Burden of illness and costs associated with eosinophilic granulomatosis with polyangiitis: evidence from a managed care database in the United States

BACKGROUND: Data on the clinical and economic burden of eosinophilic granulomatosis with polyangiitis (EGPA) are limited. OBJECTIVE: To assess the real-world clinical and economic outcomes of patients diagnosed with EGPA vs patients with asthma (present in > 90% of EGPA cases) receiving treatment in the United States. METHODS: This retrospective cohort study (HO-17-17742) used administrative claims data (July 1, 2007-May 31, 2017) from the Optum Research Database. Eligible patients were aged at least 18 years at index (first date that patients met the EGPA or asthma cohort definition), with a minimum of 6 months of continuous health plan coverage before the index (baseline) period and 12 months following and including the index date (follow-up period). Patients with EGPA were identified either via published algorithms using claim code combinations for conditions and medications (before October 1, 2015) or via a claim with the EGPA ICD-10-CM code (M30.1, after October 1, 2015). Patients with asthma were identified based on ICD-9-CM and ICD-10-CM diagnosis codes and at least 3 pharmacy asthmarelated medication claims within a year of diagnosis. Outcomes included all-cause health care costs (primary), all-cause health care resource utilization (HCRU), systemic corticosteroid (SCS) use, and EGPA relapses requiring hospitalization and EGPA-related (based on EGPA-related HCRU) relapses during the follow-up period (all secondary). EGPA and asthma cohorts were matched (1:3) via propensity score matching based on demographic, insurance, and index timing covariates. RESULTS: 8,904 patients were included in the matched EGPA (n = 2,226) and asthma (n = 6,678) cohorts (mean [SD] age: 59.7 [14.2] vs 59.6 [14.7] years; Quan-Charlson Comorbidity Index scores: 1.8 [1.7] vs 0.8 [1.4]). During follow-up, mean (SD) all-cause costs ($49,593 [$88,161] vs $21,122 [$40,110]; P < 0.001), all-cause HCRU (P < 0.001), and the proportion of patients with 1 or more SCS claims (72.3% vs 66.9%; P < 0.001) were significantly greater in the EGPA vs asthma cohorts, respectively. Mean daily SCS dose (43.6-45.5 mg/day) was similar between cohorts; patients with EGPA had significantly (P < 0.001) longer periods taking SCS doses at least 4 mg/day (mean [SD]: 64.9 [95.6] vs 14.6 [39.3] days) and at least 7 mg/day (52.8 [82.0] vs 12.1 [30.6] days). 35.2% (n = 784/2,226) and 44.1% (n = 981/2,226) of patients with EGPA experienced a minimum of 1 EGPA relapse requiring hospitalization, and at least 1 EGPA-related relapse, respectively. Mean (SD) total all-cause costs were greater than 3-fold higher in patients with vs without a relapse requiring hospitalization ($92,825 [$128,562] vs $26,087 [$38,082]; P < 0.001) and for patients with vs without an EGPA-related relapse ($78,081 [$120,775] vs $27,145 [$35,584]; P < 0.001). CONCLUSIONS: Patients with EGPA have more comorbidities, greater health care costs and HCRU, and use SCS more frequently than patients with asthma. Additionally, more than one third of patients with EGPA experienced disease relapses over 12 months. These results highlight the high disease burden in patients with EGPA and the need for improved treatment options.

