Abstract
Even though new drugs for the treatment of rheumatoid arthritis (RA) have been developed, methotrexate (MTX) remains a commonly used drug for RA management. In addition to monitoring disease activity during RA treatment, bone erosion should be closely assessed throughout long-term RA management. In this review article, we present a systematic review of MTX effectiveness in reducing the risk of bone erosion. We reviewed randomized controlled trial studies that involved MTX monotherapy or MTX in combination with placebo. Evaluation of the progression of bone erosion was examined by radiographic assessment such as total Sharp score (TSS) or van der Heijde score (SvdH or vdH TSS), joint space narrowing (JSN), erosion score (ERO), and proportion of radiographic nonprogressors. Several key factors were found to influence the response to MTX treatment, such as gene polymorphism. The exact mechanism of the prevention of bone erosion by MTX remains unclear, which warrants future investigations. The variability of RA disease activity in study subjects resulted in variations in the results reported by individual studies. Collective analysis suggests that MTX could slow down the progression of bone erosion based on a radiographic score of less than 0.5–1/year.
Similar content being viewed by others
References
Coulson KA, Reed G, Gilliam BE, Kremer JM, Pepmueller PH (2009) Factors influencing fracture risk, T score, and management of osteoporosis in patients with rheumatoid arthritis in the consortium of rheumatology researchers of North America (CORRONA) registry. J Clin Rheumatol 15(4):155–160
Mundy GR (2007) Osteoporosis and inflammation. Nutr Rev 65(suppl_3):S147–SS51. https://doi.org/10.1111/j.1753-4887.2007.tb00353.x
Srirangan S, Choy EH (2010) The role of interleukin 6 in the pathophysiology of rheumatoid arthritis. Ther Adv Musculoskelet Dis 2(5):247–256
Gabay C., MJ, Nissen, Jacob ML (2016) Rheumatoid arthritis: Pathogenesis and clinical features. Eular Textbook on Rheumatic Disease. 2nd ed: BMJ; p. 229–42. ISBN: 978-0-7279-1924-3
Briot K., CR, Cyrus C (2016) Osteoporosis: pathogenesis and clinical features. In: Eular textbook on rheumatic disease. 2nd edn. BMJ; p. 870–90. ISBN: 978-0-7279-1924-3
Zhou Y-z, L-d Z, Chen H, Zhang Y, Wang D-f, Huang L-f et al (2018) Comparison of the impact of Tripterygium wilfordii Hook F and methotrexate treatment on radiological progression in active rheumatoid arthritis: 2-year follow up of a randomized, non-blinded, controlled study. Arthritis Res Ther 20(1):70. https://doi.org/10.1180/s13075-018-1563-6
Strand V, Scott DL, Emery P, Kalden JR, Smolen JS, Cannon GW, Tugwell P, Crawford B, Leflunomide Rheumatoid Arthritis Investigators Groups (2005) Physical function and health related quality of life: analysis of 2-year data from randomized, controlled studies of leflunomide, sulfasalazine, or methotrexate in patients with active rheumatoid arthritis. J Rheumatol 32(4):590–601
Lipsky PE, van der Heijde DM, St. Clair EW, Furst DE, Breedveld FC, Kalden JR et al (2000) Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med 343(22):1594–1602. https://doi.org/10.1056/NEJM200011303432202
Świerkot J, Gruszecka K, Matuszewska A, Wiland P (2015) Assessment of the effect of methotrexate therapy on bone metabolism in patients with rheumatoid arthritis. Arch Immunol Ther Exp 63(5):397–404
Fonseca JE., EV, Peter T (2016) Rheumatoid arthritis: treatment. In: Eular textbook on rheumatic disease. 2nd edn. BMJ; p. 265–94. ISBN: 978-0-7279-1924-3
Cronstein BN, Sitkovsky M (2017) Adenosine and adenosine receptors in the pathogenesis and treatment of rheumatic diseases. Nat Rev Rheumatol 13(1):41–51. https://doi.org/10.1038/nrrheum.2016.178
Friedman B, Cronstein B (2019) Methotrexate mechanism in treatment of rheumatoid arthritis. Joint Bone Spine 86(3):301–307. https://doi.org/10.1016/j.jbspin.2019.07.004
Haynes D, Crotti T, Loric M, Bain G, Atkins G, Findlay D (2001) Osteoprotegerin and receptor activator of nuclear factor kappaB ligand (RANKL) regulate osteoclast formation by cells in the human rheumatoid arthritic joint. Rheumatology 40(6):623–630. https://doi.org/10.1093/rheumatology/40.6.623
Salaffi F, Carotti M, Carlo M (2016) Conventional radiography in rheumatoid arthritis: new scientific insights and practical application. Int J Clin Exp Med 9(9):17012–17027
Indonesia, PR (2014) Rekomendasi Perhimpunan Reumatologi Indonesia Untuk diagnosis dan Pengelolaan Artritis Reumatoid. Jakarta: Perhimpunan Reumatologi Indonesia:1–18
Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJM, Gavaghan DJ, McQuay HJ (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17(1):1–12
Pradipta IS, Houtsma D, van Boven JF, Alffenaar J-WC, Hak E (2020) Interventions to improve medication adherence in tuberculosis patients: a systematic review of randomized controlled studies. NPJ Prim Care Respir Med 30(1):1–10
Bijlsma JW, Welsing PM, Woodworth TG, Middelink LM, Pethö-Schramm A, Bernasconi C et al (2016) Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-Early): a multicentre, randomised, double-blind, double-dummy, strategy trial. Lancet 388(10042):343–355. https://doi.org/10.1016/S0140-6736(16)30363-4
Stamm TA, Machold KP, Aletaha D, Alasti F, Lipsky P, Pisetsky D, Landewe R, van der Heijde D, Sepriano A, Aringer M, Boumpas D, Burmester G, Cutolo M, Ebner W, Graninger W, Huizinga T, Schett G, Schulze-Koops H, Tak PP, Martin-Mola E, Breedveld F, Smolen J (2018) Induction of sustained remission in early inflammatory arthritis with the combination of infliximab plus methotrexate: the DINORA trial. Arthritis Res Ther 20(1):174. https://doi.org/10.1186/s13075-018-1667-z
Stouten V, Westhovens R, Pazmino S, De Cock D, Van der Elst K, Joly J et al (2019) Effectiveness of different combinations of DMARDs and glucocorticoid bridging in early rheumatoid arthritis: two-year results of CareRA. Rheumatology 58(12):2284–2294. https://doi.org/10.1093/rheumatology/kez213
Verschueren P, De Cock D, Corluy L, Joos R, Langenaken C, Taelman V et al (2017) Effectiveness of methotrexate with step-down glucocorticoid remission induction (COBRA slim) versus other intensive treatment strategies for early rheumatoid arthritis in a treat-to-target approach: 1-year results of CareRA, a randomised pragmatic open-label superiority trial. Ann Rheum Dis 76(3):511–520. https://doi.org/10.1136/annrheumdis-2016-209212
O'Dell JR, Curtis JR, Mikuls TR, Cofield SS, Bridges SL Jr, Ranganath VK, Moreland LW, for the TEAR Trial Investigators (2013) Validation of the methotrexate-first strategy in patients with early, poor-prognosis rheumatoid arthritis: results from a two-year randomized, double-blind trial. Arthritis Rheum 65(8):1985–1994. https://doi.org/10.1002/art.38012
Lee EB, Fleischmann R, Hall S, Wilkinson B, Bradley JD, Gruben D, Koncz T, Krishnaswami S, Wallenstein GV, Zang C, Zwillich SH, van Vollenhoven R, ORAL Start Investigators (2014) Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med 370(25):2377–2386. https://doi.org/10.1056/NEJMoal1310476
