The Efficacy and Evidence-Based Use of Biologics in Children and Adolescents
Using monoclonal antibodies and fusion proteins as treatments
Background: Monoclonal antibodies (mAb) and fusion proteins (FP) are increasingly being used in children and adolescents. In this review, we analyze the evidence for their safety and efficacy in the treatment of the most common chronic inflammatory diseases.
Methods: We systematically searched PubMed, AWMF.org, and other databases for high-quality trials (i.e., randomized controlled trials with clinical primary endpoints) and guidelines published at any time up to 10 December 2018 that dealt with mAb and FP that are approved for pediatric use. The search term was “monoclonal antibody/fusion protein [e. g. adalimumab] AND children.”
Results: The 620 hits included 25 high-quality trials (20 of them manufacturer-sponsored) on 9 mAb/FP (omalizumab, adalimumab, etanercept, ustekinumab, infliximab, golimumab, anakinra, canakinumab, tocilizumab, and abatacept), as well as 6 guidelines (3 each of levels S3 and S2k) on the treatment of bronchial asthma, psoriasis, juvenile idopathic arthritis, and chronic inflammatory bowel diseases. For none of these conditions are mAb and FP the drugs of first choice. Adverse drug effects are rare but sometimes severe (infection, immune dysregulation, tumors).
Conclusion: The retrieved trials have deficiencies that make it difficult to reliably evaluate the efficacy, safety, and utility of mAb/FP for children and adolescents with chronic inflammatory diseases. mAb/FP nonetheless represent a treatment option to be considered in case conventional immune-modulating drugs are ineffective. Researcher-initiated, high-quality trials and manufacturer-independent, systematic long-term evaluations of adverse effects (e.g., tumors) are sorely needed.
Bronchial asthma (prevalence about 4%), psoriasis (about 0.7%), chronic inflammatory bowel disease (0.1%), and juvenile idiopathic arthritis (about 0.1%) are among the most common chronic inflammatory diseases in children. They are immune-modulated diseases (1–3). An important part in their pathogenesis is played by cytokines, including interleukin (IL)-1, IL-6 in juvenile idiopathic arthritis with systemic onset [sJIA], and tumor necrosis factor-α (TNFα) in polyarticular forms of juvenile idiopathic arthritis, psoriasis, and chronic inflammatory bowel disease) (Figure 1). Selective blockade of these cytokines by therapeutic monoclonal antibodies (mAb) and fusion proteins (FP) has the potential to intervene in the disease more specifically and less toxically than treatment with conventional immunomodulatory drugs (e.g., nucleoside analogs) that act nonspecifically on the metabolism of all cells. Nevertheless, adverse effects are also to be expected from monoclonal antibodies and fusion proteins, because the target antigens play an important part in the physiological immune response (e.g., TNFα in immunity to tuberculosis), and also because it must be assumed that “off-target” activity will occur, i.e., mAb/FP will bind nonspecifically to other antigens than the target (4–6).
mAb/FP are biologic agents and are substances that are produced by living organisms in a biological process, as distinct from a chemical process (Figure 2). They are administered parenterally and have a long half-life of up to 3 to 4 weeks (7–9). There is an insufficiency of data on the pharmacology of mAb/FP in children (among other things, dosage is given in “weight bands”, i.e. not strictly linearly according to body weight, and there is a lack of clarity about the extent to which data on adult dosages can be extrapolated to children, and about dosage increase during disease exacerbations).
The aim of the present article is to briefly present the standard (guideline-concordant) therapy of the most common chronic inflammatory diseases of children and adolescents, and then to analyze the available evidence for the efficacy and safety of mAb and FP in these diseases.
On 10 December 2018 a literature search was carried out on PubMed, awmf.org, and other databases for published reports and guidelines on the use of approved mAb and FP in children and adolescents (eMethods, eTable 1). For the commonest chronic inflammatory diseases (with a prevalence ≥ 0.1%), we identified a total of 25 high-quality studies (i.e., that randomized mAb/FP against placebo or another intervention, and had clinical primary endpoints) that had investigated the efficacy of mAb/FP and had been included in guidelines.
In a stepped approach, short-acting inhaled β2-agonists as needed (step 1), leukotriene receptor antagonists (LTRA) or low/medium-dose inhaled corticosteroids (ICS) (steps 2 and 3), and long-acting β2-agonists, long-acting anticholinergics, or LTRA combined with medium- or high-dose ICS (steps 4 and 5) are used (10).
