RA Treatments - Methotrexate
Abstract 1854 Effect of Folic and Folinic Acid Supplementation on Toxicity and Efficacy of Methotrexate in Rheumatoid Arthritis
A Van Edee, R Laan, M Rood, T Huizinga, M Van De Laar, J Van Denderen, A Westgeest, A Romme, D-J De Rooij, M Jacobs, T De Boo, B Dijkmans, F Breedveld, L Van De Putte The Netherlands
Methotrexate (MTX) dosing is primarily limited by toxicity. These investigators compared the ability of folic acid and folinic acid to inhibit the side effects typically associated with MTX therapy. 453 patients were enrolled in a 48-week multicenter study and randomly assigned to 1 of 3 treatment groups: 1) MTX alone; 2) MTX + folic acid 1-2 mg/dy; and, 3) MTX + folinic acid 2.5 mg/wk. One alcoholic drink per day was allowed. Toxicity and joint activity were assessed at predetermined intervals. Characteristics of the groups at baseline were not statistically significantly different from one another for any parameter.
Toxicity related discontinuations of MTX occurred in 38% of patients in the MTX alone group, compared to 17% in the folic acid group (p < .001) and 12% in the folinic acid group (p < .001). Discontinuation of MTX was almost entirely due to hepatotoxicty. Other side effects such as nausea, mouth ulcers, other GI symptoms were not increased in the MTX alone group, compared to the MTX + folic acid/folinic acid groups. All parameters of disease activity improved similarly among the three groups (assessed by the ACR composite scores and the DAS score). At the end of 48 weeks, patients on folic acid and folinic acid were on higher doses of MTX than the MTX alone group (18.0, 16.4 and 14.5 mg/week, respectively). The authors conclude that folate and folinic acid reduce liver toxicity from MTX with equivalent potency without reducing the clinical efficacy of MTX.
Editorial comment: These are important findings. Based on these and other studies, it can be argued strongly that all patients who begin MTX therapy should receive concomitant folic/folinic acid supplementation. It is interesting that folic/folinic acid supplementation reduced the incidence of liver toxicity but not of mouth ulcers or other GI symptoms. Several clinical trials with MTX in Europe have reported a higher incidence of liver toxicity than in the U.S.; this may be related to a more generous allowance of alcohol in Europe.
We do not know from this study whether MTX was increased according to a predetermined algorithm or at the discretion of the investigators. If the latter, this may have biased the data although the investigators were blinded to the treatment.
Abstract 1853 Reduction in Cumulative Disability with Increasing Exposure to Methotrexate in Rheumatoid Arthritis
BWE Wang, F Wolfe, JF Fries Stanford, CA, Wichita, KS
This study investigated the effect of time of exposure on methotrexate (MTX) on cumulative disability in rheumatoid arthritis (RA). 1,532 longitudinally followed RA patients from one university-based and one community-based arthritis centers were evaluated. Start and stop dates on MTX were obtained and therapeutic segments on drug were calculated. The authors found that MTX containing treatment regimens were associated with better disability outcomes than non-MTX containing regimens. They also found that cumulative disability scores (calculated as Area Under Curve, AUC) were more meaningful than assessing disability by one final end-of-study HAQ score.
Editorial comment: This approach to analysis of the impact of a DMARD on disability in RA using therapeutic segments and AUCs appears to be more sensitive than traditional single HAQ scores and, therefore, may enhance the ability to detect differences between DMARDs. However, the change in disability score over time is still related to a single HAQ score defined at study entry.