scholarly journals Anakinra Treatment for Refractory Cerebral Autoinflammatory Responses

2021 ◽  
Author(s):  
Yoonhyuk Jang ◽  
Woo-Jin Lee ◽  
Han Sang Lee ◽  
Kon Chu ◽  
Sang Kun Lee ◽  
...  
Keyword(s):  
Granulomatosis With Polyangiitis ◽  
Therapeutic Option ◽  
Interleukin 1 ◽  
Autoimmune Encephalitis ◽  
Progressive Multiple Sclerosis ◽  
Primary Progressive Multiple Sclerosis ◽  
Modified Rankin Scale ◽  
Expanded Disability Status Scale ◽  
Disability Status ◽  
Anakinra Treatment

Abstract BackgroundRefractory cerebral autoinflammatory-autoimmune diseases are often associated with dysregulated innate immunity, which are targeted by anakinra, an interleukin-1 receptor antagonist. Here, we analyzed the therapeutic effect of anakinra in refractory cerebral autoinflammatory response (CAIR).MethodsWe analyzed single institutional patients treated with anakinra for CAIR from January 2017 to May 2021. Anakinra was sympathetically used for patients with intractable CAIR at 100 mg/day subcutaneously. A good response was defined as any improvement of the modified Rankin Scale, Clinical Assessment Scale in Autoimmune Encephalitis, or Expanded Disability Status Scale.ResultsA total of twelve patients with various diagnostic etiologies were treated with anakinra (mean age=45.1; male=7). Four patients showed good responses, and eight patients had unclear responses. Among the good responders, 75% of the patients had pathologically demonstrated CAIR. The two very good responders had primary progressive multiple sclerosis and cerebral granulomatosis with polyangiitis in each, and microglia/macrophage infiltration was prominent in their brain biopsies. No patient had a serious adverse effect.ConclusionsAnakinra may be a therapeutic option for refractory cerebral autoinflammatory diseases with microglia and macrophage infiltrations.

Differences in the progression of primary progressive multiple sclerosis in Brazilians of African descent versus white Brazilian patients

2010 ◽  
Vol 16 (5) ◽  
pp. 597-603 ◽  
Author(s):  
Claudia Cristina Ferreira Vasconcelos ◽  
Luiz Claudio Santos Thuler ◽  
Gutemberg Augusto Cruz dos Santos ◽  
Marcos Papais Alvarenga ◽  
Marina Papais Alvarenga ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
African Descent ◽  
Progressive Multiple Sclerosis ◽  
Primary Progressive Multiple Sclerosis ◽  
Expanded Disability Status Scale ◽  
Primary Progressive ◽  
Kaplan Meier ◽  
Disability Status ◽  
Multiple Sclerosis Patients ◽  
White Patients

Recent studies have suggested faster clinical progression and greater disability in multiple sclerosis patients of African descent. This study analysed the effect of ethnicity on progression and disability. Sixty-five patients with primary progressive multiple sclerosis were selected and classified as being of African descent or white. Time from onset of the disease until reaching Expanded Disability Status Scale grades 3, 6, and 8 was assessed, as well as irreversible disability (Expanded Disability Status Scale grade maintained for ≥6 months). In the African descent group, the median time to reach Expanded Disability Status Scale 3 was 1 year shorter (1 year vs 2 years, p= 0.02), and to reach Expanded Disability Status Scale 6 was 2 years shorter (3 years vs 5 years, p= 0.01) than in the group of white patients. According to the Kaplan—Meier survival curves, patients of African descent reached every disability stage faster than white patients ( p= 0.03, p = 0.04, and p = 0.03, respectively, for Expanded Disability Status Scale grades 3, 6, and 8). As in United States and European patients of African descent, the more severe and faster progression of multiple sclerosis seen in Brazilian primary progressive multiple sclerosis patients of African descent suggests a possibly greater effect of ethnicity rather than environment on the progression of multiple sclerosis.

