Long-Term Disease Stability Assessed by the Expanded Disability Status Scale in Patients Treated with Cladribine Tablets 3.5 mg/kg for Relapsing Multiple Sclerosis: An Exploratory Post Hoc Analysis of the CLARITY and CLARITY Extension Studies

Background Multiple sclerosis (MS) diagnostic criteria have changed since the ORACLE-MS study was conducted; 223 of 616 patients (36.2%) would have met the diagnosis of MS vs clinically isolated syndrome (CIS) using the newer criteria. Objective The objective of this paper is to assess the effect of cladribine tablets in patients with a first clinical demyelinating attack fulfilling newer criteria (McDonald 2010) for MS vs CIS. Methods A post hoc analysis for subgroups of patients retrospectively classified as fulfilling or not fulfilling newer criteria at the first clinical demyelinating attack was conducted. Results Cladribine tablets 3.5 mg/kg ( n = 68) reduced the risk of next attack or three-month confirmed Expanded Disability Status Scale (EDSS) worsening by 74% vs placebo ( n = 72); p = 0.0009 in patients meeting newer criteria for MS at baseline. Cladribine tablets 5.25 mg/kg ( n = 83) reduced the risk of next attack or three-month confirmed EDSS worsening by 37%, but nominal significance was not reached ( p = 0.14). In patients who were still CIS after applying newer criteria, cladribine tablets 3.5 mg/kg ( n = 138) reduced the risk of conversion to clinically definite multiple sclerosis (CDMS) by 63% vs placebo ( n = 134); p = 0.0003. Cladribine tablets 5.25 mg/kg ( n = 121) reduced the risk of conversion by 75% vs placebo ( n = 134); p < 0.0001. Conclusions Regardless of the criteria used to define CIS or MS, 3.5 mg/kg cladribine tablets are effective in patients with a first clinical demyelinating attack. ClinicalTrials.gov registration: The ORACLE-MS study (NCT00725985).

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Potential of Timed 25-Foot Walk Values in Predicting Maximum Walking Distance in Persons with Multiple Sclerosis

International Journal of MS Care ◽

10.7224/1537-2073.2019-052 ◽

2020 ◽

Vol 22 (5) ◽

pp. 215-218

Author(s):

Foziah Alshamrani ◽

Warren Berger ◽

Hind Alnajashi ◽

Michael W.C. Payne ◽

Sarah A. Morrow

Keyword(s):

Multiple Sclerosis ◽

Walking Distance ◽

Walk Test ◽

Expanded Disability Status Scale ◽

Post Hoc Analysis ◽

Adult Participants ◽

Disability Status ◽

Relapsing Remitting ◽

Edss Score ◽

Post Hoc

Abstract Background: Expanded Disability Status Scale (EDSS) scores of 4.0 or greater are determined primarily by maximum walking distance (MWD). Estimation of MWD by persons with multiple sclerosis (MS) is often used due to the impracticality of formally walking a person with MS in a clinic setting. Previous studies have demonstrated discrepancies between estimated and actual MWDs. Whether Timed 25-Foot Walk test (T25FW) values can be used to predict MWD is currently unknown. This study aimed to determine whether T25FW time is predictive of MWD in persons with MS. Methods: This study is a post hoc analysis of a previously described prospective cohort study. Persons with MS with an EDSS score of 3.5 to 5.5 were included. The participant’s T25FW values and MWD were measured. Results: Of the 38 adult participants (mean age, 50.8 years; 27 women [71%]), 24 (63%) had relapsing-remitting MS. The median EDSS score was 4.5 (range, 3.5–5.5). The T25FW times were divided into seven categories (<5.0, 5.0–5.9, 6.0–6.9, 7.0–7.9, 8.0–8.9, 9.0–9.9, and ≥10.0 seconds). The MWDs were divided into corresponding EDSS score categories: ≥500, 300–499, 200–299, 100–199, and ≤99 m. Ordinal logistic regression, when controlled for age, found the T25FW categories to be predictive of EDSS score (χ2 = 17.630, df = 7, P = .014). Conclusions: The T25FW value may be used as a surrogate estimate of MWD. Further studies are needed to confirm the reliability of the T25FW in predicting MWD.

