Oral corticosteroid use, morbidity and mortality in asthma: A nationwide prospective cohort study in Sweden

Abstract Background Patterns and determinants of long‐term oral corticosteroid (OCS) use in asthma and related morbidity and mortality are not well‐described. In a nationwide asthma cohort in Sweden, we evaluated the patterns and determinants of OCS use and risks of OCS‐related morbidities and mortality. Methods Data for 217 993 asthma patients (aged ≥ 6 years) in secondary care were identified between 2007 and 2014 using Swedish national health registries. OCS use at baseline was categorized: regular users (≥5 mg/d/y; n = 3299; 1.5%); periodic users (>0 but <5 mg/d/y; n = 49 930; 22.9%); and nonusers (0 mg/d/y; n = 164 765; 75.6%). Relative risks of becoming a regular OCS user and for morbidity and mortality were analysed using multivariable Cox regression. Results At baseline, 24% of asthma patients had used OCS during the last year and 1.5% were regular users. Of those not using OCS at baseline, 26% collected at least one OCS prescription and 1.3% became regular OCS users for at least 1 year during the median follow‐up of 5.3 years. Age at asthma diagnosis, increasing GINA severity and Charlson Comorbidity Index were associated with regular OCS use. Compared to periodic and non‐OCS use, regular use was associated with increased incidence of OCS‐related morbidities and greater all‐cause mortality, adjusted HR 1.34 (95% CI 1.24‐1.45). Conclusions Oral corticosteroids use is frequent for asthma patients, and many are regular users. Regular OCS use is associated with increased risk of morbidity and mortality. These findings indicate that there is a need of other treatment options for patients with severe asthma who are using regular OCS.

need treatment with oral corticosteroids (OCS), both as short-term treatment for exacerbations, and as a regular long-term maintenance treatment for asthma control. 3 Regular OCS use is associated with both short-and long-term OCS-related complications, such as osteoporosis, fractures, ischaemic heart disease, hypertension and changes in glucose metabolism. [5][6][7][8][9][10] Whilst regular OCS use still plays a significant part in the treatment of patients with severe asthma, few population studies have to date investigated the patterns and determinants of long-term OCS use, changes in treatment patterns over time and the impact of OCS use on morbidity and mortality. This may be due to limited number of countries with access to complete nationwide data. Sweden, with its nationwide, longitudinal and mandatory registers is an ideal setting to study OCS treatment in asthma from a whole population perspective. 11 This enables inclusion of all patients in the country diagnosed with asthma in a secondary care setting, with linkage to near complete data on all collected medications from pharmacies, diagnosed diseases and causes of death.
The aim of this study was to evaluate the patterns of OCS use and its potential determinants, and the associations between OCS use and the risk of OCS-related morbidities and all-cause and causespecific mortality for asthma patients diagnosed in secondary care.

| Study design and data sources
This was a prospective, longitudinal, observational cohort study utiliz-  [11][12][13] Individual patient data were linked by the Swedish National Board of Health and Welfare using each person's unique social security number. The study protocol was approved by the Stockholm Regional Ethics Committee (registration number 2017/4:2). 14,15

| Study population
The study population included all asthma patients between 12 and 45 years in Sweden during 2007-2014 in outpatient or inpatient secondary care, and a drug claim for obstructive lung disease (ATC R03).
A defined index date and baseline period was utilized to classify patients into different OCS usage groups. The index date was the date of first asthma diagnosis and the baseline period was from the index date up to 365 days post index.
The following exclusion criteria were used: • asthma diagnosis only before the age of 6 years, • patients with <365 days of follow-up from index date, • drug claim of oral glucocorticoid other than prednisolone (ATC H02AB06) and betamethasone (ATC H2AB01) any time prior to index date or during the baseline period.
The reason for this is that prednisolone and betamethasone are the only OCS recommended for treatment of asthma in the Swedish Asthma Guidelines. 16 Use of OCS equivalent to >20 mg/d of prednisolone during the full 1-year baseline period as a higher dose would typically be used for conditions other than asthma.

