From the *Paediatric Rheumatology Unit, and †Paediatric Infectious Diseases Unit, University Children’s Hospital Basel, Switzerland; and ‡Unit of Paediatric Immunology, Haematology and Rheumatology, Université Paris-Descartes and Hôpital Necker-Enfants Malades, Paris, France.
Accepted for publication December 11, 2012.
The authors have no funding or conflicts of interest to disclose.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.pidj.com).
The ESPID Reports and Reviews of Pediatric Infectious Diseases series topics, authors and contents are chosen and approved independently by the Editorial Board of ESPID.
Address for correspondence: Andreas Woerner, MD, University Children’s Hospital Basel, Spitalstrasse 33, CH-4031 Basel, Switzerland. E-mail: firstname.lastname@example.org.
Biological agents target specific components of the immune response that are dysregulated in autoimmune and autoinflammatory diseases. They bind to either cytokines, their receptors or cell surface molecules on antigen-presenting cells (Table, Supplemental Digital Content 1, http://links.lww.com/INF/B431). In children, biological agents have been licensed for use in a number of diseases, including juvenile idiopathic arthritis (JIA), inflammatory bowel disease and hereditary autoinflammatory syndromes. The spectrum of licensed biological agents and treatment recommendations agents vary between countries. Since the approval of the first biological agent more than a decade ago, they have contributed to major improvements in the prognosis of severe forms of autoimmune and autoinflammatory diseases in children. The increasing availability and evidence of efficacy of these agents has influenced treatment practice, with a trend toward earlier and longer-term use.1,2 Safety concerns have been raised, since first use of biological agents. A recent meta-analysis investigating the safety of 9 of the most commonly used biological agents in adults shows that the risk for serious infections (SIs) (usually defined as infections associated with death, hospitalization or use of intravenous antibiotics) and tuberculosis (TB) is increased under treatment with biological agents.3 However, evaluation of the safety of biological agents is complicated by the fact the underlying disease and severity of disease per se may increase the risk for infections.4 In addition, concomitant immune-modulatory medication including corticosteroids further influences the risk for infections.5 Extrapolation from adult data to children is difficult, as there are differences in the underlying diseases and disease severity and children have less comorbidity. This review summarizes the current evidence on the risk of infections in children treated with biological agents.
Serious Infections Under Tumor Necrosis Factor Inhibitor Treatment
Tumor necrosis factor (TNF) inhibitors were the first licensed biological agents and therefore evidence on safety and adverse effects is best for these agents.
Etanercept was the first licensed TNF inhibitor treatment approved for pediatric use, and it is the most extensively studied biological agent in children. The first randomized controlled trial (RCT) including pediatric patients with JIA receiving up to 8 years of treatment with etanercept reported 9 SI corresponding to 0.028 SI per patient-year (Table 1).6–9 Subsequent studies reported similar rates of SI ranging from 0.007 to 0.035 per patient-year.5,10–14 One of these studies also compared SI rates in different treatment groups including methotrexate alone, etanercept alone or etanercept plus methotrexate.11 Interestingly, the SI rates among the 3 treatment groups did not differ significantly. Contrasting results were found in another observational study including patients on etanercept alone or etanercept plus methotrexate.13 Both groups reported a similar proportion of nonserious infections; however, SI occurred in 1% of patients on etanercept alone compared with 5% of patients treated with etanercept plus methotrexate. The only study including children <4 years of age with JIA reported 2 varicella-zoster virus (VZV) infections, of which 1 case was complicated by necrotizing bacterial fasciitis.14 Neither patient had received prior VZV immunization. Another study also reported primary VZV infection during treatment with etanercept,7,13 and 3 studies reported herpes zoster infection.9,11,13
One of the most recent studies using Medicaid data from children with JIA also included a group without treatment.5 In the group with TNF inhibitor treatment, SI was highest but not significantly different to the methotrexate group. Importantly, the use of corticosteroids increased the risk for infection in all groups by two- to three-fold. In addition, this study also included a comparator group of children with attention deficit hyperactivity disorder, and showed that rates of SI were 2.8 times higher in children with JIA compared with children with attention deficit hyperactivity disorder.
