Genetics, CFTR modulators predict sinonasal improvement: Study

CF patients with certain gene mutations, no prior treatment respond better

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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People with cystic fibrosis (CF) who carry two disease-causing F508del mutations and those who have had no prior treatment with CFTR modulators are up to five times more likely to see greater improvement of sinonasal symptoms after starting highly effective modulator treatment, a study found.

An improvement of 8.5 points or more on the 22-item Sinonasal Outcome Test (SNOT-22) — a patient-reported measure of severity of chronic rhinosinusitis, or lasting inflammation of the nose and sinuses — was considered clinically meaningful, and may help doctors set treatment goals.

The study, “Predictors of Sinonasal Improvement After Highly Effective Modulator Therapy in Adults with Cystic Fibrosis,” was published in The Laryngoscope by researchers in the U.S. It was based on data from four previous studies.

Many people with CF experience symptoms of chronic rhinosinusitis, such as a stuffy nose and tenderness around the nose and forehead. Such symptoms can make it difficult to breathe through the nose, and in many cases add to existing shortness of breath caused by a buildup of thick, sticky mucus along the airways.

SNOT-22 measures how chronic rhinosinusitis interferes with quality of life. While the meaningful change threshold for the condition is known for some diseases, it’s unclear for CF. Knowing the smallest change that represents clinically meaningful improvement could help tailor more effective treatments for people with CF.

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Stuffy nose is big SNOT-22 concern for CF patients with sinusitis

Higher SNOT-22 scores as start linked to better odds of symptom improvement

Against this backdrop, the researchers pooled data from four studies across 10 medical centers in the U.S. to identify factors that could predict how much SNOT-22 scores would improve after three to six months of treatment with Trikafta (elexacaftor, tezacaftor, and ivacaftor), a highly effective modulator treatment.

The data came from 184 people with CF, with a mean age of 34, who also had a diagnosis of chronic rhinosinusitis. Nine (5%) were adolescents. About two-thirds (66.7%) had been treated with a CFTR modulator prior to starting Trikafta, and 72.2% had undergone sinus surgery.

Average SNOT-22 scores dropped from 39 points at baseline (before treatment) to 28 points three to six months after treatment with Trikafta. That indicates improvement: SNOT-22 scores rate the severity of symptoms on a scale from 0 to 110, with higher scores representing worse symptoms.

The researchers calculated that an average improvement of 8.5 points on SNOT-22 was significant enough to be considered clinically meaningful for people with CF and chronic rhinosinusitis. That means that if someone’s scores improved by 8.5 points or more, it likely made a meaningful difference in how the person felt.

Among the 97 patients with data available in three of the studies, 54 had a change in SNOT-22 scores that exceeded the minimal clinically important difference of 8.5 points. Before Trikafta, their average SNOT-22 scores were significantly higher than those of patients who didn’t meet the threshold (47.1 points vs. 31.5 points).

Patients with higher baseline SNOT-22 scores had higher odds of experiencing greater improvement of sinonasal symptoms after starting treatment with Trikafta. For every point increase in baseline SNOT-22 scores, the odds of improving beyond the meaningful change threshold increased by nearly 5%.

Being homozygous for F508del (that is, having a F508del mutation in each CFTR gene copy) increased the odds of greater improvement by more than four times compared with being heterozygous (having just one mutation). To be eligible for Trikafta, patients need to have at least one copy of F508del or another of a list of responsive mutations.

Patients who had never been treated with CFTR modulators were five times as likely to exceed the meaningful change threshold of 8.5 points than those with a history of modulator treatment.

“Worse baseline sinonasal symptoms, F508del homozygosity, and absence of prior modulator therapy predicted greater improvement after [highly effective modulator treatment] initiation,” the researchers wrote. The minimal clinically important difference of 8.5 points, they noted, is similar to that of non-CF patients.