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Published in: Pediatric Rheumatology 1/2019

Open Access 01-12-2019 | Juvenile Rheumatoid Arthritis | Research article

A prediction rule for lack of achievement of inactive disease with methotrexate as the sole disease-modifying antirheumatic therapy in juvenile idiopathic arthritis

Authors: Cecilia Bava, Federica Mongelli, Angela Pistorio, Marta Bertamino, Giulia Bracciolini, Sara Dalprà, Sergio Davì, Stefano Lanni, Valentina Muratore, Silvia Pederzoli, Silvia Rosina, Benedetta Schiappapietra, Chiara Suffia, Giulia Varnier, Sara Verazza, Gabriella Giancane, Alessandro Consolaro, Angelo Ravelli

Published in: Pediatric Rheumatology | Issue 1/2019

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Abstract

Background

To investigate the frequency of achievement of inactive disease (ID) in children with juvenile idiopathic arthritis (JIA) treated with methotrexate (MTX) as the sole disease-modifyng antirheumatic (DMARD) therapy and to develop a prediction model for lack of attainment of ID.

Methods

The clinical charts of consecutive patients started with MTX as the sole DMARD between 2000 and 2013 were reviewed. Patient follow-up was censored at first episode of ID or, in case ID was not reached, at last follow-up visit or when a biologic DMARD was prescribed. The characteristic at MTX start of patients who achieved or did not achieve ID were compared with univariate and multivariable analyses. Regression coefficients (β) of variables that entered the best-fitting logistic regression model were converted and summed to obtain a “prediction score” for lack of achievement of ID.

Results

A total of 375 patients were included in the study. During MTX administration, 8.8% were given systemic corticosteroids and 44.1% intra-articular corticosteroids. After MTX start, 229 (61%) patients achieved ID after a median of 1.7 years, whereas 146 patients (39%) did not reach ID after a median of 1.2 years. On multivariable analysis, independent correlations with lack of achievement of ID were identified for the disease categories of systemic arthritis, enthesitis-related arthritis (ERA) and polyarthritis and C-reactive protein (CRP) >  1.4 mg/dl. The prediction score ranged from 0 to 3 and its cutoff that discriminated best between patients who achieved or did not achieve ID was > 0.5. The categories of systemic arthritis or ERA, both of which had a score greater than 0.5, were sufficient alone to predict a lower likelihood to reach ID. Polyarthritis and increased CRP, whose score was 0.5, assumed a predictive value only when present in association.

