BACKGROUND: To derive a list of opportunistic infections (OI) through the analysis of the juvenile idiopathic arthritis (JIA) patients in the Pharmachild registry by an independent Safety Adjudication Committee (SAC). METHODS: The SAC (3 pediatric rheumatologists and 2 pediatric infectious disease specialists) elaborated and approved by consensus a provisional list of OI for use in JIA. Through a 5 step-procedure, all the severe and serious infections, classified as per MedDRA dictionary and retrieved in the Pharmachild registry, were evaluated by the SAC by answering six questions and adjudicated with the agreement of 3/5 specialists. A final evidence-based list of OI resulted by matching the adjudicated infections with the provisional list of OI. RESULTS: A total of 772 infectious events in 572 eligible patients, of which 335 serious/severe/very severe non-OI and 437 OI (any intensity/severity), according to the provisional list, were retrieved. Six hundred eighty-two of 772 (88.3%) were adjudicated as infections, of them 603/682 (88.4%) as common and 119/682 (17.4%) as OI by the SAC. Matching these 119 opportunistic events with the provisional list, 106 were confirmed by the SAC as OI, and among them infections by herpes viruses were the most frequent (68%), followed by tuberculosis (27.4%). The remaining events were divided in the groups of non-OI and possible/patient and/or pathogen-related OI. CONCLUSIONS: We found a significant number of OI in JIA patients on immunosuppressive therapy. The proposed list of OI, created by consensus and validated in the Pharmachild cohort, could facilitate comparison among future pharmacovigilance studies. TRIAL REGISTRATION: Clinicaltrials.gov NCT01399281; ENCePP seal: awarded on 25 November 2011.

1st Faculty of Medicine Department of Pediatrics and Adolescent Medicine Charles University Prague and General University Hospital Praha Czech Republic

2nd Department of Pediatrics Athens Medical School National and Kapodistrian University of Athens Athens Greece

Asklepios Clinic Sankt Augustin Department of General Paediatrics Sankt Augustin Germany

Clinic Bremen Mitte Prof Hesse Children's Hospital and Pediatric Intensive Care Medicine Bremen Germany

Clinica Pediatrica dell'Università di Brescia Spedali Civili Unità di Immunologia e Reumatologia Pediatrica Brescia Italy

Department of Clinical and Molecular Medicine Faculty of Medicine and Health Sciences NTNU Norwegian University of Science and Technology Trondheim Norway

Department of Infectious Diseases IRCCS Istituto Giannina Gaslini Genoa Italy

Department of Pediatric Immunology and Rheumatology Wilhelmina Children's Hospital University Medical Center Utrecht University Utrecht European Reference Network RITA Utrecht The Netherlands

Department of Pediatrics St Olavs University Hospital of Trondheim Trondheim Norway

Department of Rheumatology Oslo University Hospital Oslo Norway

Dipartimento di Neuroscienze Riabilitazione Oftalmologia Genetica e Scienze Materno Infantili Università degli Studi di Genova Genoa Italy

Division of Rheumatology Cincinnati Children's Hospital Medical Center Cincinnati OH USA

Faculty of Medicine Department of Paediatrics and Adolescent Medicine Pavol Jozef Šafárik University in Košice Kosice Slovakia

Hospital Universitario Pedro Ernesto Nucleo de Estudos da Saúde do Adolescente Universidade do Estado do Rio de Janeiro Rio de Janeiro Brazil

Infectious Disease Research Program Department of Pediatric Hematology and Oncology University Children's Hospital Münster Germany

Institute of Rheumatology of Belgrade Division of Pediatric Rheumatology Belgrade Serbia

Instituto de Puericultura e Pediatria Martagao Gesteira Universidade Federal do Rio de Janeiro Rio de Janeiro Brazil

IRCCS Istituto Giannina Gaslini Clinica Pediatrica e Reumatologia PRINTO Genoa Italy

IRCCS Istituto Giannina Gaslini Servizio di Epidemiologia e Biostatistica Genoa Italy

Medical Faculty Department of Paediatric and Adolescents Medicine University Hospital of Cologne Cologne Germany

