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Pamela McCombe

The University of Queensland, Australia, UQCCR, Faculty Member

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Cristina Ramo-Tello

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University of Melbourne

Bakirkoy Research & Training Hospital for Psychiatry, Neurology and Neurosurgery

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Papers by Pamela McCombe

008 Disease reactivation after cessation of disease-modifying therapy in relapsing-remitting multiple sclerosis

Oral abstracts

compared to 1/14 LGI1-Ab+patients(p=0.0024) and 1/12 healthy controls. Conclusion Neuropathic pai... more compared to 1/14 LGI1-Ab+patients(p=0.0024) and 1/12 healthy controls. Conclusion Neuropathic pain may be present in both LGI-Ab + and CASPR2-Ab+patients, and is immunotherapy responsive. Serum IgG from CASPR2-Ab+patients more frequently bound sensory neurons and dorsal root ganglia, suggesting pathophysiological differences which may underlie the more severe pain in these patients.

Variability of the response to immunotherapy among subgroups of patients with multiple sclerosis

European Journal of Neurology

MSJ868990_online_supplement – Supplemental material for Risk of secondary progressive multiple sclerosis: A longitudinal study

Supplemental material, MSJ868990_online_supplement for Risk of secondary progressive multiple scl... more Supplemental material, MSJ868990_online_supplement for Risk of secondary progressive multiple sclerosis: A longitudinal study by Adam Fambiatos, Vilija Jokubaitis, Dana Horakova, Eva Kubala Havrdova, Maria Trojano, Alexandre Prat, Marc Girard, Pierre Duquette, Alessandra Lugaresi, Guillermo Izquierdo, Francois Grand'Maison, Pierre Grammond, Patrizia Sola, Diana Ferraro, Raed Alroughani, Murat Terzi, Raymond Hupperts, Cavit Boz, Jeannette Lechner-Scott, Eugenio Pucci, Roberto Bergamaschi, Vincent Van Pesch, Serkan Ozakbas, Franco Granella, Recai Turkoglu, Gerardo Iuliano, Daniele Spitaleri, Pamela McCombe, Claudio Solaro, Mark Slee, Radek Ampapa, Aysun Soysal, Thor Petersen, Jose Luis Sanchez-Menoyo, Freek Verheul, Julie Prevost, Youssef Sidhom, Bart Van Wijmeersch, Steve Vucic, Edgardo Cristiano, Maria Laura Saladino, Norma Deri, Michael Barnett, Javier Olascoaga, Fraser Moore, Olga Skibina, Orla Gray, Yara Fragoso, Bassem Yamout, Cameron Shaw, Bhim Singhal, Neil Shuey, Suzanne ...

MSJ936823_supplement – Supplemental material for Prediction of on-treatment disability worsening in RRMS with the MAGNIMS score

Supplemental material, MSJ936823_supplement for Prediction of on-treatment disability worsening i... more Supplemental material, MSJ936823_supplement for Prediction of on-treatment disability worsening in RRMS with the MAGNIMS score by Amy Kunchok, Jeannette Lechner-Scott, Franco Granella, Maria Trojano, Raed Alroughani, Patrizia Sola, Diana Ferraro, Alessandra Lugaresi, Marco Onofrj, Serkan Ozakbas, Guillermo Izquierdo, Pierre Grammond, Jose Luis Sanchez-Menoyo, Bart Van Wijmeersch, Cavit Boz, Eugenio Pucci, Pamela McCombe, Francois Grand'Maison, Daniele Spitaleri, Steve Vucic, Raymond Hupperts, Vilija Jokubaitis, Maria Pia Sormani, Helmut Butzkueven and Tomas Kalincik in Multiple Sclerosis Journal

004 Pregnancy-related relapse in natalizumab, fingolimod and dimethyl fumarate-treated women with multiple sclerosis

Oral abstracts, 2021

IgG (CSF) and 78% of GAD65-IgG (CSF/serum) cohorts (OR=1.32, p=0.002, OR=2.78, p<0.001, respectiv... more IgG (CSF) and 78% of GAD65-IgG (CSF/serum) cohorts (OR=1.32, p=0.002, OR=2.78, p<0.001, respectively). Men accounted for 62% of the LGI1-IgG cohort (OR=1.87, p <0.001). Age and sex interacted for NMDA-R-IgG, particularly in females <20 years (OR=7.72, p <0.001). Conclusion The most frequently detected were NMDA-R-IgG, LGI1-IgG, GAD65-IgG and MOG-IgG1. Age and sex associations may suggest paraneoplastic, endocrinological or aging influences on neurological autoimmunity.

The effectiveness of natalizumab vs fingolimod–A comparison of international registry studies

Multiple Sclerosis and Related Disorders, 2021

Background Natalizumab and fingolimod were the first preparations recommended for disease breakth... more Background Natalizumab and fingolimod were the first preparations recommended for disease breakthrough in priorly treated relapsing-remitting multiple sclerosis. Of three published head-to-head studies two showed that natalizumab is the more effective to prevent relapses and EDSS worsening. Methods By re-analyzing original published results from MSBase, France, and Denmark using uniform methodologies, we aimed at identifying the effects of differences in methodology, in the MSpopulations, and at re-evaluating the differences in effectiveness between the two drugs. We gained access to copies of the individual amended databases and pooled all data. We used uniform inclusion/exclusion criteria and statistical methods with Inverse Probability Treatment Weighting. Results The pooled analyses comprised 968 natalizumab-and 1479 fingolimod treated patients. The ontreatment natalizumab/fingolimod relapse rate ratio was 0.77 (p=0.004). The hazard ratio (HR) for a first relapse was 0.82 (p=0.030), and the HR for sustained EDSS improvement was 1.4 (p=0.009). There were modest differences between each of the original published studies and the replication study, but the conclusions of the three original studies remained unchanged: in two of them natalizumab was more effective, but in the third there was no difference between natalizumab and fingolimod. Conclusion The results were largely invariant to the epidemiological and statistical methods but differed between the MS populations. Generally, the advantage of natalizumab was confirmed.

