The role of synthetic drugs in the biologic era: therapeutic strategies for treating juvenile idiopathic arthritis

References

• Ravelli A, Martini A. Juvenile idiopathic arthritis. Lancet. 2007 Mar 3;369(9563):767–778.
   PubMed Web of Science ®Google Scholar
• 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 Feb;31(2):390–392.
   PubMed Web of Science ®Google Scholar
• Anink J, Prince FH, Dijkstra M, et al. Long-term quality of life and functional outcome of patients with juvenile idiopathic arthritis in the biologic era: a longitudinal follow-up study in the Dutch Arthritis and Biologicals in Children Register. Rheumatology (Oxford). 2015 Nov;54(11):1964–1969.
   PubMed Web of Science ®Google Scholar
• Horneff G. Update on biologicals for treatment of juvenile idiopathic arthritis. Expert Opin Biol Ther. 2013 Mar;13(3):361–376.
   PubMed Web of Science ®Google Scholar
• Hinze C, Gohar F, Foell D. Management of juvenile idiopathic arthritis: hitting the target. Nat Rev Rheumatol. 2015 May;11(5):290–300.
   PubMed Web of Science ®Google Scholar
• Chan ES, Cronstein BN. Molecular action of methotrexate in inflammatory diseases. Arthritis Res. 2002;4(4):266–273.
   PubMedGoogle Scholar
• Giannini EH, Brewer EJ, Kuzmina N, et al. Methotrexate in resistant juvenile rheumatoid arthritis. Results of the U.S.A.-U.S.S.R. double-blind, placebo-controlled trial. The Pediatric Rheumatology Collaborative Study Group and The Cooperative Children’s Study Group. N Engl J Med. 1992 Apr 16;326(16):1043–1049.
   PubMed Web of Science ®Google Scholar
• Woo P, Southwood TR, Prieur AM, et al. Randomized, placebo-controlled, crossover trial of low-dose oral methotrexate in children with extended oligoarticular or systemic arthritis. Arthritis Rheum. 2000 Aug;43(8):1849–1857.
   PubMed Web of Science ®Google Scholar
• Ravelli A, Viola S, Migliavacca D, et al. The extended oligoarticular subtype is the best predictor of methotrexate efficacy in juvenile idiopathic arthritis. J Pediatr. 1999 Sep;135(3):316–320.
   PubMed Web of Science ®Google Scholar
• Ruperto N, Murray KJ, Gerloni V, 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 Jul;50(7):2191–2201.
   PubMed Web of Science ®Google Scholar
• Becker ML, Rose CD, Cron RQ, et al. Effectiveness and toxicity of methotrexate in juvenile idiopathic arthritis: comparison of 2 initial dosing regimens. J Rheumatol. 2010 Apr;37(4):870–875.
   PubMed Web of Science ®Google Scholar
• Gottlieb BS, Keenan GF, Lu T, et al. Discontinuation of methotrexate treatment in juvenile rheumatoid arthritis. Pediatrics. 1997 Dec;100(6):994–997.
   PubMed Web of Science ®Google Scholar
• Tynjälä P, Vähäsalo P, Tarkiainen M, et al. Aggressive combination drug therapy in very early polyarticular juvenile idiopathic arthritis (ACUTE-JIA): a multicentre randomised open-label clinical trial. Ann Rheum Dis. 2011 Sep;70(9):1605–1612.
   PubMed Web of Science ®Google Scholar
• Klein A, Kaul I, Foeldvari I, et al. Efficacy and safety of oral and parenteral methotrexate therapy in children with juvenile idiopathic arthritis: an observational study with patients from the German Methotrexate Registry. Arthritis Care Res (Hoboken). 2012 Sep;64(9):1349–1356.
   PubMed Web of Science ®Google Scholar
• Harel L, Wagner-Weiner L, Poznanski AK, et al. Effects of methotrexate on radiologic progression in juvenile rheumatoid arthritis. Arthritis Rheum. 1993 Oct;36(10):1370–1374.
   PubMed Web of Science ®Google Scholar
• Ravelli A, Viola S, Ramenghi B, et al. Radiologic progression in patients with juvenile chronic arthritis treated with methotrexate. J Pediatr. 1998 Aug;133(2):262–265.
