Human Leukocyte Antigen B27‐Negative Axial Spondyloarthritis: What Do We Know?

Axial spondyloarthritis (axSpA) is a chronic, immune‐mediated disease characterized by inflammatory axial skeleton involvement and extra‐musculoskeletal manifestations. The continuum of axSpA ranges from nonradiographic axSpA (nr‐axSpA) to ankylosing spondylitis, also known as radiographic axSpA; the latter is defined by definitive radiographic sacroiliitis. Human leukocyte antigen B27 (HLA‐B27) is a genetic marker strongly associated with axSpA; it aids in the diagnosis of axSpA, and its absence leads to delay in diagnosis. For HLA‐B27‐negative patients, disease pathogenesis is poorly understood, signs and symptoms are frequently underrecognized, and diagnosis and treatment are commonly delayed. The proportion of HLA‐B27‐negative patients may be higher among non‐White patients and those with nr‐axSpA, who can face additional diagnostic challenges related to lack of definitive radiographic sacroiliitis. In this narrative review, we discuss the role of HLA‐B27 in the diagnosis and pathogenesis of axSpA and highlight various pathways and genes that may be related to axSpA pathogenesis in HLA‐B27‐negative patients. We also emphasize the need to characterize gut microbial communities in these patients. Adequate understanding of clinical and pathological features underlying HLA‐B27‐negative patients with axSpA will improve diagnosis, treatment, and outcomes for this complex inflammatory disease.