ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 372

TRAF1/C5 Locus Is Associated with Response to Anti-Tumor Necrosis Factor Therapy in Patients with Rheumatoid Arthritis

Helena Canhao1, Ana M. Rodrigues2, Maria José Santos3, Diana Carmona-Fernandes4, Bruno Bettencourt5, Jing Cui6, Fabiana Rocha5, Jose canas Silva3, Joaquim Polido Pereira7, Jose Alberto Pereira Silva8, José Antonio Costa9, Domingos Araujo10, Candida Silva11, Helena Santos12, Catia Duarte13, Fernando Pimentel-Santos14, Jaime C. Branco14, Robert M. Plenge15, Daniel H. Solomon16, Jacome Bruges Armas5, José A. P. Da Silva17, João E. Fonseca18 and Elizabeth W. Karlson19, 1Rheumatology Research Unit, Rheumatology Research Unit, on behalf of the Rheumatic Diseases Portuguese Register, Instituto de Medicina Molecular, Rheumatology Research Unit, Rheumatology Research Unit, on behalf of the Rheumatic Diseases Portuguese Register, Lisbon, Portugal, 22- Rheumatology Research Unit,, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Lisbon, Portugal, 3Rheumatology Department, Hospital Garcia de Orta, E.P.E., Almada, Portugal, 4Rheumatology Research Unit Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, Lisbon, Portugal, 5Seebmo, Hospital de Santo Espirito da Ilha Terceira, Ilha Terceira, Portugal, 6Rheumatology, Brigham and Women's Hospital, Boston, MA, 7Rheumatology Research Unit, Instituto Medicina Molecular, Lisbon, Portugal, 8Rheumatology Department, Santa Maria Hospital, Lisbon, Portugal, 9Rheumatology, Centro Hospitalar do Alto Minho, Hospital de Ponte de Lima, Ponte de Lima, Portugal, 10Rheumatology Department, Unidade Local de Saude, Ponte de Lima, Portugal, 11Reumatology, Instituto Portugues Reumatologia, Lisbon, Portugal, 12Rheumatology, Instituto Português de Reumatologia, Lisboa, Portugal, 13Rheumatology, Hospitais da Universidade de Coimbra, Coimbra, Portugal, 14Rheumatology, Centro Hospitalar de Lisboa Ocidental, Hospital Egas Moniz, Lisboa, Portugal, 15Division of Rheumatology, Immunology and Allergy and Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 16Division of Rheumatology, Brigham and Women's Hospital, Boston, MA, 17Serviço de Reumatologia, Centro Hospitalar e Universitário de Coimbra – Hospitais da Universidade de Coimbra, E.P.E., Coimbra, Portugal, 18Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa and Rheumatology Department, Centro Hospitalar de Lisboa Norte, EPE, Hospital de Santa Maria, Lisboa, Portugal, 19Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords:

Session Information

Title: Rheumatoid Arthritis - Clinical Aspects I: Drug Studies/Drug Safety/Drug Utilization/Disease Activity & Remission

Session Type: Abstract Submissions (ACR)

Background/Purpose:  Some of the allelic variants associated with rheumatoid arthritis (RA) susceptibility are related to tumor necrosis factor (TNF) signaling pathways. We hypothesized that they might influence the response to anti-TNF drugs.  The primary aim of our work was to investigate potential associations between RA risk alleles specifically selected for their relevance on RA biologic pathways and the response to anti-TNF treatment in a Southern European population using a nationwide register. 

Methods:  We evaluated 383 RA patients for associations between anti-TNF treatment response, assessed by an absolute change in DAS28 at six months as the primary outcome, and single nucleotide polymorphisms (SNP) from TRAF1/C5, TNFAIP3, REL, PADI4, PTPN22 and PTPRC loci and HLA-DRB1*04high-resolution genotyping. We also studied the same association taking the proportion of EULAR good responders and non responders at six months as the outcome. Univariate and multivariate linear and logistic regression analyses were performed, adjusting for clinical variables known to influence treatment response.

Results: Our study sample included 383 Caucasian individuals with RA, 89.5% were women. 72.6% were seropositive.  At six months, 119 (31.1%) patients were classified as good responders, 175 (45.7%) as moderate responders and 89 (23.2%) as non-responders according to the EULAR response criteria.

The minor allele (G), which is the risk allele for RA susceptibility, rs3761847 SNP in the TRAF1/C5region was associated with a poor anti-TNF treatment response either in linear (coefficient -0.24; 95% confidence interval (CI) -0.43, -0.06; p-value 0.009) and in logistic univariate (odds ratio (OR) 0.61; CI 0.41, 0.92; p-value 0.018) and multivariate regression analyses. P-value of 0.009 for linear models either univariate and multivariate was very close to the level of significance set to 0.0083 after Bonferroni correction to multiple comparisons (Table 1).

No significant associations were observed between HLA-DRB1or the other allele variants with the response to anti-TNF treatment. 

Table 1- Association of the rs3761847 single nucleotide polymorphism of TRAF1/C5 locus with the response to anti-TNF treatment

Change in DAS

Absolute change in DAS

n=383

EULAR good response vs non-response n=208 (good=119, non=89)

 

Linear regression models

Logistic regression models

1.95 (1.26) 1.82 (1.31)

1.38 (1.19)

Univariate

Coef. -0.24

CI -0.43,-0.06

P 0.009

Multivariate

Coef. -0.23

CI -0.40,-0.06

P 0.009

Univariate

OR 0.61

CI 0.41,0.92

P 0.018

Multivariate

OR 0.58

CI 0.37,0.91

P 0.019

Conclusion: The rs3761847 TRAF1/C5 RA risk locus influenced the anti-TNF treatment response in the Southern European population assessed in this study. Additional studies in other populations are necessary to confirm the relevance of this finding.

Disclosure:

H. Canhao,
None;

A. M. Rodrigues,
None;

M. J. Santos,
None;

D. Carmona-Fernandes,
None;

B. Bettencourt,
None;

J. Cui,
None;

F. Rocha,
None;

J. canas Silva,
None;

J. Polido Pereira,
None;

J. A. Pereira Silva,
None;

J. A. Costa,
None;

D. Araujo,
None;

C. Silva,
None;

H. Santos,
None;

C. Duarte,
None;

F. Pimentel-Santos,
None;

J. C. Branco,
None;

R. M. Plenge,
None;

D. H. Solomon,

Amgen,

2,

Abbott Immunology Pharmaceuticals,

2,

Eli Lilly and Company,

2,

Pfizer Inc,

;

J. Bruges Armas,
None;

J. A. P. Da Silva,
None;

J. E. Fonseca,
None;

E. W. Karlson,
None.

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