Expression of interleukin (IL)-17A and IL-17F and the functional response to these cytokines were found to be comparable in spondyloarthritis (SpA) and rheumatoid arthritis (RA) synovitis, according to research results published in The Journal of Rheumatology.
The study included 70 patients with SpA who fulfilled the Assessment of Spondyloarthritis International Society criteria for peripheral SpA. Of these, 31 patients were diagnosed with psoriatic arthritis (PsA) as defined in the Classification Criteria for Psoriatic Arthritis, and 47 patients met the American College of Rheumatology classification criteria for RA. The participants were assigned to 1 of 3 cohorts: Cohort 1 included patients with PsA with active psoriasis, from whom researchers collected lesional skin and paired synovial tissue biopsies; cohort 2 included patients with SpA and RA from whom synovial tissue biopsies were collected; and cohort 3 included patients with SpA and RA from whom synovial fluid samples from inflamed joints were collected.
Investigators examined the expression of cytokines in psoriasis skin and paired synovial tissue samples from patients in cohort 1. The expression of IL-17A and IL-17F in the synovial tissue samples was lower compared with that in matched psoriasis skin biopsies. The IL-17A to IL-17F ratio was inversed in synovial tissue compared with skin. In lesional skin, the expression ratios of IL-17A and IL-17F relative to a housekeeping gene were 7.76 and 23.6, respectively. In psoriatic lesional skin, mRNA levels of IL-17F were 2.68-fold higher than IL-17A (P =.0078).
To determine whether the expression of IL-17 cytokine and receptors accounted for the differential response to IL-17A blocking therapy in patients with SpA vs RA, investigators measured IL-17A/IL-17F expression in cohort 2. IL-17A mRNA expression was similar in synovial tissue from patients with SpA and RA, and synovial fluid IL-17A protein levels were also similar (292.4 vs 228.3 pg/mL, respectively). IL-17F mRNA expression and protein levels were comparable in patients with SpA vs RA.
Due to the relationship between IL-17A, IL-17F, and pro-inflammatory mediators like tumor necrosis factor (TNF), researchers also examined whether TNF receptors (TNFRI and II) were differentially expressed in the synovial tissue and fibroblast-like synoviocytes from patients with SpA and RA. Levels of mRNA for TNFRI and TNFRII were similar in both groups, indicating that “mRNA expression levels of the IL-17 and TNF receptors do not differ ex vivo and in vitro between SpA and RA synovitis,” according to researchers.
Further evaluation indicated that neither SpA nor RA fibroblast-like synoviocytes produced “significant” amounts of IL-6 or IL-8 when stimulated with either IL-17A or Il-17F.
Finally, investigators pooled synovial fluid from patients with SpA or RA and stimulated SpA fibroblast-like synoviocytes with 20% synovial fluid, supplemented with either IL-17A or IL-17F. Pooled synovial fluid resulted in increased production of IL-6, with no differences between SpA and RA synovial fluid conditions. A similar trend was observed for IL-8 production.
Study limitations include the comparison of receptors at the mRNA level (due to the scarcity of human synovial tissue samples), as well as limitations inherent to translational studies.
“The expression of and functional response to IL-17A and IL-17F appear to be similar in SpA and RA synovitis, failing to explain the differential response to IL-17A inhibition in these two diseases,” the researchers concluded. “Strikingly, IL-17A/IL-17F expression ratio is markedly higher in SpA [synovial tissue] compared [with] skin inflammation, suggesting that the relative contribution of IL-17F to chronic tissue inflammation may be more prominent in skin than in joints.”
Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.
Chen S, Blijdorp I, van Mens L, et al. IL-17A and IL-17F expression and functional responses in rheumatoid arthritis and peripheral spondyloarthritis [published online January 15, 2020]. J Rheumatol. doi:10.3899/jrheum.190571