   PubMed Web of Science ®Google Scholar
• Petty RE, Smith JR, Rosenbaum JT. Arthritis and uveitis in children. A pediatric rheumatology perspective. Am J Ophthalmol. 2003 Jun;135(6):879–884.
   PubMed Web of Science ®Google Scholar
• Heiligenhaus A, Michels H, Schumacher C, et al. Evidence-based, interdisciplinary guidelines for anti-inflammatory treatment of uveitis associated with juvenile idiopathic arthritis. Rheumatol Int. 2012 May;32(5):1121–1133.
   PubMed Web of Science ®Google Scholar
• Niehues T, Lankisch P. Recommendations for the use of methotrexate in juvenile idiopathic arthritis. Paediatr Drugs. 2006;8(6):347–356.
   PubMedGoogle Scholar
• Ortiz-Alvarez O, Morishita K, Avery G, et al. Guidelines for blood test monitoring of methotrexate toxicity in juvenile idiopathic arthritis. J Rheumatol. 2004 Dec;31(12):2501–2506.
   PubMed Web of Science ®Google Scholar
• Rouster-Stevens KA, Ardoin SP, Cooper AM, et al. Choosing Wisely: the American College of Rheumatology’s Top 5 for pediatric rheumatology. Arthritis Care Res (Hoboken). 2014 May;66(5):649–657.
   PubMed Web of Science ®Google Scholar
• Killeen OG, Gardner-Medwin JM. In juvenile idiopathic arthritis, is folate supplementation effective against methotrexate toxicity at the expense of methotrexate’s efficacy? Arch Dis Child. 2006 Jun;91(6):537–538.
   PubMed Web of Science ®Google Scholar
• Shea B, Swinden MV, Tanjong Ghogomu E, et al. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database Syst Rev. 2013;5:CD000951.
   PubMed Web of Science ®Google Scholar
• Bulatovic M, Heijstek MW, Verkaaik M, et al. High prevalence of methotrexate intolerance in juvenile idiopathic arthritis: development and validation of a methotrexate intolerance severity score. Arthritis Rheum. 2011 Jul;63(7):2007–2013.
   PubMed Web of Science ®Google Scholar
• van der Meer A, Wulffraat NM, Prakken BJ, et al. Psychological side effects of MTX treatment in juvenile idiopathic arthritis: a pilot study. Clin Exp Rheumatol. 2007 May-Jun;25(3):480–485.
   PubMed Web of Science ®Google Scholar
• Scheuern A, Fischer N, Haas J-P, et al. [SAT0496] Countermeasures against Methotrexate Intolerance in Juvenile Idiopathic Arthritis instituted by Parents show no Effect. Ann Rheum Dis. 2015;74(Suppl 2):840.
   Google Scholar
• Beukelman T, Xie F, Baddley JW, et al. Brief report: incidence of selected opportunistic infections among children with juvenile idiopathic arthritis. Arthritis Rheum. 2013 May;65(5):1384–1389.
   PubMed Web of Science ®Google Scholar
• Foell D, Frosch M, Schulze Zur Wiesch A, et al. Methotrexate treatment in juvenile idiopathic arthritis: when is the right time to stop? Ann Rheum Dis. 2004 Feb;63(2):206–208.
   PubMed Web of Science ®Google Scholar
• Foell D, Wulffraat N, Wedderburn LR, et al. Methotrexate withdrawal at 6 vs 12 months in juvenile idiopathic arthritis in remission: a randomized clinical trial. JAMA. 2010 Apr 7;303(13):1266–1273.
   PubMed Web of Science ®Google Scholar
• Hashkes PJ, Laxer RM. Medical treatment of juvenile idiopathic arthritis. JAMA. 2005 Oct 5;294(13):1671–1684.
   PubMed Web of Science ®Google Scholar
• Van Rossum MA, Fiselier TJ, Franssen MJ, et al. Sulfasalazine in the treatment of juvenile chronic arthritis: a randomized, double-blind, placebo-controlled, multicenter study. Dutch Juvenile Chronic Arthritis Study Group. Arthritis Rheum. 1998 May;41(5):808–816.