A single-center, randomized, double-blind, placebo-controlled study of interferon beta-1b on primary progressive and transitional multiple sclerosis

2009 ◽  
Vol 15 (10) ◽  
pp. 1195-1205 ◽  
Author(s):  
X. Montalban ◽  
J. Sastre-Garriga ◽  
M. Tintoré ◽  
L. Brieva ◽  
FX Aymerich ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Beneficial Effect ◽  
Interferon Beta ◽  
Progressive Multiple Sclerosis ◽  
Neurological Deterioration ◽  
Primary Progressive Multiple Sclerosis ◽  
Expanded Disability Status Scale ◽  
Double Blind ◽  
Primary Progressive ◽  
Disability Status

Inflammation and neurodegeneration may have differential impacts on disease evolution in the different forms of multiple sclerosis. However, a beneficial effect of immunomodulatory drugs should not be ruled out in primary progressive multiple sclerosis. Our aim is to investigate the safety and efficacy of interferon beta-1b in primary progressive multiple sclerosis. We conducted a double-blind, stratified, randomized, parallel group, phase II pilot study where patients with primary progressive multiple sclerosis or ‘transitional’ forms of multiple sclerosis received interferon beta-1b at doses of 8 MIU or placebo for 24 months. The main objective of the study was to investigate the safety and tolerability of interferon beta-1b. The primary efficacy variable was the time to neurological deterioration (Expanded Disability Status Scale) confirmed at 3 months. Seventy-three patients were included and three dropped out the study. More patients in the treatment arm had at least one related adverse event (94.4% versus 45.9%; p < 0.001); no other significant differences in safety endpoints were observed. Time to neurological deterioration was not different between trial arms (log-rank test, p = 0.3135). Statistically significant differences favoring treatment were observed for the Multiple Sclerosis Functional Composite score at several timepoints, T1 and T2 lesion volume changes at 12 and 24 months, mean number of active lesions and proportion of patients with active lesions at 24 months. We conclude that interferon beta-1b is safe and well tolerated in patients with primary progressive multiple sclerosis and transitional multiple sclerosis. Positive effects of interferon beta on secondary clinical and magnetic resonance imaging outcomes were observed, but a beneficial effect on Expanded Disability Status Scale progression was not demonstrated.

scholarly journals Pilot trial of intravenous autologous culture-expanded mesenchymal stem cell transplantation in multiple sclerosis

2017 ◽  
Vol 24 (4) ◽  
pp. 501-511 ◽  
Author(s):  
Jeffrey A Cohen ◽  
Peter B Imrey ◽  
Sarah M Planchon ◽  
Robert A Bermel ◽  
Elizabeth Fisher ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Scale Score ◽  
Pilot Trial ◽  
Progressive Multiple Sclerosis ◽  
Expanded Disability Status Scale ◽  
Serious Adverse Events ◽  
Mesenchymal Stem Cell Transplantation ◽  
Disability Status ◽  
Magnetic Resonance Imaging Mri

Background: Mesenchymal stem cells (MSCs) exhibit immunomodulatory, tissue-protective, and repair-promoting properties in vitro and in animals. Clinical trials in several human conditions support the safety and efficacy of MSC transplantation. Published experience in multiple sclerosis (MS) is modest. Objective: To assess feasibility, safety, and tolerability and explore efficacy of autologous MSC transplantation in MS. Methods: Participants with relapsing-remitting multiple sclerosis (RRMS) or secondary progressive multiple sclerosis (SPMS), Expanded Disability Status Scale score 3.0–6.5, disease activity or progression in the prior 2 years, and optic nerve involvement were enrolled. Bone-marrow-derived MSCs were culture-expanded and then cryopreserved. After confirming fulfillment of release criteria, 1–2 × 106 MSCs/kg were thawed and administered IV. Results: In all, 24 of 26 screened patients were infused: 16 women and 8 men, 10 RRMS and 14 SPMS, mean age 46.5, mean Expanded Disability Status Scale score 5.2, 25% with gadolinium-enhancing magnetic resonance imaging (MRI) lesions. Mean cell dosage (requiring 1–3 passages) was 1.9 × 106 MSCs/kg (range, 1.5–2.0) with post-thaw viability uniformly ⩾95%. Cell infusion was tolerated well without treatment-related severe or serious adverse events, or evidence of disease activation. Conclusion: Autologous MSC transplantation in MS appears feasible, safe, and well tolerated. Future trials to assess efficacy more definitively are warranted.

scholarly journals Ocrelizumab reduces progression of upper extremity impairment in patients with primary progressive multiple sclerosis: Findings from the phase III randomized ORATORIO trial

2018 ◽  
Vol 24 (14) ◽  
pp. 1862-1870 ◽  
Author(s):  
Edward J Fox ◽  
Clyde Markowitz ◽  
Angela Applebee ◽  
Xavier Montalban ◽  
Jerry S Wolinsky ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Upper Extremity ◽  
Progressive Multiple Sclerosis ◽  
Phase Iii ◽  
Primary Progressive Multiple Sclerosis ◽  
Primary Progressive ◽  
Intention To Treat ◽  
Disability Status ◽  
Upper Extremity Impairment ◽  
Post Hoc

