Available online at www.sciencedirect.com

(2008) 174–178www.elsevier.com/locate/autrev

Autoimmunity Reviews 7

Lessons from the “Euro-Phospholipid” project

Ricard Cervera ⁎

Department of Autoimmune Diseases, Institut Clínic of Medicine and Dermatology, Hospital Clínic, Barcelona, Catalonia, Spain

Available online 3 December 2007

Abstract

The “Euro-Phospholipid” project started in 1999 with a multicentre, consecutive and prospective design. A total cohort of1000 patients with antiphospholipid syndrome (APS), derived from 13 countries (Belgium, Bulgaria, Denmark, France,Germany, Greece, Hungary, Israel, Italy, the Netherlands, Portugal, Spain and United Kingdom), has been followed since thenby a European consortium that was created as part of the network promoted by the “European Forum on AntiphospholipidAntibodies”, a study group devoted to the development of multicentre projects with large populations of APS patients. Thisproject allowed the identification of the prevalence and characteristics of the main clinical and immunological manifestations atthe onset and during the evolution of APS and demonstrated that it is possible to recognize more homogeneous subsets ofclinical significance.© 2007 Elsevier B.V. All rights reserved.

Keywords: Antiphospholipid syndrome; Antiphospholipid antibodies; Anticardiolipin antibodies; Lupus anticoagulant

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1742. General characteristics of the “Euro-Phospholipid” cohort . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1753. Clinical manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1764. Patterns of disease expression. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1765. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178

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⁎ Servei de Malalties Autoimmunes, Hospital Clínic, Villarroel 170,08036-Barcelona, Catalonia, Spain.

E-mail address: rcervera@clinic.ub.es.

1568-9972/$ - see front matter © 2007 Elsevier B.V. All rights reserved.doi:10.1016/j.autrev.2007.11.011

1. Introduction

The antiphospholipid syndrome (APS) is a systemicautoimmune disorder characterized by a combination ofarterial and/or venous thrombosis, recurrent fetal losses,often accompanied by a mild-to-moderate thrombocyto-penia, and elevated titers of antiphospholipid antibodies

Table 1Main cumulative clinical features during the evolution of the disease in1000 patients with APS

Manifestations No. (%)

Peripheral thrombosisDeep vein thrombosis 389 (38.9)Superficial thrombophebilitis in legs 117 (11.7)Arterial thrombosis in legs 43 (4.3)Venous thrombosis in arms 34 (3.4)Arterial thrombosis in arms 27 (2.7)

Neurologic manifestationsMigraine 202 (20.2)Stroke 198 (19.8)Transient ischemic attack 111 (11.1)Epilepsy 70 (7)Multiinfarct dementia 25 (2.5)Chorea 13 (1.3)

Pulmonary manifestationsPulmonary embolism 141 (14.1)Pulmonary hypertension 22 (2.2)Pulmonary microthrombosis 15 (1.5)

Cardiac manifestationsValve thickening/dysfunction 116 (11.6)Myocardial infarction 55 (5.5)Angina 27 (2.7)Myocardiopathy 29 (2.9)Vegetations 27 (2.7)

Intraabdominal manifestationsRenal manifestations 27 (2.7)Gastrointestinal 15 (1.5)Splenic infarction 11 (1.1)Pancreatic infarction 5 (.5)Addison's syndrome 4 (.4)Hepatic manifestations 7 (.7)

Cutaneous manifestationsLivedo reticularis 241 (24.1)Ulcers 55 (5.5)Pseudovasculitic lesions 39 (3.9)Digital gangrene 33 (3.3)

Ophthalmologic manifestationsAmaurosis fugax 54 (5.4)Retinal artery thrombosis 15 (1.5)Retinal vein thrombosis 9 (.9)Optic neuropathy 10 (1)

Hematological manifestationsThrombocytopenia

(b100,000/μl)296 (29.6)

Hemolytic anemia 97 (9.7)

Obstetric manifestations (pregnant female=590)Pre-eclampsia 56 (9.5)Eclampsia 26 (4.4)

Table 1 (continued)

Manifestations No. (%)

Fetal manifestations (pregnancies=1580)Early fetal losses (b10 weeks) 560 (35.4)Late fetal losses (N10 weeks) 267 (16.9)

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(aPL), namely the lupus anticoagulant (LA) and/or theanticardiolipin antibodies (aCL) [1]. First recognized inpatients with systemic lupus erythematosus (SLE) andlater less frequently in other autoimmune disorders, it isnow well known that the development of this syndromemay also be independent of any underlying disease, beingtermed “primary” APS [2]. More recently, a subset hasbeen described in which multiple vascular occlusiveevents, usually affecting small vessels supplying organsand presenting over a short period of time, are the out-standing features. This subset has been termed “cata-strophic” APS [3].

