Tumor necrosis factor-alpha (TNF-α) inhibitors are effective treatment for juvenile idiopathic arthritis (JIA) but may increase infection rates. However, active JIA may also render patients vulnerable to infection. In this study, we prospectively assessed infection rates in JIA patients treated with and without TNF-α inhibitors and correlated disease activity with infection risk. TNF-α inhibitor-naïve JIA subjects were followed up for 12 months. Subjects initiated on TNF-α inhibitors after enrollment were analyzed in the TNF group. Subjects treated without TNF-α inhibitors were analyzed in the non-TNF group. Questionnaires captured mild or severe infections. JIA disease activity by Childhood Health Assessment Questionnaire (CHAQ) disability index/pain score and physician joint count/global assessment was recorded. Twenty TNF and 36 non-TNF subjects were analyzed. The total infection rate ratio for TNF versus non-TNF group subjects was 1.14 (95 % CI, 0.78–1.66; p = 0.51). The average rate of infections per month was 0.29 for TNF and 0.24 for non-TNF subjects. No severe infections or hospitalizations occurred in either group. Secondary infectious outcomes were also similar between groups. Controlling for study group, an increase in CHAQ pain score correlated with an increase in several infectious outcome measures. Our results suggest no difference in infection rates between JIA subjects treated with and without TNF-α inhibitors. Additionally, JIA disease activity may have contributed to infection risk in our cohort, irrespective of immunosuppressive therapy. Future analysis of the relationship between treatment regimens, disease activity, and infection rates may help to further delineate predictors of infection risk in JIA patients.
This is a preview of subscription content, log in to check access.
Study data were collected and managed using Research Electronic Data Capture (REDCap) tools hosted at Weill Cornell Medical College. REDCap is a secure, web-based application designed to support data capture for research studies. Grant support (CTSC GRANT UL1-RR024996) has been used to fund REDCap at this institution. We acknowledge Dr. Zhengming Chen for his contribution to parts of our statistical analysis. We also acknowledge Dr. Farzana Nuruzzaman, Dr. Sarah Taber, and Chahait Singh for their contributions to subject recruitment and data collection.
This study was approved by the Institutional Review Board at the Hospital for Special Surgery and was therefore performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All persons gave their informed consent prior to their inclusion in the study. Informed consent was provided by legal guardians for all minors under the age of 18 years. All persons between the ages of 7 and 17 years gave their assent prior to their inclusion in the study.
Ruperto N, Lovell DJ, Cuttica R, Wilkinson N, Woo P, Espada G et al (2007) A randomized, placebo-controlled trial of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis. Arthritis Rheum 56:3096–3106CrossRefPubMedGoogle Scholar
Gerloni V, Pontikaki I, Gattinara M, Fantini F (2008) 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 67:1145–1152CrossRefPubMedGoogle Scholar
Lovell DJ, Giannini EH, Reiff A, Cawkwell GD, Silverman ED, Nocton JJ et al (2000) Etanercept in children with polyarticular juvenile rheumatoid arthritis. N Engl J Med 342:763–769CrossRefPubMedGoogle Scholar
Lovell DJ, Reiff A, Ilowite NT, Wallace CA, Chon Y, Lin S et al (2008) Safety and efficacy of up to eight years of continuous etanercept therapy in patients with juvenile rheumatoid arthritis. Arthritis Rheum 58:1496–1504CrossRefPubMedGoogle Scholar
Lovell DJ, Ruperto N, Goodman S, Reiff A, Jung L, Jarosova K (2008) Adalimumab with or without methotrexate in juvenile rheumatoid arthritis. N Engl J Med 359:810–820CrossRefPubMedGoogle Scholar
Bracaglia C, Buonuomo PS, Tozzi AE, Pardeo M, Nicolai R, Campana A et al (2012) Safety and efficacy of etanercept in a cohort of patients with juvenile idiopathic arthritis under 4 years of age. J Rheumatol 39:1287–1290CrossRefPubMedGoogle Scholar
Mori M, Takei S, Imagawa T, Imanaka H, Nerome Y, Higuchi R et al (2012) Safety and efficacy of long-term etanercept in the treatment of methotrexate-refractory polyarticular-course juvenile idiopathic arthritis in Japan. Mod Rheumatol 22:720–726CrossRefPubMedGoogle Scholar
Hashkes PJ, Uziel Y, Laxer RM (2010) The safety profile of biologic therapies for juvenile idiopathic arthritis. Nat Rev Rheumatol 6:561–571CrossRefPubMedGoogle Scholar
