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Fresh Evidence on the Relationship Between IL-17A and TNFα in Psoriatic Arthritis

– Dual targeting may confer additive benefits in coping with destructive synovitis in PsA


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Despite their clear roles in the pathogenesis of psoriatic arthritis (PsA), the relationship between interleukin-17A (IL-17A) and tumor necrosis factor (TNF)α in PsA synovitis is still not fully understood.

That was the primary issue a Dutch research team recently set out to clarify. Their report was published in Arthritis & Rheumatology. Highlights have been excerpted and are summarized here.

What key question did this study attempt to answer?

Activated T cells excrete a wide range of proinflammatory cytokines, including IL-17A and TNFα, both of which have been shown to be elevated in PsA synovial fluid (SF).

However, the functional relationship between the two in PsA synovitis has not been fully elucidated.

In addition, the study attempted to shed more light on whether CD8+ T cells secrete IL-17A under more physiological conditions.

What were the key findings?

The study revealed evidence that CD4+, but not CD8+, T cells from the SF of PsA patients excrete IL-17A upon ex vivo activation.

PsA-SF CD4+ (0.71% [0.35-1.50]) and CD8+ T-cells (0.44% [0.17-1.86]) were IL-17A+ using flow cytometry.

However, only CD4+ T cells secreted IL-17A after anti-CD3/anti-CD28 activation (P<0.05). Similar results were observed in co-cultures with PsA monocytes or PsA fibroblast-like synoviocytes (P<0.05).

The authors noted that CD8+ T cells "remarkably" secreted only IL-17A after 4- or 72-hour stimulation with phorbol myristate acetate and ionomycin (PMA/ion). Anti-IL-17A and anti-TNF treatments both inhibited PsA synovitis.

What are the overarching takeaways from these results?

Previous reports had suggested that CD8+ T cells are predominant in PsA. However, these findings showed that CD4+ T cells are the major T-cell subset in PsA-SF.

Possible explanations for the discrepancy may lie in the methods of handling samples. First, during the experiments, surface staining was performed directly after cell pelleting without density gradient separation to keep all subsets as genuine as in vivo.

Secondly, percentages of cell subsets were analyzed without ex vivo stimulation and separated from intracellular staining.

PMA/ion stimulation conventionally used during intracellular staining can strongly downregulate CD4, but not CD8, surface expression. Therefore, research conditions should represent the infiltrated immune cell characteristics in the SF of patients with PsA as closely as possible.

Whether SF CD56+ (bright) natural killer cells modulate IL-23 expression by monocytes/dendritic cells and thereby influence the IL-23/IL-17 axis is still not known and warrants further research, the study authors noted.

What next steps are envisioned?

Further validation of a combination or sequential therapy in patients with IL-17A and TNFα neutralizing agents is needed, the researchers suggested.

In the meantime, they wrote, the study results indicated that targeting both IL-17A and TNFα may complement each other and may possess additive benefits in coping with destructive synovitis in patients with PsA.

You can read expert commentary on the clinical implications of this study here and review the study abstract here.

Study co-author Erik Lubberts received a research grant from Novartis. No other study co-author disclosed any relevant financial relationship with industry.