ABSTRACT SUPPLEMENT
2010 ANNUAL SCIENTIFIC MEETING
November 6–11, 2010
Atlanta, Georgia
AN OFFICIAL JOURNAL OF THE AMERICAN COLLEGE OF RHEUMATOLOGY
Arthritis & Rheumatism
AMERICAN COLLEGE OF RHEUMATOLOGY
ABSTRACT SUPPLEMENT
American College of Rheumatology
74
thAnnual Scientific Meeting
Association of Rheumatology Health Professionals
45
thAnnual Scientific Meeting
November 6 -11, 2010 · Atlanta, Georgia
ACR/ARHP 2010 Annual
Scientific Meeting Overall Needs
Assessment/Practice Gaps
The American College of Rheumatology and the Association of Rheumatology Health Professionals are committed to providing comprehensive education to improve the knowledge and performance of physicians, health professionals and scientists. Through evidence-based educational programs, the organization strives to enhance practice performance and improve the quality of care in those with or at risk for arthritis, rheumatic and musculoskeletal diseases. The 2010 ACR/ARHP Annual Scientific Meeting program has been developed independent of commercial influence. The following groups were involved in the planning process: the ACR Committee on Education; the ACR Annual Meeting Planning Committee; the ARHP Education Committee and the ARHP Annual Meeting Program Planning Committee.
The program is the result of a planning process that identified educational needs to change or enhance the knowledge, competence or performance of rheumatology professionals. The program’s content was derived from both needs assessment and practice gap analysis based on professional activities, practice setting, ABIM recertification requirements and physician attributes.
Program Highlights
Educational tracks to help attendees identify content targeted •
to them. Tracks include: business of rheumatology, clinical, clinical and research, clinical practice, educators, fellow-in-training, pediatrics, pediatrics and clinical, and research Latest science and best-practices presented through peer-•
reviewed and selected clinical and scientific abstracts, and invited speakers providing clinical, evidence-based and quality focused content
Diverse formats of education delivery, including: didactic •
lectures, debates, and interactive sessions, such as poster tours, Meet the Professors and Workshop sessions
A larger forum for discussion of practical management issues •
such as the Curbside Consults – Ask the Professors session and Medical Aspects lectures
Extensive learning opportunities in the basic science of •
rheumatology, an area of the program developed by a subcommittee of U.S. and internationally prominent basic scientists. Offerings include: the Basic Science Symposia, State-of-the-Art Lectures, a series of Immunology Updates for the Clinicians, and a Basic Science pre-meeting course Clinical management sessions, including the Thieves’ Market •
and basic management of difficult issues
A specific pediatric rheumatology track plus content •
integrated throughout the program designed to provide a high-level educational program to pediatric rheumatologists; and relevant updates to adult rheumatologists
Formal presentations of new practice guidelines provided •
to alert the membership and explain, in an open forum, the data supporting the guidelines and propose approaches for implementation
Over 40 workshops designed to provide hands-on skills training •
About ACR/ARHP Education
ACR/ARHP Program ObjectivesThe American College of Rheumatology and the Association of Rheumatology Health Professionals, a division of the ACR, are organizations of physicians, health professionals and scientists serving members through programs, including education and research. Through these programs, the ACR and the ARHP foster excellence in the care of people with rheumatic and musculoskeletal diseases.
The 2010 ACR/ARHP Annual Scientific Meeting programs have been independently planned by the ACR Committee on Education, the ACR Annual Meeting Planning Committee, the ARHP Annual Meeting Program Committee, and the ARHP Clinical Focus Course Task Force.
This program is sponsored by the American College of Rheumatology for educational purposes only. The material presented is not intended to represent the only or the best methods appropriate for the medical conditions being discussed, but rather are intended to present the opinions of the authors/ presenters, which may be helpful to other healthcare professionals. Attendees participating in this medical education program do so with the full knowledge that they waive any claim they may have against the ACR for reliance on any information presented during these educational activities. The ACR does not guarantee, warrant or endorse any commercial products or services.
Program Objectives
At the conclusion of the 2010 ACR/ARHP Annual Scientific Meeting, participants should be able to:
identify recent developments in the diagnosis and •
management of patients with rheumatic diseases
outline new technologies for the treatment of rheumatologic •
problems
describe potential challenges in the delivery of care to •
patients with rheumatic diseases and to specify possible solutions
utilize new research data to improve the quality of care of •
patients with rheumatic diseases
CME Credit and Certificates
of Participation
Accreditation Statement: The American College of Rheumatology
is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.
Statement of Designation: This activity has been approved for 48.5 AMA PRA Category 1 Credit™.
International Physicians: International physicians, who register as
part of a group and require AMA PRA Category 1 Credit(s)™, must provide the following information to your tour leader: full name, mailing address, telephone and fax numbers, and e-mail address. The information will be used to verify your meeting attendance.
Health Professional participants may claim hours to receive a
Certificate of Participation for an activity designated for AMA PRA
Category 1 Credit(s)™ credit.
For non-CME sessions, attendees may also request a certificate of participation.
Meeting Evaluations, CME Credit/
Certificates of Participation
Computers are available on-site for you to complete your CME/ Certificate of Participation application and meeting evaluation form online during the meeting. In addition, you can complete the evaluation and print your certificate after you return home. Paper
CME application forms will not be available.
If you are an international physician and require a Certificate of Attendance, this is enclosed in your meeting bag. If your country recognizes AMA PRA Category 1 Credit(s)™ in accordance with AMA PRA requirements, please complete a meeting evaluation and CME application.
Your evaluation of the meeting is very important. The ACR/ARHP annual meeting planning committees use feedback from attendees to assist in the development of future educational activities; therefore, we encourage you to complete your evaluation and CME/Certificate application online.
Conflict of Interest/Disclosure Statement
As an educational provider accredited by the Accreditation Council for Continuing Medical Education, the American College of Rheumatology must ensure balance, independence, objectivity and scientific rigor in all its educational activities. Therefore, all speakers and moderators participating in an ACR-sponsored activity are required to disclose to the planning committee and audience any financial or other relationships including, but not limited to: None: Nothing to disclose
Stock, stock options or bond holdings in a for-profit 1.
corporation or self-directed pension plan Research grants
2.
Employment (full or part-time) 3.
Ownership or partnership 4.
Consulting fees or other remuneration (payment) 5.
Non-remunerative positions of influence such as officer, 6.
board member, trustee or public spokesperson Receipt of royalties 7. Speakers’ bureau 8. Other 9.
Speakers, moderators and abstract authors submitted their disclosure online prior to publication. Disclosures for invited speakers are listed in the indices by presenters’ last name. Abstract author disclosures are published online as well as in this supplement. Disclosures for the Late-Breaking Abstracts are published online and in the December issue of Arthritis &
Rheumatism. Any individual who refuses to disclose relevant
financial relationships will be disqualified from being a planning committee member, a presenter, an author of a CME activity, and cannot have control of, or responsibility for, the development, management, presentation or evaluation of the CME activity.
Copyright
The annual meeting is not a public event. Programs presented at the meeting are for the education of attendees and purchasers of recorded presentations as authorized by the ACR. The information and materials displayed and presented during this meeting are the property of the American College of Rheumatology and the presenter and cannot be photographed, copied, photocopied, transformed to electronic format, reproduced, or distributed without written permission of the American College of Rheumatology and the presenter. Any use of the program content for commercial purposes, which includes, but is not limited to oral presentations, audiovisual materials used by speakers, and program handouts without the written consent of the ACR is prohibited. This policy applies before, during and after the meeting. The ACR will enforce its intellectual property rights and penalize those who infringe upon it. The names, insignias, logos and acronyms of the ACR, the ARHP and the REF are proprietary marks. Use of the names in any fashion, by any entity, for any purpose, is prohibited without the express written permission of the American College of Rheumatology.
Monday, noveMber 8, 2010
9:00
am- 6:00
pmACR Poster Session A
Poster presenters will be available from 9:00 – 11:00
am.
(Abstracts # 1-619). . . .
11:00
am- 12:30
pmACR Plenary Session I
Discovery 2010
(Abstracts #620-624) . . . .
11:15
am– 12:15
pmARHP Concurrent Abstract Session
Issues in Lupus
(Abstracts #625-628) . . . .