The rates of SI in JIA patients treated with infliximab ranged from 0.007 to 0.081 per patient-year (Table 1).10,15,16 Pneumonia was the most common SI in both an RCT including 122 JIA patients and an observational study including 68 JIA patients.10,15,16 Other types of SI including gastrointestinal infections, sepsis and abscess were reported in a randomized open-label study in 112 patients with JIA.17,18 Additional case reports in pediatric inflammatory bowel disease patients reported other infections, including listeriosis, disseminated histoplasmosis and pneumocystis pneumonia.19,20
The rates of SI in JIA patients treated with adalimumab were similar to those treated with infliximab and ranged from 0.027 to 0.086 per patient-year (Table 1).21–24 The spectrum of SI was also similar in patients on adalimumab compared with infliximab with upper and lower respiratory infection, abscess and gastrointestinal infections being the most commonly reported. The most severe SI was reported in this group of biological agents leading to death in an 18-year-old woman with JIA.21 The patient had previously received adalimumab for 2 years, was switched to etanercept for 9 months because of waning response and subsequently restarted on adalimumab. Two months after the restart she presented with a febrile illness after returning from foreign travel (not further specified) and subsequently died in septic shock. No pathogen was identified. This case suggests a potential increased risk for SI when switching biological agents.
Reactivation of TB Under TNF Inhibitor Treatment
TNF plays a critical role in the host response and control of TB. Soon after the introduction of TNF inhibitor therapy, the first cases of TB reactivation with dissemination and fatal outcome were reported. Evidence from adult studies suggests that autoimmune and autoinflammatory diseases per se are associated with an increased risk of TB reactivation. Treatment with TNF inhibitor therapy further increases the risk in the majority of reported studies (summarized in Salgado et al25). In adults, reactivation usually occurs soon after initiation of treatment and rapid progressive courses have been described. Evidence from studies in adults suggests that the type of TNF inhibitor therapy influences the risk of reactivation with the highest risk being associated with TNF antibodies (infliximab and adalimumab) and a lower or negligible risk with soluble TNF receptor antibodies (etanercept).25 In children, only one RCT reported a case of asymptomatic pulmonary TB with tuberculin skin test conversion, infiltrates on chest radiography and positive polymerase chain reaction testing for Mycobacterium tuberculosis complex (Table 1).15,16 Infliximab was discontinued and pulmonary TB resolved after 9 months of antituberculous treatment. Additional case reports of TB reactivation in children treated with both infliximab and etanercept have been published.26–28
Current treatment guidelines therefore recommend screening for latent TB before starting TNF inhibitor treatment. Controversy remains about the best screening test and whether interferon-γ release assays may be more accurate than tuberculin skin tests. As there are concerns about the performance of interferon-γ release assays in children, some experts recommend performing both a tuberculin skin test and an interferon-γ release assay to achieve highest sensitivity.29 A positive result in one of the screening tests necessitates further investigations for active TB disease. If further investigations are suggestive of latent TB infection, isoniazid preventative therapy is recommended and start of TNF inhibitor therapy deferred for at least 1–2 months.30
Serious Infections Under Treatment With Other Biological Agents
Interleukin-1 Inhibition (Anakinra)
Only few studies including mostly children with JIA investigated the safety of anakinra. In 1 of the first studies including 86 patients with polyarticular JIA treated for a maximum of 40 weeks, 1 SI (hepatitis due to cytomegalovirus infection) was reported.31 In another study including 46 patients with systemic-onset JIA and a mean follow-up of 14.5 months, 3 SI occurred (one case each of parainfluenza infection, followed by pneumococcal bacteraemia; skin infection at a healed gastric feeding tube site; and pneumonia).32 A further RCT including 22 patients with systemic-onset JIA and a follow-up of 12 months, 44 infections (2.9 per patient-year) were described, none were classified by the authors as SI.33 Anakinra may also be used for treatment of severe autoinflammatory syndromes but safety information in this setting is scarce. A study of 12 patients with Muckle–Wells syndrome with a follow-up period of 11 months did not report any SI.34
Interleukin-6 Inhibition (Tocilizumab)