The indication for use of the mAb omalizumab, which targets immunoglobulin E (IgE), is based on high-quality studies and is given only in the last therapeutic step, step 6. The criteria are IgE-mediated asthma, positive skin test/in-vitro activity against a perennial airborne allergen, serum IgE concentration within the treatable range, and the elimination of avoidable allergen exposure.
State of the evidence
In four studies (two of them manufacturer-independent) of severe, refractory bronchial asthma, preseason administration of omalizumab was effective in terms of reducing the number of exacerbations during the fall and spring (11–14) (eTable 2).
Safety of omalizumab
In regard to children and adolescents, apart from the above-mentioned studies, little can be said because omalizumab is rarely used. The most frequent adverse effects are headache and reactions at the injection site (Table). Life-threatening anaphylactic reactions can occur hours or days after the injection, even when the antibody has been tolerated for a year or more (15).
In patients with mild psoriasis, topical corticoids can be given first, alone or in combination with topical vitamin D derivatives (calcipotriol, tacalcitol) (16). In cases of moderate or severe psoriasis, systemic methotrexate p.o. or s.c. or adalimumab (for TNFα blockade) is indicated. If there is insufficient response to treatment, ustekinumab (IL-12 and IL-23 blockade) or etanercept (TNFα blockade) is recommended. The stated indication for adalimumab, etanercept, and ustekinumab is based partly on distorted data from high-quality studies. Regarding the use of other mAb/FP as a last resort, data from high-quality studies are lacking for the child and adolescent age groups. In adults, the following have proved effective: infliximab, certolizumab pegol (TNFα blockade), guselkumab (IL-12, IL-23), ixekizumab, secukinumab (IL-17A), and brodalumab (IL-17 receptor A) (17, 18).
Studies in severe, refractory chronic plaque psoriasis
In a company-sponsored head-to-head study (adalimumab versus methotrexate), the results are distorted by a too-low initial dose of methotrexate in the control group (0.1 mg/kg body weight (BW)/week; standard dosage of methotrexate in inflammatory disease: 0.3 to 0.6 mg/kg BW/week) (19, 20). Etanercept and ustekinumab were more effective than placebo in terms of the Psoriasis Area and Severity Index (PASI 75) (21, 22) (eTable 2).
Ustekinumab is very rarely used in children and adolescents, and that only recently, so little systematically recorded experience has been accumulated. An increased incidence of infections is noted (Table).
Juvenile idiopathic arthritis and associated uveitis
Guideline-concordant therapy of juvenile idiopathic arthritis
With the nonsystemic forms of juvenile idiopathic arthritis (these include persistent oligoarthritis, enthesitis-related arthritis [EAA], and seronegative polyarthritis), conventional guideline-concordant treatment starts with nonsteroidal anti-inflammatory drugs (NSAIDs) and intra-articular injections of crystalloid glucocorticoids (e.g., triamcinolone hexacetonide) (23). At the next step up, methotrexate is given for a period of 6 months. If this is insufficiently effective, etanercept or adalimumab is indicated on the basis of studies with methodological weaknesses, in some cases quite considerable weaknesses (Figure 3). In the subtype of juvenile idiopathic arthritis with systemic onset (sJIA), steroid pulses are indicated, and if the steroids result in adverse effects or insufficient response, the IL-1 and IL-6 blocking drugs anakinra, canakinumab, or tocilizumab are indicated. The basis for their use is high-quality studies with in some cases very short observation periods (eTable 2).
State of the evidence
No high-quality studies are available for the most common form of juvenile idiopathic arthritis, persistent oligoarticular juvenile idiopathic arthritis. For the polyarticular form, in one independent and one company-sponsored study of TNFα blockers (etanercept, infliximab) the primary clinical endpoints were not reached (24, 25) (eTable 2).
In two open head-to-head studies, the combination of either etanercept or infliximab with methotrexate proved to be superior to monotherapy with methotrexate (juvenile idiopathic arthritis [ACR 70 and 75 respectively]), although in each case with a bias in favor of the combination containing TNFα blocker (26, 27). For the subtypes enthesitis-associated arthritis and juvenile ankylosing spondylitis, small studies have shown a reduction in the number of actively arthritic joints with adalimumab (28, 29). For systemic juvenile idiopathic arthritis, the IL-1 blocker canakinumab or the IL-6 blocker tocilizumab are effective (30–32). All other studies (including abatacept) used the withdrawal study design, which is inadequate for accurate measurement of efficacy (Figure 3) (33–39).
Guideline-compliant therapy of juvenile idiopathic arthritis-associated uveitis
As the first step, treatment is with topical steroids (40). If there is a threat of loss of vision, steroid pulses are given until conventional immunomodulatory drugs (usually methotrexate) start to take effect. At the third step, although TNFα blockers (golimumab, adalimumab, infliximab) are recommended, high-quality evidence is available only for adalimumab (e1).
