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Advances in dermatology and venereology Acta Dermato-Venereologica
Folate Supplementation During Methotrexate Therapy : A Population-based Retrospective Cohort Study
Canelle MAZAUD 1 and Laurence FARDET 1 , 2 *
1
Department of Dermatology , Hôpital Henri Mondor , 51 Avenue du Maréchal de Lattre de Tassigny , FR-94010 Créteil , and 2 EA 7379 , EpiDermE , UPEC Université Paris Est Créteil , Créteil , France . E-mail : laurence . fardet @ aphp . fr Accepted Feb 13 , 2018 ; Epub ahead of print Feb 13 , 2018
Methotrexate ( MTX ) is a well-established therapy for many dermatological conditions ( e . g . psoriasis ) and non-dermatological conditions ( e . g . rheumatoid arthritis ). Prescribed at an immunomodulatory dosage ( i . e . ≤ 30 mg / week ), MTX is inexpensive and has a good efficacytoxicity ratio . Serious adverse events are rare and no more frequent than those observed with placebo ( 1 ). However , minor adverse events , such as mild increases in transaminase level or gastrointestinal symptoms , are more frequent with the drug , which results in a 30 % increase in the rate of discontinuation of MTX compared with placebo ( 1 ). Two meta-analyses have shown that some of these adverse events may be limited by folate supplementation ( 2 , 3 ), without lowering MTX efficacy ( 3 – 5 ). Furthermore , folate supplementation may relieve MTX-related hyperhomocysteinaemia ( 4 ). Finally , folate supplementation is usually inexpensive and is not , in itself , associated with adverse events . Therefore , guidelines recommend prescribing at least 5 mg folic or folinic acid weekly for all patients with dermatological conditions requiring MTX prescriptions ( 6 – 11 ). However , very few data are available regarding adherence to these recommendations . The aims of this study were to assess the prevalence of adequate folate supplementation in individuals exposed to MTX ≤ 30 mg / week , to define determinants of good practices , and to analyse association between folate supplementation and early MTX withdrawal .
METHODS
Data were extracted from the French medico-economic database Echantillon Généraliste de Bénéficiaires ( EGB ), a representative 1 / 97 th random sample of the French population ( 12 ). For this study , all patients who had at least one reimbursement for MTX were identified ( ATC codes L04AX03 or L01BA01 ) during 2006 to 2016 . Only incident users ( defined by reimbursement of MTX during a given year with no previous prescription in the preceding year ) were included in this cohort study . For all these patients , we searched for co-prescription of folate ( i . e . folic or folinic acid , ATC codes B03BB01 or V03AF03 ) during MTX exposure . Adequate folate supplementation was defined as a mean weekly dose of folate ≥ 5 mg over the MTX exposure . Covariates of interest that were analysed included : ( i ) patient sex and age , ( ii ) the underlying condition requiring MTX , ( iii ) data on MTX exposure , ( iv ) data on co-prescription of systemic glucocorticoids during the first 3 months of MTX exposure , and ( v ) data on MTX prescriber . Baseline variables are reported as mean ± standard deviation ( SD ) or median ( interquartile range ; IQR ) for continuous variables and number (%) for categorical variables . Groups were compared using a χ 2 test for categorical variables and Student t-test or Kruskal – Wallis test for continuous variables . A logistic regression model was used to assess determinants of good practice . A Cox proportional hazard model was used to assess whether adequate folate supplementation was associated with early ( i . e ., < 3 months after MTX initiation ) discontinuation of MTX . Linearity for continuous variables was checked . The proportional-hazard assumption for the Cox model was checked graphically . All statistical analyses were 2-tailed and were tested at the significance threshold α = 0.05 . All analyses were performed using Stata 14.0 . The study was approved by the national Institut des Données de Santé committee ( number 291 / 216 ).
RESULTS
During the study period , 771,190 individuals were recorded for at least one day in the EGB . Among them , 3,771 individuals ( 0.49 %) were incident MTX users ( 64.2 % women ; mean age 54.1 ± 17.8 years ) ( Table SI 1 ). The median weekly MTX dose was 12.2 mg ( 9.3 – 16.0 ); the dose varied widely according to patients ’ and prescribers ’ characteristics ( Table SII 1 ). The median duration of exposure was 614 days ( 164 – 1,526 ). MTX was most frequently prescribed orally ( 71.8 %), mainly for rheumatoid arthritis ( 28.3 %) or psoriasis / psoriatic arthritis ( 23.3 %).
Overall , 2,774 individuals ( 73.6 %) had adequate folate supplementation . These patients were older ( 63.0 % of those ≤ 40 years received adequate supplementation by comparison with 78.2 % of those aged ≥ 60 years ), received MTX at a higher dosage ( 59.5 % and 79.9 % for those prescribed MTX < 10 mg / week or ≥10 mg / week received adequate supplementation , respectively ) and for a longer time , and probably had more severe disease ( indirectly assessed using concomitant systemic glucocorticoid prescriptions ) than those with inadequate folate supplementation ( Table I ). Furthermore , prescribers probably more familiar with MTX prescriptions ( i . e . dermatologists , rheumatologists , internists , gastroenterologists and hospital-based physicians ) were more likely to adequately prescribe folates . Adequate folate supplementation was associated with less early discontinuation of MTX ( adjusted hazard ratio ( HR ): 0.46 ( 95 % confidence interval ( 95 % CI ) 0.39 – 0.55 ), p < 0.001 ). The results were similar when accounting for an adequate folate supplementation over the first 3 months of exposure ( adjusted HR 0.48 ( 0.41 – 0.57 )).
DISCUSSION
Folate supplementation decreases the number of patients with adverse events ( 1 ). The relative risk of gastrointestinal
1 https :// www . medicaljournals . se / acta / content / abstract / 10.2340 / 00015555-2904 doi : 10.2340 / 00015555-2904 Acta Derm Venereol 2018 ; 98 : 536 – 538
This is an open access article under the CC BY-NC license . www . medicaljournals . se / acta Journal Compilation © 2018 Acta Dermato-Venereologica .