12 months following and including the index date (follow-up period). Patients with EGPA were identified either via published algorithms using claim code combinations for conditions and medications (before October 1, 2015) or via a claim with the EGPA ICD-10-CM code (M30.1, after October 1, 2015). Patients with asthma were identified based on ICD-9-CM and ICD-10-CM diagnosis codes and at least 3 pharmacy asthmarelated medication claims within a year of diagnosis. Outcomes included all-cause health care costs (primary), all-cause health care resource utilization (HCRU), systemic corticosteroid (SCS) use, and EGPA relapses requiring hospitalization and EGPA-related (based on EGPA-related HCRU) relapses during the follow-up period (all secondary). EGPA and asthma cohorts were matched (1:3) via propensity score matching based on demographic, insurance, and index timing covariates. RESULTS: 8,904 patients were included in the matched EGPA (n = 2,226) and asthma (n = 6,678) cohorts (mean [SD] age: 59.7 [14.2] vs 59.6 [14.7] years; Quan-Charlson Comorbidity Index scores: 1.8 [1.7] vs 0.8 [1.4] What is already known about this subject • Eosinophilic granulomatosis with polyangiitis (EGPA) is characterized by vascular inflammation and multisystem organ damage.
• Data on the clinical and economic burden of EGPA are limited owing to the previous lack of EGPA-specific diagnosis codes and limited regulatory approved treatments.

What this study adds
• This retrospective cohort study demonstrated that all-cause health care costs are approximately 2.5-fold higher in patients with EGPA than in patients with asthma who have similar demographic and insurance characteristics.
• Patients with EGPA also require more health care utilization and systemic corticosteroid use than patients with asthma, with more than one third of those with EGPA experiencing relapses.
• These results highlight the high burden of disease in patients with EGPA and the need for improved treatment options.
Eosinophilic granulomatosis with polyangiitis (EGPA), formerly Churg-Strauss Syndrome, is a rare disorder characterized by vascular inflammation and multisystem organ damage that manifests as chronic rhinosinusitis, asthma, and peripheral blood eosinophilia. 1,2 The prevalence of EGPA is estimated to range from 2 to 38 cases per million people, 3,4 and the incidence to be 0.6-3.4 cases per million. 3,5 The management of EGPA is based on the reduction of active inflammation, suppression of the immune response, and treatment of disease-specific and/or treatment-related complications. 2,6 Although there are currently no strong recommendations for the treatment of EGPA and few regulatory approved treatments, corticosteroids are a cornerstone therapy for inducing and maintaining remission in the treatment of patients regardless of EGPA prognosis. 2,6,7 Some patients achieve remission with corticosteroid therapy alone 8 ; however, the addition of more potent immunosuppressive therapies (eg, azathioprine, methotrexate, or mycophenolate mofetil) is frequently required to maintain remission. 2,6 Despite these treatments leading to successful EGPA remission, patients frequently experience relapses during corticosteroid tapering. 2,6 In addition, corticosteroids and immunosuppressants may be associated with adverse events. 2,9 For patients with a poor prognosis, cytotoxic therapy such as cyclophosphamide is required to induce remission, with a switch to less toxic immunosuppressant therapy (eg, azathioprine or methotrexate) for maintenance of remission. 6 In clinical practice, EGPA is confirmed by the presence of at least 4 of the following characteristics: asthma, blood eosinophil count more than 10%, mononeuritis multiplex or polyneuropathy, pulmonary infiltrates, paranasal sinusitis, or extravascular eosinophils. [10][11][12] However, a specific diagnosis code for use in identifying patients with EGPA from health records was only established in the United States in October 2015 with the adoption of the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM); before ICD-10-CM, studies evaluating the burden of EGPA via retrospective analyses of administrative claims data relied on a series of coding algorithms (eg, International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] diagnosis and procedures codes, Current Procedural Terminology [CPT] codes, and physician specialties). [13][14][15][16][17][18] Owing to the previous lack of EGPA-specific diagnosis codes and limited number of regulatory approved treatments, data are limited on the clinical and economic burden of EGPA. Comparing clinical outcomes in EGPA with those in patients with asthma, in which the disease burden is well established, 19 is a useful way to measure the burden of EGPA for patients and payers.
Using data from an administrative claims database, this retrospective US cohort study aimed to assess clinical and economic outcomes in a cohort of patients with EGPA compared with a cohort of patients with asthma who were treated in real-world clinical practice.

