The incomplete nature of multiple sclerosis relapse resolution

doi:10.1016/j.jns.2007.01.062

Journal of the Neurological Sciences

Volume 256, Supplement 1, 15 May 2007, Pages S14-S18

https://doi.org/10.1016/j.jns.2007.01.062 Get rights and content

Abstract

Relapsing–remitting multiple sclerosis (RRMS) is often associated with accrual of disability, even though it precedes the progressive phase of the disease, in which clinical disability is most apparent. Changes in T1 and T2 magnetic resonance imaging (MRI) findings, as well as clinical trials of drugs that target RRMS, have established correlations between relapse episodes and disability progression. Briefly reviewed herein are relevant data that link relapses with disability accrual, including a recent direct analysis of well-defined clinical trial databases that shows MS relapses to have a measurable and sustained effect on disability. These studies pinpoint the measurable residual deficits of relapses that had, up to this point, only been implied by prior research, confirming the existence of relapse-associated step-wise worsening in patients with RRMS and lending credence to the continued development of long-term treatment targeted at the early phases of the disorder.

Introduction

In the majority of cases, multiple sclerosis (MS) becomes established clinically as the relapsing–remitting (RR) form. It is during the early stages of RRMS that the types of neurological disability seen in later phases of the disease first become evident and are customarily characterized as relapses. Clinical trials have shown that the disease-modifying therapies alter the pattern of these relapses, as well as the extent of presumed neurological damage that is revealed by magnetic resonance imaging. Direct evidence of a role for relapses in the accumulation of such damage has been provided by an analysis of patients participating in a large number of clinical trials. Briefly reviewed here are the various studies describing the contributions relapses make to a step-wise accumulation of neurological disability deficit in MS, particularly with respect to the lifelong nature of MS and its progression over a course of years.

Section snippets

Clinical patterns of MS

Despite the need to establish characteristics of patients with MS for purposes of study, prior to 1994 there was no agreed-upon list of definitions categorizing the phenotypes of MS, no common denominator to account for the variety of symptomatic and clinical presentations that would allow patients to be grouped in a useful way. An international survey of clinicians established 4 consensus definitions of distinct clinical courses of MS (Fig. 1) [1].

RRMS presents with clearly defined relapses

Natural history of relapsing forms of MS

Multiple sclerosis is a central nervous system (CNS) disorder with extensive variability in site of lesion development, clinical presentation, and rate of accumulation of dysfunction [3]. MS typically begins with clinically isolated initiating episodes that involve lesions of the spinal cord, optic nerve, or brainstem/cerebellum. The most common form of continued disease, accounting for up to 80% of diagnosed MS, is the relapsing–remitting type. Over time this form can evolve into the

Mechanisms of worsening in MS

MS is a chronic disorder of the CNS in which disability accrual appears to occur via 2 mechanisms (see Table 1). In those patients whose course of disease involves only relapses, disability accumulation occurs when recovery from relapses is incomplete, which results in a step-wise pattern of worsening. In patients whose disease course begins with or evolves into progressive MS, there is a gradual and unrelenting deterioration of their condition, although the extent and type of their

Clinical trial relapse experience

Early trial-derived indications of the role of relapses in influencing disease outcome were provided by Weinshenker [4] in a study measuring the frequency of relapses (attacks) in the first and second years of MS, the interval between first and second attacks, and the rate at which moderate disability (Disability Status Scale [DSS] level 3) was reached. Outcome was also assessed as number of years to reach DSS level 6. DSS level 6 was reached earlier in patients with a higher number of attacks,

Measuring relapse-induced disability

We have described an analysis of clinical trial data that was intended to directly measure relapsed-induced disability [13]. The data set used was the existing National Multiple Sclerosis Society (NMSS)–identified MS clinical trial and historic data set, plus one additional study. Only the placebo arms of the clinical trials were used, to minimize the effects of any treatments. The data sets were searched for placebo-arm patients with RRMS who had EDSS and Scripps Neurological Rating Scale

Conclusions

Our most recent studies have directly shown what prior natural history, clinical trial, and MRI studies have implied: relapses produce measurable residual deficits that are durable through at least 2 subsequent evaluations 2–5 months after the relapse, and there is little change in the size of this effect with time. These are likely conservative estimates of the magnitude of relapse-associated damage, and they corroborate the presence of relapse-associated step-wise worsening in patients with

Acknowledgements

This supplement was supported by an educational grant from Teva Neuroscience. BioScience Communications contributed to the editorial refinement of this article and to the production of this supplement. Authors may have accepted honoraria for their supplement contributions.

