A 2016 study explored the safety and efficacy of a year-long, two-phase regimen of high doses of methotrexate injected under the skin for the treatment of plaque-type psoriasis. It was found that the methotrexate injection regimen reduces psoriasis severity, improves quality of life, and is well tolerated by patients.
Though widely prescribed as a first line of defence against moderate to severe psoriasis –a disease in which the immune system attacks skin cells, resulting in inflamed, scaly skin – the safety and efficacy of methotrexate under different dosing regimens and through different routes of administration has been understudied.
In a 2016 study published in The Lancet, researchers explored the safety and efficacy of high doses of methotrexate applied under the skin for the treatment of moderate to severe plaque-type psoriasis, and to better understand the drug’s mechanism of action. In total, 120 adult psoriasis patients were recruited from 13 centres across Germany, France, the Netherlands, and the United Kingdom. Patients were included in the study if diagnosed with moderate to severe plaque-type psoriasis 6 months or more before the trial but had never received methotrexate. Patients with psoriatic arthritis, liver dysfunction, or low white blood cell counts were excluded.
In phase 1 of the trial, lasting 16 weeks, the subjects received a weekly injection with either 17.5 mg of 50 mg/mL methotrexate or an equivalent volume of the placebo. If a 50% reduction in psoriasis severity according to the PASI scale – higher scores representing greater psoriasis severity – was not observed by week 8, then 22.5 mg of 50 mg/mL methotrexate or the equivalent volume of placebo was applied. In phase 2, lasting 36 weeks, all subjects received 22.5 mg of 50 mg/mL methotrexate. If a 75% reduction in PASI score was not observed by week 24, patients were excluded from further study. Injections were self-administered in both phases, except for the first dose in each phase. Each injection was followed up at 24 hours with 5 mg of oral folic acid to prevent low red blood cell counts, a common side effect of methotrexate. Treatment safety was assessed based on adverse events, physical examination, vital signs, quality of life, and the drug’s tolerability in patients. Tissue samples from psoriatic plaques were taken at the start of each phase and analyzed for indicators of certain immune responses.
In total, 99 patients (83%) completed phase 1 and 71 patients (72%) completed phase 2. At the end of phase 1, PASI scores were reduced by 75% in 37 subjects (41%) in the methotrexate group and 3 (10%) in the placebo group. A 90% decrease in PASI score was experienced by 16 (18%) in the methotrexate group but none in the placebo group. Notably, 28 (31%) in the methotrexate group did not experience a 50% reduction at 8 weeks and as such had their dose raised to 22.5 mg. At the end of phase 2, a PASI reduction of at least 75% was observed in 41 (45%) who received methotrexate all throughout the study and in 10 (34%) who switched from placebo to methotrexate between phases. For 29 patients (78%) this response carried through from the 16th week to the 52nd. Reductions of 90% were seen for 28% of all participants. At 24 weeks, the dose was increased to 22.5 mg of methotrexate in 5 subjects (23%) who switched from placebo to methotrexate and in 5 (55%) who remained on methotrexate throughout. Of the patients who remained on methotrexate for the duration of the trial, 18% experienced a 100% reduction in PASI score.
No serious adverse events were reported. A minority of patients experienced headaches or gastrointestinal upset, or contracted a mild infection, which are fairly common with methotrexate treatment. Quality of life improved to at least mild disability in 59% of patients on methotrexate, of which 43% experienced no disability, compared to 34% and 10% in the placebo group.
Of the 27 patients from whom tissue samples were taken at the start of each phase, 13 patients – 6 (23%) on placebo and 7 (26%) on methotrexate – did not experience and 14 (52%) experienced a decrease in PASI score of at least 75%. Indicators of CD11c+ dendritic cells and CD3+ T cells, immune cells which aid in the identification and destruction of infected or damaged cells, were lower in samples where treatment was effective, reaching levels close to healthy skin in samples taken at the start of phase 2.
The study found injection of 50 mg/mL methotrexate under the skin at 17.5 mg for 16 weeks followed by 22.5 mg for 36 weeks to significantly reduce plaque-type psoriasis severity and improve quality of life. This regimen was generally well tolerated. The association found between CD11c+ dendritic cells and CD3+ T cells and disease severity suggests methotrexate combats psoriasis by reducing the misidentification of healthy skin cells and their white blood cell-effected destruction by these cell types. To determine conclusively whether this methotrexate injection regimen reduces psoriasis severity, studies in larger, more heterogeneous populations will be necessary. Research comparing a similar dosing regimen of oral methotrexate may help to determine the most effective route of administration.
Written By: Raishard Haynes, MBS