Cladribine: a multicentre, LOng-term efficacy Biomarker Australian Study (CLOBAS). A six- Otherwise we list them as CLOBAS investigators year, real-world study of multiple sclerosis patients (Preprint)

BACKGROUND Background: Cladribine tablets (marketed as Mavenclad®) is a new oral therapy, which h... more BACKGROUND Background: Cladribine tablets (marketed as Mavenclad®) is a new oral therapy, which has recently been listed on the pharmaceuticals benefit scheme (PBS) in Australia for treatment of relapsing MS. The current dosing schedule is for 2 courses given a year apart, which has been shown to be effective for treatment of MS up to 4 years in 75% of patients (based on annualised relapse rate). However, re-initiation of therapy after year 4 has not been studied. OBJECTIVE Objective: The Objective of this study is to METHODS Methods: This will be a multicentre, 6-year, phase IV, low interventional observational study that incorporates clinical, haematological, biochemical, epigenetic, and radiological and cognitive biomarkers of disease. Subjects considered for treatment with cladribine as part of their routine clinical care, will be consented to take part in the study. They will be monitored at regular intervals during the initial course of medication administration in year 1 and ...

Determinants of therapeutic lag in multiple sclerosis

Multiple Sclerosis Journal, 2021

Background: A delayed onset of treatment effect, termed therapeutic lag, may influence the assess... more 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 ...

Delay from treatment start to full effect of immunotherapies for multiple sclerosis

Brain, 2020

In multiple sclerosis, treatment start or switch is prompted by evidence of disease activity. Whi... more In multiple sclerosis, treatment start or switch is prompted by evidence of disease activity. Whilst immunomodulatory therapies reduce disease activity, the time required to attain maximal effect is unclear. In this study we aimed to develop a method that allows identification of the time to manifest fully and clinically the effect of multiple sclerosis treatments (‘therapeutic lag’) on clinical disease activity represented by relapses and progression-of-disability events. Data from two multiple sclerosis registries, MSBase (multinational) and OFSEP (French), were used. Patients diagnosed with multiple sclerosis, minimum 1-year exposure to treatment, minimum 3-year pretreatment follow-up and yearly review were included in the analysis. For analysis of disability progression, all events in the subsequent 5-year period were included. Density curves, representing incidence of relapses and 6-month confirmed progression events, were separately constructed for each sufficiently represente...

Prediction of on-treatment disability worsening in RRMS with the MAGNIMS score

Multiple Sclerosis Journal, 2020

Background: The magnetic resonance imaging in multiple sclerosis (MAGNIMS) score combines relapse... more Background: The magnetic resonance imaging in multiple sclerosis (MAGNIMS) score combines relapses and magnetic resonance imaging (MRI) lesions to predict disability outcomes in relapsing–remitting multiple sclerosis (RRMS) treated with interferon-β. Objective: To validate the MAGNIMS score and extend to other disease-modifying therapies (DMTs). To examine the prognostic value of gadolinium contrast-enhancing (Gd+) lesions. Methods: This RRMS MSBase cohort study ( n = 2293) used a Cox model to examine the prognostic value of relapses, MRI activity and the MAGNIMS score for disability worsening during treatment with interferon-β and three other DMTs. Results: Three new T2 lesions (hazard ratio (HR) = 1.60, p = 0.028) or two relapses (HR = 2.24, p = 0.002) on interferon-β (for 12 months) were predictive of disability worsening over 4 years. MAGNIMS score = 2 (1 relapse and ⩾3 T2 lesions or ⩾2 relapses) was associated with a greater risk of disability worsening on interferon-β (HR = 2....

Clinical and therapeutic predictors of disease outcomes in AQP4-IgG+ neuromyelitis optica spectrum disorder

Multiple Sclerosis and Related Disorders, 2019

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Risk of secondary progressive multiple sclerosis: A longitudinal study

Multiple Sclerosis Journal, 2019

Background: The risk factors for conversion from relapsing-remitting to secondary progressive mul... more Background: The risk factors for conversion from relapsing-remitting to secondary progressive multiple sclerosis remain highly contested. Objective: The aim of this study was to determine the demographic, clinical and paraclinical features that influence the risk of conversion to secondary progressive multiple sclerosis. Methods: Patients with adult-onset relapsing–remitting multiple sclerosis and at least four recorded disability scores were selected from MSBase, a global observational cohort. The risk of conversion to objectively defined secondary progressive multiple sclerosis was evaluated at multiple time points per patient using multivariable marginal Cox regression models. Sensitivity analyses were performed. Results: A total of 15,717 patients were included in the primary analysis. Older age (hazard ratio (HR) = 1.02, p < 0.001), longer disease duration (HR = 1.01, p = 0.038), a higher Expanded Disability Status Scale score (HR = 1.30, p < 0.001), more rapid disability...

002 Therapeutic lag in relapsing multiple sclerosis

Journal of Neurology, Neurosurgery & Psychiatry, 2019

IntroductionIn multiple sclerosis (MS), treatment start or switch is prompted disease activity, o... more IntroductionIn multiple sclerosis (MS), treatment start or switch is prompted disease activity, often represented by relapses. Immunomodulatory therapies have potent effects on relapse rates but the time required to attain maximal effect is unclear. We aim to develop a method that allows identification of the time to full clinically manifest effect of treatment on relapses.MethodsData from MSBase, a multinational MS registry, were used. Inclusion criteria consisted of patients with remitting relapsing MS or clinically isolated syndrome (CIS), minimum 3-year pre-treatment follow up, 1-year treatment persistence, yearly review and availability of the minimum dataset. Stratified by therapy, density curves representing relapses occurrence were created. The first local minimum of the first derivative after treatment start was identified, representing stabilisation of treatment effect. Similar method was utilised to calculate the last pre-treatment point of stabilisation. Annualised relap...

