e

MISCELLANEOUS

Relapsing Catastrophic AntiphospholipidSyndrome Potential Role of

Microangiopathic Hemolytic Anemia in Disease Relapses1

Gerard Espinosa, MD, PhD, Ignasi Rodríguez-Pintó, MD,José A. Gomez-Puerta, MD, Guillermo Pons-Estel, MD, PhD, and

Ricard Cervera, MD, PhD, FRCP for the Catastrophic AntiphospholipidSyndrome (CAPS) Registry Project Group (European Forum on

Antiphospholipid Antibodies)2

Objective: To analyze the clinical and laboratory characteristics of patients with catastrophicantiphospholipid syndrome (APS) who suffer relapses.Methods: We analyzed the Web site--based international registry of patients with catastrophic APS(“CAPS Registry”) http://infmed.fcrb.es/es/web/caps and selected those cases that relapsed.Results: Relapses were reported in 9 of 282 (3.2%) patients with catastrophic APS. A total of 35episodes of catastrophic APS were found: 6 patients presented 2 relapses, 2 patients suffered 3 relapses,and 1 patient developed 17 relapses. However, the last patient was not included in the statistical analysisbecause his clinical and immunologic characteristics were not fully described. Therefore, a total of 18episodes were analyzed. In 9 (50%) episodes, a precipitating factor was identified. The most frequentprecipitating factor, found in 5 (28%) episodes, was infection. Brain, kidney, heart, and lung were themost common organs involved. Laboratory features of microangiopathic hemolytic anemia (MHA)were present in 13 of 18 (72%) episodes (definitive in 9, corresponding to 4 patients, and probable in4, corresponding to 2 patients). Three relapses did not present with features of MHA and in theremaining 2 these data were not reported. The mortality rate was 38%.Conclusions: Although relapses are rare in patients with catastrophic APS, these results support thehypothesis that an association between MHA and relapsing of catastrophic APS could be present.© 2013 Elsevier Inc. All rights reserved. Semin Arthritis Rheum 42:417-423Keywords: catastrophic antiphospholipid syndrome, microangiopathic hemolytic anemia, antiphospho-

lipid antibodies, relapsing catastrophic antiphospholipid syndrome

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The antiphospholipid syndrome (APS) is an auto-immune condition characterized by vascularthromboses or pregnancy morbidity in the pres-

nce of antiphospholipid antibodies (aPL) (1). A minority

Department of Autoimmune Diseases, Hospital Clinic, Barcelona, Catalonia, Spain.1This article is devoted to the memory of Ronald A. Asherson, who died while

preparing this manuscript.2See complete list of members of the CAPS Registry Project Group (European

Forum on Antiphospholipid Antibodies) in the appendix.This study was supported by Grant PI030280 from the Ministerio de Sanidad y

Consumo of Spain.The authors have no conflicts of interest to disclose.Address reprint requests to Gerard Espinosa, MD, PhD, Department of Autoim-

cmune Diseases, Hospital Clinic, Villarroel 170, 08402, Barcelona, Catalonia, Spain.E-mail: gespino@clinic.ub.es.

0049-0172/13/$-see front matter © 2013 Elsevier Inc. All rights reserved.http://dx.doi.org/10.1016/j.semarthrit.2012.05.005

f APS patients develops life-threatening multiple organhromboses, which have been recognized as catastrophicPS (2). This is a condition characterized by multipleascular occlusive events, usually affecting small vessels,resenting over a short period of time, and poor prognosisespite multimodal treatment (3). Due to the diversity ofhe clinical and serologic presentations, an internationalonsensus on classification criteria for catastrophic APSas been developed (2) and diagnostic algorithms haveeen updated (4).Catastrophic APS recurrence is unusual and patients

enerally have a stable course with continued anticoagu-ation. In the only cross-sectional survey of the published

ase reports, it was demonstrated that 36% of patients

417

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1a(ml

Pa

Ts(misr(ti

sbisdi

418 Relapsing catastrophic antiphospholipid syndrome

who survive an initial catastrophic APS event developfurther APS-related events but no catastrophic APS (5).

