The arthritis connection to inflammatory bowel disease (IBD): why has it taken so long to understand it?

Abstract

Inflammatory bowel disease (IBD) associated arthritis is a subgroup of spondyloarthritis (SpA) that has suffered from lack of recognition in rheumatology clinical and research circles for over 100 years. Although clinically distinguishable from rheumatoid arthritis and ankylosing spondylitis, it took advances in detection systems in the middle of the last century (rheumatoid factor, HLA-B27) to convincingly make the final separations. We now know that significant numbers of patients with SpA have associated clinical IBD and almost half of them show subclinical gut inflammation, yet the connection between the gut and the musculoskeletal system has remained a vexing problem. Two publications from Nathan Zvaifler (one in 1960, the other in 1975) presciently described the relationship between the gut and the spine/peripheral joints heralding much of the work present today in laboratories around the world trying to examine basic mechanisms for the connections (there are likely to be many) between the gut, the environment (presumably our intestinal flora) and the downstream effect on the musculoskeletal system. The role of dysregulated microbiome along with microbiome-driven T helper 17 cell expansion and immune cell migration to the joints has been recognised, all of which occur in the appropriate context of genetic background inside and outside of the human leucocyte antigen system. Moreover, different adhesion molecules that mediate immune cells homing to the gut and joints have been noted. In this review, we studied the origins and evolution of IBD-arthritis, proposed pathogenic mechanisms and the current gaps that need to be filled for a complete understanding of IBD-arthritis.

Inflammatory bowel disease: focus on enteropathic arthritis and therapy

“…According to the current literature, microbiome dysregulation and its driven T helper 17 cell expansion and immune cell migration to the joint in a proper genetic background may play a role. [ 6 ]…”

Cytokine competent gut-joint migratory T Cells contribute to inflammation in the joint

“…As many as 10% of individuals with axial SpA (axSpA) are diagnosed with co-morbid IBD, and up to 50% of individuals with axSpA will present with sub-clinical bowel inflammation that is detectable by biopsy but is not sufficient for a diagnosis of IBD (8). This observation has led to the generation for the gutjoint hypothesis in axSpA (9)(10)(11), which proposes that inflammatory disease begins and is driven by host-microbe interactions in the gut and then spreads to distal sites, ultimately presenting as inflammatory back pain. Multiple studies have reported increases in circulating and synovial populations of Th17 polarized T cells, ILC3s, mucosa-associated invariant T cells (MAITs), and TCRgd+ T cells (12)(13)(14)(15), all of which are generally thought to be generated and/or activated through microbiome-mediated mechanisms at the mucosa and are capable of production of TNF and IL-17 (16), the primary mediators of disease in axSpA (3).…”

Improvement of early diagnosis of axial spondyloarthritis in intestinal infectious diseases

“…Establishing the diagnosis of IID-associated SpA at an early stage is a very difficult task: the clinical manifestations are minor, but the radiological manifestations are reliable and are usually detected on average 7.1 years after the onset of symptoms [13]. A group of Italian researchers reported that the diagnosis of SpA in patients with IID is after around 5.2 years from the onset of dorsal pain.…”