Rheumatoid arthritis (RA) is the most common chronic autoimmune disease in adults1,2 is characterized by progressive polyarticular disease3,4 and is associated with long-term functional disability.5,6 Worldwide, its prevalence is estimated to be between 0.3% and 1.2% of the population, being more frequent in women than in men, and in Latin America it has a prevalence between 0.2% and 0.5% among the population over 16 years of age.7 In Colombia, RA is considered the most frequent autoimmune disease with joint involvement with a prevalence between 0.5% and 1.5%, being more frequent in people over 70 years of age.8

To assess the level of RA activity the most widely used clinimetric index is DAS28 (Disease Activity Score 28), which is a measure that combines clinical information from 28 joints9 and guides therapeutic decision-making for disease control.10 The main objective of current RA treatment is to keep as many patients as possible in remission, i.e., the minimum clinical condition of the disease where there is a greater probability of the patient having less long-term disability.6

Within the therapeutic strategy for RA, Methotrexate (MTX) is usually prescribed as the standard first-line drug.11,12 This treatment regimen has prevailed for more than 30 years,13 and is commonly used in Colombia and Europe, due to its ease of use and long-term tolerance.11

MTX can be administered orally, subcutaneously (SC) or parenterally.12 Some studies have highlighted the role of MTX SC in improving long-term adherence to the drug and emphasize its rapid absorption.14 There are different combinations of treatment with MTX SC, including with other conventional DMARDs (Disease Modifying Drugs) – either double or triple therapy – and glucocorticoid treatments.1

Several studies have documented the benefits of MTX SC over oral administration, particularly in patients with early RA. In Switzerland, a retrospective study with real-world data on 70 patients from the St. Gallen cohort showed that more than 50% of patients treated with MTX SC from the outset did not require the addition of biological therapy during an average follow-up of 1.8 years, achieving disease control rates of 70% and 80% at 12 and 24 months, respectively.13 Meanwhile, a Japanese study by Tanaka et al. (2023)15 evaluated the SC MTX (MJK101 formulation) in a population of RA patients and demonstrated that SC MTX allowed for effective dose escalation up to 15mg/week, with good gastrointestinal tolerability, supporting its use in long-term treatments.

More recently, a multicenter study conducted in Poland by Kotyla et al. (2019)16 analyzed 771 RA patients treated with MTX SC (Metex®), of whom 69.5% achieved a clinical response, 34.2% achieved low disease activity, and 19.2% achieved remission after 6 months of treatment. This research also highlighted that patients with early RA were more likely to have a clinical response and that the treatment was well tolerated, with a very low rate of serious adverse events.

In the literature review carried out and to the best of our knowledge, no article was found that studied the long-term effectiveness of MTX SC. Most of the studies worldwide on RA are of a descriptive cross-sectional type where the prevalence and clinical practice of the disease are studied in depth.

MTX SC has been shown to be effective in multiple international studies. However, its evaluation in the Colombian population is limited. Within this context, this study is clinically relevant given that in Colombia, the use of MTX SC has increased steadily over the last six years for three main reasons: first, because gastric intolerance to oral MTX is common in people with RA. Second, because of the insufficient clinical response to oral doses above 15–20mg/week, and finally, also because of the limited availability of the oral formulation in the healthcare system. On the other hand, unlike other countries where oral MTX continues to be widely used, in Colombia the subcutaneous route has become a common alternative in the early stages of treatment. These clinical factors are relevant to therapeutic efficacy, both in terms of adherence and persistence in a middle-income country such as Colombia, which highlights the need to generate local evidence on the effectiveness and long-term behavior of SC MTX.

In the present study, we analyze the long-term effectiveness of drug therapy with MTX SC in prefilled syringe, either in monotherapy or in combination with another drug, in terms of changes in DAS28 from 6 to 48 months in patients with RA treated at a reference center in Colombia.

Considering patients’ initial disease activity levels, our findings demonstrate a consistent improvement among those who began with active disease. From six months up to four years of follow-up, there was a marked increase in the proportion of patients reaching remission, accompanied by a steady decline in moderate and high disease activity indicating therapeutic success across all baseline severity levels. In the cohort of patients treated with SC MTX analyzed in this study, a high rate of remission of disease activity was observed, which was evident from six months of follow-up and progressively increased until 4 years of follow-up. At one year of follow-up, 53.2% of patients went from active disease to remission, 8.2% remained in low activity, and 10.9% went from moderate or high disease to low activity. At the end of follow-up, 85.5% of patients were in remission or low activity, which shows that SC MTX therapy as monotherapy or in combination with another csDMARDs was effective in the treatment of RA.