The pathogenic mechanisms of catastrophic APS arenot completely understood, but they include features ofboth thrombotic microangiopathy and systemic inflam-matory response syndrome. Interestingly, thrombotic mi-croangiopathy is also a hallmark of thrombotic thrombo-cytopenic purpura (TTP) (6). Our group has shown thatcatastrophic APS is one of the most frequent clinical pre-sentations in patients with microangiopathic hemolyticanemia (MHA) associated with aPL (7). In addition, Cer-veny et al. (8) described a patient with relapsing cata-strophic APS with MHA features and proposed that TTPand catastrophic APS share pathophysiologic mecha-nisms.

In the present study, we describe the clinical and labo-ratory features of 9 patients with catastrophic APS whorelapse, and analyze the relationship between MHA andrelapsing catastrophic APS.

MATERIALS AND METHODS

We analyzed the case reports included in the Web site�based international registry of patients with catastrophicAPS (“CAPS Registry”) until December 2011. This reg-istry was created by the European Forum on Antiphos-pholipid Antibodies, a study group devoted to the devel-opment of multicenter projects with large populations ofAPS patients. It contains clinical, laboratory, and thera-peutic data on all reported cases of catastrophic APS andcan be consulted through the Internet http://infmed.fcrb.es/es/web/caps. The sources of information are thepersonal communications of the physicians who treatedthese patients and the periodically computer-assistedsearch (MEDLINE) of published reports to locate allcases of patients with catastrophic APS (keywords: cata-strophic, antiphospholipid, catastrophic antiphospho-lipid syndrome). Patients included in the “CAPS Regis-try” fulfilled the classification criteria for catastrophic APSthat include the evidence of involvement of 3 or moreorgans, systems, or tissues, the development of manifesta-tions simultaneously or in less than a week, the confirma-tion by histopathology of small-vessel occlusion in at least1 organ or tissue, and finally, the laboratory confirmationof the presence of aPL (2).

We selected those patients who suffered relapses andanalyzed their clinical manifestations and laboratory fea-tures. Similarly to the proposed definition of the TTPrelapse (9), we considered relapse of catastrophic APSwhen the manifestations appeared more than 30 days af-ter an apparent clinical and hematological remission. Weconsidered the presence of definitive MHA when the fol-lowing criteria were present: hemolytic anemia, erythro-cyte fragmentation (schistocytes) on peripheral-bloodsmears, and negative Coombs test associated with throm-bocytopenia. We summarized data from these patients

using a standardized form, including gender, age, and r

diagnosis of the underlying disorder, precipitating factors,main clinical manifestations, immunologic features,treatment, and outcome.

We compared the main clinical and laboratory featuresof the present series with the remaining patients includedin “CAPS Registry” who did not relapse. The statisticalanalysis was performed with SPSS/Windows statisticalsoftware (version 18.0). Mean values are reported withSD. Mean values of continuous variables were comparedusing the Student’s t test or nonparametric Mann–Whit-

ey U test. The �2 test and Fisher’s exact test were per-ormed to evaluate differences between categorical data inatients. All statistical tests were 2-tailed and only associ-tions with P � 0.05 were considered statistically signif-cant.

ESULTS

eneral Characteristics

f the 282 patients included in the “CAPS Registry”ntil December 2011, relapses were reported in 9 (3.2%).or statistical analysis, each episode of catastrophic APSas considered separately: 6 patients presented 2 relapses,patients suffered 3 relapses, and 1 patient developed 17

elapses. A total of 35 episodes of catastrophic APS wereound, but 17 of them, corresponding to the last patient10), were not included because their clinical and immu-ologic characteristics were not fully described. There-ore, we analyzed 18 episodes from 8 patients (Table 1).

