Teriflunomide treatment for relapsing-remitting multiple sclerosis: An experience from Saudi Arabia

Abstract

Multiple sclerosis (MS) is a disease of the central nervous system in which the immune system attacks the myelin sheath that covers nerve fibers. It is an immune-mediated chronic inflammatory disease. Teriflunomide is a once-daily oral disease modifying therapy that was approved by the FDA for relapsing-remitting MS. This study aims to assess the effectiveness and tolerability of teriflunomide in MS patients in Saudi Arabia. A multicenter retrospective study conducted in 2 tertiary medical centers with specialized MS clinics in Saudi Arabia. All patients who used teriflunomide from March 2016 to September 2020 were included. A total of 38 people with MS (pwMS) were included which were predominantly female (60.5%) with a mean age of 37.1 years. In our study, 23.7% of pwMS on teriflunomide experienced at least 1 clinical relapse. Following the initiation of teriflunomide, 26.3% of the patients developed at least 1 new lesion on magnetic resonance imaging of the brain. No evidence of disease activity 3 was achieved in 63.2% of pwMS. Teriflunomide was discontinued in 14 (36.8%) patients. The most common reason for discontinuation was adverse effects (AEs) as reported by 8 (57.1%) patients. Overall, 18 (47.4%) of patients have experienced treatment AEs. The most reported type of AEs was hair thinning or loss which was reported by 15.8% of patients. Teriflunomide was modestly effective in controlling disease activity in pwMS in Saudi Arabia with the majority achieving no evidence of disease activity 3, although the mean expanded disability status scale increased slightly. However, the discontinuation rate was high most commonly due to AEs. Overall, the safety profile was consistent with real-world experience. Larger local studies are needed to confirm this finding.

1. Introduction

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system.^[1] It is one of the most common causes of disability in young adults, yet its etiology remains unknown.^[1] However, a mixture of genetic susceptibility and environmental factors have been identified.^[2] People with MS (pwMS) accumulate disabilities through 2 pathways: relapse-associated worsening or progression independent of relapse activity.^[3] The use of disease modifying therapies (DMTs) aims to prevent relapses and disabilities.^[4] Teriflunomide is a once-daily oral DMT that was approved by the FDA in September 2012 for relapsing-remitting multiple sclerosis (RRMS).^[5] It selectively inhibits an enzyme, dihydroorotate dehydrogenase, which is required for pyrimidine synthesis. Teriflunomide decreases the growth of activated T and B cells, which are thought to play a role in the inflammatory process in the central nervous system.^[6] More than 86,000 MS patients around the world are being treated with teriflunomide.^[7] The safety and tolerability profile of teriflunomide was clearly described in phase II and III studies in the teriflunomide clinical development program.^[8,9] Two placebo-controlled trials (TEMSO and TOWER) showcased the efficacy of teriflunomide use for RRMS treatment.^[8,10] The 14-mg dose decreased annualized relapse rate with a 31.5% reduction and showed an improvement in magnetic resonance imaging (MRI) parameters.^[11] Adverse events (AEs) reported in patients treated with teriflunomide included transaminitis, alopecia, nausea, upper respiratory tract infection, and numbness.^[11] These AEs were mild to moderate intensity, self-resolving, and infrequently resulted in treatment discontinuation.^[10] The use of teriflunomide in Saudi Arabia is not well understood and there is limited literature available on the subject. This study aims to describe the experience with teriflunomide at 2 tertiary care centers in Saudi Arabia.