   PubMed Web of Science ®Google Scholar
• Van Rossum MA, Van Soesbergen RM, Boers M, et al. Long-term outcome of juvenile idiopathic arthritis following a placebo-controlled trial: sustained benefits of early sulfasalazine treatment. Ann Rheum Dis. 2007 Nov;66(11):1518–1524.
   PubMed Web of Science ®Google Scholar
• Burgos-Vargas R, Vazquez-Mellado J, Pacheco-Tena C, et al. A 26 week randomised, double blind, placebo controlled exploratory study of sulfasalazine in juvenile onset spondyloarthropathies. Ann Rheum Dis. 2002 Oct;61(10):941–942.
   PubMed Web of Science ®Google Scholar
• Brooks CD. Sulfasalazine for the management of juvenile rheumatoid arthritis. J Rheumatol. 2001 Apr;28(4):845–853.
   PubMed Web of Science ®Google Scholar
• Beukelman T, Patkar NM, Saag KG, 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 (Hoboken). 2011 Apr;63(4):465–482.
   PubMed Web of Science ®Google Scholar
• Petty R, Cassidy JT. Enthesitis-related arthritis (juvenile ankylosing spondylitis). In: Cassidy JT, Petty R, Laxer RM, et al., editors. Textbook of pediatric rheumatology. 6th ed. Philadelphia (PA): Elsevier; 2011. p. 272–286.
   Google Scholar
• Huang JL, Hung IJ, Hsieh KH. Sulphasalazine therapy in chronic uveitis of children with chronic arthritis. Asian Pac J Allergy Immunol. 1997 Jun;15(2):71–75.
   PubMed Web of Science ®Google Scholar
• Munoz-Fernandez S, Hidalgo V, Fernandez-Melon J, et al. Sulfasalazine reduces the number of flares of acute anterior uveitis over a one-year period. J Rheumatol. 2003 Jun;30(6):1277–1279.
   PubMed Web of Science ®Google Scholar
• Van Rossum MA, Fiselier TJ, Franssen MJ, et al. Effects of sulfasalazine treatment on serum immunoglobulin levels in children with juvenile chronic arthritis. Scand J Rheumatol. 2001;30(1):25–30.
   PubMed Web of Science ®Google Scholar
• Hertzberger-ten Cate R, Cats A. Toxicity of sulfasalazine in systemic juvenile chronic arthritis. Clin Exp Rheumatol. 1991 Jan-Feb;9(1):85–88.
   PubMed Web of Science ®Google Scholar
• Fragoso YD, Brooks JB. Leflunomide and teriflunomide: altering the metabolism of pyrimidines for the treatment of autoimmune diseases. Expert Rev Clin Pharmacol. 2015 May;8(3):315–320.
   PubMed Web of Science ®Google Scholar
• Osiri M, Shea B, Robinson V, et al. Leflunomide for treating rheumatoid arthritis. Cochrane Database Syst Rev. 2003;(1):CD002047. DOI:10.1517/14656566.2015.1056735.
   Google Scholar
• Silverman E, Mouy R, Spiegel L, et al. Leflunomide or methotrexate for juvenile rheumatoid arthritis. N Engl J Med. 2005 Apr 21;352(16):1655–1666.
   PubMed Web of Science ®Google Scholar
• Silverman E, Spiegel L, Hawkins D, et al. Long-term open-label preliminary study of the safety and efficacy of leflunomide in patients with polyarticular-course juvenile rheumatoid arthritis. Arthritis Rheum. 2005 Feb;52(2):554–562.
   PubMed Web of Science ®Google Scholar
• Alcântara AC, Leite CA, Leite AC, et al. A longterm prospective real-life experience with leflunomide in juvenile idiopathic arthritis. J Rheumatol. 2014 Feb;41(2):338–344.
   PubMed Web of Science ®Google Scholar
• Foeldvari I, Wierk A. Effectiveness of leflunomide in patients with juvenile idiopathic arthritis in clinical practice. J Rheumatol. 2010 Aug 1;37(8):1763–1767.