Mean age of the patients was 45.1 � 17.2 years, 47.5 �7.1 years, and 49.5 � 10.6 years at time of first, second,nd third episode of catastrophic APS, respectively. Five63%) patients were female, 7 (88%) suffered from pri-ary APS, and 1 (12%) was associated with systemic

upus erythematosus.

recipitating Factorsnd Clinical Manifestations

he demographic and clinical characteristics of the epi-odes of catastrophic APS are summarized in Table 1. In 950%) episodes, precipitating factors were identified. Theost frequent precipitating factor, found in 5 (28%) ep-

sodes, was infection (respiratory tract infection in 4 epi-odes and periodontal infection in 1 episode). Problemselated to anticoagulation treatment were identified in 422%) episodes (anticoagulation withdrawal in 3 and sub-herapeutic international normalized ratio in the remain-ng).

Cerebral involvement was present in 14 (78%) epi-odes and mainly consisted of encephalopathy and cere-rovascular accidents, but occasionally seizures. Kidneynvolvement was also frequent, present in 14 (78%) epi-odes and consisted of renal failure and proteinuria. Car-iac involvement was present in 8 (44%) episodes and

ncluded cardiac failure, myocardial infarction, nonbacte-

ial endocarditis, and silent valve lesions. The liver was

G. Espinosa et al. 419

affected in 8 (44%) episodes. Pulmonary involvement waspresent in 7 (39%) episodes, mainly as acute respiratory dis-tress syndrome and pulmonary embolism. Skin manifesta-tions were described in 4 (22%) episodes, consisting ofLivedo reticularis, leg ulcers, gangrene, and microthrombosisof small vessels. The adrenal glands were affected in 4 (22%)episodes, the small bowel in 3 (17%), and the spleen in 2(11%). Other organs occasionally involved were the pan-creas, the gallbladder, and the peripheral nerves.

When we compared the demographic and clinicalmanifestations of patients with catastrophic APS from the“CAPS Registry” who relapsed with those who did not

Table 1 Demographic Characteristics and Organ InvolvemRelapse

Case (Ref.)CAPS

RegistryaEpisodes of

CAPS Dx Gende

1 (20) 5 1st PAPS M

2nd

2 (21) 21 1st PAPS F

2nd

3 (22) 70 1st SLE F2nd

3rd

4 (8) 83 1st PAPS F

2nd

5 (7) 221 1st PAPS M

2nd

6 (PC) 225 1st PAPS F

2nd7 (24) 281 1st PAPS F

2nd

3rd

8 (24) 282 1st PAPS M

2nd

Abbreviations: AA, antiaggregants; AC, anticoagulation; CAPS, cadeep venous thrombosis; Dx, diagnosis; F, female; GG, intravenousreported; PAPS, primary antiphospholipid syndrome; PAT, peripherS, steroids; SLE, systemic lupus erythematosus.aReferred to as the number in the “CAPS Registry.”

relapse, no significant statistical differences were found.

Laboratory Features

The laboratory features are summarized in Table 2. A low plate-let count (�100,000/mm3) was found in 15 of 16 (94%) epi-sodes of catastrophic APS. The IgG isotype of anticardiolipinantibodies (aCL) and lupus anticoagulant were reported as pos-itive in all episodes in which these tests were determined and theIgM aCL in 8 of 9 (89%) episodes. Interestingly, all patientsexceptonehadhightiters (�50GPL)ofIgGaCL.In3patients,the cut-off point for high aCL antibodies was not specified.However, no significant statistical relationship was found be-tween the IgG aCL titer and the development of catastrophic

