Response to biologics for asthma varies by outcome
Click Here to Manage Email Alerts
Key takeaways:
- A 50% or greater reduction in exacerbation rate was one of the four criteria for response.
- Criteria also included a 50% or greater reduction in daily long-term oral corticosteroid dose.
Patients with greater impairment before initiating biologic treatment for asthma had better response across all assessed outcomes, according to a study published in The Journal of Allergy and Clinical Immunology: In Practice.
But there were variations in responder rates based on the type and number of domains used by different definitions of response, Ghislaine Scelo, PhD, senior epidemiologist, Observational and Pragmatic Research Institute, Singapore, and colleagues wrote.
Study population
The longitudinal cohort study included data from 2,210 patients from 21 countries (29.2% from the United States, 19.3% from the United Kingdom and 16.7% from Italy) who used anti-IgE (n = 665), anti-IL-5/R (n = 1,405) or anti-IL-4R-alpha (n = 140) treatment.
The cohort was mostly white (n = 1,540 of 1,911; 80.6%) and women (n = 1,319 of 2,210; 59.7%) with a median age of 55 years, median BMI of 27.9 kg/m2 and median duration of asthma of 20 years. Also, 66% (n = 1,142 of 1,731) had never smoked.
Before biologic treatment, patients had elevated blood eosinophil counts (BEC), fractional exhaled nitric oxide and IgE indicating type 2-high disease, including 94.7% (n = 1,750 of 1,847) with an eosinophilic endotype, the researchers said.
Further, 84% (n = 895 or 1,065) tested positive for an aeroallergy. Across the full cohort of 2,210 patients, 53.1% had a history of allergic rhinitis, 52.6% had a history of chronic rhinosinusitis, and 30% had a history of nasal polyposis.
Patients also had a median of two exacerbations per year before biologic treatment, 57.1% (n = 1,129 of 1,978) had used long-term oral corticosteroids (LTOCS) and 74.2% (n = 1,005 of 1,355) had asthma classified as uncontrolled.
The cohort also included 1,005 of 1,355 (74.2%) patients whose percent-predicted FEV1 was less than 80%. Generally, asthma was more severe among patients who began anti-IL-5/5R treatment and less severe among those who began anti-IL-4R-alpha treatment.
Proportions of responses
The researchers used a 50% or greater reduction in exacerbation rate, a 50% or greater reduction in daily LTOCS doses, improvements in one or more asthma control categories and a 100 mL or greater improvement in FEV1 as domains defining response to treatment.
With treatment, 80.7% had a 50% or greater reduction in exacerbations, 44.3% had a 50% or greater reduction in daily LTOCS doses, 51.1% had improved asthma control in one or more categories and 53.6% had an improvement of 100 mL or more in their FEV1.
Proportions of patients who achieved response in more than one domain included 33.1% with improvements in both exacerbations and LTOCS doses; 18.5% with improvements in exacerbations, LTOCS doses and control; 13.6% with improvements in exacerbations, LTOCS doses and FEV1; and 10.6% with improvements in all four domains. These proportions were similar across classes of biologics, the researchers said.
Improvements in FEV1 for those who experienced them (n = 1,030) included 100 mL to 200 mL for 11.8% (n = 122), 200 mL to 500 mL for 21.9% (n = 226) and 500 mL and higher for 19.8% (n = 204).
Among the 409 patients who had three or more exacerbations or one or more exacerbations that required hospitalization before beginning biologic treatment, 12.7% (n = 52) still had one or more that required hospitalization or three or more exacerbations per year after beginning treatment.
The researchers also classified 53.2% (n = 188 of 353) of the patients who used more than 10 mg of LTOCS each day before biologic treatment as responders, although 19.1% of them (n = 36 of 188) still used more than 5 mg of LTOCS each day after beginning biologics.
The 441 patients with uncontrolled asthma before beginning biologic treatment and then were classified as achieving control afterward included 46.7% (n = 206) whose control was only considered partial, the researchers said.
Percentages of patients who achieved response in lung function with treatment but who still had a percent-predicted FEV1 under 80% ranged from 33.3% to 82% based on the magnitude of that improvement, with similar patterns across the biologic classes.
Associations with response
Greater impairments in each domain prior to biologic initiation increased the odds for being a responder in each domain, the researchers said, with other characteristics that increased the odds for meeting criteria for being a responder varying by domain.
The researchers found associations between greater odds for achieving exacerbation responder status and lower daily LTOCS doses (OR = 0.85; 95% CI, 0.77-0.95 for each 5 mg increase in LTOCS daily doses before biologic treatment).
There also was an association between greater odds for achieving exacerbation responder status and a lack of a prescription for theophylline before biologic treatment (OR = 0.77; 95% CI, 0.52-1.14 among patients who used theophylline).
Additional associations included the absence of osteoporosis (OR = 0.6; 95% CI, 0.34-1.08 for the presence of osteoporosis) and a history of atopic dermatitis (OR = 1.54; 95% CI, 0.73-3.25).
However, there were no associations between greater odds for meeting criteria for exacerbation response and higher BEC, IgE or FeNO levels before beginning biologic treatment, the researchers said.