Association of Initial Disease-Modifying Therapy With Later Conversion to Secondary Progressive Multiple Sclerosis

JAMA, 2019

; for the MSBase Study Group IMPORTANCE Within 2 decades of onset, 80% of untreated patients with... more ; for the MSBase Study Group IMPORTANCE Within 2 decades of onset, 80% of untreated patients with relapsing-remitting multiple sclerosis (MS) convert to a phase of irreversible disability accrual termed secondary progressive MS. The association between disease-modifying treatments (DMTs), and this conversion has rarely been studied and never using a validated definition. OBJECTIVE To determine the association between the use, the type of, and the timing of DMTs with the risk of conversion to secondary progressive MS diagnosed with a validated definition. DESIGN, SETTING, AND PARTICIPANTS Cohort study with prospective data from 68 neurology centers in 21 countries examining patients with relapsing-remitting MS commencing DMTs (or clinical monitoring) between 1988-2012 with minimum 4 years' follow-up. EXPOSURES The use, type, and timing of the following DMTs: interferon beta, glatiramer acetate, fingolimod, natalizumab, or alemtuzumab. After propensity-score matching, 1555 patients were included (last follow-up, February 14, 2017). MAIN OUTCOME AND MEASURE Conversion to objectively defined secondary progressive MS. RESULTS Of the 1555 patients, 1123 were female (mean baseline age, 35 years [SD, 10]). Patients initially treated with glatiramer acetate or interferon beta had a lower hazard of conversion to secondary progressive MS than matched untreated patients (HR, 0.71; 95% CI, 0.61-0.81; P < .001; 5-year absolute risk, 12% [49 of 407] vs 27% [58 of 213]; median follow-up, 7.6 years [IQR, 5.8-9.6]), as did fingolimod (HR, 0.37; 95% CI, 0.22-0.62; P < .001; 5-year absolute risk, 7% [6 of 85] vs 32% [56 of 174]; median follow-up, 4.5 years [IQR, 4.3-5.1]); natalizumab (HR, 0.61; 95% CI, 0.43-0.86; P = .005; 5-year absolute risk, 19% [16 of 82] vs 38% [62 of 164]; median follow-up, 4.9 years [IQR, 4.4-5.8]); and alemtuzumab (HR, 0.52; 95% CI, 0.32-0.85; P = .009; 5-year absolute risk, 10% [4 of 44] vs 25% [23 of 92]; median follow-up, 7.4 years [IQR, 6.0-8.6]). Initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion than initial treatment with glatiramer acetate or interferon beta (HR, 0.66; 95% CI, 0.44-0.99; P = .046); 5-year absolute risk, 7% [16 of 235] vs 12% [46 of 380]; median follow-up, 5.8 years [IQR, 4.7-8.0]). The probability of conversion was lower when glatiramer acetate or interferon beta was started within 5 years of disease onset vs later (HR, 0.77; 95% CI, 0.61-0.98; P = .03; 5-year absolute risk, 3% [4 of 120] vs 6% [2 of 38]; median follow-up, 13.4 years [IQR, 11-18.1]). When glatiramer acetate or interferon beta were escalated to fingolimod, alemtuzumab, or natalizumab within 5 years vs later, the HR was 0.76 (95% CI, 0.66-0.88; P < .001; 5-year absolute risk, 8% [25 of 307] vs 14% [46 of 331], median follow-up, 5.3 years [IQR], 4.6-6.1). CONCLUSIONS AND RELEVANCE Among patients with relapsing-remitting MS, initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion to secondary progressive MS vs initial treatment with glatiramer acetate or interferon beta. These findings, considered along with these therapies' risks, may help inform decisions about DMT selection.

Incidence of pregnancy and disease-modifying therapy exposure trends in women with multiple sclerosis: A contemporary cohort study

Multiple Sclerosis and Related Disorders, 2019

Highlights  We performed a retrospective study of women with relapsing-remitting MS  There was ... more Highlights  We performed a retrospective study of women with relapsing-remitting MS  There was a low pregnancy incidence rate over the last twelve years  An increasing number of pregnancies were conceived on treatment over this time  Treatment exposure during pregnancy was short, with a median of 30 days

Cladribine versus fingolimod, natalizumab and interferon β for multiple sclerosis

Multiple Sclerosis Journal, 2017

Objective: This propensity score–matched analysis from MSBase compared the effectiveness of cladr... more Objective: This propensity score–matched analysis from MSBase compared the effectiveness of cladribine with interferon β, fingolimod or natalizumab. Methods: We identified all patients with relapse-onset multiple sclerosis, exposure to the study therapies and ⩾1-year on-treatment follow-up from MSBase. Three pairwise propensity score–matched analyses compared treatment outcomes over 1 year. The outcomes were hazards of first relapse, disability accumulation and disability improvement events. Sensitivity analyses were completed. Results: The cohorts consisted of 37 (cladribine), 1940 (interferon), 1892 (fingolimod) and 1410 patients (natalizumab). The probability of experiencing a relapse on cladribine was lower than on interferon ( p = 0.05), similar to fingolimod ( p = 0.31) and higher than on natalizumab ( p = 0.042). The probability of disability accumulation on cladribine was similar to interferon ( p = 0.37) and fingolimod ( p = 0.089) but greater than natalizumab ( p = 0.021)....

