Subcutaneous Methotrexate Enhances Efficacy for Psoriasis, Raises Adverse Effect Risk

A new study suggests subcutaneous administration of methotrexate (MTX) for psoriasis, as opposed to oral administration, may enhance the effectiveness of this drug in patients but also increase their risk of adverse effects.1

Chloé Paris, from Hôpital Edouard Herriot in Lyon, France, led a team of investigators in this analysis, assessing the effects of the initial route of administration of MTX on patients’ drug survival rates. Paris and coauthors noted that prior research on rheumatoid arthritis via the prospective Canadian Early Arthritis Cohort suggested that initial treatment with subcutaneous MTX was linked with both a decreased rate of treatment changes and no difference in toxicity.2

“This raises the question of the potential benefits to use subcutaneous MTX rather than oral MTX in psoriasis at MTX initiation, in terms of effectiveness and hazard of treatment failure, as well as the ability to defer the use of biotherapy,” Paris and colleagues wrote.1 “Our primary objective was to evaluate the impact of the initial route of administration on drug survival of MTX monotherapy in cutaneous psoriasis.”

Study Design and Findings

The investigative team's multicenter, prospective cohort study implemented the Psobioteq registry and was conducted in France. The team enrolled adult participants living with moderate-to-severe psoriasis who were being treated with systemic therapy. Various data were collected by dermatologists at participating centers, including clinical data, demographic details, treatment information, and rationale for any drug discontinuations, all using standardized case report forms on routine visits.

Treatment selection was made independently by clinicians as part of standard clinical practice, and Paris and coauthors noted was not influenced by inclusion in the Psobioteq registry. In this ancillary cohort analysis, nested within the Psobioteq registry, the investigators looked at individuals who began MTX monotherapy. Those deemed eligible participants were patients with plaque, erythrodermic, or guttate psoriasis who had also not previously been given biologic therapy, MTX, or apremilast, and who initiated MTX as a single-agent treatment.

Patients with concomitant nail involvement were included, though individuals with isolated nail disease were excluded. Follow-up extended from the date of MTX initiation until discontinuation, loss to follow-up, death, or January 2023, whichever occurred first. The primary endpoint was MTX drug survival, defined as the duration from the start of MTX monotherapy to treatment discontinuation.

Discontinuation was characterized as an interruption of MTX for 180 days or longer, a treatment switch, or the addition of another systemic agent. Baseline data collected at treatment initiation included patient sex, age, body mass index (BMI), disease course, disease duration, phototype, subtype, severity scores, and prior medications. Comorbidities and relevant medical history were also documented by Paris et al. They used Kaplan–Meier survival estimates and Cox regression models to identify any factors linked with MTX drug survival.

Overall, the investigative team assessed 406 subjects, with 58.1% having been treated with oral methotrexate (MTX-PO) and 41.9% with subcutaneous methotrexate (MTX-SC). At the time of their treatment initiation, these participants' median Psoriasis Area and Severity Index (PASI) score was 11. Additionally, Paris and colleagues highlighted that 67.3% of subjects reported a Dermatology Life Quality Index (DLQI) score of ≥6.

Adjusted drug survival was found by the team not to significantly differ between administration routes (P = .15). The authors noted that statistical power may have been limited due to the sample size, and residual confounding could not be excluded due to the research's observational design.

“Our results showed that the initial route of administration was not significantly associated with the drug survival of methotrexate monotherapy,” they wrote.1 “However, we found that oral administration of MTX was associated with a higher rate of discontinuation for lack of effectiveness and more dosage adjustments, while subcutaneous administration was associated with a higher rate of discontinuation for adverse effects, contrary to what has been shown in other studies.”

The analysis provides a nuanced look at strategy related to MTX therapy. Physicians seeking to prescribe the drug may consider beginning patients on MTX-SC for individuals at risk of poor response to the medication, while monitoring closely for tolerability. This, the investigators noted, could allow for more individualized treatment strategies in psoriasis management.

References

1. Paris C, Curmin R, Jullien D, et al. PSOBIOTEQ study group. Impact of methotrexate administration route on drug survival in psoriasis: Results from PSOBIOTEQ. J Eur Acad Dermatol Venereol. 2025 Sep 30. doi: 10.1111/jdv.70044. Epub ahead of print. PMID: 41024667.

2. Hazlewood GS, Thorne JC, Bykerk VP, et al. CATCH Investigators. The comparative effectiveness of oral versus subcutaneous methotrexate for the treatment of early rheumatoid arthritis. Ann Rheum Dis. 2016 Jun;75(6):1003-8. doi: 10.1136/annrheumdis-2014-206504. Epub 2015 May 15. PMID: 25979945.