Axial spondyloarthritis (axSpA) is a chronic immune mediated inflammatory disease, characterized by inflammation and structural damage, including new bone formation, at the axial and peripheral skeleton. The worldwide prevalence is about 1% and disease starts usually before the age of 45 years. AxSpA is a disease entity that includes both radiographic disease with structural changes of the SI joint that can be classified according to the modified NY criteria, also called ankylosing spondylitis (AS), as well as non-radiographic (nr) disease, lacking these changes on x-ray imaging [1].

With the insight of a clear role of the TNF, IL-17 and JAK-STAT pathways in axSpA pathogenesis, in the past 8 years IL-17A inhibitors, and more recently JAK inhibitors have been added to TNF inhibitors as treatment options in patients failing NSAIDs [2]. These treatments effectively target inflammation in axSpA resulting in improved quality of life.

Although the exact mechanisms that initiate the disease are not fully delineated, genetic and environmental risk factors as well as molecular and cellular alterations at key disease sites have been implicated in the pathophysiology of axSpA. At these disease sites, that include the axial and peripheral joints, entheses, skin and gut, variation is seen in the disease mechanisms and perturbations of the key cytokine pathways at play. These tissue-based variations are most likely associated with the dissimilar clinical responses observed between, for instance, the spine, peripheral joints and the gut during treatment with cytokine inhibitors.

In the recent years there have been great technological advances in the techniques available to investigate genetics as well as immunological perturbations [3] implicated in the immunopathogenesis of axSpA. The rapid development of next-generation sequencing technologies (including e.g. whole-genome sequencing, RNA sequencing) as well as single-cell based technologies (e.g. flow cytometry, mass cytometry, single cell RNA sequencing) has facilitated detailed high-throughput analysis of blood and target tissues involved. The combination of single-cell analysis with spatial information, and the analysis of biosamples with various techniques during the course of disease is expected to further contribute to our understanding of pivotal disease mechanisms.

In contrast to rheumatoid arthritis, where ultrasound guided synovial tissue biopsy sampling made the hallmark target tissue involved in disease pathophysiology quite easily accessible [4], access to the target tissues involved in axSpA pathogenesis, such as axial or peripheral entheses, has been challenging. However, several groups have managed to obtain these tissue samples safely in patients, as well as in individuals with non-inflammatory disease undergoing elective surgery [[5], [6], [7], [8], [9], [10]]. As such, they have built on the insights previously gained from studies in SpA-like animal models.

In this review we describe the current insights into the pathophysiology and immunological basis of axSpA. We will discuss genetic risk factors with a focus on HLA-B27 and link this to immune activation of key disease pathways, and mechanisms in the gut and entheses related to these pathways.