EPID-MS Evaluation of the drivers of the therapy switch in active RRMS and active SPMS patients.

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Introduction and aims
The clinical course of MS is increasingly considered as a continuum but the classification in classic clinical phenotypes remains fundamental in clinal practice and academic world. Approximately 85% of people with MS are initially diagnosed with the relapsing-remitting form of MS (RRMS), typically between the ages of 20 and 40 years. Primary progressive MS (PPMS) is not considered as a separate entity but part of the spectrum of progressive disease, including the challenging definition of secondary progressive MS (SPMS).
Moreover, different recently published therapeutic studies have included patients with relapsing MS (RMS), a term that comprises active RRMS and SPMS patients, and consequently health authorities have granted the authorization of DMTs to patients with RMS.
The therapeutic scenario for MS patients has widely expanded during the past 20 years but a large proportion of patients continue to experience clinical and subclinical disease activity.
Reasons for suboptimal response to DMTs may vary considering the highly heterogeneous nature of the disease, but switching patients who experience a suboptimal treatment response on one DMT to a more effective option is crucial to minimize the accumulation of disability and delay disease progression. In patients who experience first-line treatment failure or who have a high risk of reactivation of the disease after discontinuation of treatment, it is reasonable to consider highly effective therapies.
The primary objective of this study is to assess clinical and therapeutic characteristics of the RMS patients in the Italian Multiple Sclerosis Registry (IMSR), in order to evaluate the percentage of patients switching DMT due to disease activity, defined as occurrence of relapses, and to describe the different drivers of treatment patterns during the disease course.

Results
The study has been conducted using longitudinal, retrospectively acquired clinical data extracted from the Italian MS register.
Patients with RRMS and SPMS disease course, with ≥ 5 year follow-up, with a first medical visit within 3 years from the disease onset and at least 3 Expanded Disability Status Scale (EDSS) score evaluations were extracted from the IMSR database.
In order to define the MS phenotypes, we used the following definitions:
- RRMS definition according to McDonald 2010 criteria;
- SPMS definition: data-driven SPMS definitions based on a modified version of the Lorscheider’s algorithm (DDA);
- Active RRMS and SPMS: RRMS and SPMS with at least one relapse in the last 2 years of follow up available;
- All RMS: Population of all patients with active RRMS and active SPMS (as above).
To evaluate the impact of disease activity in the choice of the next therapeutic strategy, we have first determined the proportion of patients with relapses occurred during treatment, then we evaluated how these disease activity measures can influence the treatment switch.
The effect of demographic, clinical and DMT exposure on the risk of treatment switch was assessed using multivariable logistic regression models.
The role of DMTs exposure was assessed in 2 different models including: last recorded DMT or last DMTs grouped according to their efficacy and mechanism of action (MoA) (moderate efficacy (ME), high efficacy (HE) DMTs, anti-CD20 drugs).
The final cohort was composed of 21,174 RRMS and 1153 SPMS patients. Using a clinical definition, we identified 4161 RR (19.7%) and 578 SP (50.1%) active patients, of whom 2694 (56.8 %) switched DMT. RMS patients were significantly younger (median (IQR) years: 36.50 (29.10-44.80) years vs 39.60 (32.80-48.00), p<0.0001), less disabled (median (IQR) EDSS score: 2.00 (1.00-3.50) vs 2.50 (1.50-4.00), p<0.0001), more frequently affected by a RR disease course (89.8% vs 85.2%, p<0.0001) in comparison with not active patients. The multivariable logistic regression model performed revealed that Alemtuzumab (OR 0.08 95% CI 0.02-0.37), Natalizumab (OR 0.48 95% CI 0.30-0.76), Ocrelizumab (OR 0.1 95% CI 0.02-0.45) and Rituximab (OR 0.23 95% CI 0.06-0.82) were protective factors against treatment switch due to relapses in comparison with patients exposed to Interferon beta products. Our model also revealed that the use of HE DMTs was a protective factor against the treatment switch due to a relapse (OR 0.43 95% CI 0.31-0.59), especially considering anti-CD20 drugs (OR 0.14 95% CI 0.05-0.37) in comparison with the use of ME DMTs.

Conclusions
In conclusions, our results showed that clinical disease activity is an important trigger of treatment switch in RMS patients. HE DMTs, especially those with anti-CD20 MoA, significantly reduce the risk of disease activity in RMS.



Pubblicazioni e Comunicazioni a Congressi/ Publications and Congress Presentations
The present work has been accepted for poster presentation at the following congresses:
• 38th Congress of ECTRIMS - OCTOBER 2022: “Drivers of therapy switch in relapsing multiple sclerosis: a study from the Italian MS Registry” - Session Title: Poster Session 1; Session Date: 26.10.2022; Presenting Time: 16:30 h; Poster Number: P371.
• -52° SIN Congress - Milano 2022: “Evaluation of determinants of therapy switch in Relapsing Multiple Sclerosis: a study from the Italian MS Register” - Session Title: Poster Session Multiple Sclerosis 1; Session

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