Background ERAP1 trims peptides to the correct length to fit into the binding groove of MHC class I allowing antigen presentation. The association of ERAP1 with Ankylosing Spondylitis (AS) has been confirmed in a number of studies in both Caucasian and Asian cohorts, and requires the presence of HLA-B27. ERAP1 is highly polymorphic forming distinct allotypes, with both chromosomal copies of ERAP1 being co-dominantly expressed. These ERAP1 allotypes form three functional groups; “normal”, “hypo-” or “hyper-” trimmers of peptides. The prevalence of different ERAP1 allotype combinations has been shown to be different between AS cases and controls.1
Objectives The aim of the study was to determine whether ERAP1 allotype combinations were associated with disease severity in AS patients. The need for biological therapy was used as a surrogate for classification of patients as having severe AS, as patients in the United Kingdom needed to fulfil criteria to gain access to biological therapy [AS confirmed, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)>4 on two occasions, failure to respond to non-steroidal anti-inflammatory drugs (NSAIDs)].
Methods We have recently sequenced both copies of the full ERAP1 gene in 25 individuals with AS to determine their allotype combinations and describe the consequence of these on peptide trimming function. Demographics, clinical characteristics, laboratory results and biological therapy use were also recorded. Following a detailed review of outpatient and inpatient clinical records we then compared the ERAP1 allotype combinations present in individuals with the severity of their disease using the need for biological therapies as a surrogate for severe disease.
Results In total, 88.0% of patients were HLA-B27*05 positive. 72.0% were males, and all were Caucasian. Mean age was 52.1±13.0 years. 92.0% of patients satisfied the Modified New York criteria for AS (defining sacroilitis on magnetic resonance imaging or X-ray), whilst 100.0% of patients satisfied the ASAS criteria for axial spondyloarthritis. 68.0% of patients had inflammatory back pain, 16.0% had enthesitis, 44.0% had uveitis, 4.0% had peripheral arthritis, and 16.0% had history of inflammatory bowel disease. 28.0% of patients reported a family history of spondyloarthritis. Only 48.0% of patients reported improvement of symptoms with NSAIDs. 32.0% (8/25) of patients were on biological therapy. The ERAP1 allotype combinations in patients in order of frequency were: 001 and 005 (36.0%), 001 and 001 (12.0%), 001 and 007 (8.0%) and other combinations (44%). However, no unique ERAP1 allotype combination was associated with severe AS in our cohort.
Conclusions ERAP1 allotype combinations that have an overall hypo- or hyper-functional peptide trimming function are associated with AS. However, initial work suggests that this is associated with the classification of AS rather than its severity.
Reeves E, Colebatch-Bourn A, Elliott T, Edwards CJ, James E. Functionally distinct ERAP1 allotype combinations distinguish individuals with Ankylosing Spondylitis. Proc Natl Acad Sci U S A. 2014;111(49):17594-9.
Disclosure of Interest None declared