2:30 - 4:00
pmACR Concurrent Abstract Sessions
Biology and Pathology of Bone and Joint:
Molecular Basis of Osteoarthritis
(Abstracts #629-634). . . .
Cytokines, Mediators, Gene Regulation
(Abstracts #635-639). . . .
Epidemiology and Health Services Research: Rheumatoid
Arthritis
(Abstracts #640-645). . . .
Fibromyalgia and Soft Tissue Disorders
(Abstracts #646-651). . . .
Pediatric Rheumatology – Pathogenesis and Genetics:
Biological Basis for Pediatric Rheumatic Disease
(Abstracts #652-657). . . .
Rheumatoid Arthritis – Clinical Aspects: Preclinical RA and
Early RA
(Abstracts #658-663). . . .
Spondylarthropathies and Psoriatic Arthritis- Clinical Aspects
and Treatment: Imaging
(Abstracts #664-669). . . .
Systemic Sclerosis, Fibrosing Syndromes, and Raynaud’s:
Pathogenesis, Animal Models and Genetics
(Abstracts #670-675). . . .
ANCA- Associated Vasculitis
(Abstracts #676-681). . . .
2:30 - 4:00
pmACR/ARHP Combined Abstract Session
ACR/ARHP Combined Epidemiology and Health Services
Research: Impact on Osteoarthritis
(Abstracts #682-687) . . . .
2:30 - 4:00
pmARHP Concurrent Abstract Session
Physical Activity: Just “Move It”
(Abstracts #688-693) . . . .
4:30 - 6:00
pmACR Concurrent Abstract Sessions
Infection- elated Rheumatic Disease
(Abstracts #694-699) . . . .
Miscellaneous Rheumatic and Inflammatory Diseases
(Abstracts #700-705). . . .
Osteoarthritis – Clinical Aspects: Genetics, Novel Approaches,
and Therapy
(Abstracts #706-711) . . . .
Rheumatoid Arthritis – Animal Models: Insight in
Pathogenesis and Novel Therapeutic Targets
(Abstracts #712-717). . . .
Rheumatoid Arthritis Treatment – Small Molecules, Biologics
and Gene Therapy: Safety and Efficacy
(Abstracts #718-723). . . .
Systemic Sclerosis, Fibrosing Syndromes, and Raynaud’s –
Clinical Aspects and Therapeutics
(Abstracts #724-729). . . .
4:30 - 6:00
pmACR REF Special Session
REF Edmond L. Dubois, MD, Memorial Lectureship: The Path
from Gene to Function: Analysis of a Lupus Susceptibility
Gene
(Abstracts #730-732) . . . .
Tuesday, noveMber 9, 2010
9:00
am- 6:00
pmACR/ARHP Poster Session B
Poster presenters will be available from 9:00 – 11:00
am.
(Abstracts #733-1345) . . . .
Table of Contents
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9:15 - 10:15
amARHP Concurrent Abstract Session
Physical and Psychosocial Challenges in Scleroderma
(Abstracts #1346-1349). . . .
11:00
am- 12:30
pmACR Plenary Session II
Discovery 2010
(Abstracts #1350-1355) . . . .
2:30 - 4:00
pmACR Concurrent Abstract Sessions
Antiphospholipid Syndrome
(Abstracts # 1356-1361). . . .
Epidemiology and Health Services: Gout
(Abstracts #1362-1367). . . .
Imaging of Rheumatic Disease: X-ray and MRI
(Abstracts #1368-1373). . . .
Muscle Biology, Myositis and Myopathies: Insights into the
Pathogenesis and Outcomes of Myositis
(Abstracts #1374-1379). . . .
Orthopedics, Low Back Pain and Rehabilitation
(Abstracts #1380-1385). . . .
Rheumatoid Arthritis – Human Etiology and Pathogenesis: RA
Human Etiology and Pathogenesis
(Abstracts #1386-1391). . . .
Rheumatoid Arthritis Treatment – Small Molecules, Biologics
and Gene Therapy: Existing Non-Biologic DMARDs
(Abstracts #1392-1397). . . .
Systemic Lupus Erythematosus – Clinical Aspects and
Treatment: Renal
(Abstracts #1398-1403). . . .
2:30 - 4:00
pmACR /ARHP Combined Concurrent Abstract Session
ACR/ARHP Combined Pediatric Rheumatology – Clinical
and Therapeutic Aspects: Quality of Life in Children and
Adolescents with Arthritis
(Abstracts #1404-1409) . . . .
4:30 - 6:00
pmACR Concurrent Abstract Sessions
B-Cell Biology and Targets in Autoimmune Disease
(Abstracts #1410-1415). . . .
Cell-Cell Adhesion, Cell Trafficking and Angiogenesis
Cytokines, Mediators, Gene Regulation
(Abstracts #1422-1427). . . .
Education
(Abstracts #1428-1433). . . .
Pediatric Rheumatology – Clinical and Therapeutic Aspects –
Therapeutics
(Abstracts #1434-1439). . . .
Rheumatoid Arthritis – Clinical Aspects: Outcomes Associated
with Biologic Therapy for RA
(Abstracts #1440-1445). . . .
Spondylarthritis and Psoriatic Arthritis: Pathogenesis,
Etiology, and Animal Models
(Abstracts #1446-1451). . . .
Systemic Lupus Erythematosus – Clinical Aspects and
Treatment: New Therapies
(Abstracts #1452-1457). . . .
4:30 – 6:00
pmACR REF Special Session
REF Marshall J. Schiff, MD, Memorial Lectureship:
Everything a Rheumatologist Should Know About Spine
Surgery but Was Afraid to Ask
(Abstracts #1458-1459). . . .
4:30 - 6:00
pmARHP Concurrent Abstract Session
Don’t Despair Over Health Disparities
(Abstracts #1460-1465). . . .
Wednesday, noveMber 10, 2010
9:00
am- 6:00
pmACR/ARHP Poster Session C
Poster presenters will be available from 9:00 – 11:00
am.
(Abstracts #1466-2079 & 2089). . . .
9:15 - 10:15
amARHP Concurrent Abstract Session
Be Creative with Rheumatic Education: Where and How to Get It
(Abstracts #2080-2083). . . .
11:00
am- 12:30
pmACR Plenary Session III
Discovery 2010
(Abstracts #2084-2088) . . . .
Table of Contents
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2:30 - 4:00
pmACR Concurrent Abstract Sessions
Epidemiology and Health Services Research: Osteoarthritis
(Abstracts #2090-2095). . . .
Osteoarthritis – Clinical Aspects: Pain and Biomechanics
(Abstracts #2096-2101). . . .
Pediatric Rheumatology – Clinical and Therapeutic
Aspects-Outcomes
(Abstracts #2102-2107). . . .
Quality Measures and Innovation in Practice Management and
Care Delivery
(Abstracts #2108-2113) . . . .
Rheumatoid Arthritis – Human Etiology and Pathogenesis:
Anti – CCP in RA Etiology and Pathogenesis
(Abstracts #2114-2119) . . . .
Systemic Lupus Erythematosus – Clinical Aspects and
Treatment: SLE and Cardiovascular Disease
(Abstracts #2120-2125). . . .
T–Cell Biology and Targets in Autoimmune Disease
(Abstracts #2126-2131). . . .
2:30 - 4:00
pmACR/ARHP Combined Abstract Session
ACR/ARHP Combined Orthopedics, Low Back Pain and
Rehabilitation: Hips and Knees- Focus on Function
(Abstracts #2132-2137). . . .
2:30 - 4:00
pmARHP Concurrent Abstract Session
Keep Working with Arthritis
(Abstracts #2138-2143). . . .
4:30 - 6:00
pmACR Concurrent Abstract Sessions
Genetics, Genomics and Proteomics: SLE
(Abstracts #2144-2149). . . .
Metabolic and Crystal Arthropathies – Pathogenesis,
Prevalence, Imaging, and New Therapy
(Abstracts #2150-2155). . . .
Osteoporosis and Metabolic Bone Disease: Clinical Aspects
and Pathogenesis
(Abstracts #2156-2161). . . .
Rheumatoid Arthritis – Clinical Aspects: RA and
Cardiovascular Disease
(Abstracts #2162-2167). . . .
Rheumatoid Arthritis Treatment – Small Molecules, Biologics
and Gene Therapy: Novel Compounds
(Abstracts #2168-2173). . . .
Sjögren’s Syndrome
(Abstracts #2174-2179). . . .
