2003;120(18):681–5. [20] Oh D, Kim SH, Kang MS, Kim NK, Chang NS, Na BW, et al. Acquired activated protein C resistance, high tissue factor expression, and hyper-homocysteinemia in systemic lupus erythematosus. Am J Hematol 2003;72(2):103–8. [21] Petri M, Roubenoff R, Dallal GE, Nadeau MR, Selhub J, Rosenberg IH. Plasma homocysteine as a risk factor for atherothrombotic events in systemic lupus erythematosus. Lancet 1996;348(9035):1120–4. [22] Refai TM, Al-Salem IH, Nkansa-Dwamena D, Al-Salem MH. Hyperhomocysteinaemia and risk of thrombosis in systemic lupus erythematosus patients. Clin Rheumatol 2002;21(6):457–61. [23] Fijnheer R, Roest M, Haas FJ, De Groot PG, Derksen RH. Homocysteine, methylenetetrahydrofolate reductase polymorphism, antiphospholipid antibodies, and thromboembolic events in systemic lupus erythematosus: a retrospective cohort study. J Rheumatol 1998;25(9):1737–42. [24] Male C, Mitchell L, Julian J, Vegh P, Joshua P, Adams M, et al. Acquired activated protein C resistance is associated with lupus anticoagulants and thrombotic events in pediatric patients with systemic lupus erythematosus. Blood 2001;15:844–9. [25] Ames PR, Alves J, Pap AF, Ramos P, Khamashta MA, Hughes GR. Fibrinogen in systemic lupus erythematosus: more than an acute phase reactant? J Rheumatol 2000 May;27(5):1190–5. [26] Pereira J, Alfaro G, Goycoolea M, Quiroga T, Ocqueteau M, Massardo L, et al. Circulating platelet-derived microparticles in systemic lupus erythematosus. Association with increased thrombin generation and procoagulant state. Thromb Haemost 2006;95(1):94–9. [27] Ekdahl KN, Bengtsson AA, Andersson J, Elgue G, Rönnblom L, Sturfelt G, et al. Thrombotic disease in systemic lupus erythematosus is associated with a maintained systemic platelet activation. Br J Haematol 2004;125(1):74–8.
293
[28] Tam LS, Fan B, Li EK, Thomas GN, Yim SF, Haines CJ, et al. Patients with systemic lupus erythematosus show increased platelet activation and endothelial dysfunction induced by acute hyperhomocysteinemia. J Rheumatol 2003 Jul;30(7):1479–84. [29] Booth S, Chohan S, Curran J, Karrison T, Schmitz A, Utset T. Whole blood viscosity and arterial thrombotic events in patients with systemic lupus erythematosus. Arthritis Care Res 2007;57(5):845–50. [30] Banyai S, Banyai M, Koppensteiner R. Blood rheology in deep venous thrombosis: relation to persistent and transient risk factors. Thromb Res 2002;107: 101–7. [31] Rocha A, Paiva E, Lichtenstein A, Milani R, Cavalheiro-Filho C, Maffei F. Risk-assessment algorithm and recommendations for venous thromboembolism prophylaxis in medical patients. Vasc Health Risk Manag 2007;3(4):533–53. [32] Hill J, Treasure T. National Clinical Guideline Centre for Acute and Chronic Conditions. Reducing the risk of venous thromboembolism in patients admitted to hospital: summary of NICE guidance. BMJ 2010;27:340. [33] Ruiz-Irastorza G, Egurbide MV, Pijoan JI, Garmendia M, Villar I, Martinez-Berriotxoa A, et al. Effect of antimalarials on thrombosis and survival in patients with systemic lupus erythematosus. Lupus 2006;15(9):577–83. [34] Ruiz-Irastorza G, Ramos Casals M, Brito-Zeron P, Kamashta M. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann Rheum Dis 2010;69:20–8. [35] Jennette C, Falk R. Small vessel vasculitis. N Engl J Med 1997;337:1512–23. [36] Weidner S, Hafezi- Rachti S. Thromboembolic events as a complication of antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 2006;55:146–9. [37] Merkel P. Brief communication: high incidence o venous thrombotic events among patients with Wegener granulomatosis: the Wegener´s clinical occurrence of thrombosis (weCLOT) study. Ann Intern Med 2005;142:620–6. [38] Ames P, Steuer A. Thrombosis in Behçet disease: a retrospective survey from a single UK centre. Rheumatology 2001;40:652–5. [39] Kural-Seyahi E, Fresko I. The long term mortality and morbidity of Behçet syndrome. A 2 decade outcome survey of 387 patients followed at a dedicated center. Medicine 2003;82(6):60–76. [40] Calamia KT, Schirmer M, Melikoglu M. Major vessel involvement in Behçet disease. Curr Opin Rheumatol 2005;17(1):1–8. [41] La Regina M, Gasparyan A, Orlandini F, Prisco D. Behçet disease as a model of venous thrombosis. Open Cardiovasc Med J 2010;4:71–7. [42] Kiraz S, Ertenli I, Oztürk MA, Haznedaroğlu IC, Celik I, Calgüneri M. Pathological haemostasis and prothrombotic state in Behçet’s disease. Thromb Res 2002;105(2):125–33. [43] Hatemi G, Silman A, Bang D, Bodaghi B, Chamberlain C, Gul A, et al. EULAR recommendations for the management of Behcet disease. Ann Rheum Dis 2008;67:1656–62. [44] Mendoza-Pinto C, García-Carrasco M, Jiménez-Hernández M, Jiménez Hernández C, Riebeling-Navarro C, Nava Zavala A, et al. Etiopathogenesis of Behcet's disease. Autoimmun Rev 2010;9:241–5. [45] Cervera R. Lessons from the ‘Euro-phospholipid’ project. Autoimmun Rev 2008;7: 174–8. [46] Cervera R, Khamashta MA, Shoenfeld Y, Camps MT, Jacobsen S, Kiss E, et al. Euro-Phospholipid Project Group (European Forum on Antiphospholipid Antibodies). Morbidity and mortality in the antiphospholipid syndrome during a 5-year period: a multicenter prospective study of 1000 patients. Ann Rheum Dis 2009;68(9):1428–32. [47] Alessandri C, Conti F, Pendolino M, Mancini R, Valesini G. New autoantigens in the antiphospholipid syndrome. Autoimmun Rev 2011;10:609–16. [48] Erkan D, Harrison MJ, Levy R, Peterson M, Petri M, Sammaritano L, et al. Aspirin for Primary Thrombosis Prevention in the Antiphospholipid Syndrome. A randomized, double-blind, placebo-controlled trial in asymptomatic antiphospholipid antibody‐ positive individuals. Arthritis Rheum 2007;56(7):2382–91. [49] Roldan V, Lecumberri R, Muñoz-Torrero JF, Vicente V, Rocha E, Brenner B, et al. Thrombophilia testing in patients with venous thromboembolism. Findings from the RIETE registry. Thromb Res 2009;124(2):174–7. [50] 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;101:1827–32. [51] 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;33:2214–21. [52] Tarr T, Lakos G, Bhattoa H, Shoenfeld Y, Szegedi G, Kiss E. Analysis of risk factors for the development of thrombotic complications in antiphospholipid antibody positive lupus patients. Lupus 2007;16:39–45. [53] Ruffatti A, Del Ross T, Ciprian M, Nuzzo M, Rampudda M, Bertero M, et al. Risk factors for a first thrombotic event in antiphospholipid antibody carriers. A multicentre, retrospective follow-up study. Ann Rheum Dis 2009;68:397–9. [54] Harris EN, Chan JKH, Asherson RA, Aber VA, Gharavi AE, Hughes GRV. Thrombosis, recurrent fetal loss, thrombocytopenia: predictive value of IgG anticardiolipin antibodies. Arch Intern Med 1986;146:2153–6. [55] Martinez-Berriotxoa A, Ruiz-Irastorza G, Egurbide M, Garmendia M, Erdozain J, Villar I, et al. Transiently positive anticardiolipin antibodies and risk of thrombosis in patients with systemic lupus erythematosus. Lupus 2007;16:810–6. [56] Soltész P, Veres K, Lakos G, Kiss E, Muszbek L, Szegedi G. Evaluation of clinical and laboratory features of antiphospholipid syndrome: a retrospective study of 637 patients. Lupus 2003;12:302–7. [57] Wahl DG, Guillemin F, de ME, Perret-Guillaume C, Lecompte T, Thibaut G. Meta-analysis of the risk of venous thrombosis in individuals with antiphospholipid antibodies without underlying autoimmune disease or previous thrombosis. Lupus 1998;7:15–22.
