Redefining the Multiple Sclerosis Severity Score (MSSS): The effect of sex and onset phenotype

Background: The Multiple Sclerosis Severity Score (MSSS) is a widely used measure of the disability progression rate. However, the global MSSS may not be the best basis for comparison between all patient groups. Objective: We evaluated sex-specific and onset phenotype–specific MSSS matrices to determine if they were more effective than the global MSSS as a basis for comparison within these subsets. Methods: Using a large international dataset of multiple sclerosis (MS) patient records and the original MSSS algorithm, we constructed global, sex-specific and onset phenotype–specific MSSS matrices. We compared matrices using permutation analysis. Results: Our final dataset included 30,203 MS cases, with 28.9% males and 6.5% progressive-onset cases. Our global MSSS matrix did not differ from previously published data ( p > 0.05). The progressive-onset-specific matrix differed significantly from the relapsing-onset-specific matrix ( p < 0.001), with lower MSSS attributed to cases with the same Expanded Disability Status Score (EDSS) and disease duration. When evaluated with a simulation, using an onset-specific MSSS improved statistical power in mixed cohorts. There were no significant differences by sex. Conclusion: The differences in the disability accrual rate between progressive- and relapsing-onset MS have a significant effect on MSSS. An onset-specific MSSS should be used when comparing the rate of disability progression among progressive-onset cases and for mixed cohorts.

Download Full-text

Determinants of therapeutic lag in multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458520981300 ◽

2021 ◽

pp. 135245852098130

Author(s):

Izanne Roos ◽

Emmanuelle Leray ◽

Federico Frascoli ◽

Romain Casey ◽

J William L Brown ◽

...

Keyword(s):

Multiple Sclerosis ◽

Expanded Disability Status Scale ◽

Disability Progression ◽

Delayed Onset ◽

Disease Characteristics ◽

Disability Status ◽

Male Sex ◽

Pre Treatment ◽

Patient Subgroups

Background: A delayed onset of treatment effect, termed therapeutic lag, may influence the assessment of treatment response in some patient subgroups. Objectives: The objective of this study is to explore the associations of patient and disease characteristics with therapeutic lag on relapses and disability accumulation. Methods: Data from MSBase, a multinational multiple sclerosis (MS) registry, and OFSEP, the French MS registry, were used. Patients diagnosed with MS, minimum 1 year of exposure to MS treatment and 3 years of pre-treatment follow-up, were included in the analysis. Studied outcomes were incidence of relapses and disability accumulation. Therapeutic lag was calculated using an objective, validated method in subgroups stratified by patient and disease characteristics. Therapeutic lag under specific circumstances was then estimated in subgroups defined by combinations of clinical and demographic determinants. Results: High baseline disability scores, annualised relapse rate (ARR) ⩾ 1 and male sex were associated with longer therapeutic lag on disability progression in sufficiently populated groups: females with expanded disability status scale (EDSS) < 6 and ARR < 1 had mean lag of 26.6 weeks (95% CI = 18.2–34.9), males with EDSS < 6 and ARR < 1 31.0 weeks (95% CI = 25.3–36.8), females with EDSS < 6 and ARR ⩾ 1 44.8 weeks (95% CI = 24.5–65.1), and females with EDSS ⩾ 6 and ARR < 1 54.3 weeks (95% CI = 47.2–61.5). Conclusions: Pre-treatment EDSS and ARR are the most important determinants of therapeutic lag.

Download Full-text

Should We Use Clinical Tools to Identify Disease Progression?

