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Evolving concepts of new bone formation in axial spondyloarthritis: Insights from animal models and human studies

https://doi.org/10.1016/j.berh.2018.07.007Get rights and content

Abstract

New bone formation potentially leading to ankylosis of the sacroiliac joints and the spine is the main type of structural damage to the skeleton that characterizes axial spondyloarthritis. New data from animal models, imaging, and patient cohort studies support the view that sustained suppression of inflammation by therapeutic interventions can slow down the ankylosing process, at least in a large proportion of the patients. Although specific growth factor molecular signaling pathways are the key to drive the progenitor cell differentiation process that leads to ankylosis, inflammation plays an important role, most likely in combination with biomechanical and environmental factors, in both the onset and progression of the disease. Therefore, early and effective treatment strategies and smoking cessation are important in daily patient management, in particular in those individuals at risk to develop progressive ankylosis. It should be further explored whether different treatment strategies will have distinct effects on ankylosis.

Section snippets

Molecular signals that directly affect the ankylosing process

During bone healing e.g., after fractures and in pathological bone growth, as seen in the ankylosing process in AxSpA, reactivation of endochondral bone formation is a likely mechanism (Fig. 1). This process is essential for normal bone development and growth [4]. It can be summarized as a series of cell differentiation steps triggered by the condensation and proliferation of progenitor cells at the site of the prospective skeletal elements. Within this cell condensation, cells commit to

Searching for the relationship between inflammation and ankylosis

The precise relationship between inflammation and the ankylosing process has been heavily discussed [6], [27], [28], [29], a debate strongly influenced by the initial observations that anti-TNF did not affect the ankylosing process in the spontaneous mouse model of ankylosis described above [17] and in the initial follow-up cohorts of the clinical trials in AS with etanercept, infliximab, and adalimumab [30], [31], [32] (Fig. 2). These data appeared at odds with the concept that inflammation

Human data: predictors of progression

Although animal model data provide essential pathophysiological insights into the process of new bone formation, clinical translation remains a challenge, not in the least because of the difference between bipedal humans and quadrupedal mice or rats. Hence improving our understanding of the processes and factors determining disease progression in this disease is also highly dependent on high-quality patient data. A study by the SPARTAN consortium identified clear risk factors for radiographic

Structural disease modification

As highlighted above, initial studies did not find a significant effect of 2-year treatment with different TNF inhibitors on the radiographic progression of disease as compared to the historical OASIS cohort. More recent data have shifted this rather pessimistic view (Fig. 2). A study from North America including the Toronto and Psoas cohorts, demonstrated that the use of TNF inhibitors slowed down radiographic progression, and that early use of TNF inhibitors had a positive impact on the

Translational data from genetics and biomarker studies

AxSpA is considered a complex disease with both genetic and environmental factors contributing to its onset and progression. As mentioned above, smoking appears to be one of the important environmental factors. In line with the animal model data, biomechanical stress may also play a role as an interesting study indicated that manual labor in blue-collar workers was a risk factor for structural disease progression as compared to so-called white collar professional activities [54].

Although many

Conclusion

Increasing evidence supports the view that long-term and sustained control of inflammation in patients with AxSpA is beneficial to avoid or limit structural disease progression in patients with AxSpA. Although mostly based on animal model data, direct inhibition of ankylosis will likely require targeting of growth factor cascades. With IL-17 inhibition emerging as a powerful new strategy in patients with AxSpA, detailed studies will be required to document eventual differential effects of IL-17

Acknowledgements – conflicts of interest and funding statement

Leuven Research and Development, the technology transfer office of KU Leuven, has received speaker's and consultancy fees on behalf of R.L from AbbVie, Boehringer-Ingelheim, Celgene, Eli-Lilly, Janssen, Novartis, Merck, Pfizer, and UCB. N.H. has no conflict of interest to declare.

Practice points

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    Developmental molecular signaling pathways could become a specific target to prevent ankylosis in high-risk patient groups. Serum levels of the growth factors involved and their soluble antagonists may

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