   PubMed Web of Science ®Google Scholar
• Rezaieyazdi Z Efficacy study of leflunomide to treat juvenile idiopathic arthritis (JIA). 2013 [updated 2013 Dec 25; cited 2015 Sep 20]. Available from: https://clinicaltrials.gov/ct2/show/NCT02024334.
   Google Scholar
• Molina C, Modesto C, Martín-Begué N, et al. Leflunomide, a valid and safe drug for the treatment of chronic anterior uveitis associated with juvenile idiopathic arthritis. Clin Rheumatol. 2013 Nov;32(11):1673–1675.
   PubMed Web of Science ®Google Scholar
• Bichler J, Benseler SM, Krumrey-Langkammerer M, et al. Leflunomide is associated with a higher flare rate compared to methotrexate in the treatment of chronic uveitis in juvenile idiopathic arthritis. Scand J Rheumatol. 2015 Jul;44(4):280–283.
   PubMed Web of Science ®Google Scholar
• Smolen JS, Kalden JR, Scott DL, et al. Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial. European Leflunomide Study Group. Lancet. 1999 Jan 23;353(9149):259–266.
   PubMed Web of Science ®Google Scholar
• Chickermane PR, Khubchandani RP. Evaluation of the benefits of sequential addition of leflunomide in patients with polyarticular course juvenile idiopathic arthritis failing standard dose methotrexate. Clin Exp Rheumatol. 2015 Mar-Apr;33(2):287–292.
   PubMed Web of Science ®Google Scholar
• Rozman B. Clinical experience with leflunomide in rheumatoid arthritis. Leflunomide Investigators’ Group. J Rheumatol Suppl. 1998 Jul;53:27–32.
   PubMedGoogle Scholar
• Temprano KK, Bandlamudi R, Moore TL. Antirheumatic drugs in pregnancy and lactation. Semin Arthritis Rheum. 2005 Oct;35(2):112–121.
   PubMed Web of Science ®Google Scholar
• Brunner HI, Huggins J, Klein-Gitelman MS. Pediatric SLE–towards a comprehensive management plan. Nat Rev Rheumatol. 2011 Apr;7(4):225–233.
   PubMed Web of Science ®Google Scholar
• Brewer EJ, Giannini EH, Kuzmina N, et al. Penicillamine and hydroxychloroquine in the treatment of severe juvenile rheumatoid arthritis. Results of the U.S.A.-U.S.S.R. double-blind placebo-controlled trial. N Engl J Med. 1986 May 15;314(20):1269–1276.
   PubMed Web of Science ®Google Scholar
• Giannini EH, Brewer EJ, Kuzmina N, et al. Characteristics of responders and nonresponders to slow-acting antirheumatic drugs in juvenile rheumatoid arthritis. Arthritis Rheum. 1988 Jan;31(1):15–20.
   PubMed Web of Science ®Google Scholar
• Rynes RI. Antimalarial drugs in the treatment of rheumatological diseases. Br J Rheumatol. 1997 Jul;36(7):799–805.
   PubMedGoogle Scholar
• Marmor MF, Kellner U, Lai TY, et al. Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology. 2011 Feb;118(2):415–422.
   PubMed Web of Science ®Google Scholar
• True DG, Bryant LR, Harris MD, et al. Clinical images: Hydroxychloroquine-associated mucocutaneous hyperpigmentation. Arthritis Rheum. 2002 Jun;46(6):1698.
   PubMedGoogle Scholar
• Kemmenoe AV. An infant fatality due to hydroxychloroquine poisoning. J Anal Toxicol. 1990 May-Jun;14(3):186–188.
   PubMed Web of Science ®Google Scholar
• Markowitz HA, McGinley JM. Chloroquine Poisoning in a Child. JAMA. 1964 Sep 21;189:950–951.
   PubMed Web of Science ®Google Scholar
• Kvien TK, Høyeraal HM, Sandstad B. Azathioprine versus placebo in patients with juvenile rheumatoid arthritis: a single center double blind comparative study. J Rheumatol. 1986 Feb;13(1):118–123.
   PubMed Web of Science ®Google Scholar
• Gerloni V, Cimaz R, Gattinara M, et al. Efficacy and safety profile of cyclosporin A in the treatment of juvenile chronic (idiopathic) arthritis. Results of a 10-year prospective study. Rheumatology (Oxford). 2001 Aug;40(8):907–913.