Spondylarthropathies and Psoriatic Arthritis – Clinical Aspects
and Treatment: Biomarkers
(Abstracts #2180-2185). . . .
Systemic Lupus Erythematosus – Animal Models
(Abstracts #2186-2191). . . .
Systemic Sclerosis, Fibrosing Syndromes, and Raynaud’s –
Clinical Aspects and Therapeutics
(Abstracts #2192-2197). . . .
Vasculitis II
(Abstracts #2198-2203). . . .
Thursday, noveMber 11, 2010
7:45 - 8:45
amARHP Concurrent Abstract Session
Rheumatic Medications: More or Less
(Abstracts #2204-2207). . . .
9:00 - 10:30
amACR Concurrent Abstract Sessions
Epidemiology and Health Services Research: General Interest
(Abstracts #2208-2213). . . .
Genetics, Genomics and Proteomics: RA and Other Rheumatic
Diseases
(Abstracts #2214-2219). . . .
Imaging of Rheumatic Disease: Ultrasound
(Abstracts #2220-2225). . . .
Innate Immunity and Rheumatic Disease
(Abstracts #2226-2231). . . .
Rheumatoid Arthritis – Animal Models: T cell Pathogenesis
and Novel Therapeutic Targets
(Abstracts #2232-2237). . . .
Systemic Lupus Erythematosus – Clinical Aspects and Treatment
(Abstracts #2238-2243). . . .
9:15 - 10:45
amARHP Concurrent Abstract Session
What a Pain Rheumatic Disease Can Be!
(Abstracts #2244-2249). . . .
Table of Contents
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11:00
am- 12:30
pmACR Concurrent Abstract Sessions
Antiphospholipid Syndrome
(Abstracts #2250-2255). . . .
Rheumatoid Arthritis – Clinical Aspects: Radiographic and
Other Outcomes in RA
(Abstracts #2256-2261). . . .
Rheumatoid Arthritis Treatment – Small Molecules, Biologics
and Gene Therapy: Existing Biologics
(Abstracts #2262-2267). . . .
Spondylarthropathies and Psoriatic Arthritis Clinical Aspects
and Treatment – Therapy
(Abstracts #2268-2273). . . .
Systemic Lupus Erythematosus – Human Etiology and
Pathogenesis: Etiology and Pathogenesis
(Abstracts #2274-2278). . . .
11:00
am- 12:30
pmARHP Concurrent Abstract Session
Rheumatoid Arthritis: From Clinic to Home
(Abstracts #2279-2284). . . .
Table of Contents
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ACR Poster Session A
Antiphospholipid Syndrome
Monday, November 8, 2010, 9:00AM–6:00PM
1
Acquired Resistance to Activated Protein C Is a Feature of Both Systemic Lupus Erythematosus (SLE) and Antiphospholipid Syndrome
(APS) and Is More Marked in Patients with SLE and APS. Denis Wahl3
, Ste´phane Zuily4 , Agne`s Brunette2 , Marie Prestat-Tilly4 , Ve´ronique Reg-nault2 , Jean Devignes1
and Thomas Lecompte1
.1
Biological Haematology Department, Nancy University Hospital, Vandoeuvre les Nancy, France,
2
INSERM U961, Nancy Universite´, Vandoeuvre les Nancy, France,3
Vascu-lar Medicine Unit, Vandoeuvre les Nancy, France,4
Vascular Medicine Unit, Nancy University Hospital, Vandoeuvre les Nancy, France
Vascular manifestations of antiphospholipid syndrome (APS) include both venous (VTE) and arterial (ATE) thromboembolic events. However VTE are more frequent than ATE. Among the underlying mechanisms of VTE in APS, it has been suggested that acquired activated protein C (APC) resistance may be a candidate mechanism. However this is difficult to demonstrate with tests based on aPTT because of the effects of lupus anticoagulants on this parameter. In order to investigate APC resistance in APS we have conducted a study with a thrombin generation test (calibrated automated thrombography). APC resistance was determined with measure-ment of endogenous thrombin potential (ETP) at baseline and after addition of APC. The APC sensitivity ratio (sr) was defined as ETP with APC/baseline ETP.
We included 92 patients (37 with primary antiphospholipid syndrome, 15 with SLE without antiphospholipid antibodies PAPS, 11 with both APS and SLE and 29 with antiphospholipid antibodies (APA) but without APS) and 39 controls. APCsr was higher in all patient groups compared to controls indicating resistance to activated protein C: APCsr was 0.45⫾ 0.20, p⫽0.005 in PAPS, 0.55⫾ 0.16,p⬍0.001 in in SLE, 0.65 ⫾ 0.16,p⬍0.0001 in patients
with both PAPS and SLE and 0.53⫾ 0.22,p⬍0.0001 in patients with APA
without APS whereas controls 0.30⫾ 0.11. Of note APCsr was also higher in patients with both SLE and APS than in patients with PAPS (p⫽0.009). Moreover APCsr in patients with venous thrombosis was higher than in controls: 0.47⫾ 0.22 vs 0.30 ⫾ 0.11, p⬍ 0.001.
Overall these results suggest that acquired APC resistance is a potential risk factor for thrombosis in SLE and PAPS and is more marked when both conditions are present. Furthermore APC resistance seems to be more specifically associated with venous thromboembolism.
Disclosure: D. Wahl: None; S. Zuily: None; A. Brunette: None; M. Prestat-Tilly:
None; V. Regnault: None; J. Devignes: None; T. Lecompte: None.
2
AGTRL1 and PRKCH Are Genetic Risk Factors for Antiphospholipid
Syndrome. Hisako Nakagawa1
, Tetsuya Horita2 , Toshio Odani2 , Yuichiro Fujieda2 , Masaru Kato2 , Kotaro Otomo2 , Yasuko Nakagawa2 , Shinsuke Yasuda2 , Tatsuya Atumi2
and Takao Koike2
. 1
Department of Medicine II, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan,2
Department of Medicine II, Hokkaido University Graduate School of Medicine.
Background: Single nucleotide polymorphisms (SNPs) of Angiotensin
receptor-like1 (AGTRL1) and Protein kinase C eta (PRKCH) were reported to be associated with cerebral infarction in recent genomewide association study in Japanese population. AGTRL1, also named APJ, is a member of the G protein-coupled receptor gene family and has important roles for the modulation of angiogenesis and also act as a human immunodeficiency virus coreceptor. PRKCH regulates various important cellular functions including proliferation, differentiation and apoptosisis is mainly expressed in vascular endothelial cells and foamy macrophages in human atherosclerotic lesions. In this study, we investigated the possible association of the functional SNP in an Sp1-binding site of AGTRL1 gene (rs9943582, G/A) and the nonsynony-mous SNP (rs223050, G/A, Val372Ile) in PRKCH gene with antiphospho-lipid syndrome (APS) in Japanese population.
Patients and Methods: Genomic DNA samples were obtained from 111
patients with APS (45 primary APS and 66 secondly APS), 296 patients with systemic lupus erythematosus (SLE) in the absence of APS and 428 healthy controls. Among APS group, seventy nine patients (71%) had arterial or thrombosis, 58 (52%) arterial thrombosis, 37 (33%) venous thrombosis and 52 (47%) cerebral infarction, respectively. AGTRL1 SNP (rs9943582) was genotyped using TaqMan SNP genotyping assay and PRKCH SNP (rs2230500) was genotyped using direct sequencing. Chi-square tests and Odds ratio were used for statistical analysis after evaluation for Hardy-Weinberg equilibrium. In addition, the stratification analysis by thrombotic events was performed.
Results: Both AGTRL1 rs9943582 G allele and PRKCH rs2230500 A
allele frequencies were significantly increased in patients with APS
(OR⫽1.43, 95%Cl:1.03–2.31 and OR⫽1.89, 95%Cl: 1.17–3.05,
respec-tively). No association was found between these 2 SNPs and SLE in the absence of APS. In the stratification analysis by clinical manifestations of APS, both AGTRL1 and PRKCH alleles were associated with arterial or venous thrombotic events in patients with APS (OR⫽1.69, 95%Cl:1.15–2.49 and OR⫽1.58, 95%Cl: 1.04–2.38, respectively)
Conclusion: The functional SNP in an Sp1-binding site of AGTRL1 gene
(rs9943582, G/A) and the nonsynonymous SNP (rs223050, G/A, Val372Ile) in PRKCH are associated with APS and thrombotic events in patients with APS. Our results suggest that these 2 SNPs are additional genetic risk factors for APS, especially thrombotic events in APS in Japanese population.