Time of Catastrophic Antiphospholipid Syndrome

ge Organs Involvement Treatment Evolution

40 Brain, heart, kidney,skin

S, AC Recovery

42 Brain, heart, kidney,lung, adrenal

NR Death

65 Brain, kidney, smallbowel

S, AC, PE Recovery

68 Brain, peripheralnerve, adrenal

S, cyclo, AC,PE, GG

Recovery

32 Brain, liver, spleen S, AC Recovery40 Brain, heart, kidney,

lung, skinS, AC, cyclo,

AARecovery

42 Brain, kidney, lung,liver, skin

S, AC Death

67 Brain, heart, lung,liver, adrenal

S, AC Recovery

71 Brain, heart, lung,liver, adrenal

S, AC Recovery

32 Brain, heart, kidney,bowel

S, AC, PE Recovery

34 Heart, kidney, skin,pancreas

S, AC, PE Recovery

21 Kidney, lung, liver,spleen

S, AC, PE,GG

Recovery

21 Brain, kidney, DVT S, AC, PE Recovery56 Brain, kidney, lung,

liverS, AC, PE,

GG, cycloRecovery

57 Brain, kidney, liver S, AC, PE,GG, cyclo

Recovery

57 Brain, kidney, liver,PAT

S, AC, PE,GG,rituximab

Recovery

45 Heart, kidney, lung,gallbladder

S, AC, PE,GG

Recovery

47 Brain, heart, kidney,lung, bowel, DVT

S, AC, PE,GG,rituximab

Death

hic antiphospholipid syndrome; cyclo, cyclophosphamide; DVT,noglobulins; INR, international normalized ratio; M, male; NR, noty thrombosis; PC, personal communication; PE, plasma exchange;

ent at

r A

tastropimmu

al arter

APS relapses (data not shown).

9

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ToPbsetrwnniw

ep5ws((i

420 Relapsing catastrophic antiphospholipid syndrome

Laboratory features of MHA were present in 13 of 18(72%) episodes (definitive in 9, corresponding to 4 pa-tients [number 2, 4, 5, and 7], and probable in 4, corre-sponding to 2 patients [number 6 and 8]). Three relapsesdid not present with features of MHA (patient 3) andthese data were not reported in the remaining 2 episodes(patient 1). Two patients presented data suggesting prob-able MHA: 1 patient (patient 6) presented hemolysis withnegative Coombs test but schistocytes were not observedand, in the other patient (patient 8), schistocytes werefound on peripheral blood smears but Coombs test wasnot reported. Interestingly, the prevalence of MHA fea-tures in patients with catastrophic APS who relapsed wassignificantly higher than in those who did not relapsefrom the “CAPS Registry” (72% versus 7%; P � 0.0001;5% CI 0.459 to 0.841).

reatment and Outcome

he treatment and outcome of the 8 patients who devel-ped relapses of catastrophic APS are shown in Table 1.atient 1 died suddenly at home after a week of increasingreathlessness and fatigue. Therefore, he did not receivepecific treatment for catastrophic APS. Therefore, 17pisodes were analyzed. Steroids and anticoagulation werehe most common treatments and they were used in allelapses. Intravenous heparin was used in 6 episodes andarfarin in 5; in the remaining 5 episodes, these data wereot specifically reported. Steroids were given as intrave-ous pulses (1 g/d for 3 days) in 4 episodes and as oral or

ntravenous dosages of 0.5 to 2 mg/kg/d in 4. These data

Table 2 Laboratory features at time of catastrophic antipho

Case (Ref.)CAPS

RegistryaEpisodesof CAPS Platelets Hemol

1 (20) 5 1st2nd

LowNR

NRNR

2 (21) 21 1st2nd

LowLow

��

3 (22) 70 1st2nd3rd

LowNormalLow

���

4 (8) 83 1st2nd

LowLow

��

5 (7) 221 1st2nd

LowLow

��

6 (PC) 225 1st2nd

LowLow

��

7 (23) 281 1st2nd3rd

LowLowLow

���

8 (23) 282 1st2nd

LowLow

NRNR

aCL IgG, IgG isotype of anticardiolipin antibodies; aCL IgM, IgM issyndrome; GPL, units of aCL IgG; LA, lupus anticoagulant; (�), poscommunication.aReferred to as the number in the “CAPS Registry.”

ere not available in the remaining 9 episodes. Plasma

xchange was used in 11 (65%) episodes. Fresh frozenlasma was the replacement fluid in 4 of them, whereas% albumin solution was used in 2 episodes. These dataere not specifically described in the remaining 5 epi-

odes. Intravenous immunoglobulins were used in 741%) episodes and intravenous cyclophosphamide in 423%). Finally 2 (12%) episodes were treated with ritux-mab at 375 mg/m2 once weekly for 4 weeks and 2 infu-

sions of 1000 mg 2 weeks apart, respectively.Most patients received a combination of therapies (Ta-

ble 1). Anticoagulation plus steroids was the most com-mon combination (29%) followed by anticoagulationplus steroids plus plasma exchange (24%).

