Initial high-efficacy disease-modifying therapy in multiple sclerosis

Buron, Mathias Due; Chalmer, Thor Ameri; Sellebjerg, Finn; Barzinji, Ismael; Bech, Danny; Christensen, Jeppe Romme; Christensen, Mette Kirstine; Hansen, Victoria; Illés, Zsolt; Jensen, Henrik Boye; Kant, Matthias; Papp, Viktória; Petersen, Thor; Prakash, Sivagini; Rasmussen, Peter Vestergaard; Schäfer, Jakob; Theódórsdóttir, Ásta; Węglewski, Arkadiusz; Sørensen, Per Soelberg; Magyari, Melinda

doi:10.1212/wnl.0000000000010135

Cited by 103 publications

(101 citation statements)

References 36 publications

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“…Four recent real-world retrospective studies compared the ESC and the EIT strategies, suggesting an association of the latter strategy with a lower hazard of clinical relapses, a lower mean change in EDSS score at 5 years, a higher median time to sustained accumulation of disability and a lower risk of conversion to secondary progressive MS (SPMS), compared with initial treatment with first-line agents. 12 , 13 , 22 , 27 …”

Section: Discussionmentioning

confidence: 99%

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Long-term disability trajectories in relapsing multiple sclerosis patients treated with early intensive or escalation treatment strategies

Iaffaldano

Lucisano

Caputo

et al. 2021

Ther Adv Neurol Disord

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Background and aims: No consensus exists on how aggressively to treat relapsing–remitting multiple sclerosis (RRMS) nor on the timing of the treatment. The objective of this study was to evaluate disability trajectories in RRMS patients treated with an early intensive treatment (EIT) or with a moderate-efficacy treatment followed by escalation to higher-efficacy disease modifying therapy (ESC). Methods: RRMS patients with ⩾5-year follow-up and ⩾3 visits after disease modifying therapy (DMT) start were selected from the Italian MS Registry. EIT group included patients who received as first DMT fingolimod, natalizumab, mitoxantrone, alemtuzumab, ocrelizumab, cladribine. ESC group patients received the high efficacy DMT after ⩾1 year of glatiramer acetate, interferons, azathioprine, teriflunomide or dimethylfumarate treatment. Patients were 1:1 propensity score (PS) matched for characteristics at the first DMT. The disability trajectories were evaluated by applying a longitudinal model for repeated measures. The effect of early versus late start of high-efficacy DMT was assessed by the mean annual Expanded Disability Status Scale (EDSS) changes compared with baseline values (delta-EDSS) in EIT and ESC groups. Results: The study cohort included 2702 RRMS patients. The PS matching procedure produced 363 pairs, followed for a median (interquartile range) of 8.5 (6.5–11.7) years. Mean annual delta-EDSS values were all significantly ( p < 0.02) higher in the ESC group compared with the EIT group. In particular, the mean delta-EDSS differences between the two groups tended to increase from 0.1 (0.01–0.19, p = 0.03) at 1 year to 0.30 (0.07–0.53, p = 0.009) at 5 years and to 0.67 (0.31–1.03, p = 0.0003) at 10 years. Conclusion: Our results indicate that EIT strategy is more effective than ESC strategy in controlling disability progression over time.

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Section: Discussionmentioning

confidence: 99%

“…Finally, a Danish observational study proved a lower probability of a 6-month confirmed EDSS score worsening and of a first relapse over a follow-up of 4 years for 194 patients starting their therapy with high-efficacy DMTs compared with 194 PS matched patients starting with medium-efficacy DMTs. 27 …”

Section: Discussionmentioning

confidence: 99%

Long-term disability trajectories in relapsing multiple sclerosis patients treated with early intensive or escalation treatment strategies

Iaffaldano

Lucisano

Caputo

et al. 2021

Ther Adv Neurol Disord

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“…The current disease modifying therapies (DMTs) effectively inhibit formation of focal lesions (Buron et al, 2020), but their effect on non-lesional inflammatory activities is unknown. Understanding contributions of lesional versus non-lesional MS inflammatory activity to CNS tissue destruction requires reliable and simultaneous measurements of both processes in the same patients.…”

