Abstract
The treatment of juvenile idiopathic arthritis (JIA) has been revolutionized by the use of novel biologic agents that have much improved patients' short-term and, according to early evidence, long-term outcomes. Currently available biologic agents used to treat patients with JIA include tumor necrosis factor (TNF) blockers, various agents that target interleukin (IL)-1 and the IL-6 receptor, T-cell co-stimulation inhibitors and antibodies to B-lymphocyte antigen CD20. These agents are increasingly used early in the course of the disease (often in combination with other immunosuppressive medications) and often for long periods of time, as patients can be difficult to wean from their use. Safety concerns (especially the long-term effects of biologic therapy) are, therefore, being examined more closely. For instance, in 2009, the FDA issued a warning related to the development of malignancies in patients with JIA who had used anti-TNF medications for >2.5 years. In this Review, data related to the safety profile of all currently available biologic agents used to treat JIA are examined, with a particular focus on anti-TNF therapy, the most studied biologic agent for JIA. Safety issues that need further study, including the implementation of registries to monitor long-term drug safety, are also discussed.
Key Points
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The short-term safety of biologic agents used to treat juvenile idiopathic arthritis (JIA) seems to be good, even when they are used in combination with other DMARDs
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Most adverse events associated with short-term biologic therapy are related to injection-site or infusion reactions and common childhood infections
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Opportunistic infections (including with Mycobacterium species) and development of autoimmune disease seem to be rare in patients with JIA who are treated with biologic agents
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Individuals with JIA who are treated with biologic agents might have an increased risk of malignancies
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Large registries of long-term data are necessary to monitor rare adverse effects (particularly the development of malignancies and autoimmune diseases) that can be associated with some biologic therapies
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References
Hashkes, P. J. & Laxer, R. M. Medical treatment of juvenile idiopathic arthritis. JAMA 294, 1671–1684 (2005).
Wallace, C. A. & Levinson, J. E. Juvenile rheumatoid arthritis: outcome and treatment for the 1990s. Rheum. Dis. Clin. North Am. 17, 891–905 (1991).
Levinson, J. E. & Wallace, C. A. Dismantling the pyramid. J. Rheumatol. 19 (Suppl. 33), 6–10 (1992).
Giannini, E. H. & Cawkwell, G. D. Drug treatment in children with juvenile rheumatoid arthritis. Pediatr. Clin. North Am. 42, 1099–1125 (1995).
Prince, F. H. et al. When and how to stop etanercept after successful treatment of patients with juvenile idiopathic arthritis. Ann. Rheum. Dis. 68, 1228–1229 (2009).
Lovell, D. J. et al. Etanercept in children with polyarticular juvenile rheumatoid arthritis. N. Engl. J. Med. 342, 763–769 (2000).
Smith, J. A. et al. A randomized, placebo-controlled double-masked clinical trial of etanercept for the treatment of uveitis associated with juvenile idiopathic arthritis. Arthritis Rheum. 53, 18–23 (2005).
Lovell, D. J. et al. Long-term efficacy and safety of etanercept in children with polyarticular-course juvenile rheumatoid arthritis: interim results from an ongoing, multicenter, open-label, extended-treatment trial. Arthritis Rheum. 48, 218–226 (2003).
Lovell, D. J. et al. Long-term safety and efficacy of etanercept in children with polyarticular-course juvenile rheumatoid arthritis. Arthritis Rheum. 54, 1987–1994 (2006).
Lovell, D. J. et al. Safety and efficacy of up to eight years of continuous etanercept therapy in patients with juvenile rheumatoid arthritis. Arthritis Rheum. 58, 1496–1504 (2008).
Prince, F. H. et al. Long-term follow-up on effectiveness and safety of etanercept in JIA: the Dutch national register. Ann. Rheum. Dis. 68, 635–641 (2009).
Horneff, G. et al. The German etanercept registry for treatment of juvenile idiopathic arthritis. Ann. Rheum. Dis. 63, 1638–1644 (2004).
Horneff, G. et al. Safety and efficacy of combination of etanercept and methotrexate compared to treatment with etanercept only in patients with juvenile idiopathic arthritis (JIA). Preliminary data from the German JIA Registry. Ann. Rheum. Dis. 68, 519–525 (2009).
Gerloni, V., Pontikaki, I., Gattinara, M. & Fantini, F. Focus on adverse events of tumour necrosis factor alpha blockade in juvenile idiopathic arthritis in an open monocentric long-term prospective study of 163 patients. Ann. Rheum. Dis. 67, 1145–1152 (2008).
