The association between SE and rheumatoid arthritis susceptibility and severity is well established. However, the gene–dose effect of the SE remains more controversial. Some studies described this dose effect in populations such as white southern Europeans and Asians, though not in Greeks.23
In early rheumatoid arthritis, the SE was associated with erosive disease in white subjects.24,25
Again in retrospective studies, the presence of a double SE dose was associated with a greater risk of developing rheumatoid arthritis.26,27
Other reports did not find such an SE dose effect.28
In this large population, we found a clear gene–dose effect on radiological joint destruction in rheumatoid arthritis. The SE impact increased with disease duration. The same dose effect was observed between the SE and selection for infliximab treatment. These patients with active disease despite methotrexate had both more active and more destructive disease, extending the link between the SE and severity.
To our knowledge, this is the first report showing a dose effect between the SE and selection for anti‐TNFα treatment (infliximab, the first commercially available TNF inhibitor). As the effect of the SE on joint destruction was not obvious before the disease had been present for than two years, detection of the SE at an early stage of disease might help to select patients for early aggressive treatment, in particular with TNF inhibitors. Such an early decision might improve the final outcome significantly.29
A potential selection bias was reduced here since during the recruitment period (January 2000 to July 2003) all rheumatoid patients were enrolled in the study in four university hospitals whether or not they were receiving infliximab.
This post‐marketing study was conducted to test whether genetic markers could explain the clinically heterogeneous improvement resulting from treatment with infliximab combined with methotrexate. We found no link between the SE status and infliximab response. This may not come as a surprise: as the SE was already associated with selection for treatment one would not expect an additional effect on response. However, previous studies showed that the SE could be a prognosis factor for a DMARD. In fact, SE positive patients were much more likely to achieve a good response if treated with methotrexate‐sulfasalazine‐hydroxychloroquine than with methotrexate alone. In contrast, SE negative patients did equally well regardless of treatment.30
In a small population of 48 rheumatoid patients treated with etanercept, 55% (six of 11) of the non‐responders were SE negative but only 8% of the responders (two of 37).31
In another study of 457 rheumatoid patients, two copies of the SE was a significant predictive factor for response to etanercept treatment.32
However, in another small population of 78 rheumatoid patients treated with infliximab, the SE carrier rate was the same in responders and in non‐responders.33
In this study, it was suggested that genetic determinants inside the HLA complex could predict the response to infliximab.
We found no significant linkage between some selected cytokine SNPs and the clinical response to infliximab. Surprisingly, no difference in the ACR20 response was observed in our population with respect to the TNFA −308 genotype. In a previous study involving 59 rheumatoid patients, Mugnier et al
found that those carrying the rare allele A were twice as likely to have no response as those with the common G/G genotype.34
A higher level of TNFα production in different conditions has been associated with the rare allele A at position −308 of the TNF promoter.35,36,37
The explanation for the discrepancy between our study and Mugnier's is unclear. The two populations were both from France, with a rather similar genetic background, although our study was more powerful, with four times as many patients. The rheumatoid disease activity appeared the same in the two studies (DAS28
5.36 (1.08) v
5.7 (1.0); NS). However, our data were similar to those showing the absence of an influence of the −308 TNFA SNP on the response to infliximab in Crohn's disease.38
This post‐marketing study in a large cohort of patients with rheumatoid arthritis showed a linkage between rheumatoid disease severity and selection for treatment with infliximab. The SE was associated with rheumatoid arthritis severity in the whole population. Furthermore, patients carrying the SE, in particular homozygotes, were more likely to receive such treatment, extending the link to severity. This result needs to be extended to other TNFα blockers. As the effect of the SE on joint destruction only becomes apparent after at least two years of disease evolution, early detection of the SE may be useful for identifying patients at risk of joint destruction and starting protective treatment at an early stage of the disease.