Biomarker response to asthma treatment shouldn’t be neglected

Biomarkers can guide treatment choice in severe asthma but may also provide clinically useful information from the subsequent effects of treatment on biomarkers, Australian researchers say.

A review of the evidence, led by Professor John Upham from the University of Queensland Diamantina Institute, shows the available data is inconsistent and biomarker response to treatment can vary.

For example, mepolizumab can reduce sputum and blood eosinophils by 48-60% however it, and other biologics targeting the IL-5 pathway do not generally reduce FeNO.

“FeNO may even rise in some situations during IL-5 blockade (our unpublished observations): this may reflect erratic adherence to ICS, recent allergen exposure or sinonasal inflammation, but may also indicate that IL-5-regulated eosinophilia, and IL-13-regulated FeNO represent distinct mechanistic pathways,” the review said.

The review said omalizumab produces a significant reduction in serum free IgE but given the free IgE assay was not readily available to clinicians, it was of little practical value.

Omalizumab also significantly reduced FeNO, airway and blood eosinophils.

“The significance of an unexpected increase in FeNO in omalizumab- treated patients is unclear but should raise suspicions of non-adherence to ICS or recent allergen exposure,” the review said.

Dupilumab produces consistent reductions in FeNO, serum total IgE and blood eosinophilia although transient elevations of blood eosinophils have also been observed.

The review found there was evidence fevipiprant caused a 4.5 fold reduction in sputum eosinophils but appeared to have no effect on blood eosinophils. Yet another study showed its use led to reductions in FeNO but not total IgE.

“However, since total IgE changes quite slowly in response to interventions, longer studies will be needed to determine if DP2 antagonism reduces total IgE.”

The review authors said while the perfect biomarker was elusive, serial measurements of biomarkers would be useful especially in patients who did not appear to improve after a reasonable period on treatment.

“If the level of a treatment-responsive biomarker (e.g. blood eosinophil count) has fallen on an anti-IL-5 monoclonal antibody, this confirms that the therapy is having its expected biological effect,” they said.

“The lack of clinical improvement may indicate that eosinophils are not the main driver of disease activity in this particular patient and should prompt consideration of other factors responsible for treatment failure e.g. other co-morbidities contributing to symptom burden, ongoing environmental exposure, sub-optimal inhaler technique or adherence, involvement of other inflammatory pathways etc.”

“In contrast, if the treatment-responsive biomarker (e.g. blood eosinophil count) has not fallen, this may indicate that drug doses are insufficient, that blocking antibodies have developed, or that other causes of eosinophilia such as eosinophilic granulomatosis with polyangiitis (EGPA), parasitic infection or even an uncommon FIP1L1-PDGFRA gene mutation should be considered.”

The review also noted that some biomarkers traditionally associated with a type 2 immune response may not fall despite therapies which appear to be clinically beneficial.

“As new novel therapies for severe asthma are developed, and as new biomarkers enter clinical practice, there will be an ongoing need for studies that examine how these biomarkers change with treatment, and the implications this has for patient management,” it concluded.

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