Frontiers in Neurology ◽

10.3389/fneur.2020.628542 ◽

2021 ◽

Vol 11 ◽

Author(s):

Hernan Inojosa ◽

Undine Proschmann ◽

Katja Akgün ◽

Tjalf Ziemssen

Keyword(s):

Multiple Sclerosis ◽

Clinical Markers ◽

Disability Progression ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Secondary Progressive ◽

Disability Status ◽

Relapsing Remitting ◽

Clinical Tools

The presence of disability progression in multiple sclerosis (MS) is an important hallmark for MS patients in the course of their disease. The transition from relapsing remitting (RRMS) to secondary progressive forms of the disease (SPMS) represents a significant change in their quality of life and perception of the disease. It could also be a therapeutic key for opportunities, where approaches different from those in the initial phases of the disease can be adopted. The characterization of structural biomarkers (e.g., magnetic resonance imaging or neurofilament light chain) has been proposed to differentiate between both phenotypes. However, there is no definite threshold between them. Whether the risk of clinical progression can be predicted by structural markers at early disease phases is still a focus of clinical research. However, several theories and pathological evidence suggest that both disease phenotypes are part of a continuum with common pathophysiological mechanisms. In this case, the clinical evaluation of the patients would play a preponderant role above destruction biomarkers for the early identification of disability progression and SPMS. For this purpose, the use of clinical tools beyond the Expanded Disability Status Scale (EDSS) should be considered. Besides established functional tests such as the Multiple Sclerosis Functional Composite (MSFC), patient's neurological history or digital resources may help neurologists in the decision-taking. In this article, we discuss arguments for the use of clinical markers in the detection of secondary progressive MS and the characterization of progressive disease activity.

Download Full-text

Impact of natural menopause on multiple sclerosis: a multicentre study

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2019-320587 ◽

2019 ◽

Vol 90 (11) ◽

pp. 1201-1206 ◽

Cited By ~ 8

Author(s):

Damiano Baroncini ◽

Pietro Osvaldo Annovazzi ◽

Nicola De Rossi ◽

Giulia Mallucci ◽

Valentina Torri Clerici ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cigarette Smoking ◽

Relapse Rate ◽

Disability Progression ◽

Natural Menopause ◽

Multicentre Cohort Study ◽

Disability Status ◽

Speed Up ◽

Multicentre Cohort

ObjectiveTo study the effect of natural menopause on multiple sclerosis clinical course.MethodsThis was an observational, retrospective, multicentre, cohort study. Menopause onset was defined by the final menstrual period (FMP) beyond which no menses occurred for 12 months. We included multiple sclerosis (MS) patients with FMP occurred after 2005 and a recorded follow-up of at least 2 years pre-FMP and post-FMP. We excluded patients with primary progressive course, iatrogenic menopause and with other confounders that could mask menopause onset. We compared relapse-rate and expanded disability status scale (EDSS) scores pre-FMP and post-FMP, searching for possible interactions with age, disease duration, cigarette smoking and nulliparity status.Results148 patients were included (mean observation: 3.5 years pre-FMP and post-FMP). Most patients (92%) received disease-modifying therapies, mainly first-lines. After menopause the annualised relapse rate (ARR) significantly decreased (from 0.21±0.31 to 0.13± 0.24; p=0.005), while disability worsened (increase of mean 0.4 vs 0.2 points after menopause; p<0.001). Older age and long-lasting disease were associated with ARR reduction (p=0.013), but not with disability worsening. Cigarette smokers showed a trend to a higher disability accumulation after menopause (p=0.059).ConclusionNatural menopause seems to be a turning point to a more progressive phase of MS. Relapse rate is also reduced after menopause, but this effect could be driven most by ageing and shifting to progressive phase in patients with long-lasting disease. Cigarette smoking could speed up disability progression after menopause.

Download Full-text

Greater sensitivity to multiple sclerosis disability worsening and progression events using a roving versus a fixed reference value in a prospective cohort study

Multiple Sclerosis Journal ◽

10.1177/1352458517709619 ◽

2017 ◽

Vol 24 (7) ◽

pp. 963-973 ◽

Cited By ~ 15

Author(s):

Ludwig Kappos ◽

Helmut Butzkueven ◽

Heinz Wiendl ◽

Timothy Spelman ◽

Fabio Pellegrini ◽

...

