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Dr Brown and his colleagues1 are to be congratulated for performing a logistically formidable, but necessary, epidemiological study testing the currently in vogue hypothesis that the B*2703 subtype of HLA-B27 is not related to ankylosing spondylitis (AS). They conclude that the B*2705 subtype, as well as B*2703, possesses a lower risk for developing AS in a group of B27 positive west Africans, the Fula from Gambia, when compared with B27 positive white subjects invoking the potential protective role of an environmental factor(s). This conclusion is based on an assumed risk of developing AS in B27 positive persons of 11.1% for men and 1.5% for women.2 No cases of AS were seen among 900 adult Fula men and 215 first degree relatives of 48 B27 positive Fula twin pairs. We would argue that the data warrant the more conservative conclusion implied in their discussion, namely, the risk for AS among B27 positive Fula subjects would need to be at least 2.7% in men and 1% in women to assign significance to the finding of no AS in this population.
The risk of developing AS in HLA-B27 positive subjects clearly varies among different ethnic groups, but it is now generally accepted that among white populations, the prevalence of AS is nearer 1–2% rather then 11.1%.3 ,4 The Norwegian survey of 14 539 subjects2 quoted by the authors is in fact based on a highly selected sample of only 375 people responding positively to a questionnaire for low back pain or stiffness who actually turned up for examination and had x rays of sacroiliac joints. You arrive at an entirely different conclusion if you apply the AS prevalence figures of 1.4% for B27 subjects from the Busselton population study3 or 1.3% of Dutch B27 positive subjects.4 The second study examined 2956 subjects older than 44 years who all had sacroiliac x rays and only three B27 positive subjects had AS according to the New York criteria leading to a prevalence of 0.1%. Recalculating the data of Brown et al according to these more generally accepted prevalence rates leads to the following conclusions. The probability of observing no cases of AS in 900 adult Fula men would be 46.9% (that is, p=0.47). The number of B*2703 persons expected to develop AS would be zero, as in fact observed in this population. Even assuming a risk of 2.7% for AS in B27 positive subjects, the likelihood that no cases of AS would be found in 900 adult Fula men is 23.2% (that is, p=0.232). Furthermore, we calculate that the prevalence of AS in the population of B27 positive adult Fula men would need to be at least 5.54% before the finding of zero observed cases of AS in 900 adult Fula men would be statistically significantly different.
We conclude that the issue of B*2703 and risk for AS remains an open question and in need of further more extensive population prevalence studies.
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Authors’ reply
We would like to thank Dr Maksymowych for his interest in our study. We agree with his conclusion that our study shows that B27 is not associated with ankylosing spondylitis (AS) in the Gambia, as long as the risk of AS in B27 positive men is greater than 2.7% and women is greater than 1% (which we believe to be the case). We feel that most of his criticisms can be satisfactorily answered.
The risk of developing AS in B27 positive subjects is uncertain. The studies mentioned by Dr Maksymowych are among the lowest estimates that have been reported for white populations. Other studies have reported that as many as 20% of B27 positive subjects may develop the disease.1-1 The survey by Gran et al is by far the largest reported1-2: 21 329 subjects were invited to participate in a study of cardiovascular disease, of whom 16 621 attended screening sessions. Of these, 14 539 (87%) completed questionnaires including questions about back problems; 2907 reported a history of pain or stiffness in the back—the remainder were asymptomatic. From this group a random sample of 806 were invited to attend for clinical screening, of which 449 did; 375 of these had sacroiliac radiography. Comparisons at each step demonstrated that selection bias was minimal. We believe therefore that not only is this study significantly larger than either of the studies mentioned by Dr Maksymowych, but is also reliable. It is also the only study of sufficient size to determine the risk for AS among men and women with B27 separately, which was a requirement for our analysis.
The risk for AS among B27 positive men is significantly greater than B27 positive women. In our study 1008 participants were male and 107 female. Therefore it was important to use sex-specific risk estimates, which Dr Maksymowych has not used in his calculations. Also, the study examined 215 relatives of 48 B27 positive subjects in addition to the 900 adult Fula men used in Dr Maksymowych’s calculations. Analysing the total study population (n=1115), we showed that AS was not associated with B27 in the Gambia (p<0.05), assuming that the risk of AS was ⩾1.85% in B27 positive subjects, and that men were 2.7 times more likely to develop disease than women (both of these assumptions are conservative). Using a higher male:female ratio would allow us to exclude even lower degrees of association of B27 with AS.
Our study confirmed the previous finding that AS is extremely rare in west Africa— indeed no case has yet been reported from the Gambia.1-3-1-5 This is despite the prevalence of B27 being as high as 7.8% in some ethnic groups.1-6 The fact that 68% of B27 positive subjects in this area carry B*2705 indicates that it is not a difference in B27 subtypes that explains the rarity of the disease. Furthermore, two separate groups have now reported cases of AS in B*2703 subjects.1-7 1-8
It remains possible that B*2703 has a lower risk for AS than other disease associated subtypes. However AS is not associated with either B*2703 or B*2705 in the Gambia. Future comparisons of the strength of association of B27 subtypes with AS need to consider other environmental and genetic differences between the different populations studied.