Section: Introductionmentioning

confidence: 99%

Cerebrospinal Fluid Biomarkers of Myeloid and Glial Cell Activation Are Correlated With Multiple Sclerosis Lesional Inflammatory Activity

et al. 2021

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Multiple sclerosis (MS)-related inflammation can be divided into lesional activity, mediated by immune cells migrating from the periphery to the central nervous system (CNS) and non-lesional activity, mediated by inflammation compartmentalized to CNS tissue. Lesional inflammatory activity, reflected by contrast-enhancing lesions (CELs) on the magnetic resonance imaging (MRI), is effectively inhibited by current disease modifying therapies (DMTs). While, the effect of DMTs on non-lesional inflammatory activity is currently unknown. Reliable and simultaneous measurements of both lesional and non-lesional MS activity is necessary to understand their contribution to CNS tissue destruction in individual patients. We previously demonstrated that CNS compartmentalized inflammation can be measured by combined quantification of cerebrospinal fluid (CSF) immune cells and cell-specific soluble markers. The goal of this study is to develop and validate a CSF-biomarker-based molecular surrogate of MS lesional activity. The training cohort was dichotomized into active (CELs > 1 or clinical relapse) and inactive lesional activity (no CELs or relapse) groups. Matched CSF and serum samples were analyzed for 20 inflammatory and axonal damage biomarkers in a blinded fashion. Only the findings from the training cohort with less than 0.1% probability of false positive (i.e., p < 0.001) were validated in an independent validation cohort. MS patients with lesional activity have elevated IL-12p40, CHI3L1, TNFα, TNFβ, and IL-10, with the first two having the strongest effects and validated statistically-significant association with lesional activity in an independent validation cohort. Marker of axonal damage, neurofilament light (NfL), measured in CSF (cNfL) was also significantly elevated in MS patients with active lesions. NfL measured in serum (sNfL) did not differentiate the two MS subgroups with pre-determined significance, (p = 0.0690) even though cCSF and sNfL correlated (Rho = 0.66, p < 0.0001). Finally, the additive model of IL12p40 and CHI3L1 outperforms any biomarker discretely. IL12p40 and CHI3L1, released predominantly by immune cells of myeloid lineage are reproducibly the best CSF biomarkers of MS lesional activity. The residuals from the IL12p40/CHI3L1-cNfL correlations may identify MS patients with more destructive inflammation or contributing neurodegeneration.

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“…However, the optimal treatment strategy with DMTs in RRMS remains elusive [2,[7][8][9]. Current treatment approaches may miss a window of opportunity for achieving the highest effectiveness of DMTs [9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Initial treatment strategy and clinical outcomes in Finnish MS patients: a propensity-matched study

Hänninen

Viitala²,

Atula

et al. 2021

J Neurol

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Background The optimal treatment strategy with disease-modifying therapies (DMTs) in relapsing–remitting multiple sclerosis (RRMS) remains uncertain. Objective To compare outcomes of initial treatment with infusion therapies and starting therapy with medium efficacy therapy in a propensity-matched cohort of Finnish RRMS patients. Methods A total of 154 RRMS patients initiating natalizumab, alemtuzumab, ocrelizumab or rituximab as first DMT (high efficacy DMT, heDMT group) and 1771 patients initially treated with injectable therapies, teriflunomide or dimethylfumarate and escalated based on disease activity (moderate efficacy DMT, meDMT group) were identified from the Finnish MS registry. Nearest neighbor propensity matching (1:1, caliper 0.1) was performed for age, sex, baseline Expanded Disability Status Scale (EDSS), annual relapse rate (ARR) one year prior DMT and time since MS symptom onset. Primary outcome was time to 6-month confirmed EDSS progression and the secondary outcome time to first relapse. Results In the propensity-matched group comparisons, the probability of 6-month confirmed disability progression (CDP) at 5 years after DMT start was 28.4% (95% CI 15.7–39.3) in the heDMT group (n = 66) and 47.0% (95% CI 33.1–58.1) in meDMT group (n = 66), p = 0.013. Probability of relapse at 5 years was 34.6% (95% CI 24.1–43.6) for heDMT (n = 105) and 47.2% (95% CI 36.6–56.1) for meDMT (n = 105), p = 0.019. Conclusions Initiating MS-therapy with heDMT significantly reduced the risk of 5-year disability progression and relapse compared to using meDMT as first DMT choice in propensity-matched groups of Finnish MS-patients.

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Initial high-efficacy disease-modifying therapy in multiple sclerosis

Cited by 103 publications

References 36 publications

Long-term disability trajectories in relapsing multiple sclerosis patients treated with early intensive or escalation treatment strategies

Long-term disability trajectories in relapsing multiple sclerosis patients treated with early intensive or escalation treatment strategies

Cerebrospinal Fluid Biomarkers of Myeloid and Glial Cell Activation Are Correlated With Multiple Sclerosis Lesional Inflammatory Activity

Initial treatment strategy and clinical outcomes in Finnish MS patients: a propensity-matched study

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