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Prescribing Patterns and Impact of Factors Associated with Time to Initial Biologic Therapy among Children with Non-systemic Juvenile Idiopathic Arthritis

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A Correction to this article was published on 21 April 2021

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Abstract

Objective

The aim of this study was to examine patterns of initial prescriptions, investigate time to initiation of biologic disease-modifying anti-rheumatic drugs (bDMARDs), and evaluate the impact of clinical and other baseline factors associated with the time to first bDMARD in treating children with newly diagnosed non-systemic juvenile idiopathic arthritis (JIA).

Methods

Using longitudinal patient-level data extracted from electronic medical records (EMR) in a large Midwestern pediatric hospital from 2009 to 2018, the initial prescriptions and prescribing patterns of bDMARDs, conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids within 3 months of JIA diagnosis were examined. Kaplan-Meier analyses were performed to assess time to initiation of bDMARDs. Cox proportional hazard models were used to identify factors associated with time to first bDMARD.

Results

Of 821 children, the proportion of patients with initial csDMARDs increased from 45.3% in 2009 to 60.3% in 2018. Around 57.5% of polyarthritis rheumatoid factor-positive (Poly RF+) patients and 43.2% of polyarthritis rheumatoid factor-negative (Poly RF−) patients received a bDMARD therapy within 3 months of diagnosis, 14.4% as monotherapy and 28.3% in combination with a csDMARD. Among patients who received combination therapy, combination of methotrexate with adalimumab increased from 16.7% in 2009 to 40% in 2018. The proportion of patients treated with adalimumab gradually increased and passed etanercept in 2016. The predictors of earlier initiation of biologic therapy were JIA category enthesitis-related arthritis (ERA) [hazard ratio (HR) vs persistent oligoarthritis 4.82; p < 0.0001], psoriatic arthritis (PsA) (HR 2.46; p = 0.0002), or Poly RF− (HR 2.43; p = 0.0002); the number of joints with limited range of motion (HR 1.02; p = 0.0222), and erythrocyte sedimentation rate (ESR, HR 1.01; p = 0.0033).

Conclusions

There was a substantial increase in the proportion of patients receiving the combination of methotrexate and adalimumab among patients receiving combination therapy. Adalimumab overtook etanercept as the most frequently prescribed bDMARD. Multiple factors affect the time to biologic initiation, including the number of joints with limited range of motion, ESR, and JIA category.

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References

  1. Thierry S, Fautrel B, Lemelle I, Guillemin F. Prevalence and incidence of juvenile idiopathic arthritis: a systematic review. Jt Bone Spine. 2014;81(2):112–7.

    Article  Google Scholar 

  2. Ringold S, Angeles-Han ST, Beukelman T, et al. 2019 American College of Rheumatology/Arthritis Foundation guideline for the treatment of juvenile idiopathic arthritis: therapeutic approaches for non-systemic polyarthritis, sacroiliitis, and enthesitis. Arthritis Care Res. 2019;71(6):717–34.

    Article  Google Scholar 

  3. Prakken B, Albani S, Martini A. Juvenile idiopathic arthritis. Lancet. 2011;377(9783):2138–49.

    Article  PubMed  Google Scholar 

  4. Schenck S, Niewerth M, Sengler C, et al. Prevalence of overweight in children and adolescents with juvenile idiopathic arthritis. Scand J Rheumatol. 2015;44(4):288–95.

    Article  CAS  PubMed  Google Scholar 

  5. Sacks JJ, Helmick CG, Luo Yh, Ilowite NT, Bowyer S. Prevalence of and annual ambulatory health care visits for pediatric arthritis and other rheumatologic conditions in the United States in 2001–2004. Arthritis Care Res. 2007;57(8):1439–45.

    Article  Google Scholar 

  6. Harris JG, Kessler EA, Verbsky JW. Update on the treatment of juvenile idiopathic arthritis. Curr Allergy Asthma Rep. 2013;13(4):337–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Upchurch KS, Kay J. Evolution of treatment for rheumatoid arthritis. Rheumatology. 2012;51(suppl_6):vi28–36.

    CAS  PubMed  Google Scholar 

  8. Ruperto N, Martini A. Emerging drugs to treat juvenile idiopathic arthritis. Expert Opin Emerg Drugs. 2011;16(3):493–505.

