Multiple sclerosis (MS) is an inflammatory, demyelinating, neurodegenerative, and progressive autoimmune disease of the central nervous system (1). The exact aetiology of MS is not known. Various hypotheses have linked infection, genetics, and a possible autoimmune mechanism to MS (2). In most cases, patients with MS first experience an acute inflammatory demyelinating event and progress to relapsing–remitting MS, which is marked by distinct acute events of deteriorating neurological function (relapses) followed by partial or total recovery (remission). The relapsing–remitting disease course may evolve into a secondary progressive stage with or without occasional relapse, minor remissions, and plateaus (3). MS imposes a considerable burden on patients, caregivers, and society because of the early age of MS disease onset (4). Without a definitive cure for MS, disease-modifying drugs (DMDs) are the current mainstream treatment, aiming to alleviate symptoms, reduce the number of MS relapses, prevent new lesion formation, and potentially slow down disability progression (5–7).

As MS is a chronic condition, its successful treatment requires adherence to prolonged therapy. Maintaining a dosing regimen is critical for achieving the defined therapeutic outcomes. Several studies have shown that adherence to MS treatment is associated with fewer relapses, a slower rate of disease progression, less patient disability, reduced healthcare resource utilisation, lower costs, and improved quality of life (8, 9). However, evidence suggests that adherence to MS treatments is suboptimal (10), with 41–88% of patients not adhering to the DMDs as prescribed (11). In addition, poor drug adherence or treatment gaps have been linked to a higher risk of relapse (12).

The treatment gap associated with DMD use is frequently influenced by patient beliefs and choices, resulting in an unmet need for effective long-term treatment support and management. Several strategies have been investigated and implemented to improve drug adherence, including patient support programmes (PSPs) and innovative injectable devices (13, 14). PSPs may improve treatment adherence as well as clinical outcomes (13, 15). Real-world adherence studies on RebiSmart®, an autoinjector device for MS treatment, have shown that the device helps patients adhere to therapy and potentially improve clinical outcomes (14, 16).

Subcutaneous interferon beta-1a (sc IFN β-1a) is a well-established immunomodulating DMD for clinically isolated syndrome and relapsing multiple sclerosis (RMS) (17) with an estimated cumulative exposure of 1,908,836 patient-years (until September 2022) (18). The effectiveness of sc IFN β-1a in lowering MS disease activity (as measured by clinical outcomes and magnetic resonance imaging surrogate measures) has previously been demonstrated (17, 19, 20). In clinical trials, 22 or 44 μg three times weekly (tiw) sc IFN β-1a has been shown to have a positive benefit, to risk profile and is well tolerated (17, 19, 20). In addition to sc IFN β-1a, the current landscape of MS therapies includes injectables such as other interferons (intramuscular IFN β-1a and IFN β-1b) and glatiramer acetate; oral DMDs such as teriflunomide, dimethyl fumarate, fingolimod, cladribine tablets, and siponimod; and infusion therapies such as natalizumab, alemtuzumab, and ocrelizumab (21–24). Considering patient characteristics, disease severity, the number of alternative therapies (oral and injectable) available for MS management, recent guidelines suggest individualised therapies (21). In the context of an ever-evolving treatment landscape, sc IFN β-1a, recognised for its clinical efficacy and established safety profile, continues to address the unique needs of patients with MS (24).

This study assessed adherence and clinical outcomes of patients with relapsing MS who were prescribed sc IFN β-1a (with or without RebiSmart® device) over a period of 24 months. We also assessed the benefits of additional support through enrolment in a PSP.

Because MS is a chronic disease, long-term adherence to treatment can be challenging to achieve desired clinical outcomes. Adherence to medication is a critical factor for patients with MS, as long-term use of the healthcare professionals (HCPs) prescribed DMDs that are usually associated with reduced relapse rates, reduced disease progression, and increased drug efficacy (9, 11, 12, 27). The most common reasons for failure to adherence to treatment are forgetting to take the medication, patient-perceived lack of efficacy, injection anxiety, as well as AEs related to injection site reactions, flu-like symptoms, and fatigue (28). The use of support strategies (15, 29) and treatment maintenance methods (14, 30, 31) are being investigated to overcome poor adherence.

In this study, it was observed that more than 50% of the patients self-reported high adherence to the sc IFN β-1a treatment as assessed using the MGLS score at 24 months. The sensitivity analysis to include the last observed non-missing MGLS scores further increased the proportion of patients reporting high adherence to 77%. Another important observation in this study was that adherence to sc IFN β-1a treatment remained relatively stable over the study period at 6, 12, and 18 months when considering evaluable non-missing MGLS scores. Patients continued to report high adherence over 6–18 months. Adherence to sc IFN β-1a treatment has been studied previously; a narrative review of the literature on treatment adherence to DMDs by Menzin et al. has reported high medication adherence rates, ranging from 58.5 to 77.6% for sc IFN β-1a treatment in patients with relapsing MS (11).