Norwegian National Advisory Unit on Rheumatic Diseases in Children and Adolescents Oslo Norway

Pediatric Rheumatology Unit Aarhus University Hospital Aarhus Denmark

Sir Ganga Ram Hospital Marg Centre for Child Health Sir Ganga Ram Hospital New Delhi India

Unit of Pediatric Rheumatology Immunology 2nd Department of Pediatrics Semmelweis University Budapest Hungary

Zobrazit více v PubMed

Lovell DJ, Giannini EH, Reiff A, Cawkwell D, Silverman ED, Nocton JJ, et al. Etanercept in children with polyarticular juvenile rheumatoid arthritis. N Engl J Med. 2000;342(11):763–769. doi: 10.1056/NEJM200003163421103. PubMed DOI

Lovell DJ, Reiff A, Ilowite NT, Wallace CA, Chon Y, Lin SL, et al. Safety and efficacy of up to eight years of continuous etanercept therapy in patients with juvenile rheumatoid arthritis. Arthritis Rheum. 2008;58(5):1496–1504. doi: 10.1002/art.23427. PubMed DOI

Giannini EH, Ilowite NT, Lovell DJ, Wallace CA, Rabinovich CE, Reiff A, et al. Effects of long-term etanercept treatment on growth in children with selected categories of juvenile idiopathic arthritis. Arthritis Rheum. 2010;62(11):3259–3264. doi: 10.1002/art.27682. PubMed DOI

Horneff G, Burgos-Vargas R, Constantin T, Foeldvari I, Vojinovic J, Chasnyk VG, et al. Efficacy and safety of open-label etanercept on extended oligoarticular juvenile idiopathic arthritis, enthesitis-related arthritis and psoriatic arthritis: part 1 (week 12) of the CLIPPER study. Ann Rheum Dis. 2014;73(6):1114–1122. doi: 10.1136/annrheumdis-2012-203046. PubMed DOI PMC

Constantin T, Foeldvari I, Vojinovic J, Horneff G, Burgos-Vargas R, Nikishina I, et al. Two-year efficacy and safety of etanercept in pediatric patients with extended oligoarthritis, enthesitis-related arthritis, or psoriatic arthritis. J Rheumatol. 2016;43(4):816–824. doi: 10.3899/jrheum.150430. PubMed DOI

Verazza S, Davi S, Consolaro A, Bovis F, Insalaco A, Magni-Manzoni S, et al. Disease status, reasons for discontinuation and adverse events in 1038 Italian children with juvenile idiopathic arthritis treated with etanercept. Pediatr Rheumatol Online J. 2016;14(1):68. doi: 10.1186/s12969-016-0126-0. PubMed DOI PMC

Ruperto N, Lovell DJ, Cuttica R, Woo P, Meiorin S, Wouters C, 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. 2010;69(4):718–722. doi: 10.1136/ard.2009.100354. PubMed DOI PMC

Lovell DJ, Ruperto N, Goodman S, Reiff A, Jung L, Jarosova K, et al. Adalimumab with or without methotrexate in juvenile rheumatoid arthritis. N Engl J Med. 2008;359(8):810–820. doi: 10.1056/NEJMoa0706290. PubMed DOI

Ruperto N, Lovell DJ, Quartier P, Paz E, Rubio-Perez N, Silva CA, et al. Abatacept in children with juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled withdrawal trial. Lancet. 2008;372(9636):383–391. doi: 10.1016/S0140-6736(08)60998-8. PubMed DOI

Ruperto N, Lovell DJ, Quartier P, Paz E, Rubio-Perez N, Silva CA, et al. Long-term safety and efficacy of abatacept in children with juvenile idiopathic arthritis. Arthritis Rheum. 2010;62(6):1792–1802. doi: 10.1002/art.27431. PubMed DOI

Lovell DJ, Ruperto N, Mouy R, Paz E, Rubio-Perez N, Silva CA, et al. Long-term safety, efficacy, and quality of life in patients with juvenile idiopathic arthritis treated with intravenous abatacept for up to seven years. Arthritis Rheumatol. 2015;67(10):2759–2770. doi: 10.1002/art.39234. PubMed DOI PMC