Towards personalized therapy for multiple sclerosis: prediction of individual treatment response

Brain, 2017

,6,44 on behalf of the MSBase Study Group Timely initiation of effective therapy is crucial for p... more ,6,44 on behalf of the MSBase Study Group Timely initiation of effective therapy is crucial for preventing disability in multiple sclerosis; however, treatment response varies greatly among patients. Comprehensive predictive models of individual treatment response are lacking. Our aims were: (i) to develop predictive algorithms for individual treatment response using demographic, clinical and paraclinical predictors in patients with multiple sclerosis; and (ii) to evaluate accuracy, and internal and external validity of these algorithms. This study evaluated 27 demographic, clinical and paraclinical predictors of individual response to seven disease-modifying therapies in MSBase, a large global cohort study. Treatment response was analysed separately for disability progression, disability regression, relapse frequency, conversion to secondary progressive disease, change in the cumulative disease burden, and the probability of treatment discontinuation. Multivariable survival and generalized linear models were used, together with the principal component analysis to reduce model dimensionality and prevent overparameterization. Accuracy of the individual prediction was tested and its internal validity was evaluated in a separate, non-overlapping cohort. External validity was evaluated in a geographically distinct cohort, the Swedish Multiple Sclerosis Registry. In the training cohort (n = 8513), the most prominent modifiers of treatment response comprised age, disease duration, disease course, previous relapse activity, disability, predominant relapse phenotype and previous therapy. Importantly, the magnitude and direction of the associations varied among therapies and disease outcomes. Higher probability of disability progression during treatment with injectable therapies was predominantly associated with a greater disability at treatment start and the previous therapy. For fingolimod, natalizumab or mitoxantrone, it was mainly associated with lower pretreatment relapse activity. The probability of disability regression was predominantly associated with pre-baseline disability, therapy and relapse activity. Relapse incidence was associated with pretreatment relapse activity, age and relapsing disease course, with the strength of these associations varying among therapies. Accuracy and internal validity (n = 1196) of the resulting predictive models was high (480%) for relapse incidence during the first year and for disability outcomes, moderate for relapse incidence in Years 2-4 and for the change in the cumulative disease burden, and low for conversion to secondary progressive disease and treatment discontinuation. External validation showed similar results, demonstrating high external validity for disability and relapse outcomes, moderate external validity for cumulative disease burden and low external validity for conversion to

Incidence and prevalence of NMOSD in Australia and New Zealand

Journal of neurology, neurosurgery, and psychiatry, Aug 26, 2017

We have undertaken a clinic-based survey of neuromyelitis optica spectrum disorders (NMOSDs) in A... more We have undertaken a clinic-based survey of neuromyelitis optica spectrum disorders (NMOSDs) in Australia and New Zealand to establish incidence and prevalence across the region and in populations of differing ancestry. NMOSD is a recently defined demyelinating disease of the central nervous system (CNS). The incidence and prevalence of NMOSD in Australia and New Zealand has not been established. Centres managing patients with demyelinating disease of the CNS across Australia and New Zealand reported patients with clinical and laboratory features that were suspicious for NMOSD. Testing for aquaporin 4 antibodies was undertaken in all suspected cases. From this group, cases were identified who fulfilled the 2015 Wingerchuk diagnostic criteria for NMOSD. A capture-recapture methodology was used to estimate incidence and prevalence, based on additional laboratory identified cases. NMOSD was confirmed in 81/170 (48%) cases referred. Capture-recapture analysis gave an adjusted incidence ...

Treatment effectiveness of alemtuzumab compared with natalizumab, fingolimod, and interferon beta in relapsing-remitting multiple sclerosis: a cohort study

The Lancet. Neurology, Apr 10, 2017

Alemtuzumab, an anti-CD52 antibody, is proven to be more efficacious than interferon beta-1a in t... more Alemtuzumab, an anti-CD52 antibody, is proven to be more efficacious than interferon beta-1a in the treatment of relapsing-remitting multiple sclerosis, but its efficacy relative to more potent immunotherapies is unknown. We compared the effectiveness of alemtuzumab with natalizumab, fingolimod, and interferon beta in patients with relapsing-remitting multiple sclerosis treated for up to 5 years. In this international cohort study, we used data from propensity-matched patients with relapsing-remitting multiple sclerosis from the MSBase and six other cohorts. Longitudinal clinical data were obtained from 71 MSBase centres in 21 countries and from six non-MSBase centres in the UK and Germany between Nov 1, 2015, and June 30, 2016. Key inclusion criteria were a diagnosis of definite relapsing-remitting multiple sclerosis, exposure to one of the study therapies (alemtuzumab, interferon beta, fingolimod, or natalizumab), age 65 years or younger, Expanded Disability Status Scale (EDSS) sc...

Higher latitude is significantly associated with an earlier age of disease onset in multiple sclerosis

Journal of neurology, neurosurgery, and psychiatry, Jan 3, 2016

Age at onset (AAO) in multiple sclerosis (MS) is an important marker of disease severity and may ... more Age at onset (AAO) in multiple sclerosis (MS) is an important marker of disease severity and may have prognostic significance. Understanding what factors can influence AAO may shed light on the aetiology of this complex disease, and have applications in the diagnostic process. The study cohort of 22 162 eligible patients from 21 countries was extracted from the MSBase registry. Only patients with MS aged ≥16 years were included. To reduce heterogeneity, only centres of largely European descent were included for analysis. AAO was defined as the year of the first symptom suggestive of inflammatory central nervous system demyelination. Predictors of AAO were evaluated by linear regression. Compared with those living in lower latitudes (19.0-39.9°), onset of symptoms was 1.9 years earlier for those at higher latitudes (50.0-56.0°) (p=3.83×10(-23)). A reciprocal relationship was seen for ambient ultraviolet radiation (UVR), with a significantly increasing AAO for patients with MS per eac...