Conclusion

A conventional treatment regimen based on MTX as the sole DMARD led to achievement of ID in a sizeable proportion of children with JIA. Our findings help to outline the characteristics of patients who may deserve a synthetic DMARD other than MTX or the introduction of a biologic DMARD from disease outset.
Literature
1.
go back to reference Ravelli A, Martini A. Juvenile idiopathic arthritis. Lancet. 2007;369:767–78.CrossRef Ravelli A, Martini A. Juvenile idiopathic arthritis. Lancet. 2007;369:767–78.CrossRef
2.
go back to reference Miller ML, LeBovidge J, Feldman B. Health-related quality of life in children with arthritis. Rheum Dis Clin N Am. 2002;28:493–501.CrossRef Miller ML, LeBovidge J, Feldman B. Health-related quality of life in children with arthritis. Rheum Dis Clin N Am. 2002;28:493–501.CrossRef
3.
go back to reference Brunner HI, Giannini EH. Health-related quality of life in children with rheumatic diseases. Curr Opin Rheumatol. 2003;15:602–12.CrossRef Brunner HI, Giannini EH. Health-related quality of life in children with rheumatic diseases. Curr Opin Rheumatol. 2003;15:602–12.CrossRef
4.
go back to reference Solari N, Viola S, Pistorio A, Magni-Manzoni S, Vitale R, Ruperto N, et al. Assessing current outcomes of juvenile idiopathic arthritis: a cross-sectional study in a tertiary center sample. Arthritis Rheum. 2008;59:1571–9.CrossRef Solari N, Viola S, Pistorio A, Magni-Manzoni S, Vitale R, Ruperto N, et al. Assessing current outcomes of juvenile idiopathic arthritis: a cross-sectional study in a tertiary center sample. Arthritis Rheum. 2008;59:1571–9.CrossRef
5.
go back to reference Magnani A, Pistorio A, Magni-Manzoni S, Falcone A, Lombardini G, Bandeira M, et al. Achievement of a state of inactive disease at least once in the first 5 years predicts better outcome of patients with polyarticular juvenile idiopathic arthritis. J Rheumatol. 2009;36:628–34.CrossRef Magnani A, Pistorio A, Magni-Manzoni S, Falcone A, Lombardini G, Bandeira M, et al. Achievement of a state of inactive disease at least once in the first 5 years predicts better outcome of patients with polyarticular juvenile idiopathic arthritis. J Rheumatol. 2009;36:628–34.CrossRef
6.
go back to reference Fries JF, Williams CA, Morfeld D, Singh G, Sibley J. Reduction of long-term disability in patients with rheumatoid arthritis by disease-modifying antirheumatic drug-based treatment strategies. Arthritis Rheum. 1996;39:616–22.CrossRef Fries JF, Williams CA, Morfeld D, Singh G, Sibley J. Reduction of long-term disability in patients with rheumatoid arthritis by disease-modifying antirheumatic drug-based treatment strategies. Arthritis Rheum. 1996;39:616–22.CrossRef
7.
go back to reference Grigor C, Capell H, Stirling A, McMahon AD, Lock P, Vallance R, et al. Effect of a treatment strategy of tight control of rheumatoid arthritis (the TICORA study): a single-blind randomized controlled trial. Lancet. 2004;364:263–9.CrossRef Grigor C, Capell H, Stirling A, McMahon AD, Lock P, Vallance R, et al. Effect of a treatment strategy of tight control of rheumatoid arthritis (the TICORA study): a single-blind randomized controlled trial. Lancet. 2004;364:263–9.CrossRef
8.
go back to reference Consolaro A, Ravelli A. It is worth including assessment of disease activity state in juvenile arthritis clinical trials. Arthritis Care Res. 2013;65:1207–10.CrossRef Consolaro A, Ravelli A. It is worth including assessment of disease activity state in juvenile arthritis clinical trials. Arthritis Care Res. 2013;65:1207–10.CrossRef
9.
go back to reference Hinze C, Gohar F, Foell D. Management of juvenile idiopathic arthritis: hitting the target. Nat Rev Rheumatol. 2015;11:290–300.CrossRef Hinze C, Gohar F, Foell D. Management of juvenile idiopathic arthritis: hitting the target. Nat Rev Rheumatol. 2015;11:290–300.CrossRef
10.
go back to reference 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 Suppl 73):157–62. 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 Suppl 73):157–62.
11.
