Multiple sclerosis (MS) is a lifelong, inflammatory, demyelinating, and neurodegenerative disease of the central nervous system. It typically affects young adults at working age,1 substantially reducing their work productivity and impairing their quality of life.2 Relapsing–remitting multiple sclerosis (RRMS) is the most common form of MS, and it is characterized by the occurrence of unpredictable but reversible episodes of neurological deficits (relapses) and the risk of disability progression. During the past 3 decades, the prevalence of MS has increased in many regions, including western Europe.3 In Spain, this increasing trend has also been observed, with a current MS prevalence as high as 80 to 180 cases per 100, 000 inhabitants.4

The number of disease-modifying treatments (DMTs) aimed at reducing disease activity and disability progression has considerably risen from the 1990s, with more than 12 DMTs available.5 The growing therapy armamentarium has simultaneously broadened treatment options for patients and poses disease management challenges for clinicians. When customizing treatment strategies, the efficacy and safety profile of the agent together with patient's individual disease must be considered.6

Teriflunomide 14 mg is a once-daily oral immunomodulator approved by the European Medicines Agency in August 2013 for the treatment of relapsing forms of MS or RRMS, depending on the local label. Randomized controlled trials consistently showed the efficacy of teriflunomide in reducing the annualized relapse rate (ARR),7,8 magnetic resonance imaging (MRI) markers of disease activity,7,9 brain volume loss,10 and delaying disability worsening.7,8 Its efficacy was also demonstrated in patients with a first clinical episode suggestive of MS.11 The consistent safety and tolerability profile of teriflunomide has been observed for up to 9 years of treatment, without unexpected adverse events (AEs).12,13

Real-world data (RWD) on the effectiveness and safety of teriflunomide in everyday clinical use, with a more heterogeneous patient population, is still limited, and published RWD mainly comes from studies conducted in central and northern Europe.14–17 Since MS management differs by region in terms of treatment guidelines, availability of DMTs, and prescribing practices, collecting RWD from routine clinical practice in different regions will provide further insights on the clinical outcomes of teriflunomide. The aim of the present study was to assess the effectiveness and safety profile of teriflunomide in RRMS under clinical practice conditions in two Spanish regions.

The EFFECT study showed that teriflunomide administered to RRMS patients under clinical practice conditions enabled clinical effectiveness to be achieved for up to 36 months. The ARR during teriflunomide treatment was 0.16, the incidence of relapses was lower after teriflunomide treatment, and more than 81% of patients were relapse-free at all follow-up visits. Disability stabilization was also observed, as EDSS scores remained constant over treatment. Additionally, the percentage of patients with MRI markers of disease activity decreased over teriflunomide treatment, supporting its clinical effectiveness.

These results confirm the efficacy of teriflunomide 14 mg reported in the pivotal clinical trials TEMSO7,9 and TOWER.8 In fact, the ARR after teriflunomide initiation in our study was numerically lower (0.16) than the ARR in the TEMSO (0.37) and TOWER (0.32) studies. It is worth noting that patients in our study were older (44.3, max: 70.8 years) than in TEMSO (37.8) and TOWER (38.2), where only patients up to 55 years were included. The absence of changes in the EDSS score observed here is also consistent with the slowdown in disability accumulation previously reported.7,8,18

Effectiveness of teriflunomide was not only clinically confirmed, but also radiologically. Active inflammatory lesions decreased after teriflunomide treatment, with approximately 92% of patients free from T1 Gd + lesions and 90% free from new/enlarged T2 lesions at 36 months. These findings provide further evidence for the beneficial effect of teriflunomide in attenuating MRI activity observed in clinical trials, which also reported that other MRI outcomes, such as total lesion volume or volume of T1-hypointense lesions, were lower in the teriflunomide groups compared to placebo.7,9 Similar to findings from the TEMSO study,9 the effect of MRI activity was consistent with the magnitude of relapses in our study, as both measures decreased at each follow-up visit compared to baseline. Altogether, our findings suggest that the effectiveness of teriflunomide in everyday clinical practice is similar to that observed in clinical trials.

The effectiveness of teriflunomide in our study was also similar to that reported in other RWD studies in Europe.14,16,17,19 TAURUS-MS was a prospective observational study conducted in Germany that included a larger cohort of patients (n = 1128) but with similar demographic and clinical characteristics, including age (44.3 years in our study versus 44.9 years in TAURUS-MS), previous DMT use (74.8% in our study versus 75.2% in TAURUS-MS), and median EDSS at baseline (2.0 in both).14 In both studies, the ARR was lower after teriflunomide treatment, although this reduction achieved statistical significance in the TAURUS-MS study, and only a trend towards statistical significance in our study. The lack of statistical significance in our study could be due to our smaller sample size and lower ARR prior to teriflunomide (0.20 in our study versus 0.87 in the TAURUS-MS study). The low ARR in our study is consistent with the ARR observed in other three real-world studies: 0.16 at month 12 in the TACO study—conducted in Switzerland—16 0.17 in the teri-LIFE study—conduced in Norway, Sweden, and Denmark—17 and 0.17 at year 2 in the teri-CARE study—conducted in Spain.20 Importantly, 75% of patients switched to teriflunomide due to AEs, which could also contribute to explain the low ARR observed in our study, both at baseline and during teriflunomide treatment. Stable EDSS scores up to 24 months of teriflunomide treatment were observed in these real-world studies.14,16,17,20 Our study confirmed stable EDSS at month 24 and provided further evidence of the absence of disability progression up to 36 months.

