Methotrexate injection: An old drug with a newly developing landscape

Since the approval of methotrexate (MTX) for the treatment of rheumatoid arthritis (RA) by the United States Food and Drug Administration in 1988,1 the drug has been widely used in rheumatology for more than 35 years. In the history of RA treatment, MTX has been first positioned as a second-line drug and, subsequently, as a first-line drug and an anchor drug. It has, therefore, become an extensively recognized drug among rheumatologists worldwide. However, with regard to the use of this cost-effective and long-standing drug in the field of immune-related inflammation, numerous concepts still merit thorough examination and revitalization, including the routes of administration, the onset of action, and new therapeutic areas. We have summarized several key points of MTX in Table 1. In the treatment of rheumatic diseases, MTX can be administered orally or via injection. The traditional belief holds that no difference exists between the effects of oral administration and injection of MTX; therefore, oral administration is generally adopted during RA treatment. However, our long-term experience in clinical practice has shown that MTX injection is superior to oral administration in terms of the effects observed. In particular, the administration of MTX by injection is recommended for induction therapy in active RA, whereas oral administration2, 3 is recommended for maintenance therapy. The results of a phase IV clinical trial in 2008 revealed that subcutaneous injection of MTX was superior to oral administration.4 Furthermore, a study conducted in 2014 found dose-dependent differences in the bioavailability of MTX. At an MTX dose of <15 mg, there was little difference in the bioavailability of MTX between oral administration and injection. However, at a dose of ≥15 mg, the bioavailability of orally administered MTX was considerably lower than that of injected MTX.5 The use of MTX for the treatment of RA was initiated in the 1990s. During the initial period, injectable MTX formulations were used for treatment because of the extremely limited availability of MTX tablets at pharmacies in China. When MTX tablets became widely available 3 years later, MTX injections were replaced by oral MTX administration, in line with the prevailing mainstream beliefs. However, many patients soon complained about the poor effects of orally administered MTX and requested a reversion to MTX injections. The prevailing literature asserts that there are no differences between the effects of oral administration and injection of MTX. Therefore, we attempted to explain this phenomenon through the placebo effect, but the placebo effect did not explain certain clinical phenomena. For instance, patients with acute arthritis who received injections of MTX at 15 mg exhibited a considerable alleviation of joint redness, swelling, and pain, but the same therapeutic effect was not achieved with oral administration of the same dose of MTX. Furthermore, in febrile patients with adult-onset Still's disease, the fever subsided the day following the MTX injection, whereas oral administration of an equivalent MTX dose did not yield the same therapeutic effect. Studies in the past decade have generally revealed that patients with RA who responded poorly or were intolerant to orally administered MTX exhibited a significant improvement in the therapeutic effect after switching to subcutaneous MTX injection.6-8 A study conducted in the United Kingdom in 2013 found that therapeutic effects were improved in the majority of patients with RA who switched to subcutaneous MTX injections following oral MTX treatment failure. With this approach, the use of expensive biologics was also reduced, leading to a significant lowering of health insurance costs.8 A multicenter cohort study conducted in Canada in 2022 showed that subcutaneous injection was significantly superior to oral administration in single-agent MTX treatment of early RA. The use of MTX as the initial medication for early RA also significantly reduced the use of biological disease-modifying antirheumatic drugs (DMARDs), thereby contributing to healthcare cost savings.9 Dermatological studies have also revealed that subcutaneous injection of MTX is significantly superior to oral administration in the treatment of severe psoriasis.10 Currently, subcutaneous injection of MTX is generally regarded as a second-line treatment worldwide and is used in patients who are dissatisfied with or intolerant to orally administered MTX. Certain European countries, such as Germany and Sweden, recommend subcutaneous MTX injection as a first-line treatment for induction therapy, and researchers in Japan have also suggested the use of subcutaneous MTX injection for first-line treatment.11 The viewpoint that MTX injection is superior to oral administration has increasingly become a consensus in the treatment of rheumatic