A strategy towards disentangling treatment refractory from misdiagnosed axial Spondyloarthritis

Axial spondyloarthritis (axSpA) encompasses radiographic axial SpA (r-axSpA), formally designated as ankylosing spondylitis (AS) and non-radiographic axial SpA (nr-axSpA). The advent of MRI permitted the description of the "pre-radiographic" (nr-AxSpA) stage characterized by bone marrow oedema lesions, histologically an osteitis, not yet visible on X-rays. Most subjects with a diagnosis of nr-axSpA do not progress to r-axSpA and the risk of misdiagnosis of nr-axSpA is considerable because back pain related to malalignment, degenerative conditions or biomechanical stress including intense exercise may lead to positive MRI scans. Even when nr-axSpA or r-axSpA are accurately diagnosed only about 40-50% achieve the ASAS40 responses with licensed therapies. It is likely that spinal enthesitis/osteitis leading to structural damage and associated damage contributes to post inflammatory disc territory secondary pain responses. Things are complicated as the concept of refractory axSpA itself is not well defined since there is no gold standard test to capture the full burden of inflammatory disease and, in any event, MRI has not been systematically applied. Nevertheless, there is sufficient evidence to borrow from the refractory rheumatoid arthritis field to propose two types of refractory axial SpA- a persistent inflammatory refractory ax-SpA (PIRaxSpA) and non-inflammatory refractory ax-SpA (NIRaxSpA). Both axSpA refractoriness and misdiagnosis need careful considerations when evaluating treatment failure. The immunological basis for axSpA immunotherapeutics non-responses is still rudimentary beyond the knowledge of HLA-B27 positivity status, CRP elevation, and MRI bone oedema that represents osteitis being equated with responder status.