2
Biologic targeted therapies in pediatric rheumatology
EDITORIAL Fact sheets on biologic targeted therapies in pediatric rheumatology The CRI Fact Sheets will soon celebrate their tenth anniversary. Their considerable popularity is ascribable to their practical focus on the issues raised by biotherapy use in adults and children seen in the real-life setting. The CRI Fact Sheets present recommendations developed by experts in various medical fields, based both on published scientific evidence and, in the absence thereof, on expert opinion. The CRI guidelines are available online, free of charge, in both English and French. They are updated on average every 3 years to ensure that new scientific evidence and medical practices are promptly taken into account. In 2010, we felt that a stronger collaboration with our pediatric colleagues was timely, and we therefore developed pediatric CRI Fact Sheets on tocilizumab. This endeavor proved beneficial, and the CRI then established pediatric guidelines for using TNFα antagonists, abatacept, rituximab, and IL-1 receptor antagonists, the last one being edited in french. The Fact Sheets come with model letters for primary-care physicians, pediatricians, and rheumatologists, for both tocilizumab and IL-1 receptor antagonists. Additional model letters will be created during the updates of the Fact Sheets on other biotherapies. These model letters fit to the French medical community, being thus available in french. Please feel free to read and download these documents on the CRI web site (www.cri-net.com). To further strengthen the ties between the CRI and the pediatric rheumatology community, we have gathered all the pediatric recommendations about biotherapies in this Englishlanguage issue, which we are pleased to place at your disposal. For the CRI and all its partners, this issue is an important event that is perfectly in line with the SHARE program for harmonizing recommendations established by Professor WULFFRAAT. We thank all the authors and co-authors who contributed to this compelling issue created thanks to institutional support from Pfizer and a strong commitment on the part of Joint Bone Spine and its Editor-in-Chief, Professor Marie-Christophe BOISSIER, to whom we extend our deepest gratitude.
Dr. Séverine GUILLAUME-CZITROM and Prof. Jean SIBILIA
Biologic targeted therapies in pediatric rheumatology
Editor Dr. Séverine Guillaume-Czitrom, Service de Pédiatrie Générale et Rhumatologie Pédiatrique, CHU Bicêtre, Le Kremlin-Bicêtre, FRANCE Tél. : +33 1 45 21 32 42 or +33 1 45 21 32 52 E-mail : [email protected]
Disclosure of interests Séverine Guillaume-Czitrom: Clinical trials: as a co-investigator, non-principal investigator, study collaborator (Roche, Novartis); Occasional interventions: consultant (Genzyme); Conferences: invitated speaker (BMS) and attendee (Genzyme, Novartis, BMS, Wyeth).