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Cited by (30)

Relapses add to permanent disability in relapsing multiple sclerosis patients
2021, Multiple Sclerosis and Related Disorders
Citation Excerpt :
If EDSS worsening and relapses were independent manifestations of the background intensity of the disease without direct causal relationship, one wold expect that patients with breakthrough relapses worsened more in the post-relapse period than those without in similar periods, but that was not what we found. The discussion whether relapses by themselves worsen the disease has still not come to a settlement (Schmierer and Giovannoni, 2021), and this could in part can be ascribed differences in defining EDSS worsening, the fluctuating nature of EDSS assessments (Lublin, 2007; Lublin et al., 2003), and observation times which may be shorter than the recovery time from relapses, particularly when defining 3 or 6 months for worsening after a relapse to be “sustained” or “confirmed”. Residual worsening was reported when assessed after a few months (Hirst et al., 2008; Lublin et al., 2003), but in another study the worsening endured one year for the half of the relapses (Vercellino et al., 2009), and in a study of long-term disability worsening in natalizumab-treated patients, relapses also proved to have a significant effect (Trojano et al., 2018).
Whether relapses have direct effects on permanent disability in multiple sclerosis is still an unsettled issue. We aimed at investigating the cumulative effect of breakthrough relapses on the Expanded Disability Status Scale (EDSS) in relapsing-onset MS patients under disease modifying therapy (DMT).
From the Danish Multiple Sclerosis Registry we identified all patients in Denmark with relapsing-onset MS who had started DMT and followed them from the first day of treatment. We included patients aged 18-59 with Kurtzke's EDSS score < 6.0 at entry, and we compared patients with and without relapses during follow-up. Endpoints were 1) annualized increase in EDSS; 2) time to 6-month sustained EDSS-worsening; 3) time to EDSS 6.0; and 4) time to increase in pyramidal- and cerebellar functional systems. Patients with and without relapses after entry were 1:1 matched by sex, EDSS, and age at entry. We analysed EDSS-worsening with adjusted Generalized Linear Models and time to the endpoints with adjusted Cox regression.
We included 1,428 patients with breakthrough relapses and 1,428 without. The adjusted annualized increase in EDSS was 0.179 in patients with relapses (95% CI 0.164 – 9.194) and 0.086 in patients without relapses (95% CI 0.074 – 0.097), but in patients with EDSS ≥ 4.0 at entry there was no difference. The hazard ratio for irreversible worsening of EDSS was 1.83 (95% CI 1.58 – 2.12) and for irreversible increase to EDSS 6.0 or more 1.62 (95% CI 1.25 – 2.10). Irreversible increase in pyramidal and cerebellar functional system scores also happened significantly earlier in patients with breakthrough relapses.
Our results indicate that breakthrough relapses under DMT is associated with increasing permanent disability in patients with EDSS < 4.0 at treatment start which calls for effective prevention of relapses.
Early initiation of fingolimod reduces the rate of severe relapses over the long term: Post hoc analysis from the FREEDOMS, FREEDOMS II, and TRANSFORMS studies
2019, Multiple Sclerosis and Related Disorders
Relapse frequency is often correlated with the prognosis of multiple sclerosis (MS). In patients with relapsing-remitting MS (RRMS), relapses vary in severity and may affect activities of daily living, require steroid intervention, or hospitalization. Incomplete recovery from relapses results in increasing disability. In pivotal phase III studies of fingolimod (FREEDOMS, FREEDOMS II, and TRANSFORMS), the frequency of overall and severe relapses was significantly reduced in patients with RRMS treated with fingolimod compared with placebo or intramuscular interferon β-1a (IFN β-1a). The objective of this study was to report the effect of early initiation of fingolimod on relapse severity in patients with RRMS.