Quartier, P. et al. Efficacy of etanercept for the treatment of juvenile idiopathic arthritis according to the onset type. Arthritis Rheum. 48, 1093–1101 (2003).
Kuemmerle-Deschner, J. B. & Horneff, G. Safety and efficacy of once-weekly application of Etanercept in children with juvenile idiopathic arthritis. Rheumatol. Int. 28, 153–156 (2007).
Horneff, G. et al. Safety and efficacy of once weekly etanercept 0.8 mg/kg in a multicentre 12 week trial in active polyarticular course juvenile idiopathic arthritis. Rheumatology (Oxford) 48, 916–919 (2009).
Tzaribachev, N. Kuermmerle-Deschner, J., Eichner, M. & Horneff, G. Safety and efficacy of etanercept in children with juvenile idiopathic arthritis below the age of 4 years. Rheumatol. Int. 28, 1031–1034 (2008).
Takei, S. et al. Safety and efficacy of high dose etanercept in treatment of juvenile rheumatoid arthritis. J. Rheumatol. 28, 1677–1680 (2001).
Giannini, E. H. et al. Long-term safety and effectiveness of etanercept in children with selected categories of juvenile idiopathic arthritis. Arthritis Rheum. 60, 2794–2804 (2009).
Southwood, T. R. et al. Adverse events in juvenile idiopathic arthritis patients treated with etanercept or the combination of etanercept and methotrexate [abstract 137]. Arthritis Rheum. 52 (Suppl.), S85 (2005).
Lovell, D. J. et al. Adalimumab with or without methotrexate in juvenile rheumatoid arthritis N. Engl. J. Med. 359, 810–820 (2008).
Lovell, D. J. et al. Responses are maintained for up to 3 years of adalimumab treatment in polyarticular juvenile idiopathic arthritis [abstract 1187]. Arthritis Rheum. 58 (Suppl.), S609 (2008).
Burmester, G. R. et al. Adalimumab safety and mortality rates from global clinical trials of six immune-mediated inflammatory diseases. Ann. Rheum. Dis. 68, 1863–1869 (2009).
Durmoqicz, E. L. Pediatric focused safety review: adalimumab. FDA [online], (2010).
Ruperto, N. et al. A randomized, placebo-controlled trial of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis. Arthritis Rheum. 56, 3096–3106 (2007).
Ruperto, N. et al. Long-term efficacy and safety of infliximab plus methotrexate for the treatment of polyarticular course juvenile rheumatoid arthritis: findings from an open-label treatment extension. Ann. Rheum. Dis. 69, 718–722 (2010).
Zannin, M. et al. Safety and efficacy of anti-TNF agents in refractory uveitis in juvenile idiopathic arthritis: The Italian registry [abstract]. Arthritis Rheum. 60 (Suppl. 10), 260 (2009).
Lahdenne, P., Vähäsalo, P. & Honkanen, V. Infliximab or etanercept in the treatment of children with refractory juvenile idiopathic arthritis: on open label study. Ann. Rheum. Dis. 62, 245–247 (2003).
Tynjälä, P. Vähäsalo, P., Honkanen, V. & Lahdenne, P. Drug survival of the first and second course of anti-TNF agents in juvenile idiopathic arthritis. Ann. Rheum. Dis. 68, 552–557 (2009).
Armbrust, W. et al. Tuberculosis in a nine-year-old girl treated with infliximab for systemic juvenile idiopathic arthritis. Rheumatology 43, 527–529 (2004).
Saag, K. G. et al. American College of Rheumatology recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 59, 762–784 (2008).
Lee, J. H. et al. Life-threatening histoplasmosis complicating immunotherapy with tumor necrosis factor α antagonists infliximab and etanercept. Arthritis Rheum. 46, 2565–2570 (2002).
Kanakoudi-Tsakalidou, F., Tzimouli, V., Pratsidou-Gertsi, P., Chronopoulou, E. & Trachana, M. The significance of persistent newly developed autoantibodies in JIA patients under long-term anti-TNF treatment. Cytokine 42, 293–297 (2008).
Lepore, L., Marchetti, F., Facchini, S., Leone, V. & Ventura, A. Drug-induced systemic lupus erythematosus associated with etanercept therapy in a child with juvenile idiopathic arthritis. Clin. Exp. Rheumatol. 21, 276–277 (2003).
Bout-Tabaku, S., Rivas-Chacon, R. & Restrepo, R. Systemic lupus erythematosus in a patient treated with etanercept for polyarticular juvenile rheumatoid arthritis. J. Rheumatol. 34, 2503–2504 (2007).
