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)

Athimalaipet V Ramanan, Andrew D Dick, Diana Benton, Sandrine Compeyrot-Lacassagne, Dalia Dawoud, Ben Hardwick, Helen Hickey, Dyfrig Hughes, Ashley Jones, Patricia Woo, Clive Edelsten, Michael W Beresford, SYCAMORE Trial Management Group, Athimalaipet V Ramanan, Andrew D Dick, Diana Benton, Sandrine Compeyrot-Lacassagne, Dalia Dawoud, Ben Hardwick, Helen Hickey, Dyfrig Hughes, Ashley Jones, Patricia Woo, Clive Edelsten, Michael W Beresford, SYCAMORE Trial Management Group

Abstract

Background: Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children. Children with JIA are at risk of inflammation of the uvea in the eye (uveitis). Overall, 20% to 25% of paediatric uveitis is associated with JIA. Major risk factors for development of uveitis in JIA are oligoarticular pattern of arthritis, an age at onset of arthritis of less than seven years of age, and antinuclear antibody positivity. In the initial stages of mild to moderate inflammation the uveitis is asymptomatic. This has led to current practice of screening all children with JIA for uveitis. Approximately 12% to 38% of patients with JIA develop uveitis in seven years following onset of arthritis. In 30% to 50% of children with JIA-associated uveitis structural complications are present at diagnosis. Furthermore about 50% to 75% of those with severe uveitis will eventually develop visual impairment secondary to ocular complications such as cataract and glaucoma. Defining the severity of inflammation and structural complications in uveitis patients is now possible following Standardised Uveitis Nomenclature (SUN) guidelines, and modified to incorporate the consensus of end point and outcome criteria into the design of randomised trials. Despite current screening and therapeutic options (pre-biologics) 10% to 15% of children with JIA-associated uveitis may develop bilateral visual impairment and certified legally blind. To date, there remains no controlled trial evidence of benefits of biologic therapy.

Methods/design: This study will randomise 154 patients aged 2 to 18 years with active JIA-associated uveitis (despite methotrexate (MTX) treatment for at least 12 weeks). All participants will be treated for 18 months, with follow up of 3 years from randomisation (continuing on MTX throughout). All participants will receive a stable dose of MTX and in addition either adalimumab (20 mg/0.8 ml for patients<30 kg or 40 mg/0.8 ml for patients weighing 30 kg or more, subcutaneous (s/c) injection every 2 weeks based on body weight), or placebo (0.8 ml as appropriate according to body weight) s/c injection every 2 weeks.

Discussion: This is the first randomised controlled trial that will assess the clinical effectiveness, safety and cost effectiveness of adalimumab in combination with methotrexate for the treatment of juvenile idiopathic arthritis associated uveitis.

Trial registration: ISRCTN10065623.

Figures

Figure 1
Figure 1
Schematic of trial design and patient journey. AE, adverse event; CRF, case report form; MTX, methotrexate; OPD, Outpatient Department; QoL, quality of life.

