Frequency, severity and costs of flares increase with disease severity in newly diagnosed systemic lupus erythematosus: a real-world cohort study, United States, 2004–2015

Introduction

SLE is a chronic autoimmune disease characterised by episodes of increased disease activity, referred to as flares.1 A total of 65%–70% of patients experience at least one flare each year.2 Patients with severe SLE experience higher frequencies of severe flares and flares of any severity, compared with patients with mild SLE.3–5 While the occurrence of any flare increases healthcare costs, severe flares incur the greatest cost.3 6–8 Compared with patients without SLE, annualised direct SLE medical costs are $914, $4305 and $18 952 higher for patients with mild, moderate and severe SLE, respectively.6 Even among patients with SLE who experienced no flares, annualised direct costs are $441 higher compared with patients without SLE.6 Because there is no curative therapy for SLE, a key treatment goal is to prevent or reduce frequency and severity of disease flares, with the aim of preventing or slowing disease progression.1

There are limited data on the real-world burden of SLE flares and healthcare costs following a flare and how they may be affected by flare severity. To understand the clinical burden of SLE flares in a US cohort of patients with newly diagnosed SLE and to obtain a comprehensive picture of the patient population, we used administrative commercial claims data linked to electronic medical records (EMRs). We evaluated flare frequency and annualised rates of mild, moderate, and severe flares by disease severity during 1 year after SLE diagnosis. We also evaluated the economic burden of SLE flares by estimating healthcare costs associated with flares at 30, 60 and 90 days after a mild, moderate or severe flare.

Patients and methods

Study design and patient selection

Eligible patients from the linked IBM MarketScan and GE EMR dataset were adults ≥18 years old with evidence of newly diagnosed SLE from 1 January 2005 to 31 December 2014 (selection window). The first observed SLE diagnosis during the selection window was characterised as the index date. A confirmed SLE diagnosis was defined as having ≥1 inpatient SLE diagnosis or ≥2 outpatient SLE diagnosis codes (including index diagnosis) that were ≥60 days apart (ICD-9-CM: 710.0x, ICD-10-CM: M32.9) in EMR records or claims in any position; and record of prescribed SLE-related medications within 6 months before and after the index date. Patients were further required to have continuous enrolment in a health plan for at least 12 months before index (baseline period) and 12 months after index (post-diagnosis or follow-up period). Patients with an SLE or lupus nephritis diagnosis during the 12 months prior to index and patients with incomplete or missing data in the linked dataset were excluded.

Figure 1 provides details of the study design, inclusion and exclusion criteria, and attrition of the study population.

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Figure 1

(A) Study design and (B) attrition of the identified study population of US patients with newly diagnosed SLE between January 2005 and December 2014. The study population included patients ≥18 years old with evidence of SLE. Application of the inclusion and exclusion criteria and categorisation into groups based on SLE disease severity over the 1-year period after diagnosis.

Results

SLE flare frequency during 1 year after diagnosis

The mean (SD) annual flare rate was 3.5 (1.9) for all patients. Patients with severe and moderate SLE experienced significantly more flares post-diagnosis compared with patients who had mild SLE. Mean (SD) annual flare rates were 4.2 (1.9) for severe SLE, 3.7 (1.7) for moderate SLE and 2.2 (1.6) for mild SLE, p<0.0001 (figure 2A). Severe flares were observed more frequently among patients with severe SLE than among patients with moderate or mild SLE (figure 2B, p<0.0001). Moderate flares occurred more frequently among patients with severe and moderate SLE than among patients mild SLE (p<0.0001) (figure 2C). Mild flares occurred more frequently in patients with mild SLE than among patients who had moderate or severe SLE (p<0.0001) (figure 2D).

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Figure 2

Mean annual number of flares per patient during the 1-year post-diagnosis period, for all patients with newly diagnosed SLE and by SLE disease severity. (A) Mean annual number of flares of any severity, (B) of severe flares, (C) of moderate flares and (D) of mild flares. P values are for differences between the three disease severity groups.

The majority (95.1%) of patients experienced ≥1 flare post-diagnosis. Nearly all patients with moderate and severe SLE had ≥1 flare (99.5% and 98.4%, respectively), compared with those who had mild SLE (83.8%, p<0.0001). A total of 79.6% of patients with severe SLE and 74.4% with moderate SLE experienced ≥3 flares compared with 42.0% with mild SLE (p<0.0001) (figure 3A). Overall, mean (SD) time to first flare was 36.4 (62.7) days, with a median (min, max) time to first flare of 11 (1, 365) days. Mean (SD) time to first flare decreased with increasing disease severity: mild, 48.7 days; moderate, 34.3 days; and severe, 29.3 days (p<0.0001; figure 3B), as did median time (min, max) to first flare: mild, 18 (1, 363) days; moderate, 9 (1, 365) days; and severe, 7.5 days (1, 344).