008 Disease reactivation after cessation of disease-modifying therapy in relapsing-remitting multiple sclerosis

Oral abstracts

compared to 1/14 LGI1-Ab+patients(p=0.0024) and 1/12 healthy controls. Conclusion Neuropathic pai... more compared to 1/14 LGI1-Ab+patients(p=0.0024) and 1/12 healthy controls. Conclusion Neuropathic pain may be present in both LGI-Ab + and CASPR2-Ab+patients, and is immunotherapy responsive. Serum IgG from CASPR2-Ab+patients more frequently bound sensory neurons and dorsal root ganglia, suggesting pathophysiological differences which may underlie the more severe pain in these patients.

Variability of the response to immunotherapy among subgroups of patients with multiple sclerosis

European Journal of Neurology

MSJ868990_online_supplement – Supplemental material for Risk of secondary progressive multiple sclerosis: A longitudinal study

Supplemental material, MSJ868990_online_supplement for Risk of secondary progressive multiple scl... more Supplemental material, MSJ868990_online_supplement for Risk of secondary progressive multiple sclerosis: A longitudinal study by Adam Fambiatos, Vilija Jokubaitis, Dana Horakova, Eva Kubala Havrdova, Maria Trojano, Alexandre Prat, Marc Girard, Pierre Duquette, Alessandra Lugaresi, Guillermo Izquierdo, Francois Grand'Maison, Pierre Grammond, Patrizia Sola, Diana Ferraro, Raed Alroughani, Murat Terzi, Raymond Hupperts, Cavit Boz, Jeannette Lechner-Scott, Eugenio Pucci, Roberto Bergamaschi, Vincent Van Pesch, Serkan Ozakbas, Franco Granella, Recai Turkoglu, Gerardo Iuliano, Daniele Spitaleri, Pamela McCombe, Claudio Solaro, Mark Slee, Radek Ampapa, Aysun Soysal, Thor Petersen, Jose Luis Sanchez-Menoyo, Freek Verheul, Julie Prevost, Youssef Sidhom, Bart Van Wijmeersch, Steve Vucic, Edgardo Cristiano, Maria Laura Saladino, Norma Deri, Michael Barnett, Javier Olascoaga, Fraser Moore, Olga Skibina, Orla Gray, Yara Fragoso, Bassem Yamout, Cameron Shaw, Bhim Singhal, Neil Shuey, Suzanne ...

MSJ936823_supplement – Supplemental material for Prediction of on-treatment disability worsening in RRMS with the MAGNIMS score

Supplemental material, MSJ936823_supplement for Prediction of on-treatment disability worsening i... more Supplemental material, MSJ936823_supplement for Prediction of on-treatment disability worsening in RRMS with the MAGNIMS score by Amy Kunchok, Jeannette Lechner-Scott, Franco Granella, Maria Trojano, Raed Alroughani, Patrizia Sola, Diana Ferraro, Alessandra Lugaresi, Marco Onofrj, Serkan Ozakbas, Guillermo Izquierdo, Pierre Grammond, Jose Luis Sanchez-Menoyo, Bart Van Wijmeersch, Cavit Boz, Eugenio Pucci, Pamela McCombe, Francois Grand'Maison, Daniele Spitaleri, Steve Vucic, Raymond Hupperts, Vilija Jokubaitis, Maria Pia Sormani, Helmut Butzkueven and Tomas Kalincik in Multiple Sclerosis Journal

004 Pregnancy-related relapse in natalizumab, fingolimod and dimethyl fumarate-treated women with multiple sclerosis

Oral abstracts, 2021

IgG (CSF) and 78% of GAD65-IgG (CSF/serum) cohorts (OR=1.32, p=0.002, OR=2.78, p<0.001, respectiv... more IgG (CSF) and 78% of GAD65-IgG (CSF/serum) cohorts (OR=1.32, p=0.002, OR=2.78, p<0.001, respectively). Men accounted for 62% of the LGI1-IgG cohort (OR=1.87, p <0.001). Age and sex interacted for NMDA-R-IgG, particularly in females <20 years (OR=7.72, p <0.001). Conclusion The most frequently detected were NMDA-R-IgG, LGI1-IgG, GAD65-IgG and MOG-IgG1. Age and sex associations may suggest paraneoplastic, endocrinological or aging influences on neurological autoimmunity.

The effectiveness of natalizumab vs fingolimod–A comparison of international registry studies

Multiple Sclerosis and Related Disorders, 2021

Background Natalizumab and fingolimod were the first preparations recommended for disease breakth... more Background Natalizumab and fingolimod were the first preparations recommended for disease breakthrough in priorly treated relapsing-remitting multiple sclerosis. Of three published head-to-head studies two showed that natalizumab is the more effective to prevent relapses and EDSS worsening. Methods By re-analyzing original published results from MSBase, France, and Denmark using uniform methodologies, we aimed at identifying the effects of differences in methodology, in the MSpopulations, and at re-evaluating the differences in effectiveness between the two drugs. We gained access to copies of the individual amended databases and pooled all data. We used uniform inclusion/exclusion criteria and statistical methods with Inverse Probability Treatment Weighting. Results The pooled analyses comprised 968 natalizumab-and 1479 fingolimod treated patients. The ontreatment natalizumab/fingolimod relapse rate ratio was 0.77 (p=0.004). The hazard ratio (HR) for a first relapse was 0.82 (p=0.030), and the HR for sustained EDSS improvement was 1.4 (p=0.009). There were modest differences between each of the original published studies and the replication study, but the conclusions of the three original studies remained unchanged: in two of them natalizumab was more effective, but in the third there was no difference between natalizumab and fingolimod. Conclusion The results were largely invariant to the epidemiological and statistical methods but differed between the MS populations. Generally, the advantage of natalizumab was confirmed.

