Background/Purpose: Methotrexate (MTX) is the most commonly used disease modifying agent for rheumatoid arthritis (RA), although liver enzyme (LFT) elevations limit its use in some patients. Folic acid has been shown in a randomized controlled trial to dramatically reduce the incidence of elevated LFTs in patients taking MTX (van Ede et al, 2001). Although national guidelines recommend universal folic acid use for MTX users, the prevalence of folic acid prescription among MTX users in an older, population-based cohort of patients with rheumatic diseases is unknown.

Methods: We used national Veterans Health Administration (VHA) data to assess (1) folic acid prescription among new users of low-dose (< 40 mg/weekly), oral MTX and (2) predictors of not being prescribed folic acid.  We created a national cohort of incident MTX users ≥ age 65 using linked medical, pharmacy, and laboratory data from the VHA during fiscal years 2007-2008. Patients were included if they had a new, ≥ 28-day supply of MTX dispensed and evidence of continuous use of VHA services.  We excluded subjects who may have obtained care outside of the VHA by removing those with any encounter billed to Medicare. Folic acid prescription through the VHA pharmacy was assessed up to 30 days after the first MTX dispensation. We examined patients for elevated LFTs (AST or ALT ≥ 1.5 x upper limit of normal) during the 6 months after the first MTX dispensation.  We used multivariate regression to estimate (1) the relative risk of not being prescribed folic acid among different subgroups, and (2) the odds of LFT elevations among patients not prescribed folic acid, in both cases adjusting for demographic and clinical factors (sex, age, race, comorbid conditions, MTX dose, baseline LFT levels, # of specialty visits, and # of outpatient medications).

Results: Out of 717 new MTX users, 27% were not prescribed folic acid through the VHA pharmacy within 30 days of MTX initiation. Our cohort was mostly male (97%), white (87%), mean age 71.4 (SD 6.4), and carried a diagnosis of rheumatoid arthritis or psoriasis/psoriatic arthritis (57% and 22%, respectively). 52% of patients had a rheumatologist visit before the first MTX prescription was dispensed. Patients not followed by rheumatologists were 20% less likely (RR 0.8, 95% CI (0.7, 0.9)) to be prescribed folic acid compared with patients with a rheumatologist visit prior to their first MTX prescription, even after adjusting for the other factors listed above. Notably, patients who were not prescribed folic acid were significantly more likely to have LFT elevations after starting MTX in both univariate (9.7% vs. 5.0%, p = 0.02) and multivariate (OR 2.2, 95% CI (1.1, 4.2)) analysis.

Conclusion: Many new oral MTX users were not prescribed folic acid, and these patients were significantly more likely to have elevated LFTs.  Rheumatologists were more likely to prescribe folic acid than other providers. Improving folic acid prescription, especially in an older adult cohort, has the potential to significantly reduce the incidence of LFT abnormalities and may allow more widespread and persistent use of MTX, an effective and inexpensive medication for RA and other rheumatic diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/folic-acid-prescription-among-older-adult-methotrexate-initiators-is-poor/