Members of the expert committee in France Hervé Bachelez (1), Jean-Marie Berthelot (2), Yoram Bouhnik (3), Eric Bruckert (4), Pascal Claudepierre (5), Arnaud Constantin (6), Michel de Bandt (7), Bruno Fautrel (8), Philippe Gaudin (9), Vincent Goëb (10), Laure Gossec (11), Jacques-Eric Gottenberg (12), Philippe Goupille (13), Eric Hachulla (14), Isabelle Huet (15), Denis Jullien (16), Odile Launay (17), Marc Lemann f (18), Thierry Lequerré (19), Jean-Francis Maillefert (20), Xavier Mariette (21), Jean-Pierre Marolleau (22), Valérie Martinez (23), Charles Masson (24), Jacques Morel (25), Luc Mouthon (26), Thao Pham (27), Stanislas Pol (28), Xavier Puéchal (29), Pascal Richette (30), Alain Saraux (31), Thierry Schaeverbeke (32), Jérémie Sellam (33), Jacques Blacher (34), Martin Soubrier (35), Anne Sudre (36), Manuelle Viguier (37), Olivier Vittecoq (38), Daniel Wendling (39), Jean Sibilia (40) (1) Service de Dermatologie, CHU Saint-Louis, Paris. (2) Service de Rhumatologie, CHU Hôtel-Dieu, Nantes. (3) Service de Gastro-entérologie, CHU Hôpital Beaujon, Clichy. (4) Service Endocrinologie-Métabolisme, CHU Pitié-Salpétrière, Paris.(5) Service de Rhumatologie, CHU Henri Mondor, Créteil. (6) Service de Rhumatologie, CHU Rangueil, Toulouse. (7) Unité de Rhumatologie, Hôpital Robert Ballanger, Aulnay-sous-Bois. (8) Service de Rhumatologie, CHU Pitié-Salpétrière, Paris. (9) Service de Rhumatologie, CHU Grenoble, Grenoble. (10) Service de Rhumatologie, CHU Edouard Herriot, Lyon. (11) Service de Rhumatologie, CHU Cochin, Paris. (12) Service de Rhumatologie, CHU Hautepierre, Strasbourg. (13) Service de Rhumatologie, CHU Trousseau, Tours. (14) Service de Médecine Interne, CHU Hôpital Claude Huriez, Lille. (15) Service de Pneumologie, CHU Pitié-Salpêtrière, Paris. (16) Service de Dermato-vénérologie, CHU Edouard Herriot, Lyon. (17) Service d’infectiologie, CHU Cochin, Paris. (18) Service d’hépato-Gastro-Entérologie, CHU Saint Louis, Paris. (19) Service de Rhumatologie, CHU de Rouen-Hôpitaux de Rouen, Rouen. (20) Service de Rhumatologie, CHU Dijon, Dijon. (21) Service de Rhumatologie, CHU Bicêtre, Le Kremlin-Bicêtre. (22) Service d’Hématologie, CHU Amiens-Picardie, Amiens. (23) Service de Médecine Interne et Immuno-Rhumatologie, CHU Lapeyronie, Montpellier. (24) Service de Rhumatologie, CHU Angers, Angers. (25) Service d’Immuno-Rhumatologie, CHU Lapeyronie, Montpellier. (26) Service de Médecine Interne, CHU Cochin, Paris. (27) Service de Rhumatologie, CHU Conception, Marseille. (28) Unité d’Hépatologie, CHU Cochin, Paris. (29) Service de Médecine Interne, CHU Cochin, Paris. (30) Service de Rhumatologie, CHU Laboisière, Paris. (31) Service de Rhumatologie, CHU Cavale- Blanche, Brest. (32) Service de Rhumatologie, CHU Pellegrin, Bordeaux. (33) Service de Rhumatologie, Hôpital Saint-Antoine, Paris. (34) Service de Cardiologie, CHU Hôtel-Dieu, Paris. (35) Service de Rhumatologie, CHU Gabriel-Montpied, Clermont-Ferrand. (36) Service de Rhumatologie, CHU Grenoble, Grenoble. (37) Service de Dermatologie, CHU Saint-Louis, Paris. (38) Service de Rhumatologie, CHU Bois-Guillaume, Rouen. (39) Service de Rhumatologie, CHU Jean Minjoz, Besançon. (40) Service de Rhumatologie, CHU Hautepierre, Strasbourg.
The individual who wrote and coordinated these fact sheets didn’t receive fees. Katana Santé ensured the scientific coordination of the project and was in charge of formatting the document. Issue produced with institutional support of Pfizer.