Hetland ML, Stengaard-Pedersen K, Junker P, Østergaard M, Ejbjerg BJ, Jacobsen S et al (2010) Radiographic progression and remission rates in early rheumatoid arthritis–MRI bone oedema and anti-CCP predicted radiographic progression in the 5-year extension of the double-blind randomised CIMESTRA trial. Ann Rheum Dis 69(10):1789–1795. https://doi.org/10.1136/ard.2009.125534
Kavanaugh A, Fleischmann RM, Emery P, Kupper H, Redden L, Guerette B, Santra S, Smolen JS (2013) Clinical, functional and radiographic consequences of achieving stable low disease activity and remission with adalimumab plus methotrexate or methotrexate alone in early rheumatoid arthritis: 26-week results from the randomised, controlled OPTIMA study. Ann Rheum Dis 72(1):64–71. https://doi.org/10.1136/annrheumdis-2011-201247
Burmester GR, Rigby WF, van Vollenhoven RF, Kay J, Rubbert-Roth A, Kelman A, Dimonaco S, Mitchell N (2016) Tocilizumab in early progressive rheumatoid arthritis: FUNCTION, a randomised controlled trial. Ann Rheum Dis 75(6):1081–1091. https://doi.org/10.1136/annrheumdis-2015-207628
Smolen JS, Emery P, Fleischmann R, van Vollenhoven RF, Pavelka K, Durez P, Guérette B, Kupper H, Redden L, Arora V, Kavanaugh A (2014) Adjustment of therapy in rheumatoid arthritis on the basis of achievement of stable low disease activity with adalimumab plus methotrexate or methotrexate alone: the randomised controlled OPTIMA trial. Lancet 383(9914):321–332. https://doi.org/10.1016/s0140-6736(13)61751-1
Conaghan PG, Østergaard M, Bowes MA, Wu C, Fuerst T, van der Heijde D, Irazoque-Palazuelos F, Soto-Raices O, Hrycaj P, Xie Z, Zhang R, Wyman BT, Bradley JD, Soma K, Wilkinson B (2016) Comparing the effects of tofacitinib, methotrexate and the combination, on bone marrow oedema, synovitis and bone erosion in methotrexate-naive, early active rheumatoid arthritis: results of an exploratory randomised MRI study incorporating semiquantitative and quantitative techniques. Ann Rheum Dis 75(6):1024–1033. https://doi.org/10.1136/annrheumdis-2015-208267
Fleischmann R, Schiff M, van der Heijde D, Ramos-Remus C, Spindler A, Stanislav M, Zerbini CAF, Gurbuz S, Dickson C, de Bono S, Schlichting D, Beattie S, Kuo WL, Rooney T, Macias W, Takeuchi T (2017) Baricitinib, methotrexate, or combination in patients with rheumatoid arthritis and no or limited prior disease-modifying antirheumatic drug treatment. Arthritis Rheumatol 69(3):506–517. https://doi.org/10.1002/art.39953
van der Heijde D, Durez P, Schett G, Naredo E, Østergaard M, Meszaros G, de Leonardis F, de la Torre I, López-Romero P, Schlichting D, Nantz E, Fleischmann R (2018) Structural damage progression in patients with early rheumatoid arthritis treated with methotrexate, baricitinib, or baricitinib plus methotrexate based on clinical response in the phase 3 RA-BEGIN study. Clin Rheumatol 37(9):2381–2390. https://doi.org/10.1007/s10067-018-4221-0
Nam J, Villeneuve E, Hensor E, Wakefield R, Conaghan P, Green M et al (2014) A randomised controlled trial of etanercept and methotrexate to induce remission in early inflammatory arthritis: the EMPIRE trial. Ann Rheum Dis 73(6):1027–1036. https://doi.org/10.1136/annrheumdis-2013-204882
Ideguchi H, Ohno S, Hattori H, Senuma A, Ishigatsubo Y (2006) Bone erosions in rheumatoid arthritis can be repaired through reduction in disease activity with conventional disease-modifying antirheumatic drugs. Arthritis Res Ther 8(3):R76
van der Linden MP, Boja R, Klarenbeek NB, Huizinga TW, van der Heijde DM, van der Helm-van AH (2010) Repair of joint erosions in rheumatoid arthritis: prevalence and patient characteristics in a large inception cohort. Ann Rheum Dis 69(4):727–729
