Therapeutic lag in multiple sclerosis
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2021
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Melbourne Authors
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Medicine (RMH)
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PhD thesis
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Open Access
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© 2021 Izanne Craill Roos
Abstract
Multiple sclerosis is a heterogenous neurological disorder characterised by an interplay between neuroinflammation and neurodegeneration. Treatment decisions are frequently prompted by the presence of disease activity presenting as relapses or progression-of-disability events. Treatment initiation and switch are therefore two critical periods in multiple sclerosis management. There is a delay between treatment initiation and the onset of full clinically manifest effect of therapy, referred to as ‘therapeutic lag’. It has been suggested that not accounting for delayed treatment effects may obscure treatment response in clinical trials of progressive multiple sclerosis. Further exploration of the influence of therapeutic lag and its determinants, however depends on development of a robust method to detect when treatments attain full clinical effect. Similar to therapeutic lag, there is a delay between treatment stop and the return of disease activity. Disease reactivation after treatment cessation has been identified as a risk factor for disability accrual. Understanding of the optimal timing of the start of the next treatment however remains limited.
All studies used data from the two largest multiple sclerosis registries: MSBase (multinational) and OFSEP (French). The first study developed, and externally validated, an objective differential-calculus based method to estimate the duration of therapeutic lag for clinical measures of treatment effect. Time to full clinical treatment effect was estimated as 12-30 weeks for relapses and 30-70 weeks for disability progression. The second study applied this method to groups of patients with different clinical and disease characteristics to investigate the determinants of lag duration. Pre-treatment level of disability and annualised rate of relapse were identified as the most important influencers of therapeutic lag. The third study investigated the effect of high and low-efficacy therapy in secondary progressive multiple sclerosis, after accounting for therapeutic lag. High-efficacy therapy was found to be superior to low-efficacy therapy in reducing relapses in patients with episodic inflammatory activity in the two years before starting therapy. High- and low-efficacy therapies however had comparable effectiveness on disability progression. In the fourth study, the focus was shifted from treatment start to the period after treatment cessation. The rate of disease reactivation after the cessation of disease-modifying therapies was explored. Risks of disease reactivation were highest after cessation of anti-trafficking therapies and were reduced by starting a new treatment. On-treatment rates of relapse, age, sex, and level of disability further influenced the risk of disease reactivation.
These findings are highly relevant to clinical decision-making in a number of contexts: (i) patients who experience early on-treatment disease activity should be re-evaluated after the lapse of therapeutic lag, (ii) the selection of immunotherapy in patients with active secondary progressive multiple sclerosis should carefully consider the amount of preceding relapsing activity and the risk-vs-benefit ratio, (iii) decisions regarding wash-out durations after discontinuation of disease-modifying therapies should be individualised based on the discontinued therapy and a patient’s clinical profile. Moreover, treatment outcomes in cohorts enriched with patients with higher disability scores should be interpreted with the expected duration of therapeutic lag in sight.
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Keywords
multiple sclerosis, clinical outcomes, observational, therapeutic lag