go back to reference Ravelli A, Martini A. Methotrexate in juvenile idiopathic arthritis: answers and questions. J Rheumatol. 2000;27:1830–3.PubMed Ravelli A, Martini A. Methotrexate in juvenile idiopathic arthritis: answers and questions. J Rheumatol. 2000;27:1830–3.PubMed
12.
go back to reference Gutiérrez-Suárez R, Burgos-Vargas R. The use of methotrexate in children with rheumatic diseases. Clin Exp Rheumatol. 2010;28(5 Suppl 61):122–7. Gutiérrez-Suárez R, Burgos-Vargas R. The use of methotrexate in children with rheumatic diseases. Clin Exp Rheumatol. 2010;28(5 Suppl 61):122–7.
13.
go back to reference Van Dijkhuizen EHP, Wulffraat N. Prediction of methotrexate efficacy and adverse events in patients with juvenile idiopathic arthritis: a systematic literature review. Pediatr Rheumatol Online J. 2014;12:51.CrossRef Van Dijkhuizen EHP, Wulffraat N. Prediction of methotrexate efficacy and adverse events in patients with juvenile idiopathic arthritis: a systematic literature review. Pediatr Rheumatol Online J. 2014;12:51.CrossRef
14.
go back to reference Giannini EH, Brewer EJ, Kuzmina N, Shaikov A, Maximov A, Vorontsov I, et al. Methotrexate in resistant juvenile rheumatoid arthritis. Results of the U.S.a.-U.S.S.R. double-blind, placebo-controlled trial. N Engl J Med. 1992;326:1043–9.CrossRef Giannini EH, Brewer EJ, Kuzmina N, Shaikov A, Maximov A, Vorontsov I, et al. Methotrexate in resistant juvenile rheumatoid arthritis. Results of the U.S.a.-U.S.S.R. double-blind, placebo-controlled trial. N Engl J Med. 1992;326:1043–9.CrossRef
15.
go back to reference Ruperto N, Murray KJ, Gerloni V, Wulffraat N, de Oliveira SK, Falcini F, et al. A randomized trial of parenteral methotrexate comparing an intermediate dose with a higher dose in children with juvenile idiopathic arthritis who failed to respond to standard doses of methotrexate. Arthritis Rheum. 2004;50:2191–201.CrossRef Ruperto N, Murray KJ, Gerloni V, Wulffraat N, de Oliveira SK, Falcini F, et al. A randomized trial of parenteral methotrexate comparing an intermediate dose with a higher dose in children with juvenile idiopathic arthritis who failed to respond to standard doses of methotrexate. Arthritis Rheum. 2004;50:2191–201.CrossRef
16.
go back to reference Bartoli M, Tarò M, Magni-Manzoni S, Pistorio A, Traverso F, Viola S. The magnitude of early response to methotrexate therapy predicts long-term outcome of patients with juvenile idiopathic arthritis. Ann Rheum Dis. 2008;67:370–4.CrossRef Bartoli M, Tarò M, Magni-Manzoni S, Pistorio A, Traverso F, Viola S. The magnitude of early response to methotrexate therapy predicts long-term outcome of patients with juvenile idiopathic arthritis. Ann Rheum Dis. 2008;67:370–4.CrossRef
17.
go back to reference Foell D, Wulffraat N, Wedderburn LR, Wittkowski H, Frosch M, Gerss J, et al. Methotrexate withdrawal at 6 vs 12 months in juvenile idiopathic arthritis in remission: a randomized clinical trial. JAMA. 2010;303:1266–73.CrossRef Foell D, Wulffraat N, Wedderburn LR, Wittkowski H, Frosch M, Gerss J, et al. Methotrexate withdrawal at 6 vs 12 months in juvenile idiopathic arthritis in remission: a randomized clinical trial. JAMA. 2010;303:1266–73.CrossRef
18.
go back to reference Wallace CA, Giannini EH, Spalding SJ, Hashkes PJ, O’Neil KM, Zeft AS, et al. Clinically inactive disease in a cohort of children with new-onset polyarticular juvenile idiopathic arthritis treated with early aggressive therapy: time to achievement, total duration, and predictors. J Rheumatol. 2014;41:1163–70.CrossRef Wallace CA, Giannini EH, Spalding SJ, Hashkes PJ, O’Neil KM, Zeft AS, et al. Clinically inactive disease in a cohort of children with new-onset polyarticular juvenile idiopathic arthritis treated with early aggressive therapy: time to achievement, total duration, and predictors. J Rheumatol. 2014;41:1163–70.CrossRef
19.
go back to reference Hissink Muller P, Brinkman DMC, Schonenberg-Meinema D, van den Bosch WB, Koopman-Keemink Y, Brederije ICJ, et al. Treat to target (drug-free) inactive disease in DMARD-naive juvenile idiopathic arthritis: 24-month clinical outcomes of a three-armed randomised trial. Ann Rheum Dis. 2019;78:51–59.CrossRef Hissink Muller P,  Brinkman DMC,  Schonenberg-Meinema D, van den Bosch WB, Koopman-Keemink Y,  Brederije ICJ, et al. Treat to target (drug-free) inactive disease in DMARD-naive juvenile idiopathic arthritis: 24-month clinical outcomes of a three-armed randomised trial. Ann Rheum Dis. 2019;78:51–59.CrossRef
