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

Abstract

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.

Figure 1

Patients with axSpA face significant diagnostic delays, which are potentially longer for HLA‐B27‐negative individuals (18, 19, 20). This figure represents an idealized graph based on data from the cited references. axSpA, axial spondyloarthritis; HLA‐B27, human leukocyte antigen B27.

Figure 2

Potential HLA‐B27 independent drivers of axSpA pathogenesis and disease progression. axSpA, axial spondyloarthritis; CARD9, caspase recruitment domain‐containing protein 9; HLA‐B, human leukocyte antigen B; IL, interleukin; IL‐1R2, interleukin 1 receptor type 2; MIF, macrophage migration inhibitory factor; NOD2, nucleotide‐binding oligomerization domain‐containing 2; Th17, T helper 17.

Figure 3

Differences in clinical phenotypes between HLA‐B27‐positive and ‐negative patients with axSpA (19, 46, 47, 137, 138, 139, 140, 141, 142, 143, 144). *As measured by C‐reactive protein and Ankylosing Spondylitis Disease Activity Score with C‐reactive protein. AS, ankylosing spondylitis; axSpA, axial spondyloarthritis; IBD, inflammatory bowel disease; nr‐axSpA, nonradiographic axial spondyloarthritis; SIJ, sacroiliac joint; TNFi, tumor necrosis factor inhibitor.