Association of HLA-DR3 with anti-cyclic citrullinated peptide antibody-negative rheumatoid arthritis.
OBJECTIVE
Recent data have shown that the most prominent and longest known genetic risk factors for rheumatoid arthritis (RA), HLA-DRB1 shared epitope alleles, are only associated with RA that is characterized by the presence of antibodies against cyclic citrullinated peptide (anti-CCP antibodies) and not with anti-CCP-negative RA. We undertook this study to investigate whether anti-CCP-negative RA is associated with other HLA-DRB1 alleles.


METHODS
HLA typing was performed for 377 patients from the Leiden Early Arthritis Clinic who were diagnosed as having RA within the first year of followup (206 anti-CCP-positive patients and 171 anti-CCP-negative patients), 235 patients who, after 1 year, had undifferentiated arthritis (UA) (28 anti-CCP-positive patients and 207 anti-CCP-negative patients), and 423 healthy control subjects. Odds ratios (ORs) with 95% confidence intervals (95% CIs) for HLA-DRB1 allele frequencies were determined for all patient groups compared with the healthy control group.


RESULTS
HLA-DR3 was more frequently present in the anti-CCP-negative RA group than in the control group (OR 1.84, 95% CI 1.26-2.67). This was not the case for anti-CCP-positive RA (OR 0.92, 95% CI 0.60-1.40). HLA-DR3 was also more frequently present in anti-CCP-negative UA patients (OR 1.59, 95% CI 1.10-2.28), but not in anti-CCP-positive UA patients (OR 0.68, 95% CI 0.17-1.92).


CONCLUSIONS
HLA-DR3 is associated with anti-CCP-negative arthritis and not with anti-CCP-positive arthritis. These data show that distinct genetic risk factors are associated with the presence of anti-CCP antibodies in RA and indicate that different pathogenetic mechanisms underlie anti-CCP-positive and anti-CCP-negative RA.
Verpoort
Kirsten N
KN
Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. K.N.Verpoort@lumc.nl
van Gaalen
Floris A
FA
van der Helm-van Mil
Annette H M
AH
Schreuder
Geziena M T
GM
Breedveld
Ferdinand C
FC
Huizinga
Tom W J
TW
de Vries
Rene R P
RR
Toes
Rene E M
RE
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology*; D001323:Autoantibodies; D005260:Female; D005787:Gene Frequency; D015803:HLA-DR3 Antigen / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000276:immunology*; D012307:Risk Factors
D001323:Autoantibodies; D015803:HLA-DR3 Antigen; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide