Summary of findings: folic or folinic acid (any) 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,Either Folic or Folinic Acid | |||||
| GI side effects (nausea, vomiting, abdominal pain) Followup: 24 to 52 weeks | 346 per 1000 | 256 per 1000 (204 to 318) | RR 0.74 (0.59–0.92) | 644 (6) | Moderate1 | Absolute risk reduction −9.0% (−14.2% to −2.8%; p = 0.008). Relative risk reduction −26.0% (−1.0% to −8.1%). NNT = 11 (7 to 35). |
| Stomatitis/mouth sores (incidence) Followup: 24 to 52 weeks | 223 per 1000 | 161 per 1000 (109 to 236) | RR 0.72 (0.49–1.06) | 575 (4) | Moderate1 | Absolute risk difference −6.2% (−11.4% to 1.3%). Relative risk difference −27.8% (−51.1% to 5.8%). Not statistically significant. |
| Liver toxicity (incidence of transaminase elevation) Followup: 8 to 52 weeks | 208 per 1000 | 48 per 1000 (31 to 71) | RR 0.23 (0.15–0.34) | 551 (4) | Moderate1 | Absolute risk reduction −16.0% (−17.7% to −13.7%; p < 0.00001). Relative risk reduction −76.9% (−85.1% to −65.9%). NNT = 6 (6 to 7). |
| Hematological disorders (neutropenia, etc.) Followup: 24 to 52 weeks | < 10 per 1000 | See comment | RR 1.55 (0.40–5.91) | 443 (2) | Low1 | This is a rare event2. The studies included in this review were underpowered to detect a meaningful difference in rates of neutropenia. |
| Total withdrawals Followup: 8 to 52 weeks | 250 per 1000 | 98 per 1000 (70 to 133) | RR 0.39 (0.28–0.53) | 640 (6) | Moderate1 | Absolute risk reduction −15.2% (−18.0% to −11.7%) (p < 0.00001) Relative risk reduction −60.8% (−72.0% to −46.8%). NNT = 7 (6 to 9). |
| No. swollen joints Change in no. swollen joints Followup: 8 to 52 weeks | Mean no. swollen joints per patient in the control group is 18.24 | Mean no. swollen joints per patient = 18.47 | See comment | 142 (4) | Moderate1 | SMD between groups in no. swollen joints 0.05 (−0.28 to 0.38). Absolute risk difference 4.82% (−27.01% to 36.6%). Relative risk difference 26.42% (−148.08% to 201.04%). Not statistically significant |
| No. tender joints Change in no. tender joints Followup: 8 to 52 weeks | Mean no. tender joints per patient in control group is 15.23 | Mean no. tender joints per patient = 16.05 | See comment | 122 (3) | Moderate1 | SMD between groups in no. tender joints 0.09 (−0.27 to 0.45). Absolute risk difference 4.55% (−13.65% to 22.75%). Relative risk difference 29.88% (−89.63% to 149.38%). 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 is < 300.
↵2 The incidence of clinically important cytopenia in patients treated with low-dose MTX is estimated to be < 1%. RR: risk ratio; NNT: number needed to treat; SMD: standardized mean difference.