3
Biologic targeted therapies in pediatric rheumatology
Use of TNFα antagonists in juvenile idiopathic arthritis Evidence Based Medicine
Official Recommendations
Expert opinion
TNFα antagonists have been tested not only in adults with RA or AS, but also in international studies of patients with juvenile idiopathic arthritis (JIA). These new medications have radically changed the management of our patients. Trials were conducted thanks to the 1999 FDA Pediatric Rule requiring pharmaceutical companies to test biological agents in children with JIA simultaneously with the trials in adults. The first TNFα antagonist licensed for use in patients with polyarticular-course JIA refractory to methotrexate therapy was etanercept in 2000 in Europe and the USA, a fusion protein composed of human IgG1 and the human soluble TNFα receptor p75. The monoclonal antibodies adalimumab and infliximab have also been evaluated in patients with polyarticular-course JIA. Adalimumab was licensed for use in this indication in 2008. The primary objective of the infliximab trial in JIA was not achieved, and this drug is not licensed for use in paediatric joint disease. Finally, the most recent TNFα antagonists golimumab and certolizumab, have not yet been evaluated in paediatric patients with joint disease. Indications in JIA Etanercept and adalimumab are currently indicated in polyarticular-course JIA, that is, polyarticular disease, extended oligoarticular disease, and systemic disease with progression to polyarthritis. TNFα antagonist therapy has been used successfully in openlabel trials in patients with juvenile spondyloarthropathies (jSpA) refractory to conventional treatment (NSAIDs, and DMARDS in peripheral forms) (1, 2) and approved in Europe in 2012 for children with jSpA or juvenile psoriatic arthritis (jPsA). The use of TNFα antagonist therapy for refractory chronic uveitis (white eye) in oligoarticular or polyarticular JIA or refractory acute uveitis (red eye) in jSpA is hotly debated and is not approved to date in paediatric patients [see the relevant paragraphs]. Infliximab is licensed for use in severe Crohn’s disease in children older than 6 years of age, based on an open-label trial showing a significant therapeutic effect in this situation (3). Published openlabel studies suggest that adalimumab may be effective also (4). Finally, etanercept has been licensed for use in severe chronic plaque psoriasis refractory to conventional therapies including phototherapy, in children older than 8 and more recently 6 years of age, based on a randomised controlled trial showing beneficial effects (5). Proof of efficacy in the different forms of JIA
Etanercept 1- In refractory polyarticular-course JIA
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Biologic targeted therapies in pediatric rheumatology
1a- In a randomised placebo-controlled trial, etanercept was effective in polyarticularcourse JIA unresponsive to methotrexate (>10 mg/m2/week). This trial comprised a 3-month lead-in period during which all patients took etanercept, followed by random allocation of the ACR Pedi30 responders to placebo or etanercept for 4 months or until the first relapse and, finally, by an open extension phase (6). The assessment of the efficacy of etanercept therapy in JIA was based on the six ACR Pedi criteria (global VAS score by the physician, global VAS score by the patient or parent, C-HAQ, number of joints with active arthritis, number of joints with limited motion, and ESR). An ACR Pedi30 response is defined as a greater than 30% improvement in at least three of the six criteria with a greater than 30% worsening of no more than one of the six criteria (7). The trial included 69 patients with severe polyarticular-course JIA (mean disease duration, 6 years). Previous DMARD therapy was stopped. The 51 (74%) patients with an ACR Pedi30 response were randomised. Relapses occurred in 21 (81%) of the 26 placebo patients and 7 (28%) of the 25 etanercept patients (p=0.003). The time to relapse was 28 days in the placebo group and more than 116 days in the etanercept group (p 80%) than in systemic JIA (ACR Pedi30, 40%) (5, 12, 1719). In some patients with systemic JIA, the initial benefits provided by etanercept therapy may be transient (20, 21). Other treatment options are being evaluated for systemic JIA, which, according to some studies, may respond better to biological agents that target interleukin-1 (IL-1) or interleukin-6 (IL-6) (22-28). It should be borne in mind that systemic JIA is a heterogeneous disease and that among recurrent forms some will continue to produce systemic manifestations (e.g., fever, rash, lymphadenopathy, and/or splenomegaly), whereas others will become strictly articular. The role for TNFα antagonists, as well as for IL-1 or IL-6 antagonists, in the various facets of systemic JIA remains to be determined. TNFα antagonists are not recommended for the first-line treatment of systemic JIA but remain a therapeutic option in patients who do not respond to IL-1 or IL-6 antagonists. 