Keyword(s):

Multiple Sclerosis ◽

Reference Value ◽

Cumulative Probability ◽

Baseline Score ◽

Disability Progression ◽

Open Label ◽

Disability Status ◽

Relapsing Remitting ◽

Fixed Reference ◽

Relapsing Remitting Multiple Sclerosis

Background: Confirmed Expanded Disability Status Scale (EDSS) progression occurring after a fixed-study entry baseline is a common measure of disability increase in relapsing-remitting multiple sclerosis (RRMS) studies but may not detect all disability progression events, especially those unrelated to overt relapses. Objective: To evaluate possible measures of disability progression unrelated to relapse using EDSS data over ≈5.5 years from the Tysabri® Observational Program (TOP). Methods: TOP is an ongoing, prospective, open-label study in RRMS patients receiving intravenous 300 mg natalizumab every 4 weeks. Measures of increasing disability were assessed using as a reference either study baseline score or a “roving” system that resets the reference score after ⩾24- or ⩾48-week confirmation of a new score. Results: This analysis included 5562 patients. Approximately 70% more EDSS progression events unrelated to relapse and 50% more EDSS worsening events overall were detected with a roving reference score (cumulative probability: 17.6% and 29.7%, respectively) than with a fixed reference baseline score (cumulative probability: 10.1% and 20.3%, respectively). Conclusion: In this long-term observational RRMS dataset, a roving EDSS reference value was more efficient than a study baseline EDSS reference in detecting progression/worsening events unrelated to relapses and thus the transition to secondary progressive disease.

Download Full-text

Baseline EDSS proportions in MS clinical trials affect the overall outcome and power: A cautionary note

Multiple Sclerosis Journal ◽

10.1177/1352458516670733 ◽

2016 ◽

Vol 23 (7) ◽

pp. 982-987 ◽

Cited By ~ 3

Author(s):

Guoqiao Wang ◽

Gary R Cutter ◽

Stacey S Cofield ◽

Fred Lublin ◽

Jerry S Wolinsky ◽

...

Keyword(s):

Clinical Trials ◽

Randomized Clinical Trials ◽

Progression Rate ◽

Disability Progression ◽

Cautionary Note ◽

Trial Outcome ◽

Disability Status ◽

Relapsing Remitting ◽

Event Rates ◽

Relapsing Remitting Multiple Sclerosis

Background: In randomized clinical trials, when treatments do not work equally effectively across stratifications of participants, observed event rates may differ from those hypothesized leading to deviations in estimated power. Objectives: To investigate the effect of distributions of baseline Expanded Disability Status Scale (EDSS) proportions in relapsing-remitting multiple sclerosis (RRMS) on the trial outcome, confirmed disability progression rate (CDPR), and power. Methods: We reported CDPRs in the CombiRx trial by baseline EDSS and by groups (1st (0, 1), 2nd (1.5, 2), 3rd (2.5, 3), and 4th (⩾3.5)) and investigated the effect of different combinations of baseline EDSS proportions on the trial outcome and power. Results: There were 244 (25.4%) participants in the 1st group, 368 (38.4%) in the 2nd group, 223 (23.3%) in the 3rd group, and 124 (12.9%) in the 4th group with CDPRs of 40.1%, 13.9%, 11.2%, and 16.9%, respectively. Both CDPR and power increased when the proportion of the 1st group increased in hypothetical trials with equal sample sizes in each arm, and a 10% increase in the 1st group led to a 5% increase in power. Conclusion: Various baseline EDSS proportions yielded different CDPRs and power, suggesting caution in interpretation of treatment effects across trials that enrolled participants with different proportions of baseline EDSS.

Download Full-text

Age Related Multiple Sclerosis Severity Score: Disability ranked by age

Multiple Sclerosis Journal ◽

10.1177/1352458517690618 ◽

2017 ◽

Vol 23 (14) ◽

pp. 1938-1946 ◽

Cited By ~ 41

Author(s):

Ali Manouchehrinia ◽

Helga Westerlind ◽

Elaine Kingwell ◽

Feng Zhu ◽

Robert Carruthers ◽

...

