Research News

Collaborative research between clinicians and scientists at Cleveland Clinic has revealed a potential genetic link between certain patients with psoriatic arthritis (PsA) and failing to respond to drugs that block an inflammatory protein called tumor necrosis factor alpha (TNFα).

TNFα is an overactive immune signal in the blood, joints and skin of patients with PsA. Many PsA patients are prescribed anti-TNF therapy to block the inflammation and pain that characterize the condition. Anti-TNF therapy includes medications that inhibit, or block the action of, TNFα proteins. In a study recently published online in Annals of the Rheumatic Diseases, researchers focused on a mutation in a TNFα receptor called the tumor necrosis factor receptor 2 (TNFR2) gene.

“TNF blockers were the first big breakthrough for psoriatic arthritis,” says Elaine Husni, MD, MPH, Vice Chair of the Department of Rheumatic and Immunologic Diseases. “These drugs are effective and reduce inflammation for 60% of patients—but that means 40% do not respond well, and physicians currently cannot predict who will or will not respond. That 40 percent is the population we focused on in our research.”

A common genetic variant makes a big difference with anti-TNF therapy

The researchers sought to discover whether there were any connections between genetic variants and response to anti-TNF therapy. Genetic testing of a cohort of 164 patients who had stopped taking anti-TNF drugs within 12 months revealed that 80% had inherited an “R variant” of TNFR2. This variant changes how one amino acid is coded in the protein. Although the variant is only in one molecule, it had a significant effect on how the protein acted and whether the patient responded to anti-TNF therapy.

“The mere presence of an R variant in a patient made them about five times more likely than patients with the other variants to stop their anti-TNF therapy within 12 months because it was not working,” says Unnikrishnan Chandrasekharan, PhD, staff researcher in Dr. Husni’s lab. “Additional cell studies showed that TNFR2-R resulted in higher basal levels of pro-inflammatory gene expression. What this suggests is that TNFR2-R is a risk factor for poor response.”

Looking to the future for patients with psoriatic arthritis

Cleveland Clinic researchers are now building on these findings to advance more personalized treatment for psoriatic arthritis and other immune-mediated diseases. This study raises the possibility that a simple genetic test for the TNFR2-R variant could one day help physicians anticipate which patients are less likely to benefit from anti-TNF therapy and tailor treatment plans accordingly.

Mechanistic studies in cellular models also revealed that standard anti-TNF antibodies did not fully suppress the increased activity in the R variant. However, pathway activity did cease when researchers blocked other enzymes in the signaling pathway. This data suggests that alternative signaling inhibitors could be a promising new therapeutic strategy, particularly for patients who carry this variant.

“Our results are encouraging for further testing and exploration of TNFR2-R,” Dr. Husni says. “Testing for the presence of an R allele would help predict which patients are less likely to respond to anti-TNF drugs and guide physicians to prescribe certain treatments over others, reducing some of the trial and error. Ultimately, our goal is to translate these insights into better treatment options while always keeping patients’ outcomes and quality of life at the center of our work.”