Detection and importance of relapses

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Do you want to be relapse free? Do relapses matter? #MSBlog #MSResearch

“Health economists and payers are always looking to see if DMTs and clinical services are cost effective and worth what they have to pay for them. The study below describes a method of looking for relapses in electronic records using proxies; it seems to work and maybe useful for looking at cost-effectiveness of DMTs in the future.”

“Interestingly, the relapses themselves don’t make much difference to most MS DMT cost-effectiveness models. However, relapses themselves consume health care resources (appointments, steroids, bed days, rehab services, etc.) and do impact on MSers occupational and social functioning. In short they cause MSers to have to miss work. I also find relapses affect mood; in particular relapses remind you that have a disease and rekindle anxiety about the future. In the past MSers expected to have a relapse or two a year; this is what living with MS was about. Now that the expectation is to become free of disease activity, particularly with the more effective therapies, MSers don’t like having relapses. Why would you?”

“It is also clear that relapses in the context of DMTs mean something completely different to relapses occurring in MSers on no treatment. Several groups have found that relapses in natural history studies beyond the first two years and/or an EDSS 4.0 don’t add anything to models that predict future disability. In comparison relapses on DMTs are strongly predictive of further relapses and disease progression. I am sure that at the heart of this this conundrum lies something very important concerning the pathogenesis or cause of MS.

“My hypothesis is that relapses are a proxy to focal inflammatory events and indicate that your immune system is responding to something in the brain and spinal cord that is causing MS. If you are on no treatment it does not matter whether your immune system responds, or not, because the cause of MS is active and causing damage. However in the context of a DMT a relapse indicates that the treatment (DMT) is not stopping or down-regulating the disease process in the brain and spinal cord; a relapse is therefore an indicator of this and is hence a poor prognostic sign.”

“Despite the natural history data on relapses beyond two years not predicting disability, it is clear that relapses within the first two years are highly predictive of future disability. I have posted on this before and have included the picture from Professor Ebers’ seminal paper on this indicating the time to needing a walking stick.”


“Another aspect that is down played when it come to relapses is that they cause disability and in some cases MSers never return to baseline.”

“The bottom line is relapses are not a good thing; they cost money (health care utilization), they affect the mood of MSers (anxiety and depression), they cause disability (poor or incomplete recovery), they tell you that you are not responding to your DMT  (evidence of disease activity) and predict a poor long term outcome. So don’t let anyone tell you relapses don’t count; they do.”

EpubBergamaschi et al. Detection of clinical relapses in multiple sclerosis cohorts: construction and validation of a model based on administrative data. Neurol Sci. 2013 Jul 20.


Background: MS is the main cause of chronic disability in young people during their most productive years of life and therefore carries a high social and economic burden. 

Aims: The present study aimed to: (1) verify the capacity of an administrative data source to furnish data for constructing a model able to detect the occurrence of clinical relapses in MSers (2) validate the constructed theoretical model on a set of real-world data. 

Methods: Two MS experts identified some administrative variables as proxies of clinical relapses. Thereafter, the two MS experts analysed 889 events in 100 MSers, considering only the administrative data relating to these MSers, while a third neurologist independently analysed the real-world data (documented medical history) of the same MSers in the same period. 

The following proxies for possible relapses were used:
  1. Hospitalisations
  2. Day-hospital admissions
  3. Steroid treatments
  4. Immune-modulating therapies
  5. Other therapies
  6. MRI examinations
Results: Absolute concordance between the theoretical model and the real-world data was found in 86 % of the events. 

