The favorable 52-week risk–benefit profile of subcutaneous methotrexate in patients with moderate to severe plaque-type psoriasis merits consideration of this administration route and of an intensified dosing schedule, a new study has found. Results from the randomized, placebo-controlled, METOP trial was published online December 21, 2016, in the Lancet.
“Our study suggests that methotrexate can be started at a higher dose with no detrimental effect on risk, that a subcutaneous formulation and dosing scheme could lead to a more rapid and sustained response than that typically seen with oral regimens, and that the clinical response to methotrexate is associated with prominent effects on cutaneous T-helper-cell type 1 and type 17 pathways,” write Richard B. Warren, MBChB (Hons), MRCP, PhD, from the Dermatology Centre, Salford, Royal NHS Foundation Trust, University of Manchester, United Kingdom, and colleagues. “These findings have potential implications and applicability for dermatologists and other users of methotrexate, such as rheumatologists and gastroenterologists, when treating inflammatory disorders.”
At week 16, 41% of patients receiving methotrexate and 10% of those receiving placebo achieved the primary efficacy endpoint of 75% reduction from baseline in Psoriasis Area and Severity Index score (PASI 75). Subcutaneous methotrexate was well tolerated overall.
However, in an accompanying comment, Dafna D. Gladman, MD, FRCPC, from the Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Hospital in Ontario, Canada, notes that biological agents are more effective for psoriasis and challenge the role of methotrexate as first-line therapy. Additional long-term studies are needed to address comorbid inflammatory conditions as well as skin manifestations.
Although methotrexate is one of the systemic drugs most often prescribed for moderate to severe psoriasis, few high-quality data are available, especially for oral administration. METOP was the first randomized, prospective, double-blind trial of an intensified two-step dosing schedule of subcutaneous methotrexate in this population.
Multicenter European Trial Shows Safety, Efficacy
At 16 sites in Germany, France, Netherlands, and the United Kingdom, METOP assessed an intensified dosing schedule of subcutaneous methotrexate. Inclusion criteria were age 18 years or older, diagnosis of chronic plaque psoriasis for at least 6 months before baseline, current moderate to severe disease, and no previous methotrexate treatment.
Using computer-generated randomization, the researchers randomly assigned 120 participants in a 3:1 ratio to receive subcutaneous methotrexate (17.5 mg/week initially; n = 91) or placebo (n = 29) for 16 weeks between February 22, 2013, and May 13, 2015. After 8 weeks, the dose was increased to 22.5 mg/week in patients not achieving PASI 50 (28 patients; 31%). Patients receiving placebo had corresponding increases in injection volumes. After 16 weeks, all patients received open-label methotrexate for up to 52 weeks. All participants also received folic acid 5 mg/week.
At week 16, 37 patients (41%) in the methotrexate group achieved PASI 75 vs three patients (10%) in the placebo group. Clearing was complete or nearly complete in 27% of patients receiving methotrexate vs 7% in the placebo group, and 18% vs none had PASI 90.
Relative risk for PASI 75 was 3.93 (95% confidence interval, 1.31 – 11.81; P = .0026) on the basis of analysis by modified intention to treat with nonresponder imputation. At week 52, PASI 75 response rates were 45% with methotrexate–methotrexate and 34% with placebo–methotrexate.
Biopsies confirmed clinical efficacy, with reduced inflammatory cells and T-helper-17 mediated cytokines, suggesting that subcutaneous methotrexate inhibits CD11c-positive dendritic cells and T cells. Improvements in health-related quality of life paralleled improvements in signs of psoriasis.
Tolerability of subcutaneous methotrexate was generally good, with no deaths, serious infections, malignancies, or major adverse cardiovascular events. However, three patients (3%) who received methotrexate for the full 52 weeks had serious adverse events. Dropout rate over the course of 52 weeks was 39% (n = 35/91), most often because of liver enzyme elevation or because of poor efficacy in eight patients. About 30% had gastrointestinal adverse events, typically mild and not causing study discontinuation.
Study limitations include relatively small number of participants, lack of an active comparator group with oral methotrexate, and predominantly white study population.
“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,” the study authors write. “Our findings might also help to guide future recommendations for the optimum dosing of methotrexate.”
However, they warn that appropriate patient selection and monitoring are required, especially for gastrointestinal and hepatic adverse effects.
Role for Biological Agents
Dr Gladman notes that findings of METOP are similar to those of studies comparing methotrexate with biological agents. PASI 75 response rate to methotrexate was 45% vs 60% to 80% reported with infliximab, adalimumab, and ustekinumab. These agents also yielded higher PASI 90 response rates of 44% to 60%.
Efficacy of subcutaneous methotrexate appears to exceed that of oral methotrexate. A previous 52-week study showed that oral methotrexate (5-25 mg/week) yielded PASI 75 responses of 24% and PASI 90 responses of 18%. Nonetheless, Dr Gladman questions whether methotrexate should remain the first-line systemic therapy for moderate to severe psoriasis.
“Because we now know that psoriasis is not just skin deep, and that many of the comorbidities, including psoriatic arthritis, metabolic syndrome, and cardiovascular events, in addition to premature death, are related to the extent of skin involvement, perhaps drugs that effectively control inflammation should be used initially,” Dr Gladman concludes. “This approach could only be addressed via long-term observations of prospective studies of patients treated with methotrexate compared with those treated with biological therapy, with collection of information not only about clinical improvement of skin disease, but also about comorbidities.”
Medac funded this study. Some of the study authors reported various financial relationships including Abbott/AbbVie, Almirall, Amgen, BASF, Biogen Idec, Boehringer Ingelheim Pharma, Celgene, Centocor, Delenex, Dermapharm, Eli Lilly, Foamix, Forward Pharma, Galderma, GSK, Janssen-Cilag, Leo, Lilly, Medac, Merck Sharp & Dohme, MSD, Miltenyi Biotech, Novartis, Pfizer, Regeneron, Takeda, Teva, UCB Pharma, VBL, and/or Xenoport. Dr Gladman reports financial relationships including with Amgen, AbbVie, BMS, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, and UCB