Comparison of the clinical efficacy and safety of subcutaneous versus oral administration of methotrexate in patients with active rheumatoid arthritis: Results of a six‐month, multicenter, randomized, double‐blind, controlled, phase IV trial

Braun, Jürgen; Kästner, Peter; Flaxenberg, P.; Währisch, J.; Hanke, Petra; Demary, W.; Hinüber, Ulrich von; Rockwitz, Karin; Heitz, W.; Pichlmeier, Uwe; Guimbal-Schmolck, Cécile; Brandt, Andreas

doi:10.1002/art.23144

Cited by 323 publications

(252 citation statements)

References 30 publications

(50 reference statements)

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“…Alternatively, MTX can be administered by the subcutaneous or intramuscular route, resulting in improved bioavailability (30). In a recent study, subcutaneous administration of MTX was associated with a significantly improved response at 24 weeks as compared with oral administration (31). It would be of interest to know whether the observed improved clinical response seen with subcutaneous administration occurred at an earlier time point compared with oral administration.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of oral methotrexate in patients with rheumatoid arthritis

Dalrymple¹,

Stamp²,

O’Donnell³

et al. 2008

Arthritis & Rheumatism

172

136

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Objective. There is evidence supporting a therapeutic range for methotrexate polyglutamate ( Conclusion. There is wide interpatient variability of RBC MTXGlu 1-5 accumulation and elimination in adults with RA. These data also suggest that after a dose change, >6 months are required for RBC MTXGlu 1-5 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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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of oral methotrexate in patients with rheumatoid arthritis

Dalrymple¹,

Stamp²,

O’Donnell³

et al. 2008

Arthritis & Rheumatism

172

136

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“…In all these studies MTX was given orally, which may be suboptimal in light of a recent trial in RA indicating superiority of subcutaneous (s.c.) over oral MTX after a 24-week treatment period. 11 The aim of this study was to test an intensified s.c. dosing scheme of MTX in psoriasis with a starting dose of 17.5 mg/week and a possible dose increase to 22.5.mg/week against placebo over a 16-week induction period with a second MTX treatment period over a total of 52 weeks to better understand the potential of the drug in the treatment of this condition. Since the exact mechanism of action of MTX in psoriasis is unknown, we also investigated pairs of skin biopsies obtained before therapy and at week 16 with the intention to obtain insight into the effects of the drug on selected inflammatory disease pathways.…”

Section: Introductionmentioning

confidence: 99%

An intensified dosing schedule of subcutaneous methotrexate in patients with moderate to severe plaque-type psoriasis (METOP): a 52 week, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

Warren

Mrowietz

Kiedrowski³

et al. 2017

The Lancet

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Background: We report the study of an intensified dosing schedule of subcutaneous methotrexate (MTX) in patients with moderate-tosevere psoriasis. Methods: In this prospective, double-blind, multicentre phase 3 study (METOP) eligible patients were 18 years or older with a diagnosis of chronic plaque psoriasis at least 6 months before baseline, had a psoriasis area and severity index (PASI) of 10 or more or 10% or greater body-surface area involvement or a dermatology life quality index (DLQI) of 10 or more and were naïve to treatment with MTX. Participants were randomly assigned 3:1 by computer-generated random sequence integrated in the electronic data capture system to receive either MTX at a starting dose of 17.5 mg/week or placebo for the first 16 weeks, followed by openlabel MTX treatment of all patients up to 52 weeks (MTX/MTX and PLC/MTX groups, respectively). Dose escalation to 22.5 mg/week was allowed after 8 weeks of MTX therapy if patients failed to achieve an at least 50% improvement of their baseline PASI (PASI50); blinding was maintained by a corresponding volume increase of placebo injections. Treatment was combined with folic acid 5 mg/week. The primary efficacy endpoint was the proportion of patients achieving a PASI75 response at week 16 analysed by intention to treat with non-responder imputation. This study is registered with the European Medicines Agency, EudraCT number 2012-002716-10. Findings: Between February 2013 and May 2015 120 patients were randomly assigned to receive subcutaneous MTX (n=91) or placebo (n=29). The primary endpoint was met; the PASI75 response rate at week 16 was 41% (n=37) in the MTX group compared to 10% (n=3) in the placebo group [p=0.0026; effect size 30.3% (95% CI 15.3-45.3) MTX vs placebo]. Subcutaneous MTX was generally well tolerated; no cases of serious infections, malignancies, major adverse cardiovascular events or deaths were noted. Serious adverse events were observed in 3 patients started on MTX during the 52-week study period. Interpretation: The study documents a favourable 52-week benefit-risk profile of subcutaneous MTX in psoriasis. The route of administration and the intensified dosing schedule should be considered when using MTX in patients with psoriasis. Role of the funding source (see also below)The study was an investigator-initiated trial supported by a grant from Medac to K.R. Manuscript 2 SummaryBackground: We report the study of an intensified dosing schedule of subcutaneous methotrexate (MTX) in patients with moderate-to-severe psoriasis.

