Update April 4, 2019


Content 4



What are the possible roles of HLA-B27 in this condition? What other factors may be involved?

B. Although HLA-B27 has been linked to the spondyloarthropathies for decades, how it interfaces with the immune system to facilitate disease initiation and propagation remains unclear. One hypothesis is that “self” or foreign (microbial) antigens, bound to the HLA-B27 binding groove, may be recognized by the T-cell receptors of autoreactive CD8+ T cells, inciting an inflammatory response. An alternative hypothesis is that a misfolding of the B27 molecule within the cell results in endoplasmic reticulum stress that triggers an unfolded protein response and an upregulation of IL-23 cytokine levels. A third hypothesis is that, when expressed at the cell surface, B27 free heavy chains are recognized by cells bearing killer immunoglobulin-like receptors and trigger an inflammatory response.

The cytokine milieu is also an important component of the inflammation associated with this spondyloarthropathy. An emerging and prominent role for IL-17 and IL-23 has come to light in the pathogenesis of the spondyloarthropathies, particularly ankylosing spondylitis and psoriatic arthritis. Elevated levels of IL-12 have been detected as well. Genome-wide association studies have demonstrated a linkage between the IL-23 receptor and single nucleotide polymorphisms of the IL-12 receptor in ankylosing spondylitis. Further, an intergenic region between these two loci modulates enhancer activity and heightened levels of TH1 cell differentiation. In addition, in patients with high disease activity, TH17 cells have been detected in the circulation, spinal facet joints, and synovium. These activated cytokines and effector cells also play a role in bone resorption and remodeling.


What potential treatments could be offered to this patient?

C. Older, established agents used in the treatment of ankylosing spondylitis are anti-inflammatory drugs, including nonsteroidal anti-inflammatory agents, methotrexate, and sulfasalazine. Newer, more targeted agents that have more recently been approved by the FDA for the treatment of ankylosing spondylitis (and other spondyloarthropathies) include TNFα inhibitors (eg, etanerceptadalimumab), an IL-17A inhibitor (secukinumab), and a novel monoclonal antibody that targets IL-12 and IL-23 (ustekinumab).


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