FROM THE LANCET
Subcutaneous high-dose methotrexate can be safely initiated in people with moderate to severe psoriasis, and produces a rapid and sustained response, researchers found.
Although methotrexate is a first-line agent in moderate to severe psoriasis, and is considerably cheaper than biological agents, much remains unknown about its ideal dosage and route of administration.
Authors of a 2016 systematic review noted that, despite the fact that methotrexate has been used for more than 50 years in psoriasis, high-quality trial evidence remains wanting (PLoS One 2016 May 11. doi: 10.1371/journal.pone.0153740). Recent, well-designed trials have compared methotrexate to biological drugs used in psoriasis rather than placebo. These studies also have used oral formulations of methotrexate, in a range of starting doses as low as 5 mg, rather than subcutaneous formulations.
Richard B. Warren, MD, of the University of Manchester, England, and his colleagues carried out the first double-blind, placebo-controlled study of a two-step dosing regimen of subcutaneous methotrexate in this population, in research published in the Feb. 4 issue of the Lancet ( Lancet 2017;389:528-37 ).
In their 52-week, multicenter trial conducted across 13 study sites in Europe, Dr. Warren and his colleagues randomized 120 patients to subcutaneous methotrexate at a dose of 17.5 mg/week (n = 91) or sham injections (n = 29) for 16 weeks. Patients in the intervention arm who did not achieve at least 50% improvement on the baseline Psoriasis Area and Severity Index (PASI) score at 8 weeks were increased to 22.5 mg methotrexate per week; 31% received this dose increase.
The study’s primary endpoint was reduction of the PASI score by 75% or more at 16 weeks, which 41% of the intervention arm achieved, compared with 10% of patients in the placebo arm (relative risk 3.93, P = .0026). After 16 weeks, all patients in the cohort were converted to open-label methotrexate for the remainder of the trial, following the same dosing schedule of between 17.5 and 22.5 mg, depending on response at 8 weeks after initiation.
At week 52, PASI 75 response rates were 45% in the methotrexate-methotrexate group and 34% in the placebo-methotrexate group. This compared favorably, the researchers wrote, with a previous study in which the PASI 75 response rate at week 52 was 24% with oral methotrexate at doses of up to 25 mg per week.
No serious adverse events were associated with methotrexate, although gastrointestinal problems (mostly nausea) and elevated liver enzymes were more common in patients receiving the treatment.
“Our findings encourage the use of subcutaneous methotrexate for treatment of psoriasis, and suggest long-term clinical outcomes better than previously reported for oral administration, although final confirmation will be needed in a direct head-to-head trial of subcutaneous versus oral dosing. Our findings might also help to guide future recommendations for the optimum dosing of methotrexate,” the investigators wrote.
Medac Pharma funded the study. Dr. Warren and six of his coauthors disclosed financial relationships with multiple pharmaceutical firms, including the study sponsor, while three coauthors declared no financial conflicts of interest.