State of the evidence
In one independent study, adalimumab in combination with methotrexate was more effective in terms of an intraocular inflammation score than was methotrexate monotherapy (e1). By contrast, etanercept was shown in a very small study to be ineffective (e2).
TNFα blockers (etanercept, adalimumab, infliximab, golimumab) are usually well tolerated. The incidence of all severe adverse effects in the company-sponsored Pharma Child Register during the observation period for 8274 children with juvenile idiopathic arthritis was around 6% to 7% (e3). There is an increased risk (especially when combined with other immunomodulatory drugs) of the reactivation of tuberculosis and other infections, some of which may be severe (Table). The part played by mAb/FP in the development of cancer is the subject of debate, because juvenile idiopathic arthritis is itself associated with an increased risk of cancer (e4, e5). Diseases of immune dysregulation have been described, including demyelinating diseases, induction of uveitis (etanercept), and chronic inflammatory bowel disease (e6–e8).
IL-1 and IL-6 blockers are less frequently used than TNF blockers, and the cytotoxic T-lymphocyte associated protein 4 (CTLA-4) blockade even less often. Severe infections and immune dysregulation have been reported (Table), including six fatalities in the tocilizumab study and four in the canakinumab study in patients with systemic juvenile idiopathic arthritis; it is unclear whether there was a direct relation to the study medication (31, 32).
Chronic inflammatory bowel disease
When disease activity is mild in a child with Crohn’s disease, enteral nutritional therapy (ENT) should be started, and if this fails and there is ileocecal involvement, budesonide should be given (e9). Where disease activity is moderate or severe, ENT should be used; systemic steroids and an immunomodulator (azathioprine [AZA], 6-mercaptopurine [6-MP], methotrexate, and others) may also be given. Despite a lack of high-quality studies, TNFα blockers (adalimumab, infliximab) are recommended for treatment and maintenance of remission if conventional immunomodulators (steroids, AZA, 6-MP, methotrexate) fail.
In patients with ulcerous colitis, to induce remission of mild or moderately active proctitis, first mesalazine is given as a suppository only; unlike in Crohn’s disease, ENT has little effect (e10).
If this fails, topical steroids are added. To induce remission of mild to moderate ulcerous colitis, combined treatment with rectal and oral mesalazine is given. If this fails, the next step is to use systemic steroids and immunomodulators (AZA, 6-MP) or TNFα blockers (infliximab, adalimumab). Severe exacerbations are treated initially with a systemic steroid and/or with TNFα blockers, CSA/tacrolimus, or thiopurines; in some cases proctocolectomy may be necessary. To intensify maintenance of remission, depending on preceding treatment, 5-ASA, thiopurine, a TNFα blocker, or the integrin inhibitor vedolizumab is used. As in Crohn’s disease, there is no scientific evidence that mAb are effective in children and adolescents.
State of the evidence
In one meta-analysis in adults with moderate to severe Crohn’s disease, infliximab or adalimumab were effective in inducing remission; in ulcerous colitis only infliximab was effective (e11). The relatively widespread use of mAbs in chronic inflammatory bowel disease in children is based exclusively on the above-mentioned adult data and numerous lower-quality studies of mAb, all of which lacked the appropriate control groups to prove efficacy. In regard to vedolizumab, no controlled studies have been carried out in children (e12).
TNFα blockers have been used for many years in chronic inflammatory bowel disease, and on the whole are well tolerated. Very rarely, patients with chronic inflammatory bowel disease develop hepatosplenic T-cell lymphoma, which has a high mortality rate. The lymphoma has been linked to the combination of AZA and infliximab, but was seen even before the era of biologic agents (e13). Vedolizumab has only recently come into use, is very rarely used in children and adolescents, and no systematic data collection has been carried out.
Care aspects of the use of mAb/FP
In all the treatment guidelines for the diseases discussed in this article, it is seen as important for children and adolescents to be under the care of, not just their local pediatrician, but also pediatric specialists (e.g., pediatric pneumologist, pediatric rheumatologist, pediatric hematologist, pediatric nephrologist, pediatric gastroenterologist) in centers where decisions regarding treatment with mAb/FP are usually made. For a successful treatment outcome, an interdisciplinary approach is always important, drawing on expertise in dermatology, ophthalmology, surgery, physiotherapy, and others.
