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

Abstract

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 represented therapy. Monte Carlo simulations were performed to identify the first local minimum of the first derivative after treatment start; this point represented the point of stabilization of treatment effect, after the maximum treatment effect was observed. The method was developed in a discovery cohort (MSBase), and externally validated in a separate, non-overlapping cohort (OFSEP). A merged MSBase-OFSEP cohort was used for all subsequent analyses. Annualized relapse rates were compared in the time before treatment start and after the stabilization of treatment effect following commencement of each therapy. We identified 11 180 eligible treatment epochs for analysis of relapses and 4088 treatment epochs for disability progression. External validation was performed in four therapies, with no significant difference in the bootstrapped mean differences in therapeutic lag duration between registries. The duration of therapeutic lag for relapses was calculated for 10 therapies and ranged between 12 and 30 weeks. The duration of therapeutic lag for disability progression was calculated for seven therapies and ranged between 30 and 70 weeks. Significant differences in the pre- versus post-treatment annualized relapse rate were present for all therapies apart from intramuscular interferon beta-1a. In conclusion we have developed, and externally validated, a method to objectively quantify the duration of therapeutic lag on relapses and disability progression in different therapies in patients more than 3 years from multiple sclerosis onset. Objectively defined periods of expected therapeutic lag allows insights into the evaluation of treatment response in randomized clinical trials and may guide clinical decision-making in patients who experience early on-treatment disease activity. This method will subsequently be applied in studies that evaluate the effect of patient and disease characteristics on therapeutic lag.

Determinants of therapeutic lag in multiple sclerosis

“…7 Td and Tr was only estimated for subgroups in which more than 300 relapses or progression events occurred as the underlying method is dependent on a critical mass of events to consistently identify the first local minimum of the first derivative of relapse incidence. 7 Where an insufficient number of events were present analyses were discontinued. There are A c c e p t e d m a n u s c r i p t therefore groups of determinants, particularly in the assessment of Td in groups defined by multiple interacting patient characteristics, for which therapeutic lag could not be calculated.…”

“…By separately plotting the incidence of relapses and disability progression events in subgroups stratified by patient and disease characteristics, the duration of therapeutic lag was calculated by identifying the first local minimum of the first derivative after treatment start (supplementary figure 1). 7 This local minimum represents the timepoint A c c e p t e d m a n u s c r i p t at which stabilisation of the effect of treatment is reached on disability progression (Td) and relapses (Tr). Therapeutic lag estimates were recalculated by non-parametric bootstrap with 10,000 repetitions.…”

“…6 Using an objective, differential calculusderived method, the duration of therapeutic lag has been estimated to range between 12-30 weeks for relapses and 30-70 weeks for disability progression. 7 It has been suggested that the duration of therapeutic lag is not uniform amongst patients, and may increase proportionate to the degree of pre-existing disability. 3 A randomised placebo-controlled trial of interferon beta-1b in primary progressive MS failed to detect a beneficial treatment response after 2 years.…”

Stem Cell Therapies for Progressive Multiple Sclerosis

“…In patients presenting with aggressive inflammatory disease at onset, consensus is that a more beneficial approach is to employ an induction immune therapy using second-line DMTs from the beginning of treatment (Roos et al, 2020), conferring a significantly lower risk of SPMS conversion (versus first-line escalation therapy) (Brown et al, 2019). Such an approach is more effective in reducing the risk of reaching a disability milestone, albeit with a worse safety profile (Prosperini et al, 2020).…”

Multiple Sklerose Therapie Konsensus Gruppe (MSTKG): Positionspapier zur verlaufsmodifizierenden Therapie der Multiplen Sklerose 2021 (White Paper)

“…Da die DMTs jedoch unterschiedlich lange benötigen, um ihre volle Wirkung zu entfalten, und auch das Auftreten potenzieller Nebenwirkungen sehr unterschiedlich ist, sind die Behandlungs- und Monitoringzeiträume sowohl in den Zulassungs- als auch in „Real-World“-Studien unterschiedlich gewählt. In einer retrospektiven Kohortenanalyse wurde die Zeit von Therapiebeginn bis zum Wirkeintritt auf die Schubratenreduktion als ungefähr 3 bis 4 Monate beschrieben (12 bis 30 Wochen, [ 99 , 119 ]), was sich mit langjährigen klinischen Erfahrungen deckt. Insbesondere bei Schub- oder MRT-Aktivität innerhalb der ersten 4 bis 8 Wochen nach Therapiebeginn sollte individuell entschieden werden, ob diese bis zu einem vollen Wirkeintritt der gestarteten DMT toleriert werden kann oder aufgrund des Einflusses auf die Erkrankungsschwere im Einzelfall bereits direkt eine Umstellung auf eine höheraktive Therapie erfolgen sollte.…”