Multiple sclerosis (MS) is the most common chronic neurological disorder in young adults, usually diagnosed when patients are between 20 and 40 years old. The disease is a potentially severe cause of disability throughout adult life, impairing work capacity1 and health-related quality of life (HRQoL),2 among other aspects of patients' lives. MS prevalence has increased in western Europe,3 including in Spain,4 in recent decades, and the disease affects at least 2.8 million people worldwide.5

A considerable number of disease modifying treatments (DMTs) that substantially improve the prognosis of MS are now available.6 Growing therapy options for patients have also posed challenges for clinicians in terms of disease management. The efficacy and safety profile of the DMT along with the patient's individual disease should be taken into consideration when designing personalized treatment strategies.7,8 Patient preferences are also a key factor for the DMT choice, since choosing a DMT according to patients priorities may increase treatment acceptance and adherence9 and decrease the healthcare resource use.10 For instance, route of administration plays an important role in patients' preference, and most MS patients have reported to prefer an oral DMT.11

Teriflunomide, a once-daily oral DMT, is approved for the treatment of relapsing forms of MS (RMS) or relapsing–remitting MS (RRMS), depending on the jurisdiction. The efficacy and safety of teriflunomide were established in several randomized clinical trials (RCT) and follow-up studies. The TEMSO and TOWER RCT showed that, compared to placebo, teriflunomide reduced the risk of relapses and the annualized relapse rate (ARR), and delayed disability worsening.12,13 Teriflunomide also was shown to be effective in reducing lesion volume and brain volume loss (BVL) observed on brain magnetic resonance imaging (MRI).12,14,15 Teriflunomide's efficacy was similar to high-dose subcutaneous interferon-beta-1a in the TENERE RCT, but patients' satisfaction with teriflunomide was higher.16 RCT and real-world evidence (RWE) has confirmed that teriflunomide has a manageable safety profile and is generally well-tolerated for up to 9 years of treatment.17–21 Most common (>10%) adverse events (AE)—nasopharyngitis, hair thinning, gastrointestinal disorders, and alanine aminotransferase (ALT) elevation—are usually transient and mild to moderate in severity.

Even though the safety and effectiveness profile of teriflunomide in the real-world patient had been confirmed by several RWE studies in Europe,20,22–24 only 2 of the published studies were conducted in Spain, and they were limited to the Valencian Community25 or the southern regions.26 Due to differences in MS management guidelines, treatment availability, and prescribing practices between regions, collecting data from the clinical practice of different regions will provide valuable insights into the outcomes of patients treated with teriflunomide. Here, we present data on teriflunomide safety and effectiveness in RRMS patients treated according to the clinical practice of the central regions of Spain (Community of Madrid and surrounding areas).

The TERICAM study retrospectively collected data from 776 adults diagnosed with RRMS receiving teriflunomide according to the clinical practice of 15 hospitals in Spain. The study provides insights into the real-world outcomes of teriflunomide over 24-months, confirming the effectiveness and safety reported in RCTs12,13,17 and other real-world studies.20,25–30 The main value of real-world studies, such as the present study, is that the effect of treatment can be observed in a more heterogeneous sample of patients (usually older and with a longer history of prior treatments), providing further evidence to data from RCTs and other observational studies conducted in different clinical settings.

Here, and in line with other real-world studies,25–28 patients were older and with longer disease duration than in RCTs.12,13,17 Even in this population, the ARR after teriflunomide treatment observed here was lower than in RCT,12,13,17 and it was comparable with the very low ARR observed in the routine clinical practice.25,26,28,31 ARR decreases during teriflunomide treatment seem to be independent of age. In fact, analysis of the TAURUS-MS I study showed significant improvements in clinical activity both in younger and in older patients.32

In our cohort, the proportion of patients who received another treatment prior to teriflunomide (usually a BRACE) was considerably higher than the percentage of treatment-naïve patients. This was the case even if teriflunomide was recommended by the Spanish guideline as initial treatment, similarly to the recommendation regarding initiating BRACE or dimethyl fumarate treatment.33 The fact that teriflunomide was beneficial, even if it was not always used as recommended by the Spanish guideline, provide further evidence of its effectiveness in RRMS patients regardless of treatment line. The effectiveness of teriflunomide in patients who have discontinued other DMTs has been shown by post-hoc analysis from the TEMSO and TOWER RCTs34 and by a recent analysis of the real-world TAURUS-MS I study.32 We did not have data on the satisfaction of previously treated patients, but the TERI-PRO real-world study showed that patients switching from other DMTs to teriflunomide were more satisfied after teriflunomide initiation (assessed after 4 and 48 weeks), regardless of the reason for switching.35 The recently published Teri-LIFE study also showed that satisfaction with teriflunomide resulted in high treatment adherence and decreased healthcare utilization.10 Future studies assessing patient satisfaction after switching to teriflunomide are warranted.

The effect of teriflunomide on radiological activity was consistent with the magnitude of improvement in relapses. Measures of clinical (ARR, relapse-free patients) and radiological activity (number of patients with Gd+ T1 lesions or new/enlarged T2 lesions) decreased throughout the 24-month follow-up compared to baseline. A significant reduction of these MRI lesions after 2 years was also observed in patients from the TEMSO trial across age groups.36 Few studies from the clinical practice have provided MRI data during teriflunomide treatment,25–27 and hence the availability of radiological data in a high number of patients here constitutes a strength of the present study.