   PubMed Web of Science ®Google Scholar
• Reiff A, Rawlings DJ, Shaham B, et al. Preliminary evidence for cyclosporin A as an alternative in the treatment of recalcitrant juvenile rheumatoid arthritis and juvenile dermatomyositis. J Rheumatol. 1997 Dec;24(12):2436–2443.
   PubMed Web of Science ®Google Scholar
• Ruperto N, Ravelli A, Castell E, et al. Cyclosporine A in juvenile idiopathic arthritis. Results of the PRCSG/PRINTO phase IV post marketing surveillance study. Clin Exp Rheumatol. 2006 Sep-Oct;24(5):599–605.
   PubMed Web of Science ®Google Scholar
• Mouy R, Stephan JL, Pillet P, et al. Efficacy of cyclosporine A in the treatment of macrophage activation syndrome in juvenile arthritis: report of five cases. J Pediatr. 1996 Nov;129(5):750–754.
   PubMed Web of Science ®Google Scholar
• Henter JI, Horne A, Arico M, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007 Feb;48(2):124–131.
   PubMed Web of Science ®Google Scholar
• Savolainen HA. Chlorambucil in severe juvenile chronic arthritis: longterm followup with special reference to amyloidosis. J Rheumatol. 1999 Apr;26(4):898–903.
   PubMed Web of Science ®Google Scholar
• Lehman TJ, Schechter SJ, Sundel RP, et al. Thalidomide for severe systemic onset juvenile rheumatoid arthritis: A multicenter study. J Pediatr. 2004 Dec;145(6):856–857.
   PubMed Web of Science ®Google Scholar
• Hayward K, Wallace CA. Recent developments in anti-rheumatic drugs in pediatrics: treatment of juvenile idiopathic arthritis. Arthritis Res Ther. 2009;11(1):216.
   PubMed Web of Science ®Google Scholar
• Goebel JC, Roesel M, Heinz C, et al. Azathioprine as a treatment option for uveitis in patients with juvenile idiopathic arthritis. Br J Ophthalmol. 2011 Feb;95(2):209–213.
   PubMed Web of Science ®Google Scholar
• Foeldvari I, Nielson S, Tzaribachev T, et al. Results of a Multinational Survey Regarding the use of Cyclosporine A in the Treatment of Juvenile Idiopathic Arthritis associated Uveitis. Ann Rheum Dis. 2006;65(Suppl. II):251.
   Google Scholar
• Tappeiner C, Roesel M, Heinz C, et al. Limited value of cyclosporine A for the treatment of patients with uveitis associated with juvenile idiopathic arthritis. Eye (Lond). 2009 May;23(5):1192–1198.
   PubMed Web of Science ®Google Scholar
• Heiligenhaus A, Mingels A, Heinz C, et al. Methotrexate for uveitis associated with juvenile idiopathic arthritis: value and requirement for additional anti-inflammatory medication. Eur J Ophthalmol. 2007 Sep-Oct;17(5):743–748.
   PubMed Web of Science ®Google Scholar
• Fleischmann R, Kremer J, Cush J, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med. 2012 Aug 9;367(6):495–507.
   PubMed Web of Science ®Google Scholar
• Van Vollenhoven RF, Fleischmann R, Cohen S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med. 2012 Aug 9;367(6):508–519.
   PubMed Web of Science ®Google Scholar
• Simmons DL. Targeting kinases: a new approach to treating inflammatory rheumatic diseases. Curr Opin Pharmacol. 2013 Jun;13(3):426–434.
   PubMed Web of Science ®Google Scholar
• Pfizer. Pharmacokinetics of CP-690,550 in pediatric patients with juvenile idiopathic arthritis (JIA). 2013 [updated 2015 Aug 21; cited 2015 Sep 20]. Available from: https://clinicaltrials.gov/ct2/show/NCT01513902
   Google Scholar
• Pfizer. Long-term safety study of CP-690,550 in patients with juvenile idiopathic arthritis. 2013 [updated 2013 Dec 25; cited 2015 Sep 20]. Available from: https://clinicaltrials.gov/ct2/show/NCT01500551.
