Table 3.

Folinic acid compared to placebo for reducing side effects in patients receiving methotrexate (MTX) for rheumatoid arthritis.

OutcomesIllustrative Comparative Risks* (95% CI)Relative Effect (95% CI)No. Participants (No. studies)Quality of Evidence (GRADE)Comments
Assumed Risk, PlaceboCorresponding Risk, Folinic Acid
GI side effects (i.e., nausea, vomiting, abdominal pain) Followup: 24 to 52 weeks346 per 1000270 per 1000 (204 to 353)RR 0.78 (0.59–1.02)426 (4)Moderate1,2Absolute risk difference −7.6% (−14.2% to 0.7%). Relative risk difference −22.0% (−41.0 to 2.0%). Not statistically significant
Stomatitis/mouth sores (incidence) Followup: 24 to 52 weeks223 per 1000156 per 1000 (103 to 239)RR 0.70 (0.46–1.07)410 (3)Moderate1,2Absolute risk difference −6.7% (−12.0% to 0.16%). Relative risk difference −30.0% (−53.8% to 7.2%). Not statistically significant
Liver toxicity (incidence of transaminase elevation) Followup: 8 to 52 weeks208 per 100056 per 1000 (33 to 92)RR 0.27 (0.16–0.44)358 (3)Moderate1,2Absolute risk reduction −15.2% (−17.5% to −11.6%; p < 0.00001). Relative risk reduction −73.1% (−84.1% to −55.8%). NNT = 7 (6 to 9)
Hematological disorders (neutropenia, etc.) Followup: 52 weeks< 10 per 10003See commentRR 1.46 (0.25–8.59)278 (1)Low1This is a rare event3. The studies included in this review were underpowered to detect a meaningful difference in rates of neutropenia
Total withdrawals Followup: 8 to 52 weeks250 per 100088 per 1000 (58 to 133)RR 0.35 (0.23–0.53)386 (3)Moderate1,2Absolute risk reduction −16.2% (−19.2% to −11.7%; p < 0.00001). Relative risk reduction −64.8% (−76.8% to −46.8%). NNT = 6 (5 to 9)
No. swollen joints with folinic acid (≤ 7 mg/wk). Change in no. swollen joints Followup: 8 to 52 weeksMean no. swollen joints per patient = 19.13Mean no. swollen joints per patient = 20.29See comment100 (3)Moderate1,2Mean differences between groups in no. swollen joints (absolute difference) −1.72 (−3.47 to 6.92)4. Relative risk difference 8.1% (−16.3% to 32.6%). Not statistically significant
No. tender joints with folinic acid (≤ 7 mg/wk) Change in no. tender joints Followup: 8 to 52 weeksMean no. tender joints per patient = 14Mean no. tender joints per patient = 13.88See comment80 (2)Moderate1,2Mean difference between groups in no. tender joints 1.13 (−4.25 to 6.51)5. Relative risk difference: 6.3% (−23.9% to 36.6%). 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 Less than 400 participants.

  • 3 The 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; GI: gastrointestinal.