References

    1. Edelsten C, Reddy MA, Stanford MR, Graham EM. Visual loss associated with pediatric uveitis in English primary and referral centers. Am J Ophthalmol. 2003;135:676–680. doi: 10.1016/S0002-9394(02)02148-7.
    1. Smith JA, Mackensen F, Sen HN, Leigh JF, Watkins AS, Pyatetsky D, Tessler HH, Nussenblatt RB, Rosenbaum JT, Reed GF, Vitale S, Smith JR, Goldstein DA. Epidemiology and course of disease in childhood uveitis. Ophthalmology. 2009;116:1544–1551.e1. doi: 10.1016/j.ophtha.2009.05.002.
    1. Kanski JJ. Uveitis in juvenile chronic arthritis: incidence, clinical features and prognosis. Eye (Lond) 1988;2:641–645. doi: 10.1038/eye.1988.118.
    1. Kotaniemi K, Kautiainen H, Karma A, Aho K. Occurrence of uveitis in recently diagnosed juvenile chronic arthritis: a prospective study. Ophthalmology. 2001;108:2071–2075. doi: 10.1016/S0161-6420(01)00773-4.
    1. Saurenmann RK, Levin AV, Feldman BM, Rose JB, Laxer RM, Schneider R, Silverman ED. Prevalence, risk factors, and outcome of uveitis in juvenile idiopathic arthritis: a long-term followup study. Arthritis Rheum. 2007;56:647–657. doi: 10.1002/art.22381.
    1. Chia A, Lee V, Graham EM, Edelsten C. Factors related to severe uveitis at diagnosis in children with juvenile idiopathic arthritis in a screening program. Am J Ophthalmol. 2003;135:757–762. doi: 10.1016/S0002-9394(03)00225-3.
    1. Holland GN, Denove CS, Yu F. Chronic anterior uveitis in children: clinical characteristics and complications. Am J Ophthalmol. 2009;147:667–678.e5. doi: 10.1016/j.ajo.2008.11.009.
    1. Woreta F, Thorne JE, Jabs DA, Kedhar SR, Dunn JP. Risk factors for ocular complications and poor visual acuity at presentation among patients with uveitis associated with juvenile idiopathic arthritis. Am J Ophthalmol. 2007;143:647–655. doi: 10.1016/j.ajo.2006.11.025.
    1. Edelsten C, Lee V, Bentley CR, Kanski JJ, Graham EM. An evaluation of baseline risk factors predicting severity in juvenile idiopathic arthritis associated uveitis and other chronic anterior uveitis in early childhood. Br J Ophthalmol. 2002;86:51–56. doi: 10.1136/bjo.86.1.51.
    1. Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of Uveitis Nomenclature for reporting clinical data: results of the First International Workshop. Am J Ophthalmol. 2005;140:509–516.
    1. Thorne JE, Woreta F, Kedhar SR, Dunn JP, Jabs DA. Juvenile idiopathic arthritis-associated uveitis: incidence of ocular complications and visual acuity loss. Am J Ophthalmol. 2007;143:840–846. doi: 10.1016/j.ajo.2007.01.033.
    1. Wolf MD, Lichter PR, Ragsdale CG. Prognostic factors in the uveitis of juvenile rheumatoid arthritis. Ophthalmology. 1987;94:1242–1248. doi: 10.1016/S0161-6420(87)80007-6.
    1. de Boer J, Wulffraat N, Rothova A. Visual loss in uveitis of childhood. Br J Ophthalmol. 2003;87:879–884. doi: 10.1136/bjo.87.7.879.
    1. Takken T, van der Net JJ, Helders PPJM. Methotrexate for treating juvenile idiopathic arthritis. Cochrane Database Syst Rev. 2001;4 CD003129.
    1. Beresford MW, Baildam EM. New advances in the management of juvenile idiopathic arthritis—1: non-biological therapy. Arch Dis Child Educ Pract Ed. 2009;94:144–150. doi: 10.1136/adc.2008.144576.
    1. Foeldvari I, Wierk A. Methotrexate is an effective treatment for chronic uveitis associated with juvenile idiopathic arthritis. J Rheumatol. 2005;32:362–365.
    1. Weiss AH, Wallace CA, Sherry DD. Methotrexate for resistant chronic uveitis in children with juvenile rheumatoid arthritis. J Pediatr. 1998;133:266–268. doi: 10.1016/S0022-3476(98)70232-X.
    1. Yu EN, Meniconi ME, Tufail F, Baltatzis S, Foster CS. Outcomes of treatment with immunomodulatory therapy in patients with corticosteroid-resistant juvenile idiopathic arthritis-associated chronic iridocyclitis. Ocul Immunol Inflamm. 2005;13:353–360. doi: 10.1080/09273940590951061.
