Targeting tumor necrosis factor receptors in ankylosing spondylitis

Abstract

Over the past two decades, considerable advances in our understanding of inflammatory and immune pathways have allowed for the growing use of targeted biologic therapy. Most notably, the introduction of tumor necrosis factor (TNF) inhibitors has dramatically changed the management of autoimmune inflammatory disorders, including ankylosing spondylitis (AS). Despite the efficacy of TNF inhibitors documented in multiple clinical trials, anti-TNF therapy in AS is far from foolproof; it is associated with serious adverse effects and limited response to therapy in some patients. Moreover, specific questions regarding the role of TNF as a mediator of AS remain unanswered. Therefore, additional efforts are needed in order to better understand the role of TNF in the pathogenesis of AS and to develop safer and more effective treatment strategies. The purpose of this review is to better the understanding of the physiologic and pathogenic roles of TNF signaling in the course of AS. Relevant TNF biology and novel approaches to TNF blockade in AS are discussed.

Keywords: TNF inhibitors; TNFR1; TNFR2; ankylosing spondylitis; progranulin.

Figure 1

The role of TNF in the progression of ankylosing spondylitis. This figure illustrates the opposing roles of two TNF receptors, TNFR1 and TNFR2, in inflammation, bone erosion, and new bone formation in ankylosing spondylitis. In general, TNFR1 is pro-inflammatory and mediates tissue catabolism, whereas TNFR2 is anti-inflammatory and mediates tissue anabolism. The pathways and molecular mediators involved are indicated. Abbreviations: ADAMTS, a disintegrin and metalloproteinase with thrombospondin motifs; BMP, bone morphogenetic protein; DKK-1, dickkopf-related protein-1; MMP, matrix metalloproteinase; NFκB, nuclear factor kappa-B, RANK/RANKL, receptor activator of nuclear factor kappa-B/RANK ligand; TNFR, tumor necrosis factor receptor.