Randomised, double-blind, placebo-controlled trial of methotrexate in steroid-dependent asthma

Shiner, Robert J.; Nunn, AJ; Chung, Kian Fan; Geddes, Duncan M.

doi:10.1016/0140-6736(90)91659-x

Cited by 143 publications

(69 citation statements)

References 18 publications

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“…This has been confirmed in doubleblind placebo-controlled trials [12,13]. One criticism of the present clinical observations is that the study was open-label without a placebo control group and was too short to draw conclusions with regard to the clinical effects of MTX [9].…”

Section: Discussionsupporting

confidence: 51%

Low-dose methotrexate treatment in severe glucocorticoid-dependent asthma: effect on mucosal inflammation and in vitro sensitivity to glucocorticoids of mitogen-induced T-cell proliferation

et al. 2000

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Low-dose methotrexate treatment in severe glucocorticoid-dependent asthma: effect on mucosal inflammation and in vitro sensitivity to glucocorticoids of mitogen-induced T-cell proliferation. B. Vrugt, S. Wilson, A. Bron, J. Shute, S.T. Holgate, R. Djukanovic, R. Aalbers. #ERS Journals Ltd 2000. ABSTRACT: The authors have investigated whether the steroid-sparing effect of methotrexate (MTX) in severe orally glucocorticoid-insensitive asthmatics may be accounted for by the ability of this drug to increase the T-cell responsiveness sensitivity to dexamethasone in vitro. In addition the authors have investigated whether low-dose MTX treatment is associated with anti-inflammatory effects in peripheral blood and the bronchial mucosa.In eight patients with severe atopic asthma, using $15 mg . day -1 prednisolone, the inhibitory effect of dexamethasone on mitogen stimulated peripheral blood mononuclear cells (PBMC) in vitro was tested before and after 8 weeks of uncontrolled treatment with MTX. Endobronchial biopsies were taken before and after MTX therapy in seven subsequent patients, and analysed using immunohistochemistry. In eight patients, serum was drawn for measuring levels of free interleukin (IL)-8.The in vitro sensitivity of PBMC to dexamethasone (at 1.6310 -9 and 3.2310 -10 mol . L -1 ) was significantly lower in the asthmatics before treatment when compared with the control subjects (p=0.03 and =0.001) but increased significantly after MTX treatment (p=0.04 and =0.02) to normal responsiveness. This was not associated with a decrease in peripheral blood T-cell numbers or activation. Except for a significant increase in the numbers of CD3+ (p=0.04), no significant numerical changes in activated T-cells, eosinophils, or mast cells were found (p>0.05). However, MTX treatment was associated with a significant fall in serum levels of free .It is hypothesized that the steroid-sparing effect of methotrexate originates from increased sensitivity of lymphocytes to the inhibitory effects of glucocorticoids. The absence of an inhibitory effect on inflammatory cells in blood and mucosa suggests that this effect is achieved by modulating cell function rather than cell number. Eur Respir J 2000; 15: 478±485.

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Section: Discussionsupporting

confidence: 51%

Low-dose methotrexate treatment in severe glucocorticoid-dependent asthma: effect on mucosal inflammation and in vitro sensitivity to glucocorticoids of mitogen-induced T-cell proliferation

et al. 2000

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“…We have used this inhibitor to demonstrate its capacity to reverse corticosteroid insensitivity. Immunosuppressive drugs, such as cyclosporin A and methotrexate have been administered in patients with steroid-dependent asthma to lower maintenance oral corticosteroid dosage, while allowing the control of asthma to remain unchanged [28,29], but these drugs have not proven to be useful. A p38 MAPK inhibitor could be effective in reversing corticosteroid insensitivity at lower doses than those needed to inhibit inflammation with a lesser risk of side-effects, but will need to be used concomitantly with corticosteroids.…”

Section: Discussionmentioning

confidence: 99%

Effect of p38 MAPK inhibition on corticosteroid suppression of cytokine release in severe asthma

