Published literature indicates an unmet need for patients of achieving relapse resolution in a timely and comprehensive manner, ideally with their first treatment and with their first round of treatment [23, 24], i.e. without trying mutiple treatments nor multiple rounds of treatment. Survey results reported from the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry participants indicate an unmet need in relapse therapies; a “sizeable” percentage of patients reported lack of treatment effectiveness with CS at 1 month and 3 months and that corticosteroid treatment had no effect on or worsened their relapse symptoms [25, 26]. In a study by Nickerson and Marrie, 30% of patients given IVMP and 38% of those given OCS reported that their treatment worsened their relapse symptoms or had no effect . In contrast, we observed unresolved relapses among a low percentage of patients, particularly with OCS (9.5%) and RCI (3.1%). The NARCOMS data were patient-reported and based on patient survey, whereas this study uses administrative claims data; both study designs have their advantages and disadvantages, yet provide important insights.
Prior research indicates patients with longer relapses are significantly more likely to feel negatively about treatment , which may ultimately affect therapeutic compliance and/or treatment-seeking behavior. In keeping, recent study of neurology clinic patients showed increasing prevalence of escalating relapse treatment, in which a second course of treatment was given for an unresolved or refractory relapse . Relapse resolution is also of critical importance given that residual deficits caused by refractory or protracted relapse, along with those related to inevitable disease progression, may contribute to neurologic disability .
Our study quantified the magnitude of unresolved relapse and relapse treatment effectiveness in resolving relapse using health plan administrative claims data. The coverage policy of the health plan for the treatment of MS relapse at the time of this study was consistent with NMSS guidelines, which promote the use of CS or alternative therapies in cases of corticosteroid contraindications or corticosteroid intolerance . More than 90% of relapses were first treated with CS (OCS or IVMP), in keeping with the standard of care and insurance medical policy. Of the approximately 10% of relapses first treated with corticosteroid alternatives, IVIG was used most often. Although IVIG lacks consistent supportive evidence, it may be considered for relapses in certain cases such as during pregnancy and afterward [2, 3, 27]. Reasons for medication use could not be determined using this data source.
An ARR of 1.0 was determined among patients who experienced relapse (i.e., all patients experienced at least 1 relapse during the study). This rate is higher than usually reported by other publications, which can calculate ARR differently, i.e., among all MS patients regardless of the incidence of relapse and length of follow-up [28,29,30]. Other research also illustrates variable relapse frequency among patients, i.e., with one study indicating > 20% of relapsing patients reporting more than two relapses in a year . Of patients who experienced relapse in our study, over one-third experienced at least one unresolved relapse and required additional healthcare visits and relapse treatments within 30 days to resolve their relapse.
To quantify relapse treatment effectiveness in resolving relapse, two scenarios were evaluated. The first utilized a cohort with open health plan enrollment. Of the treatments of interest, OCS and RCI were found to be most effective in resolving the relapse with the first treatment (i.e., 90.5% and 96.9% of patients, respectively). Relapse resolution was evaluated in a second cohort of patients with continuous enrollment receiving corticosteroid alternatives. Continuous enrollment, a common requirement/approach in observational claims analysis, ensures patients are eligible to receive all relevant sources of care under health insurance benefits, facilitating reliable capture of healthcare use paid for with health insurance . In our study, the continuous enrollment requirement further ensured robust relapse identification. Results of both relapse resolution analyses confirmed a high magnitude of effectiveness with RCI in patients with presumed intolerance or contraindications to CS (96.9% vs. 95.7%).
The mean age (early 50s) and enrollment in Medicare Advantage in patients receiving corticosteroid alternatives may have correlated with longer disease duration, more progressive disease, and/or worse baseline functioning. MS study cohorts typically evaluated within US health plans are often comprised of younger, commercially insured patients. These cohort characteristics may further explain the lower overall DMT use observed here, as no DMTs were approved for use in progressive forms of MS during the study period. Other explanations for the less common use of DMTs in the IVIG/plasma group than in the RCI group could include other unmeasurable factors (i.e., less inflammatory or type of MS) in claims, as these clinical details were not available in this data source. As suggested by the coverage policy, patients taking corticosteroid alternatives were likely intolerant and/or had poor response or nonresponse to corticosteroid treatment and therefore required different therapy. Considering their baseline characteristics, these patients could be impacted even more substantially by MS relapse in the short term and by lingering effects of unresolved MS relapse and its residual burden in the longer term.
Although no significant differences were found in mean age between those receiving corticosteroid alternatives RCI vs. PMP/IVIG, a significantly higher proportion of patients receiving RCI were female, enrolled in Medicare Advantage plans, and had significantly increased presence of all MS functional impairment indicators evaluated despite significantly increased use of DMTs. Similarly, this may signal advanced MS disease and worse baseline functioning in RCI-treated patients (e.g., walking impairment) vs. the PMP/IVIG cohort.
