Why subcutaneous methotrexate should be a prerequisite to biologic use in patients with rheumatoid arthritis

Why subcutaneous methotrexate should be a prerequisite to biologic use in patients with... Since the first randomized controlled trial of low-dose MTX demonstrated that MTX 7.5 mg/week gave a greater reduction in the number of tender and swollen joints compared with placebo, has been widely accepted as the first-line strategy for managing RA across Europe and USA [1]. It has the highest 5-year retention rate of all DMARDs [2]. MTX 20 mg/week may be sufficient treatment for up to a third of patients with RA. In the UK, MTX has become the gateway to biologic treatment. On the basis of current evidence, it seems there is no debate about the place or the starting dose of MTX in the management of RA. Therefore, accepted practice is that prior to commencing biologic therapies, patients with RA need to have tried and failed MTX and one other DMARD. However, the main debate is around the absence of an agreed recommendation on the route of administration, and the resulting lack of homogenization of practice across clinical settings. It is possible that there may be a window where introduction of disease-modifying treatment in RA may alter the trajectory of the disease [3]. This window of opportunity may last for as little as 3 months from the onset of symptoms. This has fed into the development of the National Institute of Health and Care Excellence guidance for treating RA in the UK and subsequently the quality standard for commencing treatment within 6 weeks of a referral. In reality however, a national arthritis audit in England and Wales demonstrated that the median delay in referring a patient with suspected inflammatory arthritis to secondary care is 20 days; there is a further delay after referral. A third of patients wait for over 6 weeks before commencing any disease-modifying agent [4]. Considering the possibility that there will also be a delay between actual onset of disease and presentation to primary care, the actual ‘window of opportunity’ is significantly narrower than published in literature. The clinical efficacy of subcutaneous MTX is superior to oral MTX at the same dose. In a randomized, double-blind, placebo-controlled trial, MTX 15 mg/week as a subcutaneous injection delivered ACR20/70 of 78%/41% at 24 weeks vs 70%/33% for oral MTX (P < 0.05) [5]. This is unsurprising because subcutaneous administration consistently delivers a greater plasma concentration and area under the plasma concentration curve. This difference probably increases at doses above 15 mg/week. Stamp et al. [6] demonstrated that the polyglutamate signature of MTX shifted towards more glutamate residues attached to the MTX when the mode of administration was switched to the subcutaneous route and that the presence of longer chain residues was significantly associated with greater fall in DAS28 [6]. Real-world evidence shows that subcutaneous MTX is underutilized [7]. There are no direct head-to-head studies of subcutaneous MTX and biologics; however there are a few retrospective studies comparing the costs. In a recent study from the USA, the total 5 year costs for patients who switched to biologics were four to eight times higher than the costs of patients who continued to use oral or subcutaneous MTX [8]. Another retrospective observational study evaluated patients who were switched from oral to subcutaneous MTX. In this study, only 17% of patients required biologic therapy over a 5-year period. Continuation rates were also higher [9]. Another cost-effectiveness study from the UK has shown that routine use of subcutaneous MTX following oral MTX failure has the potential to save an estimated £7000 per patient in the first year of therapy and £9 m per year nationally in new patients [10] compared with biologic use. A switch from oral to parenteral MTX may enable more patients to achieve disease remission without having to add a biologic. Furthermore, it allows the opportunity to postpone or even avoid expensive therapies with biologics. This offers a potential considerable financial saving that could ultimately lead to a reduction of the financial burden on the over-stretched healthcare system. Consensus treatment recommendations developed by the ACR