Management of steroid-dependent asthma with methotrexate: a meta-analysis of randomized clinical trials

Abstract

Our objective was to determine whether methotrexate is an effective steroid-sparing agent for patients with severe asthma. Published reports of controlled trials assessing the use of methotrexate in asthma were identified by a search of the MEDLINE, EMBASE, CINAHL, Biological Abstracts on CD, and Current Contents databases. Bibliographies from identified studies and from review articles were manually searched. Published and unpublished reports in any language were identified and assessed for inclusion in the meta-analysis. We selected randomized, double-blind, placebo-controlled trials in which low-dose methotrexate was administered to corticosteroid-dependent asthmatics, and oral steroids were subsequently tapered according to the patients' clinical status. Data were extracted independently by two reviewers. For all eligible trials, the mean reduction in oral corticosteroid dose, the mean change in FEV1, and the standard deviations, were calculated for the treatment and control groups. Data concerning side-effects of therapy were also extracted. Data from 12 studies, reporting on a total of 250 patients, were pooled using a weighted average method, with weights proportional to the inverse of the variance of the treatment effect. Compared to placebo, the use of methotrexate was associated with a pooled 6.0% improvement in FEV1 (95% CI, 1.0-11%) and an 18.2% reduction in oral steroid use (95% CI, 11.7-24.7%). This corresponded to a 3.3 mg day-1 greater reduction in oral steroid use for patients taking methotrexate than for those taking placebo (95% CI, 2.1-4.4 mg day-1). Gastrointestinal complications and transient increases in liver enzymes were more common in patients randomized to methotrexate. Three potentially life-threatening side-effects (two pneumonias and one liver dysfunction) occurred in 159 patients randomized to methotrexate vs. none in those patients on placebo. It was concluded that methotrexate allowed a modest reduction in oral corticosteroid compared to patients receiving placebo. The benefit is relatively small, however, and should be balanced against the potential for side-effects associated with the use of methotrexate.

Global strategy for asthma management and prevention: GINA executive summary

“…These medications should be used only in selected patients under the supervision of an asthma specialist, as their potential steroid-sparing effects may not outweigh the risk of serious side-effects. Two metaanalyses of the steroid-sparing effect of low-dose methotrexate showed a small overall benefit but a relatively high frequency of adverse effects [128,129]. This small potential to reduce the impact of glucocorticosteroid side-effects is probably insufficient to offset the adverse effects of methotrexate [130].…”

Children with Difficult Asthma: A Practical Approach

“…It has been shown in many studies to reduce steroid use in adults with asthma; these studies have recently been subjected to two meta-analyses (87,88). Both concluded that methotrexate allowed a modest reduction in daily prednisone dosage (4.3 mg and 3.3 mg) compared to placebo.…”

Management of asthma in adults: Current trends and future directions

“…Although there is some evidence that these agents have steroidsparing effects in asthma each has its own safety concerns and their use should be limited to specialist units. 35,36 There is also need for individualised treatment plans, required for different settings due to differences in circumstances regarding clinical presentation, and even in terms of personnel and resources. For instance, the severity of symptoms in asthma differs in pattern across the globe in epidemiology, risk profile and manifestations.…”