STUDY DESIGN
This was a retrospective cohort study (HO-17-17742) conducted using administrative claims data collected from July 1, 2007, to May 31, 2017, from the Optum Research Database. In 2017, the database contained data on approximately 19 million commercial and Medicare Advantage enrollees. This study used fully deidentified data and as such was not classified as research involving human participants. Therefore, institutional review board approval was not sought.

PATIENTS
Patients meeting the EGPA or asthma cohort definitions for the first time (defined as the index date) between January 1, 2008, and May 31, 2016 (identification period) were included (Supplementary Figure 1, available in online article). Patients were aged at least 18 years at the start of the index year, with continuous coverage in a health plan with both medical and pharmacy benefits for a minimum of 6 months before the index date (baseline period) and 12 months following and inclusive of the index date (follow-up period). Patients with missing geographic region, sex, or insurance type were excluded. 14

CONCLUSIONS:
Patients with EGPA have more comorbidities, greater health care costs and HCRU, and use SCS more frequently than patients with asthma. Additionally, more than one third of patients with EGPA experienced disease relapses over 12 months. These results highlight the high disease burden in patients with EGPA and the need for improved treatment options.
patients utilizing each health care resource and mean [SD] number of visits/stays/days/claims) included ambulatory visits, ED visits, inpatient stays and number of days, and pharmacy claims.
Clinical outcomes and treatment patterns included the proportion of patients with blood eosinophil count data available; SCS use (proportion of patients with 1 or more claims, mean daily dosing among all days with SCS, proportion of patients with at least 4 or at least 7 mg/day, number of days with at least 4 or at least 7 mg/day); non-SCS immunosuppressant use; and the proportion of patients with EGPA who experienced EGPA relapses requiring hospitalization and EGPA-related relapses during the follow-up period, as defined below; all-cause HCRU and associated costs were compared between patients who experienced relapses during the follow-up period and those who did not.
An EGPA relapse requiring hospitalization was identified by an inpatient admission for any reason in the primary position of a claim, starting at least 30 days after the index date. An EGPA-related relapse was defined as meeting any of the following 7 predefined conditions starting after the index date plus 30 days: (1) at least 1 nondiagnostic inpatient, ED, or outpatient claim for vasculitis; (2) at least 1 nondiagnostic inpatient, ED, or outpatient claim for a relapse-related condition based on major items in the Birmingham Vasculitis Activity Score (BVAS); (3) at least 1 nondiagnostic inpatient claim with an asthma diagnosis in the primary position; (4) at least 1 nondiagnostic ED claim with resulting inpatient stay within 1 day, with an asthma diagnosis in the primary position; (5) at least 1 nondiagnostic ED claim (no inpatient stay within 1 day) or outpatient claim with an asthma diagnosis in the primary position and at least 1 claim for oral corticosteroid (OCS)/SCS in the 7 days before or after; (6) at least 1 nondiagnostic outpatient claim for allergic rhinitis, nasal polyposis, or acute/chronic sinusitis in the primary position AND includes either a new OCS/SCS claim, a new immunosuppressant claim, or an increase in OCS dose to more than 4 mg/day in the 7 days before or after; or (7) at least 1 nondiagnostic inpatient claim with allergic rhinitis, nasal polyposis, or acute/ chronic sinusitis in the primary position. International Classification of Diseases and Related Health Problems codes for conditions are included in Supplementary Table 2 (available in online article).