Combe B, Landewé R, Lukas C, Bolosiu HD, Breedveld F, Dougados M et al (2007) EULAR recommendations for the management of early arthritis: report of a task force of the European Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 66(1):34–45. https://doi.org/10.1136/ard.2005.044354
Keen HI, Brown AK, Wakefield RJ, Conaghan PG (2005) MRI and musculoskeletal ultrasonography as diagnostic tools in early arthritis. Rheum Dis Clin 31(4):699–714
Saleem B, Brown AK, Keen H, Nizam S, Freeston J, Karim Z, Quinn M, Wakefield R, Hensor E, Conaghan PG, Emery P (2009) Disease remission state in patients treated with the combination of tumor necrosis factor blockade and methotrexate or with disease-modifying antirheumatic drugs: a clinical and imaging comparative study. Arthritis Rheum 60(7):1915–1922
Saleem B, Brown AK, Quinn M, Karim Z, Hensor EM, Conaghan P et al (2012) Can flare be predicted in DMARD treated RA patients in remission, and is it important? A cohort study. Ann Rheum Dis 71(8):1316–1321
Naredo E, Valor L, De la Torre I, Martínez-Barrio J, Hinojosa M, Aramburu F et al (2013) Ultrasound joint inflammation in rheumatoid arthritis in clinical remission: how many and which joints should be assessed? Arthritis Care Res 65(4):512–517
Lillegraven S, Bøyesen P, Hammer HB, Østergaard M, Uhlig T, Sesseng S et al (2011) Tenosynovitis of the extensor carpi ulnaris tendon predicts erosive progression in early rheumatoid arthritis. Ann Rheum Dis 70(11):2049–2050
Janta I, Stanciu D, Hinojosa M, Nieto-González JC, Valor L, Bello N, Serrano B, Mata-Martínez C, Martínez-Barrio J, Ovalles-Bonilla JG, González CM, López-Longo FJ, Monteagudo I, Naredo E, Carreño L (2016) Structural damage in rheumatoid arthritis: comparison between tendon damage evaluated by ultrasound and radiographic damage. Rheumatology 55(6):1042–1046
Chen J-F, Hsu C-Y, Yu S-F, Ko C-H, Chiu W-C, Lai H-M, Chen YC, Su YJ, Cheng TT (2020) The impact of long-term biologics/target therapy on bone mineral density in rheumatoid arthritis: a propensity score-matched analysis. Rheumatology 59:2471–2480
Orsolini G, Fassio A, Rossini M, Adami G, Giollo A, Caimmi C, Idolazzi L, Viapiana O, Gatti D (2019) Effects of biological and targeted synthetic DMARDs on bone loss in rheumatoid arthritis. Pharmacol Res 147:104354
Aletaha D, Smolen JS (2018) Diagnosis and management of rheumatoid arthritis: a review. Jama 320(13):1360–1372
Weinblatt ME (2013) Methotrexate in rheumatoid arthritis: a quarter century of development. Trans Am Clin Climatol Assoc 124:16
Nam JL, Takase-Minegishi K, Ramiro S, Chatzidionysiou K, Smolen JS, Van Der Heijde D et al (2017) Efficacy of biological disease-modifying antirheumatic drugs: a systematic literature review informing the 2016 update of the EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis 76(6):1113–1136
Manova M, Savova A, Vasileva M, Terezova S, Kamusheva M, Grekova D, Petkova V, Petrova G (2018) Comparative price analysis of biological products for treatment of rheumatoid arthritis. Front Pharmacol 9:1070
Knijff-Dutmer E, Drossaers-Bakker W, Verhoeven A, Van der Sluijs Veer G, Boers M, van Der Linden S et al (2002) Rheumatoid factor measured by fluoroimmunoassay: a responsive measure of rheumatoid arthritis disease activity that is associated with joint damage. Ann Rheum Dis 61(7):603–607
Hider SL, Buckley C, Silman AJ, Symmons DP, Bruce IN (2005) Factors influencing response to disease modifying antirheumatic drugs in patients with rheumatoid arthritis. J Rheumatol 32(1):11–16