Value of mAb/FP in comparison to standard immunomodulators
For none of the diseases analyzed here are mAb or FP the treatment of first choice. In the treatment of asthma, omalizumab is safe, but appears only in the very last treatment step and is rarely contemplated. In psoriasis, in polyarticular and nonsystemic forms of juvenile idiopathic arthritis, enthesitis-related arthritis, juvenile idiopathic arthritis-associated uveitis, and chronic inflammatory bowel disease, mAb/FP are only used when steroids/conventional immunomodulators (e.g., methotrexate in juvenile idiopathic arthritis, 5-acetylsalicic acid, thiopurine in chronic inflammatory bowel disease) are insufficiently effective or are not tolerated. In children, oral administration of conventional immunomodulators can be associated with compliance problems (e.g., aversion to methotrexate). Whether parenteral administration of mAb/FP is better remains, in the absence of comparative studies, an open question.
In systemic juvenile idiopathic arthritis, while it is true that IL-1 and IL-6 blockers carry safety risks such as severe infection, they are effective and may be of greater benefit than steroid pulses. No high-quality studies on this topic exist.
Safety assessment of mAb/FP compared to standard immunomodulators
Since severe infusion reactions can occur with mAbs, the first administration is usually monitored in the inpatient or daypatient setting. Because of the inadequacy of existing evidence (lack of high-quality comparative studies against conventional immunomodulators, inhomogeneous definitions of severe adverse effects, low patient numbers, very short observation periods), it remains unclear whether the safety of mAb/FP is comparable to that of conventional immunomodulators. Severe adverse effects and deaths are not always adequately detailed in company-sponsored studies, or are not mentioned in core elements of publications (e.g., abstracts) (31, 32).
Quality of mAb/FP studies and scope for improvement
Many uncontrolled studies have been carried out on mAb/FP. In its recommendations on the ethics of carrying out clinical studies in children, the European Medicines Agency (EMA) rejects uncontrolled studies as a basis for evidence of efficacy, and recommends study designs that minimize bias (e14).
Many company-sponsored registers are collecting long-term data on mAb/FP. These are often used as a basis to determine the efficacy and safety of these substances in children with chronic inflammatory diseases. The use of registry data to investigate cause-and-effect relationships is inappropriate (e15). There is a risk that ‘facts’ will be created from registry data that lack deep scientific underpinnings. One example of current healthcare provision for children and adolescents with rheumatic disease is the prescription in 2017 of mAb/FP to >10% (319/3006) of children with the most common form of juvenile idiopathic arthritis (so-called persistent oligoarticular juvenile idiopathic arthritis) in the absence of evidence from a single high-quality study (e16).
Our analysis shows that only 20% of studies (5/25) classified as high-quality were carried out independently of pharmaceutical companies. To improve the evidence regarding the use of mAb/FP, more researcher-initiated studies with the following characteristics are needed:
- Classical double-blind, randomized study design; in particular, more head-to-head trials of TNFα blockers versus methotrexate/thiopurine (juvenile idiopathic arthritis/chronic inflammatory bowel disease) or IL-1/IL-6 blockers versus cortisone pulses (systemic juvenile idiopathic arthritis)
- Longitudinal studies (e.g., 6 to 12 months) with a large enough number of patients, in order to capture chronic diseases with a relapsing course over months or years better than is possible with a short observation period of 12 or at most 16 weeks
- Cohort studies and pharmacovigilance registries (like the German Child Cancer Registry, Deutsches Kinderkrebsregister) that are independent of pharmaceutical companies
- Studies on the pharmacokinetics of mAb/FP.
The UN Convention on the Rights of the Child guarantees a child’s right to the highest attainable standard of health (article 24, paragraph 1), and this includes the highest standard of evidence for interventions (e17). The mAb/FP studies suffer from qualitative weaknesses that make it difficult to assess the efficacy and safety of mAb/FP. Despite the unsatisfactory state of the evidence, and the adverse effects, some of which can be severe, mAb and FP do represent a therapeutic option for children and adolescents in whom conventional immunomodulatory treatment is insufficiently effective. When there is a risk of severe complications of a chronic inflammatory disease in a child or adolescent, the use of mAbs and FPs, after a calculation of the risks and benefits, can be justified.
It would not have been possible to produce this manuscript without the professional secretarial assistance of A. Groth and I. Bruins (Helios Klinikum Krefeld). We are grateful to Drs. A. Christaras and A. Ballauff (Helios Klinikum Krefeld) for critical reading of the manuscript. Dr. Turul Özgür’s work was supported by the Krefeld Childen’s Cancer Hospital Parents’ Association (Elternverein der Kinderkrebsklinik Krefeld e. V.).
