This review included 7 trials of 307 patients, of which 147 were treated with folate supplementation, 80 patients with folinic acid and 67 patients with folic acid. A 79% reduction in mucosal and gastrointestinal (GI) side effects was observed for folic acid. For folinic acid, a clinically but non-statistically significant reduction of 43% was found. No major differences were observed between low and high doses of folic or folinic acid. Not enough information on blood disorder side effects was available to perform an analysis. No consistent differences in disease activity measures were observed when comparing patients taking placebo or folic or folinic acid at low or high doses, although patients on high dose folinic acid had an increase in the number of tender joints, but not swollen joints. Large differences in costs across countries were found, but folinic acid was more expensive in all.
The results support the protective effect of folate supplementation in reducing methotrexate (MTX) side effects related to the oral and GI systems. We could not determine if folic was different from folinic acid. Therefore, for folinic acid to be considered cost-effective it must be found more effective than folic acid at reducing MTX side effects.