Ardizzone 2003.

Methods	Randomized, investigator blind, 1 center, 2 arm: (methotrexate, azathioprine)
Participants	Patients with chronic active Crohn's disease defined as the need for steroid therapy of > 10 mg/day for at least 4 months during preceding 12 months, with at least one attempt to discontinue treatment. Crohn's disease had to be clinically active at entry (CDAI > 200) No immunosuppressives 3 months prior to entry N = 54
Interventions	Intraveneous methotrexate 25 mg/wk (n = 27) or oral azathioprine 2 mg/kg/day (n = 27) for 6 months After 3 months the methotrexate was switched to oral administration maintaining the same dose At entry, all patients received prednisolone (40 mg once a day) for 2 weeks, then 30 and 20 mg/day for the following 2 and 4 weeks After 8 weeks if the patients condition was stable or improved prednisolone was tapered by 5 mg/week until withdrawal For patients whose condition worsened prednisolone dosage was increased to a maximum daily dose of 40 mg after which tapering was attempted as described above During the study the use of oral and topical aminosalicylates, other immunosuppressive agents, antibiotics for perianal disease, tube feeding, parenteral nutrition, or topical corticosteroids was not permitted
Outcomes	The primary outcome was the proportion of patients entering first remission after 3 and 6 months of treatment Secondary outcomes: decrease in steroid requirements, decrease in mean CDAI scores, decrease in mean CRP and ESR, fistula closure
Notes	Clinical remission was defined as lack of need for steroid treatment and CDAI < 150 at each scheduled visit
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomized by a computer‐generated list
Allocation concealment (selection bias)	Unclear risk	Not described in published report
Blinding (performance bias and detection bias) All outcomes	High risk	The study was investigator‐blind Patients and Chief of the Institute (GBP), who supervised the randomization, were aware of the treatment The principal investigator (SA), who was blinded to treatment assignment, evaluated the efficacy of treatment at each scheduled visit and at the end of the study, according to the information provided by the other physicians in the investigation team (SB, GM, VB, EC), all of whom were also blinded and evaluated each patient’s clinical condition, computed the CDAI on the basis of patient diaries, recorded all the biochemical parameters considered in the study, and monitored compliance and toxicity
Incomplete outcome data (attrition bias) All outcomes	Low risk	No patients were lost to follow‐up Six patients (three in AZA and three in MTX group) discontinued treatment due to adverse events Withdrawal from the trial medication was considered to be a treatment failure
Selective reporting (reporting bias)	Low risk	All outcomes were reported
Other bias	Low risk	No other issues