Subcutaneous Methotrexate Shows Promise Over Oral Route in Plaque Psoriasis Treatment

A recent literature review examined the effectiveness of subcutaneous methotrexate in patients with plaque psoriasis.¹

The review, published in the International Journal of Dermatology, reported greater efficacy in cases of subcutaneous administration versus oral therapy.

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Background and Methods

While methotrexate has long been used in psoriatic disease due to its efficacy and cost-effectiveness,² the choice between oral and subcutaneous administration routes has remained an area of ongoing clinical discussion.

To better understand the comparative benefits and drawbacks of oral versus subcutaneous methotrexate, researchers conducted a structured literature review evaluating key clinical domains including drug absorption, safety, efficacy, patient satisfaction, adherence, and cost.

Using a systematic approach, the investigators searched MEDLINE/PubMed and Cochrane databases for English- and French-language publications between January 2015 and May 2023. Out of an initial pool of 230 studies, 32 met the inclusion criteria.

Findings

Several international clinical guidelines recommend methotrexate as a first-line systemic therapy for moderate to severe psoriasis, but they vary significantly in their endorsement of oral versus subcutaneous administration.

Researchers observed that the European guidelines notably favored subcutaneous methotrexate due to its improved bioavailability and tolerability profile; meanwhile, the American and Canadian guidelines presented both oral and subcutaneous routes as options, while British and Brazilian guidelines restricted their recommendations primarily to oral formulations. Despite growing support for subcutaneous use in clinical protocols, these differences reflect a lack of consensus and potential regional practice variability.

Real-world data further highlighted the disparity between guideline recommendations and clinical practice. A large international survey conducted in 2012 across 63 countries found that oral methotrexate remained the dominant mode of administration (87.9%), with subcutaneous use accounting for only 4.4% of prescriptions.

This trend contrasts sharply with recent national data from Sweden and France, where subcutaneous methotrexate constituted 93% and 44.8% of prescriptions, respectively. Conversely, data from Turkey and Israel continue to support high rates of oral methotrexate use, at 52% and 89%, respectively.

Pharmacokinetic studies also demonstrated that subcutaneous methotrexate offers superior and more predictable bioavailability compared to oral formulations, particularly at doses above 15 mg/week. While 1 microdialysis study reported similar methotrexate skin levels between oral and subcutaneous routes, the small sample size and methodological limitations temper the generalizability of this finding.

In terms of efficacy, the METOP trial, a randomized controlled study, found that subcutaneous methotrexate significantly outperformed placebo, achieving PASI75 in a greater proportion of patients at 16 weeks.

When comparing oral and subcutaneous methotrexate directly, limited but promising evidence suggested higher PASI response rates and faster clinical improvement with subcutaneous administration. For example, 1 study reported PASI90 responses in 57.1% of patients treated with subcutaneous methotrexate versus only 7.1% of those on oral therapy. However, recurrence rates did not differ significantly between groups in follow-up.

Conclusions

"Despite the paucity and heterogeneity of the literature, available data suggest that subcutaneous methotrexate may overcome some of the limitations of the oral route in terms of intestinal absorption, bioavailability, and safety," according to revies authors Viguier et al. "Subcutaneous application may also lead to a faster response when compared to the oral route. Similarly, subcutaneous methotrexate may result in better patient adherence to therapy as well as higher patient satisfaction."

While further research is needed, current evidence points to subcutaneous methotrexate as a promising alternative to the oral route, potentially offering improved absorption, fewer gastrointestinal adverse effects, and greater treatment satisfaction for patients with psoriasis.

References

1. Viguier M, Carrascosa-Carrillo JM, Rakvit P, et al. Comprehensive literature review evaluating the use, safety, and efficacy of subcutaneous methotrexate in the treatment of adult patients with moderate-to-severe plaque-type psoriasis. Int J Dermatol. Published online April 1, 2025. doi:10.1111/ijd.17758
2. Ellis CN, Reiter KL, Bandekar RR, Fendrick AM. Cost-effectiveness comparison of therapy for psoriasis with a methotrexate-based regimen versus a rotation regimen of modified cyclosporine and methotrexate. J Am Acad Dermatol. 2002;46(2):242-250. doi:10.1067/mjd.2002.119196