Abstract
Background:
To date, there are no available factors to predict the outcome after multiple sclerosis relapse.
Aim:
To investigate factors that may be useful for predicting response to methylprednisolone treatment, following a relapse of multiple sclerosis (MS).
Methods:
The study included 48 MS patients enrolled in a double-blind multicenter trial to receive intravenous versus oral high-dose methylprednisolone treatment. Associations were sought between the disability status prior to relapse and the relapse severity, determined by changes in the Expanded Disability Status Scale (EDSS) score, as well as the improvements after treatment. We also analyzed the relationships between the number of magnetic resonance imaging (MRI) gadolinium-enhancing lesions (Gd+) and improvement.
Results:
A higher EDSS score before relapse was associated with more severe relapses (p = 0.04) and less marked improvement (odds ratio (OR) 1.8; 95% CI (1.2–2.2); p = 0.05) after methylprednisolone treatment. Relapse severity (p = 0.29) and the number of Gd+ lesions at relapse (p = 0.41) were not related with improvement.
Conclusions:
Clinical baseline status prior to MS relapse is a predictor of response to methylprednisolone treatment.
Introduction
Relapsing–remitting multiple sclerosis (RRMS) is a chronic, demyelinating inflammatory disease of the central nervous system (CNS) of unknown etiology. It is characterized by periods of neurological dysfunction (relapses), followed by periods of clinical remission. In around 30% of patients, a residual increase in disability of ⩾ 1.0 point on the Expanded Disability Status Scale (EDSS) is seen at 64–127 days after a relapse. 1 To date, there are no available factors to predict which patients will have increased disability and which will return to pre-relapse status, after an exacerbation. The aim of this study was to investigate the factors that may be useful for predicting a response to methylprednisolone (MP) treatment, following relapse in RRMS patients.
Methods
Patients
We studied 48 patients, from 7 Catalonian centers, after inclusion in a multicenter, double-blind, randomized, Phase IV, non-inferiority clinical trial conducted to compare bioequivalent high-dose (1250 mg/24 h during 3 days) oral methylprednisolone (oMP) versus high-dose (1000 mg/24 h during 3 days) intravenous methylprednisolone (ivMP), to treat multiple sclerosis (MS) relapses. The trial provided confirmatory evidence that bioequivalent high-dose oMP is not clinically nor radiologically inferior to ivMP, and is equally well-tolerated and safe. 2
All participants in the present study were adults who had met the 2005 McDonald criteria 3 for RRMS, and had experienced a recent (< 15 days) moderate or severe relapse. All patients had an EDSS score ⩽ 5.0, acquired in the previous 6-month relapse-free period (EDSS T-1). EDSS scores were recorded at the time of relapse (EDSS T0) and at week 1 (EDSS T+1), week 4 (EDSS T+4), and week 12 (EDSS T+12) after the first MP dose. EDSS was determined by one neurologist in each center throughout the trial. The neurologists have experience in multicenter clinical trials and having undergone standardized training.
Brain magnetic resonance imaging (MRI) studies were done at baseline, 1 and 4 weeks.
Statistical analysis
Clinical baseline status was measured by the EDSS score prior to relapse (T-1); functional recovery was defined as an EDSS improvement ⩾ 1.0 at T+1, T+4, and T+12 after the first MP dose, and relapse intensity was classified as an EDSS change of 1.0 or >1.0 at T0, compared to T-1. Moderate relapse was defined as an EDSS change of 1 to 2.5 points, at T0 relative to T-1; and severe relapse as a change of ⩾ 3 points, compared to T-1 (Table 1). 4
Calculations of relapse intensity prior to and after relapse.
EDSS: Kurtzke’s Expanded Disability Status Scale.
The percentage of patients with an EDSS improvement ⩾ 1.0 was compared between the patients with pre-relapse EDSS scores EDSS T-1 < 3.0 or ⩾ 3.0, using the chi-square test. This cut-off score was chosen based on previous literature 5 that established 3.0 as the maximum score for being mildly disabled and predicts the long-term prognosis. 6 The relationship between improvement and EDSS T-1 was also examined by univariate analysis, using EDSS T-1 as a continuous variable. We performed a logistic regression analysis to evaluate the odds ratio (OR) between the pre-relapse EDSS score, EDSS T-1 (dependent variable), an EDSS improvement at T+12. Age and disease duration were included in the model.
The relationship between the relapse intensity at T0 and the clinical baseline status at T-1 was examined by univariate analysis, using EDSS as a continuous variable. We compared the number of gadolinium lesions on the brain MRI, between patients with a relapse intensity of 1.0 or > 1.0, using the Student t-test. A p value of < 0.05 was considered statistically significant.
Results
Sample characteristics
Mean (SD) age was 39 (7.8) years and women comprised 81.3% of the sample. The median (range) EDSS score was 2.0 (1.5–3.0) at T-1; 3.5 (2.5–4.0) at T-0; 2.5 (1.5– 3.5) at T+4; and 2.0 (1.5–3.0) at T+12. Prior to their relapse, 29 patients had an EDSS score < 3.0; 20 patients an EDSS score ⩾ 3.0. Both groups were well-balanced in terms of sex, age, MRI findings and the proportion of patients receiving oMP versus ivMP or disease modifying treatment (DMT).
Relapse intensity at EDSS T0 was 1.0 in 21 patients and > 1.0 in 28 patients. There were no significant differences regarding sex, age, DMT, proportion of patients with a post-relapse residual increase in disability, the duration of disease and DMT, the number and time from the previous relapse prior to the study entry, between both groups.