De Benedetti F, Brunner HI, Ruperto N, Kenwright A, Wright S, Calvo I, et al. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012;367(25):2385–2395. doi: 10.1056/NEJMoa1112802. PubMed DOI

Brunner HI, Ruperto N, Zuber Z, Keane C, Harari O, Kenwright A, 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;74(6):1110–1117. doi: 10.1136/annrheumdis-2014-205351. PubMed DOI PMC

Ruperto N, Brunner HI, Quartier P, Constantin T, Wulffraat N, Horneff G, et al. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012;367(25):2396–2406. doi: 10.1056/NEJMoa1205099. PubMed DOI

Brunner HI, Ruperto N, Tzaribachev N, Horneff G, Chasnyk VG, Panaviene V, et al. Subcutaneous golimumab for children with active polyarticular-course juvenile idiopathic arthritis: results of a multicentre, double-blind, randomised-withdrawal trial. Ann Rheum Dis 2017 May 15;[Epub ahead of print]. PubMed PMC

FDA . FDA: cancer warnings required for TNF blockers. 2009.

Ruperto N, Vesely R, Saint-Raymond A, Martini A. Impact of the European paediatric legislation in paediatric rheumatology: past, present and future. Ann Rheum Dis. 2013;72(12):1893–1896. doi: 10.1136/annrheumdis-2013-204168. PubMed DOI

Magnusson B, Board of Registry The Swedish paediatric JIA-registry. Pediatric Rheumatol. 2014;12(S1):P5. doi: 10.1186/1546-0096-12-S1-P5. DOI

McErlane F, Foster HE, Davies R, Lunt M, Watson K, Symmons DPM, et al. Biologic treatment response among adults with juvenile idiopathic arthritis: results from the British Society for Rheumatology Biologics Register. Rheumatology. 2013;52:1905–1913. doi: 10.1093/rheumatology/ket248. PubMed DOI PMC

Mourao AF, Santos M, Melo-Gomes JA. Effectiveness and long-term retention of anti-tumour necrosis factor treatment in juvenile and adult patients with juvenile idiopathic arthritis: data from Reuma.pt. Rheumatology (Oxford) 2016;55(4):697–703. doi: 10.1093/rheumatology/kev398. PubMed DOI

Horneff G. Biologic-associated infections in pediatric rheumatology. Curr Rheumatol Rep. 2015;17:66. doi: 10.1007/s11926-015-0542-z. PubMed DOI

Horneff G, Schulz AC, Klotsche J, Hospach A, Minden K, Foeldvari I, et al. Experience with etanercept, tocilizumab and interleukin-1 inhibitors in systemic onset juvenile idiopathic arthritis patients from the BIKER registry. Arthritis Res Ther. 2017;19(1):256. doi: 10.1186/s13075-017-1462-2. PubMed DOI PMC

Becker I, Horneff G. Risk of serious infection in juvenile idiopathic arthritis patients associated with tumor necrosis factor inhibitors and disease activity in the German biologics in pediatric rheumatology registry. Arthritis Care Res (Hoboken) 2017;69(4):552–560. doi: 10.1002/acr.22961. PubMed DOI

Horneff G, Foeldvari I, Minden K, Moebius D, Hospach T. Report on malignancies in the German juvenile idiopathic arthritis registry. Rheumatology (Oxford) 2011;50(1):230–236. doi: 10.1093/rheumatology/keq361. PubMed DOI

Prince FH, Ferket IS, Kamphuis S, Armbrust W, ten CR, Hoppenreijs EP, et al. Development of a web-based register for the Dutch national study on biologicals in JIA: www.ABC-register.nl. Rheumatology (Oxford). 2008;47(9):1413–6. PubMed

Prince FH, Twilt M, ten CR VRMA, Armbrust W, Hoppenreijs EP, 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(5):635–641. doi: 10.1136/ard.2007.087411. PubMed DOI