Disclosure: H. Nakagawa: None; T. Horita: None; T. Odani: None; Y. Fujieda:
None; M. Kato: None; K. Otomo: None; Y. Nakagawa: None; S. Yasuda: None; T.
Atumi: None; T. Koike: None.
3
Anti-2 Glycoprotein I Antibodies from Leprosy Patients Do Not Show
Thrombogenic Effects in an In Vivo Animal Model. Ricardo Forastiero2,
Marta Martinuzzo2 , Mariano Vega-Ostertag2 , Gabriela de Larranaga2 and Silvia S. Pierangeli1 .1
Univ of TX Medical Branch, Galveston, TX,2
Univer-sidad Favaloro, Buenos Aires, Argentina
Background: The APS-associated aPL are autoantibodies directed
against2GPI and prothrombin. Patients with leprosy present high frequency
of IgM aPL that bind2GPI, but they do not develop thrombosis.
Anti-2GPI from APS mainly bind to domain I of Anti-2GPI while in leprosy are directed against domain V. There is convincing evidence that aPL/anti-2GPI from APS are pathogenic in vivo and in vitro.
Objective: to investigate the thrombogenic and pro-inflammatory effects
of aPL from leprosy and to compare with aPL from APS.
Methods: Sera from 6 patients with APS and 6 with leprosy were used as
the source of IgM. All APS and 5 leprosy patients had strong LA activity, and high titers of IgM aCL/anti-2GPI. The remaining leprosy patient was aPL negative (control). We treated CD1 mice, in groups of 5, at 0 hours and 48 hours later with IgM aPL/anti-2GPI isolated from patients with leprosy (IgM-leprosy) or APS (IgM-APS) or with IgM from 2 healthy controls (IgM-NHS) or 1 leprosy aPL negative control. Seventy-two hours after the first injection, the adhesion of leukocytes (#WBC) to endothelial cells (EC) in cremaster muscle (as an indication of EC activation in vivo), as well as the size of an induced thrombus in the femoral vein of the mice were examined.
Results: IgM-APS significantly increased the thrombus size (in mum2)
when compared to IgM-NHS or IgM-leprosy treated mice (p⬍0.001). There
was no difference in mice injected with leprosy, NHS or IgM-leprosy control. IgM-APS increased the #WBC adhering to EC, when
compared to IgM-NHS or IgM-leprosy (p⬍0.001).
IgM-APS IgM-leprosy IgM-NHS
IgM-leprosy control Mean thrombus size 4446 1378 748 851 #WBC 5.1⫾ 2.2 2.0⫾ 1.0 3.5⫾ 1.6 1.3⫾ 0.5
Conclusions: Our data shown that aPL/anti-2GPI from leprosy patients
have not thrombogenic and pro-inflammatory effects in vivo when compared with aPL derived from APS.
Disclosure: R. Forastiero: None; M. Martinuzzo: None; M. Vega-Ostertag: None; G. de Larranaga: None; S. S. Pierangeli: None.
Monday,
November
4
Antiphospholipid Antibodies in Children with Systemic Lupus
Erythem-atosus – 18 Years of Clinical Experience from North India. Surjit Singh2,
Jasmina Ahluwalia1
, Shano Naseem3
, Deepti Suri2
and Amit Rawat2
.
1
Department of Hematology, Post Graduate Institute of Medical Education and Research, Chandigarh, India,2
Division of Pediatric Allergy and Immu-nology, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India,3
Division of Pediatric Hematol-ogy, Advanced Pediatrics Centre, Post Graduate Institute of Medical Educa-tion and Research, Chandigarh, India
Background: Pediatric systemic lupus erythematosus (p-SLE) is usually
more severe than its adult counterpart and frequently involves vital organs (e.g. kidneys). Anti-phospholipid antibodies (APLA) have been reported in 38–87% patients with p-SLE in and reports suggest that presence of APLA can modify disease expression. Higher incidence of neuropsychiatric, renal and hematological manifestations has been reported in APLA positive p-SLE, but influence of APLA on disease course remains unclear. While APLA have been extensively studied in adults with SLE, there is paucity of data on APLA in p-SLE.
Materials and Methods: We report a single centre study on 64 patients
with p-SLE seen during the period June 1992 - May 2010 in whom APLA testing was performed. Diagnosis of SLE was based on ACR criteria. Mean age at diagnosis was 10.3 years (range 3–17) with a female:male ratio of 3:1. Of these 24 (37.5%) had renal, 17 (26.6%) hematological (7-hemolytic anemia, 6-thrombocytopenia and 4-leucopenia), 14 (21.9%) neurological, 8 (12.5%) pulmonary, 29 (45.3%) musculo-skeletal and 42 (65.6%) had mucocutaneous involvement. APLA tested included: i) lupus anticoagulant [by kaolin clotting time, diluted Russell viper venom time (LA Screen and LA Confirm, Dade Behring) and STACLOT-LA kit] ii) anticardiolipin antibodies (ACLA) – IgG, IgM and iii) anti-2 glycoprotein I (2 GPI) antibodies – IgG, IgM (Orgentec GmBH by ELISA). Our laboratory is registered in World Health Organization’s United Kingdom National External Quality Assurance Scheme for these tests.
Summary of Results: Patients was tested for APLA on 155 occasions
-minimum being once and maximum being 10 during a mean follow-up period of 59.3 months (range 1–211 months). Thirty eight (59.4%) patients were positive for one or other APLA at some point of time of their disease. Overall LA was positive in 39.1%, IgG ACA in 23.4% and IgM ACA in 18.6%. At diagnosis, 37.8% children were positive for LA, 16.3% for IgG ACA and 20.9% for IgM ACA. During follow-up LA was positive in 26.2% patients,
IgG ACA in 31%, IgM ACA in 19% patients. Anti-2GPI (IgG and IgM)
could be tested in 10 patients only and was found to be positive for anti-2GPI IgG in 1 patient.
Thrombosis was seen in 5 patients - of these, 4 (80%) were positive for APLA. Of the 24 patients with nephritis, class II nephritis was seen in 4—of these none was positive for any of the APLA; class III nephritis was seen in 1–patient tested positive for APLA; class IV nephritis was seen in 15—of these 9 (60%) were positive for 1 of the APLA; class V nephritis was seen in 3–of these 2 (66.6%) were positive for APLA. Of the 17 patients with hematological involvement, 11 (64.7%) had positive APLA; of 14 with neurological involvement, 12 (85.7%) had positive APLA. Six (9.4%) children had a fatal course—5 (83.3%) of these had positive APLA.
Conclusion: 59.4% p-SLE patients had APLA positivity during the
disease course. The commonest APLA was LA (39.1%), followed by IgG ACA (23.4%) and IgM ACA (18.6%). APLA positivity is more common in p-SLE patients with advanced nephritis, neurological involvement, thrombo-sis and a fatal course. Presence or perthrombo-sistence of these antibodies, however, may not always predict thrombosis in children with p-SLE.
Disclosure: S. Singh: None; J. Ahluwalia: None; S. Naseem: None; D. Suri: None; A. Rawat: None.
5
Antiphospholipid Score (aPL-S): A Comprehensive Predictive Marker of
Developing Thrombosis in Autoimmune Diseases. Kotaro Otomo1
, Tat-suya Atsumi2 , Yuichiro Fujieda3 , Masaru Kato3 , Olga Amengual3 , Tetsuya Horita3 , Shinsuke Yasuda3
and Takao Koike3
.1
Hokkaido Graduate School of Medicine, Department of Medicine II, Sapporo, Hokkaido, Japan,2
Hok-kaido Graduate School of Medicine, Department of Medicine II, Sapporo, Japan,3
Hokkaido Graduate School of Medicine, Department of Medicine II
Objective: We have previously defined the Antiphospholipid Score
(aPL-S) by testing multiple antiphospholipid antibodies (aPL), and evaluated
its efficacy for the diagnosis of antiphospholipid syndrome (APS) as well as its predictive value for the development of thrombotic events in patients with autoimmune diseases (Presentation Number 1216 in ACR 2009). In the present study, we further analyzed the associated-risk of thrombosis for each aPL assay in autoimmune diseases. Further, we investigated the relationship between the aPL-S and each single aPL test.
