Disease-modifying agents (DMAs) are considered the primary therapeutic option for patients with multiple sclerosis (MS) to reduce the annualized relapse rate (ARR) and to delay disability progression (Comi and Radaelli, 2017; Rae-Grant et al., 2018). Historically, conventional treatment of MS involved first-line, self-injectable DMAs (interferon-beta and glatiramer acetate) that reduce the ARR by about 30% (Järvinen et al., 2016; Scolding et al., 2015). However, the introduction of oral DMAs into the United States (US) in 2010 changed MS prescribing practices. For MS patients, oral DMAs (fingolimod [FIN], teriflunomide [TER], dimethyl fumarate [DMF], siponimod, cladribine, diroximel fumarate, monomethyl fumarate, ponesimod, and ozanimod) offer more flexible dosing and convenient administration. Furthermore, oral DMAs have shown similar or greater effectiveness than conventional injectable DMAs, reducing ARR by 31%−58% (Ontaneda et al., 2019a). Since the first oral DMA was approved over a decade ago, several studies have reported a significant increase in the overall number of prescriptions for oral DMAs in the US (Elsisi et al., 2020; Earla et al., 2020a). Furthermore, oral DMAs offer ease of administration, and have superior adherence than injectable DMAs (Higuera et al., 2016; Earla et al., 2020b; Longbrake et al., 2016).

Lack of relapse, referred to as ‘no evidence of disease activity (NEDA),’ is a crucial clinical indicator when evaluating the treatment outcomes of DMAs in MS (Damasceno et al., 2016; Nicholas et al., 2011). Several meta-analyses based on randomized controlled trials have shown that FIN had relatively higher efficacy in reducing the ARR compared to other oral DMAs (Liu et al., 2021). Furthermore, the evaluation of relapse based on the claims-based algorithm is often used in real-world studies to compare the effectiveness of MS treatments (Kantor et al., 2020; Freeman et al., 2021). Previous comparative effectiveness studies that allow direct comparisons found that among oral DMAs, fingolimod (FIN) and dimethyl fumarate (DMF) are equally efficacious and are superior to teriflunomide (TER) in lowering the risk of relapse (Ontaneda et al., 2019b; Fox et al., 2017).

Adherence to DMAs is vital for the disease management of MS (Williams et al., 2018; Erbay et al., 2018). Poor adherence to DMA treatment could lead to higher relapse rates, more active disease progression, lower health-related quality of life, and higher healthcare utilization and costs (Higuera et al., 2016; Erbay et al., 2018). According to a recent meta-analysis, about one in five oral DMA users did not adhere to their treatment, and one in four oral DMA users discontinued their treatment within one year after their treatment initiation (Nicholas et al., 2020). However, based on the existing evidence from previous observational studies, longitudinal adherence patterns were not considered when evaluating the treatment effectiveness of oral DMAs (Kantor et al., 2020; Freeman et al., 2021). Therefore, this study aims to evaluate the association of oral DMAs and their adherence trajectories with ARR in patients with MS.