Although a great variety of clinical features havebeen described in patients with the APS, the real pre-valence of most of these manifestations was not wellknown. Another question that arose was whether theassociation with SLE, the gender, or the age at onset ofthe disease could modify the disease expression anddefine some specific APS subsets. In order to answerthese questions, the “Euro-Phospholipid” project startedin 1999 with a multicentre, consecutive and prospectivedesign. In order to gather a sizeable series of patients,twenty tertiary referral university centres, with sub-stantial experience in the management of APS patients,from thirteen countries, agreed to take part in the study.This European consortium was created as part of thenetwork promoted by the “European Forum on aPL”, astudy group devoted to the development of multicentreprojects with large populations of APS patients.

The final cohort included 1000 unselected patientswhomet the proposed preliminary criteria for the classificationof definite APS [4]. The aims of this studywere to analyzethe prevalence and characteristics of the main clinical andimmunological manifestations at the onset and during theevolution of the disease, as well as to clearly define pat-terns of disease expression in this condition.

2. General characteristics of the“Euro-Phospholipid” cohort

The general characteristics of this cohort at the be-ginning of the study were published in 2002 [5]. Theentire cohort consisted of 820 (82%) female and 180(18%) male patients (female/male ratio, 5/1). Mean ageat the onset of symptoms attributable to the disease was

176 R. Cervera / Autoimmunity Reviews 7 (2008) 174–178

34±13 years (range, 0–81 years; median, 31) and at thestudy was 42±14 years (range, 0–82 years; median, 40).Fifty-three percent had primary APS, 36% had APSassociated to SLE, 5% associated to lupus-like syn-drome and 5% associated to other diseases. Acatastrophic APS occurred in 8 (0.8%) patients and in6 of them, this was the presenting event of the APS.

3. Clinical manifestations

In the “Euro-Phospholipid” project we analyzed theprevalence and characteristics of the most relevantclinical and immunological features in the largest cohortof APS patients that has been reported so far. Deepvenous thrombosis (38.9%), stroke (19.8%), pulmonaryembolism (14.1%), superficial thrombophlebitis(11.7%), transient ischemic attacks (11.1%), andobstetric morbidity (including both fetal and maternalcomplications) were very common manifestations.However, several other manifestations that are consid-ered “minor” in the revised classification criteria [6]were also frequently found, and these included throm-bocytopenia (29.6%), livedo reticularis (24.1%), heartvalve lesions (14.3%), hemolytic anemia (9.7%),epilepsy (7%), leg ulcers (5.5%), myocardial infarction(5.5%), and amaurosis fugax (5.4%), among others(Table 1).

Interestingly, one of the most common clinicalmanifestations of the APS and, at the same time, aspecial characteristic among thrombophilic disorders isfetal morbidity, including abortions, fetal deaths,intrauterine growth restriction and prematurity. Addi-tionally, maternal morbidity (pre-eclampsia, eclampsia,and abruptio placentae) is also relatively common inpregnant patients with APS. The most common fetalcomplications in the “Euro-Phospholipid” project –where 75% of the females experienced 1 or morepregnancies – were early fetal losses (35.4% of thepregnancies), late fetal losses (16.9% of the pregnan-cies), and premature birth (10.6% of live births), whilethe most common obstetric maternal complications werepre-eclampsia (9.5% of pregnant females), eclampsia(4.4%), and abruptio placentae (2%). However, itshould be stressed that 74% of female patients whobecame pregnant in the present cohort succeeded inhaving one or more live births. This is one of the mostimportant advances made in the last decade after theclose follow-up and medical awareness of these patientstogether with the widespread use of antiaggregant andanticoagulant drugs (mainly, low dose aspirin and lowmolecular weight heparin) and the careful monitoring ofthese pregnancies [7–10].

4. Patterns of disease expression

This project allowed to study the patterns of diseaseexpression in specific APS groups. Although the APSwas first recognized in patients with SLE or a lupus-likesyndrome, the “primary”APS is the first different subsetthat was described [2] and the “Euro-Phospholipid”project allowed to know that this subset is even morefrequent (53%) than the APS associated to SLE orlupus-like syndrome (42%). The question of whether thefeatures of APS are in any way influenced by thepresence or absence of SLE is important for diagnosticand therapeutic reasons. In the “Euro-Phospholipid”cohort, we observed that both groups had similarprofiles, with the following exceptions: Patients withAPS associated with SLE had more episodes of arthritis,and livedo reticularis, and more frequently exhibitedthrombocytopenia and leucopenia. It is therefore reason-able to hypothesize that other factors than the aPL (i.e.antiplatelet or lymphocytotoxic antibodies) could play arole in SLE patients in the pathogenesis of thesemanifestations.