Bhavsar¹,

Khorasani²,

Hew³

et al. 2009

European Respiratory Journal

101

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Patients with severe asthma respond less well to corticosteroids than those with non-severe asthma. Increased p38 mitogen-activated protein kinase (MAPK) activation in alveolar macrophages (AMs) from severe asthma patients has been associated with a reduced inhibition of cytokine release by dexamethasone.We determined whether p38 MAPK inhibitors would modulate corticosteroid suppression of cytokine release from AMs and peripheral blood mononuclear cells (PBMCs).PBMCs were isolated from venous blood and AMs by bronchoalveolar lavage in severe and non-severe asthma patients. PBMCs and AMs were exposed to lipopolysaccharide (LPS) with and without the p38 MAPK inhibitor, SD282, or dexamethasone. We determined the concentrationdependent effects of another p38 MAPK inhibitor, GW-A, on dexamethasone-induced inhibition of interleukin (IL)-8 release from PBMCs. Cytokines were assayed using an ELISA-based method.

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“…Follow-up assessments of patients treated with D-penicillamine, aurothiomalate and other DMARDs gave conflicting results, with only some of them developing obstructive ventilatory defects [19][20][21]. MTX has been recommended as an effective and safe glucocorticoidsparing agent in asthma [25,26]. However, its efficacy remains controversial [27].…”

Section: Discussionmentioning

confidence: 99%

Pulmonary Function in Rheumatoid Arthritis Treated With Low-Dose Methotrexate: A Longitudinal Study

et al. 1996

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SUMMARYLung volumes and gas exchange were investigated prospectively in 96 patients with rheumatoid arthritis selected without regard to pulmonary disorders and treated with i.m. methotrexate (MTX) injections [mean weekly dose 13.0 mg (5th-95th percentile (5-95 PC) 7.6-20.8)]. Individual changes over time during MTX treatment [mean duration 2.9 yr (5-95 PC 0.4-5.3)] were assessed by regression analyses in each individual. Forced vital capacity (FVQ remained stable in the majority of patients [mean annual change +0.8% (5-95 PC -8.1 to +14.0) of calculated normal value]. In addition, transfer factor using the indicator gas CO (Tuco) was unaltered in most patients [mean annual change -2.1% (5-95 PC -16.2 to +11.8) of predicted value]. However, there were significant decreases in the forced expiratory volume in 1 s (FEV,) before and after inhalation of 0.2 mg salbutamol [mean annual change -0.8% (5-95 PC -8.4 to +3.2) and -1.3% (5-95 PC -7.8 to +3.9) of the FVC measured, respectively]. In addition, there were significant increases in alveolar-arterial Po, gradients (P(A-.W)J) at rest and after exercise [mean annual change +1.7 mmHg (5-95 PC -5.2 to +12.2) and +1.8 mmHg (5-95 PC -3.5 to 9.0), respectively]. Nevertheless, the amounts were small in view of the reliability of the methods applied and reflect, at least in part, the normal process of ageing. The annual change in FEVi/FVC was negatively correlated with FEV,/FVC at baseline (R, = -0.46, P < 0.001). The annual change in T U co was also negatively correlated with Ti^o at baseline (Rs = -0.31, P = 0.028). No other risk factors for deterioration of lung volumes or gas exchange were found, including mean weekly MTX dose, age, gender, smoking, presence of rheumatoid factor and pulmonary function at baseline. We conclude that MTX has no major effect on pulmonary function in the majority of patients and that there is no evidence that patients with pre-existing pulmonary disease are at increased risk for further deterioration of lung function.

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Randomised, double-blind, placebo-controlled trial of methotrexate in steroid-dependent asthma

Cited by 143 publications

References 18 publications

Low-dose methotrexate treatment in severe glucocorticoid-dependent asthma: effect on mucosal inflammation and in vitro sensitivity to glucocorticoids of mitogen-induced T-cell proliferation

Low-dose methotrexate treatment in severe glucocorticoid-dependent asthma: effect on mucosal inflammation and in vitro sensitivity to glucocorticoids of mitogen-induced T-cell proliferation

Effect of p38 MAPK inhibition on corticosteroid suppression of cytokine release in severe asthma

Pulmonary Function in Rheumatoid Arthritis Treated With Low-Dose Methotrexate: A Longitudinal Study

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