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Disease severity and economic burden in Japanese patients with systemic lupus erythematosus: A retrospective, observational study

Abstract Aim To describe the healthcare resource utilization (HRU), direct medical costs and clinical characteristics for Japanese patients with mild, moderate or severe systemic lupus erythematosus (SLE). The primary objectives were to describe HRU and examine the direct medical costs for Japanese patients with mild, moderate, or severe SLE over the 3‐year study period. Secondary objectives included recording patient demographics, clinical characteristics and frequency and cost of mild, moderate or severe flares. Exploratory objectives included a description of treatment patterns, and to explore which factors affect medical costs. Methods This retrospective, observational cohort study identified patients with SLE (diagnosed April 2010 to March 2012), from the Japan Medical Data Center claims database. Result The study cohort comprised 295 patients with mild (28, 9.5%), moderate (134, 45.4%), or severe (133, 45.1%) SLE. Outpatient visits, hospitalizations and emergency room stays were experienced by 295 (100%), 116 (39.3%) and 31 (10.5%) patients, respectively, over the 3‐year study period. Over the 3‐year period, the mean total direct medical cost was US$27 004, and cost increased with SLE severity: mild, $5549 moderate, $15 290; and severe, $43 322 (analysis of variance, P < 0.0001). During this period, the majority of patients (282, 95.6%) experienced at least one flare episode and the mean (standard deviation) frequency was 5.5 (3.3) flares. The mean total direct medical cost per flare increased with SLE severity. Conclusion This descriptive study provides information on the economic burden and clinical characteristics of Japanese patients with SLE based on claims data; high levels of HRU and direct medical costs were exhibited, particularly in patients with moderate or severe disease.


| INTRODUCTION
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by periods of exacerbation (flare), and remission. [1][2][3] Patients with SLE experience substantial impairment in their healthrelated quality of life (HRQoL), both physically and mentally. 4 Symptoms of SLE range from general malaise, arthralgia and fever, to more severe manifestations including fatigue, nephritis, cognitive impairment and cardiovascular diseases. 2,5,6 Approximately 90% of patients with SLE are female and symptoms and diagnosis of SLE occur most often between the ages of 15 and 45 years. The global incidence and prevalence of SLE varies considerably, with the overall incidence ranging from 0.3 to 31.5 per 100 000 per year and the prevalence ranging from 3.2 to 517.5 per 100 000; in Japan the prevalence ranges from 3.7 to 37.7 per 100 000. 7 Boers et al reported that Asian patients at a medical center in Australia presented with more severe disease than Caucasians; at baseline, south-eastern Asian/Chinese patients had a median SLE Disease Activity Index (SLEDAI) of 13, compared with 8 (P = 0.002) among Caucasians. 8 The treatment options for patients with SLE remain limited compared with those for other rheumatic diseases, such as rheumatoid arthritis, and many existing therapies are ineffective or poorly tolerated in some subsets of patients. 9 In 2011, belimumab was the first drug to be approved in the USA and Europe for over 50 years as an add-on treatment for SLE. [10][11][12] In addition, belimumab has recently been approved in Japan. 13 Given the ongoing need for more efficacious and cost-effective therapies, it is important to understand the economic burden among Japanese patients with SLE. 14 The disease burden of Japanese patients with SLE, in terms of costs and HRQoL, is not fully understood. The aim of this observational retrospective cohort study was to use medical and pharmacy administrative claims data to describe the healthcare resource utilization (HRU) and direct medical costs for Japanese patients with SLE.

| ME TH ODS
The primary objective of this study was to describe the HRU and direct medical costs of SLE for all patients with mild, moderate or severe SLE defined by a proxy disease severity algorithm, using insurance claims data. Other objectives were to describe clinical characteristics, and the frequency and cost of a mild, moderate or severe flares, a description of treatment patterns, and to explore which factors affect medical costs (cost predictors).

| Study design
This observational retrospective study (GSK study HO-15-16208) was conducted using the Japan Medical Data Center Co. Ltd claims database (JMDC-CDB). 15