Safety data on tocilizumab mainly included children treated for systemic-onset JIA. An RCT in 56 children with systemic-onset JIA reported 2 SI (one infectious mononucleosis in the tocilizumab group and 1 herpes zoster infection in the placebo group).35 In the open-label extension of this study, 4 further SI were reported during 48 weeks (2 cases each of bronchitis and gastroenteritis). Another study including 112 children with systemic-onset JIA reported 15 SI after 52 weeks of treatment, of which 6 were considered to be related to tocilizumab (one case each of gastroenteritis, VZV infection, septic arthritis, otitis media, tonsillopharyngitis and upper respiratory tract infection).36
Inhibition of T-cell Costimulation (Abatacept)
Abatacept is used in patients with JIA who do not respond or tolerate TNF inhibitor treatment and therefore only few studies have investigated safety of this biological agent in children. In a double-blind randomized controlled withdrawal study including 190 patients with different JIA subtypes, no SI were reported.37 In the open-label extension of this study, including 153 patients with a median treatment duration of 2.9 years, 6 SI were reported (one case each of dengue fever, cellulitis, gastroenteritis, herpes zoster infection, bacterial meningitis and pyelonephritis).38
Inhibition of B-cells (Rituximab)
Rituximab is used for treatment of hematological and oncological disorders, vasculitis and for JIA patients with inadequate response to TNF inhibitor treatment. In an open-label prospective study including 55 children with JIA refractory to infliximab and other immunosuppressive therapy with a follow-up of 96 weeks, 8 SI were reported (all pneumonias—3 cases each of pneumocystis pneumonia or pneumocystis pneumonia and mycoplasma coinfection, and 2 cases with an unknown pathogen). An additional 18 nonsevere infections were recorded (8 cases of ear, nose and throat infections, 6 cases of skin infection, 4 cases of “herpes infection” not further specified).39
Prevention and Treatment of Serious Infections Under Biological Agents
There is limited guidance for the prevention and treatment of infections under biological agents. Acute infections should be treated before start of biological agents. Repeated and careful clinical evaluation during regular follow-ups is critical. Diagnosis of infections can be challenging, as clinical presentation may be atypical and symptoms including fever may be absent. Laboratory results, including white blood cells and C-reactive protein measurement, may also be influenced as a result of the underlying disease, the use of biological agents, corticosteroid or other immunosuppressive treatments. When a SI occurs, the biological agent is usually temporarily stopped and specific antimicrobial treatment initiated. Immunizations including those against VZV, influenza and pneumococcus before treatment with biological agents may be of benefit and are commonly recommended.40 However, evidence on safety and protective efficacy of such recommendations is limited.
Current evidence suggests that children with autoinflammatory or autoimmune diseases have an increased risk for infection. The relative contribution from the underlying disease, the treatment with biological agents and concomitant other immunomodulatory treatment to the risk of infection is unclear and generally the benefit of using a biologic agent outweighs the risk for infection. The risk of SI in children treated with biological agents is best studied for TNF inhibitor treatment. The most commonly reported SI were VZV primary infection or reactivation and invasive bacterial infections leading to pneumonia, bacteremia/septicemia, pyelonephritis, gastrointestinal and skin/wound infections. TB reactivation under TNF inhibitor treatment, commonly described in adult studies, seems to be a rare event in children. This may be a result of increased awareness of the risk of TB under biological agents, leading to improved screening practices in children. Additionally, most children receiving biological agents currently live in low TB prevalence countries and therefore have a reduced risk for TB exposure. Evidence on SI for children under treatment with other biological agents is limited.
In the future, data from national registries that include children receiving biological agents in combination with other immunosuppressive treatments, as well as long-term follow-up studies in children with autoimmune and autoinflammatory diseases, will be key to assessing the risk of infection. This information will be crucial for the selection of the optimal treatment while reducing the risk for infections. Until further evidence is available, clinicians need to be aware of and inform their patients about the potential for serious infections.
