Prefilled pen versus prefilled syringe: evaluation of methotrexate subcutaneous intake method in patients with juvenile idiopathic arthritis – results of the pilot study

BACKGROUND Methotrexate is the most commonly used disease-modifying antirheumatic drug recommended in the treatment of juvenile idiopathic arthritis. It can be administered orally or subcutaneously, the latter method is associated with fewer side effects and higher drug bioavailability. Nevertheless, the pain associated with injection is a considerable drawback of this treatment option in the pediatric population. Currently, there are two single-use subcutaneous injection devices available: the prefilled syringe and the prefilled pen. This prospective, two-sequence crossover study aimed to compare ease of use, frequency of therapy side effects, injection-site pain and patient preference of those methotrexate parenteral delivery systems. METHODS 23 patients with juvenile idiopathic arthritis, already treated with subcutaneous methotrexate in the form of prefilled syringe in the period October 2018 – April 2019 completed a questionnaire evaluating their experience with this device. Subsequently, children received a one-month supply of pen autoinjector and completed the same questionnaire, regarding their experience with the new methotrexate delivery system. The results obtained in both questionnaires were compared using the Wilcoxon matched-pairs signed-rank test. RESULTS 82,6% patients and their caregivers voted for the prefilled pen as their preferred method of subcutaneous methotrexate administration. Moreover, the injection with the prefilled pen was reported as less painful in comparison to the prefilled syringe (p<0.01). Side effects of methotrexate were less pronounced after the prefilled pen treatment, this difference was most prominent regarding gastrointestinal adverse events associated with the injection (p<0.01). CONCLUSIONS using the device is a promising way of subcutaneous methotrexate delivery in children with juvenile idiopathic arthritis, as the

injection is less painful and associated with fewer side effects.

Background
Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children, with an estimated prevalence between 16 and 150 per 100 000 [ 1 ]. It is defined by the International League of Associations for Rheumatology (ILAR) as arthritis of an unknown etiology that persists for at least 6 weeks in children under the age of sixteen [ 2 ]. Although biologic agents are increasingly used in the management of this condition, methotrexate (MTX) remains the mainstay of JIA treatment [ 3,4 ]. MTX is administered weekly at a dose of 10-15 mg/m 2 either via oral or parenteral route [ 5 ].The bioavailability of MTX is about 15 % higher after subcutaneous administration than after oral intake, leading to the improvement of treatment efficacy [ 6 , 7 ]. Moreover, the most common side effect of MTX therapy: gastrointestinal toxicity, is less pronounced after the MTX injection [ 8 ]. Nevertheless, pain and stress associated with subcutaneous injections are a significant drawback of this treatment, particularly prominent in younger patients.Subcutaneous MTX may be administered via two devices: the prefilled syringe or, recently introduced to the market, the pen autoinjector. The latter device was preferred by patients with rheumatoid arthritis (RA) with regards to overall satisfaction and ease of use [ 9 ]. The aim of this study was to assess the experience of patients with JIA and their caregivers who used both the prefilled syringes and the prefilled pens, concerning patients' preference, usability, and tolerability outcomes.

Patients And Methods
This was a prospective, two-sequence crossover study performed in one pediatric rheumatology center in Poland. It was conducted in accordance with the International Conference on Harmonization Guideline for Good Clinical Practice and the Declaration of Helsinki. The approval of local ethical committee was obtained before commencing the study. Written, informed consents from all participants of the study or their legal representatives were obtained.

Inclusion/ exclusion criteria
Patients were eligible for the study if they were between 2 and 18 years of age and had the diagnosis of JIA made according to ILAR criteria [ 2 ]. Moreover, the ongoing subcutaneous MTX therapy using the prefilled syringe (dose 10-15 mg/m2) was required to be included in the study group. Exclusion criteria comprised previous treatment with the autoinjecting device and the presence of contraindications to continuing MTX therapy at the baseline of the study.

Study intervention
Patients eligible for the study received a questionnaire in which they have assessed theirexperience with the preceding prefilled syringe (Metex®; Medac GmbH) treatment. If the patient was not giving the MTX injections himself, the questionnaire was completed by the caregiver, with the exception for the question assessing the pain associated with injection using the Faces Pain Scale-Revised (FPS-R [10]). The questionnaire consisted of Subsequently, patients received 4-weeks supply of the prefilled pen (Metex Pen®; Medac GmbH), at the same MTX dose as used during the prefilled syringe treatment.Before the first injection, patients and their caregiverswere made familiar with the new injection system by the study nurse. After the one-month period of prefilled pen treatment patients received the questionnaire again, this time evaluating their experience with the new drug delivery system. In the second questionnaire patients were also required to answer the question about their overall preference of subcutaneous MTX delivery method.

Study endpoints
The primary end point of the study was the number of patients preferring the MTX prefilled pen over the prefilled syringe after one month of treatment. Secondary end points included a comparison of the self-injection experience of the patients after each treatment period and frequency of treatment side effects.

Statistical analysis
Results from the questionnaire subcategories 1 and 3 were transferred to 0-10 numeric scale, in which 0 was associated with the worst and 10 with the best patient experience.
Outcomes of FLACC were assessed using the calculator available online [ 12 ]. In the case of multiple-choice questions, the following converter applied: answer a -10, b-7.5, c-5, d-2.5, e-0. The median values and interquartile ranges (IQR) achieved in each subcategory were calculated using the simple descriptive statistics. The normality of distribution was checked using the Kolmogorov-Smirnov (K-S) test. Subsequently, the results obtained in both questionnaires were compared using the Wilcoxon matched-pairs signed-rank test. All statistical calculations were made using Statistica 13.1 software (StatSoft, Poland, 2016).

