Clinical Rheumatology

, Volume 35, Issue 5, pp 1123–1127 | Cite as

Response to methotrexate predicts long-term patient-related outcomes in rheumatoid arthritis

  • Dietmar KrauseEmail author
  • Bernadette Gabriel
  • Gertraud Herborn
  • Juergen Braun
  • Rolf Rau
Original Article


This study was conducted to investigate the predictive value of the initial response to methotrexate (MTX) on long-term patient-related outcomes (PROs) in rheumatoid arthritis (RA). All RA patients starting MTX treatment between 1980 and 1987 in our department were enrolled in a prospective observational study. After an average of 18 years, patient-related outcomes were assessed in three dimensions according to the International Classification of Functioning, Disability and Health (ICF). Statistical analyses employed multivariable models with baseline values for age, gender, disease duration, rheumatoid factor positivity, disease activity, response to MTX after 1 year and continuous use of MTX as covariates. The 271 patients enrolled had a mean disease duration of 8.5 years, a mean number of swollen joints of 18 (out of 32), and a mean erythrocyte sedimentation rate of 55 mm/h. After 18 years, PRO was available in 89 patients (33 %). A clinical improvement of at least 20 % 1 year after the initiation of MTX was associated with a favourable outcome in all three dimensions of the ICF, independent of continuation of MTX (p < 0.05). The initial response to MTX is an independent predictor of PRO in RA as assessed after an average of 18 years.