Conflict of interest statement
Professor Niehues has received authorship fees from uptodate.com (Wellesley, Massachusetts, USA) and reimbursement of travel expenses during consultancy work for the European Medicines Agency (EMA), steering committees of the PENTA Paediatric European Network for Treatment of AIDS (Padua, Italy), the Juvenile Inflammatory Cohort (JIR) (Lausanne, Switzerland), and, until 2017, the FIND-ID Initiative (supported by the Plasma Protein Therapeutics Association [PPTA] [Brussels, Belgium]).
Dr. Turul Özgür declares that no conflict of interest exists.
Manuscript received on 27 December 2018, revised version accepted on 23 July 2019
Prof. Dr. med. Tim Niehues
Zentrum für Kinder- und Jugendmedizin
Helios Klinikum Krefeld
Lehrkrankenhaus der RWTH Aachen
47805 Krefeld, Germany
Cite this as:
Niehues T, Turul Özgür T: The efficacy and evidence-based use of biologics in children and adolescents—using monoclonal antibodies and fusion proteins as treatments. Dtsch Arztebl Int 2019; 116: 703–10. DOI: 10.3238/arztebl.2019.0703
For e-References please refer to:
Prof. Dr. med. Tim Niehues, Dr. med. Tuba Turul Özgür, MD
|1.||Benchimol EI, Fortinsky KJ, Gozdyra P, Van den Heuvel M, Van Limbergen J, Griffiths AM: Epidemiology of pediatric inflammatory bowel disease: a systematic review of international trends. Inflamm Bowel Dis 2011; 17: 423–39 CrossRef MEDLINE|
|2.||Robert Koch-Institut: Asthma bronchiale. Faktenblatt zu KiGGS Welle 1: Studie zur Gesundheit von Kindern und Jugendlichen in Deutschland – Erste Folgebefragung 2009 – 2012. RKI, Berlin. Robert Koch-Institut, Gesundheitsberichterstattung des Bundes 2014.|
|3.||Thomschke S, Schulz M, Bätzing J: Epidemiologie der juvenilen idiopathischen Arthritis (JIA) in der ambulanten Versorgung – eine Analyse anhand bundesweiter vertragsärztlicher Abrechnungsdaten der Jahre 2009 bis 2015. Versorgungsatlas 2018.|
|4.||Boyman O, Comte D, Spertini F: Adverse reactions to biologic agents and their medical management. Nat Rev Rheumatol 2014; 10: 612–27 CrossRef MEDLINE|
|5.||Davis BP, Ballas ZK: Biologic response modifiers: Indications, implications, and insights. J Allergy Clin Immunol 2017; 139: 1445–56 CrossRef MEDLINE|
|6.||Feyen O, Lueking A, Kowald A, et al.: Off-target activity of TNF-alpha inhibitors characterized by protein biochips. Anal Bioanal Chem 2008; 391: 1713–20. CrossRef MEDLINE|
|7.||Oude Munnink TH, Henstra MJ, Segerink LI, Movig KL, Brummelhuis-Visser P: Therapeutic drug monitoring of monoclonal antibodies in inflammatory and malignant disease: Translating TNF-alpha experience to oncology. Clin Pharmacol Ther 2016; 99: 419–31 CrossRef MEDLINE|
|8.||Malik P, Edginton A: Pediatric physiology in relation to the pharmacokinetics of monoclonal antibodies. Expert Opin Drug Metab Toxicol 2018; 14: 585–99 CrossRef MEDLINE|
|9.||Edlund H, Melin J, Parra-Guillen ZP, Kloft C: Pharmacokinetics and pharmacokinetic-pharmacodynamic relationships of monoclonal antibodies in children. Clin Pharmacokinet 2015; 54: 35–80 CrossRef MEDLINE|
|10.||NVL-Programm von BÄK, AWMF: Nationale Versorgungs-Leitlinie Asthma. www.awmf.org/leitlinien/detail/ll/nvl-002.html (last accessed on 12 August 2019)|
|11.||Teach SJ, Gill MA, Togias A, et al.: Preseasonal treatment with either omalizumab or an inhaled corticosteroid boost to prevent fall asthma exacerbations. J Allergy Clin Immunol 2015; 136: 1476–85 CrossRef MEDLINE PubMed Central|
|12.||Busse WW, Morgan WJ, Gergen PJ, et al.: Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children. N Engl J Med 2011; 364: 1005–15 CrossRef MEDLINE PubMed Central|
|13.||Lanier B, Bridges T, Kulus M, Taylor AF, Berhane I, Vidaurre CF: Omalizumab for the treatment of exacerbations in children with inadequately controlled allergic (IgE-mediated) asthma. J Allergy Clin Immunol 2009; 124: 1210–6 CrossRef MEDLINE|