Cladribine: a multicentre, LOng-term efficacy Biomarker Australian Study (CLOBAS). A six- Otherwise we list them as CLOBAS investigators year, real-world study of multiple sclerosis patients (Preprint)

BACKGROUND Background: Cladribine tablets (marketed as Mavenclad®) is a new oral therapy, which h... more BACKGROUND Background: Cladribine tablets (marketed as Mavenclad®) is a new oral therapy, which has recently been listed on the pharmaceuticals benefit scheme (PBS) in Australia for treatment of relapsing MS. The current dosing schedule is for 2 courses given a year apart, which has been shown to be effective for treatment of MS up to 4 years in 75% of patients (based on annualised relapse rate). However, re-initiation of therapy after year 4 has not been studied. OBJECTIVE Objective: The Objective of this study is to METHODS Methods: This will be a multicentre, 6-year, phase IV, low interventional observational study that incorporates clinical, haematological, biochemical, epigenetic, and radiological and cognitive biomarkers of disease. Subjects considered for treatment with cladribine as part of their routine clinical care, will be consented to take part in the study. They will be monitored at regular intervals during the initial course of medication administration in year 1 and ...

Determinants of therapeutic lag in multiple sclerosis

Multiple Sclerosis Journal, 2021

Background: A delayed onset of treatment effect, termed therapeutic lag, may influence the assess... more 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 ...

Delay from treatment start to full effect of immunotherapies for multiple sclerosis

Brain, 2020

In multiple sclerosis, treatment start or switch is prompted by evidence of disease activity. Whi... more In multiple sclerosis, treatment start or switch is prompted by evidence of disease activity. Whilst immunomodulatory therapies reduce disease activity, the time required to attain maximal effect is unclear. In this study we aimed to develop a method that allows identification of the time to manifest fully and clinically the effect of multiple sclerosis treatments (‘therapeutic lag’) on clinical disease activity represented by relapses and progression-of-disability events. Data from two multiple sclerosis registries, MSBase (multinational) and OFSEP (French), were used. Patients diagnosed with multiple sclerosis, minimum 1-year exposure to treatment, minimum 3-year pretreatment follow-up and yearly review were included in the analysis. For analysis of disability progression, all events in the subsequent 5-year period were included. Density curves, representing incidence of relapses and 6-month confirmed progression events, were separately constructed for each sufficiently represente...

Prediction of on-treatment disability worsening in RRMS with the MAGNIMS score

Multiple Sclerosis Journal, 2020

Background: The magnetic resonance imaging in multiple sclerosis (MAGNIMS) score combines relapse... more Background: The magnetic resonance imaging in multiple sclerosis (MAGNIMS) score combines relapses and magnetic resonance imaging (MRI) lesions to predict disability outcomes in relapsing–remitting multiple sclerosis (RRMS) treated with interferon-β. Objective: To validate the MAGNIMS score and extend to other disease-modifying therapies (DMTs). To examine the prognostic value of gadolinium contrast-enhancing (Gd+) lesions. Methods: This RRMS MSBase cohort study ( n = 2293) used a Cox model to examine the prognostic value of relapses, MRI activity and the MAGNIMS score for disability worsening during treatment with interferon-β and three other DMTs. Results: Three new T2 lesions (hazard ratio (HR) = 1.60, p = 0.028) or two relapses (HR = 2.24, p = 0.002) on interferon-β (for 12 months) were predictive of disability worsening over 4 years. MAGNIMS score = 2 (1 relapse and ⩾3 T2 lesions or ⩾2 relapses) was associated with a greater risk of disability worsening on interferon-β (HR = 2....

Clinical and therapeutic predictors of disease outcomes in AQP4-IgG+ neuromyelitis optica spectrum disorder

Multiple Sclerosis and Related Disorders, 2019

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Risk of secondary progressive multiple sclerosis: A longitudinal study

Multiple Sclerosis Journal, 2019

Background: The risk factors for conversion from relapsing-remitting to secondary progressive mul... more Background: The risk factors for conversion from relapsing-remitting to secondary progressive multiple sclerosis remain highly contested. Objective: The aim of this study was to determine the demographic, clinical and paraclinical features that influence the risk of conversion to secondary progressive multiple sclerosis. Methods: Patients with adult-onset relapsing–remitting multiple sclerosis and at least four recorded disability scores were selected from MSBase, a global observational cohort. The risk of conversion to objectively defined secondary progressive multiple sclerosis was evaluated at multiple time points per patient using multivariable marginal Cox regression models. Sensitivity analyses were performed. Results: A total of 15,717 patients were included in the primary analysis. Older age (hazard ratio (HR) = 1.02, p < 0.001), longer disease duration (HR = 1.01, p = 0.038), a higher Expanded Disability Status Scale score (HR = 1.30, p < 0.001), more rapid disability...

002 Therapeutic lag in relapsing multiple sclerosis

Journal of Neurology, Neurosurgery & Psychiatry, 2019

IntroductionIn multiple sclerosis (MS), treatment start or switch is prompted disease activity, o... more IntroductionIn multiple sclerosis (MS), treatment start or switch is prompted disease activity, often represented by relapses. Immunomodulatory therapies have potent effects on relapse rates but the time required to attain maximal effect is unclear. We aim to develop a method that allows identification of the time to full clinically manifest effect of treatment on relapses.MethodsData from MSBase, a multinational MS registry, were used. Inclusion criteria consisted of patients with remitting relapsing MS or clinically isolated syndrome (CIS), minimum 3-year pre-treatment follow up, 1-year treatment persistence, yearly review and availability of the minimum dataset. Stratified by therapy, density curves representing relapses occurrence were created. The first local minimum of the first derivative after treatment start was identified, representing stabilisation of treatment effect. Similar method was utilised to calculate the last pre-treatment point of stabilisation. Annualised relap...

