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: ACR/ARHP Annual Meeting 2012

Keywords: rheumatoid arthritis (RA) and treatment

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,

Abbott Immunology Pharmaceuticals,

Eli Lilly and Company,

Pfizer Inc,

;

J. Bruges Armas,
None;

J. A. P. Da Silva,
None;

J. E. Fonseca,
None;

E. W. Karlson,
None.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/traf1c5-locus-is-associated-with-response-to-anti-tumor-necrosis-factor-therapy-in-patients-with-rheumatoid-arthritis/