Three (38%) patients died. One of them (patient 1)did not receive any treatment and diagnosis of cata-strophic APS was done by the autopsy findings. The sec-ond patient was treated with the combination of steroidsplus anticoagulation and, in the third patient, the combi-nation of steroids plus anticoagulation plus plasma ex-change plus intravenous immunoglobulins plus ritux-imab was ineffective.

DISCUSSION

Relapse is a rare complication in patients with cata-strophic APS. In the only published study until now thatanalyzed the long-term prognosis of patients who survivean initial catastrophic APS event, 66% of the patientsremained symptom-free with anticoagulation during anaverage follow-up of 67.2 months. More interestingly,

lipid syndrome relapse

Schistocytes Coombs LAaCL IgG(GPL)

aCL IgM(MPL)

NRNR

NRNR

�NR

�150NR

�NR

��

��

��

136 GPLHigh

NRNR

NRNRNR

��NR

NR�

NR

NR16�

NR�NR

��

��

��

83 GPL103 GPL

8 MPL11 MPL

��

��

��

65.6 GPLNR

68 MPLNR

��

��

��

HighHigh

HighHigh

���

���

NRNRNR

�120NRNR

56NRNR

��

NRNR

�NR

75NR

64NR

of anticardiolipin antibodies; CAPS, catastrophic antiphospholipid), negative; MPL, units of aCL IgM; NR, not reported; PC, personal

spho

ysis

otypeitive; (–

none of them developed further catastrophic APS (5). In

G. Espinosa et al. 421

the present study, relapsing was reported in only 9 (3.2%)patients.

The frequencies of the major demographic, clinical,and immunologic features of relapsing catastrophic APSin the present series are also comparable to the most recentreview of catastrophic APS corresponding to the “CAPSRegistry” (11); the differences were also not in the organinvolvement at time of catastrophic APS episode. How-ever, there was a significant difference in laboratory char-acteristics. The prevalence of MHA features in patientswith relapsing catastrophic APS was significantly higherthan in those from the “CAPS Registry” who remainedsymptom-free during the follow-up.

The MHA is also a hallmark of TTP. A severe defi-ciency of von Willebrand factor (vWF)-cleaving protease,1-5ADAMTS13 (a disintegrin-like metalloprotease withthrombospondin type 1 repeats), is found in most pa-tients with TTP, and this deficiency is thought to beresponsible for platelet aggregation and microthrombiformation in the circulation, which in turn cause typicalthrombotic microangiopathies to develop (6). It is alsopossible that secondary deficiency of ADAMTS13 mayaccount for the development of microthrombi formationin disease states other than TTP, such as sepsis-induceddisseminated intravascular coagulation (12), and, possi-bly, catastrophic APS. In fact, thrombotic MHA featureshave been described in 16% of patients with catastrophicAPS (11). The presence of schistocytes makes the differ-ential diagnosis between catastrophic APS and TTP dif-ficult in aPL-positive patients with predominantly renaland neurological involvement. However, schistocytes incatastrophic APS patients are scanty (13).

Although decreased levels of ADAMTS13 activity andanti-ADAMTS13 antibodies have been detected in sev-eral patients with APS (14-17), until now, the levels ofvWF cleaving protease have been investigated in only 1systemic lupus erythematosus patient with aPL who de-veloped TTP or a TTP-like syndrome, but we considerthat this patient could be categorized as suffering fromcatastrophic APS (18). Another indirect proof of the po-tential relationship between catastrophic APS andADAMTS13 deficiency is represented by the findings ofMukai et al. (19), who described a patient with arterialthromboses in the context of APS associated with an ex-cess of a large multimer of vWF. This patient fulfilled thecriteria for “probable” catastrophic APS. Unfortunately,these authors did not measure the activity of ADAMTS13or the ADAMTS13 inhibiting antibodies. Until now,there has not been any published case report of relapsingcatastrophic APS with ADAMTS13 deficiency.