294
R. Silvariño et al. / Autoimmunity Reviews 12 (2012) 289–294
[58] Horbach DA, Oort EV, Donders RCJM, Derksen RHWM, De Groot PG. Lupus anticoagulant in the strongest risk factor for both venous and arterial thrombosis in patients with systemic lupus erythematosus: comparison between different assays for the detection of antiphospholipid antibodies. Thromb Haemost 1996;76:916–24. [59] Pengo V, Ruffatti A, Legnani C, Testa S, Fierro T, Marongiu F, et al. Incidence of a first thromboembolic event in asymptomatic carriers of high-risk antiphospholipid antibody profile: a multicenter prospective study. Blood 2011;118(17):4714–8. [60] Girón-González JA, García del Río E, Rodríguez C, Rodríguez-Martorell J, Serrano A. Antiphospholipid syndrome and asymptomatic carriers of antiphospholipid antibody: prospective analysis of 404 individuals. J Rheumatol 2004;8:1560–7. [61] Brouwer JL, Bijl M, Veeger NJ, Kluin-Nelemans HC, van der MJ. The contribution of inherited and acquired thrombophilic defects, alone or combined with antiphospholipid antibodies, to venous and arterial thromboembolism in patients with systemic lupus erythematosus. Blood 2004;104:143–8. [62] Hudson M, Herr AL, Rauch J, Neville C, Chang E, Ibrahim R, et al. The presence of multiple prothrombotic risk factors is associated with a higher risk of thrombosis in individuals with anticardiolipin antibodies. J Rheumatol 2003;30: 2385–91. [63] Ruiz-Irastorza G, Cuadrado MJ, Ruiz-Arruza I, Brey R, Crowther M, Derksen R, et al. Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid antibody-positive patients: report of a task force at the 13th International Congress on antiphospholipid antibodies. Lupus 2011;20(2):206–18. [64] 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;44:1466–7.
[65] Erkan D, Yazici Y, Peterson MG, Sammaritano L, Lockshin MD. A crosssectional study of clinical thrombotic risk factors and preventive treatments in antiphospholipid syndrome. Rheumatology (Oxford) 2002;41:924–9. [66] Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey KL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295–306. [67] Asherson RA, Cervera R. Unusual manifestations of the antiphospholipid syndrome. Clin Rev Allergy Immunol 2003;25:61–78. [68] Cervera R, Piette JC, Font J, Khamashta MA, Shoenfeld Y, Camps MT, et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum 2002;46:1019–27. [69] Ruiz-Irastorza G, Hunt B, Khamashta M. A systematic review of secondary thromboprophylaxis in patients with antiphospholipid antibodies. Arthritis Rheum 2007;57(8):1487–95. [70] Cervera R. Estrategias terapéuticas en el sindrome antifosfolipídico. Reumatol Clin 2010;6(1):37–42. [71] Ruiz-Irastorza G, Crowther M, Branch W, Khamashta M. Antiphospholipid syndrome. Lancet 2010;376(9751):1498–509. [72] Espinosa G, Berman H, Cervera R. Management of refractory cases of catastrophic antiphospholipid syndrome. Autoimmun Rev 2011;10:664–8. [73] Scoble T, Wijetilleka S, Khamashta MA. Management of refractory anti-phospholipid syndrome. Autoimmun Rev 2011;10:669–73. [74] Tincani A, Taraborelli M, Cattaneo R. Antiphospholipid antibodies and malignancies. Autoimmun Rev 2010;9:200–2.
Cyclic nucleotide phosphodiesterase 4 (PDE4) inhibitors are effective in the treatment of nephropathy in lupus-prone mice Cyclic nucleotide phosphodiesterases (PDE) belong to an enzyme superfamily which modulates cyclic AMP/GMP intracellular metabolism, thus regulating inflammatory cell response. In particular, the PDE4 family hydrolyses cAMP in peripheral leucocytes and macrophages and essentially modulates TNFα production by these inflammatory cells. In order to investigate whether specific inhibition of PDE4 activity could be a potential therapeutic strategy for systemic lupus erythematosus (SLE), Keravis et al. (Plos ONE 2012;7:e28899) have recently evaluated the effects of in vivo treatment with different kidney PDE4 inhibitors on the disease progression in MRL/lpr lupus-prone female mice. PDE4 activity and protein expression, determined using a radioenzymatic assay and immunoblotting in kidney extracts, significantly increased during the course of the disease in lupus-prone mice compared with age-matched controls. The treatment of MRL/lpr mice with NCS 613, a selective PDE4C subtype inhibitor, was the most effective and potent in decreasing proteinuria and delaying disease progression, as demostrated by the significant increase of survival rate in NCS-treated mice compared to the untreated mice as well as the mice treated with other non-selective PDE inhibitors. Furthermore, NCS 613 treatment was effective either in vivo or ex vivo in significantly reducing LPS-induced TNFα secretion by peripheral blood leucocytes from NCS-treated lupus-prone mice and from three SLE patients. In conclusion, the anti-inflammatory potential of PDE4 inhibitors could be beneficial in the treament of SLE nephropathy. Anna Ghirardello