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“…Until now there is no consensus as to which route of administration is to be preferred. While a controlled prospective study comparing oral versus parenteral administration in adult patients with rheumatoid arthritis (RA) showed significantly higher American College of Rheumatology (ACR) 20% and 70% improvement criteria response rates in patients with parenteral MTX, this remains to be analyzed in JIA patients (13). However, the data suggest a number needed to treat of 12.5 for adult RA patients for 1 patient to benefit from subcutaneous MTX over oral MTX.…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of oral and parenteral methotrexate therapy in children with juvenile idiopathic arthritis: An observational study with patients from the German Methotrexate Registry

Klein

Kaul

Foeldvari

et al. 2012

Arthritis Care & Research

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Objective. The German Methotrexate Registry has been collecting data concerning the efficacy and safety of methotrexate (MTX) treatment since 2005. The aim of this retrospective analysis is to compare oral and parenteral MTX treatment regarding efficacy and safety. Methods. Inclusion criteria were diagnosis of juvenile idiopathic arthritis, MTX treatment for at least 6 months, a consistent route of administration of MTX, and no previous or concomitant treatment with biologic agents. Efficacy was measured by the American College of Rheumatology (ACR) pediatric (Pedi) criteria. Primary outcome was efficacy defined as the number of patients reaching ACR Pedi 30 improvement criteria after 6 months of treatment. Secondary outcome criteria were the ACR Pedi 50 and Pedi 70 criteria at 6 and 12 months, respectively. Analyses were performed with the intent-to-treat population. Results. Of the 411 eligible patients, 259 (63%) received oral MTX and 152 (37%) received subcutaneous MTX. In both patient groups, a comparable weekly dose of MTX (0.4 mg/kg versus 0.42 mg/kg) was used, and a comparable number of patients received concomitant steroids. The primary outcome in both treatment groups was that a comparably high number of patients showed a clinical response according to the ACR Pedi 30 score after 6 months of treatment (73% versus 72%; P ‫؍‬ 0.87). Twenty-two percent of patients with oral therapy and 27% with subcutaneous therapy had at least 1 documented adverse event. Discontinuation of treatment was observed in both groups with equal frequency, while significantly more patients with subcutaneous application discontinued MTX because of adverse events (11% versus 5%; P ‫؍‬ 0.02). Conclusion. In this retrospective analysis, parenteral MTX was not superior to oral administration regarding efficacy and tolerability.

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Comparison of the clinical efficacy and safety of subcutaneous versus oral administration of methotrexate in patients with active rheumatoid arthritis: Results of a six‐month, multicenter, randomized, double‐blind, controlled, phase IV trial

Cited by 323 publications

References 30 publications

Pharmacokinetics of oral methotrexate in patients with rheumatoid arthritis

Pharmacokinetics of oral methotrexate in patients with rheumatoid arthritis

An intensified dosing schedule of subcutaneous methotrexate in patients with moderate to severe plaque-type psoriasis (METOP): a 52 week, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

Efficacy and safety of oral and parenteral methotrexate therapy in children with juvenile idiopathic arthritis: An observational study with patients from the German Methotrexate Registry

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