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Inadequate response to treat-to-target methotrexate therapy in patients with new-onset rheumatoid arthritis: development and validation of clinical predictors
  1. Xavier M Teitsma1,
  2. Johannes W G Jacobs1,
  3. Paco M J Welsing1,
  4. Pascal H P de Jong2,3,
  5. Johanna M W Hazes2,
  6. Angelique E A M Weel2,3,
  7. Attila Pethö-Schramm4,
  8. Michelle E A Borm5,
  9. Jacob M van Laar1,
  10. Floris P J G Lafeber1,
  11. Johannes W J Bijlsma1
  1. 1 Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
  2. 2 Department of Rheumatology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
  3. 3 Department of Rheumatology, Maasstad Hospital, Rotterdam, The Netherlands
  4. 4 F Hoffmann-La Roche, Basel, Switzerland
  5. 5 Roche Nederland BV, Woerden, The Netherlands
  1. Correspondence to Xavier M Teitsma, Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht 3584 CX, The Netherlands; x.m.teitsma{at}


Objective To identify and validate clinical baseline predictors associated with inadequate response (IR) to methotrexate (MTX) therapy in newly diagnosed patients with rheumatoid arthritis (RA).

Methods In U-Act-Early, 108 disease-modifying antirheumatic drug (DMARD)-naive patients with RA were randomised to initiate MTX therapy and treated to target until sustained remission (disease activity score assessing 28 joints (DAS28) <2.6 with four or less swollen joints for ≥24 weeks) was achieved. If no remission, hydroxychloroquine was added to the treatment regimen (ie, ‘MTX+’) and replaced by tocilizumab if the target still was not reached thereafter. Regression analyses were performed to identify clinical predictors for IR, defined as needing addition of a biological DMARD, to ‘MTX+’. Data from the treatment in the Rotterdam Early Arthritis Cohort were used for external validation of the prediction model.

Results Within 1 year, 56/108 (52%) patients in U-Act-Early showed IR to ‘MTX+’. DAS28 (adjusted OR (ORadj) 2.1, 95% CI 1.4 to 3.2), current smoking (ORadj 3.02, 95% CI 1.1 to 8.0) and alcohol consumption (ORadj 0.4, 95% CI 0.1 to 0.9) were identified as baseline predictors. The area under the receiver operator characteristic curve (AUROC) of the prediction model was 0.75 (95% CI 0.66 to 0.84); the positive (PPV) and negative predictive value (NPV) were 65% and 80%, respectively. When applying the model to the validation cohort, the AUROC slightly decreased to 0.67 (95% CI 0.55 to 0.79) and the PPV and NPV to 54% and 80%, respectively.

Conclusion Higher DAS28, current smoking and no alcohol consumption are predictive factors for IR to step-up ‘MTX+’ in DMARD-naive patients with new-onset RA.

Trial registration NCT01034137; Post-results, ISRCTN26791028; Post-results.

  • rheumatoid arthritis
  • methotrexate
  • tocilizumab
  • prediction
  • treat-to-target

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  • Handling editor Josef S Smolen

  • Contributors All authors were involved with drafting the article or revising it critically and approved the final draft to be published and agree to be accountable for all aspects. Study conception or design: XMT, JWGJ, PMJW, PHPdJ, FPJGL, JWJB. Acquisition of data: XMT, JWGJ, PMJW, PHPdJ, AP-S, MEAB. Analysis or interpretation of data: XMT, JWGJ, PMJW, PHPdJ, JMWH, AEAMW, AP-S, MEAB, JMvL, FPJGL, JWJB.

  • Funding The U-Act-Early trial was funded by Roche Nederland BV and the work within the tREACH trial was supported by an unrestricted grant from Pfizer.

  • Competing interests The department of the authors who included patients (JWGJ and JWJB) in the U-Act-Early trial received reimbursements from Roche Nederland BV. JWJB reported grants and fees from Roche, AbbVie, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer and UCB. JMvL received fees from Arthrogen, MSD, Pfizer, Eli Lilly and BMS, and research grants from Astra Zeneca and Roche-Genentech. FPJGL reports grants from Roche. AP-S is an employee of F Hoffmann-La Roche and MEAB is an employee of Roche Nederland BV.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Presented at This paper is based on work that was previously presented at the 2017 Annual Meeting of the American College of Rheumatology (ACR), 3–8 November 2017, San Diego, CA, USA, and were published as conference abstracts: Teitsma XM et al. Arthritis Rheumatol 2017;69(suppl 10), Teitsma XM et al. Arthritis Rheumatol 2017;69(suppl 10) and at the 2016 and 2017 Annual Meeting of the European League Against Rheumatism (EULAR), 14–17 June 2017, Madrid, Spain, and were published as conference abstracts: Teitsma XM et al. Ann Rheum Dis 2016;75:504, Teitsma XM et al. Ann Rheum Dis 2017;76:855.