The patients with lower rates of exacerbations before beginning biologic treatment had greater odds for response defined as a reduction in daily LTOCS doses of 50% or more.
Those patients categorized as responders based on these reductions in LTOCS doses also were more likely to have higher BEC (OR = 1.15; 95% CI, 1.03-1.27 for each doubling of concentration before biologic initiation).
Lower BMI (OR = 0.89; 95% CI, 0.8-0.98 for each increase of five units), a lack of theophylline use before biologic initiation (OR = 0.66; 95% CI, 0.46-0.96 for those who used theophylline) and a history of sleep apnea (OR = 2.24; 95% CI, 1.58-3.17) and T2-related comorbidity all were more likely among these patients as well.
Patients with better lung function, fewer exacerbations per year, and lower daily LTOCS doses prior to initiating biologic treatment were more likely to be responders based on the asthma control domain.
Patients with higher BEC levels before initiating biologic treatment also had higher odds for achieving response status in control (OR = 1.32; 95% CI, 1.18-1.48 for each doubling in concentration).
Other factors associated with a greater likelihood for improvements in one or more categories in control status after beginning biologic treatment include a lower BMI (OR = 0.72; 95% CI, 0.65-0.8 for each five-unit increase before treatment) and a lack of a theophylline prescription (OR = 0.51; 95% CI, 0.33-0.78 for theophylline users) or sleep apnea (OR = 0.68; 95% CI, 0.46-1 for those with sleep apnea).
Patients who had histories of chronic rhinosinusitis, allergic rhinitis and nasal polyposis also were more likely to achieve improvements in one or more asthma control categories after beginning biologic treatment.
Patients who were classified as responders based on FEV1 improvements were more likely to have lower daily LTOCS doses (OR = 0.92; 95% CI, 0.84-1 for each 5 mg increase prior to biologic initiation) and higher BEC levels (OR = 1.31; 95% CI, 1.17-1.47 for each doubling in concentration) and FeNO (OR = 1.2; 95% CI, 1.1-1.31 for each increase of 25 ppb) before beginning biologic treatment.
Asthma onset and duration only were risk factors for response in lung function, with later onset and shorter durations indicating grater odds for this response after beginning biologic treatment.
With each 5 years after asthma onset, odds for response in lung function increased by 1.11 (95% CI, 1.06-1.17). With each 10-year increase in duration of asthma, odds for response in lung function decreased by 0.81 (95% CI, 0.73-0.9).
Other factors increasing odds for lung function response included lower BMI before biologic treatment, a lack of a theophylline prescription, a lack of osteoporosis and the presence of chronic rhinosinusitis, allergic rhinitis or nasal polyposis.
Patients who began treatment with anti-IgE and anti-IL-5/5R biologics experienced similar trends, the researchers said, with some significant differences in odds ratios for BECs (P for heterogeneity < .05).
The researchers noted a positive association between higher BEC and exacerbation response among patients taking IL-5/5R biologics (OR = 1.23; 95% CI, 1.01-1.49) as well as a negative association between higher BEC and exacerbation response among patients taking anti-IgE biologics (OR = 0.65; 95% CI, 0.45-0.94).
Further, the patients taking anti-IL-5/5R biologics saw an association between higher BEC and achieving response in the control domain (OR = 1.55; 95% CI, 1.34-1.8), but the patients taking anti-IgE biologics did not. There were not enough patients taking anti-IL-4R-alpha biologics to draw any similar conclusions.
Conclusions
These wide variations in findings led the researchers to conclude that response may be complex and depend on patients and the assessed outcomes. Also, the researchers said these findings indicate the need to exercise caution when interpreting data about biologic response across studies as well as a need for a unified theory of response.
Further, the persistence of symptoms after the initiation of treatment and even after otherwise achieving criteria for response underscore the need to provide patients with realistic expectations about their treatment when it begins, the researchers said.
By using these data to predict how individual patients will respond to biologics in specific domains, the researchers continued, physicians may be able to optimize treatment that is aligned with each patient’s personalized goals.
Perspective
Back to Top
The 80% of patients who were responders in the 50% reduction in exacerbations domain is expected, as the pivotal trials for these asthma biologics have shown about a 50% reduction in exacerbations compared with placebo. However, the 54% response in FEV1 improvement is low compared with the pivotal trials.
It is surprising that this study saw no association between higher baseline eosinophil count, IgE or FeNO and exacerbation responder rate, as we tend to expect that the higher the biomarker before starting biologic therapy, the more likely we are to see a response.
The study highlights the complexity of comorbidities that complicate asthma control, such as sleep apnea.
My own experience is similar to these findings. In real life, we find the assessment of biologic response to asthma hard to assess.
We also need to provide a realistic expectation of the outcomes of biologic therapy to our patients. We need to individualize our assessment of control for each patient, based on that patient’s pre-biologic characteristics. We need to use these findings to educate and empower our patients about asthma and asthma biologics to improve compliance and quality of life.
Finally, we need more research toward identifying better predictive biomarkers, and we always need research into better and more efficacious yet safe therapies.
Collapse
Click Here to Manage Email Alerts