   Google Scholar
• Weinblatt ME, Kavanaugh A, Genovese MC, et al. Effects of fostamatinib (R788), an oral spleen tyrosine kinase inhibitor, on health-related quality of life in patients with active rheumatoid arthritis: analyses of patient-reported outcomes from a randomized, double-blind, placebo-controlled trial. J Rheumatol. 2013 Apr;40(4):369–378.
   PubMed Web of Science ®Google Scholar
• Weinblatt ME, Kavanaugh A, Genovese MC, et al. An oral spleen tyrosine kinase (Syk) inhibitor for rheumatoid arthritis. N Engl J Med. 2010 Sep 30;363(14):1303–1312.
   PubMed Web of Science ®Google Scholar
• Genovese MC, Van Der Heijde DM, Keystone EC, et al. A phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study of 2 dosing regimens of fostamatinib in patients with rheumatoid arthritis with an inadequate response to a tumor necrosis factor-α antagonist. J Rheumatol. 2014 Nov;41(11):2120–2128.
   PubMed Web of Science ®Google Scholar
• Dueckers G, Guellac N, Arbogast M, et al. Evidence and consensus based GKJR guidelines for the treatment of juvenile idiopathic arthritis. Clin Immunol. 2012 Feb;142(2):176–193.
   PubMed Web of Science ®Google Scholar
• Ringold S, Weiss PF, Beukelman T, et al. 2013 update of the 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: recommendations for the medical therapy of children with systemic juvenile idiopathic arthritis and tuberculosis screening among children receiving biologic medications. Arthritis Rheum. 2013 Oct;65(10):2499–2512.
   PubMed Web of Science ®Google Scholar
• Practitioners TRACoG. Clinical guideline for the diagnosis and management of juvenile idiopathic arthritis. South Melbourne: The Royal Australian College of General Practitioners; 2009 Aug.
   Google Scholar
• Bader-Meunier B, Wouters C, Job-Deslandre C, et al. Recommandations pour le diagnostic et le traitement de la forme systémique d’arthrite juvénile idiopathique. Arch Pediatr. 2010 Jul;17(7):1085–1089.
   PubMed Web of Science ®Google Scholar
• DeWitt EM, Kimura Y, Beukelman T, et al. Consensus treatment plans for new-onset systemic juvenile idiopathic arthritis. Arthritis Care Res (Hoboken). 2012 Jul;64(7):1001–1010.
   PubMed Web of Science ®Google Scholar
• Ringold S, Weiss PF, Colbert RA, et al. Childhood Arthritis and Rheumatology Research Alliance consensus treatment plans for new-onset polyarticular juvenile idiopathic arthritis. Arthritis Care Res (Hoboken). 2014 Jul;66(7):1063–1072.
   PubMed Web of Science ®Google Scholar
• Ilowite NT, Laxer RM. Pharmacology and drug therapy. In: Cassidy JT, Petty R, Laxer RM, et al., editors. Textbook of pediatric rheumatology. 6th ed. Philadelphia (PA): Elsevier; 2011. p. 71–126.
   Google Scholar
• Landewe RB, Boers M, Verhoeven AC, et al. COBRA combination therapy in patients with early rheumatoid arthritis: long-term structural benefits of a brief intervention. Arthritis Rheum. 2002 Feb;46(2):347–356.
   PubMed Web of Science ®Google Scholar
• Mottonen T, Hannonen P, Leirisalo-Repo M, et al. Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial. FIN-RACo trial group. Lancet. 1999 May 8;353(9164):1568–1573.
   PubMed Web of Science ®Google Scholar
• Cannella AC, O’Dell JR. Is there still a role for traditional disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis? Curr Opin Rheumatol. 2003 May;15(3):185–192.
   PubMed Web of Science ®Google Scholar
• Wallace CA. On beyond methotrexate treatment of severe juvenile rheumatoid arthritis. Clin Exp Rheumatol. 1999 Jul-Aug;17(4):499–504.
   PubMed Web of Science ®Google Scholar
• Ravelli A, Martini A. Methotrexate in juvenile idiopathic arthritis: answers and questions. J Rheumatol. 2000 Aug;27(8):1830–1833.