The percentage of patients who improved (⩾ 1 point on EDSS score) at each time point after MP treatment was smaller in the group with the higher EDSS scores at baseline
Results for EDSS T-1 ⩾ 3.0 were (T+1 = 18.2%; T+4 = 45.5%; and T+12 = 54.5%) versus EDSS T-1 < 3.0 (T+1 = 47.2%; T+4 = 66.7%; and T+12 = 75%). The OR and CI 95% at T+1 was 2.8 (2.0–3.3), at T+4 was 1.7 (1.5–2.0), and at T+12 was 1.8 CI 95% (1.2–2.2); p = 0.05 (Figure 1). When the EDSS was analyzed as a continuous variable, a spectrum of response was observed. Patients with a higher EDSS score at baseline (EDSS 3.0–5.0) had less improvement at T+12 than patients with a lower EDSS score at baseline (EDSS 0–2.5) (p = 0.05) (Figure 2).
The percentage of patients who improved (⩾ 1 point on the EDSS score) at week 1, week 4 and week 12 after MP treatment was smaller in the group with higher EDSS scores at baseline (EDSS > 3.0).
The percentage of patients who improved (⩾ 1 point on the EDSS score) at week 12, after the MP treatment was smaller, in the patients with a higher EDSS scores at baseline.
Relapses were more severe (> 1 point of EDSS impairment) in those patients with a higher EDSS score at baseline
The percentage of patients with EDSS T0 impairment >1.0 was significantly higher in the group with greater disability prior to relapse (EDSS 3.0–5.0) than in those with less severe disability, prior to relapse (EDSS 0–2.5) (p = 0.05) (Figure 3).
The percentage of patients with > 1 point of EDSS impairment at relapse was higher in patients with a higher EDSS score at baseline.
Relapse intensity was not related with functional recovery at T+12 (p = 0.29)
Relapse intensity was not associated with the number of Gd+ lesions at T0
EDSS impairment =1, mean number of Gd+ 2.7±4.3 versus EDSS impairment >1, mean number of Gd+ 3.65 ± 6.9 (p = 0.41).
A considerable percentage of patients showed no improvement at T+1 (54%), T+4 (32%), nor T+12 (27%).
Discussion
The outcome of relapses in patients with RRMS remains poorly understood. Few studies have attempted to correlate baseline data with the response to MP treatment. 4 To date, no relationships have been established. The aim of this study was to assess the relationships between the clinical baseline status (EDSS T-1) and functional recovery, after a course of high-dose MP, the clinical baseline status (EDSS T-1) and relapse intensity (EDSS T0), the relapse intensity (EDSS T0) and functional recovery (EDSS T+12), or the relapse intensity (EDSS T0) and number of Gd+ lesions.
Our results indicate that the EDSS score prior to relapse is related with recovery after the exacerbation and the residual disability 12 weeks later. Patients with greater previous disability (EDSST-1 = 3.0–5.0) had more severe relapses and smaller improvements after high-dose MP treatment.
These findings contrast with those of Hirst et al., 7 who reported that the percentage of patients with a residual change ⩾ 1 EDSS point was higher in those with lower EDSS scores at T-1. Our study included MS patients with a maximum EDSST-1 score of 5.0, and Hirst et al. analyzed MS patients with EDSST-1 from 0 to 8.0. We believe the difference lies in our EDSS T-1 definition. We define low EDSS between 0 and 2.5, and high EDSS between 3.0 and ⩽ 5.0; while for Hirst et al., low EDSS is between 0 and 5.0, and high EDSS is between 5.5 and 8.0.
We believe that it is more likely for patients with lower EDSS T-1 to be in a relapsing-remitting phase of MS; and for patients with higher EDSS T-1, to be in a progressive phase of MS. It may be that in the latter, with predominant neurodegeneration and lower inflammatory response, the EDSS T0 increase is lower. 8
Hirst et al. 7 found greater residual disability in those patients with more severe relapses; yet Nos et al. 4 found that those patients with more severe relapses were more likely to improve. In our study, relapse intensity was not related with improvement. There are methodological defects in the aforementioned studies.4,7 They were retrospective, included RRMS and progressive MS, 7 EDSS had not increased in all patients at the time of relapse, 4 or only 30% of patients were treated with a steroid, which suggests that a significant proportion of patients included did not have functionally disabling relapses. 7
Our data is the result of a prospective, randomized and controlled trial, appropriately designed and conducted in a cohort of RRMS with EDSS T-1 ⩽ 5.0, confirmed relapse and all were treated with the same high dose of MP. Previous knowledge of patients’ EDSS score prior to relapse was advantageous, to identify markers of treatment response.
In accordance with other published studies, the nonlinearity of the EDSS scale and that a change of 1 point in the EDSS does not always represent the same level of improvement, must be taken into account, when interpreting the results.
As patients with greater disability had more severe relapses and showed slower improvement after high-dose MP treatment, the patient’s prior disability status can be considered a baseline predictor of outcome. Relapse intensity did not have any effect on the degree of functional recovery, and was not related to the number of Gd+ lesions on the brain, upon MRI study at relapse.
Footnotes
Conflict of interest
The authors report that there are no conflicts of interest.
Funding statement
This work was supported by the Spanish Ministry of Health (grant number EC07/90278) and by Biogen Idec.