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Figure 3

Distribution of patients by number of flares and time to first flare during the 1-year post-diagnosis period for all patients with newly diagnosed SLE and by SLE disease severity. (A) Distribution of patients with SLE with 0, 1, 2, or ≥3 flares, and (B) mean time from index date to first flare. P value is for difference between the three disease severity groups.

All-cause costs per SLE flare during 1 year after diagnosis, by flare severity

The all-cause costs at 30 days after flare were $1672, $3831 and $16 856 for mild, moderate and severe flares, respectively (figure 4). Average all-cause flare costs increased from 30 to 90 days after flare (costs 90 days after flare; mild: $3312, moderate: $8582, severe: $27 468). Severe flares incurred the highest cost at each time point compared with moderate and mild flares (p<0.0001 for all time points) (online supplemental tables S4 and S5, figure 4). Across 30, 60 and 90 days after a flare, the main cost driver for severe flares was inpatient stay (72.3%, 63.0% and 56.5% of costs, respectively), followed by outpatient visits (17.3%, 23.2% and 27.7%, respectively) (online supplemental table S4, figure 4). The main cost drivers for moderate flares were also outpatient visits (38.0%, 40.5% and 41.0% of costs), followed by inpatient stay (26.0%, 23.8% and 23.8%, at 30, 60 and 90 days, respectively), while mild flare costs were mainly driven by outpatient visits (40.8%, 43.0% and 42.7% of costs, respectively) and pharmacy costs (26.1%, 25.3% and 25.6%, respectively) (online supplemental table S4, figure 4).

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Figure 4

Costs per flare for patients with newly diagnosed SLE who had a flare during the 1-year post-diagnosis period at 30, 60, and 90 days after flare by flare severity and setting of care. P<0.0001 for differences between groups for all settings at all time points. A detailed breakdown of costs per care setting is available in online supplemental tables S4 and S5.

Discussion

This study of newly diagnosed patients with SLE in the USA identified a mean annual flare rate of 3.5 in the year following diagnosis, and an average of 36.4 days from diagnosis to first SLE flare. Patients with moderate and severe SLE had flare rates that were 1.7-fold and 1.9-fold higher, respectively, than those with mild SLE. Patients with moderate and severe SLE had a 1.4-fold and 1.6-fold shorter time to first SLE flare, respectively, than patients with mild disease. Our findings show the increasing mean healthcare costs of flares by 30 days through 90 days after a flare, with the largest healthcare costs attributable to severe flares occurring at 90 days. These findings highlight greater clinical and medical cost burden experienced by patients with moderate and severe SLE.

The annualised flare rates by disease severity observed in our study (2.2, 3.7 and 4.2 for patients with mild, moderate and severe SLE, respectively) are similar to those reported by Garris et al,3 who also used a claims-based algorithm in a similar study population. We further evaluated annualised flare rates by flare severity and found that rates of severe flare increased with increasing disease severity. Although our findings are slightly higher, similar trends were reported in a US Medicaid study population with a longer follow-up period,13 and may be a reflection of disease control over time.

Corticosteroids are the mainstay therapy used to manage SLE flares, supplementary to maintenance treatment.14 We observed frequent use of high-dose corticosteroids for moderate and severe flares sustained through 90 days post-flare. Prolonged corticosteroid use is associated with an increased risk of adverse effects and organ damage.15 16 Additionally, increased SLE disease activity and SLE flares are associated with organ damage accrual,17 18 with attendant high healthcare cost and increased mortality risk.19–22 In line with the treat-to-target initiative in SLE,23 any corticosteroid-sparing treatment to prevent flares may also reduce disease progression and associated healthcare costs.

In our study, 95% of newly diagnosed patients with SLE experienced ≥1 flare in the year after diagnosis, with 67% experiencing ≥3 flares. This finding could be due to delays between initial disease manifestation, diagnosis and initiation of appropriate medical therapy. Flare rates identified in this study are higher than previous estimates,2 possibly owing to different flare definitions or improved capacity to detect flares through our integration of both EMR and claims data. Data on flare rates in newly diagnosed patients with SLE are sparse; however, in a recent US commercial claims study, patients who were diagnosed earlier (<6 vs ≥6 months from symptom onset to diagnosis) experienced lower flare rates, healthcare utilisation and costs.24 Reducing disease activity, preventing flares and minimising drug toxicities are key treatment goals for patients with SLE that aim to improve patient outcomes and quality of life, and prevent organ damage.25 26 Our results highlight that pursuit of these treatment goals should begin early after diagnosis.

