Introduction
Multiple sclerosis (MS) is a chronic, debilitating neurological disease characterized by the emergence of new symptoms or worsening of existing symptoms leading to the accumulation of cognitive and neurological impairment. The prevalence of MS in the USA is estimated to be between 400,000 and 500,000, with most patients being female [
1,
2]. In relapsing–remitting MS (RRMS), episodes of neurological dysfunction are followed by periods of recovery. However, approximately 50% of relapses result in residual disability [
3,
4], and over time, most patients will enter the secondary progressive phase [
5] with a significant impact on the quality of life and an increasing economic burden [
6]. High relapse activity in the first 2 years after the first diagnosis is predictive of time to sustained disability, early conversion to secondary progressive MS, and earlier mortality [
7,
8].
The disease-modifying therapies (DMTs) were invented to reduce the relapse rates, delay disease progression, and reduce future disability in patients with RRMS [
5,
9]. However, switching among the first-line DMTs is common and is an important predictor of economic burden in patients with MS [
10,
11]. Moreover, the use of high-efficacy (and costly) DMTs could prevent relapses and delay disease progression leading to savings in overall costs [
12,
13].
Variation in the intensity of a relapse can lead to different clinical and financial burdens [
14‐
16]. A study in 2002 estimated that the typical costs were $12,870 per high-intensity episode of relapse, $1847 per moderate-intensity episode of relapse, and $243 per mild-intensity episode of relapse [
14]. A study by Parise et al. in 2012 estimated that the annual direct healthcare costs were higher for patients with an MS relapse. The incremental annual direct costs attributable to relapses (vs no relapse) were $8269 for patients with moderate-severity relapses and $24,180 for patients with high-severity relapses [
16]. Parise et al. estimated the cost burden after the first diagnosis of MS (index date) [
16]; thus, characterization of the cost burden incurred after a relapse may have been missed. To address this gap, the present study estimated the cost burden after a relapse event (i.e., the index date was the date of the most severe occurrence of a relapse) using more recent data to provide true characterization of the cost of relapses by severity.
Analogous to the study by Parise et al., the present study sought to (a) measure the costs after a relapse event and (b) estimate the healthcare utilization and costs associated with a relapse, stratified by relapse severity, using most recent data.
Discussion
In this US retrospective analysis, using a similar but more targeted methodology to characterize the true cost after the occurrence of a relapse event and with more contemporary data, we evaluated the direct healthcare costs associated with MS, stratified by relapse occurrence and severity, to highlight the current burden of relapse on private payers and healthcare providers. The results showed that the all-cause and MS-related direct costs increased with the severity of the relapse. MS-related costs in the MMR and SR cohorts observed in this study highlight the significant cost burden associated with a relapse. We found that the cost burden with the revised methodology and newer data was considerable compared with estimates reported by Parise et al.
The relative magnitude of the cost burden due to relapses in patients with MS remains unclear. Although some studies have assessed the healthcare costs associated with relapses, these estimates were based on data collected until 2012 [
14‐
16]. Our study evaluated the costs using large nationally representative data covering geographical areas across the USA.
Incremental costs were primarily driven by pharmacy costs in patients in the NR and MMR cohorts, whereas medical costs were the key drivers in patients in the SR cohort. These observations are in line with previous long-term observational studies that speculated the costs of DMTs to be important predictors of the increased cost burden [
10,
11]. We observed that patients with severe relapses incur a high cost burden, which underscores the need to prevent progression.
Our data shows a consistent trend in line with other US studies that reported increased healthcare costs with an increase in the severity of the relapses [
14,
29,
30]. Using the 1999 discharge data from five states across the USA, O’Brien et al. reported that the cost of managing an MS relapse was sevenfold higher for a high-intensity relapse (defined as hospitalization) than that for a medium-intensity relapse (defined as the use of an ER or observation unit or administration of acute treatments requiring formal intervention) [
14]. Another retrospective cohort analysis of claims-based data from 2006 to 2009 by Lage et al. showed that among patients who had at least one pharmacy claim for a DMT, the medical and pharmacy costs increased with the severity of the relapse [
30]. In this study, patients with severe relapses (requiring hospitalization) had threefold higher predicted all-cause costs than those with moderate relapses (requiring ER or observational unit or administration of acute treatments requiring formal intervention) [
30].
