Key Updates and Limitations of Guidelines to Treat Asthma

Recent updates to the Global Initiative for Asthma (GINA) and the European Respiratory Society/American Thoracic Society (ERS/ARS) guidelines have renewed focus on treating severe asthma. During 2 panels at CHEST 2020, experts discussed key updates, limitations of the guidelines, and more.

In the first session, Anne Reihman, MD, of the Division of Pulmonary and Critical Care Sciences at the University of Colorado, highlighted anti–interleukin (IL)-5 treatment failure when treating severe asthma. There are currently 3 FDA-approved drugs to treat the IL-5 inflammatory pathway: mepolizumab, reslizumab, and benralizumab.

“Over the past several years we’ve seen really great outcomes for many patients with these drugs, including decreased asthma exacerbation rates, decreased oral steroid use, improvement in lung function, and subjectively improving asthma symptoms,” Reihman explained.

As a result, the ERS/ATS and GINA guidelines both recommend these drugs for treating patients with severe, uncontrolled, eosinophilic asthma. However, Reihman noted, while these drugs work for many patients, there is a variable response. One study¹ showed that compared with placebo, mepolizumab reduced oral steroid dose by 50%, but while some patients had a complete reduction in oral steroid dose, others had no reduction at all.

“We know that some patients don’t respond to these anti–IL-5 therapies, and we’re just starting to get some data on who those patients are and the prevalence of that,” she said.

One of the challenges of getting a better understanding of anti–IL-5 failure is that trials use various clinical measures to describe treatment response. For instance, trials could use improvement in lung function, decreased asthma exacerbation rates, reduction in corticosteroid dose, or subjective improvement in asthma symptoms to describe adequate treatment response, Reihman explained.

“We still have no current standard criteria for defining adequate treatment response to biologic therapy,” she said. “It really creates a significant limitation in the research around biologic failure.”

Small cohort studies have shown that the frequency of IL-5 failure is anywhere from 24% to 57%. The largest study, of 250 patients, not only showed that 57% of patients did not achieve an optimal response but that about 13% of patients had their asthma worsen after they started on an anti–IL-5 therapy, Reihman said.

So far there are no large studies on the prevalence of anti–IL-5 failure, and she doesn’t expect that to change until there is a more adequate definition of treatment response.

There are some known predictors of anti–IL-5 therapy response based on findings from a variety of studies, such as that higher baseline peripheral eosinophil count and baseline asthma exacerbation rate independently predict response to anti–IL-5 therapy, Reihman noted.

Preliminary data out of the University of Colorado Severe Asthma Program looking at patients with severe eosinophil asthma over a 3-year period found that about 25% of patients were nonresponders to anti–IL-5 therapies: 50% failed mepolizumab, 30% failed reslizumab, and 20% failed benralizumab.

According to Reihman, they have looked at baseline measures, including body mass index, fractional exhaled nitric oxide (FENO), peripheral eosinophil count, Asthma Control Test score, and immunoglobulin E (IgE), to differentiate responders from nonresponders. Unfortunately, none of the differences among these baseline measures were significant between the 2 groups, she said. In a subgroup analysis of response to only mepolizumab and reslizumab, they have found that younger age was significantly associated with biologic failure in nonresponders versus responders (mean age 55 vs 62 years; P <.05) and that nonresponders had a greater number of exacerbations in the year prior to initiation of the biologic therapy.

Quite simply, “the jury is still out” on which predictors are important, Reihman said.

“To really move this field forward in terms of research, we need a set definition for what adequate treatment response to biologic therapy is, which will not only help research, but will I think provide much needed guidance for practitioners caring for these severe asthma patients in the clinical setting,” she said.

Praveen Akuthota, MD, associate professor in the Department of Medicine at the University of San Diego, and Fernando Holguin, MD, MPH, professor of medicine and director of Asthma Clinical and Research Programs at the University of Colorado Anschutz Medical Campus School of Medicine, followed with discussions on the actual updates from GINA and ERS/ATS.

The GINA guidelines update largely focused on the risks of mild asthma, explained Akuthota. He added that patients with apparently mild asthma are at risk of more serious adverse events than one would initially think. He noted that 30% to 37% of adults with acute asthma, 16% of patients with near-fatal asthma, and 15% to 20% of patients dying of asthma had symptoms less than weekly in the previous 3 months. Or, as he explained it, these patients “have what seems to be a benign disease.”