Our analyses demonstrated significant healthcare cost increases up to 90 days post-SLE flare. Healthcare costs were 10.1-fold higher for severe flares and 4.4-fold higher for moderate flares compared with mild flares. Previous studies have shown associations between flare severity and cost at 30 days and 1 year after flare3 6 13; however, all-cause healthcare costs per flare over the 30–90 days post-diagnosis have not been previously reported. Our evaluation of costs across multiple care settings identified that outpatient and inpatient stays account for 64%–90% of costs associated with moderate and severe flares at 30, 60 and 90 days after flare. The leading cost driver of severe flares in the year after diagnosis was inpatient visits, which accounted for 57%–72% of costs. This is consistent with a Canadian cohort study that also found 58% of all-cause medical costs during the year after SLE diagnosis were from hospitalisations.27 High healthcare costs in the first year after diagnosis may be the result of flares that require inpatient stay.

This study identified that 58.5% of patients with newly diagnosed SLE were from the South region of the USA, consistent with a study of 47 states and Washington, DC, that reported the highest SLE prevalence in the South (163.5 per 100 000) and the lowest in the Northeast (125.2 per 100 000) USA.28 Regional differences may reflect different patient demographics across regions, or the potential role of sunlight/ultraviolet light radiation exposure in the pathogenesis of SLE disease activity.29

There are some limitations to our findings. Most patients in the database were covered by commercial insurance (87.7%), with 12.3% covered by an employer-provided Medicare supplemental plan and did not include patients covered by Medicaid. However, by linking claims to EMR data, we captured a comprehensive view of SLE treatment and costs associated with flares. Since SLE disease and flare severity were classified using claims-based algorithms, there is potential for misclassification. Additionally, while the ability of the algorithm to define severity and calculate costs may be strengthened by using patient-level data (ie, inpatient stays), this may also introduce bias. Although we supplemented the algorithm with EMR data to improve its accuracy, occurrence and frequency of SLE flares may be potentially overestimated or underestimated. For example, we considered one flare to have ended when a flare of increased severity began, regardless of the interval between the two flares; this may overestimate flare counts. On the other hand, if the next flare was of lower severity and within 30 days, it was assumed to be a continuation of the same initial flare, potentially leading to underestimation of flare counts. Moreover, multiple inputs of the same code do not necessarily indicate multiple flares, as physicians use the same codes for patients who are in remission but are being monitored. However, given the similarities between our findings and those that have been previously published, we are confident in our application of the claims-based algorithms to the present study. Our study design intended to identify patients with incident SLE within the preceding year. The study population may have included prevalent SLE cases without a healthcare encounter or newly insured during the prior year. Furthermore, patients with lupus nephritis diagnoses pre-index were excluded and may have had higher healthcare costs than those with SLE.30 Cost estimates may also have been inflated because only patients who were receiving SLE medications were included in the analysis, meaning that some cases of mild SLE were probably excluded; however, this population is likely to be small and our exclusion criteria increased the specificity of our findings.

Strengths of our study include the use of the IBM MarketScan commercial claims database, which contains comprehensive healthcare resource utilisation data on real-world encounters of patients with SLE, including details on care settings and pharmacy claims. Data linkage with the GE EMR database allowed deeper evaluation of demographic and clinical information, such as race/ethnicity, diagnoses and written prescriptions. Together these data sources provided a comprehensive view of the study population that is not possible with use of a claims database alone because the data sources complemented and supported each other if patient data were missing within a single source. The data used in this work support a more detailed analysis of SLE flare costs than has been previously reported in studies using single data sources.3 4 13 31 Our work assessed healthcare costs at multiple time points during the interval after a flare, which has not been previously reported in patients with newly diagnosed SLE.

In conclusion, this retrospective cohort study of real-world patients with newly diagnosed SLE demonstrates that flare frequency and severity increase with disease severity in the first year after diagnosis. Additionally, the total all-cause healthcare cost after a flare increases with increasing flare severity from 30 through 90 days after flare. Preventing or decreasing the frequency and duration of flares may improve health outcomes and reduce healthcare costs for patients with SLE.