|14.||Milgrom H, Berger W, Nayak A, et al.: Treatment of childhood asthma with anti-immunoglobulin E antibody (omalizumab). Pediatrics 2001; 108: E36 CrossRef MEDLINE|
|15.||arznei-telegramm: Warnung vor Anaphylaxie durch Asthmamittel Omalizumab (Xolair) www.arznei-telegramm.de/html/2007_07/0707071_02.html (last accessed on 12 August 2019)|
|16.||Deutsche Diabetes Gesellschaft: S2k-Leitlinie Therapie der Psoriasis bei Kindern und Jugendlichen www.awmf.org/leitlinien/detail/ll/013–094.html (last accessed on 12 August 2019).|
|17.||de Carvalho AV, Duquia RP, Horta BL, Bonamigo RR: Efficacy of immunobiologic and small molecule inhibitor drugs for psoriasis: a systematic review and meta-analysis of randomized clinical trials. Drugs R D 2017; 17: 29–51 CrossRef MEDLINE PubMed Central|
|18.||Sbidian E, Chaimani A, Garcia-Doval I, et al.: Systemic pharmacological treatments for chronic plaque psoriasis: a network meta-analysis. Cochrane Database Syst Rev 2017; 12: CD011535 CrossRef MEDLINE PubMed Central|
|19.||Ramanan AV, Whitworth P, Baildam EM: Use of methotrexate in juvenile idiopathic arthritis. Arch Dis Child 2003; 88: 197–200 CrossRef MEDLINE PubMed Central|
|20.||Papp K, Thaci D, Marcoux D, et al.: Efficacy and safety of adalimumab every other week versus methotrexate once weekly in children and adolescents with severe chronic plaque psoriasis: a randomised, double-blind, phase 3 trial. Lancet 2017; 390: 40–9 CrossRef|
|21.||Paller AS, Siegfried EC, Langley RG, et al.: Etanercept treatment for children and adolescents with plaque psoriasis. N Engl J Med 2008; 358: 241–51 CrossRef MEDLINE|
|22.||Landells I, Marano C, Hsu MC, et al.: Ustekinumab in adolescent patients age 12 to 17 years with moderate-to-severe plaque psoriasis: results of the randomized phase 3 CADMUS study. J Am Acad Dermatol 2015; 73: 594–603 CrossRef MEDLINE|
|23.||Dueckers G, Guellac N, Arbogast M, et al.: Evidence and consensus based GKJR guidelines for the treatment of juvenile idiopathic arthritis. Clin Immunol 2012; 142: 176–93 CrossRef MEDLINE|
|24.||Ruperto N, Lovell DJ, Cuttica R, et al.: A randomized, placebo-controlled trial of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis. Arthritis Rheum 2007; 56: 3096–106 CrossRef MEDLINE|
|25.||Wallace CA, Giannini EH, Spalding SJ, et al.: Trial of early aggressive therapy in polyarticular juvenile idiopathic arthritis. Arthritis Rheum 2012; 64: 2012–21 CrossRef MEDLINE PubMed Central|
|26.||Tynjälä P, Vahasalo P, Tarkiainen M, et al.: Aggressive combination drug therapy in very early polyarticular juvenile idiopathic arthritis (ACUTE-JIA): a multicentre randomised open-label clinical trial. Ann Rheum Dis 2011; 70: 1605–12 CrossRef MEDLINE|
|27.||Hissink Müller PC, Brinkman DM, Schonenberg D, et al.: A comparison of three treatment strategies in recent onset non-systemic juvenile idiopathic arthritis: initial 3-months results of the BeSt for Kids-study. Pediatr Rheumatol Online J 2017; 15: 11 CrossRef MEDLINE PubMed Central|
|28.||Burgos-Vargas R, Tse SM, Horneff G, et al.: A randomized, double-blind, placebo-controlled multicenter study of adalimumab in pediatric patients with enthesitis-related arthritis. Arthritis Care Res (Hoboken) 2015; 67: 1503–12 CrossRef MEDLINE PubMed Central|
|29.||Horneff G, Fitter S, Foeldvari I, et al.: Double-blind, placebo-controlled randomized trial with adalimumab for treatment of juvenile onset ankylosing spondylitis (JoAS): significant short term improvement. Arthritis Res Ther 2012; 14: R230 CrossRef MEDLINE PubMed Central|
|30.||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: 747–54 CrossRef MEDLINE PubMed Central|
|31.||Ruperto N, Quartier P, Wulffraat N, et al.: A phase II, multicenter, open-label study evaluating dosing and preliminary safety and efficacy of canakinumab in systemic juvenile idiopathic arthritis with active systemic features. Arthritis Rheum 2012; 64: 557–67 CrossRef MEDLINE|