In conclusion, our study supports the hypothesis thatan association between MHA and relapsing of cata-strophic APS could be present. In light of the findings ofour study, the following hypothesis may be formulated:deficiency of ADAMTS13 potentially due to the exis-tence of anti-ADAMTS13 antibodies may be the main

cause of developing catastrophic APS in some patients,

especially those with recurrent episodes of catastrophicAPS. Further studies are needed to confirm this hypoth-esis and to identify ADAMTS13 as a potential antigenictarget of aPL.

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APPENDIX

The Catastrophic AntiphospholipidSyndrome Registry Project Group (EuropeanForum on Antiphospholipid Antibodies)

Coordinators: R. Cervera, Department of AutoimmuneDiseases, Hospital Clinic, Barcelona, Catalonia, Spain;G. Espinosa, Department of Autoimmune Diseases, Hos-pital Clinic, Barcelona, Catalonia, Spain; I. Rodríguez,Department of Autoimmune Diseases, Hospital Clinic,Barcelona, Catalonia, Spain; J-C. Piette, Hôpital Pitié-Salpêtrière, Paris, France; Y. Shoenfeld, Sheba MedicalCenter, Tel-Hashomer, Israel; Members: M. Abu-Shakra, Department of Medicine D, Soroka MedicalCenter, Beersheba, Israel; A. Allievi, Department of In-ternal Medicine and Autoimmune Diseases, HospitalFernandez, Buenos Aires, Argentina; M-C. Amigo, Rheu-matology Department, Instituto Nacional de Cardi-ología, Mexico City, Mexico; L. Barile-Fabris, Rheuma-tology Department, Hospital de Especialidades, CentroMedico la Raza IMSS, Mexico City, Mexico; J-J. Boffa,Department of Nephrology, Hôpital Tenon, Paris,France; M-C. Boffa, Hôpital Pitié-Salpêtrière, Paris,France; I. Chávez, Mexico City, Mexico; J. Chapman,Neuroimmunology Service, Tel Aviv Sourasky MedicalCenter, Tel Aviv, Israel; C. Davidson, Department ofCardiology, Royal Sussex Hospital, Brighton, UK; A.E.Denes, Division of Oncology, Department of Medicine,**Louis, USA; S. Derenne, CHU Nantes, France;R.H.W.M. Derksen, Department of Rheumatology andClinical Immunology, University Medical Center,Utrecht, The Netherlands; J.F. Diaz Coto, Caja Costar-ricense del Seguro Social, San Jose, Costa Rica; P. Disdier,Service de Medecine Interne, Centre Hospitalier Univer-sitaire Timone, Marseille, France; R.M. Egan, Depart-ment of Medicine, University of Kentucky Medical Cen-ter, Lexington, KY; M. Ehrenfeld, Chaim Sheba Medical

Center and Tel-Aviv University, Tel-Hashomer, Israel; R.