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Plasma neurofilament light chain concentrations as a biomarker of clinical and radiologic outcomes in relapsing multiple sclerosis: Post hoc analysis of phase 3 ozanimod trials

European Journal of Neurology ◽

10.1111/ene.15009 ◽

2021 ◽

Author(s):

Sarah Harris ◽

Giancarlo Comi ◽

Bruce A. C. Cree ◽

Douglas L. Arnold ◽

Lawrence Steinman ◽

...

Keyword(s):

Multiple Sclerosis ◽

Light Chain ◽

Phase 3 ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Post Hoc Analysis ◽

Post Hoc ◽

Relapsing Multiple Sclerosis

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Long-Term Safety and Efficacy of Subcutaneous Cladribine Used in Increased Dosage in Patients with Relapsing Multiple Sclerosis: 20-Year Observational Study

Journal of Clinical Medicine ◽

10.3390/jcm10215207 ◽

2021 ◽

Vol 10 (21) ◽

pp. 5207

Author(s):

Konrad Rejdak ◽

Adriana Zasybska ◽

Aleksandra Pietruczuk ◽

Dariusz Baranowski ◽

Sebastian Szklener ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cumulative Dose ◽

Induction Dose ◽

Disability Status ◽

Risk Of Progression ◽

Dosing Regimens ◽

Favorable Safety ◽

Relapsing Multiple Sclerosis

Cladribine is currently registered as a 10-milligram tablet formulation with a fixed cumulative dosage of 3.5 mg/kg over 2 years. It is important to investigate if an increased dosage may lead to further clinical stability with preserved safety. This study used an off-label subcutaneous (s.c.) formulation of cladribine and compared outcomes (Expanded Disability Status Scale (EDSS) scores and disease progression) between 52 relapsing multiple sclerosis (RMS) patients receiving different s.c. dosing regimens with up to 20 years of follow-up. The study group received induction therapy with s.c. cladribine (1.8 mg/kg cumulative dose; consistent with 3.5 mg/kg of cladribine tablets). Patients were subsequently offered maintenance therapy (repeated courses of 0.3 mg/kg s.c. cladribine during 5–20-year follow-up). Forty-one patients received an increased cumulative dose (higher than the induction dose of 1.8 mg/kg); 11 received the standard induction dose. Risk of progression on the EDSS correlated with lower cumulative dose (p < 0.05) and more advanced disability at treatment initiation (p < 0.05) as assessed by EDSS change between year 1 and years 5 and 10 as the last follow-up. Maintenance treatment was safe and well-tolerated, based on limited source data. Subcutaneous cladribine with increased cumulative maintenance dosage was associated with disease stability and favorable safety over a prolonged period of follow-up (up to 20 years) in RMS patients.

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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.

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Pregnancy in women with MS: Impact on long-term disability accrual in a nationwide Danish Cohort

Multiple Sclerosis Journal ◽

10.1177/13524585211057767 ◽

2021 ◽

pp. 135245852110577

Author(s):

Johanna Balslev Andersen ◽

Malthe Faurschou Wandall-Holm ◽

Per Kragh Andersen ◽

Finn Sellebjerg ◽

Melinda Magyari

Keyword(s):

Multiple Sclerosis ◽

Clinically Isolated Syndrome ◽

Time Dependent ◽

Disease Course ◽

Expanded Disability Status Scale ◽

Cox Models ◽

Disability Status ◽

Relapsing Remitting ◽

Edss Score

Background: Pregnancy is considered to influence the disease course in women with multiple sclerosis (MS). Objective: The aim of this study was to investigate the effect of pregnancy on long-term disability accrual in women with MS. Methods: The Danish Multiple Sclerosis Registry (DMSR) was used to identify women diagnosed with clinically isolated syndrome or relapsing-remitting MS. Cox models with pregnancy as a time-dependent exposure and propensity score (PS) models were used to evaluate time to reach confirmed Expanded Disability Status Scale (EDSS) score of 4 and 6. Results: A total of 425 women became parous and 840 remained nulliparous. When including pregnancy as a time-dependent exposure, a non-significant association with time to reach EDSS 4 (hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.61–1.20) and EDSS 6 (HR 0.70, 95% CI 0.40–1.20) was found. Correspondingly, the PS model showed no association with pregnancy on time to reach EDSS 4 (HR 0.85, 95% CI 0.56–1.28). Conclusion: This study concludes that pregnancy does not affect long-term disability accumulation.