Patients and Methods: This study comprised 411 patients with
auto-immune diseases who visited our Rheumatic and Connective Tissue Disease Department. Between 2002 and 2003, five Lupus Anticoagulant (LAC) assays (the mixing studies: activated partial thromboplastin time (APTT), kaolin clotting time, the dilute Russel’s viper venom test (dRVVT), and the confirmatory tests: APTT and dRVVT) and 6 ELISAs (IgG/M anticardiolipin (aCL) antibodies, IgG/M anti-beta2-glycoprotein I (a2GPI) antibodies and IgG/M phosphatidylserine dependent antiprothrombin (aPS/PT) antibodies) were performed in all subjects. Among all the patients, 296 (72.0%) were followed-up with a mean duration of 67⫾15 months. The disease profile of these patients was as follows; 17(6%) primary APS, 26(9%) APS associated with other autoimmune disease, 89(29%) SLE (without APS), 50(17%) rheumatoid arthritis and 114 patients with several other autoimmune diseases. To evaluate the predictive value of thrombosis for each aPL-analyzed test, positive results in each assay were contrasted with the presence of new thrombotic events during the follow-up period.
Results: Thirty-two patients newly developed thromboses during the
observation period; 22 arterial thromboses and 14 venous thromboses. Patients with either positive LAC or IgG aPS/PT had a stronger risk of thrombosis than those without. The odds ratio (OR [95%CI]) associated to each test was 3.26 [1.55–6.90, p⫽0.001] and 4.80 [2.03–11.04, p⫽0.0001], respectively. The OR values in patients with aPL-S more than 10, 30 and 50
were 2.86 [1.33–6.16, p⫽0.006], 5.27 [2.32–11.95, p⬍0.0001] and 5.31
[1.81–15.53, p⫽0.0008], respectively. Thus, the positive predictive values of aPL-S more than 30 and 50 were higher than any other value of each single aPL test (see figure.). The negative predictive values of aPL-S, LAC and IgG aPS/PT were within the similar levels (90.7–92.9%).
Conclusion: The aPL-S may be a useful comprehensive quantitative
marker for predicting thrombosis in autoimmune diseases.
Disclosure: K. Otomo: None; T. Atsumi: None; Y. Fujieda: None; M. Kato: None; O. Amengual: None; T. Horita: None; S. Yasuda: None; T. Koike: None.
6
Antiphospholipid Syndrome (APS) Clinical Research Task Force
(CRTF) Report. Doruk Erkan2, Ronald Derksen6
, Roger A. Levy3 , Samuel Machin5 , Thomas Ortel1 , Silvia S. Pierangeli4 , Robert A. S. Roubey7 , Michael D. Lockshin2
and on Behalf of APS Clinical Research Task Force.
1
Duke University Health System, Durham, NC,2
Hospital for Special
Sur-gery, New York, New York, NY,3
Univ Estado Do Rio de Janeiro, Rio de Janeiro, Brazil,4
Univ of TX Medical Branch, Galveston, TX,5
University
College London Hospitals, London, UK, 6
University Medical Centre, Utrecht, Netherlands,7
University of North Carolina, Chapel Hill, NC
Background: The 13th
International Congress on Antiphospholipid An-tibodies (aPL) was held in Galveston, TX in April 2010. The APS CRTF was one of six task forces developed by the meeting organization committee with the purpose of: a) evaluating the limitations of APS clinical research and developing guidelines for researchers to help improve the quality of APS research; and b) prioritizing the ideas for a well-designed multicenter clinical trial and discussing the pragmatics of getting such a trial done (organization, ideal protocols, practical protocols, and financing).
Objective: The purpose of this abstract is to summarize the discussions
and progress of APS CRTF.
Methods: The original eight members of CRTF were chosen among
experienced APS researchers. The task force working algorithm was: a) a questionnaire that was sent to the members before the congress; b) a summary report that was prepared based on the responses to facilitate discussions during the pre-meeting workshop; c) a pre-meeting workshop; d) two plenary sessions based on the conclusions of the task force discussions where input from all the meeting attendees was received; and e) a final report that was circulated among all the task force chairs for final remarks.
Results: The task force identified five major issues that impede APS
clinical research and the ability to develop evidence-based recommendations for the management of aPL positive patients: 1) aPL detection has been based on partially or non-standardized tests, and clinical (and basic) APS research studies have included patients with heterogeneous aPL profiles with different clinical event risks; 2) clinical (and basic) APS research studies have included a heterogeneous group of patients with different aPL-related manifestations
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(some controversial); 3) thrombosis and/or pregnancy risk stratification and quantification are rarely incorporated in APS clinical research; 4) most APS clinical studies include patients with single positive aPL results and/or low-titer aPL ELISA results; furthermore, study designs are mostly retrospec-tive and not-population based, with limited number of prospecretrospec-tive and/or controlled population studies; and 5) lack of information on the particular mechanisms of aPL-mediated clinical events limits the optimal clinical study design.
Conclusion: The task force recommended that there is an urgent need for
a true International collaborative approach to design and conduct well-designed prospective large-scale multi-center clinical trials of patients with persistent and clinically significant aPL profiles. An International collabora-tive meeting to formulate a good research question using “FINER” (Feasible; Interesting; Novel; Ethical; and Relevant) criteria will take place in early November and the conclusions will be presented at the ACR meeting.
Disclosure: D. Erkan: None; R. Derksen: None; R. A. Levy: None; S. Machin:
None; T. Ortel: None; S. S. Pierangeli: None; R. A. S. Roubey: None; M. D.
Lockshin: None; on Behalf of APS Clinical Research Task Force: None.
7
Decreased Fibrin Clot Porosity in Patients with Antifosfolipid Syndrome.
Anna Vikerfors2
, Aleksandra Antovic1
, Elisabet Svenungsson2
, Katarina
Bremme3
and Margareta Holmström4
.1
Department of Clinical Sciences, Karolinska Institutet/Danderyd Hospital, Stockholm, Sweden,2
Department of Medicine, Rheumatology Unit, Karolinska Institutet/Karolinska University Hospital, Stockholm, Sweden,3
Department of Woman and Child Health, Division of Obstetrics and Gynaecology, Karolinska Institutet/Karolinska University Hospital, Stockholm, Sweden,4
Hematology Division, Department of Medicine, Karolinska Institutet/Karolinska University Hospital, Stock-holm, Sweden
Background: It has been reported that patients with type 1 diabetes and
young males with myocardial infarction form a fibrin clot which is tighter and more resistant to fibrinolysis in comparison to the fibrin clot formed by healthy controls. The structure/porosity of the fibin clot in patients with the Antiphospholipid syndrome (APS) has not previously been investigated and we hypothesised that a tight fibrin clot may contribute to the procoagulant state in these patients.
Materials and Methods: We thus evaluated fibrin clot porosity in
plasma-samples from 47 patients with Antifosfolipid Syndrome (APS), strictly fulfilling the Sydney criteria for APS. Previously established flow measurement technique was used to determine the fibrin clot porosity, as expressed as the Darcy constant (Ks). A low Ks level indicates a tighter fibrin clot. Ks-levels were compared to reference Ks values used in our laboratory obtained from healthy individuals. Within the APS-group, associations between Ks-levels and clinical manifestations, specificities of antiphospho-lipid antibodies (aPL) were explored. For a majority of the patients data regarding markers of inflammation and on-going medication was available to guide interpretation.
Results: The mean Ks-levels were significantly lower in the samples from
patients with APS (6.7, ⫹/⫺2.9) as compared to reference Ks values
(10.7⫹/⫺1.6), indicating a tighter fibrin network, p⬍0,0001. Within the APS-group Ks-levels did not vary depending on different clinical APS manifestations or aPL pattern. There was however a trend towards lower Ks-levels for the 20 patients with previous obstetric morbidity (5.7,⫹/⫺2,0) as compared to the 27 patients without this clinical manifestation (7.4 ⫹/⫺3.2), p⫽0,09.
CRP-levels were generally low in the APS-patients (median 1.06, range 0–7.4, n⫽28). A majority of the patients were treated with anticoagulants: either vitamin K-antagonits or dalteparin (19/34) and many with statins (7/34). Patients treated with these two groups of drugs had all experienced a previous arterial or venous tromboembolic event. Almost half of the patients (15/34) were treated with low-dose ASA, sometimes in combination with vitamin K-antagonists or dalteparin. The majority of the ASA-treated patients (12/15) had a previous tromboembolic manifestation.