In this study, because a relatively low number of patients used the RebiSmart® device and the results of subgroup analysis were inconclusive, we have not described them further. However, previous studies have reported that the use of RebiSmart® device assists in improving adherence to sc IFN β-1a therapy (16, 30, 31). The results from the recent REBIFLICT study have shown that high adherence (97.9%) to sc IFN β-1a therapy was achieved with the RebiSmart® device over 24 months. Of note, the REBIFLICT study assessed adherence on the assumption that treatment adherence and clinical data were frequently communicated to patients by their attending physicians (30). The READOUT smart study reported a mean quantitative adherence rate of 85.3% over 24 months (31). The results from the SMART study has also shown that patients with relapsing MS using RebiSmart® device to self-inject sc IFN β-1a had excellent adherence at the end of 12 months and had good clinical outcomes. In addition, patients reported that the RebiSmart® device was convenient and easy to use (16).

Clinical efficacy was evaluated in terms of relapse rates and EDSS outcomes. More than 50% of the patients were relapse-free at 24 months or early withdrawal, and 17.2% patients had experienced mostly 1 to 3 relapses. In the pivotal PRISMS study, 45% and 32% of the patients receiving sc IFN β-1a 44 μg were relapse-free at year 1 and year 2, respectively (20). Moreover, in this study, the median EDSS scores (≤3) were stable during the assessments conducted at pre-specified timepoints throughout the study, and the proportion of patients with EDSS progression was relatively low (12.3%). The beneficial effect of sc IFN β-1a on EDSS progression observed in our study was consistent with previous findings (32–34).

Furthermore, in our study, the adherence to sc IFN β-1a was slightly higher in the patients who were relapse-free compared to patients who had at least one relapse. Previous studies have indicated that adherence to sc IFN β-1a treatment is associated with a lower probability of relapse (35, 36). For example, the STAR study by Huppert et al. showed that the proportion of patients with MS with good adherence were relapse-free at 12 months compared to those with fair or poor adherence (77.6% vs. 50.0%; p = 0.0107) (37).

There is limited information on the benefits of PSP participation in MS (29). However, PSPs have been found to provide potential benefits in other therapeutic areas such as cardiovascular disease, diabetes, and asthma (38). Structured PSPs with skilled healthcare workers and specialised nurses enable continuous patient education and provide support to patients initiating immunotherapies, which may have an immense impact on health-related outcomes in patients with MS (39). A large retrospective cohort study (N = 3,993) by Tan et al. evaluated the impact of a speciality care management programme amongst patients with MS. The findings suggested that the speciality care management programme was not only associated with improved treatment adherence and persistence but also reduced MS-related hospitalisations and decreased MS-related costs (13). Notably, a large proportion of patients in the study were receiving interferons as MS medication (intramuscular IFN β-1a: 37.3%; sc IFN β-1a: 16.6%; and IFN β-1b: 13.5%) (13). Another study by Lenz and Harms showed that, amongst patients with mild-to-moderate relapsing-remitting MS, adherence to disease-modifying therapies was significantly higher in PSP participants than in the non-PSP participants (92.9% vs. 61.8%; p = 0.0197) irrespective of treatment duration (15). Consistent with these previous reports, in the present study, the proportion of patients reporting high adherence to sc IFN β-1a was higher in the patients assigned to PSP (65.8%) compared to those not assigned to PSP (56.5%). In addition, a lower proportion of patients discontinued the treatment by 24 months in the PSP subgroup than in the non-PSP subgroup. Furthermore, the mean time-to-treatment discontinuation was longer in the PSP subgroup than in the non-PSP subgroup. It must be noted that the patients in the study had a baseline mean and median EDSS of 1.8 and 1.5, respectively, representing a mild active disease. These findings highlight the importance of enhancing and promoting strategies (such as PSPs) to manage patient expectations and AEs and educate patients, families, and caregivers about establishing patient–physician relationships and the benefits of participation in PSPs (40).

Study discontinuations and sc IFN β-1a treatment discontinuations were observed in more than 30% of the patients over the 24 months. The most common reasons for these discontinuations (study and treatment discontinuation) were AEs, being lost to follow-up, and a lack of efficacy. In a real-world cohort study by Espin and Munschauer, the discontinuation rates to sc IFN β-1a treatment were 36.9% in year 1 and 49.5% in year 2 (41). In general, previous study reports have shown higher discontinuation rates with sc IFN β-1a treatment (41, 42). The retrospective (43) and prospective observational (37) studies have shown AEs as one of the most common reason to discontinue IFN-β therapy in real-world settings.

In terms of safety, sc IFN β-1a tiw already has a well-established safety profile supported by more than 20 years of clinical and real-world evidence (44), and most AEs associated with sc IFN β-1a are mild to moderate in nature. The most commonly reported AEs with sc IFN β-1a treatment are influenza-like illness, injection site reaction, and headache (45). Overall, no new safety concerns were observed in our study. Consistent with the known safety profile of sc IFN β-1a, the most frequent AEs (reported by ≥2% of patients) in our study were influenza-like illness, pyrexia, headache, MS relapse, asthenia, and injection site reaction. The five treatment-related SAEs, which included two cases of depression and one case each of anaemia, increased liver function test values, and decreased white blood cell count, were also consistent with the known safety profile of sc IFN β-1a used in the approved indication.