2. Materials and methods

This is a retrospective multicenter observational study which utilized a consecutive sampling technique to include all pwMS who received teriflunomide for at least 1 month at King Abdulaziz Medical City in Jeddah and Riyadh, Saudi Arabia, from March 2016 to September 2020. Both centers are tertiary care hospitals with specialized MS clinics. The electronic medical records of pwMS attending these specialized clinics were reviewed to identify patients who had been treated with teriflunomide. Teriflunomide was prescribed as the label instructions 14 mg once-daily. The primary outcome of this study was to assess the effectiveness and tolerability of teriflunomide. The drug’s effectiveness was assessed by relapses and the number of new gadolinium-enhancing and T2 lesions assessed 9 months after starting teriflunomide. Tolerability was assessed based on the occurrence of AEs. The secondary outcome was to investigate the reasons for discontinuing the medication. Expanded disability status scale (EDSS) score was estimated at 2 time points: initially at the start of the study (baseline EDSS) and then at the final follow-up, either while the patient was still actively taking teriflunomide or upon discontinuation of the medication. No evidence of disease activity (NEDA) 3 was defined as the absence of clinical relapses, disability progression, and radiological activity.

Data collected consisted of demographic profile (age, gender, and nationality), disease characteristics (baseline EDSS score, prior DMTs or immunosuppression, duration of the disease, MS subtype, number of relapses in the year prior to initiation of teriflunomide), and characteristics and outcomes of teriflunomide use (duration of use, washout, and discontinuation, number of MS relapses, number of lesions on MRI brain and/or spine, final EDSS score, AEs, and reasons for discontinuation).

The data were collected and entered using Microsoft Excel and then transferred to the Statistical Package for Social Sciences version 20 (IBM Corp., Armonk ) for statistical analysis. Continuous variables with a normal distribution were represented using means and standard deviations, and continuous variables without a normal distribution were represented using median and interquartile range. Categorical variables were reported as frequencies and percentages. Coauthors had access to patients’ files from November 2020 to March 2021. Coauthors do not have access to identifiable patient information after the completion of the study.

3. Results

In the study, 38 pwMS, all of Saudi nationality, were included. The majority of these patients were between their third and fifth decade of life, with an overall age range being 18 to 66 years and a gender predilection to females (1:1.53 M:F). All patients were diagnosed with RRMS. The average duration of the disease was around 6 years ranging from 1 year to 20 years. The mean baseline EDSS score was 1.8 which slightly increased during and after treatment to 2 (range: 0–7). Only 15.8% of pwMS showed an increase in the EDSS score from baseline, while 5.3% had a decrease in their scores following treatment. Prior to the initiation of teriflunomide, 26.3% of pwMS were treatment-naive. Among those previously on DMT, the mean duration of DMT use was around 4 years and had a mean pre-teriflunomide washout period of 7.5 months. Additionally, 52.6% of the patients experienced at least 1 relapse in the year before initiating teriflunomide treatment. Prior to starting teriflunomide, almost half of patients (52.6%) underwent QuantiFERON test. The mean duration of teriflunomide use was around 2 years. Teriflunomide was discontinued in a third of patients, of those the mean washout period was 0.92 months with a range of 0 to 2 months, and cholestyramine was used for rabid elimination in 57.1% of patients. The demographics, clinical features, and reasons for discontinuation are displayed in Table 1.

Table 1.

Demographics, clinical features, and reasons for discontinuation of pwMS on teriflunomide (n = 38).

Variables	Frequency (%) or mean ± standard deviation
Age (yr)	37.1 ± 12.3
Female	23 (60.5%)
Duration of disease (yr)	6.3 ± 4.9
Duration of DMT use prior to teriflunomide (mo)	45.9 ± 43.422
Patients with baseline EDSS score ≥ 4	5 (13.2%)
Mean EDSS	1.8 ± 1.8
Patients with EDSS score ≥ 4 after treatment*	5 (13.2%)
Mean EDSS	2 ± 1.99
Duration of teriflunomide use (mo)	25.9 ± 21.9
Time to first relapse after treatment (mo)†	3.3 ± 8.3
Patients achieving NEDA 3†	24 (63.2%)
Teriflunomide discontinuation	14 (36.8%)
Reason for teriflunomide discontinuation
Adverse events	8 (57.1%)
Disease activity‡	5 (35.7%)
Patient preference	3 (21.4%)
Adverse events to teriflunomide
Hair thinning/loss	6 (15.8%)
Diarrhea	3 (7.9%)
Nausea/vomiting	2 (5.3%)
Headache	2 (5.3%)
Lymphopenia	2 (5.3%)
Abnormal LFTs	1 (2.6%)
Numbness or tingling	1 (2.6%)
Flushing	1 (2.6%)
None	20 (52.6%)

DMT = disease modifying therapy, EDSS = expanded disability status scale, LFT = liver function test, NEDA = no evidence of disease activity, pwMS = people with multiple sclerosis.