Bloom, B. J. Development of diabetes mellitus during etanercept therapy in a child with systemic-onset juvenile rheumatoid arthritis. Arthritis Rheum. 43, 2606–2608 (2000).
Fathalla, B. M., Goldsmith, D. P., Pascasio, J. M. & Baldridge, A. Development of autoimmune hepatitis in a child with systemic-onset juvenile idiopathic arthritis during therapy with etanercept. J. Clin. Rheumatol. 14, 297–298 (2008).
Livermore, P. A. & Murray, K. J. Anti-tumour necrosis factor therapy associated with cutaneous vasculitis. Rheumatology (Oxford) 41, 1450–1452 (2002).
Hashkes, P. J. & Shajrawi, I. Sarcoid-related uveitis occurring during etanercept therapy. Clin. Exp. Rheumatol. 21, 645–646 (2003).
Ruemmele, F. M., Prieur, A. M., Talbotec, C., Goulet, O. & Schmitz, J. Development of Crohn disease during anti-TNF-α therapy in a child with juvenile idiopathic arthritis. J. Pediatr. Gastroenterol. Nutr. 39, 203–206 (2004).
Wiegering, V. . Morbach, H., Dick, A. & Girschick, H. J. Crohn's disease during etanercept therapy in juvenile idiopathic arthritis: a case report and review of the literature. Rheumatol. Int. 30, 801–804 (2010).
Mohan, N. et al. Demyelination occurring during anti-tumor necrosis factor α therapy for inflammatory arthritides. Arthritis Rheum. 44, 2862–2869 (2001).
Peek, R., Scott-Jupp, R. Strike, H., Clinch, J. & Ramanan, A. V. Psoriasis after treatment of juvenile idiopathic arthritis with etanercept. Ann. Rheum. Dis. 65, 1259 (2006).
Kimura, Y. et al. Etanercept treatment in patients with refractory systemic onset juvenile rheumatoid arthritis. J. Rheumatol. 32, 935–942 (2005).
Kuek, A., Hazleman, B. L., Gaston, J. H. & Ostör, A. J. Successful treatment of refractory polyarticular juvenile idiopathic arthritis with rituximab. Rheumatology (Oxford) 45, 1448–1449 (2006).
Tauber, T., Turetz, J. Barash, J., Avni, I. & Morad, Y. Optic neuritis associated with etanercept therapy for juvenile arthritis. JAAPOS 10, 26–29 (2006).
Saurenmann, R. K. et al. Risk of new-onset uveitis in patients with juvenile idiopathic arthritis treated with anti-TNFα agents. J. Pediatr. 149, 833–836 (2006).
Imundo, L. Hodgkin's lymphoma associated with anti-TNF use in juvenile idiopathic arthritis: supplemental case report. J. Rheumatol. 35, 1681 (2008).
Yildirim-Toruner, C., Kimura, Y. & Rabinovich, E. Hodgkin's lymphoma and tumor necrosis factor inhibitors in juvenile idiopathic arthritis. J. Rheumatol. 35, 1680–1681 (2008).
Diak, P. et al. Tumor necrosis factor α blockers and malignancy in children: forty-eight cases reported to the food and drug administration. Arthritis Rheum. 62, 2517–2524 (2010).
Bernatsky, S. et al. Malignancy in juvenile idiopathic arthritis [abstract 2533]. Arthritis Rheum. 60 (Suppl. 10), S250 (2009).
Ramanan, A. V. & Schneider, R. Macrophage activation syndrome following initiation of etanercept in a child with systemic onset juvenile rheumatoid arthritis. J. Rheumatol. 30, 401–403 (2003).
Pain, C. E. & McCann, L. J. Challenges in the management of juvenile idiopathic arthritis with etanercept. Biologics 3, 127–139 (2009).
de Oliveira, S. K. et al. Indications and adverse events with the use of anti-TNFα agents in pediatric rheumatology: experience of a single center. Acta Rheumatol. Port. 32, 139–150 (2007).
Hashkes, P. J. et al. Mortality outcomes in pediatric rheumatology in the US. Arthritis Rheum. 62, 599–608 (2010).
Ilowite, N. et al. Anakinra in the treatment of polyarticular-course juvenile rheumatoid arthritis: safety and preliminary efficacy results of a randomized multicenter study. Clin. Rheumatol. 28, 129–137 (2009).
Quartier, P. et al. A multicentric, double-blind trial of anakinra versus placebo in systemic-onset juvenile idiopathic arthritis (ANAJIS trial): efficacy and tolerance over 12 months [abstract 1245]. Arthritis Rheum. 58 (Suppl.), S632 (2008).
