Patient’s experience with subcutaneous and oral methotrexate for the treatment of rheumatoid arthritis

This study is among the few that assessed the frequency of patient symptoms and side effects associated with initiation of SQ and oral methotrexate in a real-world setting. We found several significant differences in the frequency of several of these compared to biologic therapy. For example, between one-third and one-half of patients receiving either formulation of MTX reported malaise and between half and three-quarters reported fatigue, a much greater proportion than in the biologic users (22 %). At least some hair loss was reported by approximately 30 % of patients in both MTX arms. The patient-reported prevalence of diarrhea was lower among patients receiving SQ MTX than among those receiving oral MTX, although nausea was more frequent with SQ MTX. Rates of mental fog and hair loss also were highest among patients receiving SQ MTX, and the greater prevalence of these symptoms may possibly reflect higher drug levels. Both the incidence and the magnitude of injection pain associated with SQ MTX was significantly lower than that associated with etanercept and adalimumab.

Results from clinical trials of RA patients initiating MTX generally find lower rates of MTX- and biologic-associated adverse events than found in our survey. For example, the TEAR trial found relatively low rates of AEs associated with MTX monotherapy as given to early RA patients for up to 2 years [19, 20], as did the COMET trial [21]. However, observational studies, which may have better generalizability for patients seen in routine care, offer more heterogeneous results on this topic. A single-center observational study of 248 U.S. patients found low rates of MTX discontinuation [4]. A U.K. study conducted in two hospitals found that among the patients changed from oral to SQ MTX, lack of efficacy (51 %) and adverse events (44 %) were similarly common, and high rates of subsequent persistence with SQ MTX were observed (75 % at 2 years) [22]. In contrast, larger studies have generally found lower adherence and poorer tolerability. For example, a large U.K. cohort of 1257 patients (predominantly RA) found that approximately 1/3 discontinued MTX, predominaly due to GI tolerability [5]. This result is consistent with findings from an older observational Norwegian study of 1648 patients that showed that 34 % of patients had discontinued at 2 years [23].

A number of studies have found better bioavailability with SQ MTX compared to oral MTX [8, 24], which may translate into improved efficacy among patients who switch from oral to SQ MTX [13, 25‐27]. However, this effect may increase the rate of side effects associated with more bioavailable MTX. Although not specifically addressed in our survey, the adverse event profile associated with MTX also has been shown to be influenced by folate supplementation [28].

The frequency of pain associated with SQ injection was greater for biologic users (84 %) compared to SQ MTX users (55 %), as was the magnitude of pain. Injection pain might be further reduced by using an MTX auto-injector, which has been rated by patients as easy to use and nearly pain-free [10]. While patients generally did not have very high out-of-pocket co-payments for MTX, some patients receiving oral MTX expressed a higher willingness to pay if MTX might have greater effectiveness or an improved side effect profile.

The strengths of our study include representation of a patient population receiving care in routine settings. Prior findings based predominantly on clinical trials of biologics would presumably have much poorer generalizability to a real-world experience. Of importance in this study, patients needed to have started MTX or biologics in the last 12 months but had no requirement that they remain on these therapies. This design feature therefore avoided a potential selection bias if only prevalent and ongoing MTX and biologic users were eligible to participate. Were this the case, we presumably would have found a lower prevalence of various symptoms and side effects that might have prompted discontinuation. Additionally, we specifically prompted for various symptoms and AEs of interest, which patients may feel more comfortable with reporting in a survey, unlike clinical trials that passively ascertain such symptoms only if reported as an AE. We note that patients reported on the prevalence and severity of some symptoms (e.g. fatigue) that could either be drug related, drug dose related (for MTX), and/or disease related. Thus, the lower incidence of these symptoms in biologic treated patients could reflect either effects of the drugs, a lower median dose of MTX being used, or more effective control of disease-associated symptoms. We also recognize that in the analysis of MTX dose and associated symptoms, confounding by disease severity may have influenced our results. However, the comparison with the results of the patients on biologic therapy would somewhat argue against this, given that these patients presumably had more severe disease that warranted biologic use.

Despite these strengths, several limitations of this analysis deserve mention. The survey population was a convenience sample, and people who are members of an online patient community may be different than those seen in routine medical care settings. For example, they may have more severe, or more symptomatic RA, that prompts them to seek help online. Also, patients had self-reported RA, and while the positive predictive value (PPV) of patient-reported RA is relatively low, the PPV of patient reported RA among those who also report DMARD or biologic use is appreciably higher [29]. We acknowledge that medication use was self-reported and was not externally confirmed. Importantly, our survey was cross-sectional and patients’ responses were potentially subject to recall bias. We also did not collect information about comorbidities or RA disease activity, since with a cross-sectional design, it would not be possible to disentangle the relative contribution of these factors to the outcomes we studied. Also, were not able to assess improvement or worsening in patients who changed medications. For example, the differential outcomes of RA patients who experienced GI side effects (e.g. severe nausea) while on oral MTX who then subsequently changed to SQ MTX (who then experienced less nausea) could not be ascertained since longitudinal data would be required. Generating this type of data will be useful to better characterize the benefits of changing from oral MTX to SQ MTX or biologics in future studies. Additionally, 29 % of patients in the SQ MTX arm had already discontinued, a much higher proportion than in the oral MTX arm (8 %), suggesting some potential bias in the sample with respect to the prevalence of side effects that could have prompted discontinuation. We also recognize that most RA patients seldom start on SQ MTX initially but rather ‘fail’ oral MTX and then switch, suggesting the likelihood that more ill patients who need greater treatment efficacy, or those with a higher burden of GI side effects from oral therapy, probably were channeled to SQ MTX. We also recognize that etanercept and adalimumab-related injection site pain may differ according to whether patients were using the pre-filled syringe, the autoinjector pen, or the reconstituted lyophilized powder (for etanercept). The survey did not collect this information, and was therefore not able to differentiate between these different formulations. The survey also did not ask about folate use, which has the potential to mitigate MTX-associated side effects [30‐32]. Finally, although we examined a comparator of patients treated with biologics, two-thirds of them were receiving concomitant MTX and their symptom profile likely reflected the contribution of both biologic and MTX exposure. However, these subgroups were separated in relevant analyses (e.g. Table 3).