Toussi SS, Pan N, Walters HM, Walsh TJ (2013) Infections in children and adolescents with juvenile idiopathic arthritis and inflammatory bowel disease treated with tumor necrosis factor-α inhibitors: systematic review of the literature. Clin Infect Dis 57:1318–1330CrossRefPubMedCentralPubMedGoogle Scholar
Smitten AL, Choi HK, Hochberg MC, Suissa S, Simon T, Testa M et al (2008) The risk of hospitalized infection in patients with rheumatoid arthritis. J Rheumatol 35:387–393PubMedGoogle Scholar
Doran MF, Crowson CS, Pond GR, O’Fallon WM, Gabriel SE (2002) Frequency of infection in patients with rheumatoid arthritis compared with controls: a population-based study. Arthritis Rheum 46:2287–2293CrossRefPubMedGoogle Scholar
Au K, Reed G, Curtis JR, Kremer J, Jeffrey G, Strand V et al (2011) High disease activity is associated with an increased risk of infection in patients with rheumatoid arthritis. Ann Rheum Dis 70:785–791CrossRefPubMedGoogle Scholar
Beukelman T, Xie F, Chen L, Baddley JW, Delzell E, Grijalva CG et al (2012) Rates of hospitalized bacterial infection associated with juvenile idiopathic arthritis and its treatment. Arthritis Rheum 64:2773–2780CrossRefPubMedCentralPubMedGoogle Scholar
Beukelman T, Xie F, Baddley JW, Chen L, Delzell E, Grijalva CG et al (2013) Brief report: incidence of selected opportunistic infections among children with juvenile idiopathic arthritis. Arthritis Rheum 65:1384–1389CrossRefPubMedCentralPubMedGoogle Scholar
Furst DE (2010) The risk of infections with biologic therapies for rheumatoid arthritis. Semin Arthritis Rheum 39:327–346CrossRefPubMedGoogle Scholar
Crum NF, Lederman ER, Wallace MR (2005) Infections associated with tumor necrosis factor-alpha antagonists. Medicine (Baltimore) 84:291–302CrossRefGoogle Scholar
Listing J, Strangfeld A, Kary S, Rau R, von Hinueber U, Stoyanova-Scholz M et al (2005) Infections in patients with rheumatoid arthritis treated with biologic agents. Arthritis Rheum 52:3403–3412CrossRefPubMedGoogle Scholar
Askling J, Dixon W (2008) The safety of anti-tumour necrosis factor therapy in rheumatoid arthritis. Curr Opin Rheumatol 20:138–144CrossRefPubMedGoogle Scholar
Patkar NM, Teng GG, Curtis JR, Saag KG (2008) Association of infections and tuberculosis with antitumor necrosis factor alpha therapy. Curr Opin Rheumatol 20:320–326CrossRefPubMedGoogle Scholar
Salliot C, Gossec L, Ruyssen-Witrand A, Luc M, Duclos M, Guignard S et al (2007) Infections during tumour necrosis factor-alpha blocker therapy for rheumatic diseases in daily practice: a systematic retrospective study of 709 patients. Rheumatology (Oxford) 46:327–334CrossRefGoogle Scholar
Kroesen S, Widmer AF, Tyndall A, Hasler P (2003) Serious bacterial infections in patients with rheumatoid arthritis under anti-TNF-alpha therapy. Rheumatology (Oxford) 42:617–621CrossRefGoogle Scholar
Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V (2006) Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 295:2275–2285CrossRefPubMedGoogle Scholar
Giannini EH, Ilowite NT, Lovell DJ, Wallace CA, Rabinovich CE, Reiff A et al (2009) Long-term safety and effectiveness of etanercept in children with selected categories of juvenile idiopathic arthritis. Arthritis Rheum 60:2794–2804CrossRefPubMedGoogle Scholar
Horneff G, De Bock F, Foeldvari I, Girschick HJ, Michels H, Moebius D et al (2009) 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 68:519–525CrossRefPubMedGoogle Scholar
Kilic O, Kasapcopur O, Camcioglu Y, Cokugras H, Arisoy N, Akcakaya N (2012) Is it safe to use anti-TNF-α agents for tuberculosis in children suffering with chronic rheumatic disease? Rheumatol Int 32:2675–2679CrossRefPubMedGoogle Scholar
Mohan AK, Coté TR, Block JA, Manadan AM, Siegel JN, Braun MM (2004) Tuberculosis following the use of etanercept, a tumor necrosis factor inhibitor. Clin Infect Dis 39:295–299CrossRefPubMedGoogle Scholar
Wallis RS, Broder MS, Wong JY, Hanson ME, Beenhouwer DO (2004) Granulomatous infectious diseases associated with tumor necrosis factor antagonists. Clin Infect Dis 38:1261–1265CrossRefPubMedGoogle Scholar
Elbek O, Uyar M, Aydin N, Borekci S, Bayram N, Bayram H et al (2009) Increased risk of tuberculosis in patients treated with antitumor necrosis factor alpha. Clin Rheumatol 28:421–426CrossRefPubMedGoogle Scholar
Armbrust W, Kamphuis SSM, Wolfs TWF, Fiselier TJW, Nikkels PG, Kuis W et al (2004) Tuberculosis in a nine-year-old girl treated with infliximab for systemic juvenile idiopathic arthritis. Rheumatology (Oxford) 43:527–529CrossRefGoogle Scholar