Which medication is most appropriate for a patient newly diagnosed with relapsing remitting multiple sclerosis?

In the last decade neurologists have radically changed their approach to the treatment of Multiple Sclerosis (MS) due to the revision of diagnostic criteria (Thompson and Banwell, 2018), the new classification of clinical courses (Lublin et al., 2014) and the advent of more efficacious but less safe treatments, often burdened by serious side effects (Straus Farber et al., 2016). Therapeutic goal is to achieve the lowest possible level of disease activity, aiming to obtain the “No Evidence of Disease Activity (NEDA) status”, that is the absence of relapses, disability progression and Magnetic Resonance Imaging (MRI) activity (Banwell et al., 2013). These relevant developments have significantly modified the way neurologists manage MS; clinical practice often follows rules that are more flexible than the restrictive conditions imposed by Regulatory Agencies according to randomized controlled trials (RCTs) results. Choosing the first therapeutic strategy at the time of diagnosis is a complex task, with many factors contributing to the decision making process. Nowadays, European Medicine Agency (EMA) and Italian Regulatory Agency (AIFA) have approved 13 disease-modifying therapies (DMTs) to treat MS (EMA. Avonex 29/11/2018, EMA. Aubagio 27/03/2019, EMA. Betaferon 03/12/2018, AIFA Copaxone 18/01/2019, AIFA Copemyl 08/10/2016, EMA. Extavia 26/07/2018, EMA. Gilenya 09/04/2019, EMA. Lemtrada 08/02/2018, EMA.Mavenclad 08/08/2018, EMA Ocrevus 26/06/2019, EMA Rebif 13/12/2018, EMA Tecfidera 18/01/2019, EMA Tysabri 10/08/2018), each one with its own specific risk-benefit profile. Therapeutic decision must be guided by a deep knowledge of the mechanism of action and the side effects of each drug, whose efficacy was proven in RCTs (Trojano et al., 2017, Sormani and Laroni, 2017). Also, clinicians must take into account the disease status, the prognostic factors (Tintore et al., 2015 Jul) and the presence of comorbidities (Laroni et al., 2016). Finally, treatment choice is strongly dependent on MS patients’ preference that, when taken into account, can improve treatment satisfaction and adherence.

The purpose of this multicenter study is to describe the way a large group of Italian neurologists have chosen DMTs for newly diagnosed relapsing-remitting MS (RRMS) patients in the period between 2010 and 2018, to identify factors that can influence this choice and to evaluate how the new oral treatments modified neurologists’ prescriptive habits.

Study design

In this multicenter study we retrospectively enrolled patients diagnosed in 24 Italian MS centers. Inclusion criteria were: age over 16 years, diagnosis of RRMS (2001 International Panel Diagnostic Criteria and the 2010 revision) (McDonald et al., 2001, Polman et al., 2011) and initiating a DMT between January 2010 and June 2018 after the availability date of the single DMT in Italy (>2011 for Fingolimod, after 2013 for teriflunomide and after 2014 for dimethyl fumarate). Patients who

Results

A total of 3025 patients started the first therapy in the period January 2010-June 2018. Table 1. reports the patients’ characteristics according to treatment. Patients who received Azathioprine (n = 27), mitoxantrone (n = 13), Ocrelizumab (n =6) and Rituximab (n = 5) as their first treatment were not included in the analyses. Fig. 1. shows the radar chart of all demographic and clinical characteristics according to treatment.

Discussion

This retrospective, multicenter, observational study describes the frequency and the distribution of DMTs prescription at the time of diagnosis in a large Italian MS population.

We evaluated the decision-making process that leads Italian neurologists to choose the first DMT and how this process has changed in more recent years. As expected, the rate of prescription of oral drugs increased over the years at the expense of self-injectables DMTs. In fact, self-injectables therapies represented the

Conclusions

Various determinants influence first treatment choice for Italian neurologists, especially related to the degree of severity of the disease. Patient's age appears to be one of the most important factors in DMTs choice at the diagnosis. Italian neurologists preferred first-line oral drugs to self-injectables ones in the presence of unfavorable prognostic factors, as well as FTY compared to DMF. NTZ has proven to be used as a first choice in early stage of severe disease and in younger patients.

CRediT authorship contribution statement

Giorgia T. Maniscalco: Conceptualization, Writing - original draft. Francesco Saccà: Data curation. Roberta Lanzillo: Data curation. Pietro Annovazzi: Data curation. Damiano Baroncini: Data curation. Eleonora Binello: Data curation. Annamaria Repice: Data curation. Paola Perini: Data curation. Marinella Clerico: Data curation. Giorgia Mataluni: Data curation. Simona Bonavita: Data curation. Sara La Gioia: Data curation. Lorena Pareja Gutierrez: Data curation. Alice Laroni: Data curation.

Deckaration of Competing Interest

None

Acknowledgments

The authors wish to thank Novartis Pharma for supporting the meetings of the iMUST group. Novartis Pharma supported the meetings of the MUST group but was not involved in this project nor did it have any access to the data.

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