diseases. It can be anticipated that subcutaneous injection of MTX will replace oral administration in the near future as the mainstream method for induction therapy in patients with active RA. Currently, there are two types of injectable MTX formulations available to rheumatologists worldwide: the high-cost MTX prefilled syringe and the low-cost 50 mg/2 mL MTX vial. The dose for subcutaneous MTX injection in antirheumatic treatment is typically 20–25 mg per administration. Extensive use of the low-cost 50 mg/2 mL MTX vial for a long time has caused medication waste and increased environmental pollution from medical waste disposal. Therefore, we recommend that pharmaceutical companies produce low-cost 25 mg/1 mL MTX vials for the treatment of rheumatic diseases. MTX has long been classified as a slow-acting antirheumatic drug among the various types of antirheumatic medications, and it is generally believed that the effects of MTX in the treatment of rheumatic diseases only occur gradually after several weeks. Our experience has shown that oral administration of MTX for the treatment of RA indeed has a slow onset of action. However, the majority of patients with arthritis who received MTX injections reported an alleviation of joint swelling and pain on the day following the injection. In most patients with refractory adult-onset Still's disease who experience high fever, a mere change from orally administered MTX to MTX injection, while keeping other medications unchanged, can result in a decrease in body temperature by the end of the same day. During the ensuing 1–2 weeks, the levels of inflammatory markers (erythrocyte sedimentation rate, C-reactive protein, and serum ferritin) can also show significant decreases. These treatment effects suggest that the injection of MTX provides fast-acting anti-inflammatory effects, indicating that MTX is not a slow-acting drug. Similar experiences have been reported in other medical disciplines. For instance, intrathecal injection of MTX for the treatment of meningeal leukemia can rapidly alleviate central nervous system symptoms, which further supports the rapid onset of action of MTX injection. The superiority of injected MTX over orally administered MTX is often explained by the difference in bioavailability. It is generally believed that the bioavailability of MTX significantly decreases with doses ≥15 mg per administration.5 Previous research has also shown that even at a low MTX dose of 7.5 mg, the blood concentration of MTX is 35% higher after injection than after oral administration.12 However, our experience suggests that bioavailability does not explain the difference in effects between MTX injection and oral administration and can only explain the stronger therapeutic effect of injected MTX. In our clinical work, we also observed that injected MTX had a rapid onset of action, whereas orally administered MTX had a slower onset and could be considered slow-acting. In patients with acute arthritis, the injection of 10 mg of MTX alleviated arthritis symptoms by the following morning, but the same effect was not achieved following the oral administration of 15 mg of MTX. This difference in the temporal onset of action cannot be solely attributed to the difference in bioavailability, as an increase in the dose of orally administered MTX does not result in a rapid onset of action. Based on this premise, it may be hypothesized that orally administered MTX may be subjected to the effects of intestinal bacteria or the first-pass effect of the liver, thereby resulting in the formation of metabolites with different chemical structures and biological properties than those of injected MTX. However, this hypothesis requires further investigation by pharmacologists. A study by van de Meeberg et al on erythrocyte MTX-polyglutamate (MTX-PG) revealed that among various MTX-PG subtypes, MTX-PG4 and MTX-PG5 had considerably higher concentrations following subcutaneous injection of MTX than after oral administration of MTX.13 MTX inherently possesses biological activity and does not require a conversion to MTX-PGs to exert its biological effects. This is evidenced by the effectiveness of intrathecally injected MTX in meningeal leukemia and neuropsychiatric lupus erythematosus, intra-articularly injected MTX in synovitis, and intravitreally injected MTX in uveitis. Being a DMARD, MTX is not merely used to treat RA. Its therapeutic scope has gradually expanded to include various rheumatic diseases and immune-related inflammatory conditions in other medical specialties. Inflammatory diseases that are treated with corticosteroids as the basic therapy can also potentially benefit from MTX, which can serve as a steroid-sparing agent. In the past decade, the use of MTX for the treatment of systemic lupus erythematosus (SLE) has gradually reached consensus in the medical field. In the future, MTX may even replace azathioprine as the first choice of