Keyword(s):

Multiple Sclerosis ◽

Severity Score ◽

Statistical Power ◽

Disease Duration ◽

Population Based ◽

Cross Sectional ◽

The United Kingdom ◽

Age Related ◽

Versatile Tool ◽

Study Population

Background: The Multiple Sclerosis Severity Score (MSSS) is obtained by normalising the Expanded Disability Status Scale (EDSS) score for disease duration and has been a valuable tool in cross-sectional studies. Objective: To assess whether use of age rather than the inherently ambiguous disease duration was a feasible approach. Method: We pooled disability data from three population-based cohorts and developed an Age Related Multiple Sclerosis Severity (ARMSS) score by ranking EDSS scores based on the patient’s age at the time of assessment. We established the power to detect a difference between groups afforded by the ARMSS score and assessed its relative consistency over time. Results: The study population included 26058 patients from Sweden ( n = 11846), Canada ( n = 6179) and the United Kingdom ( n = 8033). There was a moderate correlation between EDSS and disease duration ( r = 0.46, 95% confidence interval (CI): 0.45–0.47) and between EDSS and age ( r = 0.44, 95% CI: 0.43–0.45). The ARMSS scores showed comparable power to detect disability differences between groups to the updated and original MSSS. Conclusion: Since age is typically unbiased and readily obtained, and the ARMSS and MSSS were comparable, the ARMSS may provide a more versatile tool and could minimise study biases and loss of statistical power caused by inaccurate or missing onset dates.

Download Full-text

Genetic Factors Associated with Risk and Disability Progression of Multiple Sclerosis in Slovak Population

Acta Medica Martiniana ◽

10.1515/acm-2017-0007 ◽

2017 ◽

Vol 17 (2) ◽

pp. 15-19

Author(s):

Sandra Hanysova ◽

D. Cierny ◽

E. Kurca ◽

J. Lehotsky

Keyword(s):

Multiple Sclerosis ◽

Genetic Basis ◽

Venous Blood ◽

Progression Rate ◽

Disability Progression ◽

Gstt1 Null Genotype ◽

Genetic Changes ◽

Slovak Population ◽

Pcr Rflp ◽

Healthy Control

AbstractObjective: The aim of our study was to determine the relation of particular genetic variants in selected genes (GSTM1, GSTT1 null genotypes; rs1695 GSTP1; rs10735781 EVI5) to the risk of multiple sclerosis (MS) development and find out the possible association with disease disability progression rate. Material and methods: Our study included 202 MS patients and 174 healthy control volunteers. MS patients were divided according to disability progression rate to three groups - slowly progressing, mid-rate progressing and rapidly progressing. All DNA samples were isolated from venous blood. Genotyping was performed by PCR-RFLP and multiplex PCR. Results: Our analysis showed that GSTT1 null genotype (OR 0.56; 95%CI 0.33 -0.95; p=0.04) and GSTM1, GSTT1 double null genotype (OR 0.32; 95%CI 0.14 - 0.74; p=0.006) are potentially protective in relation to MS. We observed similar result in GSTT1 null genotype in association with mid-rate progression (OR 0.48; 95%CI 0.24 - 0.97; p=0.05). Frequency of GSTM1 and GSTT1 double null genotype is significantly lower in subgroup of MS patients with progression rate defined as slow (OR 0.22; 95%CI 0.05 - 0.98; p=0.05) and middle (OR 0.33; 95%CI 0.11 - 0.99; p=0.045). We did not show any significant association of genetic changes rs1695 in GSTP1 and rs10735781 in EVI5 with MS or rate of disease progression. Conclusions: Genetic basis of multiple sclerosis is still not fully elucidated. Further research may clarify our results and confirm the value of studied factors for clinical practice.