|32.||de Benedetti F, Brunner HI, Ruperto N, et al.: Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med 2012; 367: 2385–95 CrossRef MEDLINE|
|33.||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 CrossRef|
|34.||Horneff G, Foeldvari I, Minden K, et al.: Efficacy and safety of etanercept in patients with the enthesitis-related arthritis category of juvenile idiopathic arthritis: results from a phase III randomized, double-blind study. Arthritis Rheumatol 2015; 67: 2240–9 CrossRef MEDLINE|
|35.||Ruperto N, Lovell DJ, Quartier P, et al.: Abatacept in children with juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled withdrawal trial. Lancet 2008; 372: 383–91 CrossRef|
|36.||Lovell DJ, Ruperto N, Goodman S, et al.: Adalimumab with or without methotrexate in juvenile rheumatoid arthritis. N Engl J Med 2008; 359: 810–20 CrossRef MEDLINE|
|37.||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: 763–9 CrossRef MEDLINE|
|38.||Brunner HI, Ruperto N, Zuber Z, 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: 1110–7 CrossRef MEDLINE PubMed Central|
|39.||Brunner HI, Rider LG, Kingsbury DJ, et al.: Pediatric Rheumatology Collaborative Study Group – over four decades of pivotal clinical drug research in pediatric rheumatology. Pediatr Rheumatol Online J 2018; 16: 45 CrossRef MEDLINE PubMed Central|
|40.||Deutsche Ophthalmologische Gesellschaft: Diagnostik und antientzündliche Therapie der Uveitis bei juveniler idiopathischer Arthritis. www.awmf.org/leitlinien/detail/ll/045–012.html (last accessed on 13 August 2019).|
|e1.||Ramanan AV, Dick AD, Jones AP, et al.: Adalimumab plus methotrexate for uveitis in juvenile idiopathic arthritis. N Engl J Med 2017; 376: 1637–46 CrossRef MEDLINE|
|e2.||Smith JA, Thompson DJ, Whitcup SM, et al.: 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 CrossRef MEDLINE|
|e3.||Swart J, Giancane G, Horneff G, 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: 285 CrossRef MEDLINE PubMed Central|
|e4.||Diak P, Siegel J, La Grenade L, Choi L, Lemery S, McMahon A: Tumor necrosis factor alpha blockers and malignancy in children: forty-eight cases reported to the Food and Drug Administration. Arthritis Rheum 2010; 62: 2517–24 CrossRef MEDLINE|
|e5.||Simard JF, Neovius M, Hagelberg S, Askling J: Juvenile idiopathic arthritis and risk of cancer: a nationwide cohort study. Arthritis Rheum 2010; 62: 3776–82 CrossRef MEDLINE|
|e6.||Kemanetzoglou E, Andreadou E: CNS demyelination with TNF-alpha blockers. Curr Neurol Neurosci Rep 2017; 17: 36 CrossRef MEDLINE|
|e7.||Kakkassery V, Mergler S, Pleyer U: Anti-TNF-alpha treatment: a possible promoter in endogenous uveitis? observational report on six patients: occurrence of uveitis following etanercept treatment. Curr Eye Res 2010; 35: 751–6 PubMed Central CrossRef MEDLINE|
|e8.||Barthel D, Ganser G, Kuester RM, et al.: Inflammatory bowel disease in juvenile idiopathic arthritis patients treated with biologics. J Rheumatol 2015; 42: 2160–5 CrossRef MEDLINE|
|e9.||Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten: S3-Leitlinie 021/004: Diagnostik und Therapie des Morbus Crohn www.awmf.org/leitlinien/detail/ll/021–004.html (last accessed on 2 September 2019).|
|e10.||Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten: S3 Leitlinie 021–009 Diagnostik und Therapie der Colitis ulcerosa. www.kompetenznetz-darmerkrankungen.de/files/cto_layout/img/Diagnostik-und-Therapie-der-Colitis-ulcerosa.pdf (last accessed on on 2 September 2019).|
|e11.||Cholapranee A, Hazlewood GS, Kaplan GG, Peyrin-Biroulet L, Ananthakrishnan AN: Systematic review with meta-analysis: comparative efficacy of biologics for induction and maintenance of mucosal healing in Crohn‘s disease and ulcerative colitis controlled trials. Aliment Pharmacol Ther 2017; 45: 1291–302 CrossRef MEDLINE PubMed Central|