^*EDSS score at the time of teriflunomide discontinuation or at the last visit if the patient was still receiving teriflunomide.

^†For patients who used teriflunomide for at least 3 months.

^‡Discontinuation due disease activity was secondary to new radiological lesions and/or clinical relapses.

Most of pwMS (76.3%) did not experience any relapse while on the teriflunomide, whereas the rest experienced 1 relapse. One or more AEs were reported in 47.4% of patients which commonly included hair thinning/loss (15.8%), gastrointestinal symptoms (diarrhea, nausea, vomiting) (13.2%), headache (5.3%), and lymphopenia (5.3%). Before initiating teriflunomide, the distribution of MRI lesions among the patients was as follows: 18.4% had no new lesions, 31.6% had 1 lesion, 10.5% each had 2 lesions, and 34.2% had 3 or more lesions. However, after initiating teriflunomide, 73.7% of the patients had no new MRI lesions, 10.5% had 1 new lesion, 5.2% had 2 new lesions, and 10.5% had 3 or more lesions. For patients who used teriflunomide for at least 3 months, 63.2% of pwMS achieved NEDA 3.

4. Discussion

This retrospective study provides insights into the use of teriflunomide in 2 of the largest medical centers in Saudi Arabia. During a 4-year period, teriflunomide was used in 38 pwMS with 36.8% of whom discontinuing the medication mainly due to AEs. Nearly half of the cohort experienced 1 or more AEs. EDSS score after treatment was slightly higher than at baseline (1.8 vs 2), with 23.7% of patients experiencing a relapse.

The basic demographics in our cohort is similar to that of the literature. PwMS using teriflunomide are typically between their 20s and 40s, with a higher prevalence among females.^[8,12–14] Baseline EDSS score in the literature is around 2 which aligns with the fact that teriflunomide is considered a first-line or first-switch treatment option.^[8,12–15] In our cohort, the duration of the disease was 6.3 years, which varies in the literature, with reports showing a median duration of 2.74 years and mean durations of 7.55 and 10.6 years.^[12–14] Further studies could incorporate genetic data to assess whether inherited variation influences teriflunomide (or any other DMT) effectiveness and tolerability.

In our study, 23.7% of pwMS on teriflunomide experienced at least 1 clinical relapse. This is higher than findings from a prospective study of 192 treatment-naive pwMS on teriflunomide for at least 3 months, where only 8.3% experienced clinical relapses and 79% showed NEDA 3 at 12 months.^[12] Additionally, a large German study reported that only 4.2% of 1139 pwMS using teriflunomide experienced a relapse.^[13] There was no notable difference in the population of our cohort and the aforementioned studies in terms of age, gender, disease duration, treatment-naive status, and baseline EDSS score. Although the proportion of clinical relapses in our study is relatively high, the EDSS score at the end of the study aligned with existing literature. Given that our center is a tertiary care center which accepts referrals from the Western region of Saudi Arabia, it is likely that our patients have a severer disease course. Furthermore, Alluqmani et al conducted retrospective study comparing 2 pwMS in Saudi Arabia with those in Canada and found that the Saudi group experienced a more severe disease course.^[16] After initiating treatment, 73.7% of our cohort showed no new gadolinium-enhancing or T2 lesions at 9 months. This suggests that despite the clinical appearance of relapses, there was no significant neuroradiologic evidence of new lesions. A study was conducted in Saudi Arabia in patients using oral DMTs and showed that out of 8 patients, the annualized relapse rate is 0.5. A study in the neighboring country Kuwait showed significant reduction in relapse rate while using teriflunomide with only 7% experiencing a relapse.^[17] Large studies on teriflunomide, which take into account genetic and environmental factors in Saudi Arabia and neighboring countries, are needed.

