Do NSAIDs Take Us Away From Treatment Goals in Axial Spondyloarthritis: A Story About Dysbiosis or Just a Matter of Bias?

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) remain the mainstay of treatment for spondyloarthritides (SpA), a group of entities with common clinical and pathophysiological aspects, but also with differential features. Although NSAIDs provide significant symptomatic relief, especially for joint pain and morning stiffness, their role in achieving and maintaining the treatment goals advocated by the treat to target strategy in SpA is not entirely clear. These agents can induce changes in the composition of the intestinal microbiota, also favoring an alteration of the barrier function in the gut epithelium. All of this, favored by a pre-disposing genetic background, could activate a specific type of aberrant immune response in the gut lamina propria, also known as type-3 immunity. This article offers a perspective on how NSAIDs, despite their undeniable value in the short-term SpA treatment, could hinder the achievement of medium and long-term treatment goals by compromising the barrier function of the gut mucosa and potentially altering the composition of the gut microbiota.

Keywords: NSAIDs; axial spondyloarthritis; disease activity; disease impact; gut dysbiosis; long-term prognosis; therapeutic goals.

Figure 1

Potential mechanisms linking the use of NSAIDs with the gut-joint axis theory in the pathogenesis of spondyloarthritis. NSAIDs (in this case exemplified by indomethacin) can modify the growth and imbalance the composition of the intestinal microbial communities (a condition known as dysbiosis). Once substantial damage is generated to the defense mechanisms of the intestinal mucosa, and pathogenic bacteria and their products reach deeper layers of the intestine, it is believed that a special type of immune response called type 3 immunity is activated in the lamina propria. In SpA patients, several cell lineages with the potential to produce IL-17 are increased in the blood, including mucosal-associated invariant T cells, Th17 cells, γδT cells and type 3 innate lymphoid cells (ILC3), all of which have been implicated in mucosal immunity. Human entheseal tissue contains IL-23-responsive γδT cells and ILC3 cells and these cells are important producers of IL-17 and IL-22 in the blood and peripheral joint synovial fluid of patients with SpA. It is believed that these type 3 cells can reach distant joint structures through the bloodstream, whereby secreting proinflammatory cytokines they can generate synovitis, osteitis, and enthesitis (gut-joint axis). See text for a more detailed explanation.