G R A P H I C A L A B S T R A C T
Annually, almost one in seven asthma patients used oral corticosteroids, which was stable over the 10-year study period. Oral corticosteroids are still a substantial part of current asthma management for many patients and are associated with severe side effects and mortality risk. There is a need for other treatments for severe asthma patients who are using regular oral corticosteroids. and current malignancy [C00-97]) were excluded.
Medical history data were retrieved from the NPR by ICD-10 codes during 10 years prior to the date of asthma diagnosis and during the baseline period, except for current malignancies which was retrieved within 12 months prior asthma diagnosis and during the baseline period.

| Oral corticosteroids use
Oral corticosteroids use during the baseline period was classified using the collected mean daily dosage per year (prednisolone equivalent) of prednisolone or betamethasone: regular users (OCS equivalent to an average ≥5 mg/d/y, corresponding to cumulative dosage≥1825mgprednisolonewithin1year);periodicusers(OCS equivalent averaging more than zero but <5 mg/d/y); and nonusers (OCS equivalent to 0 mg/d/y). During follow-up, OCS nonusers at baseline who subsequently collected OCS were further classified as regularOCSusers(average≥5mg/d/y);≥1OCScollected;andpa-tientsdispensing≥2OCS.

| Determinants of oral corticosteroids use
Data on potential determinants of OCS use was collected at index date: age, sex, severity of asthma (Global Initiative for Asthma

| Outcomes
Primary outcomes were OCS-related morbidity and mortality. For morbidity, we considered the following OCS-related complications that occurred during follow-up: diabetes, osteoporosis, fractures, glaucoma, ischaemic heart disease, hypertension, psychiatric conditions, hypercholesterolaemia and sleep disorders. For mortality, we considered death from all causes during follow-up, as well as causespecific mortality categorized using the underlying cause of death: respiratory related (ICD-10: J as main cause of death), cardiovascular related (ICD-10: I), cancer related (ICD-10: C) and other.

| Statistical analyses
Baseline characteristics were described as mean (standard deviation

| RE SULTS
Overall, 356 446 patients with a diagnosis of asthma and a collected asthma drug were identified, of whom 217 993 fulfilled the eligibility criteria during the observation period and were included in the study ( Figure 1). The mean age of the study population was 33 years (SD 25.4), and 54% were women (Table 1) At baseline, 1.5% of patients were classified as regular OCS users, 22.9% were periodic OCS users, and 75.6% were non-OCS users (Table 1). Compared with periodic and non-OCS users, patients on regular OCS treatment were older (mean age 61, vs 40 and 31 years, respectively). Women were more common for regular (62%) and periodic OCS users (60%) than in nonusers (52%). At baseline, monotherapy with inhaled corticosteroids (ICS) was more common in periodic and non-OCS users than in regular users, whereas fixed ICS/longacting ß2-agonists (LABA) combinations and fixed LABA/long-acting muscarinic antagonist (LAMA) combinations were more commonly collected by regular OCS users. Regular OCS users also had a greater prevalence of nasal polyps, glaucoma, ischaemic heart disease, heart failure, malignancy and osteoporosis at baseline ( Table 1). The periodic OCS users were older (mean age 40 vs 31 years), more often women (60% vs 52%), and showing a higher prevalence of pneumonia and nasal polys compared to the non-OCS users. The periodic OCS users also collected SABA, LABA and fixed ICS/LABA combinations more frequently compared to the non-OCS users.

| Patterns of oral corticosteroids use
Each year, approximately 15% of the patients collected at least one OCS, which was relatively stable during the follow-up period ( Figure   S1). Mean daily OCS dosage during follow-up was 5.5 mg in the regular OCS group, 0.8 mg in the periodic group and 0.4 mg in patients who did not use OCS at baseline, (P < 0.001).
During follow-up, more regular OCS users were hospitalized with asthma as the main reason for contact. Age-adjusted hospitalization rate was 3.66

| Factors associated with becoming a regular oral corticosteroids user
Of the non-OCS users at baseline, older age at asthma diagnosis was the strongest independent risk factor for becoming a regular OCS user during follow-up: people 65+ had a 19 times greater risk (HR 18.72, 95% CI 15.65-22.39) compared with people <18 years ( Table 2).
Additional risk factors were greater GINA asthma severity steps, increased Charlson Comorbidity Index and to some degree female sex.

| Oral corticosteroids use, morbidity and mortality
More patients died and were censored due to development of potential OCS-treated diseases and malignancy in the regular OCS group than the other OCS groups ( Figure S3).

F I G U R E 1 Flow chart of study population
The risk of developing a potential OCS-related morbidity was greater for regular OCS users compared to periodic and non-OCS users (Figure 3)  The present national linked data set is uniquely placed to describe the patterns of OCS use in the whole asthma population identified in secondary care in Sweden and related outcomes. The nationwide analysis ensured that the challenges with selection bias of patients because of inclusion of selected hospitals, regions or healthcare insurance systems are reduced and enhances the generalizability of the study findings.

