The Role of Methotrexate in the Management of Steroid-dependent Asthma – Methods

The Role of Methotrexate in the Management of Steroid-dependent Asthma - MethodsBronchial asthma is characterized clinically by wheeze, dyspnea, or cough secondary to reversible airways obstruction from airway smooth muscle contraction, mucosal edema, and increased mucus production. These clinical and physiologic changes are associated with increased airway hyperresponsiveness to nonspecific stimuli. Airway inflammation has been shown to play an important role in the pathogenesis of this bronchial hyperreactivity. Corticosteroids have been effective in reducing airway inflammation and controlling the symptoms of asthma. In a subset of patients, prolonged therapy with high-dose systemic corticosteroids may be required to control moderate to severe asthma. However, the side effects of longterm steroid therapy are common and may lead to debilitating complications, including infection, osteopenia, muscle weakness, hypertension, and peptic ulceration. Therefore, other anti-inflammatory agents that control asthma have been investigated to reduce the dependence on high-dose steroid therapy.
Methotrexate, an antagonist of dihydrofolate reductase, is anti-inflammatory when given in low doses (7.5 to 15 mg/wk). Low-dose methotrexate has been used extensively in the management of psoriasis and rheumatoid arthritis. In addition, it has been used with some success in Reiter’s syndrome and inflammatory bowel disease. Its mechanism of action is thought to be via inhibition of neutrophil chemotaxis induced by C5a and leukotriene B4. In addition, methotrexate has been shown to inhibit interleukin l and histamine release from basophils. However, despite initial reports of its efficacy as a steroid-sparing agent in asthma, a more recent report casts doubt on its effectiveness. Therefore, we undertook a prospective, double-blind, placebo-controlled, crossover study to evaluate whether methotrexate reduces the steroid requirement in steroid-dependent asthma. In addition, side effects of methotrexate vs placebo were assessed in blinded fashion.
Patient Selection
Patients were enrolled from the pulmonary clinic at the University of Michigan Hospitals. All subjects gave informed consent. To be included, patients must have demonstrated a 15 percent increase in absolute forced expiratory volume in 1 s (FEVj) value either spontaneously or after bronchodilator therapy within 12 months of enrollment and have fulfilled the definition of asthma as stated by the American Thoracic Society. Fourteen subjects chosen initially fulfilled the admission criteria: (1) nonsmokers; (2) age 18 to 50 years; (3) severe asthma requiring a minimum of 10 mg/d steroid therapy for the past year, or uncontrolled asthma requiring 3 hospitalizations per year, and/or 3 steroid bursts per year, and/or having steroid-related side effects, including Cushing’s syndrome, hypertension, diabetes mellitus, and osteoporosis; (4) receiving maximal therapy of inhaled bronchodilators and high-dose inhaled steroids (800 jig/d); (5) no significant smoking history (less than 0.15 pack years over 10 years and no cigarettes within 2 years); (6) no history of kidney or liver disease, a creatinine clearance greater than 60 ml/ min, and hepatic enzymes less than twice normal range; and (7) hematologic parameters of white blood cell count > 3,500 mm and platelet count > 150,000 mm. In addition, the subjects were not taking diuretics, nonsteroidal anti-inflammatory drugs, or alcohol, and were without childbearing potential or were practicing “adequate contraception.”

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