Table 2.

Reference list of 13 studies evaluating methotrexate as an oral corticosteroid-sparing agent

Author, year	Title	Method	Dosage of MTX	Duration	Patients included; patients completed=n	Results; corticosteroid mg/day (SD)	Side effects
Mullarkey et al., 1988 (15)	Methotrexate in the treatment of corticosteroid-dependent asthma: a double-blind crossover study	Oral methotrexate or matched placebo weekly administered in three divided doses 12 h apart in randomized cross-over trial.	15 mg	24 weeks. 2×12 week treatment period.	22 n=13	Start dose 24.8 mg (15.3) End 16.6 mg (15). Reduction 8.2 mg or 33.1% Discontinuation in one patient.	Nausea, rash, elevated liver enzymes.
Shiner et al., 1990 (16)	Randomized, double-blind, placebo-controlled trial of methotrexate in steroid-dependent asthma	Randomized parallel trial of oral methotrexate or matched placebo weekly.	15 mg	38 weeks. 24 weeks treatment.	69 n=60	Start dose 13.2 mg (5). End 6.6 mg (6) Reduction 6.6 mg or 50%. Discontinuation in six patients.	Elevated liver enzymes in 12 patients. Gastrointestinal symptoms, mainly heartburn, nausea, bloated abdomen and diarrhea.
Dyer et al., 1991 (17)	Methotrexate in the treatment of steroid-dependent asthma	Randomized cross-over study of oral methotrexate or matched placebo weekly.	15 mg	8 months. 2×12 weeks treatment, 4 weeks wash-out period in between	12 n=10	Start dose 13.1 mg (5.31). End 8.37 mg (2.96) Reduction 4.73 mg or 36.1%.	Mild side effects including anorexia, alopecia and stomatitis. Resolved with dose reduction.
Erzurum et al., 1991 (18)	Lack of benefit of methotrexate in severe, steroid-dependent asthma: a double-blind, placebo-controlled study	Randomized parallel trial of methotrexate or placebo intramuscularly once weekly with open trial of methotrexate at the conclusion of the double-blind study.	5 mg in week 1. 10 mg in week 2, then 15 mg weekly.	13 weeks. 12 weeks treatment.	19 n=17	Start dose 20.2 mg (5). End 12.2 mg (5.12). Reduction 8.0 mg or 39.6%.	Gastrointestinal side effects. Nausea, diarrhea, elevation of transaminases, alopecia. One patient died during follow-up of pneumocystis carinii pneumonia. No significant difference between groups.
Taylor et al., 1993 (19)	Methotrexate in the management of severe steroid dependent asthma	Randomized cross-over trial of oral methotrexate or matched placebo weekly.	7.5 mg week 1 of each period, then 15 mg.	48 weeks. 2×24 weeks treatment.	11 n=9	Start dose 16.1 mg (7.5). End 14.4 mg (6.8). Reduction 1.7 mg or 10.6%.	Frequent. Elevated liver enzymes. One case of nausea, vomiting and mild alopecia.
Trigg and Davies, 1993 (20)	Comparison of methotrexate 30 mg per week with placebo in chronic steroid-dependent asthma: a 12-week double-blind cross-over study	Increasing doses of methotrexate or placebo administered in three divided doses 12 h apart in randomized cross-over study.	7.5 mg in week 1. 15 mg in week 2, then 30 mg weekly.	24 weeks. 2×12 week treatment.	18 n=12	Start dose 17.5 mg (11.55). End 10 mg (5.3) Reduction 7.5 or 42.9%.	Frequent. Headache, pneumonia, elevated liver enzymes, stomatitis, zoster, cellulitis, pityriasis versicolor. Dose reduction necessary.
Coffey et al., 1994 (21)	The role of methotrexate in the management of steroid-dependent asthma	Prospective randomized cross-over trial of methotrexate or matched placebo in increasing doses.	7.5 mg week 1–2. Increased by 2.5 mg every 2 weeks up to 15 mg weekly.	28–34 weeks. 2×12 weeks treatment.	14 n=11	Start dose 30.78 mg (16.25) End 20.1 mg (12.6). Reduction 10.68 mg or 34.7%.	No significant difference between groups. Mainly abdominal pain, nausea and diarrhea. One patient on placebo withdrawn due to alopecia.
Stewart et al., 1994 (22)	Comparison of oral pulse methotrexate with placebo in the treatment of severe glucocorticosteroid-dependent asthma	Randomized cross-over study of oral methotrexate or matched placebo weekly.	7.5 mg first 3 weeks, then 15 mg	33 weeks. 2×12 weeks treatment, 3 weeks wash-out period in between.	24 n=21	Start dose 21.05 mg (6). End 18.4 mg (9.9). Reduction 2.65 mg or 12.6%.	Mild side effects. Nausea, headache, upper respiratory tract infections, diarrhea.
Kanzow et al., 1995 (23)	Short-Term Effect of Methotrexate in Severe Steroid-dependent Asthma	Randomized, parallel trial of oral methotrexate or matched placebo weekly.	15 mg	27 weeks. 16 weeks treatment.	24 n=21	Start dose 29.8 mg (13.9). End 22.7 mg (13.3). Reduction 7.1 mg or 23.8%.	Slight nausea in two patients.
Hedman et al., 1996 (24)	Controlled trial of methotrexate in patients with severe chronic asthma	Randomized, cross-over trial of oral methotrexate or matched placebo weekly.	15 mg	26 weeks, 2×12 weeks treatment.	13 n=12	Start dose 10.9 mg (8.4). End 7.9 (8.1). Reduction 3 mg or 38%.	One patient withdrawn due to nosebleeds. Other side effects were vomiting, nausea, abdominal pain.
Comet et al., 2005 (14)	Benefits of low weekly doses of methotrexate in steroid-dependent asthmatic patients. A double-blind, randomized, placebo-controlled study	Randomized, parallel trial of oral methotrexate or matched placebo weekly.	10 mg	12 months	46 n=39	Start dose 17.3 mg (63.39) End 7.8 mg (31.85). Reduction 9.5 mg or 54.8%.	One case of diarrhea, one of bronchospasm, one of unspecific symptoms.
Domingo et al., 2009 (4)	Twelve years’ experience with methotrexate for GINA treatment step 5 asthma patients	Oral methotrexate weekly systematically offered to all who met the inclusion criteria.	10 mg	12 month 91.3±39.5 months	44 n=42	Start dose 15.1 mg (53.14). End 2.64 mg (34.67) Reduction 12.46 mg or 82.5%. Discontinuation in 25 patients.	One patient with alopecia. Mild increase in hepatic enzymes in four patients. Normalized after discontinuation of treatment.
Knarborg et al., 2014	Methotrexate as an oral corticosteroid-sparing agent in severe asthma: the emergence of a responder asthma endotype	Patients followed from 7 months up to 8 years adjusting treatment of methotrexate and prednisolone according to condition and side effects.	5–20 mg	From 7 months to 8 years	15 n=13	Start dose 15.38 mg (SD 8.34) End 6.35 mg (SD 8.88) Reduction 9.03 mg (SD 10.44) or 58.75%. Discontinuation in six patients (46%).	One case of cystitis, one of long-term fever, one of mouth sores and abdominal pain and one of elevated liver enzymes.