   PubMed Web of Science ®Google Scholar
• Jansen G, Van Der Heijden J, Oerlemans R, et al. Sulfasalazine is a potent inhibitor of the reduced folate carrier: implications for combination therapies with methotrexate in rheumatoid arthritis. Arthritis Rheum. 2004 Jul;50(7):2130–2139.
   PubMed Web of Science ®Google Scholar
• Carmichael SJ, Beal J, Day RO, et al. Combination therapy with methotrexate and hydroxychloroquine for rheumatoid arthritis increases exposure to methotrexate. J Rheumatol. 2002 Oct;29(10):2077–2083.
   PubMed Web of Science ®Google Scholar
• Haapasaari J, Kautiainen H, Isomaki H, et al. Hydroxychloroquine does not decrease serum methotrexate concentrations in children with juvenile idiopathic arthritis. Arthritis Rheum. 2005 May;52(5):1621–1622.
   PubMed Web of Science ®Google Scholar
• Quesada-Masachs E, Castillo M, Avila G, et al. AB0681 Treatment with methotrexate plus leflunomide for juvenile idiopathic arthritis. Ann Rheum Dis. 2013;72(Suppl 3):A996.
   Google Scholar
• Alexeieva YI, Valieva SI, Bzarova TM, et al. [FRI0160] combination of cyclosporine a and methotrexate in children with refractory juvenile idiopathic arthritis (JIA). Ann Rheum Dis. 2006;65(Suppl II):335.
   PubMed Web of Science ®Google Scholar
• Brunner HI, Ruperto N, Zuber Z, et al. Efficacy and safety of tocilizumab in patients with polyarticular-course juvenile idiopathic arthritis: results from a phase 3, randomised, double-blind withdrawal trial. Ann Rheum Dis. 2015 Jun;74(6):1110–1117.
   PubMed Web of Science ®Google Scholar
• Lovell DJ, Giannini EH, Reiff A, et al. Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group. N Engl J Med. 2000 Mar 16;342(11):763–769.
   PubMed Web of Science ®Google Scholar
• Lovell DJ, Ruperto N, Goodman S, et al. Adalimumab with or without methotrexate in juvenile rheumatoid arthritis. N Engl J Med. 2008 Aug 21;359(8):810–820.
   PubMed Web of Science ®Google Scholar
• 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 Aug 2;372(9636):383–391.
   PubMed Web of Science ®Google Scholar
• Krieckaert CL, Nurmohamed MT, Wolbink GJ. Methotrexate reduces immunogenicity in adalimumab treated rheumatoid arthritis patients in a dose dependent manner. Ann Rheum Dis. 2012 Nov;71(11):1914–1915.
   PubMed Web of Science ®Google Scholar
• Administration UFaD. Drugs@FDA. 2015 [cited 2015 Sep 22]. Available from: http/www.accessdata.fda.gov/scripts/cder/drugsatdfa/.
   Google Scholar
• Cochino A, Crigorescu Sido P, Miu N, et al. [THU0413] combination therapy with etanercept and methotrexate in children with juvenile idiopathic arthritis. Ann Rheum Dis. 2008;67(Suppl II):266.
   PubMed Web of Science ®Google Scholar
• Horneff G, Schmalbach T, Foeldvari I, et al. [SAT0428] no benefit of combination of etanercept and methotrexate compared to etanercept mono therapy in juvenile idiopathic arthritis (JIA) - a matched pair analysis. Ann Rheum Dis. 2010;69(Suppl 3):626.
   Google Scholar
• Ramanan AV, Dick AD, Benton D, et al. A randomised controlled trial of the clinical effectiveness, safety and cost-effectiveness of adalimumab in combination with methotrexate for the treatment of juvenile idiopathic arthritis associated uveitis (SYCAMORE Trial). Trials. 2014;15:14.
   PubMed Web of Science ®Google Scholar
• Finckh A, Dehler S, Gabay C, et al. The effectiveness of leflunomide as a co-therapy of tumour necrosis factor inhibitors in rheumatoid arthritis: a population-based study. Ann Rheum Dis. 2009 Jan;68(1):33–39.
