Ankylosing spondylitis: History, epidemiology, and HLA‐B27

The history of ankylosing spondylitis (AS) dates back to antiquity. However, it was only in 1695 when Bernard Connor first published its anatomical description based on a skeleton of a patient with advanced AS.1, 2 The term axial spondyloarthritis (axSpA), coined to encompasses both AS and the non-radiographic form of axSpA (nr-axSpA), is now preferred to emphasize its wider spectrum.2 Disease prevalence refers to the proportion of patients in a population at or during a particular time period and is expressed as a percentage.3 Disease incidence refers to the number of patients per 100 000 individuals within a period, such as a year.3 On average, the estimates of global prevalence of AS among adult populations of North America (total subjects = 109 414 800) and Europe (total subjects = 10 312 889) range between 0.20% and 0.25%; whereas its prevalence is 0.29% in military populations in mainland China (total subjects = 54 474) and 0.35% among the Northern Arctic communities that have the world's highest prevalence of human leukocyte antigen (HLA)-B27.3-5 In contrast, AS is very rare in the indigenous populations of southern parts of Africa that lack HLA-B27,3, 4 indicating that the prevalence of AS roughly directly correlates with the prevalence of HLA-B27 in the population. The mean annual incidence of AS also shows a direct correlation with the prevalence of HLA-B27.3, 6 HLA-B27 represents a family of closely related proteins encoded by an ever-increasing number of alleles. By the year 2017 there were more than 210 known alleles of HLA-B27 based on nucleotide sequence differences, and at the translated protein level, there are more than 160 known subtypes of HLA-B27 based on amino acid sequence differences because some of the gene mutations are located within introns and thus are silent, or they occur in exons but do not result in any change in the amino acid composition.6 The HLA nomenclature has been updated to encompass this extreme heterogeneity, and as of June 2022, the 260 known alleles are numbered HLA-B*27:01 to HLA-B*27:260. They show an extremely varied racial and ethnic prevalence throughout the world. HLA-B*27:05 is the most widely distributed disease-associated subtype and the others include HLA-B*27:02 (Mediterranean populations) and HLA-B*27:04 (Chinese and other Asian populations).6 The prevalence of these subtypes influences disease prevalence because of their differences when it comes to their association with AS. For example, HLA-B*27:05 and HLA-B*27:02 seem to confer equal susceptibility to AS in Caucasian populations.6, 7 But among the people of Chinese descent, HLA-B*27:04 has a stronger association with AS and also carries a greater risk for AS than the HLA-B*27:05 subtype. On the other hand, HLA-B*27:06 (a common subtype in southeast Asia) and HLA-B*27:09 (a rare subtype found primarily on the Italian island of Sardinia) seem to lack association with typical AS, that is, they are “disease neutral”. This discovery has solved the paradox of higher prevalence of AS among Chinese Indonesians (with only 5% HLA-B27 prevalence in their general population) than in the native Indonesian population (that has up to 12% HLA-B27 prevalence). The reason for this apparent paradox is that HLA-B*27:06 is the predominant subtype among HLA-B27-positive native Indonesians, whereas the Chinese Indonesians possess the HLA-B*27:04 and HLA-B*27:05 subtypes that are disease-associated.1, 3, 6 It is of interest that HLA-B*27:06 differs from its closely related disease-associated subtype HLA-B*27:04 by only 2 amino acids, and HLA-B*27:09 differs from its closely related disease-associated subtype HLA-B*27:05 by only one amino acid substitution (Table 1).1, 3, 6 Genetic studies have demonstrated ERAP1 association with AS only in HLA-B27-positive patients, but ERAP2 is associated with AS among both HLA-B27-positive and HLA-B27-negative patients.10 There is also an HLA-B27-independent common link of AS and inflammatory lesions in the gut and skin.