The majority of systemic autoimmune diseases aremuch more frequent in females, with a 9–10/1 female/male ratio in SLE, and appear in the fertile period ofwomen, mainly between 15 and 50 years of age, thusreflecting a hormonal influence in their pathogenesis. Inthe “Euro-Phospholipid” project, we confirmed a femalepredominance (female/male ratio, 5/1), but this wasgreater in patients with SLE (7/1) than in the primaryAPS (3.5/1). In addition, we observed that female andmale groups had similar profiles, with the followingexceptions: Female patients had more frequentlyepisodes of arthritis and livedo reticularis – both con-nected with the higher prevalence of SLE-related APS inwomen –, and migraine, while male patients had morefrequently myocardial infarction, epilepsy and arterialthrombosis in inferior extremities. Additionally, somedifferences could be detected among patients withchildhood and older onset of the disease (i.e., childhoodonset patients presented more episodes of chorea andjugular vein thrombosis, while older onset patients weremore frequently male and had more strokes and anginapectoris, but less frequently livedo reticularis).

5. Conclusions

The “Euro-Phospholipid” project identified theprevalence and characteristics of the main clinical andimmunological manifestations at the onset and duringthe evolution of APS and demonstrated that it is possibleto recognize more homogeneous subsets of clinical

177R. Cervera / Autoimmunity Reviews 7 (2008) 174–178

significance. Our intention is to follow-up this cohort of1000 patients during the ensuing 10 years in order toclearly assess the morbidity characteristics and themortality rate of the different groups of patients thathave been identified.

Take-home messages

• The “Euro-Phospholipid” project identified the pre-valence and characteristics of the main clinical andimmunological manifestations at the onset and duringthe evolution of APS.

• This project also allowed to study the patterns ofdisease expression in specific APS groups.

• Patients with APS associated with SLE had moreepisodes of arthritis, and livedo reticularis, andmore frequently exhibited thrombocytopenia andleucopenia.

• Female patients had more frequently episodes ofarthritis and livedo reticularis – both connected withthe higher prevalence of SLE-related APS in women–, and migraine, while male patients had morefrequently myocardial infarction, epilepsy and arter-ial thrombosis in inferior extremities.

• Childhood onset patients presented more episodes ofchorea and jugular vein thrombosis, while older onsetpatients were more frequently male and had morestrokes and angina pectoris, but less frequently livedoreticularis.

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Increased prevalence of antimitochondrial antibodies incirrhosis

Primary biliary cirrhosis (PBC) is a chronic cholestatic liveexpectancy. PBC patients are often asymptomatic, present=90%) for anti-mitochondrial antibodies (AMAs) in sercholestasis may indicate increased risk of future PBC dpathogenesis remains enigmatic. Given the familial aggregat785-92) hypothesized that AMAs also aggregate amongprevalence of AMAs in first-degree relatives (FDRs) to eUsing a PBC family registry, AMAs was prospectively screPBC probands, and 196 controls who were age-matched,probands. The prevalence of AMA in FDRs and controls wAMAwas found in female FDRs of PBC probands (20.7%FDRs brothers (7.8%), fathers (3.7%), and sons (0%). AMAhave clinical implications for FDRs of PBC probands becauThus, the identification and follow-up of these relatives m

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Further reading

This paper is part of the Mosaic of Autoimmmunity Meeting and foradditional reading on both this subject, and also the basis of autoimmunedisease, we refer to the following papers [11–40].

first-degree relatives of patients with primary biliary

r disorder that can progress to cirrhosis, shortening lifewith biochemical cholestasis, and test positive (> orum. Although AMA positivity without biochemicalevelopment, the contribution of these antibodies toion of PBC, Lazaridis KN. et al (Hepatology 2007; 46:relatives of PBC probands, thus, investigating thexamine whether AMAs aggregate in such pedigrees.ened in the serum of 306 FDRs in 145 pedigrees, 350sex-matched, race-matched, and residence-matched toas 13.1% and 1%, respectively. Greater prevalence of), mothers (15.1%), and daughters (9.8%) than in males aggregate among FDRs of PBC probands. This datase AMA positivity may suggest susceptibility to PBC.ay lead to earlier disease diagnosisand treatment.