Summary of findings: folic acid compared to placebo for reducing side effects in patients receiving methotrexate (MTX) for rheumatoid arthritis.
| Outcomes | Illustrative Comparative Risks* (95% CI) | Relative Effect(95% CI) | No. Participants (No. studies) | Quality of Evidence (GRADE) | Comments | |
| Assumed Risk, Placebo | Corresponding Risk, Folic Acid | |||||
| GI side effects (i.e., incidence of nausea, vomiting, abdominal pain) Followup: 24 to 52 weeks | 346 per 1000 | 263 per 1000 (197 to 349) | RR 0.76 (0.57–1.01) | 355 (3) | Moderate1,2 | Absolute risk difference −8.3% (−14.9% to 0.3%). Relative risk difference −24.0% (−43.1% to 0.8%). Not statistically significant |
| Stomatitis/mouth sores (incidence) Followup: 24 to 52 weeks | 223 per 1000 | 201 per 1000 (118 to 343) | RR 0.90 (0.53–1.54) | 302 (2) | Moderate1,2 | Absolute risk difference −2.2% (−10.5% to 12.0%). Relative risk difference −9.9% (−47.1% to 53.8%). Not statistically significant |
| Liver toxicity (incidence of transaminase elevation) Followup: 24 to 52 weeks | 208 per 1000 | 40 per 1000 (21 to 75) | RR 0.19 (0.10–0.36) | 302 (2) | Moderate1,2 | Absolute risk reduction −16.8% (−18.7% to −13.3%; p < 0.00001). Relative risk difference −80.8% (−89.9% to −63.9%). NNT = 6 (5 to 8) |
| Hematological disorders (neutropenia, etc.) Followup: 24 to 48 weeks | < 10 per 1000 | See comment | RR 1.70 (0.42–6.96) | 443 (2) | Low1 | This is a rare event3. The studies included in this review were underpowered to detect a meaningful difference in rates of neutropenia |
| Total withdrawals Followup: 24 to 48 weeks | 250 per 1000* | 108 per 1000 (73 to 160) | RR 0.43 (0.29–0.64) | 343 (3) | Moderate1,2 | Absolute risk reduction −14.2% (−17.7% to −9.0%; p = 0.000039). Relative risk difference −56.8% (−70.8% to −36.0%). NNT = 7 (6 to 11) |
| No. swollen joints with folic acid (≤ 7 mg/wk) Change in no. swollen joints Followup: 48 weeks | Mean no. swollen joints per patient = 16.00 | Mean no. swollen joints per patient = 14.35 | See comment | 42 (1) | Moderate1,2 | Mean differences between groups in no. swollen joints Absolute difference −1.65 (−7.96 to 4.66)4. Relative risk difference 10.4% (−49.8% to 29.1%). Not statistically significant |
| No. tender joints with folic acid (≤ 7 mg/wk) Change in no. tender joints Followup: 48 weeks | Mean no. tender joints per patient = 17.63 | Mean no. tender joints per patient = 20.09 | See comment | 42 (1) | Moderate1,2 | Mean differences between groups in no. tender joints 2.46 (−6.08 to 11.00)5. Relative risk difference 14.0% (−34.5% to 62.4%). Not statistically significant |
↵* The basis for the assumed risk (e.g., the median control group risk across studies) is below. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
↵1 No. events < 300.
↵2 < 400 participants.
↵3 Incidence of clinically important cytopenia in patients treated with low-dose MTX is estimated to be < 1%.
↵4 Posttreatment no. swollen joints not reported. Change scores presented here.
↵5 Posttreatment no. tender joints not reported. Change scores presented here. RR: risk ratio; NNT: number needed to treat.