Conclusion: APS-patients form a tighter and more stable fibrin clot as
estimated by Ks levels, which measure in vitro fibrin clot porosity. There was a significant difference compared to reference material obtained from healthy individuals, even though a majority of the APS-patients were treated with low dose ASA, warfarin, dalteparin, statins or a combination of these drugs. To our knowledge this is a new finding.
We observed a trend towards a tighter fibrin network in APS-patients with obstetric morbidity compared to other individuals with APS. This finding could be attributed to differences in medications between the two groups.
Future studies including larger patient materials and controls may shed further light on the aetiology of APS and may thereby contribute to better risk assessment and management for APS patients.
Disclosure: A. Vikerfors: None; A. Antovic: None; E. Svenungsson: None; K. Bremme: None; M. Holmström: None.
8
Global Analyses of Antiphospholipid Antibodies That Impair
Anti-thrombin Inactivation of Procoagulant Factors. Meifang Wu2, Jennifer
M. Grossman3
, John FitzGerald2
, Bevra H. Hahn4
and Pojen P. Chen1
.
1
UCLA Schl of Medicine, Los Angeles, CA,2
UCLA School of Medicine,
3
University of California Los Angeles, Sherman Oaks, CA,4
University of California Los Angeles School of Medicine, Los Angeles, CA
Background: Previously, we reported that 6 of the 8 patient-derived IgG
monoclonal anti-phospholipid antibodies (aPL) bound to thrombin, and that one such reactive aPL (CL24) significantly impaired inactivation of thrombin by antithrombin (AT). Subsequently, we found that all 6 thrombin-reactive aPL also bound to FXa; and that all 6 thrombin-reactive aPL plus two later generated IgG monoclonal aPL (i.e., B2 and P1) also interacted with FIXa. Importantly, some of these reactive aPL (such as CL24) could reduce AT inactivation of FXa and FIXa. The purpose of this study was to study the overall effects of such aPL on hindering AT from inactivating its target procoagulant factors.
Methods: First, we developed an activated-partial-thromboplastin-time
(APTT)-based assay to study the overall effects of aPL on impairing AT function and shortening plasma clotting times. Second, to avoid the problem that some aPL possess lupus-anticoagulant activity (that prolongs clotting times) and could obscure shortened clotting time (from aPL-impaired AT function), we evaluated each test aPL (or purified IgG, or plasma sample) individually by determining its clotting times in plasma in the presence or absence of heparin (with optimal AT function, or little AT function, respectively), and then dividing the former clotting time by the latter clotting time, and expressing the result as a “clotting ratio”. Third, as a first step to translate the above findings of AT-interfering IgG aPL into a feasible clinical assay, we adapted the above assays to study two chosen patient plasma samples. Plasma P76 contained IgG aPL that reacted with FXa and FIXa; and P80 contained IgG aPL that interacted with thrombin, FXa and FIXa.
Results: First, monoclonal antibodies B2 and CL24 at the final
concen-tration of 27g/ml (representing about 0.3% of total plasma IgG) signifi-cantly shortened clotting times from 85 seconds to about 60 seconds (p⬍ 0.001), most likely reflecting that B2 and CL24 impaired AT inactivation of one or more procoagulant factors in plasma. Second, using the “clotting ratio” analyses, B2 and CL24 at the physiological concentration reduced clotting ratios from 250% for normal human IgG to 144 % (p⬍ 0.01) and 171% (p ⬍ 0.05), respectively. Moreover, purified IgG from 2 patients with antiphospho-lipid syndrome (APS) also reduced clotting ratio to 153% and 145%, as compared with a clotting ratio of 175% for normal human IgG. Third, when heparin was added, the clotting times of normal plasma, P76 and P80 were increased respectively to 96 seconds, 99 seconds and 166 seconds. These led to a clotting ratio of 178% for the normal plasma, while those of plasma P76
and the P80 were respectively 113% and 134% (p⬍ 0.001). These data
suggested that both patient plasma samples had the AT-interfering Ab. The above reduced clotting ratios apparently reflected that certain aPL reacted with the target procoagulant factors of AT and paradoxically impair AT inactivation of the involved procoagulant factors in plasma.
Conclusion: These results show the AT-interfering IgG aPL are present
in some APS patients and could contribute to thrombosis in such patients.
Disclosure: M. Wu: None; J. M. Grossman: None; J. FitzGerald: None; B. H. Hahn: None; P. P. Chen: None.
9
Influenza Vaccination Can Induce New Onset Anticardiolipins but Not
2-Glycoprotein-I Antibodies among Patients with Systemic Lupus
Erythematosus. Evan Glenn Vista3, Sherry R. Crowe3
, Amy B. Dedeke3 , Jourdan R. Anderson2 , Linda F. Thompson3 , Gillian Air4 and Judith A. James1 .1
Oklahoma Med Research Foundation, Oklahoma City, OK,2
Okla-homa Medical Research Foundation,3
Oklahoma Medical Research Founda-tion, Oklahoma City, OK,4
University of Oklahoma Health Science Center, Oklahoma City, OK
Monday,
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Background: Antiphospholipid syndrome is characterized by pathogenic
autoantibodies against anticardiolipins (aCLs), lupus anticoagulant, and In-dependent2-glycoprotein (2GPI). The factors causing production of these antiphospholipid antibodies (aPLs) remain unidentified but have been docu-mented in a large number of infectious diseases. Controversy exists as to whether vaccination triggers the same autoimmune reactions as infections in
systemic lupus erythematosus (SLE) patients. Among the aPLs,2GPI has
been described as the actual target antigen for autoimmune aPLs, but conflicting reports still exist.
Methods: A total of 102 patients fulfilling the ACR criteria for SLE and
104 age, race and gender matched healthy controls enrolled in our lupus flu cohort from 2005 to 2009 and received regular seasonal influenza vaccina-tions. Sera were tested by ELISA for aCL IgG at the time of vaccination and 2, 6 and 12 weeks after vaccination. The international standardized ratios for aCL reactivity were calculated for each and manufacture cut-offs were used to define low, moderate, and high levels of aCL. Logistic regression was used to account randomly for those enrolled in multiple years to select the unique 206 individuals. Vaccine responses were ranked either as high or low according to an overall anti-influenza antibody response index (which includes hemagglutination inhibition, relative avidity and maximum native antibody responses). Those who have new onset reactivity to aCL IgG were further tested for2GPI IgG antibodies. Paired t-testing for all patients with aCL reactivity was used to determine changes after vaccination at 2, 6, and 12 weeks compared to baseline.
Results: More SLE patients compared to healthy controls developed new
low aCL reactivity (14/102 cases and 4/104 controls; OR 4.1, p 0.02) and new moderate aCL reactivity (13/102 cases and 3/104 controls; OR 5.1, p 0.01) after influenza vaccination. From specific timepoints after vaccination, new low aCL reactivity were significant for SLE patients after 6 weeks (11/102 cases and 1/104 control) and 12 weeks (10/102 cases and 2/104 control) (OR 12.8, p 0.02 and OR 5.7, p 0.03 respectively) and for new moderate aCL reactivity only after 6 weeks (10/102 cases and 1/104 controls; OR 11.5, p 0.02). High aCL reactivity was only seen among 2 patients with low and moderate aCL reactivity pre-vaccination. Overall, vaccine response was significantly higher among patients with new onset aCL reactivity compared to controls (p 0.02). No new2GPI antibodies were detected post-vaccination among patients with new aCL reactivity. The normalized optical density measurements for patients with recorded aCL reactivity at any time points were significantly higher after 2 weeks (0.43⫾0.24, p 0.0013), 6 weeks (0.49⫾0.37, p 0.004), and 12 weeks (0.47⫾0.44, p 0.03) after vaccination compared to the baseline (0.30⫾0.15).
Conclusions: This study shows transient increases in aCLs, but not
anti-2GPI responses, after influenza vaccination supporting the possibility that these changes in autoantibody levels may not be clinically important for increased thrombosis risk post-vaccination.
Disclosure: E. G. Vista: None; S. R. Crowe: None; A. B. Dedeke: None; J. R. Anderson: None; L. F. Thompson: None; G. Air: None; J. A. James: None.
