Association between HLA class II genes and autoantibodies to CCPs influences the severity of RA

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Arthritis Rheum. 2004 Jul;50(7):2113-21.

Association between HLA class II genes and autoantibodies to cyclic

citrullinated peptides (CCPs) influences the severity of rheumatoid

arthritis.

Van Gaalen FA, Van Aken J, Huizinga TW, Schreuder GM, Breedveld FC,

Zanelli E, Van Venrooij WJ, Verweij CL, Toes RE, De Vries RR.

Leiden University Medical Center, Leiden, The Netherlands.

OBJECTIVE: The functional role of HLA class II molecules in the

pathogenesis of rheumatoid arthritis (RA) is unclear. HLA class II

molecules are involved in the interaction between T and B lymphocytes

required for long-lived B cell responses and generation of high-affinity

IgG antibodies. We undertook this study to investigate the relationship

between HLA class II gene polymorphisms and RA-specific IgG antibodies

against cyclic citrullinated peptides (anti-CCP antibodies). METHODS:

High-resolution HLA-DR and DQ typing and anti-CCP-2 antibody testing

were performed on 268 RA patients from the Early Arthritis Clinic cohort

at the Department of Rheumatology of the Leiden University Medical

Center. The presence of anti-CCP antibodies was analyzed in carriers of

the different DR and DQ alleles. Disease progression was measured over a

period of 4 years by scoring radiographs of the hands and feet using the

Sharp/van der Heijde method. RESULTS: rship of the individual

alleles HLA-DRB1*0401, DRB1*1001, DQB1*0302, and DQB1*0501 was

associated with the presence of anti-CCP antibodies. rs of DQ-DR

genotypes containing proposed RA susceptibility alleles were

significantly more often anti-CCP antibody positive. rship of one

or two HLA-DRB1 shared epitope (SE) alleles was significantly associated

with production of anti-CCP antibodies (odds ratio [OR] 3.3, 95%

confidence interval [95% CI] 1.8-6.0 and OR 13.3, 95% CI 4.6-40.4,

respectively). An increased rate of joint destruction was observed in

SE+, anti-CCP+ patients (mean Sharp score 7.6 points per year) compared

with that in SE-, anti-CCP+ patients (2.4 points per year) (P = 0.04),

SE+, anti-CCP- patients (1.6 points per year) (P < 0.001), and SE-,

anti-CCP- patients (1.6 points per year) (P < 0.001).

CONCLUSION: HLA class II RA susceptibility alleles are associated with

production of anti-CCP antibodies. Moreover, more severe disease

progression is found in RA patients with both anti-CCP antibodies and SE

alleles.

PMID: 15248208 [

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