Enriquez, Nephrology Section, Hospital General de Elx,Spain; D. Erkan, Hospital for Special Surgery, New York,NY; F. Falcini, Department of Paediatrics, University ofFlorence, Florence, Italy; L.S. Fang, Renal Associates,Massachusetts General Hospital and Harvard MedicalSchool, Boston, MA; M. García-Carrasco, BeneméritaUniversidad Autónoma de Puebla, Puebla, Mexico; J.A.Gomez-Puerta, Department of Autoimmune Diseases,Hospital Clinic, Barcelona, Catalonia, Spain; J.T. Gran-done, Neenah, WI; A. Gurjal, Division of Hematology/Oncology, Barbara Ann Karmanos Cancer Institute, De-troit, MI; G. Hayem, Department of Rheumatology,CHU Bichat-Claude-Bernard, Paris, France; G.R.V.Hughes, Lupus Research Unit, the Rayne Institute, StThomas’ Hospital, London, UK; S. Inam, Riyadh ArmedForces Hospital, Riyadh, Saudi Arabia; K.S. Kant, De-partment of Internal Medicine, University of CincinnatiCollege of Medicine, Cincinnati, OH; M.A. Khamashta,Lupus Research Unit, the Rayne Institute, St Thomas’Hospital, London, UK; C.S. Kitchens, Department ofMedicine, University of Florida, Gainesville, FL; M.J.Kupferminc, Department of Obstetrics and Gynaecol-ogy, Lis Maternity Hospital, Tel Aviv, Israel; G. de Lar-rañaga, Hospital Muñiz, Buenos Aires, Argentina; R.A.Levy, Department of Rheumatology, Faculdade de Cien-cias Médicas, Rio de Janeiro, Brazil; M.D. Lockshin,Hospital for Special Surgery, New York, NY; S.F. Lui,Department of Medicine, Prince of Wales Hospital andChinese University of Hong Kong, Shatin, Hong Kong;P.J. Maddison, Gwynedd Rheumatology Service, YsbytyGwynedd, Bangor, UK; Y.A. Mekori, Department ofMedicine, Meir Hospital, Kfar Saba, Israel; S. Menahem,Department of Renal Medicine, Alfred Hospital, Mel-bourne, Australia; T. Miyamae, Department of Paediat-rics, Yokohama City University School of Medicine, Yo-kohama, Japan; J. Moore, Department of Haematology,St Vincent’s Hospital, Sydney, Australia; H.M. Mout-sopoulos, Department of Pathophysiology, MedicalSchool, National University of Athens, Athens, Greece;F.J. Muñoz-Rodríguez, Department of AutoimmuneDiseases, Hospital Clinic, Barcelona, Catalonia, Spain;J. Musial, Jagiellonian University School of Medicine,Krakow, Poland; A. Nakajima, Institute of Rheumatol-ogy, Tokyo Women’s Medical University, Tokyo, Japan;M.C. Neuwelt, Medical Service, VA Palo Alto HealthCare System, Palo Alto, CA; A. Parke, Department ofInternal Medicine, Division of Rheumatic Diseases, Uni-versity of Connecticut Health Center, Farmington, CT;S. Praprotnik, University Clinical Center, Department ofRheumatology, Ljubljana, Slovenia; B. Roca, Depart-ment of Internal Medicine, Hospital General de Castelló,Castelló, Spain; J. Rojas-Rodriguez, Department ofRheumatology, Specialties Hospital, Manuel Avila Ca-macho National Medical Centre, Puebla, Mexico; R.Roldan, Rheumatology Department, Hospital ReinaSofia, Cordoba, Spain; A.D. Sawitzke, Division of

Rheumatology, Department of Internal Medicine,

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University of Utah School of Medicine, Salt Lake City,UT; C.G. Schaar, Department of Haematology, Le-iden University Medical Center, Leiden, The Nether-lands; A. Sipek-Dolnicar, Department of Rheumatol-ogy, University Medical Center, Ljubljana, Slovenia;A.C. Spyropoulos, Clinical Thrombosis Center, Albu-querque, NM; R. Sinico, Nephrology and DialysisUnit and Center of Clinical Immunology and Rheu-matology, San Carlo Borromeo Hospital, Milan, Italy;L. Stojanovich, Clinical Center “Bezhanijska Kosa,”,

Belgrade, Serbia and Montenegro; D. Tan, Singapore

General Hospital, Singapore; M. Tektonidou, Depart-ment of Pathophysiology, Medical School, NationalUniversity of Athens, Athens, Greece; C. Vasconcelos,Hospital General de San Antonio, Porto, Portugal;M.P. Veloso, Hospital Universitario Clementino FragaFilho, Rio de Janeiro, Brazil; M. Wislowska, Outpa-tients Department of Rheumatology, Central ClinicalHospital, Warsaw, Poland; J. Yinh, Tufts-New Eng-land Medical Center, Boston, MA; W. You, Depart-ment of Obstetrics and Gynecology, National Naval

Medical Center, Bethesda, MD.