Conclusions: The model they propose is easily and rapidly applicable, requiring the collection of just a few variables that are already present in local health authority administrative databases in Italy. It can be used to estimate, with a good level of reliability, the occurrence of relapses in various settings. Moreover, the model is also exportable to different and larger MS cohorts and could be useful for healthcare planning and for evaluating the efficacy of drugs in the real-world, thus favouring better resource allocation and management.
Other posts of interest on disability:
25 Jul 2013
Conclusions Our findings demonstrate that higher ARR in POMS relative to AOMS is sustained over 6-years, suggesting a more inflammatory nature and potential disconnect between relapses and disability measured by 
30 Jul 2013
METHODS: The 2011/2012 seasonal influenza vaccine (containing H1N1, H3N2, and B strains) was administered to patients with relapsing forms of multiple sclerosis (RMS) treated for ≥6 months with teriflunomide 7 mg (n 
19 Jul 2013
Method: Part 1 consists of 7 questions that evaluate relapse symptoms, impact on activities of daily living (ADL), overall functioning, and response to treatment for previous relapses. Part 2 consists of 7 questions that evaluate 
27 May 2013
Background: Observational studies have shown an association between lower vitamin D levels and higher risk of relapse among MSers. This has raised interest in potential clinical benefits of vitamin D supplementation in the 
24 Jun 2013
Upon recovery from the initial episode of experimental autoimmune encephalomyelitis (EAE), virtually all SJL mice develop relapsing/remitting episodes of disease. These relapses may occur due to the reactivation of memory 
16 Mar 2013
METHODS: Among 806 MSers with relapsing remitting (RR) onset MS from the London Ontario database, we used Kaplan-Meier, Cox regression and multiple logistic regression analyses to investigate the effect of baseline 
22 Feb 2013
MAIN OUTCOME MEASURE: Long-term evolution of MSers with high (≥3 attacks) and early (within the first 2 years of the disease) frequency of relapses. In the total SP population and in MSers grouped by numbers of early 
11 Feb 2013
Immunadsorption in steroid unresponsive relapses. Heigl et al. Immunoadsorption in steroid-refractory multiple sclerosis: Clinical experience in 60 patients. Atheroscler Suppl. 2013;14:167-73. BACKGROUND: Multiple 
07 May 2013
OBJECTIVE: The purpose of this study was to determine the best threshold for the rule and to demonstrate its predictive validity for risk of subsequent relapses for multiple sclerosis (MS) trials. METHODS: We used logistic 
14 Apr 2013
BACKGROUND: Multiple sclerosis (MS) is a chronic disease that affects mainly adults in the prime of their lives. However, few studies report the impact of high annual relapse rates on outcomes. The purpose of this study was 
17 Mar 2013
#MSBlog: were have all the relapses gone? Epub: Steinvorth et al. Explaining temporal trends in annualised relapse rates in placebo groups of randomised controlled trials in relapsing multiple sclerosis: systematic review 
17 Dec 2012
Multiple sclerosis (MS) is a chronic progressive inflammatory demyelinating disease affecting the central nervous system. The most common clinical type of MS tends to follow a relapsing course, affecting the vast majority of 
27 Jan 2013
Safety of Steroids for relapses. #MSBlog: How safe and well-tolerated are steroids for acute MS attacks? Shaygannejad et al. Short-Term Safety of Pulse Steroid Therapy in Multiple Sclerosis Relapses. Clin Neuropharmacol.
31 Dec 2012
Methods: The number of relapses and the annualized relapse rate (ARR) before, during and after Nz discontinuation were determined and compared between 26 MSers who switched to Fingo within 24 weeks, and 10 MSers 
26 Nov 2012
Subgroup analysis revealed a consistent effect on NFL release, regardless of previous DMT or whether patients had relapses or were in remission within 3 months prior to natalizumab treatment. No differences between pre- 
19 Nov 2012
Methods: They therefore investigated relationships between relapses and disability progression for outcomes of requiring assistance to walk, being bedridden and dying from MS [EDSS 6, 8, 10] by analysing 28 000 
17 Nov 2012
“Some of you who have been following this blog and my recent posts will realise that I have had a change of mind. I have been sceptical about the publications showing a very poor correlation between relapses (frequency 
03 Oct 2012
METHODS: 132 sequential MSers were recruited from an open access relapse clinic. Clinical data including disability (Expanded Disability Status Scale: EDSS) and depression symptoms (Hospital Anxiety and Depression 
02 Jan 2013
