The Global Initiative of Asthma (GINA) estimates that more than 17 million patients worldwide have severe uncontrolled asthma. The condition is defined as asthma that is uncontrolled despite the use of high-dose inhaled glucocorticoids and long-acting β2-agonists.^[1]* These patients are not only faced with significant disease-related morbidity and mortality, they are also frequently impacted by steroid-associated morbidities. It has been estimated that direct healthcare costs for these patients are higher than for those for type 2 diabetes and account for 60% of total asthma expenditures.^[2]

Glucocorticoid overuse represents a failure in treatment planning

Inhaled steroids are the cornerstone of asthma treatment but have lower efficacy in severe disease, where poor disease control and persistent exacerbations are common. As a consequence, oral steroids are often added to treatment regimens of severe asthma patients to improve disease control. Oral steroids can also be added to the regimen of patients on high-dose inhaled steroids/long-acting β2-agonists with similar disease control issues.  

The cumulative burden of oral glucocorticoid use in severe asthma is associated with a high prevalence of glucocorticoid-associated toxicity. Dr Jane McDowell and colleagues used the Glucocorticoid Toxicity Index in research to quantify these side-effects in severe asthma and identified the most common as being neuropsychiatric disturbances, skin toxicities and elevated body mass indices. Metabolic disturbances such as impaired glucose metabolism and hypertension were also common.^[3]

These findings reinforce the need to find strategies to minimize the use of oral steroids. Several organizations are now calling for the protection of patients with asthma against over-exposure to steroids, referring to the overuse of these agents as “treatment plan failure”. 

Biologics that target mediators of the T2 inflammatory cascade are available for patients with increased levels of T2 biomarkers. These biologics (e.g., anti-igE and anti-IL-5/5R), were proven to reduce the rate of severe asthma exacerbations in randomized controlled trials. Specific drugs such as enralizumab, dupilumab and mepolizumab have also been demonstrated to reduce oral steroid exposure. The downside of these randomized studies is their restrictive eligibility criteria, the relatively small populations studied in trials, and variability in trial design. Consequently, results rarely generalize to the broader asthma population.^[1]

The real-world impact of biologics on long-term steroid use

The prospective GLITTER study was set up to address these issues using real-world data from the International Severe Asthma Registry (ISAR). The study included data from 19 countries and collected data from January 2015 to February 2021. Patients enrolled over this period were:

• Over 18 years of age
• Severe asthmatics with uncontrolled asthma at GINA step 4 or treatment at GINA step 5
• With a history of high oral steroid treatment for at least a year, or with 4 or more bursts of steroids over the 12-month baseline period

Patients were divided into two groups:

• Biologic-initiated group
• Biologic-not-initiated group (never received biologics)

Patients were followed up with for 365 days and propensity score matching was performed to obtain unbiased effectiveness estimates for the two cohorts. The primary outcome reduction in the rate of asthma exacerbations. The secondary outcomes included:

1. improvement in asthma control,
2. reduction in steroid dose, 
3. reduced number of asthma-related emergency room visits, and 
4. reduced asthma-related hospital admissions.

Biologics reduce steroid exposure, asthma exacerbations and healthcare costs

Of the 10,606 patients in the severe asthma registry, 1412 met the inclusion criteria of the study. Patients who initiated a biologic were matched with non-initiators, yielding 996 patients per group. The results demonstrated that biological-initiation was associated with:

• 73% reduction in average asthma exacerbations per year
• Reduced exposure to steroids:
  • 4x more likely to reduce total glucocorticoid dose
  • 2.5x more likely to achieve steroid dose reduction to <5mg per day
  • 2.2x greater chance of reducing daily long-term doses to <5mg per day
• Similar asthma control and steroid-related co-morbidities
• Reduced healthcare resource utilization:
  • 65% reduction in asthma-related ER visits compared to not-initiated
  • 69% reduction in asthma-related hospitalizations

GLITTER demonstrated the importance of biologics in improving outcomes for patients with severe asthma, reducing glucocorticoid exposure and healthcare resource utilization. The results underline the importance of evaluating new therapies in the larger, more diverse cohorts that real-world studies can access. Such studies provide invaluable data to help influence guideline recommendations for biological use, access, choice and cost effectiveness. 

The study underlines the value of steroid-sparing regimes in severe asthma and the important role biologics can play in these strategies. Given the growing armory of tools to reduce steroid exposure, the authors suggest an aggressive approach of implementing personalized steroid-tapering programs. 

We recently spoke with Jane McDowell, MBBS BSc PhD, respiratory doctor and academic clinical lecturer at Queen's University Belfast in Northern Ireland, who emphasized the importance of measuring the burden of steroid-toxicity using the GTI as soon as treatment is initiated so that toxicity can be measured and minimized.

"It is disheartening to report that a considerable number of patients do not have much toxicity improvement even when steroid exposure is negligible," says Dr McDowell.

Read the full interview

In Conversation With... Jane McDowell, MBBS BSc PhD

References

1. Chen W, Tran TN, Sadatsafavi M, Murray R et al. Impact of Initiating Biologics in Patients With Severe Asthma on Long-Term Oral Corticosteroids or Frequent Rescue Steroids (GLITTER): Data From the International Severe Asthma Registry. J. allergy Clin. Immunol. Pract. 11(9):2732-2746 (2023) https://doi.org/10.1016/j.jaip.2023.05.044
2. Adatsafavi M, Lynd L, Marra C, Carleton B, Tan WC, Sullivan S et al. Direct health care costs associated with asthma in British Columbia. Can Respir J.  17: 74-80 (2010) doi: 10.1155/2010/361071
3. McDowell PJ, Stone JH and Heaney LG. The role of Quantification of Glucocorticoid-associated Toxicity in Severe Asthma. J Cell Immunol. 3(1):31-35. 2021 doi: 10.33696/immunology.3.074

*Footnote: severe asthma is consistent with asthma that is uncontrolled by the Global Initiative for Asthma (GINA) step 4 or requites GINA step 5.