Zeft, A. et al. Anakinra for systemic juvenile arthritis: the Rocky Mountain experience. J. Clin. Rheumatol. 15, 161–164 (2009).
Lequerré, T. et al. Interleukin-1 receptor antagonist (anakinra) treatment in patients with systemic-onset juvenile idiopathic arthritis or adult onset Still disease: preliminary experience in France. Ann. Rheum. Dis. 67, 302–308 (2008).
Koné-Paut, I., Retornaz, K., Garnier, J. M. & Bader-Meunier, B. Visceral leishmaniasis in a patient with systemic juvenile arthritis treated by IL-1RA agonist (anakinra). Clin. Exp. Rheumatol. 25, 119 (2007).
Lovell, D. J. et al. Long-term safety and efficacy of rilonacept in patients with systemic juvenile idiopathic arthritis (SJIA) [abstract]. Arthritis Rheum. 60 (Suppl. 10), 2053 (2009).
Ruperto, N. et al. Evaluation of safety and preliminary efficacy of canakinumab (ACZ885), a new IL-1-β blocking monoclonal antibody, in children with systemic juvenile idiopathic arthritis (sJIA) [abstract]. Arthritis Rheum. 60 (Suppl. 10), 2055 (2009).
Ruperto, N. et al. Abatacept in children with juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled withdrawal trial. Lancet 372, 383–391 (2008).
Ruperto, N. et al. Long-term safety and efficacy of abatacept in children with juvenile idiopathic arthritis. Arthritis Rheum. 62, 1792–1802 (2010).
Durmoqicz, E. L. Pediatric focused safety review: abatecept. FDA [online], (2010).
Kuemmerle-Deschner, J. B. & Benseler, S. Abatacept in difficult-to-treat juvenile idiopathic arthritis. Biologics 2, 865–874 (2008).
Yokota, S. et al. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial. Lancet 371, 998–1006 (2008).
Woo, P. et al. Open label phase II trial of single, ascending doses of MRA in Caucasian children with severe systemic juvenile idiopathic arthritis: proof of principle of the efficacy of IL-6 receptor blockade in this type of arthritis and demonstration of prolonged clinical improvement. Arthritis Res. Ther. 7, R1281–R1288 (2005).
Imagawa, T. et al. Efficacy and safety of tocilizumab, an anti-IL-6 receptor monoclonal antibody, in patients with polyarticular or oligoarticular onset juvenile idiopathic arthritis [abstract]. Arthritis Rheum. 54, S168 (2006).
Narváez, J. et al. Rituximab therapy for refractory systemic-onset juvenile idiopathic arthritis. Ann. Rheum. Dis. 68, 607–608 (2009).
Kasher-Meron, M. et al. Successful treatment with B-cell depleting therapy for refractory systemic onset juvenile idiopathic arthritis: a case report. Rheumatology (Oxford) 48, 445–446 (2009).
Sen, H. N., Uziel, Y. & Amital, H. High-dose daclizumab for the treatment of juvenile idiopathic arthritis-associated active anterior uveitis. Am. J. Ophthalmol. 148, 696–703 (2009).
Medwatch: The FDA Safety and Information and Adverse Event reporting program. FDA [online], (2010).
Wallace, C. A., Hendrickson, A. F. & Sobel, R. E. Enhanced drug safety surveillance (EDSS) pilot project [abstract]. Arthritis Rheum. 60 (Suppl. 10), 249 (2009).
Paediatric Rheumatology European Society [online], (2010).
Paediatric Rheumatology International Trials Organisation [online], (2010).
Paediatric Rheumatology experts group meeting. Long-term PHARMacovigilance for adverse effects in childhood arthritis focusing on immune modulatory drugs. European Medicines Agency [online], (2010).
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P. J. Hashkes, Y. Uziel and R. M. Laxer contributed equally to all aspects of this manuscript.
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P. J. Hashkes has received speakers bureau (honoraria) from Novartis, has received medication for research purposes from Regeneron and is a consultant for URL Pharma. Y. Uziel has received speakers bureau (honoraria) from Abbott and research support from Novartis. R. M. Laxer declares no competing interests.
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Hashkes, P., Uziel, Y. & Laxer, R. The safety profile of biologic therapies for juvenile idiopathic arthritis. Nat Rev Rheumatol 6, 561–571 (2010). https://doi.org/10.1038/nrrheum.2010.142
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DOI: https://doi.org/10.1038/nrrheum.2010.142
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