Potential Benefits of the Self-Administration of Subcutaneous Methotrexate with Autoinjector Devices for Patients: A Review

Figures & data

Figure 1 Literature search workflow diagram. From the initially identified citations, they were finally selected 58 meeting the inclusion criteria and responded to the following question using the PICO framework: “How does the use of pens/autoinjectors versus other forms of injection affect medication adherence and perceptions of patients with RA receiving long-term therapies”.

Table 1 Parenteral Self-Administration Through Pen/Autoinjectors for Long-Term Therapies and Chronic Diseases

Drug Delivered and Condition	Reference	Type of Publication	Summary
● Insulin	Cheen et al, 2014^Citation37	Research article	● Retrospective observational study, single center, N = 955 patients.
			● Outcome measure adherence in terms of: compliance (by MPR) & persistence.
● Diabetes
			● Comparison of patients using prefilled pens vs those using vial/syringe.
			● Results: despite MPR was similar, prefilled pen users were more persistent.
	Ramadan et al, 2015^Citation39	Research article	● Prospective observational study, 5 centers, N = 71 patients.
			● Primary endpoints: simplicity & safety of administration, preference & convenience of patients.
			● Comparison of patients using pens vs those using conventional vial/syringe.
			● Pen was easier to use and less painful.
	Miao et al, 2014^Citation38	Research article	● Retrospective observational study, database, N = 7856 patients of DM2 ≥ 65 years old, insulin glargine.
			● Follow-up study outcomes: persistence and adherence (by MPR).
			● Comparison of patients using disposable pens vs those using conventional vial/syringe.
			● Results: Pen users showed greater persistence, duration of persistence and adherence.
	Tiktin et al, 2016^Citation25	Narrative review	● Literature search aiming to identify factors affecting adherence to medications in DM2, N = 30 studies.
			● Authors recommend to simplify regimes, to improve provider–patient communication and to provide support and education of patients.
	Lasalvia et al, 2016^Citation40	Systematic review/meta-analysis	● Revision to evaluate efficacy of pens vs vial/syringe, finally included N = 17 studies on DM2.
			● Authors concluded that pen use yields clinical benefits and is positively correlated to patient adherence/preference.
● Biologics anti-TNF	Lopez et al, 2013^Citation41	Systematic review	● Revision of methods of assessment, prevalence and predictors of non-adherence in inflammatory bowel diseases, finally included N = 13 studies
● Autoimmune & chronic inflammatory diseases
			● Authors concluded >75% adhere to biologics and suggests that syringe vs pen might be a predictor for non-adherence.
	Kivitz & Segurado 2007^Citation70	Expert opinion	● Authors focus on adalimumab-charged HUMIRA pen (adalimumab) and the outcomes of the TOUCH study.
			● Authors suggests pens/autoinjectors would become the preferred choice.
	Vermeire et al, 2018^Citation42	Research article	● Open-label, multicenter, randomized crossover clinical trial, N = 91 moderate-to-severe ulcerative colitis patients.
			● Assessments: preference, self-injection perceptions (ease-of-use, discomfort, overall impression), safety.
			● Comparison of golimumab prefilled syringe vs autoinjector.
			● Authors concluded patients generally prefer autoinjectors.
● IFN-β1a	Seddighzadeh et al, 2014^Citation71	Research article	● Sub-study: data mining from the ATTAIN trial (extension of the ADVANCE trial: Phase III, double-blind, randomized, multi-center), N = 39 relapsing-remitting multiple sclerosis patients.
● Multiple sclerosis
			● Assessments: safety, tolerability (pain by patient & clinician), patient perceptions (ease-of-use, satisfaction).
			● Comparison of peginterferon-beta1a prefilled syringe vs autoinjector.
			● Results: similar safety & tolerability profile, patient find autoinjector easy to use and convenient.
			● Authors suggests autoinjector potentially would improve QoL.
	Limmroth & Gerbershagen 2014^Citation43	Expert opinion	● Authors focus on single-use autoinjector for once-weekly intramuscular delivery.
			● Authors described a preference for the devices and suggested that they might contribute to improve adherence and QoL.
	Wray et al, 2018^Citation48	Research article	● REDEFINE clinical trial (phase IV, randomized, multicenter, two-center, crossover study), N = 97 relapsing-remitting multiple sclerosis patients.
			● Assessments: patient perceptions (ease-of-use, satisfaction and QoL), compliance and safety.
			● Comparison of single-use autoinjector vs reusable autoinjector.
			● Results: both devices were perceived as easy or very easy to use.
			● Authors speculate having two autoinjector options may offer the potential to accommodate patient preferences.
● No drug	Berteau et al, 2010^Citation44	Research article	● Randomized, single-center, crossover study, N = 40 healthy volunteers.
● Healthy individuals			● Assessments: device performance, patient perceptions (preference and acceptance), compliance, safety.
			● Comparison of self-injections by a pen vs syringe by healthcare personnel.
			● Results: although both methods performed almost equally, patients prefer and has greater acceptance for autoinjector.
● No drug	Schwarzenbach et al, 2014^Citation47	Research article	● Randomized, single-center, crossover study, N = 65 RA patients.
● Rheumatoid arthritis			● Assessments: patient perceptions (ease/comfort of use, acceptance), usability and compliance.
			● Evaluation of an autoinjector regardless the treatment by performing mock injections finding a high level of patient acceptance.
			● Results: high acceptance and compliance.
			● Authors speculate use of autoinjector may improve compliance of patients with chronic diseases.
● DMARD-biologics	Thakur et al, 2016^Citation50	Research article	● Survey, N = 220 patients.
● Rheumatoid arthritis
			● Questionnaires to evaluate patient perceptions and preferences, ranking of attributes patient most preferred.
			● Comparison of two etanercept-charged autoinjectors.
	Schiff et al, 2016^Citation51	Research article	● Two simulated-use studies with no drug: formative with N = 54 patients and summative with N = 99 patients.
			● Assessments: usability, acceptability and patient perceptions (comfort, control, ease of use, confidence of dose).
			● Evaluation of abatacept autoinjector.
			● Results: usability without error-patterns, high acceptability, preference over competitors in those experienced patients.
	Schulze-Koops et al, 2015^Citation52	Research article	● GO-MORE clinical trial [non-randomized (parallel assignment), open-label, multinational], N = 3280 patients.
			● Efficacy outcomes.
			● Golimumab treatment: comparison of administered injections vs self-injections by an injector.
			● Results: patients self-injected less baseline disease activity.
	Kivitz et al, 2018^Citation54	Research article	● EASY clinical trial (randomized, open-label, multicenter, parallel-group), N = 217 active-to-severe RA patients.
			● Assessments: device robustness and usability, patient perceptions (diaries, survey) and satisfaction, pharmacokinetics, safety and efficacy.
			● Sarilumab: comparison of a single-use disposable pen vs prefilled syringes
			● Patient were satisfied and confident with the pen and also found it easy to use.