Although our study was not designed to, or aimed at, comparing the treatment adherence of injectable therapies and other approved MS DMDs, this is an important aspect, especially considering the evolving MS treatment landscape and shifting prescription trends. For example, data from a recent cross-sectional study showed significant changes in the initiation patterns of DMDs in MS, with patients receiving treatment earlier in their disease course and a shift towards oral therapies from the platform injectable therapies (46). The exact reasons for this shift were not determined but were attributed to factors such as convenience of administration, insurance limitations, and advertising strategies (46). Of note, prescription trends for MS vary across different regions and countries and treatment choice also depends on the availability of DMDs in the region (47). In general, adherence to the DMDs in MS varies widely between 41% and 93% and has been attributed to factors such as patient-specific factors, therapy-specific factors, management, and healthcare system-related factors (11, 48).

Considering this recent shift in prescription towards oral therapies in MS, it is also pertinent to understand the impact of the route of administration on DMD adherence. The rate of adherence to injectable therapies in patients with MS has been reported as being between 41 and 88% (11). A few studies have compared adherence between oral DMDs and injectable DMDs. A recent study by Martinez et al. reported that a change in the route of administration from injectable to oral was associated with increased adherence (49). Two retrospective analyses of short-term claims data in the US observed higher adherence to the treatment in patients initiating an oral DMD (fingolimod) compared to those initiating injectable DMDs (50, 51). Another retrospective analysis of claims data for MS patients in the US, however, observed no difference in adherence between patients initiating oral DMDs and those initiating injectable treatment (10). The study reported suboptimal adherence with both types of treatment (10). Another US claim analysis, by Munsell et al., assessing prescribing patterns for oral and self-injectable DMDs, reported that the route of administration was not a significant predictor of treatment non-adherence (52). A cross-sectional study in Spain reported higher adherence to the injectable compared to the oral therapies attributed mainly to forgetfulness (53). Furthermore, a meta-analysis by Nicholas et al. assessed the rates of adherence and persistence for once-and twice-daily oral DMDs in patients with MS using real-world data (54). The meta-analysis indicated that approximately 20% patients with MS do not adhere to, and approximately 25% discontinue, daily oral DMDs within 1 year of treatment initiation (54). Therefore, with this limited and varied evidence, it is difficult to establish a clear difference in adherence between oral and injectable DMD therapies, and further research on this topic is warranted.

There were a few limitations of this study that should be considered when interpreting the results. Because this non-interventional study was open-label and observational, there was limited control over the outcome assessments as patient monitoring and diagnoses were performed as per standard care. This could have led to potential enrolment and information bias. Regarding enrolment bias, there is a possibility that the demographic characteristics/disease status of patients who participated in this study may differ from those who did not participate. Information bias may result from differences in collected data, such as accuracy/completeness that may misclassify patients in terms of exposures or outcomes. To minimise these study limitation, standardised case report forms, systematic site training and monitoring, and other guidance documentation were used to ensure consistent data collection. However, the relatively higher study and treatment discontinuation (>30% of the enrolled patients) rates may have affected the results. To limit the effect of missing data on MGLS scores, a sensitivity analysis was performed. Furthermore, variability in the treatments received may limit reliability of the interpretations of the results.

This non-interventional study demonstrated high patient adherence to sc IFN β-1a treatment as assessed using MGLS. PSP participation had an added benefit as the number of patients reporting high adherence was slightly higher in patients assigned to a PSP than in patients not assigned to a PSP. Favourable clinical outcomes in terms of low relapses could be correlated with high drug adherence. Overall, no safety concerns were observed in this study. The safety profile was consistent with the known safety profile of sc IFN β-1a used for the approved indication. The findings of our study add to the available data regarding treatment adherence with sc IFN β-1a in patients with relapsing MS and may help HCPs to make informed decisions about treatment maintenance.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethical approval (MOH-2021-1670) was obtained from the institutional review boards at the Ain Shams University and at each of the other participating centers of the respective countries in accordance with their ethical regulations and was conducted according to the Declaration of Helsinki. An informed consent form was signed by each patient. The patients were free to withdraw consent at any time without prejudice to their medical care and were not obliged to state their reasons. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

RA-R: Conceptualization, Data curation, Formal analysis, Methodology, Supervision, Writing – review & editing. MZ: Conceptualization, Data curation, Formal analysis, Methodology, Supervision, Writing – review & editing. EC: Conceptualization, Data curation, Formal analysis, Methodology, Supervision, Writing – review & editing. KT: Conceptualization, Data curation, Formal analysis, Methodology, Supervision, Writing – review & editing.