STATISTICAL ANALYSIS
To balance the characteristics of patients with EGPA and those with asthma and to minimize confounding, the EGPA and asthma cohorts were matched (1:3) via propensity score greedy matching (ie, matched patients were no Patients with EGPA were identified using 1 of 2 criteria, depending upon the dates of the initial identifying claim. Before October 1, 2015 (during which an ICD-9-CM code for the identification of patients with EGPA was lacking), patients with EGPA were identified via published algorithms. 13,16 Seven published algorithms were slightly adapted; 4 were based on the Harrold algorithm; and 3 were based on the Sreih algorithm. The algorithms included variables found in administrative claims data, including codes for asthma; vasculitis; mononeuritis; eosinophilia; neurological conditions; immunosuppressant use including systemic corticosteroids (SCS); and physician specialties (rheumatology, allergy/immunology, nephrology, pulmonology, and otorhinolaryngology; Supplementary Table 1, available in online article). Positive predictive values ranged between 10% and 100% (Supplementary Table 1). A patient was considered to have successfully met the criteria for EGPA if all of the requirements for at least 1 of the 7 algorithms were fulfilled within a 12-month period. After October 1, 2015, the ICD-10-CM EGPA code (M30.1: polyarteritis with lung involvement [Churg-Strauss]) was used to classify EGPA cases. Before October 1, 2015, the index date was the date of the first claim containing an ICD-9-CM diagnosis code for vasculitis, and after October 1, 2015, the index date was the date of the first claim with the ICD-10-CM code for EGPA.
Patients with asthma were identified based on ICD-9-CM and ICD-10-CM diagnosis codes for asthma with at least 3 pharmacy claims for asthma-related medications within 365 days of diagnosis. The index date was the date of the first claim containing codes for asthma diagnosis during the identification period (Supplementary Table 1). Any patients identified as meeting both EGPA and asthma cohort definitions were included in the EGPA cohort.

STUDY MEASURES
The primary outcome was all-cause health care costs during the 12-month follow-up period. All-cause health care costs were computed as combined health plan and patient paid amounts, overall and by health care setting (medical [ambulatory, emergency department (ED), inpatient, other medical] and pharmacy claims) and were adjusted to 2016 US dollars based on the medical care component of the Consumer Price Index.
Secondary outcomes included demographics and clinical characteristics at index and treatment patterns including all-cause health care resource utilization (HCRU) and costs during the 6-month baseline period. All-cause HCRU, clinical outcomes and treatment patterns, and costs and HCRU associated with disease relapse were assessed during the 12-month follow-up period. All-cause HCRU (proportion of Rao-Scott chi-square statistics were used to test for differences in categorical variables and robust variance estimators to test for differences in continuous variables. 21 Standardized differences (percentages) were presented for pre-index variables. Adjusted total all-cause costs were estimated using a generalized linear model with a gamma distribution and log link, with covariates of age, sex, geographic region, insurance type, and index year. Modeling for other all-cause cost endpoints was not performed. Statistical significance was evaluated at the α = 0.05 level.
Statistical analyses were conducted using SAS software version 9.4 (SAS Institute).

STUDY POPULATION
A total of 2,226 patients met the EGPA cohort identification criteria between January 1, 2008, and May 31, 2017; 53 (2.4%) patients were identified via ICD-10-CM code M30.1 alone, 27 (1.2%) patients fulfilled 1 of the 7 algorithms and also had the EGPA ICD-10-CM diagnosis code, and the remaining 2,146 (96.4%) patients were identified solely via 1 of the 7 algorithms. Among the 48,252 patients who met the asthma cohort identification criteria, 6,678 patients with asthma were matched to patients with EGPA based on index month/year, age group, sex, health plan region, insurance type, date, and continuous enrollment duration ( Figure 1).

PATIENT CHARACTERISTICS IN THE BASELINE PERIOD AND AT INDEX
No statistically significant differences in demographics were observed because the cohorts were matched (    Table 4, available in online article), with a significantly (P < 0.001) greater proportion of patients requiring at least 1 ED visits (58.9% vs 44.9%) and at least 1 inpatient stay (42.6% vs 25.1%), respectively. The mean (SD) number of visits over 12 months of follow-up was also significantly greater among patients with EGPA vs asthma including for ambulatory visits, ED visits, inpatient stays and number of days, and pharmacy claims (Supplementary Table 4).

