Stop or not the disease-modifying therapies in secondary progressive multiple sclerosis: a comparison study of disability accrual trajectory.
SYNOPSIS AND RESULTS
Scant evidence is described about the necessity to stop or continue disease-modifying therapies (DMTs) in patients with relapsing remitting forms of multiple sclerosis (RRMS) who evolved into secondary progressive form (SPMS). No guidelines exist about the exact moment in which DMTs must be stopped. This is associated to enormous costs and burden to health services. Surveyed neurologists declared efforts to stop DMTs in SPMS, but most did not insist, even if they felt to prescribe therapy without benefit. Our study aims to compare disease course in men and women with SPMS who continued or stopped their DMTs. We aimed to compare the disability accrual trajectory in two groups of SPMS: a) patients who stopped in the first 12 months after the conversion to SPMS and did not resume DMTs for MS in the progressive phase; b) patients who stayed on their stable DMTs started during RRMS phase for at least 24 months. We will enrol all MS patients actively followed from Italian MS centres who received a diagnosis of SPMS from January 1st, 2010 to December 31st, 2018. Revised McDonald's criteria will be used to diagnose SPMS. Demographical, clinical, and therapeutic data will be collected from a “time 0” defined as baseline that will coincide with the data of SP conversion. Disability will be assessed by Expanded Disability Status Scale (EDSS). We will assess the risk of disability accrual over time correcting disease trajectories for baseline covariates. Patients will be followed until last available follow up. A hierarchic model will be built, bringing as outcome the EDSS scores longitudinally collected from baseline until the last follow up; the choose of fixed and random effects will done during preliminary analysis and the best model will be chosen according to Akaike criterion. Then, will be evaluated the necessity to introduce also balancing score (es. propensity scores). Disease trajectories in the two groups will be compared to analyze if disease course after SP conversion can be influenced by the maintenance of DMTs.
Rationale and specific aims In patients with SPMS, the pattern of disease evolution changes over time and the acute inflammatory events, which may manifest as new lesions on central nervous system (CNS) magnetic resonance images (MRIs) or as clinical relapses, decrease but disability accrual increases over time. Currently, there is a lack of defined treatment options in SPMS. However, in SPMS there is a window of opportunity as the relapse phase with ongoing inflammation can be targeted by adequate therapy. A close follow-up and utilization of clinical and radiological measures of disease activity could help a clinician decide to switch therapy timely to prevent a stage of progressively cumulative worsening and transition to established advanced SPMS. It is prudent to recognize the deterioration early, as escalation therapies used for aggressive MS may have a potential role to play in such patients, considering, cost, risk, and benefit while deciding. Furthermore, as we evolve to understand the exact pathogenesis of disease progression and identify appropriate outcome measures, targeting therapy would be more specific. Treating SPMS continues to remain a challenge as it aims at targeting not only active inflammation but also associated neurodegeneration and demyelination. After many years, we have a clearer understanding of disease process, importance of adequate outcome measures and advances in drug therapies. The evidence from trials of both RRMS and SPMS must be extrapolated to manage a patient, although we are hopeful and optimistic about targeted therapies for SPMS in future. Nearly all successful randomized controlled trials in MS enrolled relatively young, relatively unimpaired patients with a history of recent relapses or new MRI lesions. In these patients, disease modifying therapies (DMTs) decreased rates of relapses and, in some instances, short-term disability progression. But is it reasonable to continue DMTs to MS patients who do not evidence focal inflammatory activity for a prolonged period? Or to continue in very disabled patients? For all these reasons we designed this study, and we will collect clinical data to examine disease course in men and women with SPMS who continued or not to assume their DMTs. We will review the disease course of SPMS patients after entering the progressive phase of the disease comparing the two groups. We will assess the risk of disability accrual over time correcting disease trajectories for baseline covariates. Patients will be followed until last available follow up. Disease trajectories in the two groups will be compared to analyze if disease course after SP conversion can be influenced by the maintenance of DMTs. We will examine the interaction between demographic, clinical and therapeutic variables to observe any differences in terms of the trajectory of disability accrual.
