Biomarker Panel Predicts Steroid Responsiveness in Asthma

Pam Harrison

December 23, 2014

A noninvasive panel of biomarkers can predict clinical responsiveness to inhaled corticosteroids (ICS) with a high degree of accuracy in patients with steroid-naive asthma, new research indicates.

Douglas C. Cowan, MBChB, MRCP, PhD, from Dunedin School of Medicine, University of Otago, New Zealand, and colleagues report their findings online December 6 in the Journal of Allergy and Clinical Immunology.

"Probably as many as 90% of asthmatics respond really well to most of the medications we give them, including steroids, but there may be as many as 5% of patients with asthma who really don't respond well, they do not have their asthma well controlled with steroids, and they have increased number of sick days and increased number of emergency room visits, so they have a lot of problems with their asthma," coauthor Suzy Comhair, PhD, from the Cleveland Clinic in Ohio, told Medscape Medical News. "So if you can have biomarkers from someone like this, you either tweak their medication or try something else, and it's just easier for them to achieve good asthma control."

The researchers obtained data and samples from 46 patients with stable persistent asthma who were enrolled in a study made up of two phases: a steroid-naive phase and a 28-day trial phase during which patients received treatment with fluticasone, 500 μg, twice a day.

They measured fraction of exhaled nitric oxide (FENO) values, sputum eosinophil counts, and urinary bromotyrosine (BrTyr) levels during both the steroid-naive and the steroid treatment phases of the study.

The researchers based steroid responsiveness on clinical improvements seen as either a 12% or greater increase in forced expiratory volume in 1 second, a 0.5-point or greater decrease in the Asthma Control Questionnaire score, and/or a two doubling dose or greater increase in provocative concentration of AMP causing a 20% decrease in forced expiratory volume in 1 second.

Changes in biomarker levels in response to ICS treatment were variable, the investigators note.

Eighty-two percent of patients had decreased FENO values, 60% had decreased sputum eosinophil counts, and 58% had decreased urinary BrTyr levels after treatment with fluticasone twice daily.

Patients with a baseline FENO value of 35 ppm or greater had a 10.50-fold greater likelihood of responding to inhaled steroids, as measured by improvement in at least three clinical outcomes, investigators report.

More powerfully, patients with the combination of a high FENO values (≥35 ppm) and high urinary BrTyr levels (≥0.45 ng/mg of creatinine) were more than 13 times more likely (13.3-fold) to have a positive response to steroid treatment, as measured by two clinical outcomes, they add (P < .1).

Importantly, there was no association between the magnitude of decrease in biomarker levels and the magnitude of clinical responsiveness, although this needs to be confirmed by a larger study, the authors write.

The US Food and Drug Administration has approved FENO measurements, and they are already used in the diagnosis and management of asthma.

However, urinary BrTyr levels would have to be determined in special laboratories, as the test is not yet suitable for a clinic setting.

Nevertheless, Dr Comhair suggested the panel could be used both to predict how likely it is that a steroid-naive patient will respond to treatment as well as identify those patients in whom a different dose of an ICS or a different medication will be called for, based on results from the biomarker panel.

Biomarkers Continue to Emerge

Stanley Szefler, MD, director, Pediatric Asthma Research Program, The Breathing Institute/Pulmonary Medicine, Aurora, Colorado, told Medscape Medical News that information on the use of biomarkers in predicting medication response continues to emerge.

"In this report by Cowan and colleagues, investigators indicate that the combination of exhaled nitric oxide, an indicator of airway eosinophil activation and/or epithelial cell activation, along with urinary bromotyrosine, an indicator of eosinophil activation, in combination were more useful in predicting response to ICS, as measured by a number of parameters, than either measure alone or the use of sputum eosinophils," Dr Szefler said.

As he pointed out, testing for sputum eosinophils is more difficult to obtain in the clinical setting, and it is expensive.

In contrast, exhaled nitric oxide can be easily measured in the office setting.

Exhaled nitric oxide can also be used to monitor adherence to ICS therapy.

"Investigators in this study confirm the observation that exhaled nitric oxide is associated with response to ICS, and exhaled nitric oxide is reduced in the presence of ICS," Dr Szefler observed.

"Therefore, a baseline measure before starting ICS, followed by a measurement of exhaled nitric oxide after initiating treatment combined with an assessment of treatment response, can be used to identify either poor adherence to ICS therapy, or perhaps poor inhaler technique, or alternatively, an enhanced allergic inflammatory response when loss of control is noted."

Dr Szefler added that if investigators show in future studies that these biomarkers, especially in combination, predict a high risk for an asthma exacerbation — a direction the team is planning to take — then these two tests in combination would show clinical utility.

One author reports nonfinancial support from Abbott, grants and personal fees from the Cleveland Heart Lab, personal fees from Esperion, grants from Foundation LeDucq, personal fees from Frantz Biomarkers, personal fees from Lilly, grants and personal fees from Liposcience, personal fees from Merck & Co, grants and personal fees from Pfizer, grants and personal fees from Procter & Gamble, personal fees from Siemens, and grants from Takeda Pharmaceuticals during the conduct of the study. In addition, that author has a patent with Cleveland Clinic and is partially supported by a gift from the Leonard Krieger endowment. The remaining authors and Dr. Szefler have disclosed no relevant financial relationships.

Dr Comhair and Dr Szefler have disclosed no relevant financial relationships.

J Allergy Clin Immunol. Published online December 6, 2014. Full text

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