    1. Sharma SM, Dick AD, Ramanan AV. Non-infectious pediatric uveitis: An update on immunomodulatory management. Paediatr Drugs. 2009;11:229–241. doi: 10.2165/00148581-200911040-00002.
    1. Kalinina Ayuso V, van de Winkel EL, Rothova A, de Boer JH. Relapse rate of uveitis post-methotrexate treatment in juvenile idiopathic arthritis. Am J Ophthalmol. 2011;151:217–222. doi: 10.1016/j.ajo.2010.08.021.
    1. Doycheva D, Deuter C, Stuebiger N, Biester S, Zierhut M. Mycophenolate mofetil in the treatment of uveitis in children. Br J Ophthalmol. 2007;91:180–184. doi: 10.1136/bjo.2006.094698.
    1. Kilmartin DJ, Forrester JV, Dick AD. Cyclosporin A therapy in refractory non-infectious childhood uveitis. Br J Ophthalmol. 1998;82:737–742. doi: 10.1136/bjo.82.7.737.
    1. Dick AD, Forrester JV, Liversidge J, Cope AP. The role of tumour necrosis factor (TNF-α) in experimental autoimmune uveoretinitis (EAU) Prog Retin Eye Res. 2004;23:617–637. doi: 10.1016/j.preteyeres.2004.06.005.
    1. Imrie FR, Dick AD. Biologics in the treatment of uveitis. Curr Opin Ophthalmol. 2007;18:481–486. doi: 10.1097/ICU.0b013e3282f03d42.
    1. Smith JR, Hart PH, Coster DJ, Williams KA. Mice deficient in tumor necrosis factor receptors p55 and p75, interleukin-4, or inducible nitric oxide synthase are susceptible to endotoxin-induced uveitis. Invest Ophthalmol Vis Sci. 1998;39:658–661.
    1. Koizumi K, Poulaki V, Doehmen S, Welsandt G, Radetzky S, Lappas A, Kociok N, Kirchhof B, Joussen AM. Contribution of TNF-α to leukocyte adhesion, vascular leakage, and apoptotic cell death in endotoxin-induced uveitis in vivo. Invest Ophthalmol Vis Sci. 2003;44:2184–2191. doi: 10.1167/iovs.02-0589.
    1. Diaz-Llopis M, García-Delpech S, Salom D, Udaondo P, Bosch-Morell F, Quijada A, Romero FJ, Amselem L. High-dose infliximab prophylaxis in endotoxin-induced uveitis. J Ocul Pharmacol Ther. 2007;23:343–350. doi: 10.1089/jop.2006.0148.
    1. Biester S, Deuter C, Michels H, Haefner R, Kuemmerle-Deschner J, Doycheva D, Zierhut M. Adalimumab in the therapy of uveitis in childhood. Br J Ophthalmol. 2007;91:319–324. doi: 10.1136/bjo.2006.103721.
    1. Foeldvari I, Nielsen S, Kümmerle-Deschner J, Espada G, Horneff G, Bica B, Olivieri AN, Wierk A, Saurenmann RK. Tumor necrosis factor-α blocker in treatment of juvenile idiopathic arthritis-associated uveitis refractory to second-line agents: results of a multinational survey. J Rheumatol. 2007;34:1146–1150.
    1. Gallagher M, Quinones K, Cervantes-Castañeda RA, Yilmaz T, Foster CS. Biological response modifier therapy for refractory childhood uveitis. Br J Ophthalmol. 2007;91:1341–1344. doi: 10.1136/bjo.2007.124081.
    1. Saurenmann RK, Levin AV, Rose JB, Parker S, Rabinovitch T, Tyrrell PN, Feldman BM, Laxer RM, Schneider R, Silverman ED. Tumour necrosis factor α inhibitors in the treatment of childhood uveitis. Rheumatology (Oxford) 2006;45:982–989. doi: 10.1093/rheumatology/kel030.
    1. Sharma SM, Ramanan AV, Riley P, Dick AD. Use of infliximab in juvenile onset rheumatological disease-associated refractory uveitis: efficacy in joint and ocular disease. Ann Rheum Dis. 2007;66:840–841. doi: 10.1136/ard.2006.065441.
    1. Tynjälä P, Kotaniemi K, Lindahl P, Latva K, Aalto K, Honkanen V, Lahdenne P. Adalimumab in juvenile idiopathic arthritis-associated chronic anterior uveitis. Rheumatology (Oxford) 2008;47:339–344.
    1. Schmeling H, Horneff G. Etanercept and uveitis in patients with juvenile idiopathic arthritis. Rheumatology (Oxford) 2005;44:1008–1011. doi: 10.1093/rheumatology/keh658.