treatment for mild-to-moderate SLE.14, 15 Our experience has shown that the effects of injected MTX are superior to those of azathioprine when used for treating mild-to-moderate SLE or as maintenance therapy after the remission of severe SLE. Previous research has demonstrated the efficacy of MTX in controlling palindromic rheumatism in seropositive and seronegative patients over a median of 43 months of treatment.16 MTX has shown advantages in the treatment of joint arthritis, skin rash, and serositis in SLE. It is also a viable option for the treatment of mild-to-moderate systemic vasculitis and maintenance therapy.15 Hu et al reported an intriguing case of Cogan syndrome with persistent neurological symptoms and poor treatment efficacy with systemic MTX and dexamethasone. However, neurological symptoms significantly improved following intrathecal administration of MTX and dexamethasone.17 MTX has proven effective against various immune-related inflammatory diseases. MTX has also been used in the field of gastroenterology for the treatment of inflammatory bowel disease (IBD)13, 18, 19 It is recommended that MTX be administered via subcutaneous injection at a dose level of 25 mg/wk for induction therapy and 15 mg/wk for maintenance therapy.19 In dermatology, MTX is a classic medication for psoriasis and psoriatic arthritis and is also used in the treatment of atopic dermatitis,20 refractory alopecia areata,21 generalized granuloma annulare,22 and reactive inflammatory lesions of leprosy.23 Childhood RA (CRA) is a chronic autoimmune disease characterized by joint inflammation. In the management of CRA, MTX has emerged as a cornerstone treatment. However, it is worth noting that MTX might not be efficacious or well tolerated in some patients with juvenile RA, and the use of higher doses has been associated with increased toxicity.24 To better understand the mechanisms of action of MTX in CRA, various studies have been conducted. One notable study by Ruperto et al compared intermediate and higher doses of parenteral MTX in patients with polyarticular-course juvenile idiopathic arthritis who did not respond to the standard dosage of MTX. Surprisingly, the administration of higher-dosage MTX did not result in a significant increase in the proportion of patients responding to the drug.25 On the other hand, in a randomized trial conducted by Lovell et al,26 the use of etanercept in combination with MTX was explored in children with polyarticular juvenile RA. The study findings demonstrated that the addition of etanercept to MTX led to improved clinical outcomes.26 While MTX can be beneficial in managing CRA, it is essential to be mindful of its potential adverse effects in pediatric patients, including gastrointestinal symptoms and hepatotoxicity. To ensure safety and efficacy, regular monitoring and close follow-up are crucial aspects of the treatment process. Some recent studies using databases to analyze the relationships between diseases have raised interesting points. Tam et al suggested that short-term MTX might reduce the risk of ischemic stroke in patients with RA.27 Perng et al concluded that moderate and high cumulative doses of MTX might be associated with a lower risk of new cancers in patients with RA.28 Although numerous statistical methods (propensity score matching, Mendelian randomization, etc) can help remove confounding factors or increase the level of research evidence, they cannot be used to guide clinical decisions. However, they can still provide corresponding support for clinical trials in the future. In conclusion, MTX no longer serves solely as the anchor drug for the treatment of RA or as an antirheumatic drug. It has become a widely used medication for the treatment of immune-related inflammatory diseases, including lupus, IBD, psoriatic diseases, atopic dermatitis, and alopecia areata. In various inflammatory diseases that are treated with corticosteroids as the basic therapy, MTX can serve as a steroid-sparing drug. With an increasing understanding of the new concept indicating that injected MTX exhibits superior therapeutic effects, a faster onset of action, and fewer side effects compared with orally administered MTX, it is expected that MTX injection will be extensively adopted as the first-line treatment for immune-related inflammatory diseases, whereas orally administered MTX will remain the preferred choice for maintenance therapy. Ning Tan, Han-You Mo, and Xiuyan Yang were involved in conceptualization. Ning Tan, Chi-Jen Hsu, and James Cheng-Chung Wei were involved in manuscript writing. All authors are involved in final approval of manuscript. We extend our appreciation to the editors and the reviewer for their valuable feedback, which contributed to the enhancement of this paper. The authors declare that there are no conflicts of interest. Data sharing is not applicable to this article as no new data were created or analyzed in this study.