Download Full-text

The Effects of the MTHFR 677C>T (rs1801133) Genetic Variant on Susceptibility and Disability in Multiple Sclerosis Patients are Mediated by Homocysteine but Not Folate Levels

10.21203/rs.3.rs-947647/v1 ◽

2021 ◽

Author(s):

Claudia Mara Ribeiro ◽

Sayonara Rangel Oliveira ◽

Tamires Flauzino ◽

Daniela Frizon Alfieri ◽

Andrea Name Colado Simão ◽

...

Keyword(s):

Multiple Sclerosis ◽

Vitamin D3 ◽

Activity Index ◽

Inflammatory Biomarkers ◽

Disability Progression ◽

Reactive Protein ◽

Disability Status ◽

Male Sex ◽

Polymerase Chain ◽

Multiple Sclerosis Patients

Abstract We investigated whether the MTHFR 677C>T (rs1801133) variant and plasma homocysteine and folate are associated with multiple sclerosis (MS), disability, disability progression, and inflammatory biomarkers. We included 163 MS patients categorized using the Expanded Disability Status Scale (EDSS) as mild (EDSS<3) and moderate/high (EDSS≥3) disability, and 226 healthy controls. Disability progression was evaluated using Multiple Sclerosis Severity Score (MSSS) and the MTHFR 677C>T was genotyped using real time polymerase chain reaction. The levels of some inflammatory biomarkers and inflammatory activity index (IAI) were determined. There was no association between the MTHFR 677 C>T genotypes and MS, EDSS, and MSSS (p>0.05). Plasma folate and homocysteine were higher and adiponectin was lower in MS patients than controls (p<0.001). Moreover, 21.8% of the EDSS variance was explained by age, IAI and C-reactive protein (CRP) (all positively associated); 10.9% of the MSSS variance was predicted by IAI and CRP (both positively) and vitamin D3 (negatively), whereas 54.4% of the MS-EDSS-MSSS score was explained by the regression on age, IAI, homocysteine, folate, and CRP (all positively) and adiponectin, body mass index, and vitamin D3 (all negatively), female sex and the MTHFR 677 TT genotype. In patients and controls, 16.6% of the variance in the homocysteine was explained by the MTHFR 677 TT genotype and age (both positively), folate (negatively) and male sex. In conclusion, the MTHFR 677C>T variant was not directly associated with MS, disability, and disability progression; however, the TT genotype showed indirect effects on MS susceptibility and disability mediated by homocysteine.

Download Full-text

Infratentorial and spinal cord lesions: Cumulative predictors of long-term disability?

Multiple Sclerosis Journal ◽

10.1177/1352458519864933 ◽

2019 ◽

Vol 26 (11) ◽

pp. 1381-1391 ◽

Cited By ~ 1

Author(s):

Iris Dekker ◽

Madeleine H Sombekke ◽

Lisanne J Balk ◽

Bastiaan Moraal ◽

Jeroen JG Geurts ◽

...

Keyword(s):

Multiple Sclerosis ◽

Spinal Cord ◽

Odds Ratio ◽

Expanded Disability Status Scale ◽

Simultaneous Presence ◽

Disability Progression ◽

Spinal Cord Lesions ◽

Disability Status ◽

Lesion Analysis

Objective: The objective of the study was to determine whether early infratentorial and/or spinal cord lesions are long-term cumulative predictors of disability progression in multiple sclerosis (MS). Methods: We selected 153 MS patients from the longitudinal Amsterdam MS cohort. Lesion analysis was performed at baseline and year 2. Disability progression after 6 and 11 years was measured using the Expanded Disability Status Scale (EDSS) and EDSS-plus (including 25-foot walk and 9-hole peg test). Patients with spinal cord or infratentorial lesions were compared for the risk of 6- and 11-year disability progression to patients without spinal cord or infratentorial lesions, respectively. Subsequently, patients with lesions on both locations were compared to patients with only spinal cord or only infratentorial lesions. Results: Baseline spinal cord lesions show a higher risk of 6-year EDSS progression (odds ratio (OR): 3.6, p = 0.007) and EDSS-plus progression (OR: 2.5, p = 0.028) and 11-year EDSS progression (OR: 2.8, p = 0.047). Patients with both infratentorial and spinal cord lesions did not have a higher risk of 6-year disability progression than patients with only infratentorial or only spinal cord lesions. Conclusion: The presence of early spinal cord lesions seems to be a dominant risk factor of disability progression. Simultaneous presence of early infratentorial and spinal cord lesions did not undisputedly predict disability progression.