Evidence from several cross-sectional studies has demonstrated cost differences between patients with a relapse and those without a relapse [
17,
31‐
37]. Another survey-based international study (TRIBUNE) highlighted that cost per patient per year was higher for patients with RRMS and moderate and severe relapses than for those without a relapse [
6,
38,
39]. A USA-based claims study reported that high relapse activity was associated with greater resource utilization vs non-high relapse activity and thus higher costs [
40]. Analysis of patients with and without a high frequency of relapse activity found greater resource utilization and costs among patients with higher relapse activity (defined as two or more relapses per year) than in patients without high relapse activity. Mean total all-cause non-DMT costs were $12,057 higher in patients with a high frequency of relapse compared with those in patients without a high frequency of relapse [
40]. Similarly, the current analysis reported $10,203 higher all-cause medical costs (non-pharmacy costs) incurred by patients with moderate to severe relapses vs patients with no relapses.
Analogous to the USA-based studies, several studies from other countries have also characterized healthcare costs related to MS relapses [
11,
15,
41,
42]. A retrospective study of patients with MS followed for over 10 years found that among patients using DMTs, the overall annual direct costs were associated with the annualized relapse rate [
11]. A 10% increase in healthcare costs was associated with a 1% reduction in conversion to secondary progressive MS [
11]. The analysis of claims-based data from Japan that included patients with newly diagnosed MS showed that the frequency of relapses and per patient per month medical costs were directly correlated [
42]. Similar findings were reported from other studies [
15,
29,
41,
43]. Evidence from a recent systematic review suggests that early treatment with high-efficacy DMTs offers improved control of relapse activity compared with delayed therapy [
44]. Overall, the findings of these studies extend support to the current study and highlight the importance of patient management strategies and treatments aimed at reducing the frequency of MS relapses in a US commercial population.
The current analysis has several limitations. There are potential inaccuracies or omissions in the classification of MS, covariates, and outcomes as the data were identified from claims databases as opposed to medical records. Given that the MarketScan
® database does not contain data regarding the severity of the relapse, the severity of the relapse was defined by the treatment setting (hospital, ER, outpatient clinic) and may not reflect the true severity of the relapse. Mild relapses or relapses of short duration that usually do not affect the activities of daily living and therefore do not require a corticosteroid therapy or hospitalization were less likely to be considered in the present analysis. However, we have identified MS relapses using a validated medical chart review algorithm, and should therefore less likely alter our conclusions [
18]. While differences across cohorts were adjusted using a generalized linear regression model, systematic differences could exist across the study cohorts because of unknown confounders [
45]. Another limitation of this study is that the costs were not adjusted for inflation. However, we acknowledge that the cost burden after adjusting for inflation might be higher. Finally, despite the size of and inclusion of enrollees from across all US states in the MarketScan
® database, the database neither completely represents the entire private insurance market or general US population nor includes individuals outside of the USA, but it is one of the largest databases representing the commercial population in the USA. These limitations may affect the generalizability of the study findings.
Conclusions
The results from this real-world study demonstrate that all-cause and MS-related direct costs increased with the severity of the relapse. One in five relapses is severe and leads to a high cost burden. While pharmacy costs were the primary drivers among patients in the NR and MMR cohorts, medical costs were the key cost drivers in patients in the SR cohort.
Overall, this study highlights the cost burden incurred owing to MS relapses. The study provides a more accurate representation of cost burden of relapse (considered as occurrence of the event) using more recent data. The finding that the cost burden drastically increases with the level of severity underscores the need for preventing progression and relapse via optimal treatments.