Otten MH, Prince FH, Armbrust W, ten CR HEP, Twilt M, et al. Factors associated with treatment response to etanercept in juvenile idiopathic arthritis. JAMA. 2011;306(21):2340–2347. doi: 10.1001/jama.2011.1671. PubMed DOI

Beukelman T, Ringold S, Davis TE, DeWitt EM, Pelajo CF, Weiss PF, et al. Disease-modifying antirheumatic drug use in the treatment of juvenile idiopathic arthritis: a cross-sectional analysis of the CARRA registry. J Rheumatol. 2012;39(9):1867–1874. doi: 10.3899/jrheum.120110. PubMed DOI PMC

Beukelman T, Haynes K, Curtis JR, Xie F, Chen L, Bemrich-Stolz CJ, et al. Rates of malignancy associated with juvenile idiopathic arthritis and its treatment. Arthritis Rheum. 2012;64(4):1263–1271. doi: 10.1002/art.34348. PubMed DOI PMC

Beukelman T, Xie F, Chen L, Baddley JW, Delzell E, Grijalva CG, et al. Rates of hospitalized bacterial infection associated with juvenile idiopathic arthritis and its treatment. Arthritis Rheum. 2012;64(8):2773–2780. doi: 10.1002/art.34458. PubMed DOI PMC

Beukelman T, Xie F, Baddley JW, Chen L, Delzell E, Grijalva CG, et al. Brief report: incidence of selected opportunistic infections among children with juvenile idiopathic arthritis. Arthritis Rheum. 2013;65(5):1384–1389. doi: 10.1002/art.37866. PubMed DOI PMC

Winthrop KL, Novosad S, Baddley JW, Calabrese L, Chiller T, Polgreen P, et al. Opportunistic infections and biologic therapies in immune-mediated inflammatory diseases: consensus recommendations for infection reporting during clinical trials and postmarketing surveillance. Ann Rheum Dis. 2015;74(12):2107–2116. doi: 10.1136/annrheumdis-2015-207841. PubMed DOI

Winthrop KL, Chen L, Fraunfelder FW, Ku JH, Varley CD, Suhler E, et al. Initiation of anti-TNF therapy and the risk of optic neuritis: from the Safety Assessment of Biologic ThERapy (SABER) study. Am J Ophthalmol. 2013;155(1):183–189. doi: 10.1016/j.ajo.2012.06.023. PubMed DOI PMC

Abinun M. Risks of serious infections in children treated with biologic response-modifying drugs. Rheumatology. 2018;57(2):1–2. PubMed

Calzada-Hernández J, Anton J, Bou-Torrent R, Iglesias-Jiménez E, Ricart-Campos S, Martin de Carpi J, et al. Tuberculosis in pediatric patients treated with anti-TNFá drugs: a cohort study. Pediatric Rheumatology. 2015;13:54. doi: 10.1186/s12969-015-0054-4. PubMed DOI PMC

Ringold S, Weiss PF, Beukelman T, DeWitt EM, Ilowite NT, Kimura Y, 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 Care Res (Hoboken) 2013;65(10):1551–1563. doi: 10.1002/acr.22087. PubMed DOI PMC

Hsin YC, Zhuang L, Yeh K, Chang C, Horng J, Huang JL. Risk of tuberculosis in children with juvenile idiopathic arthritis: a nationwide population-based study in Taiwan. PLoS One. 2018;10(6). eCollection. PubMed PMC

Ruperto N, Martini A. Networking in paediatrics: the example of the Paediatric Rheumatology International Trials Organisation (PRINTO) Arch Dis Child. 2011;96(6):596–601. doi: 10.1136/adc.2010.188946. PubMed DOI

Swart J, Giancane G, Horneff G, Magnusson B, Hofer M, Alexeeva E, et al. Pharmacovigilance in juvenile idiopathic arthritis patients treated with biologic or synthetic drugs: combined data of more than 15,000 patients from Pharmachild and national registries. Arthritis Res Ther. 2018;20(1):285. doi: 10.1186/s13075-018-1780-z. PubMed DOI PMC