    1. Smith JA, Thompson DJ, Whitcup SM, Suhler E, Clarke G, Smith S, Robinson M, Kim J, Barron KS. A randomized, placebo-controlled, double-masked clinical trial of etanercept for the treatment of uveitis associated with juvenile idiopathic arthritis. Arthritis Rheum. 2005;53:18–23. doi: 10.1002/art.20904.
    1. Hale S, Lightman S. Anti-TNF therapies in the management of acute and chronic uveitis. Cytokine. 2006;33:231–237. doi: 10.1016/j.cyto.2005.12.012.
    1. Saurenmann RK, Levin AV, Feldman BM, Laxer RM, Schneider R, Silverman ED. Risk of new-onset uveitis in patients with juvenile idiopathic arthritis treated with anti-TNFα agents. J Pediatr. 2006;149:833–836. doi: 10.1016/j.jpeds.2006.08.044.
    1. Taban M, Dupps WJ Jr, Mandell B, Perez VL. Etanercept (Enbrel)-associated inflammatory eye disease: case report and review of the literature. Ocul Immunol Inflamm. 2006;14:145–150. doi: 10.1080/09273940600659393.
    1. Lim LL, Fraunfelder FW, Rosenbaum JT. Do tumor necrosis factor inhibitors cause uveitis? A registry-based study. Arthritis Rheum. 2007;56:3248–3252. doi: 10.1002/art.22918.
    1. Keystone EC, Kavanaugh AF, Sharp JT, Tannenbaum H, Hua Y, Teoh LS, Fischkoff SA, Chartash EK. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum. 2004;50:1400–1411. doi: 10.1002/art.20217.
    1. Lovell DJ, Ruperto N, Goodman S, Reiff A, Jung L, Jarosova K, Nemcova D, Mouy R, Sandborg C, Bohnsack J, Elewaut D, Foeldvari I, Gerloni V, Rovensky J, Minden K, Vehe RK, Weiner LW, Horneff G, Huppertz HI, Olson NY, Medich JR, Carcereri-De-Prati R, McIlraith MJ, Giannini EH, Martini A. Pediatric Rheumatology Collaborative Study Group; Pediatric Rheumatology International Trials Organisation. Adalimumab with or without methotrexate in juvenile rheumatoid arthritis. N Engl J Med. 2008;359:810–820. doi: 10.1056/NEJMoa0706290.
    1. Vazquez-Cobian LB, Flynn T, Lehman TJ. Adalimumab therapy for childhood uveitis. J Pediatr. 2006;149:572–575. doi: 10.1016/j.jpeds.2006.04.058.
    1. US Food and Drug Administration (FDA) Information for Healthcare Professionals: Tumor Necrosis Factor (TNF) Blockers (marketed as Remicade, Enbrel, Humira, Cimzia, and Simponi) FDA Alert (4 August 2009). Available at (accessed 12 December 2013)
    1. Bernatsky S, Rosenberg A, Oen KG, Ramsey-Goldman R, St Pierre Y, Turnbull E, Clarke AE. Malignancy in juvenile idiopathic arthritis [abstract] Arthritis Rheum. 2009;60(Suppl 10):250. 10.1002/art.25333.
    1. McCroskery P, Wallace C, Lovell D, Stryker S, Chernyukhin N, Blosch C, Zack DJ. Summary of worldwide pediatric malignancies reported after exposure to etanercept [abstract] Ann Rheum Dis. 2010;69(Suppl 3):627.
    1. Harrison M, Cummins C, Horneff G, Southwood T, Mines D. Cancer risk in juvenile arthritis patients exposed to etanercept: results from three observational cohorts [abstract] Ann Rheum Dis. 2010;69(Suppl 3):147.
    1. Caspersen S, Elkjaer M, Riis L, Pedersen N, Mortensen C, Jess T, Sarto P, Hansen TS, Wewer V, Bendtsen F, Moesgaard F, Munkholm P. Danish Crohn Colitis Database. Infliximab for inflammatory bowel disease in Denmark 1999–2005: clinical outcome and follow-up evaluation of malignancy and mortality. Clin Gastroenterol Hepatol. 2008;6:1212–1217. doi: 10.1016/j.cgh.2008.05.010.
    1. de Vries HS, van Oijen MG, de Jong DJ. Serious events with infliximab in patients with inflammatory bowel disease: a 9-year cohort study in the Netherlands. Drug Saf. 2008;31:1135–1144.
    1. Kempen JH, Daniel E, Dunn JP, Foster CS, Gangaputra S, Hanish A, Helzlsouer KJ, Jabs DA, Kaçmaz RO, Levy-Clarke GA, Liesegang TL, Newcomb CW, Nussenblatt RB, Pujari SS, Rosenbaum JT, Suhler EB, Thorne JE. Overall and cancer related mortality among patients with ocular inflammation treated with immunosuppressive drugs: retrospective cohort study. BMJ. 2009;339:b2480. doi: 10.1136/bmj.b2480.