Background: Upper extremity (UE) impairment is common with primary progressive multiple sclerosis (PPMS). Objective: This exploratory analysis examined the effects of ocrelizumab on confirmed progression (CP) and confirmed improvement (CI) in UE impairment in patients from ORATORIO. Methods: Patients with PPMS received ocrelizumab 600 mg or placebo every 24 weeks for ⩾120 weeks. The Nine-Hole Peg Test (9HPT) was administered at baseline (BL) and every 12 weeks thereafter. Prespecified exploratory endpoints included change in 9HPT time and proportion of patients with CP of ⩾20% in 9HPT. Analysis populations included intention-to-treat (ITT) patients and subgroups stratified by BL 9HPT time and Expanded Disability Status Scale. Post hoc analyses included the proportion of patients achieving more severe thresholds of CP and the proportion achieving CI in 9HPT. Results: Among ITT patients, ocrelizumab significantly reduced the change in 9HPT time over 120 weeks, the risk of CP of ⩾20% in 9HPT time for both hands and the risk of more severe 9HPT progression versus placebo. Numerical trends also favoured ocrelizumab versus placebo with respect to achieving CI. Consistent directional trends were observed in subgroup analyses. Conclusion: Ocrelizumab reduces the risk of UE disability progression and may increase the possibility of improvement versus placebo in PPMS.

Urinary neopterin and nitric oxide metabolites as markers of interferon β-1a activity in primary progressive multiple sclerosis

2010 ◽  
Vol 16 (9) ◽  
pp. 1066-1072 ◽  
Author(s):  
K. Rejdak ◽  
SM Leary ◽  
A. Petzold ◽  
AJ Thompson ◽  
DH Miller ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Multiple Sclerosis ◽  
Progressive Multiple Sclerosis ◽  
Primary Progressive Multiple Sclerosis ◽  
Interferon Β ◽  
Primary Progressive ◽  
Significant Difference ◽  
Disability Status ◽  
Urinary Neopterin ◽  
Nitric Oxide Metabolites

Background: Interferon beta has not been demonstrated to be effective in exploratory phase 2 clinical trials in primary progressive multiple sclerosis. However, using more sensitive indicators of a treatment response, such as biomarkers, might help to identify sub-groups of patients who may benefit from therapy. Objective: To assess the utility of measuring urinary neopterin and nitric oxide metabolite excretion for monitoring interferon β-1a (IFNβ-1a) treatment in patients with primary progressive multiple sclerosis. Methods: Fifty patients from a phase II trial of IFNβ-1a (Placebo n = 20; Avonex® 1 × 30 μg/week (IFN-30), n = 15; Avonex® 1 × 60 μg/week (IFN-60), n = 15), were enrolled. Patients were assessed using the Expanded Disability Status Scale. Urine samples were collected on each visit, 3 months apart, for a period of 24 months. Nitric oxide metabolites, nitrite/nitrate (NOx), were measured by colorimetric assay and neopterin and creatinine (Cr) were assayed using a high-performance liquid chromatography technique. NOx/creatinine ratio (NOxCR) and urinary neopterin/creatinine ratio (UNCR) quotients were calculated. Results: There was no significant difference between pre-dose, baseline levels of UNCR or NOxCR between the study groups. On the intention-to-treat analysis, there was a significant difference in UNCR levels between the placebo compared with IFN-30 ( p = 0.03) or IFN-60 ( p = 0.002) groups. The IFN-30 and IFN-60 groups did not differ. Within IFNβ-1a-treated patients with primary progressive multiple sclerosis, median UNCR values were significantly higher in clinically stable (no Expanded Disability Status Scale change) compared with progressive patients ( p = 0.002). IFNβ-1a treatment did not significantly influence NOx excretion in patients with primary progressive multiple sclerosis. Conclusions: Urinary neopterin is a potential biomarker to monitor the in vivo effects of IFNβ-1a in primary progressive multiple sclerosis and other multiple sclerosis sub-types.