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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.

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Clinical outcomes of patients with multiple sclerosis treated with ocrelizumab in a US community MS center: an observational study

BMJ Neurology Open ◽

10.1136/bmjno-2020-000108 ◽

2021 ◽

Vol 3 (2) ◽

pp. e000108

Author(s):

Kyle Smoot ◽

Chiayi Chen ◽

Tamela Stuchiner ◽

Lindsay Lucas ◽

Lois Grote ◽

...

Keyword(s):

Multiple Sclerosis ◽

Respiratory Infections ◽

Expanded Disability Status Scale ◽

Long Term Outcomes ◽

Community Based ◽

T2 Lesions ◽

Disability Status ◽

Disabled Patients ◽

Tract Infections

BackgroundTo monitor long-term outcomes of ocrelizumab treatment.ObjectiveTo evaluate safety and treatment outcomes of ocrelizumab in a community-based multiple sclerosis (MS) population.MethodsAdult patients with MS prescribed ocrelizumab were eligible. Chart reviews were conducted at the start of ocrelizumab treatment and every 6 months thereafter.ResultsOf the 355 patients enrolled, 71.9% were female; mean (SD) age was 51.8 (12.5) years; 78.3% had relapsing MS (RMS). Median baseline Expanded Disability Status Scale (EDSS) (IQR) was 3.0 (2.0–4.0) for RMS, 6.5 (6.0–7.5) for secondary progressive MS, and 6.5 (6.0–7.0) for primary progressive MS. Respiratory infections occurred in 40.1% and urinary tract infections in 33.1% of patients. There was no difference in the percentage of infections among patients <55 (68.5%, n=122), and those ≥55 of age (67.5%, n=104) (p=0.94). Twenty-five hospitalisations were due to infections; 69.2% of these patients were ≥55 with a mean EDSS of 5.7 (±1.86). Four patients have died. Serum IgM and IgG levels did not predict infection risk. Annualised relapse rate was 0.34 for the patients with RMS in the preceding 2 years and 0.09 in patients who received ≥2 ocrelizumab 600 mg courses. The first on-treatment MRI was stable in 262 (90.0%) patients, 6.9% had new T2 lesions, 2.7% had enlarging T2 lesions and 1.4% had gadolinium-enhancing lesions. Median EDSS at 12 months was unchanged.ConclusionOcrelizumab effectively controlled relapse risk and disability worsening. Although only 12.1% of patients have discontinued ocrelizumab, infections resulting in hospitalisation are a concern, especially in older and disabled patients.

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Intramuscular interferon beta-1a therapy in patients with relapsing-remitting multiple sclerosis: a 15-year follow-up study

Multiple Sclerosis Journal ◽

10.1177/1352458509360549 ◽

2010 ◽

Vol 16 (5) ◽

pp. 588-596 ◽

Cited By ~ 52

Author(s):

RA Bermel ◽

B. Weinstock-Guttman ◽

D. Bourdette ◽

P. Foulds ◽

X. You ◽

...

Keyword(s):