3- In juvenile spondyloarthropathies (jSpAs) Two pilot studies evaluated the efficacy of etanercept on enthesitis and arthritis (1, 2). Data from the German and Dutch registries indicate a nearly 80% ACR Pedi30 response rate with etanercept therapy in 11 and 8 patients, respectively (12, 18). Etanercept is being evaluated in an open-label phase lllb trial in a large international cohort of patients with jSpA or jPsA (29). In our experience, TNFα antagonists in patients with jSpA or jPsA refractory to NSAIDs with or without DMARDs are as effective as in adults with inflammatory joint disease. TNFα antagonists constitute a therapeutic option when other treatments fail. 4- The role for etanercept therapy in refractory chronic anterior uveitis associated with JIA, is extremely controversial (30-35). In a pilot randomised placebo-controlled trial, etanercept was evaluated for 6 months in 12 patients with JIA (without jSpA or jPsA). No benefits were found in the etanercept group compared to the placebo group (36). An open-label trial compared etanercept and infliximab in the same indication in 45 patients with JIA (including 3 with jSpA), for 24 months (37). Infliximab was more effective than etanercept. Retrospective studies done in Hamburg and Toronto produced similar findings (32, 38). The role for etanercept in recurrences of acute uveitis associated with jSpA has not been assessed. However, data obtained in adults indicate that etanercept fails to prevent recurrences of acute uveitis associated with SpA and may even induce the development of uveitis flares (34, 39) (see the section on safety and paradoxical reactions).
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Biologic targeted therapies in pediatric rheumatology
In sum, etanercept is not recommended for the treatment of chronic uveitis or acute uveitis.
Adalimumab 1- In a randomised placebo-controlled trial, adalimumab was proven effective in patients with polyarticular-course JIA, aged 4 years or older, with or without concomitant methotrexate therapy (10-15 mg/m2/week). During the 4-month open-label lead-in phase, all patients received adalimumab (24 mg/m2/2 weeks). ACR Pedi30 responders were then allocated at random to placebo or adalimumab therapy, for 32 months or until the first relapse. Finally, during the open-label extension phase patients received adalimumab every 2 weeks in a dosage of 20 mg or 40 mg depending on whether they weighed less than 30 kg or at least 30 kg (40). Of the 171 patients with JIA included in this study, 144 achieved an ACR Pedi30 response during the lead-in phase and were randomised to adalimumab or placebo therapy. An ACR Pedi30 response was achieved in 74% of patients not on concomitant methotrexate therapy and 94% of those on methotrexate therapy. Among the patients not on methotrexate therapy, 71% of those allocated to the placebo group experienced relapses, compared to 43% of those in the adalimumab group. Among patients on methotrexate, the relapse rate was 65% in the placebo group and 37% in the adalimumab group (p1 year) requiring replacement therapy with intravenous immunoglobulins (40%) (102); in a case-series study by Jansson et al. of children taking rituximab, the serum IgG, IgM, and IgA levels 6 months after the rituximab infusion were decreased by 7%, 38%, and 15%, respectively, compared to normal values for age; it should be noted that only 30 children were included in this study (73). The risk of persistent hypogammaglobulinemia, chiefly affecting IgM and IgA levels and requiring intravenous immunoglobulin replacement therapy, increases with the number of rituximab infusion cycles (73). Prolonged CD20+ B-cell depletion (>1 year); in the pediatric case-series study by Jansson et al., 59% of the patients had a differential lymphocyte count lower than 2% 6 months after the rituximab cycle. In 9% of patients, no reconstitution of the CD20+ B-cell population was noted after 13 to 87 months (73). Administration modalities: age, dosage, dosing interval, and route Age Rituximab is not licensed for use in pediatric patients with autoimmune diseases. Rituximab has been used to treat refractory forms of various autoimmune diseases starting at 7 months of age, usually concomitantly with a maintenance drug such as methotrexate (103).