Clinical follow-up of 304 patients with multiple sclerosis three years after mitoxantrone treatment

2007 ◽  
Vol 13 (5) ◽  
pp. 626-631 ◽  
Author(s):  
M. Debouverie ◽  
L. Taillandier ◽  
S. Pittion-Vouyovitch ◽  
S. Louis ◽  
H. Vespignani
Keyword(s):  
Multiple Sclerosis ◽  
Interferon Beta ◽  
Progressive Multiple Sclerosis ◽  
Expanded Disability Status Scale ◽  
Disability Status ◽  
Relapsing Remitting ◽  
Before And After ◽  
The Mean ◽  
Disease Modifying Treatment

The objectives of this study were to assess the benefits of 1) mitoxantrone after three years of follow-up and 2) disease-modifying treatment (DMT) after stopping mitoxantrone. A retrospective analysis was performed on 304 patients with active relapsing-remitting (RR) or progressive multiple sclerosis (PMS) who were treated with mitoxantrone. After mitoxantrone therapy, some patients received DMT (interferon-beta or glatiramer acetate) while others did not. The disease course of the two groups was evaluated by the Expanded Disability Status Scale (EDSS) before and after mitoxantrone and then every year for three years. The mean EDSS score at starting mitoxantrone and three years after stopping mitoxantrone respectively, were: 3.3 (1.3) and 3.2 (1.7) for the RRMS patients and 5.9 (1.2) and 6.4 (1.4) for the PMS patients. Before starting mitoxantrone, demographic and clinical parameters of predictive disability were not significantly different between patients who received DMT or not. The variation of EDSS between time of stopping mitoxantrone and three years later was significantly different (+0.9 versus +0.3; P=0.03) for patients with RRMS. We found that mitoxantrone treatment induces stable disease up to two years after discontinuation of mitoxantrone therapy. In the third year, patients without DMT deteriorated. Multiple Sclerosis 2007; 13: 626-631. http://msj.sagepub.com

TP1-11 MS-STAT2: a phase 3 trial of high dose simvastatin in secondary progressive multiple sclerosis

2019 ◽  
Vol 90 (3) ◽  
pp. e13.1-e13 ◽  
Author(s):  
E Williams ◽  
NA John ◽  
J Blackstone ◽  
W Brownlee ◽  
C Frost ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Unmet Need ◽  
Progressive Multiple Sclerosis ◽  
Secondary Progressive Multiple Sclerosis ◽  
High Dose ◽  
List Type ◽  
Expanded Disability Status Scale ◽  
Phase 3 ◽  
Secondary Progressive ◽  
Disability Status

ObjectivesDisease modifying treatment for secondary progressive multiple sclerosis (SPMS) represents a major unmet need. We outline here the rationale for the MS-STAT2 trial – a phase 3 study of simvastatin in decreasing clinical progression in SPMS. MS-STAT2 will be a landmark study not only for patients with SPMS, but also for the area of drug repurposing and academically led clinical trials as a whole.DesignMulticentre, double blind, parallel group randomised placebo-controlled trial. It follows the positive outcome from the phase 2 MS-STAT1 trial, which demonstrated a 43% reduction in the annualised rate of brain atrophy compared to placebo.1Subjects1180 patients with SPMS with an expanded disability status scale (EDSS) score of 4.0–6.5. Patients need to show evidence of disease progression over the preceding 2 years.MethodsSubject will be recruited at 28 sites across the UK, and randomised to simvastatin 80 mg or matched placebo and assessed every 6 months over the 3 year trial.ResultsThe primary outcome measure is time to 6 month confirmed disability progression, based on change in Expanded Disability Status Scale (EDSS) scores compared to baseline. Secondary outcomes include assessments of cognition, walking, upper limb function and vision. Sub-studies will include advanced imaging outcomes, ocular coherence tomography and fluid biomarkers.ConclusionsMS-STAT2 is set to be a pivotal trial for SPMS. Recruitment has now commenced and further sites are welcome.ReferenceChataway J, et al. MS-STAT. Lancet2014;383:2213–21.

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

Brain ◽  
2019 ◽  
Vol 142 (8) ◽  
pp. 2276-2287 ◽  
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.

scholarly journals Real-World Results of Ocrelizumab Treatment for Primary Progressive Multiple Sclerosis

2020 ◽  
Vol 2020 ◽  
pp. 1-6 ◽  
Author(s):  
K. Daniels ◽  
P. B. van der Nat ◽  
S. T. F. M. Frequin ◽  
P. J. van der Wees ◽  
D. H. Biesma ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Real World ◽  
Primary Outcome ◽  
Clinical Effectiveness ◽  
Progressive Multiple Sclerosis ◽  
Primary Progressive Multiple Sclerosis ◽  
Real World Data ◽  
Primary Progressive ◽  
Disability Status ◽  
Pre Treatment