20.
go back to reference Gottlieb BS, Keenan GF, Lu T, Ilowite NT. Discontinuation of methotrexate treatment in juvenile rheumatoid arthritis. Pediatrics. 1997;100:994–7.CrossRef Gottlieb BS, Keenan GF, Lu T, Ilowite NT. Discontinuation of methotrexate treatment in juvenile rheumatoid arthritis. Pediatrics. 1997;100:994–7.CrossRef
21.
go back to reference Ravelli A, Martini A. Early predictors of outcome in juvenile idiopathic arthritis. Clin Exp Rheumatol. 2003;21(5 Suppl 31):89–93. Ravelli A, Martini A. Early predictors of outcome in juvenile idiopathic arthritis. Clin Exp Rheumatol. 2003;21(5 Suppl 31):89–93.
22.
go back to reference Albarouni M, Becker I, Horneff G. Predictors of response to methotrexate in juvenile idiopathic arthritis. Pediatr Rheumatol Online J. 2014;12:35.CrossRef Albarouni M, Becker I, Horneff G. Predictors of response to methotrexate in juvenile idiopathic arthritis. Pediatr Rheumatol Online J. 2014;12:35.CrossRef
23.
go back to reference Klotsche J, Minden K, Niewerth M, Horneff G. Time spent in inactive disease before MTX withdrawal is relevant with regard to the flare risk in patients with JIA. Ann Rheum Dis. 2018;77:996–1002.CrossRef Klotsche J, Minden K, Niewerth M, Horneff G. Time spent in inactive disease before MTX withdrawal is relevant with regard to the flare risk in patients with JIA. Ann Rheum Dis. 2018;77:996–1002.CrossRef
24.
go back to reference Petty RE, Southwood TR, Manners P, Baum J, Glass D, Goldenberg J, et al. International league of associations of rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004;31:390–2.PubMed Petty RE, Southwood TR, Manners P, Baum J, Glass D, Goldenberg J, et al. International league of associations of rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004;31:390–2.PubMed
25.
go back to reference Wallace CA, Ruperto N, Giannini E. Preliminary criteria for clinical remission for select categories of juvenile idiopathic arthritis. J Rheumatol. 2004;31:2290–4.PubMed Wallace CA, Ruperto N, Giannini E. Preliminary criteria for clinical remission for select categories of juvenile idiopathic arthritis. J Rheumatol. 2004;31:2290–4.PubMed
26.
go back to reference Beukelman T, Patkar NM, Saag KG, Tolleson-Rinehart S, Cron RQ, DeWitt EM, et al. 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: initiation and safety monitoring of therapeutic agents for the treatment of arthritis and systemic features. Arthritis Care Res. 2011;63:465–82.CrossRef Beukelman T, Patkar NM, Saag KG, Tolleson-Rinehart S, Cron RQ, DeWitt EM, et al. 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: initiation and safety monitoring of therapeutic agents for the treatment of arthritis and systemic features. Arthritis Care Res. 2011;63:465–82.CrossRef
27.
go back to reference Scott C, Meiorin S, Filocamo G, Lanni S, Valle M, Martinoli C, et al. A reappraisal of intra-articular corticosteroid therapy in juvenile idiopathic arthritis. Clin Exp Rheumatol. 2010;28:774–81.PubMed Scott C, Meiorin S, Filocamo G, Lanni S, Valle M, Martinoli C, et al. A reappraisal of intra-articular corticosteroid therapy in juvenile idiopathic arthritis. Clin Exp Rheumatol. 2010;28:774–81.PubMed
28.
go back to reference Wallace CA, Giannini EH, Spalding SJ, Hashkes PJ, O'Neil KM, Zeft AS, et al. Childhood arthritis and rheumatology research Alliance. Trial of early aggressive therapy in polyarticular juvenile idiopathic arthritis. Arthritis Rheum. 2011;64:2012–21.CrossRef Wallace CA, Giannini EH, Spalding SJ, Hashkes PJ, O'Neil KM, Zeft AS, et al. Childhood arthritis and rheumatology research Alliance. Trial of early aggressive therapy in polyarticular juvenile idiopathic arthritis. Arthritis Rheum. 2011;64:2012–21.CrossRef
29.
