Type I Interferon Inhibitor May Benefit Lupus

September 24, 2020

Type I Interferon Inhibition Could Benefit Systemic Lupus Erythematosus

Type I interferon inhibition (IFN) can modulate cardiometabolic disease markers in systemic lupus erythematosus, researchers say.

The finding could point the way to a new treatment for the disease, write Kerry A. Casey, Ph.D., of AstraZeneca in Gaithersburg, Maryland, and colleagues. They published their findings in Arthritis & Rheumatology.

“Our results demonstrate a predominant role for IFN-α at the systemic level in lupus, although a role for locally produced, tissue-specific IFN-β cannot be ruled out,” they write.

Many people with systemic lupus erythematosus die from premature atherosclerosis, and traditional risk factors can’t fully explain why. Though researchers have speculated that immune dysregulation contributes to vascular damage, the exact mechanism remains unclear.

To evaluate the role of type I interferon inhibition, researchers analyzed blood samples from MUSE, a phase 2b randomized clinical trial.

In this trial, 99 patients received intravenous infusions of 300 mg of anifrolumab, a type I IFN receptor–blocking antibody; 104 received mg of anifrolumab; and 102 received a placebo.

The researchers took fasting plasma/sera from the patients receiving the drug and from healthy donors matched by age, race, and sex.

In 80.1% of the patients’ baseline serum samples, the researchers found quantifiable IFN-α. They found IFN-β in only 2.0%, leading them to conclude that IFN-α is the dominant type I IFN protein in circulation in lupus.

They found that neutrophil extracellular trap (NET), tumor necrosis factor alpha (TNF-α), and interleukin (IL)-10 correlated with type I IFN pathway activity. Both TNF-α and IL-10 may contribute to vascular dysfunction.

NET complexes and IL-10 were upregulated in patients with systemic lupus erythematosus versus healthy donors. The difference was statistically significant (P<0.008).

The researchers found that type I IFN receptor inhibition with anifrolumab significantly reduced neutrophil extracellular trap (NET) complexes and GlycA (a marker of cardiometabolic disease) and improved cholesterol efflux capacity (CEC) from baseline (P<0.05). Anifrolumab also decreased serum levels of both TNF-α and IL-10.

Meanwhile, patients receiving the placebo had increased levels of citrullinated histone H3 (CitH3)-DNA, though not the other NET complexes at this point (P = 0.006)

“These data support a key role for type I IFNs in modulating factors contributing to SLE vasculopathy and suggest that inhibiting this pathway could decrease cardiovascular risk in these patients,” the researchers concluded.

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REFERENCE

Casey, K.A., Smith, M.A., Sinibaldi, D., et al. (2020), Modulation of cardiometabolic disease markers by type I interferon inhibition in systemic lupus erythematosus. Arthritis Rheumatol. Accepted Author Manuscript. doi:10.1002/art.41518