Methotrexate gives more sustained control than ciclosporin in children with severe atopic dermatitis

28th September 2023

Methotrexate (MTX) is an effective treatment for children with severe atopic dermatitis and provides more sustained disease control than ciclosporin (CyA) upon discontinuation, according to the findings of a recent randomised controlled trial.

In the TREAT trial, published in the British Journal of Dermatology, a team led by King’s College London, set out to examine the safety and efficacy of these two main first-line conventional systemic immunosuppressive therapies in children and young people with severe atopic dermatitis.

The parallel group, assessor-blinded randomised trial included 103 participants aged between two and 16 years of age whose atopic dermatitis was unresponsive to potent topical treatment.

The participants were randomised to receive either 4 mg/kg/day of CyA or 0.4 mg/kg per week of MTX for a total of 36 weeks. They were also followed up for 24 weeks.

The co-primary endpoints were the change from baseline to 12 weeks in the Objective Severity Scoring of Atopic Dermatitis (o-SCORAD) and time to a first significant flare (relapse) after treatment cessation.

Among the 52 participants assigned to CyA, there was a greater improvement in disease severity by 12 weeks (mean difference o-SCORAD = -5.69 p = 0.01). In fact, more participants reached o-SCORAD-50 at 12 weeks in the CyA arm compared to the MTX (Odds ratio, OR = 2.60, 95% CI 1.23 – 5.49, p = 0.01).

However, by week 60, MTX was superior (OR = 0.33, 95% CI 0.13 – 0.85, p = 0.02). Furthermore, participant-reported post-treatment flares were higher in the CyA arm (OR = 3.22, 95% CI 0.42 – 6.01, p = 0.025) and both treatments gave rise to a similar level of serious adverse events.

The researchers also highlighted that MTX is significantly cheaper than CyA and concluded that MTX is a useful and safe treatment in paediatric patients with severe atopic dermatitis and a good alternative to CyA, especially in settings where healthcare resources are limited.

Methotrexate is potential gold standard

Until now, there has been no adequately powered randomised clinical trial evidence in relation to the safety and treatment success of methotrexate and ciclosporin for paediatric patients with atopic dermatitis. With new high-cost therapies being introduced, establishing a gold standard for treatment with the conventional systemic therapies like methotrexate and ciclosporin is deemed necessary.

Commenting on these findings study author Professor Carsten Flohr, chair in dermatology and population health sciences at King’s College London and consultant dermatologist at St John’s Institute of Dermatology, part of Guy’s and St Thomas’ NHS Foundation Trust, said: ‘This is the largest paediatric trial using conventional immuno-modulatory treatments in severe atopic dermatitis and was conducted across 13 centres in the UK and Ireland and is likely to change our treatment paradigm around this condition, not just for patients in the UK but also internationally.‘

Stopping methotrexate for 2 weeks after COVID-19 vaccination boosts immune response

30th June 2022

Halting methotrexate for two weeks after a COVID-19 vaccination boosted the level of antibodies generated compared with continued drug use

Stopping methotrexate (MTX) for two weeks after a third COVID-19 vaccination significantly enhanced the level of antibodies produced compared to continuing with the drug, according to the results of a randomised trial by a team of UK researchers.

The use of the immunomodulatory drug methotrexate, is known to adversely affect the humoral and cellular immune response to COVID-19 mRNA vaccines. In fact, studies have shown that seroconversion rates after COVID-19 vaccination are significantly lower in immunocompromised patients, especially organ transplant recipients.

As a result, it is important to implement strategies that can enable those who are immunocompromised to mount a satisfactory immune response.

It has been shown that discontinuation of immunosuppressant drugs such as methotrexate in patients with rheumatoid arthritis, for either 4 weeks before, 2 weeks before and for 2 weeks after vaccination, improves the immunogenicity of seasonal influenza vaccination.

In fact, the highest immune response occurred when MTX was discontinued two weeks after vaccination and this effect was confirmed in another study that specifically focused on stopping the drug two weeks after seasonal influenza vaccination.

Since the effectiveness of this approach has not been formally evaluated for the COVID-19 vaccine, for the present study, the UK undertook a randomised trial among immunocompromised patients prescribed methotrexate.

The Vaccine Response On/Off Methotrexate (VROOM) trial, randomised participants 1:1 to either suspension of MTX (suspend methotrexate) for two weeks immediately after their COVID-19 booster dose, or to continue with the drug as usual (continue methotrexate). Individuals were recruited from both rheumatology and dermatology clinics and who had been taking low dose MTX (< 25 mg/week) for at least 3 months. In addition, the researchers only enrolled participants who had previously received two COVID-19 vaccine doses.

The primary outcome of the study was the antibody response against the receptor-binding domain of the COVID-19 spike protein (S1-RBD) 4 weeks after receipt of the third COVID-19 vaccine dose. Secondary outcomes included S1-RBD antibody titres at 12 weeks post-vaccination and self-reported levels of disease activity.

Methotrexate suspension and S1-RBD antibody response

A total of 254 individuals with a mean age of 59.1 years (61% female) were included in the trial and randomised equally to either strategy. Overall, 51% of participants had rheumatoid arthritis, 34% psoriasis and 20% a skin condition alone. The median dose of methotrexate taken as 20 mg/week.

After 4 weeks, the geometric mean SI-RBD antibody titre was 22,750 U/ml in the suspend methotrexate group and 10,798 U/ml in the continue methotrexate group (p < 0.0001). This increase was independent of the dose and administration route of methotrexate, as well as type of immune-mediated inflammatory disease and age. Moreover, this difference in response remained significant at week 12 (16,520 vs 8094).

One downside of the study was that significantly more patients in the suspend methotrexate group self-reported at least one disease flare over the 12 week period compared to those who continued with the drug (71% vs 45%, odds ratio, OR = 2.83, 95% CI 1.64 – 4.88). However, these flares were generally self-managed and without any major impacts on quality of life.

The authors concluded that their strategy of stopping MTX was both safe and boosted the level of COVID-19 antibodies and called for further studies to examine the effect of stopping other immunosuppressant drugs on the level of antibody response.

Citation
Abhishek A et al. Effect of a 2-week interruption in methotrexate treatment versus continued treatment on COVID-19 booster vaccine immunity in adults with inflammatory conditions (VROOM study): a randomised, open label, superiority trial. Lancet Resp Med 2022