Abstract
BackgroundReduction in glucocorticoid exposure is the primary benefit of new biologic treatments in severe asthma, but there is currently no evidence that reduction in glucocorticoid exposure corresponds to a proportionate reduction in associated toxicity.ObjectivesTo use the validated Glucocorticoid Toxicity Index (GTI) to assess change in glucocorticoid toxicity after 12 months treatment with mepolizumab, and compare toxicity change to glucocorticoid reduction and change in patient-reported outcome measures (PROMs).MethodsA longitudinal, real-world prospective cohort of 101 consecutive patients with severe asthma commenced on mepolizumab in a specialist UK regional severe asthma clinic. GTI toxicity assessment, cumulative glucocorticoid exposure and PROMs were recorded on commencing mepolizumab (V1), and after 12 months treatment (V2).ResultsThere was significant reduction in oral glucocorticoid exposure (V1 median 4280 mg prednisolone per year (interquartile range 3083–5475 mg) versus V2 2450 mg prednisolone per year (1243–3360 mg), p<0.001). Substantial improvements in individual toxicities were observed, but did not correlate with oral glucocorticoid reduction. Mean±sd GTI aggregate improvement score (AIS) was −35.7±57.8 with a wide range in toxicity change at individual patient level (AIS range −165 to +130); 70% (71 out of 101) had a reduction in toxicity (AIS <0); 3% (three out of 101) had no change (AIS=0); and 27% (27 out of 101) an increase in overall toxicity. 62% (62 out of 101) of patients met the AIS minimally clinically important difference of ≤−10, but AIS did not correlate with glucocorticoid reduction or change in PROMs.ConclusionMepolizumab resulted in substantial oral glucocorticoid reduction, but this did not correlate with reduction in oral glucocorticoid toxicity, which varies widely at the individual patient level. Oral glucocorticoid reduction is not a comprehensive measure of response to mepolizumab.
Highlights
A key anticipated benefit of biologics is GC toxicity reduction given the frequently occurring, multisystem adverse events known to have an increased incidence in individuals with severe asthma exposed to GCs, when compared to matched mild-moderate asthmatics and nonasthmatic controls.[8][9][10][11] Reduction in GC exposure is the pragmatic primary outcome of clinical trials for biologics in severe eosinophilic asthma (SEA), but there is currently no evidence that reduction in GC exposure produces a corresponding reduction in toxicity
Mepolizumab, an anti-IL5 monoclonal antibody, is used in the treatment of SEA to inhibit the recruitment, activation and longevity of eosinophils in the airways.[1][5][12] In the UK, access to mepolizumab and other biologics in SEA, is governed by the National Institute for Health and Care Excellence(NICE), which advises that the decision of continuing or discontinuing biological therapy is based on the determination of an “adequate response” defined as a “clinically significant reduction in GC-requiring exacerbations” (50% reduction for mepolizumab) or a “clinically significant reduction in continuous oral GCs”.[13][14][15][16] There is no clear guidance on what constitutes a ‘clinically significant reduction’, but accepting the major problem with systemic GC are the well-recognised side effects, toxicity reduction is a central issue which is becoming more widely acknowledged.[17]
Using the Glucocorticoid Toxicity Index (GTI) [18], we have previously shown that quantification of pre-biologic GC toxicity in SEA patients with substantial systemic GC exposure demonstrates wide variation at the individual patient level.[19]
Summary
Biological therapies targeting type-2 (T2) inflammatory pathways in severe eosinophilic asthma (SEA) are effective in facilitating a decrease in systemic glucocorticoid (GC) exposure by reducing asthma exacerbations by approximately 50%,[1][2][3][4] and facilitating maintenance oral GC weaning.[5][6][7]. Mepolizumab, an anti-IL5 monoclonal antibody, is used in the treatment of SEA to inhibit the recruitment, activation and longevity of eosinophils in the airways.[1][5][12] In the UK, access to mepolizumab and other biologics in SEA, is governed by the National Institute for Health and Care Excellence(NICE), which advises that the decision of continuing or discontinuing biological therapy is based on the determination of an “adequate response” defined as a “clinically significant reduction in GC-requiring exacerbations” (50% reduction for mepolizumab) or a “clinically significant reduction in continuous oral GCs”.[13][14][15][16] There is no clear guidance on what constitutes a ‘clinically significant reduction’, but accepting the major problem with systemic GC are the well-recognised side effects, toxicity reduction is a central issue which is becoming more widely acknowledged.[17]. We evaluate the relationships between GC toxicity change, variation in cumulative GC dose and asthma outcome measures typically used to define a treatment response to biological therapies
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