Drouin J, Haraoui B (2010) Predictors of clinical response and radiographic progression in patients with rheumatoid arthritis treated with methotrexate monotherapy. J Rheumatol 37(7):1405–1410
Smolen JS, Aletaha D, Barton A, Burmester GR, Emery P, Firestein GS, Kavanaugh A, McInnes IB, Solomon DH, Strand V, Yamamoto K (2018) Rheumatoid arthritis. Nat Rev Dis Primers 4:18001. https://doi.org/10.1038/nrdp.2018.1
de Rooy DP, van der Linden MP, Knevel R, Huizinga TW, van der Helm-van Mil AH (2011) Predicting arthritis outcomes—what can be learned from the Leiden early arthritis clinic? Rheumatology 50(1):93–100
Rezaei H, Saevarsdottir S, Forslind K, Albertsson K, Wallin H, Bratt J, Ernestam S, Geborek P, Pettersson IF, van Vollenhoven RF (2012) In early rheumatoid arthritis, patients with a good initial response to methotrexate have excellent 2-year clinical outcomes, but radiological progression is not fully prevented: data from the methotrexate responders population in the SWEFOT trial. Ann Rheum Dis 71(2):186–191. https://doi.org/10.1136/annrheumdis-2011-200038
Revu, S, P Neregård, E af Klint, M Korotkova, AI Catrina (2013) Synovial membrane immunohistology in early-untreated rheumatoid arthritis reveals high expression of catabolic bone markers that is modulated by methotrexate. Arthritis Res Ther 15(6):R205
Perpétuo IP, Caetano-Lopes J, Rodrigues AM, Campanilho-Marques R, Ponte C, Canhão H, Ainola M, Fonseca JE (2017) Methotrexate and low-dose prednisolone downregulate osteoclast function by decreasing receptor activator of nuclear factor-κβ expression in monocytes from patients with early rheumatoid arthritis. RMD Open 3(1):e000365
De Jong P, Hazes J, Han H, Huisman M, van Zeben D, Van Der Lubbe P et al (2014) Randomised comparison of initial triple DMARD therapy with methotrexate monotherapy in combination with low-dose glucocorticoid bridging therapy; 1-year data of the tREACH trial. Ann Rheum Dis 73(7):1331–1339
Kanagawa H, Masuyama R, Morita M, Sato Y, Niki Y, Kobayashi T, Katsuyama E, Fujie A, Hao W, Tando T, Watanabe R, Miyamoto K, Morioka H, Matsumoto M, Toyama Y, Saya H, Miyamoto T (2016) Methotrexate inhibits osteoclastogenesis by decreasing RANKL-induced calcium influx into osteoclast progenitors. J Bone Miner Metab 34(5):526–531
Dhooria A, Pandurangan N, Mahesh KV, Sachdev S, Sharma A, Sharma S, Gupta N, Dhir V (2018) Circulating levels of osteoprotegerin and sRANKL and the effect of methotrexate in patients with rheumatoid arthritis. Indian J Rheumatol 13(2):90. https://doi.org/10.4103/injr.injr_125_17
Johnsen, AK, ME Weinblatt (2009) Methotrexate: the foundation of rheumatoid arthritis therapy. Rheumatoid Arthritis: Elsevier; p 307–14
Jenko B, Tomšič M, Jekić B, Milić V, Dolžan V, Praprotnik S (2018) Clinical pharmacogenetic models of treatment response to methotrexate monotherapy in Slovenian and Serbian rheumatoid arthritis patients: differences in patient's management may preclude generalization of the models. Front Pharmacol 9:20. https://doi.org/10.3389/fphar.2018.00020
Funding
This research was supported by grant-in-aids from Universitas Padjadjaran for RA and DPD.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Destiani, D., Naja, S., Dewi, S. et al. Efficacy of methotrexate in reducing the risk of bone erosion in patients with rheumatoid arthritis: a systematic review of randomized controlled trials. Osteoporos Int 32, 805–816 (2021). https://doi.org/10.1007/s00198-020-05743-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00198-020-05743-z