Groll A, Castagnola E, Cesaro S, Dalle J, Engelhard D, et al. Fourth European Conference on Infections in Leukaemia (ECIL-4): guidelines for diagnosis, prevention, and treatment of invasive fungal diseases in paediatric patients with cancer or allogeneic haemopoietic stem-cell transplantation. Lancet Oncol. 2014;15:327–340. doi: 10.1016/S1470-2045(14)70017-8. PubMed DOI

Mofenson LM, Brady M, Danner S, Dominguez K, Hazra R, Handelsman E, et al. Guidelines for the prevention and treatment of opportunistic infections among HIV-exposed and HIV-infected children: recommendations from CDC, the National Institutes of Health, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics. MMWR Recomm Rep. 2009;58(RR-11):1–166. PubMed PMC

Maertens J, Cesaro S, Maschmeyer G, Einsele H, Donnelly J, Alanio A, et al. ECIL guidelines for preventing Pneumocystis jirovecii pneumonia in patients with haematological malignancies and stem cell transplant recipients. J Antimicrob Chemother. 2016;71:2397–2404. doi: 10.1093/jac/dkw157. PubMed DOI

Naidoo J, Mahomed N, Moodley H. A systemic review of tuberculosis with HIV coinfection in children. Pediatr Radiol. 2017;47:1269–1276. doi: 10.1007/s00247-017-3895-9. PubMed DOI

Tragiannidis A, Kyriakidis I, Zundorf I, Groll A. Invasive fungal infections in pediatric patients treated with tumor necrosis alpha (TNF-alpha) inhibitors. Mycoses. 2017;60:222–229. doi: 10.1111/myc.12576. PubMed DOI

Davies D, FAAP COID Infectious complications with the use of biologic response modifiers in infants and children. Pediatrics. 2016;138:e11–e21. PubMed

Hashkes PJ, Uziel Y, Laxer RM. The safety profile of biologic therapies for juvenile idiopathic arthritis. Nat Rev Rheumatol. 2010;6(10):561–571. doi: 10.1038/nrrheum.2010.142. PubMed DOI

Lionetti G, Kimura Y, Schanberg L. Using registries to identify adverse events in rheumatic diseases. Pediatrics. 2013;132(5):1384–1394. doi: 10.1542/peds.2013-0755. PubMed DOI PMC

ATS Board of Directors of the american Thoracic Society Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med. 2000;161(4 Pt 2):S221–S247. PubMed

Nimmrich S, Horneff G. Incidence of herpes zoster infections in JIA patients. Rheumatol Int. 2015;35:465–470. doi: 10.1007/s00296-014-3197-6. PubMed DOI

Nicolai R, Cortis E, Rava L, Bracaglia C, Pardeo M, Insalaco A, et al. Herpes virus infections during treatment with etanercept in juvenile idiopathic arthritis. J Pediatric Infect Dis Soc. 2016;5(1):76–79. doi: 10.1093/jpids/piu078. PubMed DOI

Leuvenink R, Aeschlimann F, Baer W, Berthet G, Cannizzaro E, Hofer M, et al. Clinical course and therapeutic approach to varicella zoster virus infection in children with rheumatic autoimmune diseases under immunosuppression. Pediatr Rheumatol Online J. 2016;14(1):34. doi: 10.1186/s12969-016-0095-3. PubMed DOI PMC

Curtis JR, Xie F, Yun H, Bernatsky WKL. Real-world comparative risks of herpes virus infections in tofacitinib and biologic-treated patients with rheumatoid arthritis. Ann Rheum Dis. 2016;75(10):1843–1847. doi: 10.1136/annrheumdis-2016-209131. PubMed DOI PMC

Aeschlimann FA, Chong SL, Lyons TW, Beinvogl BC, Goez-Mogollon LM, Tan S, et al. Risk of serious infections associated with biologic agents in juvenile idiopathic arthritis: a systematic review and meta-analyses. J Pediatr. 2019;204:162–171. doi: 10.1016/j.jpeds.2018.08.065. PubMed DOI

Increased incidence of inflammatory bowel disease on etanercept in juvenile idiopathic arthritis regardless of concomitant methotrexate use

Zobrazit více v PubMed

ClinicalTrials.gov
NCT01399281