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Traitement de la Polyarthrite rhumatoïde (PR)
par le méthotrexate (MTX)

Arthritis Rheum. 2008 Nov;58(11):3299-308

Traitement de la PR par MTX : démarrer à dose élevée pour une efficacité plus rapide ?

Le méthotrexate constitue aujourd'hui le traitement de fond de référence de la polyarthrite rhumatoïde. Autrefois débuté à la dose moyenne de 7,5 mg/semaine , on considère aujourd'hui qu'il est préférable de débuter à une dose plus élevée de l'ordre de 10 voire 15 mg/semaine.

Pharmacokinetics of oral methotrexate in patients with rheumatoid arthritis.
Dalrymple JM, Stamp LK, O'Donnell JL, Chapman PT, Zhang M, Barclay ML.
University of Otago, Christchurch, New Zealand.

OBJECTIVE: There is evidence supporting a therapeutic range for methotrexate polyglutamate (MTXGlu) concentrations in the treatment of rheumatoid arthritis (RA). Knowledge of the pharmacokinetics of MTXGlu1-5 is required for optimal timing of blood sampling. The aim of this study was to determine the time to steady state and the half-life of accumulation of red blood cell (RBC) MTXGlu1-5 in patients with RA commencing oral MTX, and the time for RBC MTXGlu1-5 to become undetectable and the half-life of elimination of RBC MTXGlu1-5 in patients ceasing treatment with oral MTX.

METHODS: Ten patients beginning treatment and 10 patients stopping treatment with low-dose oral MTX were recruited. Blood samples were initially collected weekly, with gradual extension to monthly collection over the study period. RBC MTXGlu1-5 concentrations were assayed by high-performance liquid chromatography. Results were analyzed using a first-order exponential method.

RESULTS: The median times to reach steady state in RBCs (defined as 90% of the maximum concentration) were 6.2, 10.6, 41.2, 149, and 139.8 weeks, respectively, for MTXGlu1, MTXGlu2, MTXGlu3, MTXGlu4, and MTXGlu5. The median half-life of accumulation for RBC MTXGlu1-5 ranged from 1.9 weeks to 45.2 weeks. The median times for MTXGlus to become undetectable in RBCs were 4.5, 5.5, 10, 6, and 4 weeks, respectively, for MTXGlu1, MTXGlu2, MTXGlu3, MTXGlu4, and MTXGlu5. The median half-life of elimination for RBC MTXGlu1-5 ranged from 1.2 weeks to 4.3 weeks.

CONCLUSION: There is wide interpatient variability of RBC MTXGlu1-5 accumulation and elimination in adults with RA. These data also suggest that after a dose change, >6 months are required for RBC MTXGlu1-5 to reach steady state. Such delays in achieving steady state suggest that more rapid dose escalation or subcutaneous administration from the outset should be considered.

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Optimal dosage and route of administration of methotrexate
in rheumatoid arthritis: a systematic review of the literature.

Visser K, van der Heijde D.
Ann Rheum Dis. 2009 Jul;68(7):1094-9. Epub 2008 Nov 25.Click here to read Click here to read Links Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. K.Visser@lumc.nl

Au total, l'étude conclut sur une proposition de posologie de départ de 10 à 15 mg/s avec augmentation par palier de 5 mg toutes les 2 à 4 semaines jusqu’à obtention d’une dose de 20 à 30 mg/s en fonction de la réponse clinique et de la tolérance ; la voie d’administration parentérale pourrait être envisagée en cas de réponse clinique insuffisante ou d’intolérance.

OBJECTIVES: To review systematically the available literature on the optimal dosage and route of administration of methotrexate in patients with rheumatoid arthritis (RA), as an evidence base for generating clinical practice recommendations.

METHODS: A systematic literature search was carried out in MEDLINE, EMBASE, Cochrane Library and American College of Rheumatology/European League Against Rheumatism meeting abstracts, searching for randomised controlled trials evaluating various dosages or routes of administration of methotrexate in RA. Articles that fulfilled predefined inclusion criteria were systematically reviewed and the quality was appraised. Effect sizes and odds ratios for clinical, radiological and toxicity outcomes were calculated and directly or indirectly compared between study groups using methotrexate in different dosages or by different routes.

RESULTS: A total of 38 publications out of 1748 identified references was included in the review. Start doses of 25 mg/week or fast escalation with 5 mg/month to 25-30 mg/week were associated with higher clinical effect sizes and more (gastrointestinal) adverse events in comparison with doses of 5-15 mg/week or slow escalation. Starting with 15 mg/week subcutaneous versus oral methotrexate was associated with higher clinical efficacy but more withdrawal due to toxicity in early RA. In longstanding RA, after failure on 15-20 mg/week orally, a switch to 15 mg/week intramuscularly with subsequent dose escalation did not result in increased efficacy.

CONCLUSIONS: Starting on methotrexate 15 mg/week orally, escalating with 5 mg/month to 25-30 mg/week, or the highest tolerable dose, with a subsequent switch to subcutaneous administration in the case of an insufficient response, seems to be the optimal evidence-based dosing and routing recommendation for methotrexate in RA.

A une posologie moyenne de 10,5 mg/s pour une durée moyenne de traitement de 55,8 mois, 20,2% des patients présentent au moins un épisode d’augmentation des transaminases. La survenue d’une cytolyse hépatique constitue 3,7% de causes d’arrêt. Une méta-analyse avec biopsies hépatiques répétées a suggéré une fréquence des fibroses sévères ou cirrhoses de l’ordre de 3%..

OBJECTIVE: To perform a systematic literature review of the long-term safety of methotrexate (MTX) monotherapy in rheumatoid arthritis (RA).

METHODS: A search was performed in Medline, Cochrane and EMBASE. Adults with RA who had received MTX monotherapy for more than 2 years were studied.

RESULTS: 88 published studies were included. Over 12 years of treatment, the termination rate of MTX due to toxicity was less than for sulfasalazine, gold, d-penicillamine and higher than for hydroxychloroquine (level of evidence 2a-2b). Long-term use of MTX does not appear to be a risk factor for serious infections, including herpes zoster (2b-4), and could provide a survival benefit by reducing cardiovascular mortality (2b). The prevalence of raised liver enzymes (more than twice the upper limit of normal) is close to 13% of patients; 3.7% of patients stopped MTX permanently owing to liver toxicity (2b). Data on the risk for liver fibrosis/cirrhosis are conflicting: a meta-analysis showed an incidence of fibrosis of 2.7% after 4 years of MTX (2a). However, two other studies on sequential liver biopsies did not show evidence for developing severe damage (2b). Insufficient data are available to fully assess the risk of lymphoma and malignancies, although there is no strong evidence of increased risk (2b-4).

CONCLUSION: This systematic literature search on MTX monotherapy with relatively low-dose use during at least 2 years shows favourable long-term safety.

Revoir le méthotrexate
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