1. Martini A, Lovell DJ. Juvenile idiopathic arthritis: state of the art and future perspectives. Ann Rheum Dis. 2010;69:1260–1263
2. Wallace CA, Giannini EH, Spalding SJ, et al.Childhood Arthritis and Rheumatology Research Alliance. Trial of early aggressive therapy in polyarticular juvenile idiopathic arthritis. Arthritis Rheum. 2012;64:2012–2021
3. Singh JA, Wells GA, Christensen R, et al. Adverse effects of biologics: a network meta-analysis and Cochrane overview. Cochrane Database Syst Rev.. 2011:CD008794
4. Horneff G. Paediatric rheumatic disease: Biologic therapy and risk of infection in children with JIA. Nat Rev Rheumatol. 2012;8:504–505
5. Beukelman T, Xie F, Chen L, et al.SABER Collaboration. Rates of hospitalized bacterial infection associated with juvenile idiopathic arthritis and its treatment. Arthritis Rheum. 2012;64:2773–2780
6. 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;342:763–769
7. Lovell DJ, Giannini EH, Reiff A, et al.Pediatric Rheumatology Collaborative Study Group. 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. 2003;48:218–226
8. Lovell DJ, Reiff A, Jones OY, et al.Pediatric Rheumatology Collaborative Study Group. Long-term safety and efficacy of etanercept in children with polyarticular-course juvenile rheumatoid arthritis. Arthritis Rheum. 2006;54:1987–1994
9. Lovell DJ, Reiff A, Ilowite NT, et al.Pediatric Rheumatology Collaborative Study Group. Safety and efficacy of up to eight years of continuous etanercept therapy in patients with juvenile rheumatoid arthritis. Arthritis Rheum. 2008;58:1496–1504
10. Gerloni V, Pontikaki I, Gattinara M, et al. 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. 2008;67:1145–1152
11. Prince FH, Twilt M, ten Cate R, et al. Long-term follow-up on effectiveness and safety of etanercept in juvenile idiopathic arthritis: the Dutch national register. Ann Rheum Dis. 2009;68:635–641
12. Giannini EH, Ilowite NT, Lovell DJ, et al.Pediatric Rheumatology Collaborative Study Group. Long-term safety and effectiveness of etanercept in children with selected categories of juvenile idiopathic arthritis. Arthritis Rheum. 2009;60:2794–2804
13. Horneff G, De Bock F, Foeldvari I, et al.German and Austrian Paediatric Rheumatology Collaborative Study Group. 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. 2009;68:519–525
14. Bracaglia C, Buonuomo PS, Tozzi AE, et al. Safety and efficacy of etanercept in a cohort of patients with juvenile idiopathic arthritis under 4 years of age. J Rheumatol. 2012;39:1287–1290
15. Ruperto N, Lovell DJ, Cuttica R, et al.Paediatric Rheumatology International Trials Organisation; Pediatric Rheumatology Collaborative Study Group. A randomized, placebo-controlled trial of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis. Arthritis Rheum. 2007;56:3096–3106
16. Ruperto N, Lovell DJ, Cuttica R, et al.Paediatric Rheumatology INternational Trials Organization (PRINTO); Pediatric Rheumatology Collaborative Study Group (PRCSG). 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. 2010;69:718–722
17. Hyams J, Crandall W, Kugathasan S, et al.REACH Study Group. Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn’s disease in children. Gastroenterology. 2007;132:863–873 quiz 1165
18. Hyams J, Walters TD, Crandall W, et al. Safety and efficacy of maintenance infliximab therapy for moderate-to-severe Crohn’s disease in children: REACH open-label extension. Curr Med Res Opin. 2011;27:651–662
19. Stephens MC, Shepanski MA, Mamula P, et al. Safety and steroid-sparing experience using infliximab for Crohn’s disease at a pediatric inflammatory bowel disease center. Am J Gastroenterol. 2003;98:104–111
20. Tschudy J, Michail S. Disseminated histoplasmosis and pneumocystis pneumonia in a child with Crohn disease receiving infliximab. J Pediatr Gastroenterol Nutr. 2010;51:221–222
