Summary of findings 2. Folic acid compared to placebo for reducing side effects in patients receiving methotrexate for rheumatoid arthritis.
| Folic acid compared to placebo for reducing side effects in patients receiving methotrexate for rheumatoid arthritis | ||||||
| Patient or population: Patients receiving methotrexate for rheumatoid arthritis Settings: International hospital and clinic settings Intervention: Supplementation with folic acid Comparison: Placebo | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | No of Participants (studies) | Quality of the evidence (GRADE) | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Folic Acid | |||||
| GI side effects (ie, incidence of nausea, vomiting, abdominal pain) Follow‐up: 24 to 52 weeks | 346 per 1000 | 263 per 1000 (197 to 349) | RR 0.76 (0.57 to 1.01) | 355 (3 studies) | ⊕⊕⊕⊝ 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) Follow‐up: 24 to 52 weeks |
223 per 1000 |
201 per 1000 (118 to 343) |
RR 0.90 (0.53 to 1.54) | 302 (2 studies) |
⊕⊕⊕⊝ 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 (ie, incidence of transaminase elevation) Follow‐up: 24 to 52 weeks |
208 per 1000 | 40 per 1000 (21 to 75) | RR 0.19 (0.10 to 0.36) | 302 (2 studies) | ⊕⊕⊕⊝ moderate1,2 | Absolute risk reduction = ‐16.8% (‐18.7% to ‐13.3%) (P < 0.00001) Relative risk reduction = ‐80.8% (‐89.9% to ‐63.9%) NNT = 6 (5 to 8) |
|
Haematological disorders (incidence of neutropenia, etc) Follow up: 24 to 48 weeks |
<10 per 10003 | See comment |
RR 1.70 (0.42 to 6.96) |
443 (2 studies) |
⊕⊕⊝⊝ 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 Follow‐up: 24 to 48 weeks |
250 per 1000* | 108 per 1000 (73 to 160) | RR 0.43 (0.29 to 0.64) | 343 (3 studies) | ⊕⊕⊕⊝ 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) |
|
Number of swollen joints with folic acid (≤7 mg/wk)
Change in number of swollen joints Follow‐up: 48 weeks |
Mean no. of swollen joints per patient = 16.00 | Mean no. of swollen joints per patient = 14.35 | See comment | 42 (1 study) | ⊕⊕⊕⊝ moderate1,2 | Mean difference between groups in number of 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 |
|
Number of tender joints with folic acid (≤7 mg/wk)
Change in number of tender joints Follow‐up: 48 weeks |
Mean no. of tender joints per patient = 17.63 | Mean no. of tender joints per patient = 20.09 | See comment | 42 (1 study) | ⊕⊕⊕⊝ moderate1,2 | Mean difference between groups in number of tender joints = 2.46 (‐6.08 to 11.00)5 Absolute risk difference: 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 provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; NNT: Number needed to treat | ||||||
| GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. | ||||||
1 Number of events is less than 300
2 Less than 400 participants
3The incidence of clinically important cytopenia in patients treated with low dose MTX is estimated to be less than 1%.
4 Post‐treatment number of swollen joints not reported. Change scores presented here.
5 Post‐treatment number of tender joints not reported. Change scores presented here.