and EULAR advocate treating most patients with moderate or severe disease initially with MTX, unless there is a contraindication. Furthermore, Canadian Rheumatology Association and the Finnish Current Care Guidelines recommend starting treatment with subcutaneous MTX in DMARD-naïve RA patients. In 2016, 57% of the rheumatology units in England and Wales self-declared that they run an early arthritis clinic [4]. In the absence of a recommended escalation pathway, it would be reasonable to assume that there will be several versions of escalation pathways. In the absence of active infection or significant acquired immunodeficiency, MTX should be offered as first-line treatment to patients with rapid escalation to 20 mg/week. Since we have a small window of opportunity to affect long-term outcomes, it may not make pharmacokinetic sense to use oral administration, which is less predictable in drug delivery. We are not aware of any health economic analysis comparing the outcomes of oral vs subcutaneous MTX strategy for first-line treatment, but it would be reasonable to consider that the outcome would favour the oral route because of the huge price differential (£0.33 for oral 15 mg dose vs £16.57 for subcutaneous 15 mg Metoject dose). However, the health economic studies analysis is unequivocally in favour of a strategy to switch all patients to the subcutaneous dose of MTX prior to recommending biologic agents. Recommended algorithms exist for rarer diseases such as ANCA-associated vasculitis. It is high time that a similar algorithmic strategy was incorporated into UK rheumatology clinical practice. Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: The authors have declared no conflicts of interest. References 1 Smolen JS , Landewé R , Bijlsma J et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update . Ann Rheum Dis 2017 ; 76 : 960 – 77 . Google Scholar CrossRef Search ADS PubMed 2 Yazici Y , Sokka T , Kautiainen H et al. Long term safety of methotrexate in routine clinical care: discontinuation is unusual and rarely the result of laboratory abnormalities . Ann Rheum Dis 2005 ; 64 : 207 – 11 . Google Scholar CrossRef Search ADS PubMed 3 Raza K , Filer A. The therapeutic window of opportunity in rheumatoid arthritis: does it ever close? Ann Rheum Dis 2015 ; 74 : 793 – 4 . Google Scholar CrossRef Search ADS PubMed 4 HQIP . National Clinical Audit for Rheumatoid and Early Inflammatory Arthritis. 2nd Annual Report 2016. Health Quality Improvement Partnership; 22 January 2016 . https://www.hqip.org.uk/resources/rheumatoid-and-early-inflammatory-arthritis-2016/. 5 Braun J , Kastner P , Flaxenberg P et al. 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 . Arthritis Rheum 2008 ; 58 : 73 – 81 . Google Scholar CrossRef Search ADS PubMed 6 Stamp LK , Barclay ML , O’Donnell JL et al. Effects of changing from oral to subcutaneous methotrexate on red blood cell methotrexate polyglutamate concentrations and disease activity in patients with rheumatoid arthritis . J Rheumatol 2011 ; 38 : 2540 – 7 . Google Scholar CrossRef Search ADS PubMed 7 Rohr MK , Mikuls TR , Cohen SB, , Thorne JC, , O’Dell JR. Underuse of methotrexate in the treatment of rheumatoid arthritis: a national analysis of prescribing practices in the US . Arthritis Care Res 2017 ; 69 : 794 – 800 . Google Scholar CrossRef Search ADS 8 Lee J , Pelkey R , Gubitosa J , Henrick MF , Ganz ML. Comparing healthcare costs associated with oral and subcutaneous methotrexate or biologic therapy for rheumatoid arthritis in the United States . Am Health Drug Benefits 2017 ; 10 : 42 – 9 . Google Scholar PubMed 9 Scott DG , Claydon P , Ellis C. Retrospective evaluation of continuation rates following a switch to subcutaneous methotrexate in rheumatoid arthritis patients failing to respond to or tolerate oral methotrexate: the MENTOR study . Scand J Rheumatol 2014 ; 43 : 470 – 6 . Google Scholar CrossRef Search ADS PubMed 10 Fitzpatrick R , Scott DGI , Keary I. Cost-minimisation analysis of subcutaneous methotrexate versus biologic therapy for the treatment of patients with rheumatoid arthritis who have had an insufficient response or intolerance to oral methotrexate . Clin Rheumatol 2013 ; 32 : 1605 – 12 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Rheumatology Oxford University Press