| Assessments
To assess the disease burden among Japanese patients with SLE by varying disease activity, the algorithm for determining SLE disease severity combined elements of disease activity with cumulative damage, based on SLEDAI, Systemic Lupus Erythematosus Activity Measure (SLAM), and British Isles Lupus Assessment Group (BILAG), with use of SLE medications and a consensus of expert clinical opinion to adapt to claims data. [17][18][19] The algorithm for identifying SLE flares and categorizing severity is based on the Lupus Foundation of America (LFA) definition. The LFA categorizes flare severity as mild, moderate, or severe, encompassing the consensus of expert clinical opinion, and including outpatient visits, hospitalizations, and emergency room (ER) visits supported by a qualifying SLE diagnosis or SLE-related condition. 20 Detailed definitions of SLE severity and flare severity algorithms are shown in Tables S1 and S2. SLE severity was determined as the highest severity the patient experienced during the 3-year follow-up period.
All data, including demographics, were collected individually by disease, medication, procedure names or codes such as ICD-10, Anatomical Therapeutic Chemical or procedure codes, in the 3-year follow-up period, and at baseline (6-month period prior to index date). HRU, direct medical costs, comorbidities and treatments were assessed. A continuous prescription treatment period was defined by intervals of 6 months. HRU outcomes (hospital clinic services [inpatient admission, ER admission, and outpatient visit], prescribed class of medications, laboratory services, operations and procedures) were collected by SLE-severity status. The claims of interest to analyze were separated two ways, by "all-cause" or "SLE-related." Direct medical cost was computed based on the medical fee points (1 point = 10 Japanese yen [JPY]) or drug prices. Costs in JPY were converted to US dollars (1 JPY = 0.01 US$).

| Analysis
All analyses were conducted using SAS software version 9. 3

| Direct medical cost
The mean total all-cause direct medical cost per patient over the 3-year study period was $29 135 (2 913 509 JPY) and the corre-  (ANOVA, P < 0.001) ( Figure 1B). The mean SLE-related costs for the total cohort for each type of claim were: $7237 (inpatient); $12 008 (outpatient); and $7759 (pharmacy). In this study, age

| Clinical manifestations and comorbidities
The most frequently reported clinical manifestations and comorbidities (not used for SLE or flare severity definitions) were other infections (93.9%) and inflammation (94.2%) (

| Cost predictors
The direct medical costs, adjusted for corticosteroid dose, were $5538 for patients with mild SLE severity (reference), $11 621 for T A B L E 3 Prevalence of clinical manifestations and comorbidities by SLE disease severity (at index and during the study) a  ) greater costs, respectively, than those without (P < 0.001) ( Table 5). Other predictors (P < 0.05) of higher medical costs are shown in Table 5. However, the gender ratio and age distribution, with the exception of the elderly population, were similar to those described in previous studies. [22][23][24] The proportion of patients experiencing systemic comorbid conditions increased in correlation with increased SLE disease severity.

| DISCUSSION
In particular, incidence rates of hypertension and related cardiovascular disease, hyperlipidemia and anemia were significantly higher.
An increase was also observed for malignancies and herpes, although this was not significant. These findings are consistent with other studies and these conditions are linked with an increased risk of mortality and deterioration of QoL. [25][26][27] It is challenging to ascertain which HRU and costs are attributa-  (Tables S4 and S5). [35][36][37] The treatments administered to Japanese patients with SLE were similar to those in other countries except for anti-malarial therapies, which only appeared on the Japanese market after the end of the study assessment period. 38 However, the majority of the population received typical therapies for moderate or severe SLE patients (such as cyclophosphamide pulse or mycophenolate) despite the limited therapeutic guidelines for SLE in Japan to date. Corticosteroid treatment was the main standard of care therapy received. However, as long-term steroid use is associated with adverse events, reduction in treatment with steroids should be considered. 39 Anti-malarial drugs, emerging biologicals 9 or combinations of immunosuppressive agents may also prevent episodes of flare and therefore could be applied as an alternative method to improve the long-term prognosis of SLE and related damage.
There are some limitations to the data and study design. First, using administrative claims data to ascertain disease severity can be challenging. The algorithm of SLE disease and flare severity using claims databases has not been previously validated, but has been assessed using a US-managed care health plan database 20 and HRU and direct medical costs were shown to be correlated with SLE severity. Second, patients were defined based on diagnostic code only; this did not capture cases of misdiagnosis and in addition, the presence of diagnosis or examination procedure codes on a medical claim does not confirm presence of the disease of interest, as these may not be correctly coded for a prescription, or may be included as rule-out criteria. Other indicators of this limitation include the lower frequency of neuropsychiatric lupus (4.5%) compared with other lupus cohorts, and the low frequency of protein urea testing (20.0%) given 41% were coded as having lupus. Third, the database population is limited to the insurers of JMDC-contracted healthcare societies. Therefore, the socio-demographic characteristics are not directly representative of the general Japanese population, in particular those patients over 60 years of age. In addition, the principle insurer may not have been able to continue working, which may have resulted in cessation of insurance and therefore, these patients were not captured in this study. Finally, not all information is readily available in claims data and this could affect study outcomes.
In summary, this descriptive study demonstrated that Japanese patients with SLE showed high levels of HRU and associated costs, particularly in patients with moderate or severe disease activity.