It should be noted that the combination of MTX SC with low-dose corticosteroids achieved the best results in terms of bringing patients from active disease states to clinical remission in the shortest time.

This finding is consistent with previous studies that have evaluated the combination of csDMARDs with glucocorticoids.22–24 Prednisone, an oral glucocorticoid frequently used in RA, has shown significant benefits when added in low doses to conventional treatment. In patients with recent-onset RA, the use of prednisone (e.g., 7.5mg/day) has been shown to delay the progression of structural damage, increase remission rates, and reduce the need to escalate to biologic therapies, while maintaining an acceptable safety profile.25 In addition, systematic reviews have supported the synergistic effect of glucocorticoids combined with csDMARDs in controlling inflammation and radiological progression of the disease, particularly in the early stages.26

Although no studies were identified that directly evaluated this specific combination with MTX SC, the benefit observed in this cohort is supported by accumulated knowledge about the modulatory role of corticosteroids in the inflammatory response and their potential to improve clinical outcomes when used in conjunction with methotrexate. Therefore, the results presented here provide real evidence of the usefulness of this therapeutic strategy in the Colombian context and in routine clinical practice, suggesting that the combination of MTX SC with glucocorticoids could be an effective option for achieving early disease control.

Statistically significant differences were reported in the initial level of disease activity according to the type of SC MTX therapy (monotherapy or combination therapy). This could be explained by the fact that combination therapy is usually prescribed to patients with more active disease. Therefore, it is expected that the proportion of patients with low disease activity or remission is lower in this group compared to the monotherapy group (66% vs 82%).27

On the other hand, the existing literature on the effectiveness of SC MTX focuses mainly on the comparison with other administration routes or with other medications.28,29 Although these studies through literature review and real-life analysis help to understand the behavior and effectiveness of SC MTX, studies related to long-term effectiveness are still scarce. Our objective was to fill these gaps by analyzing the persistence of effectiveness over four years. As study shows, in the long-term a majority of patients maintained/achieved low disease activity/remission.

According to the guidelines of the American College of Rheumatology (ACR),30 the change to the subcutaneous administration route is one of the preferred initial strategies in treatment changes due to adverse events like gastric intolerance, given the long-term efficacy and safety of MTX SC. Although this study does not analyze the adverse events presented with another drugs, the results obtained here show that the proportion of patients who improved their level of activity was greater in contrast with those who worsened.

The effectiveness of MTX SC has been analyzed from various perspectives, either as monotherapy31 or in comparison with oral MTX.32 Nathan et al. observed that patients who achieved disease remission with SC MTX preferred to continue with this administration route rather than choosing the oral route.33 Likewise, Beena & Hugh found that people who change from oral MTX to MTX SC obtained better DAS28 scores.30

The strengths of our study include the long-term behavioral design and the large sample size that allows measuring effectiveness by two events: maintaining and reaching remission level, as well as considering maintaining and reaching a low level as part of therapeutic success.

One of the main limitations of this study is the lack of access to individual values for joint counts and acute phase reactants (such as VSG and PCR). In the electronic medical record system used by the reference center, these data are entered into a clinical algorithm that automatically calculates the DAS28 score, but the raw data are not stored separately and cannot be extracted for further analysis. For this reason, it was not possible to present or compare these components individually by group or stage. Although DAS28 is a validated and widely used measure of disease activity, the lack of these disaggregated data limits a more detailed interpretation of the response to treatment. On the other hand, one limitation of the study is the fact that it is a retrospective observational study, like other retrospective cohort studies, there were confounding factors that could not be measured, such as there was no information available on the change in dose of MTX SC or the use or discontinuation of another concomitant csDMARD medication. In addition, patients who had discontinued MTX SC at some point in time due to major adverse events were not taken into account for the analysis. It is recommended that future studies compare utility measures such as HAQ and quality of life analysis through QALYs, among others, where a before and after the patient begins to be treated with MTX SC is analyzed.

MTX SC was found to be effective in real-life for the treatment of RA in both the short- and long-term. A high percentage of patients had therapeutic success at 12 and 48 months of follow-up. This study shows that the persistence of MTX SC is quite high in the long term in the context of appropriate use for RA. Among the therapies analyzed, the one that reported the greatest therapeutic success was MTX SC associated with low-dose corticosteroids.

This work has been funded by BIOMAB IPS.

Pedro Santos-Moreno has received fees for lectures and advisory roles, as well as grants for research and participation in academic events from Abbvie, Bristol, Biopas-UCB, Pfizer, Janssen, Lilly, Novartis, Pharmetique, and Pharmalab. Rosmery Barroso, María Carrasquilla, Nelson R. Alvis, Lina Moyano Tamara, Nelson J. Alvis, and Josefina Zakzuk declared no conflicts of interest.