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Biologic targeted therapies in pediatric rheumatology
Dosage and dosing interval The dosage and dosing interval used for the first rituximab cycle were either 375 mg/m2 once a week for 4 weeks or 750 mg/m2 every 2 weeks for 4 weeks. Depending on the authors, the second rituximab cycle should be given upon reconstitution of the B-cell population, which usually coincides with a relapse of the autoimmune disease; or when evidence of activity of the treated autoimmune disease reappears. There is general agreement that the minimum interval between rituximab cycles is 6 months. The infusions should be given after intravenous premedication with acetaminophen, methylprednisolone, and dexchlorpheniramine (see next paragraph). The hemodynamic parameters should be monitored during the infusion. The initial infusion rate of 25 mg/h is increased gradually by doubling the rate every 30 minutes as long as the drug is well tolerated, up to 100 mg/h. The infusion rate is then increased further, by 50 to 100 mg/h every 30 minutes, to a maximum of 400 mg/h (diluted in 5% glucose solution or saline to a final concentration of 1 to 4 mg/mL). Equipment allowing prompt resuscitation if needed should be kept at hand (72). The incidence of infusion-related reactions is lower at the second treatment cycle then diminishes further as the number of cycles increases. These reactions usually resolve after a decrease in the infusion rate or discontinuation of the infusion combined with the administration of drugs appropriate to the intensity of the reaction (acetaminophen, antihistamines, methylprednisolone). In mild-to-moderate infusion-related reactions, halving the infusion rate and injecting acetaminophen and an antihistamine if needed often results in resolution of the symptoms. Persistence of the symptoms requires discontinuation of the infusion. The infusion can be restarted at a low rate after full resolution of all symptoms. After the end of the infusion, the patient should be monitored for at least 2 hours before being allowed to return home. Any type of severe infusion-related reaction (e.g., shock or bronchospasm) requires immediate and permanent discontinuation of rituximab therapy and the administration on an emergency basis of appropriate symptomatic treatment (injection of an antihistamine, epinephrine, and glucocorticoids in the event of anaphylaxis) (72). The half-life of rituximab is 21 days in adults. No data are available in pediatric patients. Route of administration Intravenous Routine premedication with an antipyretic agent, an antihistamine, and methylprednisolone unless the child is already receiving systemic glucocorticoid therapy (72). Pretreatment workup Thorough clinical evaluation including the items listed below. 1. Contraindications and drug-drug interactions - Latent infections (tuberculosis, contact with a varicella patient...), chronic infections, recurrent infections, severe infections, acute active infections (ENT, lower respiratory tract, urinary tract, or dental infections); the parents should be informed of the risk of infection after the rituximab infusions. - History of demyelinating disease in the patient - Deleterious drug-drug interactions
Biologic targeted therapies in pediatric rheumatology
- Severe immune deficiency (increased risk of infection and PML) - History of neutropenia 10 mm in a patient with a previous history of BCG vaccination and a mild degree of immune deficiency; whenever the test result is in doubt, particularly in a patient previously vaccinated with the BCG, a Quantiferon®or T-Spot TB® test should be obtained (but may not be reimbursed by the statutory health insurance system in France). Interpretation of these tests for children under 5 years of age should be cautious, since guidelines are not available for this population.