| D ISCUSS I ON
The limitation that some OCS use could relate to other conditions than asthma was addressed by excluding patients treated with OCS medications or high-dosage treatment not commonly used for asthma, and patients with conditions for which OCS may be prescribed. In addition, if patients were diagnosed with these conditions during follow-up, they were censored at that time. A challenge was to decide whether to include or exclud patients with closely related asthma co-morbidities (such as severe rhinitis, rhinosinusitis with or without nasal polyps or bronchiectasis), that may also be indications for OCS treatment in severe asthma patients. As our intention was to describe the OCS use directly related to asthma, we utilized a conservative approach and excluded patients with bronchiectasis in order not to overestimate the OCS use that is directly related to asthma. We did, however, include rhinitis and rhinosinusitis as regular OCS treatment is seldom use in these conditions. Furthermore, there is always a risk Register and diagnoses in medical records. 11,12 There are few comparable studies having a nationwide popula- Our results indicated that, annually, almost one in seven asthma patients had used OCS, which was stable over the 10-year study period. Of the non-OCS users at baseline, a cumulative risk of 35% and 20% for prescribing one or more than one OCS prescriptions during follow-up was observed. OCS use is considered to be a marker of uncontrolled asthma, either as exacerbation treatment or as a regular maintenance treatment to prevent disease deterioration. 3 The present findings indicate that in our population, a significant percentage of asthma patients experience a disease severity that requires OCS to manage their symptoms. Interestingly, the percentage of asthma patients falling into this category remained rather stable throughout the 10-year study period. These findings are in line with other studies with more selected asthma populations. 23 Our findings on the factors associated with regular OCS use (asthma severity level, older age and greater comorbidity burden) are in keeping with the findings from previous studies. 6,8,22 However, in our data set we did not have access to data on other potential important determinants for OCS use in asthma patients, such as smoking.
A large proportion of the regular OCS users continued with regular therapy during the 10-year study period, with a mean daily dosage of 5.5 mg, a dosage which in many countries is considered to be a low maintenance dosage and in line with GINA recommendations. 8 However, also this low maintenance dosage was associated with increased risk of developing potentially OCS-related diseases. We observed a marked increased risk of developing osteoporosis among the regular OCS users when compared to periodic or nonusers, and all other OCS-related diseases followed the same pattern. Our findings of increased risk of OCS-related adverse events are consistent with previous reports. 7,22 In addition, also the periodic users had an The present findings have several potential clinical implications.
The GINA guidelines recommend assessment, life style counselling and regular monitoring of patients with asthma who receive OCS as maintenance therapy with treatment lengths for 3 or more months. 2 New biologic treatment options have recently been introduced for the treatment of severe asthma patients. [25][26][27][28][29] Studies have demonstrated that biologics can reduce the number of exacerbations significantly compared with placebo, especially in patients on treatment with OCS, a patient group generating a high burden to health care and health-related cost for society. 10,30,31 These new treatments may allow patients to reduce the dosage and potentially stop their OCS therapy.
The GINA guidelines also recommend that patients with severe asthma should be managed by asthma specialists. 2 Interestingly, in our study, the percentage of patients having been seen in outpatient secondary care because of asthma during the observation period was approximately the same (40%) in the three OCS use groups, despite regular OCS users having a more severe asthma with more asthma-related hospitalizations. This finding may suggest that severe asthma patients might be an overlooked patient population, which is supported by a previous Swedish report that only 1 of 5 severe asthma patients in primary care was referred to secondary care. 3 Furthermore, patients in Swedish primary care suffering from frequent asthma exacerbations do not seem to be identified and managed in accordance with guideline recommendations, indicating a room for improvement. 3 In conclusion, the present findings demonstrate that OCS therapy is still a substantial part of current asthma management for a high percentage of patients and that regular OCS use is associated with severe side effects and mortality risk. The study indicates that there is a need for use of other treatment options for patients with severe asthma who are using regular OCS.

ACK N OWLED G M ENTS
The authors would like to thank Urban Olsson, Statisticon AB, for data management.

CO N FLI C T O F I NTE R E S T S
PH and GT are employed by AstraZeneca. FW is employed at Statisticon for which AstraZeneca is a client. ME, BN and CJ report no conflict of interest relevant to this article.

AUTH O R S' CO NTR I B UTI O N S
Data collection was performed by JB. Statistical analysis was conducted by FW and ME. Analysis, interpretation and drafting of the manuscript were conducted by ME and PH and in cooperation with the other authors. All authors approved the manuscript before submission.

E TH I C A L A PPROVA L
The study was approved by the Stockholm regional ethics committee (registration number 2017/4:2). The linkage of registers data was approved and performed by the Swedish National Board of Health and Welfare. Patients do not need to give consent for use of public register data in Sweden.

CO N S E NT FO R PU B LI C ATI O N
All authors read and approved the final manuscript. All authors gave consent to publish these data.