Zhang et al reported that 69.9% of pwMS on teriflunomide reported experiencing 1 or more AEs, yet only 8.3% discontinued the medication due to these AEs.^[12] Notably, 28% of those who stopped the medication within 3 months of starting did so because of AEs.^[12] In our cohort, 47.4% experienced 1 or more AE, and 57.1% of those who discontinued the medication did so because of these AEs. Similarly, Alnajashi et al reported a discontinuation rate of 15.9% which was primarily due to AEs in 42% of patients.^[15] Hair thinning/loss, abnormal liver function tests (LFTs), leukopenia, and diarrhea have been consistently reported in the literature at varying rates.^[12,13,15] Hair thinning is an important side effect which may cause psychological stress on the predominantly female patient population using teriflunomide. Monitoring liver function and blood count is essential and switching medications due to laboratory derangements remains a possibility.^[18] Liver enzyme levels were measured at baseline, then again at 1 month, and at 6 months of treatment. We found that only 1 patient experienced abnormal LFTs. Ethnic and genetic factors may play a factor into the presence or the severity of these AEs. It has been hypothesized that due “ethnic heterogeneity,” the Asian population might be more susceptible to abnormal LFTs and leukopenia.^[12] Discussing these AEs with patients is crucial to ensure they are informed about potential side effects, understand the importance of regular monitoring, and can make informed decisions about their treatment options. Regular monitoring helps in the early detection and management of these AEs, ensuring better overall patient care. Patient preference was cited as the reason for discontinuation in 21.4% of cases. Patients may opt against daily medication, especially when alternatives such as DMTs administered once a month or every 6 months are available.

According to the US Food and Drug Administration’s approved labeling for teriflunomide, pwMS should be screened for TB.^[19] Screening becomes more important in countries with high TB prevalence, such as Saudi Arabia which is endemic with TB.^[20] Our study found that nearly half of pwMS using teriflunomide did not undergo TB screening. Educating physicians and pwMS about the importance of TB screening is imperative in Saudi Arabia. It has been suggested that teriflunomide may cause false negative results in QuantiFERON test, indicating that testing pwMS after they have started teriflunomide could lead to inaccurate results.^[21]

This study was limited by its retrospective chart-based design, which relied on the accuracy and completeness of existing medical records, potentially introducing biases. The small sample size limited our ability to perform inferential analysis and hindered generalizability. Accordingly, any apparent lack of differences in demographic or clinical characteristics should be interpreted as descriptive only, since the study was underpowered to detect modest between-group differences.

Teriflunomide is an oral treatment option that offers convenient administration and a reasonable safety profile. Our findings largely align with existing literature, with the primary difference being the rate of relapse. Nearly 1-in-4 patients in our cohort experienced at least 1 relapse while using teriflunomide; however, the EDSS score after treatment remained comparable. AEs continue to be a significant factor in both the selection and discontinuation of teriflunomide. Strict compliance with QuantiFERON testing before starting teriflunomide is essential.

Acknowledgments

We extend our gratitude to Dr Rania Al Juhani for her diligent efforts in data collection.

Author contributions

Conceptualization: Morad Aljinaid, Ahmad Abulaban, Yaser Al Malik, Seraj Makkawi.

Investigation: Morad Aljinaid, Osama Khojah, Layan Arshad, Raghad Algahtani, Ziyad Alghweinem, Sultan Alshehri, Ahmad Abulaban, Yaser Al Malik, Seraj Makkawi.

Methodology: Morad Aljinaid, Osama Khojah, Ahmad Abulaban, Yaser Al Malik, Seraj Makkawi.

Supervision: Ahmad Abulaban, Yaser Al Malik, Seraj Makkawi.

Writing – original draft: Osama Khojah, Ahmad Abulaban, Yaser Al Malik, Seraj Makkawi.

Writing – review & editing: Morad Aljinaid, Osama Khojah, Layan Arshad, Raghad Algahtani, Ziyad Alghweinem, Sultan Alshehri, Ahmad Abulaban, Yaser Al Malik, Seraj Makkawi.