10
Platelet Activation and Paradoxical Inhibition of ADP Induced
Aggre-gation by Antiphospholipid Antibodies. Kenji Oku4, Tatsuya Atsumi2
, Olga Amengual3 , Masahiro Ieko1 , Shin Furukawa6 , Hirohiko Kitakawa6 , Yuji Hori6 , Kazuyoshi Nihei6 , Yuuichiro Fujieda3 , Kotaro Otomo5 , Masaru Kato3 , Tetsuya Horita3 , Shinsuke Yasuda3
and Takao Koike3
.1
Health
Sci-ences University of Hokkaido,2
Hokkaido University Graduate School of Medicine Internal Medicine II, Sapporo, Japan,3
Hokkaido University Grad-uate School of Medicine Internal Medicine II,4
Hokkaido University Gradu-ate School of Medicine Internal Medicine II, Kushiro Red Cross Hospital, Japan,5
Hokkaido UniversityGraduate School of Medicine Internal Medicine II,6
Kushiro Red Cross Hospital
Purpose: Autoantibodies against beta2-glycoprotein I (2GPI) and those
against prothrombin are two major populations of antibodies found in patients with antiphospholipid syndrome (APS). The platelet activation and aggrega-tion are crucial procedures in the development of arterial thrombosis. There are some reports suggesting a link between platelet activation and anti-2GPI
antibodies, but only little data are available regarding antiprothrombin antibodies and platelets. We previously showed that presence of IgG phosphatidylserine-dependent antiprothrombin antibodies (aPS/PT) was a strong risk of having arterial thrombosis in our cohort of 500 patients with autoimmune diseases, and that monoclonal aPS/PT affected ADP induced platelet aggregation in vitro (abstract 1594, ACR 2009).
In this study, we investigated further the in vitro behaviour of platelet
exposed by aPS/PT and anti-2GPI antibodies. Additionally, we
quantitatively-analyzed CD62P, a surface marker of activated platelets and thromboxane B2(TXB2), a member of eicosanoid family molecules produced by activated platelets.
Methods: A monoclonal aPS/PT, 231D, that shared the properties with
autoimmune aPS/PT, a human monoclonal anti-2GPI antibody, EY2C9, and
purified IgG from APS patients’ sera were used for the following experi-ments. Normal platelets were treated with monoclonal antibodies or purified IgG. Conventional ADP or collagen induced platelet aggregation assay by turbidimetric method were performed using platelet riched plasma (PRP) spiked with monoclonal antibodies or purified IgG. To explore, in this system, the involvement of P2Y12, one of the ADP receptors on platelet controlling the secondary aggregation, we evaluated the activation of vasodilator stimu-lated phosphoprotein (VASP), using a standard assay. VASP represents P2Y12 inhibition as the intra-molecular signal protein. Positive ratio of CD62P was detected by two-colored flow-cytometry. TXB2 was quantitatively-analyzed by Enzyme-Linked ImmunoSorbent Assay (ELISA.).
Results: ADP induced secondary platelet aggregation was significantly
inhibited in 231D, EY2C9, and purified IgG affected PRP, whereas collagen induced platelet aggregation was not affected by any of the antibodies. VASP activities were significantly increased in 231D and EY2C9 treated platelets (p⬍0.01).
Both positive rates of CD62P and TXB2 levels were significantly raised on platelets treated with 231D or EY2C9 in the presence of their antigen.
Conclusion: The effects of monoclonal aPS/PT on platelets were similar
to those of monoclonal anti-2GPI antibodies and IgG fractions of APS
patients’ sera. Antiphospholipid antibodies activated platelets shown by CD62P expression and TXB2 production. Paradoxical inhibition of ADP induced platelet aggregation by antiphospholipid antibodies might be corre-lated with P2Y12 signal suppression. Those observations suggest that the platelet involvements with aPS/PT and anti-2GPI are paradoxical and
complex, leading to the heterogeneous clinical features of patients with APS.
Disclosure: K. Oku: None; T. Atsumi: None; O. Amengual: None; M. Ieko: None; S. Furukawa: None; H. Kitakawa: None; Y. Hori: None; K. Nihei: None; Y. Fujieda: None; K. Otomo: None; M. Kato: None; T. Horita: None; S. Yasuda:
None; T. Koike: None.
11
Prevalence and Prognostic Significance of Thrombotic Microangiopathy in Rheumatologic Patients: Clinical and Immunological Associations.
Spyros Aslanidis, Athina Pyrpasopoulou, Stella Douma, Areti Triantafyllou, Michail Doumas and Chrysanthos Zamboulis. 2nd Propedeutic Dept of Internal Medicine, Hippokration Hospital, Thessaloniki, Greece
Background/Aim: The aim of this study was to assess the prevalence of
microangiopathy in rheumatologic patients featuring signs of vasculopathy. As the occurrence of small-vessel occlusions (thrombotic microangiopathy) in the nail fold of patients with antiphospholipid syndrome is well docu-mented, a major target point of this study was to evaluate capillaroscopy in the diagnosis of APS. Capillaroscopic findings and matching autoantibody profiling were subsequently correlated with the incidence of arterial and venous thrombotic events.
Materials/Methods: 738 patients from a Rheumatology Outpatients
cohort were consecutively screened with capillaroscopy. Criteria for selection included Raynaud’s phenomenon, livedo reticularis, diagnosis of SLE, positive antiphospholipid profile and/or previous thrombotic events, and atypical musculoskeletal symptomatology. Scleroderma patients were ex-cluded. Patients with microhemorrhages were tested for ACL and anti-b2GP1 Abs and data was analyzed with the SPSS 16.0 software.
Results: 149 of the screened patients (85.2%乆/14.8%么, 49.28⫾14.31
yrs) exhibited capillary microhemorrhages. Running diagnosis in these patients was MCTD (24.2%), SLE (18.8%), RA (16.1%), APS (12.8%), Sjogren’s syndrome (4.7%), B51 (3.4%), and vasculitis (2%). Antiphospho-lipid profile was tested in the affected individuals, and revealed an additional 14.7% of secondary laboratory APS in 28.6% of the SLE and 22.2% of the MCTD patients. The presence of ACL and anti-b2GP1 Abs was found to both independently significantly correlate with thrombotic events (p⬍0.001). Subanalysis of the type of anti-b2GP1 Abs indicated that the correlation with
thrombotic events was significant for G-type (p⬍0.001) and M-type
(p⫽0.012), but not A-type Abs (p⫽0.292, NS). No significant predilection for arterial or venous thromboses was observed in patients with ACL Abs; patients with anti-b2GP1 Abs exhibited a trend for arterial thromboses, p⫽0.174, NS.
Conclusions: Capillaroscopy is a useful microangiopathy screening tool
in rheumatologic patients featuring signs of clinical vasculopathy, and can aid
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diagnostically to screen for, or verify, APS in patients with a history of thrombotic events. Associations of autoantibody profiling of patients with capillaroscopic microangiopathy with clinically manifested thromboses re-sulted in similar findings with studies involving patients with clinical APS. The observation that, although IgA-b2GP1 Abs were detected in patients with microangiopathy, they lacked any significant association with thrombotic complications, suggests, that additional factors may be needed for the development of clinical thrombotic events.
Disclosure: S. Aslanidis: None; A. Pyrpasopoulou: None; S. Douma: None; A. Triantafyllou: None; M. Doumas: None; C. Zamboulis: None.
12
Prevalence of Antibodies to Prothrombin (PT) and Prothrombin/ Phosphatidylserine (PS) in a Cohort of Lupus Anticoagulant (LAC)
Positive Samples. R. Aguilar-Valenzuela2
, J. Dlott1 , U. Khan2 , M. Belter1 , E. Doan2 , N. Gould1 , A. Schleh2 and S. Pierangeli2 .1 Quest Diagnostics, Chantilly, VA,2
Univ of TX Med Branch, Galveston, TX
Background: ELISA tests have been developed to detect anti-PT and
anti-PT/PS antibodies in serum but the clinical diagnostic value and their relationship with the LAC remains elusive.
Objective: to evaluate anti-PT/PS and anti-PT antibodies in a cohort of
150 confirmed LAC and the corresponding controls.
