Clinical predictors of Dimethyl Fumarate response in multiple sclerosis: a real life multicentre study.

Adult Age of Onset Dimethyl Fumarate / adverse effects Disease Progression Female Humans Immunologic Factors / adverse effects Male Middle Aged Multiple Sclerosis, Chronic Progressive / drug therapy Multiple Sclerosis, Relapsing-Remitting / drug therapy Outcome Assessment, Health Care Prospective Studies Recurrence Retrospective Studies Time Factors

Dimethyl-fumarate Efficacy Multiple sclerosis Persistence Real life

Journal

Multiple sclerosis and related disorders

ISSN: 2211-0356

Titre abrégé: Mult Scler Relat Disord

Pays: Netherlands

ID NLM: 101580247

Informations de publication

Date de publication:
Feb 2020

Historique:

received: 09 05 2019

revised: 08 09 2019

accepted: 24 11 2019

pubmed: 2 12 2019

medline: 20 1 2021

entrez: 2 12 2019

Statut: ppublish

Résumé

Dimethyl-fumarate (DMF) was effective and safe in relapsing-remitting multiple sclerosis (MS) in randomized clinical trials. We aimed to evaluate the efficacy and safety of DMF and factors related to drug response in real-life setting. We analysed prospectively collected demographic and clinical data for patients treated with DMF in six multiple sclerosis (MS) centers from 2015 to 2017 in Campania region, Italy. We performed univariate and multivariate analyses to assess relationships between baseline parameters and DMF efficacy outcomes, Annualized Relapse Rate (ARR), Expanded Disability Status Scale (EDSS) progression and No Evidence of Disease Activity (NEDA-3) status. we analyzed data of 456 patients (67% female subjects, mean age 40 ± 12 years, mean disease duration 9 ± 9 years, mean treatment duration 18 ± 11 months, median EDSS 2.5, 0-8). Proportion of Naïve versus pretreated with other DMTs patients was 149/307 (32.7%), with 122 patients switching to DMF for disease activity (26.7%) and 185 for safety and tolerability issues (40.6%). During treatment with DMF, the annualized relapse rate was reduced by 75% respect to the pre-treatment ARR [incidence-rate-ratio (IRR) = 0.25, p < 0.001, CI 0.18-0.33]. Factors influencing ARR rate while on DMF were relapsing remitting (RR) MS course (IRR = 2.0, p = <0.001, CI 1.51-2.73) and previous DMTs status: de-escalating from second-line therapies was associated to higher risk of relapsing (IRR = 1.8, p < 0.001, CI 1.39-2.31). At multivariable Cox proportional hazard model, only age of onset was related with rate or relapses, with younger age being protective (HR 0.96, p = 0,02). EDSS remained stable in 88% of patients. Disease duration was associated with higher rate of NEDA-3 failure, that was instead maintained in 65% of patients at 24 months. 109 patients (22%) discontinued therapy after a mean of 1.1 ±+ 0.7 years. Reasons for DMF discontinuation over time were lack of efficacy (50%), safety issues (30%), tolerability (7%), poor compliance (7%), and pregnancy (4%). Higher pre-treatment EDSS was associated with DMF discontinuation (p = 0.009). Only 33 patients dropped out due to safety reasons (7%), the most frequent safety issues driving to drop out being lymphopenia, liver/pancreatic enzymes increase, gatrointestinal severe tolerability issues. We recorded 95 cases (24%) of lymphopenia: 60 grade I (13%), 31 grade II (7%) and 4 grade III (1%). We confirm that DMF shows a good efficacy in both naïve patients and patients switching from other first-line DMTs, especially in patients with early onset of disease. Higher baseline EDSS was a risk factor for discontinuing DMF therapy, while shorter disease duration was protective for both EDSS progression and NEDA-3 status maintenance.

Sections du résumé

BACKGROUND BACKGROUND

METHODS METHODS

We analysed prospectively collected demographic and clinical data for patients treated with DMF in six multiple sclerosis (MS) centers from 2015 to 2017 in Campania region, Italy. We performed univariate and multivariate analyses to assess relationships between baseline parameters and DMF efficacy outcomes, Annualized Relapse Rate (ARR), Expanded Disability Status Scale (EDSS) progression and No Evidence of Disease Activity (NEDA-3) status.