21. Trachana M, Pratsidou-Gertsi P, Pardalos G, et al. Safety and efficacy of adalimumab treatment in Greek children with juvenile idiopathic arthritis. Scand J Rheumatol. 2011;40:101–107
22. Lovell DJ, Ruperto N, Goodman S, et al.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
23. Imagawa T, Takei S, Umebayashi H, et al. Efficacy, pharmacokinetics, and safety of adalimumab in pediatric patients with juvenile idiopathic arthritis in Japan. Clin Rheumatol. 2012;31:1713–1721
24. Hyams JS, Griffiths A, Markowitz J, et al. Safety and efficacy of adalimumab for moderate to severe Crohn’s disease in children. Gastroenterology. 2012;143:365–374.e2
25. Salgado E, Gómez-Reino JJ. The risk of tuberculosis in patients treated with TNF antagonists. Expert Rev Clin Immunol. 2011;7:329–340
26. Mohan AK, Coté TR, Block JA, et al. Tuberculosis following the use of etanercept, a tumor necrosis factor inhibitor. Clin Infect Dis. 2004;39:295–299
27. Myers A, Clark J, Foster H. Tuberculosis and treatment with infliximab. N Engl J Med. 2002;346:623–626
28. Armbrust W, Kamphuis SS, Wolfs TW, et al. Tuberculosis in a nine-year-old girl treated with infliximab for systemic juvenile idiopathic arthritis. Rheumatology (Oxford). 2004;43:527–529
29. Solovic I, Sester M, Gomez-Reino JJ, et al. The risk of tuberculosis related to tumour necrosis factor antagonist therapies: a TBNET consensus statement. Eur Respir J. 2010;36:1185–1206
30. Ayaz NA, Demirkaya E, Bilginer Y, et al. Preventing tuberculosis in children receiving anti-TNF treatment. Clin Rheumatol. 2010;29:389–392
31. Ilowite N, Porras O, Reiff A, et al. Anakinra in the treatment of polyarticular-course juvenile rheumatoid arthritis: safety and preliminary efficacy results of a randomized multicenter study. Clin Rheumatol. 2009;28:129–137
32. Nigrovic PA, Mannion M, Prince FH, et al. Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter series. Arthritis Rheum. 2011;63:545–555
33. Quartier P, Allantaz F, Cimaz R, et al. A multicentre, randomised, double-blind, placebo-controlled trial with the interleukin-1 receptor antagonist anakinra in patients with systemic-onset juvenile idiopathic arthritis (ANAJIS trial). Ann Rheum Dis. 2011;70:747–754
34. Kuemmerle-Deschner JB, Tyrrell PN, Koetter I, et al. Efficacy and safety of anakinra therapy in pediatric and adult patients with the autoinflammatory Muckle-Wells syndrome. Arthritis Rheum. 2011;63:840–849
35. Yokota S, Imagawa T, Mori M, 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. 2008;371:998–1006
36. De Benedetti F, Brunner H, Ruperto N, et al. Efficacy and safety of tocilizumab (TCZ) in patients with systemic idiopathic juvenile arthritis (SJIA): tender 52-week data. Pediatr Rheumatology. 2011;9(suppl 1):P164
37. Ruperto N, Lovell DJ, Quartier P, et al.Paediatric Rheumatology INternational Trials Organization; Pediatric Rheumatology Collaborative Study Group. Abatacept in children with juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled withdrawal trial. Lancet. 2008;372:383–391
38. Ruperto N, Lovell DJ, Quartier P, et al.Paediatric Rheumatology International Trials Organization and the Pediatric Rheumatology Collaborative Study Group. Long-term safety and efficacy of abatacept in children with juvenile idiopathic arthritis. Arthritis Rheum. 2010;62:1792–1802
39. Alexeeva EI, Valieva SI, Bzarova TM, et al. Efficacy and safety of repeat courses of rituximab treatment in patients with severe refractory juvenile idiopathic arthritis. Clin Rheumatol. 2011;30:1163–1172
40. Heijstek MW, Ott de Bruin LM, Bijl M, et al.EULAR. EULAR recommendations for vaccination in paediatric patients with rheumatic diseases. Ann Rheum Dis. 2011;70:1704–1712