Fondazione Italiana Sclerosi Multipla – FISM – Ente del Terzo Settore/ETS e, in forma abbreviata, FISM ETS. Iscrizione al RUNTS Rep. N° 89695 - Fondazione con Riconoscimento di Personalità Giuridica - C.F. 95051730109
Stop or not the disease-modifying therapies in secondary progressive multiple sclerosis: a comparison study of disability accrual trajectory.
Scant evidence is described about the necessity to stop or continue disease-modifying therapies (DMTs) in patients with relapsing remitting forms of multiple sclerosis (RRMS) who evolved into secondary progressive form (SPMS).
No guidelines exist about the exact moment in which DMTs must be stopped. This is associated to enormous costs and burden to health services. Surveyed neurologists declared efforts to stop DMTs in SPMS, but most did not insist, even if they felt to prescribe therapy without benefit.
Our study aims to compare disease course in men and women with SPMS who continued or stopped their DMTs.
We aimed to compare the disability accrual trajectory in two groups of SPMS: a) patients who stopped in the first 12 months after the conversion to SPMS and did not resume DMTs for MS in the progressive phase; b) patients who stayed on their stable DMTs started during RRMS phase for at least 24 months.
We will enrol all MS patients actively followed from Italian MS centres who received a diagnosis of SPMS from January 1st, 2010 to December 31st, 2018. Revised McDonald's criteria will be used to diagnose SPMS.
Demographical, clinical, and therapeutic data will be collected from a “time 0” defined as baseline that will coincide with the data of SP conversion. Disability will be assessed by Expanded Disability Status Scale (EDSS).
We will assess the risk of disability accrual over time correcting disease trajectories for baseline covariates. Patients will be followed until last available follow up.
A hierarchic model will be built, bringing as outcome the EDSS scores longitudinally collected from baseline until the last follow up; the choose of fixed and random effects will done during preliminary analysis and the best model will be chosen according to Akaike criterion. Then, will be evaluated the necessity to introduce also balancing score (es. propensity scores).
Disease trajectories in the two groups will be compared to analyze if disease course after SP conversion can be influenced by the maintenance of DMTs.
Rationale and specific aims
In patients with SPMS, the pattern of disease evolution changes over time and the acute inflammatory events, which may manifest as new lesions on central nervous system (CNS) magnetic resonance images (MRIs) or as clinical relapses, decrease but disability accrual increases over time.
Currently, there is a lack of defined treatment options in SPMS. However, in SPMS there is a window of opportunity as the relapse phase with ongoing inflammation can be targeted by adequate therapy. A close follow-up and utilization of clinical and radiological measures of disease activity could help a clinician decide to switch therapy timely to prevent a stage of progressively cumulative worsening and transition to established advanced SPMS. It is prudent to recognize the deterioration early, as escalation therapies used for aggressive MS may have a potential role to play in such patients, considering, cost, risk, and benefit while deciding. Furthermore, as we evolve to understand the exact pathogenesis of disease progression and identify appropriate outcome measures, targeting therapy would be more specific.
Treating SPMS continues to remain a challenge as it aims at targeting not only active inflammation but also associated neurodegeneration and demyelination. After many years, we have a clearer understanding of disease process, importance of adequate outcome measures and advances in drug therapies.
The evidence from trials of both RRMS and SPMS must be extrapolated to manage a patient, although we are hopeful and optimistic about targeted therapies for SPMS in future.
Nearly all successful randomized controlled trials in MS enrolled relatively young, relatively unimpaired patients with a history of recent relapses or new MRI lesions. In these patients, disease modifying therapies (DMTs) decreased rates of relapses and, in some instances, short-term disability progression. But is it reasonable to continue DMTs to MS patients who do not evidence focal inflammatory activity for a prolonged period? Or to continue in very disabled patients?
For all these reasons we designed this study, and we will collect clinical data to examine disease course in men and women with SPMS who continued or not to assume their DMTs.
We will review the disease course of SPMS patients after entering the progressive phase of the disease comparing the two groups. We will assess the risk of disability accrual over time correcting disease trajectories for baseline covariates. Patients will be followed until last available follow up.
Disease trajectories in the two groups will be compared to analyze if disease course after SP conversion can be influenced by the maintenance of DMTs. We will examine the interaction between demographic, clinical and therapeutic variables to observe any differences in terms of the trajectory of disability accrual.
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