Glucocorticoid toxicity reduction with mepolizumab using the Glucocorticoid Toxicity Index.

BACKGROUND: Reduction 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. OBJECTIVES: To 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). METHODS: A 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). RESULTS: There 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. CONCLUSION: Mepolizumab 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.

Quantification of Glucocorticoid-Associated Morbidity in Severe Asthma Using the Glucocorticoid Toxicity Index.

BACKGROUND: Glucocorticoid (GC)-associated morbidity in severe asthma (SA) is well recognized but varies in individual patients; systematic measurement of GC toxicity is important to measure improvement with steroid-sparing monoclonal antibodies. OBJECTIVE: To describe for the first time individual patient GC toxicity in steroid-dependent SA using the Glucocorticoid Toxicity Index (GTI). METHODS: An observational consecutive patient cohort study was performed at a UK Regional SA Specialist clinic for systematic assessment of GC-associated morbidity using the GTI in routine clinical care. GTI was correlated with commonly used patient-reported outcome measures. An approach to GTI scoring, calculation of minimal clinically important difference (MCID), and development of digital GTI application in routine clinical care are described. RESULTS: All patients had significant oral GC exposure (cumulative prednisolone/prior year, 4280 [3083, 5475] mg) with wide distribution of toxicity in individual patients (mean GTI score, 177.5 [73.7]). GTI score had only modest correlation with recent prednisolone exposure: maintenance prednisolone dose (rho = 0.26, P = .01), cumulative exposure/prior year (rho = 0.38, P < .001), and GC boosts/prior year (rho = 0.25, P = .01). GTI toxicity demonstrated stronger associations with asthma-related quality of life (mini-Asthma Quality of Life Questionnaire [mini-AQLQ] r = -0.50, P < .001 and St. George's Respiratory Questionnaire r = 0.42, P < .001). GTI MCID was calculated as 10 points. Multiple linear regression demonstrated that age and mini-AQLQ were strongest predictors of GC toxicity. CONCLUSIONS: The GTI is a useful tool to systematically capture and quantify GC toxicity at the individual patient level. GC toxicity varies widely between individual patients with SA and correlated only modestly with GC exposure over the preceding year. Age and mini-AQLQ are better predictors of GC toxicity. The GTI and MCID will facilitate assessment of individual SA response to steroid-sparing agents in clinical trials and routine care.

Utility of fractional exhaled nitric oxide suppression as a prediction tool for progression to biologic therapy.

RATIONALE: The utility of fractional exhaled nitric oxide (F ENO) suppression (FeNOSuppT) to identify non-adherence to inhaled corticosteroid (ICS) treatment has previously been reported, but whether it can predict clinical outcome remains unclear. OBJECTIVES: We examined the utility of FeNOSuppT in prediction of progression to biologic agents or discharge from specialist care. METHODS: FeNOSuppT was measured at home using remote monitoring technology of inhaler use alongside daily F ENO measurement over 7 days. Long-term clinical outcomes in terms of progression to biologic agent or discharge from specialist care were compared for non-suppressors and suppressors. MEASUREMENTS AND MAIN RESULTS: Of the 162 subjects, 135 successfully completed the test with 81 (60%) positive F ENO suppression tests. Subjects with a negative FeNOSuppT were more likely to proceed to biologic therapy (39 of 54 patients, 72%) compared to those with a positive FeNOSuppT (35 of 81 patients, 43%, p=0.001). In subjects with a positive FeNOSuppT, predictors of progression to biologic therapy included higher dose of maintenance steroid at initial assessment and prior intensive care unit admission. These subjects had a significant rise in F ENO between post-suppression test and follow-up (median, 33 (IQR 25-55) versus 71 (IQR 24-114); p=0.009), which was not explained by altered corticosteroid dose. CONCLUSIONS: A negative FeNOSuppT correlates with progression to biologic therapy. A positive FeNOSuppT, with subsequent maintenance of "optimised" F ENO, predicts a subgroup of patients in whom asthma control is preserved with adherence to high-dose ICS/long-acting ß2 agonist and who can be discharged from specialist care.