6. In sexually active female adolescents, effective contraception is mandatory, particularly as some of these patients also receive methotrexate, which is known to be teratogenic. 7. Radiographs of the affected joints and an posteroanterior chest radiograph must be obtained. 8. Additional investigations as required by each specific autoimmune disease. In general, the use of immunosuppressant drugs concomitantly with or shortly after rituximab therapy is associated with a risk of severe infection and mandates close follow-up. Evaluating treatment response - Follow-up The follow-up should include both clinical evaluations and investigations, depending on the characteristics of each autoimmune disease. The most common schedule is a visit 3 months after the end of the first rituximab cycle then a visit every 6 months depending on the interval between cycles and on whether any adverse events develop. Routine investigations consist of absolute and differential blood cell counts 3 and 6 months after the cycle then before each new cycle; IgG, IgA, and IgM assays and B-cell phenotype determination (CD19 et CD20) 6 months after the cycle then before each new cycle (72). In every case, the effect of rituximab is gradual and should be assessed at a distance from each cycle; time to effectiveness depends on the type of autoimmune disease (e.g., 4 to 6 months in polyarthritis). The safety evaluation should include a search for adverse events during treatment, with particular attention to infections. In the event of a fever or patent infection, or of neuropsychiatric disorders, an emergency room visit is mandatory. In patients with persistent hypogammaglobulinemia, B-cell depletion, or recurrent infections, as well as in infants and very young children, continued monitoring of the IgG levels and B-cell phenotype is in order. - Prophylactic measures Intravenous immunoglobulin replacement therapy is not given routinely throughout the period of B-cell depletion. This treatment can be considered in patients with hypogammaglobulinemia and IgG levels 10 mm in children vaccinated with the BCG and having only mild immunodepression; if the result is doubtful, particularly in BCGvaccinated children, perform a QuantiFERON® or T-Spot TB®. 6. In adolescents, birth control must be discussed, particularly as concomitant methotrexate therapy is common. 7. An ophthalmologic evaluation must be performed before starting abatacept therapy. 8. Radiographs of involved joints and an anteroposterior chest radiograph must be obtained. Evaluating the treatment response in pediatric patients - The effectiveness of drugs for JIA should be evaluated using the ACR Pedi30, 50, 70, 90, and 100 criteria (7). - Monitoring of drug safety includes evaluations for adverse events during treatment, most notably infections and malignancies. - In most cases, visits are scheduled once a month at the beginning of abatacept therapy then every 3 months and later on every 6 months depending on whether a remission is obtained.
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Biologic targeted therapies in pediatric rheumatology
Use of tocilizumab in juvenile idiopathic arthritis Evidence Based Medicine
Official Recommendations
Expert opinion
In 2011, tocilizumab gained official recognition as a treatment for active, moderateto-severe, systemic forms of juvenile idiopathic arthritis (sJIA) in pediatric patients aged at least 2 years and having had an inadequate response to a previous treatment regimen with a nonsteroidal antiinflammatory drug and a systemic glucocorticoid. Tocilizumab can be given either as single-drug therapy (in patients unable to tolerate methotrexate or when methotrexate therapy is inappropriate) or in combination with methotrexate. These official positions are important, since the results of trials of tocilizumab in adults with rheumatoid arthritis (RA) or Still’s disease are not fully applicable to the pediatric population. 1- Some forms of JIA have no equivalent in adults (oligoarticular form with chronic anterior uveitis); others exist in adults but with different initial clinical manifestations (psoriatic arthritis, arthritis with enthesitis); and the frequency distribution of JIA types differs from that of chronic inflammatory joint disease in adults (juvenile RA 30 Kg and 12 mg/Kg/15 days if body weight is 30 Kg and 10 mg/Kg in those weighing 30% improvement in at least three of the six variables of the ACRPedi score, with no more than one of the six variables worsening by >30% (7). In the various studies of sJIA, the ACRPedi score was modified to take the systemic manifestations into account; in some studies, the CRP level had to remain below a predefined cutoff, which varied across studies; and in others, more comprehensive
Biologic targeted therapies in pediatric rheumatology