Background. Recently, ocrelizumab (Ocrevus®) was approved for the treatment of primary progressive multiple sclerosis (PPMS) based on data from the ORATORIO clinical trial. Real-world data about the clinical effectiveness of ocrelizumab has yet to be gathered. Objective. The aim of this study was to provide data about the clinical effectiveness of ocrelizumab for patients diagnosed with PPMS in a real-world setting. Methods. We conducted a retrospective cohort study of all patients with PPMS who started ocrelizumab treatment (n=21) in St. Antonius Hospital (Utrecht/Nieuwegein, the Netherlands) between April 2018 and December 31, 2018. Primary outcome was pre- versus post-ocrelizumab disability worsening rate (from 96 weeks prior to first ocrelizumab administration up to 24 weeks post first ocrelizumab administration). Results. Disability worsening rate while on treatment significantly differed (lower) from disability worsening rate in pre-treatment period (Z=−2.81, p≤.01). Three out of 17 patients showed a clinically relevant improvement in disability status after treatment start. Conclusion. Ocrelizumab can stabilize disability progression in patients with PPMS. Some patients even showed a clinically relevant improvement in disability status. Further research should help to identify which patients benefit most from ocrelizumab.

scholarly journals Reproductive history and progressive multiple sclerosis risk in women

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Burcu Zeydan ◽  
Elizabeth J Atkinson ◽  
Delana M Weis ◽  
Carin Y Smith ◽  
Liliana Gazzuola Rocca ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Standard Deviation ◽  
Progressive Multiple Sclerosis ◽  
Reproductive Period ◽  
Dose Effect ◽  
Expanded Disability Status Scale ◽  
Early Menopause ◽  
Natural Menopause ◽  
Disability Status ◽  
Relapsing Remitting

Abstract Being a woman is one of the strongest risk factors for multiple sclerosis. The natural reproductive period from menarche to natural menopause corresponds to the active inflammatory disease period in multiple sclerosis. The fifth decade marks both the peri-menopausal transition in the reproductive aging and a transition from the relapsing-remitting to the progressive phase in multiple sclerosis. A short reproductive period with premature/early menopause and/or low number of pregnancies may be associated with an earlier onset of the progressive multiple sclerosis phase. A cross-sectional study of survey-based reproductive history in a multiple sclerosis clinical series enriched for patients with progressive disease, and a case–control study of multiple sclerosis and age/sex matched controls from a population-based cohort were conducted. Menarche age, number of complete/incomplete pregnancies, menopause type and menopause age were compared between 137 cases and 396 control females. Onset of relapsing-remitting phase of multiple sclerosis, progressive disease onset and reaching severe disability (expanded disability status scale 6) were studied as multiple sclerosis-related outcomes (n = 233). Menarche age was similar between multiple sclerosis and control females (P = 0.306). Females with multiple sclerosis had fewer full-term pregnancies than the controls (P &lt; 0.001). Non-natural menopause was more common in multiple sclerosis (40.7%) than in controls (30.1%) (P = 0.030). Age at natural menopause was similar between multiple sclerosis (median, interquartile range: 50 years, 48–52) and controls (median, interquartile range: 51 years, 49–53) (P = 0.476). Nulliparous females had earlier age at progressive multiple sclerosis onset (mean ± standard deviation: 41.9 ± 12.5 years) than females with ≥1 full-term pregnancies (mean ± standard deviation: 47.1 ± 9.7 years) (P = 0.069) with a pregnancy-dose effect [para 0 (mean ± standard deviation: 41.9 ± 12.5 years), para 1–3 (mean ± standard deviation: 46.4 ± 9.2 years), para ≥4 (mean ± standard deviation: 52.6 ± 12.9 years) (P = 0.005)]. Menopause age was associated with progressive multiple sclerosis onset age (R2 = 0.359, P &lt; 0.001). Duration from onset of relapses to onset of progressive multiple sclerosis was shorter for females with premature/early menopause (n = 26; mean ± standard deviation: 12.9 ± 9.0 years) than for females with normal menopause age (n = 39; mean ± standard deviation: 17.8 ± 10.3 years) but was longer than for males (mean  ±standard deviation: 10.0 ± 9.4 years) (P = 0.005). There was a pregnancy-dose effect of age at expanded disability status scale 6 (para 0: 43.0 ± 13.2 years, para 1–3: 51.7 ± 11.3 years, para ≥4: 53.5 ± 4.9 years) (P = 0.013). Age at menopause was associated with age at expanded disability status scale 6 (R2 = 0.229, P &lt; 0.003). Premature/early menopause or nulliparity was associated with earlier onset of progressive multiple sclerosis with a ‘dose effect’ of pregnancies on delaying progressive multiple sclerosis and severe disability. Although causality remains uncertain, our results suggest a beneficial impact of oestrogen in delaying progressive multiple sclerosis. If confirmed in prospective studies, our findings have implications for counselling women with multiple sclerosis about pregnancy, surgical menopause and menopausal hormone therapy.

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