De-Escalation of Severe Asthma Therapy: Do We Wean the Biologic or the Inhaler First?

Abstract

Asthma is a chronic respiratory disease affecting approximately 10% of Canadians. The disease is recognized by the presence of classical symptoms (dyspnea, wheezing, chest tightness, cough, and sputum), combined with objectively measured variable airflow obstruction. However, the simplicity of this definition overlooks one of the driving features of severe disease, type-2 inflammation, which is the single most treatable immune process.

Over the past two decades, research has redefined asthma as a heterogeneous disease, recognizing type-2 inflammation as a prevalent, measurable, and treatable pathway. In clinical settings, the type-2 inflammatory phenotype is identified by the presence of increased blood/sputum eosinophils and/or elevated levels of exhaled nitric oxide (FeNO). With severe disease, this immune pathway remains active and is otherwise suppressed by corticosteroids in over 90% of patients. Indeed, the cornerstone of asthma therapy–inhaled corticosteroid and biologics–primarily functions by suppressing type-2 inflammation, with a failure to suppress this pathway being associated with adverse outcomes and, most frequently, necessitates the use of biologics.

The approval and use of six monoclonal antibodies to treat people with severe asthma have led to extraordinary benefits for patients. The currently approved biologics include omalizumab, which targets immunoglobulin (Ig)E; mepolizumab, reslizumab, and benralizumab, which target interleukin (IL)-5/5receptor(R), and finally, dupilumab and tezepelumab, which target IL-4R and thymic stromal lymophoietin (TSLP), respectively. Although omalizumab was primarily trialled in moderate allergic asthma, the latter five biologics (anti-IL-5/5R, anti-IL-4R, and anti‑TSLP) have shown marked efficacy in severe asthma. These biologics have achieved a 50% reduction in annual severe asthma attack rates over placebo, a 50% reduction in the need for maintenance oral corticosteroids (OCS) in three of the biologics, and significant improvements in lung function and symptom scores. The benefits are most pronounced in patients with high type‑2 inflammation, with approximately 30% of these patients achieving near-normalization of asthma parameters, an endpoint referred to as ‘remission’.