Methods: The MSBase international database was searched for relapses in series recording patient histories from 1980 up to 2010. The number of relapses by month was stratified by decade (1981-1990, 1991-2000, 
24 Sep 2012
DESIGN: Observational study designed to explore the effect of demographical variables and number of relapses over the disability progression in the two first years of beta-interferon treatment for multiple sclerosis. RESULTS: 
18 Nov 2012
METHODS: In 1844 MSers who were followed for a mean (+/- SD) of 11 +/- 10 years, they determined the time of the clinical onset of the disease, the initial course (relapsing-remitting or progressive) and the subsequent 
24 Sep 2012
This figures shows a clear difference in relation to the prognosis based on early relapses. MSers with zero or 1 attack in the first 2 years needed a walking stick on average 14 years later (year 20) compared to MSers with 5 or 
22 Nov 2012
CONCLUSIONS: In this observational NMO study, MTX decreased dramatically the frequency of relapses, which is directly related to progression of disability or even death in this disorder. NMO, used to be called Devics MS, 
21 Nov 2012
Research: Atrophy occurs early and relapses are important. Epub: Kalincik et al.Volumetric MRI markers and predictors of disease activity in early multiple sclerosis: a longitudinal cohort study.PLoS One. 2012;7(11):e50101.
22 Mar 2012
Relapses count. Lublin et al. Effect of relapses on development of residual deficit in multiple sclerosis. Neurology. 2003 Dec 9;61(11):1528-32. OBJECTIVE: To determine the percentage of MSers with residual deficits 
14 Jul 2011
“Contrary to recent previous comments relapses do matter; particularly within the first 2 years.” “Why do I say this?” The following study investigated the relationship between relapses and disability progression for outcomes of 
26 May 2012
In this meta-analysis we show that women who breastfeed were almost twice as likely not to have a post-partum relapse than woman would did not; in 8 prospective studies the odds ratio (OR) of having a relapse was 0.46 
22 Mar 2012
Relapses in clinical trials. Epub ahead of print: Nicholas et al. Time-patterns of annualized relapse rates in randomized placebo-controlled clinical trials in relapsing multiple sclerosis: A systematic review and meta-analysis.
13 Jul 2011
The only significant predictor of having a relapse after childbirth was an increased number of relapses in the year before pregnancy and during the pregnancy itself. Therefore, the reported association between breastfeeding 
15 Jul 2011
The average or mean rate of relapse was 0.7 per year in the year before pregnancy, 0.5 during the first trimester, 0.6 during the second trimester and 0.2 during the third. The rate increased to 1.2 during the first three months 
18 Nov 2011
Results: For the 145 persons with RRMS followed beyond one review, anti-HHV-6 IgG titer was positively associated with the hazard of relapse with a dose-dependent trend (p = 0.003), not affected by adjustment for anti-EBV 
08 Nov 2011
L. Kappos, H-P. Hartung, M. S. Freedman, A. Boyko, D. Mikol, U. Freudensprung, T. Plitz for the ATAMS study group ATAMS: a randomised trial of the B-cell-targeting agent atacicept in patients with relapsing multiple sclerosis.

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

3 comments

  • Prof G,

    I assume your hypothesis involves EBV. Can you give us any feel to when the Charcot Project might report initial findings?

    Also, if the immune system is a response to something in the brain / spinal cord doing damage, getting rid of the immune response eg using Alemtuzumab won't impact on the underlying cause!

    • Re: "if the immune system is a response to something in the brain / spinal cord doing damage, getting rid of the immune response eg using Alemtuzumab won't impact on the underlying cause!"

      It depends if the underlying cause resides in an immune cell, for example the B-cell or if the cause is triggered by the products of the immune cells, for example cytokines or HERVs.

      The Charcot project is a long way from reporting on its first trial; maybe 12-18 months. We will keep you posted.

  • So if one has multiple flares on an initial treatment but then switches treatments and stops having flares have they changed their prognosis? It would seem the flares on the initial medication would indicate an aggressive MS with more long term disability. Does the switch of therapies start the 2 year window over for predictions of future disability?

    I ask in part because drugs like Tysabri are not considered front line drugs, and the only way to get on them in most cases is to have another drug fail to control the MS.

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