Glucocorticoid toxicity reduction with mepolizumab using the Glucocorticoid Toxicity Index

Abstract

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.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 4280 mg prednisolone/year [interquartile range (IQR) 3083, 5475] versus V2 2450 mg prednisolone/year [1243, 3360], p<0.001). Substantial improvements in individual toxicities were observed but did not correlate with oral glucocorticoid reduction. Mean GTI Aggregate Improvement Score (AIS) was −35.7 (sd 57.8) with a wide range in toxicity change at individual patient level (AIS range −165 to +130); 70% (71/101) had a reduction in toxicity (AIS <0), 3% (3/101) had no change (AIS=0) and 27% (27/101) an increase in overall toxicity. Sixty-two (62/101) 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.

Proactive Risk Management: A Novel Approach to Embedding Oral Corticosteroid Stewardship into Asthma Care

“…37 Following 12 months of anti-IL-5 treatment, daily prednisolone use among the same patients reduced from 11.7 mg to 6.7 mg (p<0.001) and the number of asthma exacerbations reduced from five to one over the period of treatment (p<0.001). 38 However, AIS was found to vary widely around a mean of −35.7 (range: −165-+130), reflecting heterogeneous toxicity change at the individual patient level after treatment. 38 Although the majority of patients had a significant reduction in toxicities, 30% experienced no change or a worsening in overall Congress Review toxicity, while 39 of the 101 patients did not meet the minimal clinically important difference.…”

“…36 Although AEs associated with OCS use are traditionally considered to be dose-dependent or durationdependent, 36 the evidence increasingly suggests otherwise. 37,38 There is, therefore, a need for a method of systematically measuring toxicity when patients are seen in routine care.…”

“…The cumulative worsening score (CWS) is an additive record of glucocorticoid-related toxicities experienced by a patient from baseline, with a higher CWS indicating a greater number of new toxicities encountered. 38 The aggregate improvement score (AIS) is a measure of current toxicity, with a positive score indicating an increased total toxicity and a negative score reflecting reduced toxicity. 38 The minimal clinically important difference for the AIS has been calculated to be 10.…”

“…38 The aggregate improvement score (AIS) is a measure of current toxicity, with a positive score indicating an increased total toxicity and a negative score reflecting reduced toxicity. 38 The minimal clinically important difference for the AIS has been calculated to be 10. 37 The GTI has been validated in both real-world experience and clinical trials across multiple indications including asthma, and provides a systematic way for glucocorticoid toxicity to be measured in routine clinical care.…”

Oral corticosteroid-sparing effects of mepolizumab in severe eosinophilic asthma: evidence from randomized controlled trials and real-world studies

“…It will also be important to determine whether any OCS reductions achieved during biologic therapy use are sufficient to prevent or at least decrease the incidence of OCS-related AEs; studies to evaluate this are beginning. 76 Finally, it will be important to determine whether the OCS-sparing effect of mepolizumab extends to other eosinophilic diseases, such as eosinophilic granulomatosis with polyangiitis, hypereosinophilic syndrome, and chronic rhinosinusitis with nasal polyps, in which the clinical benefits of mepolizumab have already been shown.…”