Inhaled short-acting beta-agonists (SABAs) were the first-line treatment for 50 years, but they are not worth reexamining based on a few things:

• The use of SABAs is an indication of poor control and a predictor of poor outcomes
• The use of more than 1 canister per month is a marker for increased risk of exacerbations
• Dispensing of 3 or more canisters a year is associated with a higher risk of emergency department presentation

Overall, SABA use is quite prevalent in patients, but new research has informed changes to the GINA guidelines. As a result, GINA no longer recommends SABA-only treatment as step 1. Instead, GINA recommends that all adults and adolescents (≥12 years) with asthma receive inhaled corticosteroid–containing controlled treatment to reduce the risk of serious exacerbations.

Based on the new guidelines, SABAs are no longer the preferred reliever option and instead are relegated to the “other” reliever option.

Holguin explained that to update the ERS/ATS guidelines, a task force reviewed randomized controlled trials (RCTs) and systematic reviews of RCTs. The goal of the task force was to answer 6 questions.

1. Should a monoclonal anti–IL-5 antibody be used in adults with severe asthma?

They concluded that an anti–IL-5 strategy does reduce exacerbations in patients with severe eosinophilic asthma and suggest the strategy as an add-on therapy for adult patients with severe, uncontrolled eosinophilic asthma or with severe corticosteroid-dependent asthma.

However, this is a conditional recommendation because the quality of evidence varied across treatments and inclusion criteria across studies were not consistent with the ERS/ATS severe asthma definition.

2. Should a measurement of a specific biomarker be used to guide initiation of treatment with a monoclonal anti–IL-5 or –IL-5 receptor α antibody in adults with severe asthma?

They concluded that subjects with higher levels of blood eosinophil counts can benefit more from anti–IL-5 strategies. The recommendation in the guideline is to use a blood eosinophil count cut off of >150 cells/μL to guide anti–IL-5 initiation.

This recommendation is also conditional based on the low quality of evidence.

3. Should a measurement of a specific biomarker be used, in addition to total IgE level, to guide initiation of treatment with a monoclonal anti-IgE antibody in adults and children with severe asthma?

The task force concluded that blood eosinophil counts and FENO levels may be useful in choosing patients who are most likely to achieve a more effect on exacerbations and lung function when treated with omalizumab compared with placebo.

The guideline recommends using a blood eosinophil cut off of ≥260 cells/μL or using a FENO cut off of 19.5 parts per billion to identify those patients who will be more likely to benefit.

This recommendation is also conditional based on the low quality of evidence.

4. Should a long-acting inhaled muscarine antagonist be used in adults and children with severe asthma?

The task force determined that tiotropium improves forced expiratory volume in one second and provides beneficial effects on symptom control in patients with severe, uncontrolled asthma, and so this treatment is recommended.

This is a strong recommendation given the moderate quality of evidence.

5. Should a macrolide (ie, azithromycin, clarithromycin) be used in adults and children with severe asthma?

The task force concluded that relative to placebo, chronic macrolide therapy reduces the risk of an asthma exacerbation. As a result, the guideline recommends a trial of a macrolide treatment in adult patients but suggest against using chronic macrolide treatment in children and adolescents.

6. Should a monoclonal anti–IL-4 receptor a be used in adults and children with severe asthma?

They concluded that dupilumab as an add-on therapy substantially decreases exacerbations in moderate to severe uncontrolled asthma, and that it effectively reduces oral corticosteroid dose in patients with severe asthma who are dependent on oral steroids.

As a result, the guideline recommends dupilumab as an add-on therapy for adults with severe eosinophilic asthma and patients with severe corticosteroid-dependent asthma regardless of eosinophilic levels.

This is a conditional recommendation.

Holguin noted that the guidelines cannot make recommendations outside of existing data and cannot comment on specific clinical traits that are not systematically evaluated in clinical trials.

“Ultimately, recommendations are based on systematic data evaluation and the added values of the reviewers,” he said. “It’s definitely not perfect, so you have to consider it—guidelines are just guidelines—with a grain of salt.”

References

1. Bel EH, Wenzel SE, Thompson PJ, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371:1189-1197. doi:10.1056/NEJMoa1403291

2. Mukerjee M, Forero DF, Tran S, et al. Suboptimal treatment response to anti-IL-5 monoclonal antibodies in severe eosinophilic asthmatics with airway autoimmune phenomena. Eur Respir J. Published online October 8, 2020. doi:10.1183/13993003.00117-2020

3. Condreay L, Chiano M, Ortega H, et al. No genetic association detected with mepolizumab efficacy in severe asthma. Respir Med. 2017;132:178-180. doi:10.1016/j.rmed.2017.10.019