A small study finds that the combination of methotrexate and azathioprine is safe and effective as maintenance treatment for patients with moderate-to-severe atopic dermatitis for up to five years.
The findings were reported in the December issue of the British Journal of Dermatology.
Few other studies have looked at the short-term use of azathioprine (AZA) and methotrexate (MTX) for severe atopic dermatitis in adults and for children. The combination was found to be safe and effective for up to two years, so Dutch researchers set out to examine use of these drugs over a longer period of five years. They found that the treatment continued to appear to be effective and safe effective.
Researchers conducted an open label follow-up study of single-blinded methotrexate versus azathioprine for severe atopic dermatitis (MAcAD) in the trial that was conducted at the Academic Medical Centre (AMC) in Amsterdam in The Netherlands.
The MAcAD trial included 43 patients with moderate-to-severe atopic dermatitis, who were unresponsive, contraindicated or intolerant to cyclosporin A, randomised between September 2009 and May 2010 to receive either methotrexate (10–22•5 mg weekly) or azathioprine (1•5–2•5 mg/kg/day) for 12 weeks, followed by a 12-week follow-up period.1 A total of 35 patients - 17 originally randomised to MTX and 18 to AZA - consented to continue receiving treatment.
During the study drug doses could be increased or decreased within the dosage range as required for effective management of the condition.2 Patients could also switch between treatment groups or to other systemic treatments, or discontinue systemic treatment, and the use of concomitant topical and oral treatment was not restricted.
Data on 25 patients of the 27 patients who completed follow up were included in the analysis, as no objective outcome data were available at year 5 for two patients who participated via questionnaire.
After two years, 10 patients from the MTX group and 11 from the AZA group were still using the treatment to which they were randomised. After five years that had fallen to 5 patients from the MTX group (all from baseline) and 3 from the AZA group (1 from baseline, 2 who had restarted after a break for efficacy reasons).
Patients experienced similar relative reductions in SCORing Atopic Dermatitis (SCORAD) index of 53.8% in the azathioprine group and 52.8% in the methotrexate group. Mean absolute reduction in total SCORAD was 32.1 (SD 17.0) for the methotrexate group and 32.1 (SD 12.5) for azathioprine group. Of many more outcomes, including patient reported outcomes, data are published.
Over the five years 69 remissions were recorded, around a third (34.8%) during treatment with methotrexate and 39.1% during treatment with azathioprine. Other remissions occurred during treatment with topical agents.
The primary objective of the original study was to assess efficacy, but the main outcome of interest for this follow up study should have been safety and drug survival, the researchers noted in their paper.
Patients taking methotrexate were likely to remain on the drug for longer. Median drug survival was 28.8 months (95% CI 2.92 to 54.8) for MTX compared to 11.5 months (95% CI 9.98 to 13.0) for AZA; and at one, two and five years 76%, 53% and 29% of the patients still using MTX compared with 44%, 44% and 6% for AZA respectively.
Drug survival is useful for clinical practice because it indicates how long the signs and symptoms of atopic eczema, which is a chronic relapsing disease, can be suppressed, Professor Spuls explained. “It incorporates different reasons to stop namely due to ineffectiveness, effectiveness (remission) or adverse events.”
She added that the small number of patients limited the power of the study so it was difficult to draw firm in terms of comparing the drugs. “In the azathioprine group more patient stopped due to effectiveness of the treatment thus we cannot conclude that methotrexate is preferable. However for the patients who benefit from methotrexate, they can benefit for a long time.”
In total 723 adverse events were registered during the five years, of which 315 occurred during MTX and 244 during AZA treatment. Most were “due to flares of eczema which are not related to the treatments, besides the fact that the treatments were at that moment insufficiently effective”, Prof Phyllis Spuls, of the Department of Dermatology at the Academic Medical Centre in Amsterdam, explained.
There were 12 serious adverse events, of which three were considered possibly related to the trial medication: bladder carcinoma, hospitalization due to exacerbation of atopic dermatitis, hospitalization due to social reasons, and hospitalization due to pneumonia.
In their conclusion the researchers wrote: “In this study MTX and AZA seem to be effective and safe in the long-term treatment of moderate-to-severe AD. The relatively few patients in both groups surviving on their originally allocated drug after 5 years underline the need for effective treatments for these patients. Although no strong recommendations can be made, these are the first prospective long-term data that may guide clinical practice. More long-term and good sampled studies should be conducted to strengthen the evidence. Above all, the role of these drugs in the treatment of children with AD and other subgroups should be determined.”
Dr. Spuls told Dermatology Times that long-term, comparative and real life data on effectiveness, safety and cost-effectiveness of all photo- and systemic therapies are now needed from large-scale studies, such as multi-centre registries.
“Clinical trials patients differ from real life patients. Rare or long term adverse events need to be captured. It will not be possible to study all treatments in randomized controlled trials. Data of subgroups of patients like elderly, children, patients with specific comorbidities are needed,” she said.
She highlighted that the TREatment of ATopic eczema (TREAT) Registry Taskforce (www.treat-registry-taskforce.org) had been set up to harmonise data collection from national registries on patients receiving photo- and systemic immunomodulatory therapies and core domains and domain items had now been agreed, she said. “The ultimate goal is to reduce heterogeneity between national atopic eczema patient registries, allow direct comparability of individual country data and facilitate potential data pooling between countries.
1. Schram ME, Roekevisch E, Leeflang MM, et al. A randomized trial of methotrexate versus azathioprine for severe atopic eczema. J Allergy Clin Immunol. 2011;128(2):353-9.
2. Gerbens LAA, Hamann SAS, Brouwer MWD, Roekevisch E, Leeflang MMG, Spuls PI. Methotrexate and azathioprine in severe atopic dermatitis: a 5-year follow up study of a randomised controlled trial. Br J Dermatol. 2017 Dec 13. doi: 10.1111/bjd.16240.