go back to reference Ravelli A, Consolaro A, Horneff G, Laxer RM, Lovell DJ, Wulffraat NM, et al. Treating juvenile idiopathic arthritis to target: recommendations of an international task force. Ann Rheum Dis. 2018;77:819–28.PubMed Ravelli A, Consolaro A, Horneff G, Laxer RM, Lovell DJ, Wulffraat NM, et al. Treating juvenile idiopathic arthritis to target: recommendations of an international task force. Ann Rheum Dis. 2018;77:819–28.PubMed
30.
go back to reference Ravelli A, Davì S, Bracciolini G, Pistorio A, Consolaro A, Van Dijkhuizen EHP, 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;389:909–16.CrossRef Ravelli A, Davì S, Bracciolini G, Pistorio A, Consolaro A, Van Dijkhuizen EHP, 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;389:909–16.CrossRef
31.
go back to reference De Benedetti F, Schneider R. Systemic juvenile idiopathic arthritis. In: Petty RE, Laxer RM, Lindsley CB, Wedderburn LR, editors. Textbook of pediatric rheumatology. 7th ed. Philadelphia: Elsevier; 2016. p. 205–16.CrossRef De Benedetti F, Schneider R. Systemic juvenile idiopathic arthritis. In: Petty RE, Laxer RM, Lindsley CB, Wedderburn LR, editors. Textbook of pediatric rheumatology. 7th ed. Philadelphia: Elsevier; 2016. p. 205–16.CrossRef
32.
go back to reference Vilca I, Munitis PG, Pistorio A, Ravelli A, Buoncompagni A, Bica B, et al. Predictors of poor response to methotrexate in polyarticular-course juvenile idiopathic arthritis: analysis of the PRINTO methotrexate trial. Ann Rheum Dis. 2010;69:1479–83.CrossRef Vilca I, Munitis PG, Pistorio A, Ravelli A, Buoncompagni A, Bica B, et al. Predictors of poor response to methotrexate in polyarticular-course juvenile idiopathic arthritis: analysis of the PRINTO methotrexate trial. Ann Rheum Dis. 2010;69:1479–83.CrossRef
33.
go back to reference Halle F, Prieur AM. Evaluation of methotrexate in the treatment of juvenile chronic arthritis according to the subtype. Clin Exp Rheumatol. 1991;9:297–302.PubMed Halle F, Prieur AM. Evaluation of methotrexate in the treatment of juvenile chronic arthritis according to the subtype. Clin Exp Rheumatol. 1991;9:297–302.PubMed
34.
go back to reference Batu ED, Sönmez HE, Gülhan B, Arıcı ZS, Topaloğlu R, Bilginer Y. Predictors of methotrexate response in Turkish children with oligoarticular and polyarticular juvenile idiopathic arthritis. Turk J Pediatr. 2017;59:6–12.CrossRef Batu ED, Sönmez HE, Gülhan B, Arıcı ZS, Topaloğlu R, Bilginer Y. Predictors of methotrexate response in Turkish children with oligoarticular and polyarticular juvenile idiopathic arthritis. Turk J Pediatr. 2017;59:6–12.CrossRef
35.
go back to reference Bulatović M, Heijstek MW, Van Dijkhuizen EHP, Wulffraat NM, Pluijm SMF, De Jonge R. Prediction of clinical non-response to methotrexate treatment in juvenile idiopathic arthritis. Ann Rheum Dis. 2012;71:1484–9.CrossRef Bulatović M, Heijstek MW, Van Dijkhuizen EHP, Wulffraat NM, Pluijm SMF, De Jonge R. Prediction of clinical non-response to methotrexate treatment in juvenile idiopathic arthritis. Ann Rheum Dis. 2012;71:1484–9.CrossRef
36.
go back to reference Ravelli A, Viola S, Ramenghi B, Aramini L, Ruperto N, Martini A. Frequency of relapse after discontinuation of methotrexate therapy for clinical remission in juvenile rheumatoid arthritis. J Rheumatol. 1995;22:1574–6.PubMed Ravelli A, Viola S, Ramenghi B, Aramini L, Ruperto N, Martini A. Frequency of relapse after discontinuation of methotrexate therapy for clinical remission in juvenile rheumatoid arthritis. J Rheumatol. 1995;22:1574–6.PubMed
Metadata
Title
A prediction rule for lack of achievement of inactive disease with methotrexate as the sole disease-modifying antirheumatic therapy in juvenile idiopathic arthritis
Authors
Cecilia Bava
Federica Mongelli
Angela Pistorio
Marta Bertamino
Giulia Bracciolini
Sara Dalprà
Sergio Davì
Stefano Lanni
Valentina Muratore
Silvia Pederzoli
Silvia Rosina
Benedetta Schiappapietra
Chiara Suffia
Giulia Varnier
Sara Verazza
Gabriella Giancane
Alessandro Consolaro
Angelo Ravelli
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Pediatric Rheumatology / Issue 1/2019
Electronic ISSN: 1546-0096
DOI
https://doi.org/10.1186/s12969-019-0355-0

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