    1. Nam JL, Winthrop KL, van Vollenhoven RF, Pavelka K, Valesini G, Hensor EMA, Worthy G, Landewé R, Smolen JS, Emery P, Buch MH. Current evidence for the management of rheumatoid arthritis with biological disease-modifying antirheumatic drugs: a systematic literature review informing the EULAR recommendations for the management of RA. Ann Rheum Dis. 2010;69:976–986. doi: 10.1136/ard.2009.126573.
    1. Giannini EH, Ruperto N, Ravelli A, Lovell DJ, Felson DT, Martini A. Preliminary definition of improvement in juvenile arthritis. Arthritis Rheum. 1997;40:1202–1209.
    1. Oliveira S, Ravelli A, Pistorio A, Castell E, Malattia C, Prieur AM, Saad-Magalhães C, Murray KJ, Bae SC, Joos R, Foeldvari I, Duarte-Salazar C, Wulffraat N, Lahdenne P, Dolezalova P, de Inocencio J, Kanakoudi-Tsakalidou F, Hofer M, Nikishina I, Ozdogan H, Hashkes PJ, Landgraf JM, Martini A, Ruperto N. Pediatric Rheumatology International Trials Organization (PRINTO) Proxy-reported health-related quality of life of patients with juvenile idiopathic arthritis: the Pediatric Rheumatology International Trials Organization multinational quality of life cohort study. Arthritis Rheum. 2007;57:35–43. doi: 10.1002/art.22473.
    1. Wallace CA, Ruperto N, Giannini E. Childhood Arthritis and Rheumatology Research Alliance; Pediatric Rheumatology International Trials Organization; Pediatric Rheumatology Collaborative Study Group. Preliminary criteria for clinical remission for select categories of juvenile idiopathic arthritis. J Rheumatol. 2004;31:2290–2294.
    1. Magni-Manzoni S, Ruperto N, Pistorio A, Sala E, Solari N, Palmisani E, Cugno C, Bozzola E, Martini A, Ravelli A. Development and validation of a preliminary definition of minimal disease activity in patients with juvenile idiopathic arthritis. Arthritis Rheum. 2008;59:1120–1127. doi: 10.1002/art.23916.
    1. Ilowite NT. Update on biologics in juvenile idiopathic arthritis. Curr Opin Rheumatol. 2008;20:613–618. doi: 10.1097/BOR.0b013e3283060778.
    1. Ruperto N, Lovell DJ, Cuttica R, Wilkinson N, Woo P, Espada G, Wouters C, Silverman ED, Balogh Z, Henrickson M, Apaz MT, Baildam E, Fasth A, Gerloni V, Lahdenne P, Prieur AM, Ravelli A, Saurenmann RK, Gamir ML, Wulffraat N, Marodi L, Petty RE, Joos R, Zulian F, McCurdy D, Myones BL, Nagy K, Reuman P, Szer I, Travers S. et al.A randomized, placebo-controlled trial of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis. Arthritis Rheum. 2007;56:3096–3106. doi: 10.1002/art.22838.
    1. Department of Health. Reference Costs: 2011–12. Policy Paper (8 November 2012). Available at (accessed 12 December 2013)
    1. Curtis L. Unit Costs of Health & Social Care 2012. Kent, UK: University of Kent, Personal Social Services Research Unit; 2012. Available at (accessed 12 December 2013)
    1. Glick HA, Doshi JA, Sonnad SS, Polsky D. Economic Evaluation in Clinical Trials (Handbooks in Health Economic Evaluation) Oxford: Oxford University Press; 2007.
    1. Briggs A, Sculpher M, Claxton K. Decision Modelling for Health Economic Evaluation (Handbooks in Health Economic Evaluation) Oxford: Oxford University Press; 2006.
    1. Kotaniemi K, Arkela-Kautiainen M, Haapasaari J, Leirisalo-Repo M. Uveitis in young adults with juvenile idiopathic arthritis: a clinical evaluation of 123 patients. Ann Rheum Dis. 2005;64:871–874. doi: 10.1136/ard.2004.026955.
    1. Carvounis PE, Herman DC, Cha S, Burke JP. Incidence and outcomes of uveitis in juvenile rheumatoid arthritis, a synthesis of the literature. Graefes Arch Clin Exp Ophthalmol. 2006;244:281–290. doi: 10.1007/s00417-005-0087-3.
    1. National Institute for Health and Care Excellence (NICE) Guide to the Methods of Technology Appraisal (Process and Methods Guides) London: NICE; 2013. Available at (accessed 12 December 2013)

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