RESULTS RESULTS

we analyzed data of 456 patients (67% female subjects, mean age 40 ± 12 years, mean disease duration 9 ± 9 years, mean treatment duration 18 ± 11 months, median EDSS 2.5, 0-8). Proportion of Naïve versus pretreated with other DMTs patients was 149/307 (32.7%), with 122 patients switching to DMF for disease activity (26.7%) and 185 for safety and tolerability issues (40.6%). During treatment with DMF, the annualized relapse rate was reduced by 75% respect to the pre-treatment ARR [incidence-rate-ratio (IRR) = 0.25, p < 0.001, CI 0.18-0.33]. Factors influencing ARR rate while on DMF were relapsing remitting (RR) MS course (IRR = 2.0, p = <0.001, CI 1.51-2.73) and previous DMTs status: de-escalating from second-line therapies was associated to higher risk of relapsing (IRR = 1.8, p < 0.001, CI 1.39-2.31). At multivariable Cox proportional hazard model, only age of onset was related with rate or relapses, with younger age being protective (HR 0.96, p = 0,02). EDSS remained stable in 88% of patients. Disease duration was associated with higher rate of NEDA-3 failure, that was instead maintained in 65% of patients at 24 months. 109 patients (22%) discontinued therapy after a mean of 1.1 ±+ 0.7 years. Reasons for DMF discontinuation over time were lack of efficacy (50%), safety issues (30%), tolerability (7%), poor compliance (7%), and pregnancy (4%). Higher pre-treatment EDSS was associated with DMF discontinuation (p = 0.009). Only 33 patients dropped out due to safety reasons (7%), the most frequent safety issues driving to drop out being lymphopenia, liver/pancreatic enzymes increase, gatrointestinal severe tolerability issues. We recorded 95 cases (24%) of lymphopenia: 60 grade I (13%), 31 grade II (7%) and 4 grade III (1%).

CONCLUSIONS CONCLUSIONS

We confirm that DMF shows a good efficacy in both naïve patients and patients switching from other first-line DMTs, especially in patients with early onset of disease. Higher baseline EDSS was a risk factor for discontinuing DMF therapy, while shorter disease duration was protective for both EDSS progression and NEDA-3 status maintenance.

Identifiants

DOI: 10.1016/j.msard.2019.101871 PMID: 31786463

pubmed: 31786463

pii: S2211-0348(19)30943-5

doi: 10.1016/j.msard.2019.101871

pii:

doi:

Substances chimiques

Immunologic Factors 0

Dimethyl Fumarate FO2303MNI2

Types de publication

Journal Article Multicenter Study

Langues

eng

Sous-ensembles de citation

Pagination

101871

Informations de copyright

Déclaration de conflit d'intérêts

Declaration of Competing Interest Dr. L. Lavorgna received speaker honoraria from Sanofi, Teva, Novartis, Merck, Roche, Bayer, Biogen. Dr. L. Sinisi received speaker honoraria and/or travel grants from Merck Serono, Biogen, Teva, Novartis, Almirall, Sanofi Genzyme. Dr. G.T. Maniscalco has served on advisory boards and/or received travel grants and speaker honoraria from Almirall, Biogen, Merck Serono, Novartis and Teva. E. Signoriello received travel funding and speaker honoraria from Biogen, Novartis, Sanofi Genzyme, Bayer, Teva. G. Lus received travel funding, research support, speaker honoraria from Biogen, Novartis, Sanofi Genzyme, Bayer, Teva, Almirall, Allergan, Ipsen. Marcello Moccia received research grants from MAGNIMS-ECTRIMS and from Merck. Antonio Carotenuto received travel funding from Roche and research grants from Almirall. R. Lanzillo, F. Saccà and V. Brescia Morra received personal fees for public speaking or consultancy from Merck, Novartis, Biogen, Genzyme, Teva and Almirall. Dr. F.Romano, C.V.Russo, A. De Rosa, M.De Angelis, S. Bonavita, C. Florio and B. Ronga have nothing to disclose.