Methods: 150 LAC positive and 150 LAC negative plasma samples were
tested by ELISA for anti-PS/PT (IgG and IgM) and LAC PS/PT screening assay (kindly provided by INOVA Diagnostics) and anti-PT (IgG and IgM) in-house assay. LAC positivity was confirmed by either dRVVT Confirm (American Diagnostica) or by the STACLOT LA (Diagnostica Stago) tests (3% of samples were positive for dRVVT only and 94% were positive for STACLOT only, 3% were positive for both).
Results:
aPS/PT IgG aPS/PT IgM aPS/PT Screen aPT IgG aPT IgM
# of positive
samples (%) 43/150(29%) 33/150(22%) 32/150(21%) (29.3%)44/150 39/150(26%) All negative LAC samples were negative in the anti-PS/PT and anti-PT tests. 125/150 (83%) of all LAC positive samples were positive in at least one of the PS/PT or PT ELISA. There was no correlation between any of the tests and LAC Staclot delta values or dRVVT ratios and the PT/PS or PT tests. Strong correlation was observed between anti-PS/PT IgG or IgM and LAC Anti-PS/PT screen test.
Conclusions: PS/PT and PT antibodies altogether recognize the majority
of LAC positive samples and may represent an additional specific serological laboratory marker to confirm diagnosis of Antiphospholipid Syndrome.
Disclosure: R. Aguilar-Valenzuela: None; J. Dlott: None; U. Khan: None; M. Belter: None; E. Doan: None; N. Gould: None; A. Schleh: None; S. Pierangeli: None.
13
The Influence of Thrombovascular Events on the Quality of Life in APS and SLE Patients. Amaris K. Balitsky, Valentina Peeva, Jiandong Su, Erik
Yeo, Carol Landolt-Marticorena, Dafna D. Gladman, Murray B. Urowitz and Paul R. Fortin. University of Toronto Antiphospholipid Clinic, Division of Rheumatology, Toronto Western Hospital
Objective: The antiphospholipid syndrome (APS) is defined by the
presence of antiphospholipid antibodies (aPLs) with clinical manifestations such as: venous or arterial thrombosis or recurrent pregnancy complications. The syndrome is either primary, or secondary due to an underlying condition, most commonly systemic lupus erythematosus (SLE). The purpose of this study was to describe and compare the characteristics and quality of life (QoL) of patients with previous thrombovascular events (TE) to those with no TE. To analyze the data, we used t-tests and one-way ANOVAs with Bonferroni post-hoc tests.
Methods: Five patient groups followed at the University of Toronto SLE
and APS clinics were defined as patients with: 1) (PAPS) primary APS, 2)
(SAPS) APS secondary to SLE, 3) (SLE⫹TE) SLE patients who had a TE,
but do not have positive aPLs, (i.e., do not have APS), 4) (SLE-TE⫹aPL) SLE without TE, but with a persistent positive aPL defined as anticardiolipin
antibody of IgG and/or IgM⬎ 40 GPL or MPL, on two or more occasions,
at least 12 weeks apart, 5) (SLE-TE) SLE without TE, and without aPL. QoL was determined using the mental component score (MCS) and the physical component score (PCS) of the Medical Outcomes Study Short Form 36
(SF-36) at the most recent visit. To analyze the data, we used t-tests and one-way ANOVAs with Bonferroni post-hoc tests.
Results: The table summarizes the data and marks significant differences
with an asterisk. Mean age at the time of the questionnaire completion was similar across the five groups, except for a younger average age (42.9 years) in the SLE-TE group (p⬍.05). A high majority of patients were female across all groups, with a smaller majority (60.5%) in the PAPS group. There were more venous TEs in the PAPS group (65.8%) compared to the SAPS group (30.8%); however, the overall number of patients with arterial and venous TEs was similar. Patients with arterial events (44.7⫾11.5) scored lower than patients with venous events (49.2⫾11.6) in the MCS score (t(149.5) ⫽ ⫺2.4, p⫽.02); however there was no difference in PCS scores between arterial and venous TE. There was a difference in PCS scores across the five groups (F(4,897)⫽ 3.33, p⬍.05); however there was no difference in MCS scores.
Patients in the SLE⫹TE group showed lower scores compared to the PAPS
and SLE-TE⫹aPL groups (table). SLE⫹TE patients also scored lower on a
number of QoL subscales.
Conclusions: It appears that the combination of two severe conditions,
SLE and thrombotic events, has a more negative influence on reported PCS, compared to having SLE or APS alone. This influence was not seen for the MCS score.
Group N Age (% F)Sex TE type (% v) MCS PCS PAPS 38 47.5⫾ 15.4 60.5 65.8 48.6⫾ 12.5 43.5⫾ 11.1* SAPS 39 54.8⫾ 15.0 92.3 30.8 47.1⫾ 10.9 38.6⫾ 13.8 SLE⫹TE 79 51.1⫾ 15.8 84.8 50.6 46.0⫾ 11.7 36.5⫾ 12.15*
SLE-TE⫹aPL 79 51.1⫾ 16.8 84.8 n.a. 47.3⫾ 12.2 42.5⫾ 13.8*
SLE-TE 667 42.9⫾ 15.2* 90.1 n.a. 46.9⫾ 11.6 40.4⫾ 12.2
Disclosure: A. K. Balitsky: None; V. Peeva: None; J. Su: None; E. Yeo: None; C. Landolt-Marticorena: None; D. D. Gladman: None; M. B. Urowitz: None; P. R. Fortin: GlaxoSmithKline, 5.
14
Utility of Anti-Phosphatidylserine/Prothrombin and IgA
Antiphospho-lipid Assays in AntiphosphoAntiphospho-lipid Syndrome. Ehtisham Akhter3
, Walter L. Binder2
, Zakera Shums2
and Michelle A. Petri1
.1
Timonium, MD,2
Inova Diagnostics Inc, San Diego, CA,3
Johns Hopkins University, Baltimore, MD
Purpose: Currently three antiphospholipid assays are in wide use
clini-cally (lupus anticoagulant, anticardiolipin (aCL), and anti-beta2 glcyoprotein I (anti-beta2 GPI)). The lupus anticoagulant is the most specific assay, conferring the highest risk of thrombosis and pregnancy loss, but it cannot be validly performed in an anticoagulated patient. We investigated phosphatidylserine/prothrombin (PS/PT), which detects most lupus anti-coagulants, in terms of its association with thrombosis. We also investigated the utility of IgA assays for APS in SLE.
Methods: Stored samples from SLE patients with and without past
thrombosis were assayed for anti-beta2 GPI (IgG/IgM/IgA), Domain 1 (IgG) and Domain 4/5 (IgA), aCL (IgG/IgM/IgA) and anti-PS/PT (IgG, IgM and IgG/M).
Results: For any thrombosis, the highest association was with aCL IgA,
followed anti-beta2 GPI IgG and anti-beta2 GPI IgA. Anti-PS/PT IgG, IgM and IgG/M were similar (Table 1).
Table 1: Any Thrombosis
Assay Thrombosis (nⴝ 160) No thrombosis (nⴝ 166) Odds Ratio 95% CI P-value Number (% positive) Number (% positive)
IgG beta2 GPI 18 (5.5%) 6 (3.6%) 3.4 (1.3, 8.7) .0083 beta GPI Domain 1 11 (6.7%) 9 (5.4%) 1.3 (0.5, 3.2) .5845 Anticardiolipin 22 (13.8%) 16 (9.6%) 1.5 (0.8, 3.0) .2475 PSPT 26 (16.3%) 14 (8.4%) 2.1 (1.1, 4.2) .0315 IgM beta2 GPI 8 (5.0%) 9 (5.4%) 0.9 (0.3, 2.4) .8641 Anticardiolipin 18 (1.3%) 15 (9.0%) 1.3 (0.6, 2.6) .5077 PSPT 42 (26.3%) 26 (15.7%) 1.9 (1.1, 3.3) .0187 IgA beta2 GPI 48 (30.0%) 24 (14.5%) 2.5 (1.5, 4.4) .0007 Anticardiolipin 10 (6.3%) 2 (1.2%) 5.5 (1.2, 25.4) .0156 beta2 GPI D4/5 35 (21.9%) 28 (16.9%) 1.4 (0.8, 2.4) .2523 IgG/M PSPT 38 (23.8%) 24 (14.5%) 1.8 (1.0, 3.2) .0326 Monday, November 8
