The quality of evidence is downgraded by imprecise results (few outcome events).
Folate supplementation is recommended during methotrexate therapy for patients with rheumatoid arthritis.
Given both the efficacy of folic acid in reducing methotrexate side effects and its low cost compared to folinic acid, the use of folic acid is likely to be the more cost-effective therapy.
A Cochrane review [Abstract] 1 included 6 studies with a total of 624 subjects with rheumatoid arthritis (RA). The included studies compared folic acid (5-7 mg/week) or folinic acid (1-15 mg/week) with placebo. Supplementation with any form of exogenous folate (either folic or folinic acid) whilst on methotrexate (MTX) therapy reduced gastrointestinal (GI) side effects such as nausea, vomiting or abdominal pain, protected against abnormal serum transaminase elevation caused by MTX, and reduced withdrawal from MTX for any reason (table T1). Folic or folinic acid showed a trend towards reduction in risk of stomatitis/mouth sores, but the results were not statistically significant. It was not possible to draw meaningful conclusions on the effect on haematologic side effects of methotrexate due to small numbers of events and poor reporting of this outcome in included studies.Supplementation with either folic or folinic acid did not have a statistically significant effect on the efficacy of MTX in treating RA (as measured by RA disease activity parameters such as tender and swollen joint counts, or physician's global assessment scores).
| Outcome | Relative effect (95% CI) | Assumed risk - Placebo | Corresponding risk - Folic or folinic acid (95% CI) | NNT (95% CI) | Participants (studies) |
|---|---|---|---|---|---|
| NNT = number needed to treat | |||||
| GI side effects (nausea, vomiting, abdominal pain) | RR 0.74 (0.59 to 0.92) | 346 per 1000 | 256 per 1000(204 to 318) | 11 (7 to 35) | 644(6 studies) |
| Stomatitis / mouth sores (incidence) | RR 0.72 (0.49 to 1.06) | 223 per 1000 | 161 per 1000(109 to 236) | - | 575(4 studies) |
| Liver toxicity (incidence of transaminase elevation) | RR 0.23 (0.15 to 0.34) | 208 per 1000 | 48 per 1000(31 to 71) | 6 (6 to 7) | 551(4 studies) |
| Haematological disorders (neutropenia, etc.) | RR 1.55 (0.40 to 5.91) | <10 per 1000 | Studies included in this review were underpowered to detect a meaningful difference in rates of neutropenia. | - | 443(2 studies) |
| Total withdrawals | RR 0.39 (0.28 to 0.53) | 250 per 1000 | 98 per 1000(70 to 133) | 7 (6 to 9) | 640 (6 studies) |
When studies using folic acid were pooled together (table T2), the results were similar to the analyses of any form of exogenous folate (either folic or folinic acid) although the reduction in GI side effects did not reach statistical significance.
| Outcome | Relative effect (95% CI) | Assumed risk - Placebo | Corresponding risk - Folic acid (95% CI) | NNT (95% CI) | Participants (studies) |
|---|---|---|---|---|---|
| NNT = number needed to treat | |||||
| GI side effects (nausea, vomiting, abdominal pain) | RR 0.76 (0.57 to 1.01) | 346 per 1000 | 263 per 1000(197 to 349) | - | 355(3 studies) |
| Stomatitis / mouth sores (incidence) | RR 0.90 (0.53 to 1.54) | 223 per 1000 | 201 per 1000(118 to 343) | - | 302(2 studies) |
| Liver toxicity (incidence of transaminase elevation) | RR 0.19 (0.10 to 0.36) | 208 per 1000 | 40 per 1000(21 to 75) | 6 (5 to 8) | 302(2 studies) |
| Haematological disorders (neutropenia, etc.) | RR 1.70(0.42 to 6.96) | <10 per 1000 | Studies included in this review were underpowered to detect a meaningful difference in rates of neutropenia. | - | 443(2 studies) |
| Total withdrawals | RR 0.43 (0.29 to 0.64) | 250 per 1000 | 108 per 1000(73 to 160) | 7 (6 to 11) | 343(3 studies) |
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