At teriflunomide initiation, the mean EDSS score was below 2 (2=minimal disability in 1 functional system), suggesting that even if most patients were previously treated, their degree of disability was still mild. In terms of disability worsening, the EDSS did not show clinically significant changes during teriflunomide treatment. Even if the Wilcoxon test revealed a statistically significant result when comparing the EDSS at baseline (1.9) with the EDSS at month 24 (2.0), an increase of 0.1 points in the EDSS after 2 years is not considered clinically meaningful and therefore our data showed that disability was sustained during the 24-months period. Similar EDSS scores at teriflunomide initiation and during the following 2 years of treatment were observed in real-word studies from Germany27 and Spain.25

Concerning safety outcomes, half of the patients experienced AEs after teriflunomide initiation. The proportion of patients with AEs is identical to the real clinical practice in Denmark,20 but slightly higher than in Germany,27 and other regions in Spain.26 As expected, the number of AEs was considerably lower than in the core trials.26 No new or unexpected AEs were observed with teriflunomide treatment, supporting a safety profile consistent with outcomes from controlled37 and real20,26,27,37 clinical contexts. Gastrointestinal disorders were the most common AEs in general and the most common AE leading to discontinuation. Gastrointestinal disorders as the most frequent AE causing discontinuation is in agreement with studies from clinical practice in Denmark20 and Italy,28 but was rarely a cause of discontinuation in the pivotal trials.18

When all potential reasons for teriflunomide discontinuation were considered, lack of effectiveness, and not AEs, was the most frequent reason. The description of the characteristics of those patients discontinuing teriflunomide due to lack of effectiveness showed that these patients had a more active disease than the overall study population (66.9% patients with relapses in the 2 prior years in the subgroup of patients who discontinued due to lack of effectiveness vs 52.9% patients in the overall study population). Considering other real-world studies of teriflunomide in Spain, lack of effectiveness was the main cause of withdrawal in the study by Landete et al., where 82% of those who discontinued did so for this reason,25 but was only reported by 16% in the study by Duran et al.26 This apparent inconsistency might be explained, at least in part, by the follow-up time, which was longer in the former study25 than in the latter.26 Buceli et al. distinguished between discontinuation of teriflunomide occurring before and after 3 months of treatment and observed that early discontinuation was mainly due to AEs and tolerability, whereas later discontinuation was mainly due to disease activity.25 However, since in both studies the observation time was superior to 3 months, another possible explanation for this discrepancy could be the methodological limitations inherent to retrospective studies. That is, reasons for teriflunomide discontinuation might not have been consistently collected and in a structured format in the clinical practice. In line with this argument, almost one-quarter of our patients did not have the reason for teriflunomide discontinuation specified in their health records.

Importantly, most patients did not have fatigue increases while treated with teriflunomide, as shown by the absence of fatigue reported as an AE. Stabilization of fatigue was also observed in the TAURUS-MS study, as assessed by the Fatigue Severity Scale (FSS).27 The presence of severe relapses has been associated with increases in fatigue and HRQoL worsening.38 In our study, most patients were relapse-free, which might have contributed to fatigue control. A prospective study that evaluated fatigue using the Modified Fatigue Impact Scale (MFIS) in France showed that fatigue scores remained stable during teriflunomide treatment over 2 years.39

Methodological limitations need to be considered, however, for a proper interpretation of the study findings. First, due to the retrospective nature of the study, study variables were not available in every patient; moreover, the AEs reported here were collected using a list of pre-defined AEs, and some AEs outside of that list might have occurred and not have been reported here. Second, disability outcomes were only assessed using the EDSS, which, even if it is the most widely used tool, is not free from limitations. Future real-world studies should aim to provide results from other disability function tests such as the Timed 25-Foot Walk (T25FW) or the 9-Hole Peg Test (9HPT), together with assessments of cognitive status and patient-reported outcomes (PROs). The use of PROs to assess symptoms such as fatigue would have provided a better understanding of these symptoms. Moreover, not all patients had an EDSS assessment at baseline, and confirmed disability progression (CDP) was not assessed. Third, a comparator group treated with a different DMT was not included. Fourth, patient's drop-out may have led to incomplete AE reporting and a potential underestimation of the true incidence of AEs in our study population. Another limitation of our study is the lack of data on the number of patients lost to follow-up. Not having the exact number of patients lost to follow-up at each stage of the study may have influenced our results. The absence of this information makes it challenging to assess the potential impact of attrition bias on our findings, as well as to estimate the true proportion of patients who remained relapse-free during the study period. Lastly, we only described the characteristics of patients who discontinued teriflunomide due to lack of effectiveness but did not analyze the characteristics of those who did not discontinue teriflunomide for these reasons, nor did we compare both groups. This analysis is of interest and could be the objective of future studies. Despite these limitations, the present study still contributes to the overall understanding of teriflunomide effectiveness and safety in a real-world setting. Real-world studies describing outcomes of patients who benefit the most from teriflunomide treatment will enable healthcare providers to offer personalized treatment and better inform their patients about their options.

Most RRMS patients treated with teriflunomide had previously received other treatments for their MS. Our findings suggest that teriflunomide was associated with decreased clinical and radiological activity and a stabilization of disability. However, it is important to acknowledge that the lack of a comparator group in our study design limits our ability to draw definitive conclusions regarding the effectiveness of teriflunomide compared to other treatments. The safety profile was in line with prior observations. Most patients did not report fatigue increases after teriflunomide initiation. Overall, the benefit–risk profile of teriflunomide remains favorable. Future research involving comparator groups would be valuable in further establishing the effectiveness and safety of teriflunomide in the management of RRMS.

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  Conceptualization: Mª Luisa Martínez Ginés, Alberto Lozano Ros

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  Data curation: Mª Luisa Martínez Ginés, Alberto Lozano Ros

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  Investigation: All authors

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  Supervision: Mª Luisa Martínez Ginés, Alberto Lozano Ros

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  Writing - review & editing: All authors

This study received funding from Sanofi. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.

All patients signed written patient informed consent for using their medical data for the purpose of this research.