    Article  PubMed  Google Scholar 

  9. Consolaro A, Negro G, Lanni S, Solari N, Martini A, Ravelli A. Toward a treat-to-target approach in the management of juvenile idiopathic arthritis. Clin Exp Rheumatol. 2012;30(4):S157.

    PubMed  Google Scholar 

  10. Hinze C, Gohar F, Foell D. Management of juvenile idiopathic arthritis: hitting the target. Nat Rev Rheumatol. 2015;11(5):290.

    Article  CAS  PubMed  Google Scholar 

  11. Ravelli A, Consolaro A, Horneff G, et al. Treating juvenile idiopathic arthritis to target: recommendations of an international task force. Ann Rheum Dis. 2018;77(6):819–28.

    PubMed  Google Scholar 

  12. Giancane G, Consolaro A, Lanni S, Davì S, Schiappapietra B, Ravelli A. Juvenile idiopathic arthritis: diagnosis and treatment. Rheumatol Ther. 2016;3(2):187–207.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Wallace CA, Giannini EH, Spalding SJ, et al. Trial of early aggressive therapy in polyarticular juvenile idiopathic arthritis. Arthritis Rheum. 2012;64(6):2012–21.

    Article  PubMed  Google Scholar 

  14. Otten MH, Anink J, Prince FH, et al. Trends in prescription of biological agents and outcomes of juvenile idiopathic arthritis: results of the Dutch national Arthritis and Biologics in Children Register. Ann Rheum Dis. 2015;74(7):1379–86.

    Article  PubMed  Google Scholar 

  15. 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(6):960–77.

    Article  PubMed  Google Scholar 

  16. Dueckers G, Guellac N, Arbogast M, et al. Evidence and consensus based GKJR guidelines for the treatment of juvenile idiopathic arthritis. Clin Immunol. 2012;142(2):176–93.

    Article  CAS  PubMed  Google Scholar 

  17. Tugwell P, Singh JA, Wells GA. Biologicals for rheumatoid arthritis. BMJ. 2011;343:312–316.

    Article  Google Scholar 

  18. Wells GA, Smith C, Hossain A, et al. Drugs for the management of rheumatoid arthritis: clinical evaluation. 2018.

  19. Lovell DJ, Reiff A, Ilowite NT, et al. Safety and efficacy of up to eight years of continuous etanercept therapy in patients with juvenile rheumatoid arthritis. Arthritis Rheum. 2008;58(5):1496–504.

    Article  CAS  PubMed  Google Scholar 

  20. Prince FH, Twilt M, ten Cate R, et al. Long-term follow-up on effectiveness and safety of etanercept in juvenile idiopathic arthritis: the Dutch national register. Ann Rheum Dis. 2009;68(5):635–41.

    Article  CAS  PubMed  Google Scholar 

  21. Horneff G, Burgos-Vargas R, Constantin T, et al. Efficacy and safety of open-label etanercept on extended oligoarticular juvenile idiopathic arthritis, enthesitis-related arthritis and psoriatic arthritis: part 1 (week 12) of the CLIPPER study. Ann Rheum Dis. 2014;73(6):1114–22.

    Article  CAS  PubMed  Google Scholar 

  22. Ruperto N, Lovell DJ, Quartier P, et al. Abatacept in children with juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled withdrawal trial. Lancet. 2008;372(9636):383–91.

    Article  CAS  PubMed  Google Scholar 

  23. Burgos-Vargas R, Tse SM, Horneff G, et al. A randomized, double-blind, placebo-controlled multicenter study of adalimumab in pediatric patients with enthesitis-related arthritis. Arthritis Care Res. 2015;67(11):1503–12.

    Article  CAS  Google Scholar 

  24. Braun J. Methotrexate: optimizing the efficacy in rheumatoid arthritis. Ther Adv Musculoskelet Dis. 2011;3(3):151–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Nam JL, Takase-Minegishi K, Ramiro S, et al. 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. 2017;76(6):1113–36.

    Article  PubMed  Google Scholar 

  26. Choy E, Aletaha D, Behrens F, et al. Monotherapy with biologic disease-modifying anti-rheumatic drugs in rheumatoid arthritis. Rheumatology. 2017;56(5):689–97.

    CAS  PubMed  Google Scholar 

  27. Jones G. The AMBITION trial: tocilizumab monotherapy for rheumatoid arthritis. Expert Rev Clin Immunol. 2010;6(2):189–95.