This is a post hoc descriptive analysis of data from the pooled placebo-controlled FREEDOMS/FREEDOMS II studies and from the active-comparator TRANSFORMS study. Patients were analyzed under 2 groups: patients initially randomized to receive fingolimod 0.5 mg during the core phase and continued fingolimod 0.5 mg in the extension phase (immediate fingolimod group), and patients initially randomized to placebo or IFN β-1a during the core phase and switched to fingolimod during the extension phase (delayed fingolimod group). Annualized relapse rate (ARR) was estimated for severe relapses (defined as Expanded Disability Status Scale increase of >1 point, or >2-point change in 1 or 2 Functional Systems, respectively, or >1-point change in >4 Functional Systems). ARR was also estimated for relapses that affected activities of daily living, required steroid use, or hospitalization.
In the pooled FREEDOMS/FREEDOMS II extensions, the immediate fingolimod group showed sustained reductions in the proportion (core: 15.8% and extension: 9.3%) and in ARR over 4 years (0.032 and 0.015) for severe relapses, in relapses requiring steroids (0.149 and 0.123), hospitalization (0.049 and 0.039) and relapses affecting activities of daily living (0.155 and 0.112). In the TRANSFORMS extension, similar reductions were observed in the immedaite group for the proportion of severe relapses (core: 11.8% and extension: 9.8%). ARR remained low over 2 years for severe relapses (0.024 and 0.018), relapses affecting activities of daily living (0.112 and 0.109), relapses requiring steroids (0.156 and 0.161) and hospitalization (0.027 and 0.033). Results in the FREEDOMS/FREEDOMS II and TRANSFORMS extensions for the delayed group were similar. In the TRANSFORMS extension, the proportion of severe relapses were 18.0% (core) and 11.1% (extension); there were significant reductions in ARR for severe relapses (core: 0.079 and extension: 0.029), relapses requiring steroids (0.366 and 0.232), hospitalization (0.092 and 0.055), and relapses affecting activities of daily living (0.285 and 0.144) (all p < 0.0001). Complete recovery was reported for the majority of relapses during the core and extension phases in both the immediate and delayed fingolimod groups (Pooled FREEDOMS/FREEDOMS II: immediate group 59.7%–65.5% and delayed group 64.9%–67.7%; TRANSFORMS: 72.1%–80.0% and 65.4%–70.8%).
In patients with RRMS, the frequency of severe relapses and relapse severity remained low in the immedaite fingolimod group over a period of 4 years. Reductions in the proportion of severe relapses post switch from IFN β-1a or placebo to fingolimod underscore the clinical benefit and the relevance of an early initiation of fingolimod.
Relapse prevalence, symptoms, and health care engagement: patient insights from the Multiple Sclerosis in America 2017 survey
2018, Multiple Sclerosis and Related Disorders
Underestimation of relapse in multiple sclerosis (MS) is detrimental to the patient as well as to their relationship with their MS healthcare professional (HCP).
To obtain direct insight into relapse prevalence, symptoms, and HCP engagement from patients with MS who responded to the Multiple Sclerosis in America (MSIA) 2017 survey.
Information on patient demographics, health insurance coverage, symptoms, disability, relapses, and related HCP interactions were captured. Descriptive analyses were conducted and relapses were annualized. Chi-square tests were used to evaluate frequency of patient engagement, i.e. speaking with or seeing their HCP during relapse with annualized relapse frequency and topics discussed.
Of the 5,311 patient-respondents, the mean age was 51.2 years (84.3% female, 89.3% Caucasian); 40.1% were on disability, and 96.8% had health insurance coverage. A total of 72.2% of patients were diagnosed with relapsing-remitting MS (RRMS); 74.8% of patients not reporting a diagnosis of primary progressive MS (PPMS) (n = 4819) were using disease-modifying therapy. In the 2 years preceding the survey, 73.1% experienced a relapse for a median number of 2 relapses; this corresponded to an annualized relapse distribution among all patients of 44.1% with < 1 relapse, 35.5% with 1–2 relapses, and 20.2% with > 2 relapses. In patients reporting relapses, 62.5% cited an average relapse duration of < 1 month, 10.9% cited 1–2 months, and 13.6% cited > 2 months (12.9% were unsure/didn't recall). Leading symptoms experienced with MS relapse were fatigue (77.4%), numbness/tingling (70.0%), and walking or balance issues (68.8%). With respect to HCP engagement during relapse, 46.9% of patients reported doing so always/often, vs. sometimes (27.3%), rarely (18.5%), and never (7.3%). The most common reasons cited for not engaging an HCP were that the relapse was not severe enough (57.9%), the HCP was unhelpful or didn't specifically tell the patient to contact them (30.9%), the treatment didn't work well or wasn't tolerated (25.6%), or the preference to manage alone (24.4%). A higher percentage of patients with 1 relapse coincided with the highest frequency of HCP engagement during relapse, and the highest percentage of patients with ≥ 5 relapses coincided with the lowest frequency of HCP engagement during relapse. Key relapse-related and MS-related topics were discussed more by patients who always/often engage their HCP during relapse. HCP follow-up after relapse was variable, with 35.0% of patients reporting follow-up within 1 month of first contact, 50.3% reporting follow-up at the next office visit, and 14.7% reporting no follow-up.
MS relapse remains particularly challenging for certain patients; some experience > 2 relapses in 1 year, relapse durations > 1 month, and relapse symptoms that interfere with daily functioning (e.g. walking/balance by 68.8%). Approximately 25% of patients reported rarely or never engaging their HCP during relapse. Common reasons for not engaging, like HCP helpfulness and treatment effectiveness/tolerance, warrant further exploration. Results indicating the benefits of timely touchpoints on both the part of the patient and HCP during relapse include the relationship between higher frequency of engagement with lower relapse frequency and more discussion of both relapse-related and MS-related discussion topics. Survey limitations apply.
Relapse rates in patients with multiple sclerosis treated with fingolimod: Subgroup analyses of pooled data from three phase 3 trials
2016, Multiple Sclerosis and Related Disorders
Fingolimod is a once-daily, orally administered therapy for relapsing forms of MS. It has been shown to reduce relapse rates significantly in all phase II and phase III clinical trials when compared with placebo and intramuscular interferon β-1a (IFNβ-1a IM).
This study compared annualized relapse rates (ARRs) associated with fingolimod, placebo and IFNβ-1a IM, in patient subgroups from the pooled FREEDOMS, FREEDOMS II, and TRANSFORMS populations. This provided a large data set in which the efficacy of fingolimod could be assessed across a range of patient subgroups, including clinically relevant subgroups not previously analysed.
Compared with placebo, fingolimod was associated with significantly lower ARRs across all patient subgroups with relative reductions in ARRs ranging from 35% (patients who had previously received treatment for their MS for up to 1 year; P<0.05) to 69% (patients with symptoms for less than 3 years before study entry; P<0.001). Other relative reductions in ARR compared with placebo included 64% in patients aged 40 years or younger and 63% in those naïve to treatment (P<0.001 for both). Compared with IFNβ-1a IM, the greatest benefits to ARR were seen in patients aged 40 years or younger (55% relative ARR reduction, P<0.001) and in a small subgroup of patients who had previously received IFNβ and glatiramer acetate (55% relative ARR reduction; P<0.05). Reductions in ARR compared with IFNβ-1a IM were not statistically significant in men (33%, P=0.081), in patients aged over 40 years (23%, P=0.230) and in those who had received treatment prior to the study for 1 year or less (35%, P=0.108). Fingolimod was associated with significantly lower ARRs compared with placebo and with IFNβ-1a IM irrespective of treatment status (treatment-naïve and previously treated for MS), and regardless of type of previous therapy.
Fingolimod provided consistent efficacy benefits over placebo and IFNβ-1a IM across a range of subgroups of patients with relapsing MS. The magnitude of the beneficial effect of fingolimod over IFNβ-1a IM may depend on age, sex, and duration of previous treatment. These findings suggest that most benefit will be gained by patients who start fingolimod early in the disease course, but the findings also suggest that fingolimod treatment will benefit patients later in the disease course when they have already accrued disability.
Different MOG<inf>35-55</inf> concentrations induce distinguishable inflammation through early regulatory response by IL-10 and TGF-β in mice CNS despite unchanged clinical course
2015, Cellular Immunology
Citation Excerpt :