Why subcutaneous methotrexate should be a prerequisite to biologic use in patients with rheumatoid arthritis

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Oxford University Press
Copyright
© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com
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1462-0324
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1462-0332
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10.1093/rheumatology/key097
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Abstract

Since the first randomized controlled trial of low-dose MTX demonstrated that MTX 7.5 mg/week gave a greater reduction in the number of tender and swollen joints compared with placebo, has been widely accepted as the first-line strategy for managing RA across Europe and USA [1]. It has the highest 5-year retention rate of all DMARDs [2]. MTX 20 mg/week may be sufficient treatment for up to a third of patients with RA. In the UK, MTX has become the gateway to biologic treatment. On the basis of current evidence, it seems there is no debate about the place or the starting dose of MTX in the management of RA. Therefore, accepted practice is that prior to commencing biologic therapies, patients with RA need to have tried and failed MTX and one other DMARD. However, the main debate is around the absence of an agreed recommendation on the route of administration, and the resulting lack of homogenization of practice across clinical settings. It is possible that there may be a window where introduction of disease-modifying treatment in RA may alter the trajectory of the disease [3]. This window of opportunity may last for as little as 3 months from the onset of symptoms. This has fed into the development of the National Institute of Health and Care Excellence guidance for treating RA in the UK and subsequently the quality standard for commencing treatment within 6 weeks of a referral. In reality however, a national arthritis audit in England and Wales demonstrated that the median delay in referring a patient with suspected inflammatory arthritis to secondary care is 20 days; there is a further delay after referral. A third of patients wait for over 6 weeks before commencing any disease-modifying agent [4]. Considering the possibility that there will also be a delay between actual onset of disease and presentation to primary care, the actual ‘window of opportunity’ is significantly narrower than published in literature. The clinical efficacy of subcutaneous MTX is superior to oral MTX at the same dose. In a randomized, double-blind, placebo-controlled trial, MTX 15 mg/week as a subcutaneous injection delivered ACR20/70 of 78%/41% at 24 weeks vs 70%/33% for oral MTX (P < 0.05) [5]. This is unsurprising because subcutaneous administration consistently delivers a greater plasma concentration and area under the plasma concentration curve. This difference probably increases at doses above 15 mg/week. Stamp et al. [6] demonstrated that the polyglutamate signature of MTX shifted towards more glutamate residues attached to the MTX when the mode of administration was switched to the subcutaneous route and that the presence of longer chain residues was significantly associated with greater fall in DAS28 [6]. Real-world evidence shows that subcutaneous MTX is underutilized [7]. There are no direct head-to-head studies of subcutaneous MTX and biologics; however there are a few retrospective studies comparing the costs. In a recent study from the USA, the total 5 year costs for patients who switched to biologics were four to eight times higher than the costs of patients who continued to use oral or subcutaneous MTX [8]. Another retrospective observational study evaluated patients who were switched from oral to subcutaneous MTX. In this study, only 17% of patients required biologic therapy over a 5-year period. Continuation rates were also higher [9]. Another cost-effectiveness study from the UK has shown that routine use of subcutaneous MTX following oral MTX failure has the potential to save an estimated £7000 per patient in the first year of therapy and £9 m per year nationally in new patients [10] compared with biologic use. A switch from oral to parenteral MTX may enable more patients to achieve disease remission without having to add a biologic. Furthermore, it allows the opportunity to postpone or even avoid expensive therapies with biologics. This offers a potential considerable financial saving that could ultimately lead to a reduction