Abbreviations: DM2, type 2 diabetes mellitus; MPR, medication possession ratio; QoL, quality of life; RA, rheumatoid arthritis.

Table 2 Reports Studying MTX Pen/Autoinjectors

Reference	Summary	Device	Variables	Main Outcomes
Freundlich et al, 2014^Citation53	Phase II clinical trial (NCT01618955) to assess the performance of an MTX autoinjector together with the subject perceptions about it in RA patients with physical limitations.	OTREXUP^® (methotrexate)	● Device: reliability and robustness.	● All devices correctly functioned.
			● Patient safety, local tolerance, and ease of use.	● 98% agreed or strongly agreed device is easy to use.
				● All patients agreed that the instructions and training were easy to follow.
				● Patient experienced minimal site-injection pain (VAS scores were minimal).
	N = 101 patients.
				● ≈ 92% of patients noted no erythema.
				● There were no adverse events related to the study.
Demary et al, 2014^Citation55	Phase III clinical trial (NCT01793259) to compare (through crossover design) subject perceptions about two formats of analogous devices, prefilled syringe versus prefilled pens, in RA patients.	(methotrexate) PEN	● Preference.	● 75% of patients and 92% of nurses and investigators preferred the pen over the syringe.
			● Ease of use.	● 73–76% of patients preferred the pen in relation to use, acceptability and satisfaction.
			● Acceptability.	● Differences in local tolerability between both devices were found for pain and redness.
	N = 120 patients.		● Satisfaction.	● ≈ 32% of patients suffered adverse events, being the most frequent infections and infestations.
			● Local tolerability.
			● Safety
Pachon et al, 2014^Citation56	Clinical trial (NCT01871961) to assess the performance of an MTX autoinjector together with the subject perceptions about it in RA patients.	(methotrexate) PEN	● Patient perception of usability and label comprehension.	● Between 90 and 100% of the patients found “very easy” tasks proposed in 4 scenarios.
			● Device robustness.	● ≈ 98% of patients scored 80% in the written exam after the training.
			● Pharmacokinetics.	● ≈ 98% of patients scored 80% in the written exam after the training.
	N = 105 patients.
				● Within all the pens employed, one had liquid leak and another had a bent needle.

Abbreviations: MTX, methotrexate; RA, rheumatoid arthritis; VAS, visual analogue scale.

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