Association of the major histocompatibility complex with response to infliximab therapy in rheumatoid arthritis patients.
OBJECTIVE
To determine whether major histocompatibility complex (MHC) polymorphisms are associated with a good or poor response to infliximab therapy in patients with rheumatoid arthritis (RA).


METHODS
Seventy-eight infliximab-treated patients with RA were genotyped for HLA-DRB1, HLA-DQA1, HLA-DQB1, MHC class I chain-related gene A (MICA) transmembrane polymorphism alleles, and tumor necrosis factor a (TNFa), TNFb, TNFc, TNFd, TNFe, D6S273, HLA-B-associated transcript 2 (BAT2), and D6S2223 microsatellites. Chi-square tests were performed to compare allele proportions between responder and nonresponder patients. A control sample of 342 healthy individuals was also included to detect linkage disequilibrium between pairs of markers.


RESULTS
Among responders, the frequency of the TNFa11;b4 minihaplotype was increased (41% versus 16% in nonresponders; P = 0.01) and that of the D6S273_3 allele was decreased (32% versus 56% in nonresponders; P = 0.04). The D6S273_4/BAT2_2 pair was much more frequently observed among responders (46% versus 11% in nonresponders; P = 0.001). When compared with controls, this pair of alleles was found to be associated only with the group of responder patients (46% in responders versus 17% in controls; P = 0.00002). Most of the time, these markers are present in a DRB1*0404/D6S273_4/BAT2_2/TNFa11;b4 context. No statistically significant differences were observed for MICA and D6S2223 polymorphisms and for shared epitope status.


CONCLUSIONS
The data suggest that genetic determinants of response to infliximab therapy exist in the HLA complex.
Martinez
Alfonso
A
Hospital Clinico San Carlos, Madrid, Spain. alfmdoncel@terra.es
Salido
Marina
M
Bonilla
Gema
G
Pascual-Salcedo
Dora
D
Fernandez-Arquero
Miguel
M
de Miguel
Sonia
S
Balsa
Alejandro
A
de la Concha
Emilio G
EG
Fernandez-Gutierrez
Benjamin
B
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics*; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D006683:HLA-DQ Antigens / Q000235:genetics; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D000069285:Infliximab; D015810:Linkage Disequilibrium; D008233:Lymphotoxin-alpha / Q000235:genetics; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D010641:Phenotype; D011506:Proteins / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; C069050:HLA-DQA1 antigen; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D015395:Histocompatibility Antigens Class I; D008233:Lymphotoxin-alpha; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; C092008:PRRC2A protein, human; D000069285:Infliximab