Hepatitis B vaccination and rheumatoid arthritis
GACVS considered the potential association of hepatitis B vaccination (HBV) and rheumatoid arthritis (RA). Prior to previous discussions on this topic held in June 2006, the committee had commissioned a comprehensive literature review. At this meeting, it had reviewed more recent information, particularly on genetic issues.
The literature relating HBV to RA comprises mainly single case reports, case series and a few case–control studies. The published studies are limited and difficult to interpret owing to problems in the methodology and control of confounding. The one high-quality case–control study did not find a statistically significant association, but it had limited power and wide confidence intervals. However, as only a small proportion of cases had received HBV, there is at most a very small contribution of HBV to the incidence of RA. GACVS had also seen the preliminary results of a large study based on the United States Vaccine Safety DataLink (VSD) project in June 2006, which was analysed in several ways, but none showed a significant association between HBV and RA.
It had been suggested that the failure to find any increased risk overall following HBV may be because the adverse effect of vaccination is present only in a small subgroup that might be at increased risk of RA because of their genetic make-up. GACVS considered the preliminary results of genetic analyses conducted using the VSD case–control study, which was able to classify cases and controls according to their HLA DRB1*04 status. The choice of this marker was made largely because it has been described as a biomarker of the genetic susceptibility to develop RA.
GACVS was presented with a preliminary analysis of the interaction between HBV and HLA status in respect of the occurrence of RA. This is the relevant question if the adverse effect is limited to or occurs largely among a particular genetically-determined subgroup. It has the advantage that analysis can be done using cases of RA alone. These are compared between the genetically determined groups, which will not differ in regard to likelihood of HBV exposure. Hence, confounding is not a major problem.
There are various subtypes of HLA DRB1*04, of which 9 occurred in this study; analyses were limited to 2 of the subtypes.
HBV exposure in the 90, 180 and 365 days before onset of RA symptoms was examined. There was no statistically significant evidence of an increased risk in the genetic subgroups examined, and point estimates were less than unity. However, an increased risk in a subgroup could not be excluded because of the low power of the study, given the small numbers of vaccinated cases. This is an inevitable limitation but this also makes it clear that HBV, at most, can make very little impact on the incidence of RA. In addition, whether HLA DRB1*04 is the best genetic marker for increased risk of development of rheumatoid arthritis is still unknown.
GACVS concluded, based on a review of the limited data available, that there was no convincing evidence to support an association between HBV and RA. It will consider the topic further if new findings become available.