The bioavailability of parenteral MTX is superior to that of orally administered MTX, especially at doses ≥15mg/week (LE 2b; GR B-C; LA 100%).

Several studies (moderate-to-low quality, Oxford 2a-4) assessing the pharmacokinetics over a limited time period,16–22 show that increasing the dose of oral MTX reduces its bioavailability, which reaches its plateau at 15mg/week, a phenomenon that is not observed with parenteral MTX (positive relationship of the area under the curve on increasing the dose of parenteral MTX). That is, starting at 15mg/week, the bioavailability of parenteral MTX will be superior to that of oral MTX, while they are similar at lower doses.

In MTX-naive patients the clinical efficacy of parenteral MTX is superior to that delivered orally (at doses of 15mg/week) (LE 1b; GR A; LA 94%).

In patients with an inadequate response to oral MTX (15mg/week), escalation of the dose utilizing the parenteral route is clinically more effective (LE 2a; GR B; LA 94%).

A RCT23 involving RA patients who were naive to MTX, many with early RA, compared the efficacy of oral MTX with parenteral MTX at the same doses (15mg/week) for 6 months (good quality, Oxford 1b). The authors observed superiority (statistically significant) of the parenteral route in the ACR criteria for 20% and 70% improvement, that is, ACR20 and ACR70 responses and in the reduction of the number of swollen joints, with no differences in the ACR50 response or changes in the Health Assessment Questionnaire. On the other hand, 30% of the subgroup of patients who failed to respond to the oral formulation and switched to the parenteral route in week 16 achieved ACR20 6 months later.

In another RCT24 with a duration of 6 months (Oxford 2c), parenteral MTX was significantly superior to oral MTX in the rates of ACR20 and ACR50 responses, among other findings. There were no differences in the ACR70 response, pain severity, patient global assessment or morning stiffness.

Observational studies of low-to-moderate quality have shown that patients who switch from oral MTX (due to lack of efficacy or toxicity) to parenteral MTX can achieve a satisfactory therapeutic response, especially over the short term.25–28

The safety and tolerability profile of MTX when delivered by the parenteral route is similar to that observed when it is administered orally (LE 1b; GR B; LA 100%).

In general, both in RCT23,24 and in observational studies, parenteral MTX does not increase the rate, type or severity of the adverse events reported with the oral formulation.9,25,28–34 The rates of discontinuation or interruption of parenteral MTX are reported to be variable. Up to 1 year of follow-up, the rate of discontinuation ranged from 0% to 18%,9,25,3134,35 depending on the study, and, in an article with long-term results, the rate after 2 years of follow-up was 25% and, at 5 years, was 53%.35

However, the heterogeneity in terms of defining and coding adverse events suggests that we should interpret these data with caution.

It has been pointed out that parenteral MTX administration could reduce the rate of gastrointestinal adverse events associated with oral MTX. The findings in RCT are contradictory.23,24 A low-quality observational study specifically compared the severity of gastrointestinal adverse events occurring with the 2 formulations36 and demonstrated that, in general (although it depended on the type of adverse event), the severity was greater with the oral formulation.

It is recommended that the use of parenteral MTX be considered in patients with highly active disease and in those who showed poor adherence to oral treatment, were taking multiple drugs or were obese, and to prevent dosing errors, always taking into account the preferences of the patient (LE 4; GR D; LA 100%).

Parenteral MTX has been shown to be effective in different patient profiles, including MTX-naive patients (with or without previous disease-modifying antirheumatic drugs [DMARDs])32,37,38 and in biologic-naive patients,23,38,39 as well as in patients who did not respond to oral MTX because of its lack of efficacy or its toxicity.13,25,40,41

Moreover, there is indirect evidence concerning certain profiles. For example, in patients with poor adherence to oral therapy, the use of prefilled syringes with previous training achieves very high rates of adherence and satisfaction.33 Thus, it would be feasible to consider that parenteral MTX can improve adherence in patients whose compliance with oral treatment is poor. This same principle could be applied to patients taking multiple drugs and/or with comorbidities (avoiding oral medication), or who are overweight or obese (because of its greater bioavailability). Patient preferences, the prevention of dosing errors and economic questions concerning the health system (to avoid or delay the initiation of biological therapy) should also be taken into account.

The recommendation is to follow the same indications for the starting dose and increases and reductions applicable to the oral formulation (LE 5; GR D; LA 81%).

No starting dose or dose escalation has been shown to be clearly superior to others. In a RCT involving MTX-naive patients, parenteral MTX was begun at a dose of 15mg/week,23 and in another good-quality RCT (Oxford 1b)42 the starting dose was 7.5mg/week for 2 weeks and was then escalated to 15mg/week. Thus, the panel recommends to start with a dose of 15mg/week in MTX-naive patients. In observational studies, the starting dose in MTX-naive patients varies widely from 5mg/week to doses of ≥25mg/week.19,31,43

In patients who do not respond to oral MTX, RCT report diverse starting doses; at times, it is the same dose reached with the oral formulation,44 and others follow a scheme employing prefilled doses,24,39,45 although the majority choose the parenteral route, initially at doses of at least 15mg/week. Some observational studies start with the parenteral route at a dose utilized for oral delivery; on other occasions, the authors follow a predetermined scheme.19,31,43 Thus, the recommendation of the panel in the case of patients who switch from the oral route, is that they begin with the same dose, taking into account that, depending on the amount, it will be necessary to carry out a conversion to calculate the parenteral dose. Likewise, it is suggested that lower doses of parenteral MTX than those recommended be considered for certain types of patients or circumstances such as elderly individuals, those with a low body mass index, those with chronic kidney disease, etc.