Study group characteristics
The study group was composed of 23 patients with JIA, 17 girls and 6 boys with the mean age 11.7 years. The mean time interval between the diagnosis of JIA was 4.23 year, with a minimum of 3 months and a maximum of 13.5 years. The mean time of subcutaneous MTX treatment equaled 18.52 month, with a minimum of 3 months and a maximum of 5 years.

Overall patient preference
The overall median values of patient satisfaction equaled 5/10 (IQR 5.0) for the prefilled syringe and 10/10 (IQR 2.0) for the prefilled pen (p<0.01).19/23 patients (82.6%) voted for the prefilled pen as their preferred method of subcutaneous MTX administration. Table 1 (Tab.1) summarizes the results obtained in this section. Overall, despite the patients used the prefilled syringe for a considerably longer period than the pen, the latter device was ranked as significantly easier to use (p<0.01) (Fig.1).

Self-confidence regarding the device proper use
The caregivers' confidence regarding the device proper use was significantly higher after the period of prefilled pen treatment, what corresponded to a lower level of stress associated with MTX administration (p<0.01) (Fig.2). The detailed results are listed in table 2 (Tab.2).

Pain associated with the injection
The level of pain was significantly lower after the injection performed with the MTX prefilled pen. This observation concerned both the level of pain assessed by patients (FPS-R) and their caregivers (FLACC). The results were statistically significant (p = 0.001 for FPS-R), (p = 0.0004 for FLACC) (Fig. 3, Fig.4).

Side effects of subcutaneous MTX treatment
In general, the side effects of MTX treatment were observed in 16/23 patients (69.5%) during the prefilled syringe treatment and in 8/23 (34.7%) treated with MTX prefilled pen.
Local symptoms associated with injection were infrequent and there was no statistically significant difference between both devices (Tab.3). Nevertheless, remarkably more patients treated with prefilled syringe experienced nausea, vomiting (p = 0.007) and abdominal pain (p = 0.003).

Discussion
Up to our best knowledge, currently there are no studies assessing the features of drug delivery systems important for patients with JIA and their caregivers. Studies conducted among individuals with RA showed the preference for subcutaneous injections in comparison to intravenous infusions and tendency to select ready to use drug delivery systems, with a high preference for pen autoinjectors [13][14][15][16][17] ]. Moreover, the risk of side effects associated with treatment method was not neglectable [ 18 ]. Currently, MTX is available in Poland in two forms: oral pills and subcutaneous prefilled syringes. The parenteral way of MTX administration is preferred by clinicians, as it provides dependable efficacy, predictable bioavailability, sustained clinical outcomes, and lower risk of adverse effects [ 19 , 20 ].Nevertheless, the caregivers are frequently reluctant to this method of treatment, usually due to the pain associated with injection and low level of selfconfidence regarding the device proper use. The newly developed prefilled pen may become a long-awaited solution to this problematic issue.
In our study, we have assessed the preference for MTX pen as 82.6%. Despite the small size of the study population, the results are comparable to those obtained in patients with RA, where the preference for pen reached 75% [ 9 ]. Interestingly, despite our patients received the prefilled syringe treatment for a considerably longer period than the prefilled pen, their caregivers have evaluated the latter device as easier to use (p<0.01).
Moreover, it corresponded to the higher level of their self-confidence regarding the device proper use (p<0.01).
Pain associated with the drug administration is a significant drawback of treatment, especially pronounced in the pediatric population. In our study, the injection performed The MTX pen is equipped with a special needle cover system, which was constructed in order to diminish the risk of caregivers' needlestick injury. What is more, the invisibility of the needle during the injection may lead to a lower level of stress and pain associated with the drug administration in the children with JIA.
Although very promising, the results of our study must be interpreted with caution and a number of limitations should be borne in mind. To begin with, it was a pilot study, conducted on relatively small study group. Moreover, the JIA patients enrolled to this project were already treated with subcutaneous MTX in the form of prefilled syringe. Thus, the impact of new autoinjector novelty effect on our results can not be excluded. Future studies, including larger group of subcutaneous MTX-naive JIA patient conducted in the crossover design are needed to verify our findings.

Conclusion
The prefilled pen is a promising method of MTX parenteral delivery in children with JIA, as the injection is less painful and associated with fewer side effects that the one performed

Consent for publication
Not applicable.

Availability of data and materials
The data analyzed during this study are included in tables attached to this article.

Competing Interests
The prefilled pens used in the study were donated to the Department of Pediatric Cardiology and Rheumatology by Medac GmbH.   Figure 2 Results obtained by the methotrexate prefilled pen and prefilled syringe in "Selfconfidence regarding the device proper use" questionnaire section (0-worst possible experience, 10 -best possible experience).

Figure 3
The comparison of pain associated with the methotrexate injection using prefilled pen and prefilled syringe -results obtained using the Faces Pain Scale -Revised (FPS-R). 0 -no pain, 10 -most severe pain.

Figure 4
The comparison of pain associated with the methotrexate injection using prefilled pen and prefilled syringe -results obtained using the Face, Leg, Activity, Cry, Consolability (FLACC) scale. 0 -no pain, 10 -most severe pain.