    Article  CAS  PubMed  Google Scholar 

  28. American College of Rheumatology. Additional medications to treat children with JIA are urgently needed. In: EurekAlert. American Association for the Advancement of Science. 2019. https://www.eurekalert.org/pub_releases/2019-11/acor-amt110119.php. Accessed 20 Dec 2020.

  29. Batu ED. Glucocorticoid treatment in juvenile idiopathic arthritis. Rheumatol Int. 2019;39(1):13–27.

    Article  PubMed  Google Scholar 

  30. Riebschleger MP, Van Mater HA, Cohn LM, Clark SJ. Prescription patterns for children with juvenile idiopathic arthritis in Michigan Medicaid: a comparison by prescriber type. Pediatr Rheumatol. 2014;12(1):38.

    Article  Google Scholar 

  31. Mannion ML, Xie F, Curtis JR, Beukelman T. Recent trends in medication usage for the treatment of juvenile idiopathic arthritis and the influence of tumor necrosis factor inhibitors. J Rheumatol. 2014;41(10):2078–84.

    Article  CAS  PubMed  Google Scholar 

  32. Davies R, Carrasco R, Foster HE, et al. Treatment prescribing patterns in patients with juvenile idiopathic arthritis (JIA): analysis from the UK Childhood Arthritis Prospective Study (CAPS). Semin Arthritis Rheum. 2016;46(2):190–5.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Petty RE, Southwood TR, Manners P, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004;31(2):390.

    PubMed  Google Scholar 

  34. Consolaro A, Giancane G, Schiappapietra B, et al. Clinical outcome measures in juvenile idiopathic arthritis. Pediatr Rheumatol. 2016;14(1):23.

    Article  Google Scholar 

  35. Consolaro A, Negro G, Chiara Gallo M, et al. Defining criteria for disease activity states in nonsystemic juvenile idiopathic arthritis based on a three-variable juvenile arthritis disease activity score. Arthritis Care Res. 2014;66(11):1703–9.

    Article  Google Scholar 

  36. Consolaro A, Ruperto N, Bazso A, et al. Development and validation of a composite disease activity score for juvenile idiopathic arthritis. Arthritis Care Res. 2009;61(5):658–66.

    Article  Google Scholar 

  37. Swart JF, van Dijkhuizen EP, Wulffraat NM, de Roock S. Clinical Juvenile Arthritis Disease Activity Score proves to be a useful tool in treat-to-target therapy in juvenile idiopathic arthritis. Ann Rheum Dis. 2018;77(3):336–42.

    Article  CAS  PubMed  Google Scholar 

  38. Magni-Manzoni S, Ruperto N, Pistorio A, et al. Development and validation of a preliminary definition of minimal disease activity in patients with juvenile idiopathic arthritis. Arthritis Care Res. 2008;59(8):1120–7.

    Article  Google Scholar 

  39. Yuan YC. Multiple imputation for missing data: Concepts and new development (Version 9.0). SAS Institute Inc, Rockville, MD. 2010;49(1-11):12.

  40. Huang B, Qiu T, Chen C, et al. Timing matters: real-world effectiveness of early combination of biologic and conventional synthetic disease-modifying antirheumatic drugs for treating newly diagnosed polyarticular course juvenile idiopathic arthritis. RMD Open. 2020;6(1):e001091.

  41. Huang B, Qiu T, Chen C, et al. Comparative effectiveness research using electronic health records data: ensure data quality. 2020.

  42. Stoll ML, Cron RQ. Treatment of juvenile idiopathic arthritis: a revolution in care. Pediatr Rheumatol. 2014;12(1):13.

    Article  Google Scholar 

  43. Davies R, Carrasco R, Foster HE, et al. Treatment prescribing patterns in patients with juvenile idiopathic arthritis (JIA): analysis from the UK Childhood Arthritis Prospective Study (CAPS). Paper presented at: Seminars in arthritis and rheumatism 2016.

  44. Kalkan A, Husberg M, Hallert E, et al. Physician preferences and variations in prescription of biologic drugs for rheumatoid arthritis: a register-based study of 4010 patients in Sweden. Arthritis Care Res. 2015;67(12):1679–85.