Patients who were treated with PMP/IVIG had significantly higher use of all-cause inpatient and outpatient services, although mode of administration associated with an administered therapy would inherently lead to increased HCRU. Specific reasons for the increased HCRU were beyond the scope of the database and our study but should be examined as they may signal other important healthcare considerations and/or complexities. The ability and/or decision to use a therapy that can be self-administered (e.g., RCI) vs. the need and/or decision to have therapy administered under healthcare provider supervision (e.g., PMP/IVIG) may itself be indicative of other important patient care needs and differences.
The distinct lack of comparative studies and lack of an established treatment pathway in MS relapse to-date have been highlighted by the clinical community. An algorithm for the treatment of MS relapse recommended that RCI treatment be considered prior to treatment with PMP/IVIG in appropriate patients . Our study characterizes patients receiving RCI and PMP/IVIG and indicates they may be different in important ways, while underscoring the treatment effectiveness with each in alignment with Berkovich’s proposal . The results of this study are an important start toward evaluating an appropriate patient type and supporting a relapse treatment algorithm, given treatment effectiveness results realized by patients receiving CS alternatives.
Relapse resolution is an important measure of treatment efficacy attainment and should be considered in future research focusing on MS relapse. As we have demonstrated, timely and effective relapse resolution with the first relapse treatment should not be assumed. Methodologic consideration should be given concerning how to evaluate one-time treatments vs. treatments requiring repeated administration that could be billed in single or multiple claims (e.g., IVMP daily for 3–5 days following relapse onset) . Implications of treatment regimens (e.g., complexity, mode of administration, inconvenience) should be considered given potential challenges posed to patient compliance and ultimately to healthcare-seeking behavior.
Given the known heterogeneity of MS (e.g., as a disease state, in terms of relapse, as experienced by patients), different patient populations with MS should be evaluated with regard to their relapse frequency, relapse treatment utilization, and relapse resolution by treatment. Patient characteristics should be described to further understand treatment effectiveness for particular patient segments in order to inform more appropriate selection of relapse treatment for patients. Treatment effectiveness should be evaluated across all relapses in a given time frame in patients continuously enrolled in their health plans to increase the robustness of the supporting sample size. However, by virtue of CS being the first-line therapy, sample sizes for CS alternatives will inherently be challenged when assessing corticosteroid alternatives.
Administrative health insurance claims data lack clinical detail and indicators (e.g., disease severity, prescribing directions, MS subtype, EDSS, MRI results, disease duration, treatment history); therefore, this information is limited or unavailable to operationalize in our analysis.
Identification of relapses and health behavior from claims data assumes treatment-seeking behavior and use of health insurance on the part of patients. Mild relapses and treatments used outside of health insurance would be likely systematically missed. If a patient did not receive additional relapse treatment, we assumed the relapse was resolved; although additional healthcare-seeking behavior and treatment could be otherwise explained, we anticipate this assumption would affect all treatment groups. Humana health plan data represent a unique population, with a higher proportion of Medicare Advantage enrollees; therefore, our results have limited generalizability to other US health plans.
The first observed relapse may not have been the actual start of the relapse. The start of the relapse and the first treatment associated would impact the therapy to which the relapse was attributed; similarly, the end of the relapse episode may have been missed. Our approach to evaluating relapse resolution was systematic, and the continuous enrollment analysis further mitigated these limitations [4, 33]. The 30-day episode duration we used as an assumption, based on the accepted NMSS definition, may be reconsidered as well.
Variation in treatment regimens would impact the rate of relapse resolution. For example, IVIG and PMP may each be administered as courses of therapy of variable length, involving multiple administrations over the course of a period of time. This underscores the inherent lack of standardization in MS relapse treatment regimens. Here, we implemented an assumption regarding IVIG and PMP use based on the available literature, in the absence of established or widely recommended regimens . IVMP was not evaluated as a course of therapy in this research, which might explain why it seemed less; a 5-day oral CS taper was accounted for as a potential extension of IVMP therapy. Similarly, if oral CS tapering after IVMP therapy occurred over periods > 5 days, relapse effectiveness would likely have been higher than estimated here. Because of small patient counts, PMP- and IVIG-treated patients were combined into one cohort, as done in past research; however, results from the open-enrollment cohort indicate potential effectiveness differences, which should be examined further. Our analysis focused on the most common set of therapies used in the treatment of multiple sclerosis relapse; the frequency of relapse therapy uses vary widely. Despite creating a patient cohort from a multiyear data set from a large US commercial health plan, we were limited by the small sample size of our cohort of interest. The small sample size further limited us from conducting more sophisticated statistical analysis, which requires a larger sample size to obtain precise estimates . As such, only unadjusted analyses of treatment groups could be appropriately conducted, as presented here.