Abstract
BackgroundAxial spondyloarthritis (axSpA) has strong connections with intestinal inflammation as occurs in Crohn’s disease (CD). However, the immunologic mechanisms that distinguish axSpA, CD, and those with features of both diseases (CD-axSpA) are unknown. This study aimed to address this question by initial unbiased single cell RNA-sequencing (scRNAseq) on a pilot cohort followed by validating findings using flow cytometry and ELISA in a larger cohort.MethodsTwo individuals each with CD, axSpA, CD-axSpA, and healthy controls (HC) were recruited for a pilot discovery scRNAseq cohort, and the validation cohort consisted of 18 axSpA, 24 CD, 13 CD-axSpA, and 17 HC that was evaluated by flow cytometry on PBMCs and ELISAs for plasma cytokines.ResultsUniquely, PBMCs from subjects with CD-axSpA demonstrated a significant increase in granzyme B+ T cells of both CD4+ and CD8+ lineages by both scRNAseq and flow cytometry. T cell maturation was also greater in those with CD-axSpA, particularly the CD4+ granzyme B+ population. Pathway analysis suggested increased interferon response genes in all immune cell populations within CD-axSpA. Although IFN-γ was elevated in the plasma of a subset of subjects with CD-axSpA, IL-6 was also significantly elevated.ConclusionsOur findings support the presence of a chronic interferonopathy in subjects with CD-axSpA characterized by interferon signaling by pathway analysis and an expansion of mature, cytotoxic T cells. These data indicate fundamental immunological differences between CD-axSpA and both of the putative “parent” conditions, suggesting that it is a distinct disease with unique natural history and treatment needs.
Highlights
Axial spondyloarthritis has strong connections with intestinal inflammation as occurs in Crohn’s disease (CD)
~7% of patients with axial SpA will develop inflammatory bowel disease (IBD) [2], many more patients have subclinical bowel inflammation. In spite of this overlap, clinical trials in either IBD or axSpA fail to differentiate patients with overlapping disease. Such a concept is important as highlighted by trials with secukinumab, which is effective in axSpA but worsens CD [3]
We find that CD-axSpA subjects, compared to CD or axSpA alone, demonstrate a change towards a Type 1 helper T cells (Th1)-like immune response with cytotoxic T cells and an interferon signature, as well as evidence of accelerated T cell maturation
Summary
Axial spondyloarthritis (axSpA) has strong connections with intestinal inflammation as occurs in Crohn’s disease (CD). ~7% of patients with axial SpA (axSpA) will develop IBD [2], many more patients have subclinical bowel inflammation. In spite of this overlap, clinical trials in either IBD or axSpA fail to differentiate patients with overlapping disease. Such a concept is important as highlighted by trials with secukinumab, which is effective in axSpA but worsens CD [3]. While there is increased interest in identifying bowel inflammation in patients with axSpA using biomarkers such as fecal calprotectin, there is a lack of evidence to guide treatment of the overlapping IBD-associated axSpA
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