What is HLA-B27 (Human Leukocyte Antigen subtype) and its clinical significance?

What is HLA-B27?

HLA-B27 is a human leukocyte antigen (HLA) class I molecule—a genetic marker found on the surface of cells that presents peptides to the immune system—and it is most clinically significant for its strong association with ankylosing spondylitis and other spondyloarthropathies. 1

Basic Biology and Function

• HLA-B27 is a member of the HLA class I family of genes in the major histocompatibility complex, originally named for its role in transplanted tissue compatibility 2

• The natural immunological function of HLA-B27 is to bind antigenic peptides and present them on the cell surface to cytotoxic T lymphocytes (CD8+ T cells), defending the organism against microbes including influenza, HIV, and Epstein-Barr virus 3, 4

• HLA-B27 prevalence in the mid-European population is approximately 8%, though this varies significantly by ethnicity and geographic region 2

Genetic Diversity

• Approximately 200 subtypes of HLA-B27 exist (designated HLA-B2701 through B2720 and beyond), which have evolved from the B*2705 subtype through changes in the peptide-binding groove 5

• Two subtypes (B2706 in Southeast Asians and B2709 in Sardinians) appear to have a relatively weaker association with ankylosing spondylitis, suggesting that not all HLA-B27 variants confer equal disease risk 5

• HLA-B27 testing is performed using molecular methods that detect the genotype directly and only needs to be done once in a patient's lifetime 1

Clinical Significance in Spondyloarthropathies

Disease Association Strength

• HLA-B27 is positive in 74-89% of patients with ankylosing spondylitis, making it the strongest immune marker associated with this disease 1

• About 60-90% of axial spondyloarthritis patients worldwide carry HLA-B27, though the prevalence varies by population 2

• In psoriatic arthritis with axial involvement, only 25-75% are HLA-B27 positive, which is notably lower than in ankylosing spondylitis 6

• Approximately 10% of ankylosing spondylitis cases are HLA-B27 negative, meaning the absence of HLA-B27 does not rule out disease 7, 1

Diagnostic Interpretation

• HLA-B27 should be used as a screening parameter to increase pre-test probability, NOT as a definitive diagnostic test 1

• Among patients with chronic back pain who are HLA-B27 positive, approximately 30-40% will ultimately receive an ankylosing spondylitis diagnosis 1

• A negative HLA-B27 test should NOT rule out spondyloarthritis, as the disease can occur in HLA-B27 negative patients and can be just as severe 7

• HLA-B27 positivity should be combined with clinical criteria (inflammatory back pain characteristics, imaging findings, extra-articular manifestations) for diagnostic and referral decisions 1

Clinical Context for Testing

• HLA-B27 testing is most appropriate in patients with chronic back pain (>3 months) starting before age 45 with characteristics of inflammatory back pain: morning stiffness >30 minutes, nocturnal/early morning pain, and improvement with exercise 7

• The test costs approximately €40 (equivalent to a chest or pelvis X-ray) and is cost-effective when used appropriately in the right patient population 1

• HLA-B27 testing can be considered on a case-by-case basis in patients with axial involvement or inflammatory back pain to support the diagnosis of axial spondyloarthritis 8

Pathogenic Mechanisms (Theoretical)

• HLA-B27 explains less than 30% of the total genetic load in ankylosing spondylitis, indicating other genetic and environmental factors are involved 2

• The role of endoplasmic reticulum aminopeptidase 1 (ERAP1) polymorphisms—which are only associated with HLA-B27+ disease—supports the "arthritogenic peptide hypothesis", suggesting that HLA-B27 may present unique self-peptides that drive immunopathology 2, 4

• HLA-B27 can misfold during assembly, leading to endoplasmic reticulum stress and autophagy responses, and can form cell surface homodimers that bind to innate immune receptors with proinflammatory effects 4

Important Clinical Pitfalls

• Spondyloarthritis should not be ruled out based solely on normal inflammatory markers (CRP, ESR) or negative HLA-B27, as these can be normal even in active disease 1

• HLA-B27 negative status should not delay appropriate treatment, as the disease can be just as severe as in HLA-B27 positive patients 7

• In inflammatory bowel disease-associated spondyloarthritis, HLA-B27 prevalence is lower (25-75%), making it less reliable as a diagnostic test in this population 1