The primary-progressive course is characterized by progression from onset with temporary amelioration. In the progressive-relapsing course, there is a constant progression of the disease, with clear acute relapses [4,5]. However, the factors involved in this heterogeneity of MS are not completely understood, highlighting the importance of the use of experimental models in the effort to elucidate the MS clinical courses [5].
Multiple sclerosis (MS) shows distinct clinical courses. Experimental autoimmune encephalomyelitis (EAE), a model to study multiple sclerosis, can be induced by different protocols, which show distinct cytokine and antibody production. The factors involved in this heterogeneity remain unclear. The relevance of MOG concentration in triggering a regulatory response in the chronic model of EAE is imprecise. The aim of this study was investigate if 100 or 300 μg of MOG₃₅_–₅₅ could induce different EAE profiles. Modifications in the concentration of MOG were able to change the patterns of chemokines, cytokines, percentage of cells, inflammatory infiltrate and the development of a regulatory response. However, these changes were unable to modify the intensity of response, which explains the chronic progression of the disease in both concentrations. The results presented in this study contribute to understanding the intricate mechanisms that trigger EAE and provide insights into the pathogenesis of various forms of MS.
Mechanistic insights into corticosteroids in multiple sclerosis: War horse or chameleon?
2014, Clinical Neurology and Neurosurgery
Citation Excerpt :
Although CSs are the standard therapy used to treat MS exacerbations, several lines of evidence suggest that treatment with CSs may not always produce the expected clinical outcomes. Several studies have reported mixed results with respect to the extent and timing of MS relapse improvement [10,87,88]. Although more recent insights into the effects of CSs on inflammation suggest that CS therapies may sometimes activate or fail to inhibit the immunopathophysiological underpinnings of MS in certain situations, other unexpected effects of CSs may also involve non-inflammatory endpoints.
Relapse management is a crucial component of multiple sclerosis (MS) care. High-dose corticosteroids (CSs) are used to dampen inflammation, which is thought to hasten the recovery of MS relapse. A diversity of mechanisms drive the heterogeneous clinical response to exogenous CSs in patients with MS. Preclinical research is beginning to provide important insights into how CSs work, both in terms of intended and unintended effects. In this article we discuss cellular, systemic, and clinical characteristics that might contribute to intended and unintended CS effects when utilizing supraphysiological doses in clinical practice. The goal of this article is to consider recent insights about CS mechanisms of action in the context of MS.
We reviewed relevant preclinical and clinical studies on the desirable and undesirable effects of high-dose corticosteroids used in MS care.
Preclinical studies reviewed suggest that corticosteroids may act in unpredictable ways in the context of autoimmune conditions. The precise timing, dosage, duration, cellular exposure, and background CS milieu likely contribute to their clinical heterogeneity.
It is difficult to predict when patients will respond favorably to CSs, both in terms of therapeutic response and tolerability profile. There are specific cellular, systemic, and clinical characteristics that might merit further consideration when utilizing CSs in clinical practice, and these should be explored in a translational setting.

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The incomplete nature of multiple sclerosis relapse resolution

Abstract

Introduction

Section snippets

Clinical patterns of MS

Natural history of relapsing forms of MS

Mechanisms of worsening in MS

Clinical trial relapse experience

Measuring relapse-induced disability

Conclusions

Acknowledgements

Lancet

Defining the clinical course of multiple sclerosis: results of an international survey

Neurology

The natural history of multiple sclerosis: a geographically based study 1. Clinical course and disability

Brain

The natural history of multiple sclerosis: a geographically based study 2. Predictive value of the early clinical course

Brain

MRI metrics as surrogate markers for clinical relapse rate in relapsing–remitting MS patients

Neurology

Predictors of relapse rate in MS clinical trials

Neurology

Axonal transaction in the lesions of multiple sclerosis

N Engl J Med