The prevalence of injection-site reactions with disease-modifying therapies and their effect on adherence in patients with multiple sclerosis: an observational study

Interferon beta (IFNβ) and glatiramer acetate (GA) are first-line therapies for the long-term treatment of multiple sclerosis (MS) and are generally believed to have comparable efficacy. IFNβ-1b, IFNβ-1a, and GA are administered by either intramuscular (IM) or subcutaneous (SC) injection, the frequency of which varies from daily to weekly depending on the product. The injection of these therapies can be associated with severe adverse skin reactions, such as necrosis and lipoatrophy [1‐4], which patients may experience after years of treatment. The frequency of injections and injection-site reactions (ISRs) can be burdensome for patients and these reactions are, among other side effects, a major reason for poor adherence with these medications over the long term [5‐7]. O'Rourke and Hutchinson reported that patients stopped IFNβ therapy because of side effects after a median of 13 months [6]. Since poor medication adherence or discontinuation can lead to treatment failure and ultimately poorer long-term prognosis, it is critical that patients persist with treatment to achieve maximum benefit from therapy. The objective of this observational study was to compare the proportion of patients on different formulations of IFNβ or GA who experienced ISRs and who switched or discontinued therapy because of ISRs.

The Swiss MS Skin Project study is the first study to evaluate the relative frequency and severity of ISRs associated with the 4 injectable DMTs available for patients with MS. In our large patient population of more than 400 patients, approximately half of the patients experienced ISRs at the first evaluation even though they had been on the same therapy for at least 2 years (mean treatment duration = 5.9 years). This finding suggests that ISRs continue to be a concern for patients with MS even after they have been on therapy for several years. Indeed, ISRs and lack of efficacy were the 2 most common reasons for patients' discontinuing treatment or wanting to switch therapy at the first evaluation and 1-year follow-up.

We report potentially clinically important differences in the proportion of patients experiencing ISRs with injectable DMTs. At the first evaluation examination, significantly fewer patients on IM IFNβ-1a than on other IFN formulations experienced ISRs. A trend toward lower rates of ISRs with IM IFNβ-1a than with SC GA was also reported. Missed doses in the previous 4 weeks appeared to be associated with twice the likelihood of discontinuing or switching therapy for patients on SC IFNβ-1b, SC IFNβ-1a, or SC GA as compared with patients on IM IFNβ-1a. ISRs were the most common reason for switching or discontinuing therapy, followed by lack of efficacy and injection fatigue. At the 1-year follow-up, similar patterns of ISRs and of switching or discontinuing therapy were seen. Patients on IM IFNβ-1a were significantly less likely to have necrosis or lipoatrophy than patients on SC IFNβ-1b or SC IFNβ-1a. More patients remained on IM IFNβ-1a than on the other injectable therapies. Although lack of efficacy was the most common reason for switching or discontinuing therapy, ISRs were also a common reason.

Our findings that ISRs are common and that fewer patients treated with IM IFNβ-1a than the other injectable therapies experience ISRs are consistent with the findings of previous randomized, controlled studies comparing the therapies pairwise. The EVIDENCE trial compared IM IFNβ-1a 30 μg once weekly to SC IFNβ-1a 44 μg three times weekly [1]. In this study, ISRs were the most commonly reported adverse event. ISRs were experienced by significantly fewer patients on IM IFNβ-1a than on SC IFNβ-1a (28% vs 83%, P < 0.001) [1]. Similarly, the INCOMIN open-label trial compared IM IFNβ-1a 30 μg once weekly with SC IFNβ-1b 250 μg every other day. In this study, ISRs were reported in 8% of patients treated with IM IFNβ-1a compared with 37% of patients treated with SC IFNβ-1b (P < 0.0001) [2]. These data are further supported by Milanese et al, who showed occurrence of local reactions in 8% of IM IFNβ-1a-treated patients versus 33% of SC IFNβ-1b-treated patients [3]. Finally, BEYOND, a study of SC IFNβ-1b (250 μg or 500 μg every other day) versus SC GA (20 mg daily), reported that 48%-58% of patients across treatment groups experienced ISRs [4]. The current study is limited by its observational nature and the low number of patients on SC GA, which may be reflective of low utilization of SC GA at the study sites in Switzerland. Given the overall mean treatment duration of 5.9 years, study patients may have received other treatments prior to the current DMT. This possibility is important, since a patient may have different expectations with the first therapy than with the second or third therapy. In addition, these results may not reflect the prevalence of ISRs at the initiation of treatment or early in the treatment regime. Nevertheless, the results are generally consistent with, and may be more reflective of, clinical practice than results from controlled clinical trials. At both the first evaluation and 1-year follow-up examinations, patients on IM IFNβ-1a had fewer skin reactions and were less likely to switch therapies than patients on other therapies.

Maintaining patients with MS on DMTs can be challenging, particularly in the early stage of treatment, when the benefits of therapy may not be obvious to patients and such patients are still adjusting to their medication. Patients with MS commonly cite the frequency of injections and ISRs as reasons for missing doses or switching or discontinuing therapies [5‐8]. Patients discontinuing therapy because of side effects, such as ISRs, often do so early during in the course of therapy [6]. Selecting therapy with a lower risk for ISRs and educating patients on strategies to minimize their occurrence may help patients adhere to treatment, thus improving their chances for optimal treatment of MS over the long term. Although many factors are involved when making treatment decisions, our study may have implications in selecting initial therapy or, for patients considering switching or discontinuing therapy because of ISRs, selecting an alternative option.

More patients remained on IM IFNβ-1a compared with other DMTs over the 1-year study. Patients on IM IFNβ-1a had fewer skin reactions and better compliance and were less likely to switch to other DMTs compared with patients on other therapies. Minimizing the impact of adverse effects is crucial in helping patients adhere to their treatment regimens and in improving their chances of better health over the longer term.