The percentage of patients who had discontinued teriflunomide treatment in our study (22.8%) was similar to the one reported in the TAURUS-MS study (21.5%).14 This percentage is within the 16% to 27% discontinuation rate range associated with first-line DMTs.21 Among reasons for discontinuing teriflunomide, AEs were reported for 34% of our patients, which was inferior to the 53%15 and 40.1%14 reported in previous real-world studies, but superior to the 11% described in the extension phase of the TEMSO trial.12 A recently published retrospective study has shown that 29% discontinued teriflunomide (37% due to AEs and 15% to poor tolerability).19

Overall, teriflunomide had a good tolerability and favorable safety profile. Most of the reported AEs were consistent with the safety profile documented in the summary of product characteristics.22 The most frequent AEs (occurring in ≥10%) were hair thinning, gastrointestinal disorders, which were also among the most frequently reported AEs in the TEMSO.7 The AEs not previously reported (dysgeusia, hyperthyroidism, insomnia, and jejunoileitis) had an incidence of 0.2 and none of them were serious. Though the overall percentage of patients with AEs in our study was within the range of previous studies,14,15 the incidence of serious AEs (1.4%) was considerably lower compared to the 12.1% and 13% reported in the real-world,14,23 the 15.9% in the TEMSO,7 and the 22% in the TEMSO extension,12 which provides further evidence of the good tolerability of teriflunomide. Case-reports of MS patients treated with teriflunomide with SARS-CoV-2 infection have suggested that these patients can continue receiving treatment with teriflunomide even if they have relevant comorbidities or clinical conditions that require hospitalization.24–26

Despite the Spanish Society of Neurology recommends teriflunomide, among other DMTs, as a first-line treatment for RRMS, our results revealed that only one-quarter of these patients received teriflunomide as their first DMT. Available data from the teri-CARE study were consistent with our findings, although the percentage of treatment naïve patients was slightly higher (36%) in that study.20 In our study, among those previously treated, the majority received interferons (18.6% sc IFNβ-1b, 15.2% sc IFNβ-1a, intramuscular 9.1% IFNβ-1a). A rater-blinded trial showed that the efficacy of teriflunomide was comparable to sc IFNβ-1a, but patient satisfaction was higher in those treated with teriflunomide.27 The DMT choice should be a shared-decision process, where not only efficacy, safety, drug accessibility, and disease activity, but also patient preferences are considered and balanced. RRMS patients prefer daily oral administration (when treatment frequency and frequency of side effects were held constant) over other routes of administration.28 Whether RRMS patient preferences are considered during treatment decision-making and satisfied over teriflunomide treatment should be investigated by future studies in the Spanish routine clinical practice.

Several limitations are associated with the present study. Due to its observational nature and the retrospective collection of data, all the study variables were not collected in every patient included in the study, and the number of patients with available data decreased at each follow-up visit, which might limit the interpretation of results. The relatively low ARR in our study might reflect a selection bias, as patients with high disease activity might be underrepresented. Data on potential factors that could affect relapses were not collected and the ARR according to previous treatment was not included, despite both aspects could have affect the ARR. The absence of a control group also prevents definitive conclusions on effectiveness and safety. Additionally, the study was conducted in several hospitals of two Spanish regions, which limits the generalizability of the results to other regions in the country. Future studies are warranted to further compare the effectiveness and safety of teriflunomide to other oral DMTs to treat patients with RRMS and to further analyze teriflunomide effectiveness and safety according to prior treatments.

Overall, results from the EFFECT study showed the sustained effectiveness and safety of teriflunomide up to a 36-month period in a real-world clinical practice setting. These findings add to the body of evidence supporting a favorable benefit–risk profile for teriflunomide, and its long-term use as a DMT option for RRMS patients.

The authors declare that the procedures followed conformed to the ethical standards of the responsible human experimentation committee and in accordance with the World Medical Association and the Declaration of Helsinki and have obtained the informed consent of the patients and/or subjects referred to in the article.

Mª Carmen Durán Herrera has received consulting fees and research support from Roche Novartis; Montserrat Gómez has received consulting fees from Genzyme, Biogen, Merck and Novartis; Francisco Padilla Parrado has received consulting fees and research support from Novartis, Sanofi and Biogen. The rest of the authors declare no conflict of interests.