   PubMed Web of Science ®Google Scholar
• Zink A, Strangfeld A, Herzer P, et al. Leflunomide is an acceptable combination partner for TNF inhibitors if methotrexate is not tolerated - results from the German Biologics register. Arthritis Rheum. 2007;56(Suppl):S181.
   Google Scholar
• Horneff G, Foeldvari I, Group PRCS. [THU0422] safety and efficacy of combination therapy with etanercept and leflunomide in active juvenile idiopathic arthritis. Ann Rheum Dis. 2008;67(Suppl II):268.
   Google Scholar
• Narvaez J, Diaz-Torne C, Magallares B, et al. Comparative effectiveness of tocilizumab with either methotrexate or leflunomide in the treatment of rheumatoid arthritis. PLoS One. 2015;10(4):e0123392.
   Google Scholar
• Combe B, Codreanu C, Fiocco U, et al. Etanercept and sulfasalazine, alone and combined, in patients with active rheumatoid arthritis despite receiving sulfasalazine: a double-blind comparison. Ann Rheum Dis. 2006 Oct;65(10):1357–1362.
   PubMed Web of Science ®Google Scholar
• Fisher BA, Taylor PC. Etanercept plus sulfasalazine: added value in rheumatoid arthritis? Nat Clin Pract Rheumatol. 2007 Feb;3(2):70–71.
   PubMedGoogle Scholar
• Wallace CA, Giannini EH, Spalding SJ, et al. Trial of early aggressive therapy in polyarticular juvenile idiopathic arthritis. Arthritis Rheum. 2012 Jun;64(6):2012–2021.
   PubMed Web of Science ®Google Scholar
• Wallace CA, Giannini EH, Spalding SJ, 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 Jun;41(6):1163–1170.
   PubMed Web of Science ®Google Scholar
• Wallace CA, Ringold S, Bohnsack J, et al. Extension study of participants from the trial of early aggressive therapy in juvenile idiopathic arthritis. J Rheumatol. 2014 Dec;41(12):2459–2465.
   PubMed Web of Science ®Google Scholar
• Graham LD, Myones BL, Rivas-Chacon RF, et al. Morbidity associated with long-term methotrexate therapy in juvenile rheumatoid arthritis. J Pediatr. 1992 Mar;120(3):468–473.
   PubMed Web of Science ®Google Scholar
• American College of Rheumatology Subcommittee on Rheumatoid Arthritis G. Guidelines for the management of rheumatoid arthritis: 2002 Update. Arthritis Rheum. 2002 Feb;46(2):328–346.
   PubMedGoogle Scholar
• Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008 Jun 15;59(6):762–784.
   PubMed Web of Science ®Google Scholar
• van Riel PL, Smolen JS, Emery P, et al. Leflunomide: a manageable safety profile. J Rheumatol Suppl. 2004;71:21–24.
   PubMedGoogle Scholar
• Heijstek MW, Ott De Bruin LM, Bijl M, et al. EULAR recommendations for vaccination in paediatric patients with rheumatic diseases. Ann Rheum Dis. 2011 Oct;70(10):1704–1712.
   PubMed Web of Science ®Google Scholar
• Kapetanovic MC, Saxne T, Sjoholm A, et al. Influence of methotrexate, TNF blockers and prednisolone on antibody responses to pneumococcal polysaccharide vaccine in patients with rheumatoid arthritis. Rheumatology (Oxford). 2006 Jan;45(1):106–111.
   PubMed Web of Science ®Google Scholar
• Vastert SJ, De Jager W, Noordman BJ, et al. Effectiveness of first-line treatment with recombinant interleukin-1 receptor antagonist in steroid-naive patients with new-onset systemic juvenile idiopathic arthritis: results of a prospective cohort study. Arthritis Rheumatol. 2014 Apr;66(4):1034–1043.
   PubMed Web of Science ®Google Scholar
• Kingsley GH, Kowalczyk A, Taylor H, et al. A randomized placebo-controlled trial of methotrexate in psoriatic arthritis. Rheumatology (Oxford). 2012 Aug;51(8):1368–1377.
   PubMed Web of Science ®Google Scholar