As demonstrated in Figure 1, the mean dose of prednisone decreased in both treatment phases compared with the initial period (p<0.001), with a mean of 20 percent reduction in steroid dosage using placebo alone. There was no significant difference in mean steroid reduction comparing the methotrexate and placebo group (Table 2). Of the 11 patients who completed the study, only three responded to methotrexate. These patients reduced their steroid dose by 33 percent or more while receiving methotrexate, but they had no significant change in steroid dosing while receiving placebo (Table 3). The three patients deemed to be responders did not demonstrate any predicting factors compared with nonresponders. Specifically, there was no significant difference in the duration of asthma, FEV1 percent, although there was a trend toward a lower baseline steroid dose. All three responders had received methotrexate during the first phase, indicating that it was unlikely a placebo effect. For all parameters studied, including steroid dosage, pulmonary function testing, and symptom score, there was no evidence of a carryover effect from one phase into the other.
Daily Peak Flowmeter and Diary Cards
Of the eight patients who kept accurate diary cards, there was no significant difference between methotrexate and placebo with regard to peak flow rates (Table 2). Similarly, there was no difference between the symptom score over the duration of the whole study. There were ten exacerbations of asthma symptoms that required a boost and taper of prednisone therapy. They were equally divided between the placebo (five times) and methotrexate (five times) phases of the study. canadian healthcare mall
One patient was withdrawn from the study because of alopecia during the first treatment phase. However, upon withdrawal from the study, she was subsequently noted to be receiving placebo. Methotrexate therapy was not withdrawn completely in any of the patients. Methotrexate was omitted for a week and then reinstituted because of side effects in four patients noted by the physician monitoring toxic reactions. As demonstrated in Table 4, the incidence of side effects while receiving methotrexate was not different from that of placebo. Symptoms occurring primarily in four subjects account for the majority of the toxicity data, and it was these same subjects who had symptoms during both treatment phases. The most frequent side effects were gastrointestinal: nausea, abdominal cramps, and diarrhea. Some of the worrisome toxic reactions of methotrexate, including interstitial pneumonitis and hematologic abnormalities, did not occur. Significant hepatic function abnormalities (greater than threefold rise) did not occur in any of the 11 patients.
Figure 1. Average daily prednisone dose in 11 corticosteroid-dependent asthmatics treated with low-dose methotrexate during the initial, placebo and methotrexate phases. A different notation is used for each subject. Prednisone dose was calculated from the last 2 weeks of the initialization phase and the last 4 weeks of the placebo and methotrexate phase, respectively.
Table 3—Characteristics of Methotrexate Responders Compared with Nonresponders
|. .||Responders(n=3)||Nonresponders (n = 8)|
|Age, yr||39 ±6.0||34.6 ±3.2|
|FEV„ L||2.0 ±0.3||2.4 ±0.2|
|FVC, L||3.6 ±0.9||3.9±0.5|
|FEVj, FVC, %||58.7 ±5.6||62.2 ±5.5|
|Initialization prednisone, mg/d||23.4±4.2||33.5 ±6.5|
Table 4—Incidence of Fatients Experiencing Adverse Events in the Study Population Receiving Methotrexate and Placebo