of the financial burden on the over-stretched healthcare system. Consensus treatment recommendations developed by the ACR and EULAR advocate treating most patients with moderate or severe disease initially with MTX, unless there is a contraindication. Furthermore, Canadian Rheumatology Association and the Finnish Current Care Guidelines recommend starting treatment with subcutaneous MTX in DMARD-naïve RA patients. In 2016, 57% of the rheumatology units in England and Wales self-declared that they run an early arthritis clinic [4]. In the absence of a recommended escalation pathway, it would be reasonable to assume that there will be several versions of escalation pathways. In the absence of active infection or significant acquired immunodeficiency, MTX should be offered as first-line treatment to patients with rapid escalation to 20 mg/week. Since we have a small window of opportunity to affect long-term outcomes, it may not make pharmacokinetic sense to use oral administration, which is less predictable in drug delivery. We are not aware of any health economic analysis comparing the outcomes of oral vs subcutaneous MTX strategy for first-line treatment, but it would be reasonable to consider that the outcome would favour the oral route because of the huge price differential (£0.33 for oral 15 mg dose vs £16.57 for subcutaneous 15 mg Metoject dose). However, the health economic studies analysis is unequivocally in favour of a strategy to switch all patients to the subcutaneous dose of MTX prior to recommending biologic agents. Recommended algorithms exist for rarer diseases such as ANCA-associated vasculitis. It is high time that a similar algorithmic strategy was incorporated into UK rheumatology clinical practice. Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: The authors have declared no conflicts of interest. References 1 Smolen JS , Landewé R , Bijlsma J et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update . Ann Rheum Dis 2017 ; 76 : 960 – 77 . Google Scholar CrossRef Search ADS PubMed 2 Yazici Y , Sokka T , Kautiainen H et al. Long term safety of methotrexate in routine clinical care: discontinuation is unusual and rarely the result of laboratory abnormalities . Ann Rheum Dis 2005 ; 64 : 207 – 11 . Google Scholar CrossRef Search ADS PubMed 3 Raza K , Filer A. The therapeutic window of opportunity in rheumatoid arthritis: does it ever close? Ann Rheum Dis 2015 ; 74 : 793 – 4 . Google Scholar CrossRef Search ADS PubMed 4 HQIP . National Clinical Audit for Rheumatoid and Early Inflammatory Arthritis. 2nd Annual Report 2016. Health Quality Improvement Partnership; 22 January 2016 . https://www.hqip.org.uk/resources/rheumatoid-and-early-inflammatory-arthritis-2016/. 5 Braun J , Kastner P , Flaxenberg P et al. 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 . Arthritis Rheum 2008 ; 58 : 73 – 81 . Google Scholar CrossRef Search ADS PubMed 6 Stamp LK , Barclay ML , O’Donnell JL et al. Effects of changing from oral to subcutaneous methotrexate on red blood cell methotrexate polyglutamate concentrations and disease activity in patients with rheumatoid arthritis . J Rheumatol 2011 ; 38 : 2540 – 7 . Google Scholar CrossRef Search ADS PubMed 7 Rohr MK , Mikuls TR , Cohen SB, , Thorne JC, , O’Dell JR. Underuse of methotrexate in the treatment of rheumatoid arthritis: a national analysis of prescribing practices in the US . Arthritis Care Res 2017 ; 69 : 794 – 800 . Google Scholar CrossRef Search ADS 8 Lee J , Pelkey R , Gubitosa J , Henrick MF , Ganz ML. Comparing healthcare costs associated with oral and subcutaneous methotrexate or biologic therapy for rheumatoid arthritis in the United States . Am Health Drug Benefits 2017 ; 10 : 42 – 9 . Google Scholar PubMed 9 Scott DG , Claydon P , Ellis C. Retrospective evaluation of continuation rates following a switch to subcutaneous methotrexate in rheumatoid arthritis patients failing to respond to or tolerate oral methotrexate: the MENTOR study . Scand J Rheumatol 2014 ; 43 : 470 – 6 . Google Scholar CrossRef Search ADS PubMed 10 Fitzpatrick R , Scott DGI , Keary I. Cost-minimisation analysis of subcutaneous methotrexate versus biologic therapy for the treatment of patients with rheumatoid arthritis who have had an insufficient response or intolerance to oral methotrexate . Clin Rheumatol 2013 ; 32 : 1605 – 12 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

RheumatologyOxford University Press

Published: Apr 17, 2018

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