CLINICAL OUTCOMES AND TREATMENT PATTERNS DURING THE 12-MONTH FOLLOW-UP PERIOD
Overall, significantly more patients with EGPA had a blood eosinophil test result available than those with asthma

Discussion
Data on the real-world clinical and economic burden of EGPA are scarce. The current study addresses this data gap by describing the health care burden of EGPA through the identification and characterization of a cohort of patients with EGPA, using data from a US claims database. All-cause costs were significantly greater in the EGPA cohort than those in the asthma cohort during both the baseline and follow-up periods. Additionally, patients with EGPA more frequently used health care resources and immunosuppressants including SCS compared with patients with asthma, both before and after index. Health care costs and HCRU were found to be significantly greater in the 35%-44% of patients with EGPA experiencing relapse over 12 months than in those who did not relapse during the follow-up period, highlighting the importance of achieving good disease control to minimize disease burden. The burden of EGPA was underlined by the finding that Quan-CCI scores for the EGPA cohort at index were double those of patients with asthma. Additionally, of the top 25 comorbid conditions identified during the baseline period,
All types of HCRU counts occurred in a significantly higher proportion of patients with relapses requiring hospitalization, or EGPA-related relapses vs those without relapses (Supplementary Table 5).

FIGURE 2
All-Cause Health Care Costs for the EGPA and Asthma Cohorts During the Follow-Up Period a immunosuppressants was also 4 times higher for EGPA compared with asthma cohorts. This is likely a reflection of guideline recommendations. In asthma, OCS/SCS is only recommended in patients with uncontrolled disease or frequent exacerbations despite inhaled corticosteroid/ bronchodilator therapy. 25 By contrast, SCS and non-SCS immunosuppressants are frontline treatments for disease maintenance and disease relapses in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, reflecting the severity of the disease and limited alternative treatment options during the time this study was conducted, before the approval of mepolizumab. 6,26,27 To date, health care costs have not been described for EGPA, so the closest comparison that can be made is with granulomatosis with polyangiitis (GPA), another ANCA disease. 15 Raimundo et al reported that the annual all-cause cost of GPA per patient was $41,400 (SD $87,537) in 2013 USD, 15 which is similar to the annual all-cause cost of EGPA ($49,593; SD $88,161) observed in this study. Additionally, Raimundo et al found that the majority of total costs were accounted for by inpatient stays and ambulatory visits. 15 Accordingly, increased all-cause health care costs in the prevalence was greater in the EGPA vs asthma cohort for all conditions including those affecting the respiratory and cardiovascular systems. EGPA preferentially affects these organ systems, in addition to peripheral nerves, the kidney, and the gastrointestinal tract 22,23 and can lead to conditions such as cardiac failure and bacterial infections, which are associated with an increased risk of death. 24 Blood eosinophil counts in the EGPA cohort were also approximately double those of patients with asthma during the baseline period of the current study, as would be expected based on the 7 diagnostic criteria for EGPA, which include a blood eosinophil count greater than 10%. [10][11][12] However, it should be noted that not all patients had data on blood eosinophil counts. The exact role of eosinophils in the pathogenesis of EGPA is uncertain but may result from direct or indirect proinflammatory effects and/or ischemic damage. 23 The mean daily dose of SCS was similar for the EGPA and asthma cohorts, although patients with EGPA were prescribed high SCS doses (≥ 4 and ≥ 7 mg/day) for significantly longer durations during the follow-up period, approximately 4 times as long as patients with asthma. Additionally, the proportion of patients using non-SCS