    Article  Google Scholar 

  45. Curtis JR, Chen L, Harrold LR, Narongroeknawin P, Reed G, Solomon DH. Physician preference motivates the use of anti-tumor necrosis factor therapy independent of clinical disease activity. Arthritis Care Res. 2010;62(1):101–7.

    Article  Google Scholar 

  46. Klotsche J, Niewerth M, Haas J-P, et al. Long-term safety of etanercept and adalimumab compared to methotrexate in patients with juvenile idiopathic arthritis (JIA). Ann Rheum Dis. 2016;75(5):855–61.

    Article  CAS  PubMed  Google Scholar 

  47. Davies R, Gaynor D, Hyrich KL, Pain CE. Efficacy of biologic therapy across individual juvenile idiopathic arthritis subtypes: a systematic review. Paper presented at: Seminars in Arthritis and Rheumatism; 2017.

  48. Scott C, Meiorin S, Filocamo G, et al. A reappraisal of intra-articular corticosteroid therapy in juvenile idiopathic arthritis. Clin Exp Rheumatol. 2010;28(5):774.

    CAS  PubMed  Google Scholar 

  49. Bloom BJ, Alario AJ, Miller LC. Intra-articular corticosteroid therapy for juvenile idiopathic arthritis: report of an experiential cohort and literature review. Rheumatol Int. 2011;31(6):749–56.

    Article  CAS  PubMed  Google Scholar 

  50. Ravelli A, Davì S, Bracciolini G, et al. Intra-articular corticosteroids versus intra-articular corticosteroids plus methotrexate in oligoarticular juvenile idiopathic arthritis: a multicentre, prospective, randomised, open-label trial. Lancet. 2017;389(10072):909–16.

    Article  CAS  PubMed  Google Scholar 

  51. Gottlieb S. FDA Budget Matters: A Cross-Cutting Data Enterprise for Real World Evidence. In: FDA newsroom. U.S. Food & Drug Administration. 2018; https://www.fda.gov/news-events/fda-voices-perspectives-fda-leadership-and-experts/fda-budget-matters-cross-cutting-data-enterprise-real-world-evidence. Accessed 12 Dec 2020.

  52. Poon EG, Jha AK, Christino M, et al. Assessing the level of healthcare information technology adoption in the United States: a snapshot. BMC Med Inform Decis Mak. 2006;6(1):1.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Yue X, Huang B, Hincapie AL, et al. Comparative effectiveness and persistence of TNFi and non-TNFi in juvenile idiopathic arthritis: a large pediatric rheumatology center in US. Rheumatology. 2020.

  54. Yue X, Wu J, Ruan Z, Wolden ML, Li L, Lin Y. The burden of hypoglycemia in patients with insulin-treated diabetes mellitus in China: analysis of electronic medical records from 4 tertiary hospitals. Value Health Reg Issues. 2020;21:17–21.

    Article  PubMed  Google Scholar 

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Correspondence to Xiaomeng Yue.

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Funding

This study was partially funded by the Patient-Centered Outcomes Research Institute (ME-1408-19894).

Conflict of interest

The author(s) declare(s) that there is no conflict of interest concerning this research. Dr Guo has received research grant or unrestricted grant funding from the following: The Ohio Department of Jobs and Family Services (Medicaid Agency), Ortho-McNeil Janssen Scientific Affairs LLC, Eli-Lilly Company, Novartis Company, and Roche-Genentech Company. The opinions and conclusions expressed in this manuscript are solely those of the authors.

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This study was approved by the Institutional Review Board of Cincinnati Children’s Hospital Medical Center.

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Availability of data and materials

Datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Author contributions

Dr Xiaomeng Yue and Yuxiang Li conceived the study, analyzed the data, wrote the manuscript, and revised the manuscript; Dr Bin Huang, Dr Jeff J. Guo, and Dr Esi M. Morgan supervised data collection, statistical assessment, interpretation, and manuscript preparation for publication; Dr Patricia R. Wigle and Dr Ana L. Hincapie conceived the study and revised the manuscript; Tingting Qiu collected and analyzed the data.

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Yue, X., Huang, B., Hincapie, A.L. et al. Prescribing Patterns and Impact of Factors Associated with Time to Initial Biologic Therapy among Children with Non-systemic Juvenile Idiopathic Arthritis. Pediatr Drugs 23, 171–182 (2021). https://doi.org/10.1007/s40272-021-00436-4

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