Multiple Sclerosis ◽

Interferon Beta ◽

Short Form ◽

Expanded Disability Status Scale ◽

Short Form 36 ◽

Disability Status ◽

Scale Scores ◽

Term Tolerability

Disease-modifying drugs are initiated early and continued for years in patients with multiple sclerosis. Long-term tolerability and impact are not known. The objective of this study was to evaluate long-term tolerability of intramuscular interferon beta-1a and effects on disability and quality of life. Patients were evaluated an average of 15 years after randomization into a placebo-controlled, double-blind trial of intramuscular interferon beta-1a for relapsing multiple sclerosis. Patient-reported Expanded Disability Status Scale, the Short Form-36, a visual analog scale of self-care independence, and a living situation questionnaire were administered. Status was ascertained in 79% (136/172) of eligible patients. Analysis focused on 122 living patients. Despite open-label, non-standardized treatment after the 2-year clinical trial, 46% ( n= 56) of the patients remained on intramuscular interferon beta-1a. Expanded Disability Status Scale scores were correlated highly with Short Form-36 subcategories and visual analog scale scores. Patients currently using intramuscular interferon beta-1a had a significantly lower mean Expanded Disability Status Scale score ( p= 0.011), less progression to Expanded Disability Status Scale milestones, significantly better scores on the physical component of the Short Form-36 ( p< 0.0001), and reported better general health and greater independence. We conclude that patients continuing to use intramuscular interferon beta-1a had less disability and better quality of life compared with patients not currently using intramuscular interferon beta-1a 15 years after randomization into a clinical trial.

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Early imaging predictors of long-term outcomes in relapse-onset multiple sclerosis

Brain ◽

10.1093/brain/awz156 ◽

2019 ◽

Vol 142 (8) ◽

pp. 2276-2287 ◽

Cited By ~ 29

Author(s):

Wallace J Brownlee ◽

Dan R Altmann ◽

Ferran Prados ◽

Katherine A Miszkiel ◽

Arman Eshaghi ◽

...

Keyword(s):

Multiple Sclerosis ◽

Spinal Cord ◽

Progressive Multiple Sclerosis ◽

Secondary Progressive Multiple Sclerosis ◽

Expanded Disability Status Scale ◽

Spinal Cord Lesions ◽

Secondary Progressive ◽

Disability Status ◽

Serial Addition

Abstract The clinical course of relapse-onset multiple sclerosis is highly variable. Demographic factors, clinical features and global brain T2 lesion load have limited value in counselling individual patients. We investigated early MRI predictors of key long-term outcomes including secondary progressive multiple sclerosis, physical disability and cognitive performance, 15 years after a clinically isolated syndrome. A cohort of patients with clinically isolated syndrome (n = 178) was prospectively recruited within 3 months of clinical disease onset and studied with MRI scans of the brain and spinal cord at study entry (baseline) and after 1 and 3 years. MRI measures at each time point included: supratentorial, infratentorial, spinal cord and gadolinium-enhancing lesion number, brain and spinal cord volumetric measures. The patients were followed-up clinically after ∼15 years to determine disease course, and disability was assessed using the Expanded Disability Status Scale, Paced Auditory Serial Addition Test and Symbol Digit Modalities Test. Multivariable logistic regression and multivariable linear regression models identified independent MRI predictors of secondary progressive multiple sclerosis and Expanded Disability Status Scale, Paced Auditory Serial Addition Test and Symbol Digit Modalities Test, respectively. After 15 years, 166 (93%) patients were assessed clinically: 119 (72%) had multiple sclerosis [94 (57%) relapsing-remitting, 25 (15%) secondary progressive], 45 (27%) remained clinically isolated syndrome and two (1%) developed other disorders. Physical disability was overall low in the multiple sclerosis patients (median Expanded Disability Status Scale 2, range 0–10); 71% were untreated. Baseline gadolinium-enhancing (odds ratio 3.16, P < 0.01) and spinal cord lesions (odds ratio 4.71, P < 0.01) were independently associated with secondary progressive multiple sclerosis at 15 years. When considering 1- and 3-year MRI variables, baseline gadolinium-enhancing lesions remained significant and new spinal cord lesions over time were associated with secondary progressive multiple sclerosis. Baseline gadolinium-enhancing (β = 1.32, P < 0.01) and spinal cord lesions (β = 1.53, P < 0.01) showed a consistent association with Expanded Disability Status Scale at 15 years. Baseline gadolinium-enhancing lesions was also associated with performance on the Paced Auditory Serial Addition Test (β = − 0.79, P < 0.01) and Symbol Digit Modalities Test (β = −0.70, P = 0.02) at 15 years. Our findings suggest that early focal inflammatory disease activity and spinal cord lesions are predictors of very long-term disease outcomes in relapse-onset multiple sclerosis. Established MRI measures, available in routine clinical practice, may be useful in counselling patients with early multiple sclerosis about long-term prognosis, and personalizing treatment plans.

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