With regard to dose escalation, some authors propose increases of 2.5mg/every 2 weeks or 5mg/month; others, follow the steps of a predetermined scheme, and there are articles in which escalations depend on the clinical response.23–25,38

Finally, with respect to de-escalation, it is mentioned very little in the literature. It is carried out on the basis of the clinical outcome once the therapeutic objective has been achieved.43

The panel recommends a dose of up to 25–30mg/week of parenteral MTX (LE 5; GR D; LA 88%).

The maximum reported dose varies depending on the study and the route of administration; for example, it reaches 10–45mg with the IM route, 10–30mg using the SC route and up to 50mg with the IV formulation. The maximum dose of parenteral MTX most widely employed (due to its frequency) is around 20–25mg/week.19,23–25,31,38,43

On the other hand, there is no clear maximum dose limited by toxicity, lack of clinical efficacy or tolerance phenomena.

In accordance with the available pharmacokinetic data, the equivalences of the oral and parenteral doses would be the same up to 15mg; for 20mg of oral MTX, the equivalent dose of parenteral MTX would be 15mg and for 25mg of oral MTX, 20mg of parenteral MTX (LE 2b; GR B; LA 100%).

The majority of published studies utilize the same dose as the oral dosage or follow a predetermined scheme for the switch. However, there are 2 studies that, although in an intuitive manner, propose a conversion. One is a RCT42 in which oral MTX is changed to the IM route, assuming a mean bioavailability of 70%; thus, 15mg IM MTX would be 21.4mg of oral MTX. The other is a moderate-to-low quality observational study18 (Oxford 3b), which likewise, considered a bioavailability of 2/3 of the parenteral route.

More recently, on the basis of a study on bioavailability (pharmacokinetics),47 the authors propose a dose conversion table that is recommended by the panel (see Table 3).

Subcutaneous MTX can be cost-effective in early RA in MTX-naive patients (LE 2a; GR B; LA 94%).

A study of quality and the cost-effectiveness of parenteral MTX in MTX-naive RA patients adjusted according to the circumstances (including costs) of the Spanish health system,48 observed a cost/quality-adjusted life year (pharmacologic) at 5 years of €25,173–€35,807, which was €19,056–€25,351 for patient lifetime.

On the other hand, in cost-minimization studies,11,12 it has been seen, for example, that utilizing the costs in the United Kingdom, the use of parenteral MTX in patients having an insufficient response to oral MTX can save £7197 per patient in the first year and £9.3 million per year in new patients, by delaying the introduction of biological therapies.

Other studies,13 on the basis of their results, have calculated that for every 1000 RA patients there are 40 receiving parenteral MTX and, taking into account that in 36 of these individuals, the response is equivalent to that achieved with an anti-tumor necrosis factor agent, the savings (by not administering a biological therapy) would be £306,000 or, what is the same, £300 per patient-year.

Parenteral administration can increase adherence to MTX (LE 2b; GR B; LA 94%).

One study (of good-to-moderate quality, Oxford 2b) evaluated adherence to parenteral drugs in 40 RA patients with psoriatic arthritis, 20 of whom began with parenteral MTX. All of them received education and training on self-injection.29 There was an adherence to the treatment ≥80% in 92.5% of the patients. In another study49 of moderate-to-low quality (Oxford 3b) involving 12 patients with rheumatic diseases who switched from the oral route to IM administration. At 6 months, there were no differences in adherence, as they had interrupted MTX due to the lack of efficacy or toxicity. In another report,28 after analyzing 30 RA patients who switched from oral to parenteral MTX, at 6 months, there was only one patient who did not adhere to the treatment.

On the other hand, a number of studies evaluated the effect of self-administration with a prefilled syringe. Many of the patients receiving training in self-administration,29,30,33,38,39 and, over the short term, the authors observed a high adherence to the treatment.

Moreover, a systematic review that analyzed survival or discontinuation of parenteral MTX9,49 found that maintenance of the drug decreases over time, and that survival of the parenteral drug was superior to oral MTX.

With respect to parenteral MTX, there is also a concentrated solution (50mg/mL) that, over the short term,33,38 has been found to be preferred both by patients and by health professionals because its administration is associated with fewer errors and with greater independence, quality of life and patient satisfaction.

Finally, it is important to take into account the role that education and training can have in self-administration in the rate of adherence, as do the proposed needles and the lower prefilled volume.29,33,38

Education in self-administration results in a high rate of adherence to treatment, patient satisfaction and autonomy, and favors correct administration (LE 2b; GR B; LA 100%).

A number of studies29,30,33,38,39 of varying quality have shown that, at least over the short term, education in self-administration results in a high rate of adherence to the treatment, considerable patient satisfaction, independence, improvement in quality of life and good local tolerance. This, in turn, can have an impact on a more satisfactory control of the patient.

Finally, we wish to point out that, in terms of education, there is a wide variation in the form, format and content. In general, the nursing staff is in charge of instructing patients. Moreover, in certain training programs, materials are provided on paper.