Importantly, the association of ERAP1 with AS susceptibility is present only in HLA-B27-positive individuals (i.e., there is an epistatic interaction between the polymorphisms in the HLA-B and ERAP1 genes with regard to AS susceptibility). Similar interactions have been described for psoriasis (HLA-C*06:02 and ERAP1), Behçet’s disease (HLA-B*51 and ERAP1) and birdshot retinopathy, an inflammatory disease of the eye (HLA-A*29 and ERAP2).39-41 McGonagle has termed these diseases MHC I-opathies.38 Whether the mechanisms linking these MHC class I/ERAP pairs and disease are the same or different needs to be investigated.
HLA-B27 in Clinical Practice
HLA-B27 is included as a parameter in the Assessment of Spondyloarthritis International Society (ASAS) classification criteria for axial (see Figure 5) and peripheral SpA.43,44 However, HLA-B27 is not included in the modified New York criteria (see Figure 6), which are frequently used to diagnose AS, and HLA-B27 positivity is neither required nor sufficient for making a diagnosis of AS or SpA.45
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Figure 5: 2009 ASAS Classification Criteria for Axial SpA (in patients with back pain ≥3 months and age at onset44
Data regarding the prognostic or predictive value of HLA-B27 are heterogeneous. A recent analysis of genetic factors affecting radiographic disease severity in a cohort of 1,537 AS patients with established disease (mean disease duration ~20 years) failed to show a correlation between HLA-B27 status and radiographic disease severity in the spine.46 In contrast, HLA-B27 positivity was associated with more rapid radiographic progression in the SI joints in a cohort of patients with early axial SpA.47 HLA-B27 positivity was identified as a predictor of a good response to TNF inhibitor therapy in two studies, but not in others, possibly because the latter studies were small and did not include enough HLA-B27 negative patients.48-50 It is unclear whether the difference in response to TNF inhibition was due to an earlier diagnosis in HLA-B27+ subjects or whether there is a true difference in biology.49,51
The picture becomes even more complex when SpA is considered more broadly. A recent study from Dublin analyzed MHC class I genotypes and SpA disease manifestations in a clinically well-characterized cohort of 282 psoriatic arthritis patients.52,53 This study reproduced the well-described associations of HLA-C*06:02 with psoriasis and HLA-B*27:05 with axial disease, in particular with symmetric sacroiliitis. Importantly, additional associations between other MHC class I alleles and distinct disease phenotypes were identified, including an association of HLA-B*08:01 with asymmetric sacroiliitis, and HLA-C*02:02 with arthritis mutilans. Thus, although there is currently no added value in measuring HLA-B27 in patients with a clinical diagnosis of AS and positive radiographs of the SI joints, HLA-B27 and/or comprehensive MHC class I genotyping may have utility, pending confirmation in independent studies, to identify relevant SpA subsets and predict therapeutic responsiveness in the future.
Conclusion
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Figure 6: Modified New York Criteria for Ankylosing Spondylitis (1984)45
