Editorial: Anti–Tumor Necrosis Factor and New Bone Formation in Ankylosing Spondylitis: The Controversy Continues

Abstract

Structural damage in ankylosing spondylitis (AS) is characterized by excessive bone formation, with syndesmophytes as the typical lesion (1,2). New bone formation in AS can lead to decreased spinal mobility, which in turn diminishes the patient’s ability to perform daily activities and may severely reduce health-related quality of life (3–5). Therefore, preventing the progression of structural damage of the spine is an important goal in the treatment of AS. The processes that drive the formation of syndesmophytes are not completely understood. One theory postulates that inflammation and osteoproliferation are related, and that initially, inflammation triggered by unknown stimuli (e.g., mechanical stress or infectious agents) drives a bone catabolic process in which the Wnt pathway and up-regulation of Dkk-1 play a prominent role. Later, as inflammation fluctuates and is intermittently dampened, the bone catabolic process can give place to a bone anabolic response that is characterized by reactive osteoproliferation (6,7). Another theory suggests that inflammation and repair are uncoupled phenomena, and that the same triggers can independently activate inflammatory and stromal cells, with the activation of stromal cells leading to endochondral bone formation (8). If inflammation is indeed the principal trigger of repair responses, a strong case can be made for early and/or prolonged treatment with antiinflammatory agents, namely, with anti–tumor necrosis factor (antiTNF) drugs. On the other hand, if inflammation and repair are independent pathways triggered by common factors, specific therapies targeting stromal pathways may be needed to prevent new bone formation in AS. Magnetic resonance imaging (MRI) studies have shown that the presence of inflammation in a vertebral corner/unit slightly increases the likelihood of finding a new syndesmophyte at the corresponding site 2 years later (9–11). However, the majority of syndesmophytes in these studies developed at sites without inflammation noted on MRI, suggesting that this is a complex relationship. It has also been postulated that syndesmophytes are more likely to develop at vertebral corners in which inflammation resolves as compared to those in which inflammation persists (10,12), and that corner fatty infiltration may be one of the early signs of repair. In a recent study, the presence of a fatty lesion at a vertebral corner was associated with the subsequent development of a syndesmophyte at the same site (13). Importantly, systemic inflammation, as determined by the levels of acute-phase reactants, has also been found to be a predictor of progression of radiographic damage, both in the spine (the C-reactive protein [CRP] level and the erythrocyte sedimentation rate [ESR]) (14) and in the sacroiliac joints (the CRP level only) (15).