Treating Ankylosing Spondylitis Refractory to TNF-inhibition
Treating Ankylosing Spondylitis Refractory to TNF-inhibition
The pathogenesis of SpA is thought to be largely determined by genetic factors; although not known in detail, recent findings on the close link between HLA B27 and ERAP1 polymorphisms can be considered a major step forward in the immunological understanding of the pathomechanisms involved. Clearly, CD4 and CD8 T cells and macrophages and their products such as TNF also have an important role, as suggested by immunohistological findings and the success (anti-TNF agents) or the failure (anti-IL-1 or anti-IL-6 agents) of targeted therapy. Other factors such as cathepsin K have also been detected in spinal biopsy specimens. However, newly developed treatments for osteoporosis (odanacatib, a cathepsin K antagonist) have not yet been applied in axial SpA. Furthermore, antibodies against vascular endothelial growth factor (bevacizumab), approved by the U.S. Food and drug administration for systemic use in cancer, have not yet been tested in axial SpA either. The same is true for denosumab, a monoclonal antibody targeting RANKL that is now approved for the treatment of postmenopausal osteoporosis.
The increased local expression of RANKL compared with expression of its decoy receptor osteoprotegerin has a role in the pathogenesis of erosions in RA, its role in AS is less clear. In RA, the bone tissue directly exposed to inflammation is the cortical bone surface (synovitis), whereas in AS it is the trabecular bone of the vertebrae (osteitis). Bone formation by osteoblasts is impaired in RA, but seems to be stimulated in AS. Inhibitors of the canonical Wingless (Wnt) signaling pathway, including Dickkopf 1, have been implicated in the suppression of osteoblast function. Activation of Wnt b-catenin signaling induces an imbalance in cartilage homeostasis, and agonists and/or antagonists of Wnt (such as sclerostin, a Wnt signaling pathway antagonist produced by osteocytes and a potent inhibitor of bone formation) are potential candidates for this interaction. Sclerostin seems to be decreased in response to mechanical loading, an interesting hypothesis also for the pathogenesis of axial SpA. Finally, clinically successful TNF-inhibitors do inhibit radiographic damage in RA, but they do not halt new bone formation in AS. Blocking TNF was indeed shown to increase bone mineral density in both diseases. Whether this mechanism also has an effect on syndesmophyte formation remains to be seen.
Discussion
The pathogenesis of SpA is thought to be largely determined by genetic factors; although not known in detail, recent findings on the close link between HLA B27 and ERAP1 polymorphisms can be considered a major step forward in the immunological understanding of the pathomechanisms involved. Clearly, CD4 and CD8 T cells and macrophages and their products such as TNF also have an important role, as suggested by immunohistological findings and the success (anti-TNF agents) or the failure (anti-IL-1 or anti-IL-6 agents) of targeted therapy. Other factors such as cathepsin K have also been detected in spinal biopsy specimens. However, newly developed treatments for osteoporosis (odanacatib, a cathepsin K antagonist) have not yet been applied in axial SpA. Furthermore, antibodies against vascular endothelial growth factor (bevacizumab), approved by the U.S. Food and drug administration for systemic use in cancer, have not yet been tested in axial SpA either. The same is true for denosumab, a monoclonal antibody targeting RANKL that is now approved for the treatment of postmenopausal osteoporosis.
The increased local expression of RANKL compared with expression of its decoy receptor osteoprotegerin has a role in the pathogenesis of erosions in RA, its role in AS is less clear. In RA, the bone tissue directly exposed to inflammation is the cortical bone surface (synovitis), whereas in AS it is the trabecular bone of the vertebrae (osteitis). Bone formation by osteoblasts is impaired in RA, but seems to be stimulated in AS. Inhibitors of the canonical Wingless (Wnt) signaling pathway, including Dickkopf 1, have been implicated in the suppression of osteoblast function. Activation of Wnt b-catenin signaling induces an imbalance in cartilage homeostasis, and agonists and/or antagonists of Wnt (such as sclerostin, a Wnt signaling pathway antagonist produced by osteocytes and a potent inhibitor of bone formation) are potential candidates for this interaction. Sclerostin seems to be decreased in response to mechanical loading, an interesting hypothesis also for the pathogenesis of axial SpA. Finally, clinically successful TNF-inhibitors do inhibit radiographic damage in RA, but they do not halt new bone formation in AS. Blocking TNF was indeed shown to increase bone mineral density in both diseases. Whether this mechanism also has an effect on syndesmophyte formation remains to be seen.