|e12.||Däbritz J, Gerner P, Enninger A, Claßen M, Radke M: Inflammatory bowel disease in childhood and adolescence—diagnosis and treatment. Dtsch Arztebl Int 2017; 114: 331–8 CrossRef MEDLINE PubMed Central|
|e13.||Mackey AC, Green L, Liang LC, Dinndorf P, Avigan M: Hepatosplenic T cell lymphoma associated with infliximab use in young patients treated for inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2007; 44: 265–7 CrossRef MEDLINE|
|e14.||Ethical considerations for clinical trials on medicinal products conducted with minors. Recommendations of the expert group on clinical trials for the implementation of Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use. www.ec.europa. eu/health/sites/health/files/files/eudralex/vol-10/2017_09_18_ethical_ consid_ct_with_minors.pdf (last accessed on 12.-August 2019).|
|e15.||Windeler J, Lauterberg J, Wieseler B, Sauerland S: Patientenregister für die Nutzenbewertung: Kein Ersatz für randomisierte Studien. Dtsch Arztebl 2017; 114(16): A-783–6.|
|e16.||Gesellschaft für Kinder- und Jugendrheumatologie: Forschungsprojekte in der Kinderrheumatologie. www.gkjr.de/forschungsprojekte/forschungsprojekte-in-der-kinderrheumatologie/ (last accessed on 12 August 2019).|
|e17.||UN-Kinderrechtskonvention: Übereinkommen über die Rechte des Kindes (Convention on the Rights of the Child, CRC). www.kinderrechtskonvention.info/ (last accessed on 12 August 2019).|
|e18.||Pocock SJ: The pros and cons of noninferiority trials. Fundam Clin Pharmacol 2003; 17: 483–90 CrossRef|
|e19.||Feldman B, Wang E, Willan A, Szalai JP: The randomized placebo-phase design for clinical trials. J Clin Epidemiol 2001; 54: 550–7 CrossRef|
|e20.||Demirkaya E, Lanni S, Bovis F, et al.: A meta-analysis to estimate the placebo effect in randomized controlled trials in juvenile idiopathic arthritis. Arthritis Rheumatol 2016; 68: 1540–50 CrossRef MEDLINE|
|e21.||Abrahamyan L, Feldman BM, Tomlinson G, et al.: Alternative designs for clinical trials in rare diseases. Am J Med Genet C Semin Med Genet 2016; 172: 313–31 CrossRef MEDLINE|
|e22.||Lehman TJ: Are withdrawal trials in paediatric rheumatic disease helpful? Lancet 2008; 372: 348–50 CrossRef|
|e23.||Boyman O, Comte D, Spertini F: Adverse reactions to biologic agents and their medical management. Nat Rev Rheumatol 2014; 10: 612–27 CrossRef MEDLINE|
|e24.||Davis BP, Ballas ZK: Biologic response modifiers: Indications, implications, and insights. J Allergy Clin Immunol 2017; 139: 1445–56 CrossRef MEDLINE|
|e25.||Picard M, Galvao VR: Current knowledge and management of hypersensitivity reactions to monoclonal antibodies. J Allergy Clin Immunol Pract 2017; 5: 600–9 CrossRef MEDLINE|
|e26.||Corren J, Kavati A, Ortiz B, et al.: Efficacy and safety of omalizumab in children and adolescents with moderate-to-severe asthma: a systematic literature review. Allergy Asthma Proc 2017; 38: 250–63 CrossRef MEDLINE|
|e27.||Ehmann LM, Tillack-Schreiber C, Brand S, Wollenberg A: Malignant melanoma during ustekinumab therapy of Crohn‘s disease. Inflamm Bowel Dis 2012; 18: E199–200 CrossRef MEDLINE|
|e28.||Young L, Czarnecki D: The rapid onset of multiple squamous cell carcinomas in two patients commenced on ustekinumab as treatment of psoriasis. Australas J Dermatol 2012; 53: 57–60 CrossRef MEDLINE|
|e29.||Gratton D, Szapary P, Goyal K, Fakharzadeh S, Germain V, Saltiel P: Reversible posterior leukoencephalopathy syndrome in a patient treated with ustekinumab: case report and review of the literature. Arch Dermatol 2011; 147: 1197–202 CrossRef MEDLINE|
|e30.||Niehues T: Therapeutic monoclonal antibodies as immunomodulators and anti-cancer agents: development, evidence of efficacy, mechanisms of actions, adverse effects in antibody therapy. In: Imbach P, eds.: Antibody therapy, substitution – immunomodulation – monoclonal immunotherapy Springer Verlag 2018; 291–341 CrossRef|