Download Full-text

061 Ocrelizumab reduces disability progression independent of relapse activity in patients with relapsing multiple sclerosis (RMS) (ENCORE)

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2018-anzan.60 ◽

2018 ◽

Vol 89 (6) ◽

pp. A25.2-A25 ◽

Cited By ~ 2

Author(s):

Ludwig Kappos ◽

Jerry S Wolinsky ◽

Gavin Giovannoni ◽

Douglas L Arnold ◽

Fred Lublin ◽

...

Keyword(s):

Multiple Sclerosis ◽

Subgroup Analysis ◽

Interferon Beta ◽

Expanded Disability Status Scale ◽

Disability Progression ◽

Intention To Treat ◽

Secondary Progressive ◽

Superior Efficacy ◽

Disability Status ◽

Relapsing Multiple Sclerosis

IntroductionOcrelizumab-(OCR) showed superior efficacy vs interferon beta-1a-(IFNβ1a) in OPERA I/II trials in RMS. Confirmed disability progression-(CDP) based on composite of Expanded Disability Status Scale-(EDSS), timed 25-foot walk-(T25FW) and 9-hole peg test-(9HPT) may better characterise aspects of disability progression than EDSS alone and has improved sensitivity for assessing progression in secondary progressive MS-(SPMS).MethodsRMS patients, including relapsing SPMS patients, in OPERA I/II-(NCT01247324/NCT01412333) received IV-OCR 600 mg (q24w) or SC-IFNβ1a 44 µg (tiw) over 96 weeks. CCDP was defined as disability progression measured by EDSS (increase ≥1.0 or 0.5 if baseline >5.5) or ≥20% T25FW increase or ≥20% 9 HPT increase, confirmed after ≥12/≥24 weeks. Definition-1 of CCDP-IRA=reference EDSS/T25FW/9HPT was re-baselined at first available assessment ≥30 days, after each relapse and no relapse should occur between baseline and initial disability progression [IDP], and within 30 days post-IDP and 30 days prior to IDP confirmation. Definition-2=period of no relapse for 30 days post-IDP confirmation. Subgroup analysis included patients at potentially higher SPMS risk based on baseline-EDSS ≥4.0 and pyramidal Kurtzke Functional Systems Score ≥2.ResultsIn the pooled intention-to-treat (ITT) cohort (n=1,656), risk reduction (RR; OCR vs IFNβ1a) for 12-/24 week CCDP was 34% (30.7% vs 21.5%; p<0.001) and 31% (22.6% vs 16.1%; p=0.002). The 12-/24 week CCDP-IRA RRs for Definition-1 were 24% (25.4% vs 19.6%; p=0.010) and 22% (19.2% vs 14.9%; p=0.046); and for Definition-2, 25% (25.4% vs 19.5%; p=0.008) and 23% (19.2% vs 14.8%; p=0.039). In the subgroup at higher SPMS risk, 12-/24 week RRs for CCDP-IRA (Definition-2) were 40% (31.2% vs 19.1%; p=0.022) and 36% (26.9% vs 16.6%; p=0.064). All CCDP-IRA components in the ITT and subgroups followed similar trends.ConclusionResults show that considerable disability progression in RMS occurs independently of protocol-defined relapses. Ocrelizumab significantly reduced progression vs IFNβ1a in the OPERA ITT population of RMS patients and more so in the subgroup at higher SPMS risk.

Download Full-text