Long term follow-up Methotrexate Patient outcome assessment Rheumatoid arthritis 


Compliance with ethical standards




  1. 1.
    El Miedany Y (2013) PROMs in inflammatory arthritis: moving from static to dynamic. Clin Rheumatol 32:735–742CrossRefPubMedGoogle Scholar
  2. 2.
    Kingsley G, Scott IC, Scott DL (2011) Quality of life and the outcome of established rheumatoid arthritis. Best Pract Res Clin Rheumatol 25:585–606CrossRefPubMedGoogle Scholar
  3. 3.
    Malm K, Bergman S, Andersson M, Bremander A, BARFOT study group (2015) Predictors of severe self-reported disability in RA in a long-term follow-up study. Disabil Rehabil 37:686–691CrossRefPubMedGoogle Scholar
  4. 4.
    Tanaka E, Mannalithara A, Inoue E, Hara M, Tomatsu T, Kamatani N, Singh G, Jamanaka H (2008) Efficient management of rheumatoid arthritis significantly reduces long-term functional disability. Ann Rheum Dis 67:1153–1158CrossRefPubMedGoogle Scholar
  5. 5.
    Balsa A, Del Amo J, Blanco F et al (2010) Prediction of functional impairment and remission in rheumatoid arthritis patients by biochemical variables and genetic polymorphisms. Rheumatology (Oxford) 49:458–466CrossRefGoogle Scholar
  6. 6.
    Combe B, Logeart I, Belkacemi MC, Dadoun S, Schaeverbeke T, Daurès JP, Dougados M (2015) Comparison of the long-term outcome for patients with rheumatoid arthritis with persistent moderate disease activity or disease remission during the first year after diagnosis: data from the ESPOIR cohort. Ann Rheum Dis 74:724–729CrossRefPubMedGoogle Scholar
  7. 7.
    Lopez-Olivo MA, Siddhanamatha HR, Shea B, Tugwell P, Wells GA, Suarez-Almazor ME (2014) Methotrexate for treating rheumatoid arthritis. Cochrane Database Syst Rev 6:CD000957. doi: 10.1002/14651858.CD000957.pub2 PubMedGoogle Scholar
  8. 8.
    Singh JA, Furst DE, Bharat A et al (2012) 2012 update of the 2008 American college of rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res 64:625–639CrossRefGoogle Scholar
  9. 9.
    Smolen JS, Landewé R, Breedveld FC et al (2010) EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis 69:964–975CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Krause D, Schleusser B, Herborn W, Rau R (2000) Response to methotrexate is associates with reduced mortality in patients with severe rheumatoid arthritis. Arthritis Rheum 43:14–21CrossRefPubMedGoogle Scholar
  11. 11.
    Wilke WS, Calabrese LH, Scherbel AL (1980) Methotrexate in the treatment of rheumatoid arthritis; pilot study. Cleve Clin Q 47:305–309CrossRefPubMedGoogle Scholar
  12. 12.
    Weinblatt ME, Coblyn JS, Fox DA, Fraser PA, Holdsworth DE, Glass DN, Trendham DE (1985) Efficacy of low-dose methotrexate in rheumatoid arthritis. N Engl J Med 312:818–822CrossRefPubMedGoogle Scholar
  13. 13.
    World Health Organization Assessment, Classification and Epidemiology Group (1999) International Classification of Functioning, Disability and Health. World Health Organization, GenevaGoogle Scholar
  14. 14.
    Ropes MW, Bennett GA, Cobb S, Jacox RF, Jessar RA (1995) 1958 revision of diagnostic criteria for rheumatoid arthritis. Bull Rheum Dis 9:175–176Google Scholar
  15. 15.
    Krause D, Gabriel B, Herborn G, Braun J, Rau R (2014) The positive influence of methotrexate on the mortality of patients with rheumatoid arthritis is partly independent of its effect on disease activity: results of a re-evaluation 18 years after baseline. Clin Exp Rheumatol 32:395–400PubMedGoogle Scholar
  16. 16.
    Zochling J, Stucki G, Grill E, Braun J (2007) A comparative study of patient-reported functional outcomes in acute rheumatoid arthritis. J Rheumatol 34:64–69PubMedGoogle Scholar
  17. 17.
    Puolakka K, Kautiainen H, Möttönen T, FIN-RACo Trial Group et al (2005) Early suppression of disease activity is essential for maintenance of work capacity in patients with recent-onset rheumatoid arthritis: five-year experience from the FIN-RACo trial. Arthritis Rheum 52:36–41CrossRefPubMedGoogle Scholar
  18. 18.
    Krause D, Gabriel B, Herborn G, Braun J, Rau R (2015) Radiologic damage at baseline predicts patient related outcomes 18 years after the initiation of methotrexate therapy in patients with severe rheumatoid arthritis. Clin Exp Rheumatol 33:611–616PubMedGoogle Scholar
  19. 19.
    Combe B, Cantagrel A, Goupille P et al (2003) Predictive factors of 5-year health assessment questionnaire disability in early rheumatoid arthritis. J Rheumatol 30:2344–2349PubMedGoogle Scholar
  20. 20.
    van Nies JA, Krabben A, Schoones JW, Huizinga TW, Kloppenburg M, van der Helm-van Mil AH (2014) What is the evidence for the presence of a therapeutic window of opportunity in rheumatoid arthritis? A systematic literature review. Ann Rheum Dis 73:861–870CrossRefPubMedGoogle Scholar
  21. 21.
    Saevarsdottir S, Wallin H, Seddighzadeh M, Ernestam S, Geborek P, Petersson IF, Bratt J, van Vollenhoven RF, SWEFOT Trial Investigators Group (2011) Predictors of response to methotrexate in early DMARD naive rheumatoid arthritis: results from the initial open-label phase of the SWEFOT trial. Ann Rheum Dis 70:469–475CrossRefPubMedGoogle Scholar
  22. 22.
    Zhu H, Deng FY, Mo XB, Qiu YH, Lei SF (2014) Pharmacogenetics and pharmacogenomics for rheumatoid arthritis responsiveness to methotrexate treatment: the 2013 update. Pharmacogenomics 15:551–566CrossRefPubMedGoogle Scholar
  23. 23.
    Fransen J, Kooloos WM, Wessels JA, Huizinga TW, Guchelaar HJ, van Riel PL, Barrera P (2012) Clinical pharmacogenetic model to predict response of MTX monotherapy in patients with established rheumatoid arthritis after DMARD failure. Pharmacogenomics 13:1087–1094CrossRefPubMedGoogle Scholar
  24. 24.
    Brinker RR, Ranganathan P (2010) Methotrexate pharmacogenetics in rheumatoid arthritis. Clin Exp Rheumatol 28(Suppl 61):33–39Google Scholar
  25. 25.
    Wessels JA, de Vries-Bouwstra JK, Heijmans BT et al (2006) Efficacy und toxicity of methotrexate in early rheumatoid arthritis are associated with single-nucleotide polymorphisms in genes coding for folate pathway enzymes. Arthritis Rheum 54:1087–1095CrossRefPubMedGoogle Scholar
  26. 26.
    Kato T, Hamada A, Mori S, Saito H (2012) Genetic polymorphisms in metabolic and cellular transport pathway of methotrexate impact clinical outcome of methotrexate monotherapy in Japanese patients with rheumatoid arthritis. Drug Metab Pharmacokinet 27:192–199CrossRefPubMedGoogle Scholar
  27. 27.
    Dervieux T, Furst D, Lein DO, Capps R, Smith K, Walsh M, Kremer J (2004) Polyglutamation of methotrexate with common polymorphisms in reduced folate carrier, aminoimidazole carboxamide ribonucleotide transformylase, and thymidylate synthase are associated with methotrexate effects in rheumatoid arthritis. Arthritis Rheum 50:2766–2774CrossRefPubMedGoogle Scholar
  28. 28.
    Ponchel F, Goëb V, Parmar R et al (2014) An immunological biomarker to predict MTX response in early RA. Ann Rheum Dis 73:2047–2053CrossRefPubMedGoogle Scholar

Copyright information

© International League of Associations for Rheumatology (ILAR) 2016

Authors and Affiliations

  • Dietmar Krause
    • 1
    Email author
  • Bernadette Gabriel
    • 2
  • Gertraud Herborn
    • 3
  • Juergen Braun
    • 4
  • Rolf Rau
    • 3
  1. 1.Department of Medical Informatics, Biometry and EpidemiologyRuhr-UniversityBochumGermany
  2. 2.Primary Care OfficeGladbeckGermany
  3. 3.Department of RheumatologyEvangelisches FachkrankenhausRatingenGermany
  4. 4.Rheumazentrum RuhrgebietHerneGermany

Personalised recommendations