Association of Initial Disease-Modifying Therapy With Later Conversion to Secondary Progressive Multiple Sclerosis

JAMA, 2019

; for the MSBase Study Group IMPORTANCE Within 2 decades of onset, 80% of untreated patients with... more ; for the MSBase Study Group IMPORTANCE Within 2 decades of onset, 80% of untreated patients with relapsing-remitting multiple sclerosis (MS) convert to a phase of irreversible disability accrual termed secondary progressive MS. The association between disease-modifying treatments (DMTs), and this conversion has rarely been studied and never using a validated definition. OBJECTIVE To determine the association between the use, the type of, and the timing of DMTs with the risk of conversion to secondary progressive MS diagnosed with a validated definition. DESIGN, SETTING, AND PARTICIPANTS Cohort study with prospective data from 68 neurology centers in 21 countries examining patients with relapsing-remitting MS commencing DMTs (or clinical monitoring) between 1988-2012 with minimum 4 years' follow-up. EXPOSURES The use, type, and timing of the following DMTs: interferon beta, glatiramer acetate, fingolimod, natalizumab, or alemtuzumab. After propensity-score matching, 1555 patients were included (last follow-up, February 14, 2017). MAIN OUTCOME AND MEASURE Conversion to objectively defined secondary progressive MS. RESULTS Of the 1555 patients, 1123 were female (mean baseline age, 35 years [SD, 10]). Patients initially treated with glatiramer acetate or interferon beta had a lower hazard of conversion to secondary progressive MS than matched untreated patients (HR, 0.71; 95% CI, 0.61-0.81; P < .001; 5-year absolute risk, 12% [49 of 407] vs 27% [58 of 213]; median follow-up, 7.6 years [IQR, 5.8-9.6]), as did fingolimod (HR, 0.37; 95% CI, 0.22-0.62; P < .001; 5-year absolute risk, 7% [6 of 85] vs 32% [56 of 174]; median follow-up, 4.5 years [IQR, 4.3-5.1]); natalizumab (HR, 0.61; 95% CI, 0.43-0.86; P = .005; 5-year absolute risk, 19% [16 of 82] vs 38% [62 of 164]; median follow-up, 4.9 years [IQR, 4.4-5.8]); and alemtuzumab (HR, 0.52; 95% CI, 0.32-0.85; P = .009; 5-year absolute risk, 10% [4 of 44] vs 25% [23 of 92]; median follow-up, 7.4 years [IQR, 6.0-8.6]). Initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion than initial treatment with glatiramer acetate or interferon beta (HR, 0.66; 95% CI, 0.44-0.99; P = .046); 5-year absolute risk, 7% [16 of 235] vs 12% [46 of 380]; median follow-up, 5.8 years [IQR, 4.7-8.0]). The probability of conversion was lower when glatiramer acetate or interferon beta was started within 5 years of disease onset vs later (HR, 0.77; 95% CI, 0.61-0.98; P = .03; 5-year absolute risk, 3% [4 of 120] vs 6% [2 of 38]; median follow-up, 13.4 years [IQR, 11-18.1]). When glatiramer acetate or interferon beta were escalated to fingolimod, alemtuzumab, or natalizumab within 5 years vs later, the HR was 0.76 (95% CI, 0.66-0.88; P < .001; 5-year absolute risk, 8% [25 of 307] vs 14% [46 of 331], median follow-up, 5.3 years [IQR], 4.6-6.1). CONCLUSIONS AND RELEVANCE Among patients with relapsing-remitting MS, initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion to secondary progressive MS vs initial treatment with glatiramer acetate or interferon beta. These findings, considered along with these therapies' risks, may help inform decisions about DMT selection.

Incidence of pregnancy and disease-modifying therapy exposure trends in women with multiple sclerosis: A contemporary cohort study

Multiple Sclerosis and Related Disorders, 2019

Highlights  We performed a retrospective study of women with relapsing-remitting MS  There was ... more Highlights  We performed a retrospective study of women with relapsing-remitting MS  There was a low pregnancy incidence rate over the last twelve years  An increasing number of pregnancies were conceived on treatment over this time  Treatment exposure during pregnancy was short, with a median of 30 days

Cladribine versus fingolimod, natalizumab and interferon β for multiple sclerosis

Multiple Sclerosis Journal, 2017

Objective: This propensity score–matched analysis from MSBase compared the effectiveness of cladr... more Objective: This propensity score–matched analysis from MSBase compared the effectiveness of cladribine with interferon β, fingolimod or natalizumab. Methods: We identified all patients with relapse-onset multiple sclerosis, exposure to the study therapies and ⩾1-year on-treatment follow-up from MSBase. Three pairwise propensity score–matched analyses compared treatment outcomes over 1 year. The outcomes were hazards of first relapse, disability accumulation and disability improvement events. Sensitivity analyses were completed. Results: The cohorts consisted of 37 (cladribine), 1940 (interferon), 1892 (fingolimod) and 1410 patients (natalizumab). The probability of experiencing a relapse on cladribine was lower than on interferon ( p = 0.05), similar to fingolimod ( p = 0.31) and higher than on natalizumab ( p = 0.042). The probability of disability accumulation on cladribine was similar to interferon ( p = 0.37) and fingolimod ( p = 0.089) but greater than natalizumab ( p = 0.021)....

