Chronic Rhinosinusitis and Type 2 Inflammation

Chronic rhinosinusitis is when the nasal passages and sinuses get inflamed and tend to stay that. It is common condition, affecting between 5% and 12% of the population, depending on the study. Furthermore, a large proportion of people (between 1 in 5 and 1 in 3) with chronic rhinosinusitis develop nasal polyps, noncancerous growths in the nasal passageways that can make it difficultto breathe and lead to a loss of smell and frequent nasal infections. Large nasal polyps can be removed surgically if they are causing severe symptoms.

Short of surgery, the standard treatment for chronic rhinosinusitis with nasal polyps includes intranasal corticosteroids, washing out the inside of the nose with a saline solution, or short courses of systemic corticosteroids, which can be taken as pill, infused or delivered by injection.

But research has shown that a large percentage (perhaps as high as 85%) of cases of chronic rhinosinusitis with nasal polyps are associated with Type 2 inflammation, a complicated inflammatory pathway that has been implicated as the underlying cause of some types of asthma and atopic dermatitis.

In a review paper published earlier this month in the journal International Forum of Allergy & Rhinology, Philippe Gevaert, M.D., Ph.D., of the Ghent University Hospital in Belgium and his colleagues, discussed Type 2 inflammation and its relationship with chronic rhinosinusitis and a new wave of therapies designed to quell Type 2 inflammation that are under investigation as treatments for chronic rhinosinusitis with nasal polyps. Their review focuses on interleukin (IL)-5, a cytokine that plays an important role in the proliferation and activation of eosinophils, proinflammatory white bloods that are central to Type 2 inflammation. GlaxoSmithKline was identified as a funder of the review; the British drugmaker has anti-IL-5 agents in development.

Gevaert and his colleagues say in the review that biological therapies (monoclonal antibodies) that target Type 2 inflammation could become an important treatment choice for people with chronic rhinosinusitis who have had surgery to remove nasal polyps and have failed to respond to a short course of systemic corticosteroids.

Among the agents discussed in the review are Cinqair (reslizumab), Dupixent (dupilumab), Fasenra (benralizumab), Nucala (mepolizumab) and Xolair (omalizumab). Gevaert and his colleagues also touch upon the prospects of antolimab, another monoclonal antibody but one that isn’t yet on the market, and dexpramipexole, which was developed as a treatment for amyotrophic lateral sclerosis but is being investigated as an anti-Type 2 inflammation agent after it was discoveredt that it decreased eosinophil levels.

Citing several studies, Gevaert and his colleagues say that Nucala and Cinqair reduce eosinophil counts, nasal and peripheral IL-5 levels and eosinophil cationic proteins, a protein found in eosinophils in people with chronic rhinosinusitis with nasal polyps. They also discuss several other effects that Nucala has on Type 2 inflammation.

Early clinical trials showed Fasenra improved symptoms and reduced eosinophil levels in people with chronic rhinosinusitis with nasal polyps, the review says. However, results from the phase 3 OSTRO study of Fasenra were mixed, according to the review. “The results therefore warrant further investigation into the effects of benralizumab (Fasenra) on type 2 inflammation,” wrote Gevaert and his colleagues.

The discussion of Xolair mentions that improved clinical symptoms and several factors in Type 2 inflammation but has limited effect on IL-5 and eosinophil levels in the blood.

Dupixent improves symptoms and a number of Type 2 inflammatory factors, according to the review. The SINUS-24 and Sinus-52 studies showed improvements in symptoms, despite a temporary increase in blood eosinophil counts, Gevaert wrote, although the counts did eventually returned to pretreatment levels. Dupixent’s effect on eosinophil counts may indicate that it is effective in inhibiting the recruitment of eosinophils from the blood into tissue, says the review. And that, says the review, is the proposed mechanism of Dupixent as a treatment for severe asthma. “However,” wrote Gevaert and his colleagues, “an analysis of patients in SINUS-52 revealed no significant association between higher blood eosinophil counts and treatment response to dupilumab, suggesting that eosinophils may not be a key mediator dupilumab treatment benefits” in people with chronic rhinosinusitis with nasal polyps.

The review mentions that dexpramipexole reduced eosinophil levels in the blood and nasal polyps in small “proof of concept” study that included 16 patients, although it didn’t reduce the size of nasal polyps. Gevaert and his colleagues said “more rigorous” research of dexpramipexole is warranted.