LIMITATIONS
There are several limitations to this study that should be acknowledged. In general, administrative claims studies are limited by the fact that a diagnosis code may be used as a ruleout condition or may be incorrectly coded, which may occur with the use of either method (algorithm or ICD-10-CM code) for identifying EGPA or among patients in the asthma cohort.
A further key limitation of this study is the lack of specific ICD diagnosis codes for EGPA before October 1, 2015, which raises the possibility of misclassification and could lessen the applicability of the findings to patients who truly have EGPA. For example, the ICD-9-CM algorithm and ICD-10-CM diagnosis code (M30.1) likely identified patients newly diagnosed with EGPA relative to the study period. However, it should be noted that patients with established disease may consume greater amounts of health care services and have higher health care costs than the patients included within this study. Additionally, 3 of the algorithms we used to identify patients with EGPA before the availability of ICD-10-CM codes required specialty physician visits, which may have resulted in patients without access to these specialists being omitted.
Furthermore, patients were propensity score matched based on demographic and insurance characteristics, but not blood eosinophil counts and comorbidities, in order to retain differences in the severity of the EGPA and asthma cohorts; however, these factors may have acted as confounding variables in cost and HCRU outcomes. Additionally, clinical found that the cumulative relapse rate was 5.9% at 12 months and 26.9% by 60 months. 29 In the clinical trial setting, relapses have been observed in 56% of patients receiving mepolizumab and 82% receiving placebo over 52 weeks. 27 The large variation between studies in relapse rates may be a reflection of the different treatment practices, populations, and study methodologies used, all of which contribute to the limited ability to make direct comparisons to the current study. Furthermore, the current study used a wide-ranging definition for EGPA-related relapses that was similar to that of major GPA relapse used by Raimundo et al. 15 Associated with disease relapses in the current study was an approximately 3-fold increase in total all-cause costs, amounting to a difference of $50,936 between patients with and without EGPArelated relapses, which is similar to the difference of $57,383 reported EGPA cohort of the current study were driven by greater HCRU than in the asthma cohort, with patients with EGPA vs asthma having approximately double the mean number of ambulatory visits and inpatient stays, in addition to significantly more ED visits and pharmacy claims.
Patient relapse rates are of clinical importance as they increase the risk of permanent damage from tissue and organ vasculitis. 28 Consequently, the evaluation of treatment success in EGPA includes assessment of relapse incidence, an indicator of whether remission is maintained. 6 In the current study, 44.1% of patients experienced at least 1 EGPA-related relapse during the 12-month followup period despite 72.3% of patients being prescribed with SCS and 33.1% being prescribed with non-SCS immunosuppressants. By comparison, a retrospective chart review study in Japan of 188 patients with EGPA

DISCLOSURES
This study was funded by GlaxoSmithKline (GSK ID: HO-17-17742). Bell is an employee of GSK and holds stock/share options in GSK. Blauer-Peterson is an employee of Optum, which was funded by GSK to conduct the study. Mao was an employee of Optum at the time the study was conducted. The authors report no other potential conflicts of interest. These data have previously been presented as a poster at the American College of Rheumatology/Association of Rheumatology Health Professionals Annual Meeting, Chicago, IL, October 19-24, 2018. charts are needed to measure signs and symptoms specific to EGPA to formulate a BVAS score, yet access to laboratory data are limited among claims databases. Similarly, data on over-the-counter medication use are not included in claims databases so were not captured.
Finally, the generalizability of results is limited by the inclusion of only commercial and Medicare Advantage enrollees from the Optum Research Database with a minimum of 18 months of continuous insurance. Consequently, patients who lost insurance coverage due to their severe disease, those with shorter insurance coverage, those enrolled in Medicare Fee for Service or Medicaid, and those without insurance were not included in the study population. Therefore, future studies comparing the accuracy of algorithms, ICD-10-CM codes, and/or studies that provide more clinical data will be needed to determine the extent to which retrospective study methodologies impact the assessment of the health care burden of EGPA.

Conclusions
This study found that patients with EGPA incurred greater health care costs, utilized more health care resources, had more comorbidities and used significantly more immunosuppressants (including SCS) compared with a cohort of patients with asthma alone. Despite available treatments between 2008 and 2016, more than one third of patients had disease relapses during the 12-month follow-up period, indicating poor disease control with currently available immunosuppressant and corticosteroid therapies. These results highlight the high burden of disease in patients with EGPA and the need for improved treatment options to induce and maintain remission, prevent relapses, and reduce the health care costs of EGPA.