Towards personalized therapy for multiple sclerosis: prediction of individual treatment response

Brain, 2017

,6,44 on behalf of the MSBase Study Group Timely initiation of effective therapy is crucial for p... more ,6,44 on behalf of the MSBase Study Group Timely initiation of effective therapy is crucial for preventing disability in multiple sclerosis; however, treatment response varies greatly among patients. Comprehensive predictive models of individual treatment response are lacking. Our aims were: (i) to develop predictive algorithms for individual treatment response using demographic, clinical and paraclinical predictors in patients with multiple sclerosis; and (ii) to evaluate accuracy, and internal and external validity of these algorithms. This study evaluated 27 demographic, clinical and paraclinical predictors of individual response to seven disease-modifying therapies in MSBase, a large global cohort study. Treatment response was analysed separately for disability progression, disability regression, relapse frequency, conversion to secondary progressive disease, change in the cumulative disease burden, and the probability of treatment discontinuation. Multivariable survival and generalized linear models were used, together with the principal component analysis to reduce model dimensionality and prevent overparameterization. Accuracy of the individual prediction was tested and its internal validity was evaluated in a separate, non-overlapping cohort. External validity was evaluated in a geographically distinct cohort, the Swedish Multiple Sclerosis Registry. In the training cohort (n = 8513), the most prominent modifiers of treatment response comprised age, disease duration, disease course, previous relapse activity, disability, predominant relapse phenotype and previous therapy. Importantly, the magnitude and direction of the associations varied among therapies and disease outcomes. Higher probability of disability progression during treatment with injectable therapies was predominantly associated with a greater disability at treatment start and the previous therapy. For fingolimod, natalizumab or mitoxantrone, it was mainly associated with lower pretreatment relapse activity. The probability of disability regression was predominantly associated with pre-baseline disability, therapy and relapse activity. Relapse incidence was associated with pretreatment relapse activity, age and relapsing disease course, with the strength of these associations varying among therapies. Accuracy and internal validity (n = 1196) of the resulting predictive models was high (480%) for relapse incidence during the first year and for disability outcomes, moderate for relapse incidence in Years 2-4 and for the change in the cumulative disease burden, and low for conversion to secondary progressive disease and treatment discontinuation. External validation showed similar results, demonstrating high external validity for disability and relapse outcomes, moderate external validity for cumulative disease burden and low external validity for conversion to

Incidence and prevalence of NMOSD in Australia and New Zealand

Journal of neurology, neurosurgery, and psychiatry, Aug 26, 2017

We have undertaken a clinic-based survey of neuromyelitis optica spectrum disorders (NMOSDs) in A... more We have undertaken a clinic-based survey of neuromyelitis optica spectrum disorders (NMOSDs) in Australia and New Zealand to establish incidence and prevalence across the region and in populations of differing ancestry. NMOSD is a recently defined demyelinating disease of the central nervous system (CNS). The incidence and prevalence of NMOSD in Australia and New Zealand has not been established. Centres managing patients with demyelinating disease of the CNS across Australia and New Zealand reported patients with clinical and laboratory features that were suspicious for NMOSD. Testing for aquaporin 4 antibodies was undertaken in all suspected cases. From this group, cases were identified who fulfilled the 2015 Wingerchuk diagnostic criteria for NMOSD. A capture-recapture methodology was used to estimate incidence and prevalence, based on additional laboratory identified cases. NMOSD was confirmed in 81/170 (48%) cases referred. Capture-recapture analysis gave an adjusted incidence ...

Treatment effectiveness of alemtuzumab compared with natalizumab, fingolimod, and interferon beta in relapsing-remitting multiple sclerosis: a cohort study

The Lancet. Neurology, Apr 10, 2017

Alemtuzumab, an anti-CD52 antibody, is proven to be more efficacious than interferon beta-1a in t... more Alemtuzumab, an anti-CD52 antibody, is proven to be more efficacious than interferon beta-1a in the treatment of relapsing-remitting multiple sclerosis, but its efficacy relative to more potent immunotherapies is unknown. We compared the effectiveness of alemtuzumab with natalizumab, fingolimod, and interferon beta in patients with relapsing-remitting multiple sclerosis treated for up to 5 years. In this international cohort study, we used data from propensity-matched patients with relapsing-remitting multiple sclerosis from the MSBase and six other cohorts. Longitudinal clinical data were obtained from 71 MSBase centres in 21 countries and from six non-MSBase centres in the UK and Germany between Nov 1, 2015, and June 30, 2016. Key inclusion criteria were a diagnosis of definite relapsing-remitting multiple sclerosis, exposure to one of the study therapies (alemtuzumab, interferon beta, fingolimod, or natalizumab), age 65 years or younger, Expanded Disability Status Scale (EDSS) sc...

Higher latitude is significantly associated with an earlier age of disease onset in multiple sclerosis

Journal of neurology, neurosurgery, and psychiatry, Jan 3, 2016

Age at onset (AAO) in multiple sclerosis (MS) is an important marker of disease severity and may ... more Age at onset (AAO) in multiple sclerosis (MS) is an important marker of disease severity and may have prognostic significance. Understanding what factors can influence AAO may shed light on the aetiology of this complex disease, and have applications in the diagnostic process. The study cohort of 22 162 eligible patients from 21 countries was extracted from the MSBase registry. Only patients with MS aged ≥16 years were included. To reduce heterogeneity, only centres of largely European descent were included for analysis. AAO was defined as the year of the first symptom suggestive of inflammatory central nervous system demyelination. Predictors of AAO were evaluated by linear regression. Compared with those living in lower latitudes (19.0-39.9°), onset of symptoms was 1.9 years earlier for those at higher latitudes (50.0-56.0°) (p=3.83×10(-23)). A reciprocal relationship was seen for ambient ultraviolet radiation (UVR), with a significantly increasing AAO for patients with MS per eac...