tools were used, such as the systemic score developed by Woo et al. and based on the fever, peripheral lymphadenopathy, liver and spleen enlargement, seritis (pericardium, pleura, and peritoneum), and skin rash (140). To date, no systemic score has been validated. The glucocorticoid-sparing effect of the study treatment has also been suggested as a useful efficacy measure. Results of therapeutic trials of tocilizumab in sJIA:
Two phase III trials have been published, one conducted in Japan and the other in the West (25, 124), as well as a nearly 3-year extension of the Japanese study (123). Tocilizumab proved effective on both the systemic and the articular manifestations of sJIA refractory to conventional maintenance drugs or to TNFα antagonists or IL-1 antagonists. - The Japanese trial included 56 patients with refractory sJIA inadequately controlled by glucocorticoid therapy (25). No maintenance drugs were allowed during the trial. The trial involved three phases: a 6-week lead-in phase during which all patients received tocilizumab (8 mg/Kg/2 weeks), a double-blind randomized phase in which patients with an ACRPedi 30 response and CRP15 mg/L] under placebo therapy during the double-blind phase were automatically entered into the third phase). At completion of the lead-in phase, the ACRPedi 30, 50, and 70 response rates were 91%, 86%, and 68%, respectively. Of the 43 patients randomized during the second phase, 17% (4/23) in the placebo group and 80% (16/20) in the tocilizumab group maintained the ACRPedi 30 response and CRP
Biologic targeted therapies in pediatric rheumatology
EDITORIAL Fact sheets on biologic targeted therapies in pediatric rheumatology The CRI Fact Sheets will soon celebrate their tenth anniversary. Their considerable popularity is ascribable to their practical focus on the issues raised by biotherapy use in adults and children seen in the real-life setting. The CRI Fact Sheets present recommendations developed by experts in various medical fields, based both on published scientific evidence and, in the absence thereof, on expert opinion. The CRI guidelines are available online, free of charge, in both English and French. They are updated on average every 3 years to ensure that new scientific evidence and medical practices are promptly taken into account. In 2010, we felt that a stronger collaboration with our pediatric colleagues was timely, and we therefore developed pediatric CRI Fact Sheets on tocilizumab. This endeavor proved beneficial, and the CRI then established pediatric guidelines for using TNFα antagonists, abatacept, rituximab, and IL-1 receptor antagonists, the last one being edited in french. The Fact Sheets come with model letters for primary-care physicians, pediatricians, and rheumatologists, for both tocilizumab and IL-1 receptor antagonists. Additional model letters will be created during the updates of the Fact Sheets on other biotherapies. These model letters fit to the French medical community, being thus available in french. Please feel free to read and download these documents on the CRI web site (www.cri-net.com). To further strengthen the ties between the CRI and the pediatric rheumatology community, we have gathered all the pediatric recommendations about biotherapies in this Englishlanguage issue, which we are pleased to place at your disposal. For the CRI and all its partners, this issue is an important event that is perfectly in line with the SHARE program for harmonizing recommendations established by Professor WULFFRAAT. We thank all the authors and co-authors who contributed to this compelling issue created thanks to institutional support from Pfizer and a strong commitment on the part of Joint Bone Spine and its Editor-in-Chief, Professor Marie-Christophe BOISSIER, to whom we extend our deepest gratitude.
Dr. Séverine GUILLAUME-CZITROM and Prof. Jean SIBILIA
Biologic targeted therapies in pediatric rheumatology
Editor Dr. Séverine Guillaume-Czitrom, Service de Pédiatrie Générale et Rhumatologie Pédiatrique, CHU Bicêtre, Le Kremlin-Bicêtre, FRANCE Tél. : +33 1 45 21 32 42 or +33 1 45 21 32 52 E-mail : [email protected]
Disclosure of interests Séverine Guillaume-Czitrom: Clinical trials: as a co-investigator, non-principal investigator, study collaborator (Roche, Novartis); Occasional interventions: consultant (Genzyme); Conferences: invitated speaker (BMS) and attendee (Genzyme, Novartis, BMS, Wyeth).
Members of the expert committee in France Hervé Bachelez (1), Jean-Marie Berthelot (2), Yoram Bouhnik (3), Eric Bruckert (4), Pascal Claudepierre (5), Arnaud Constantin (6), Michel de Bandt (7), Bruno Fautrel (8), Philippe Gaudin (9), Vincent Goëb (10), Laure Gossec (11), Jacques-Eric Gottenberg (12), Philippe Goupille (13), Eric Hachulla (14), Isabelle Huet (15), Denis Jullien (16), Odile Launay (17), Marc Lemann f (18), Thierry Lequerré (19), Jean-Francis Maillefert (20), Xavier Mariette (21), Jean-Pierre Marolleau (22), Valérie Martinez (23), Charles Masson (24), Jacques Morel (25), Luc Mouthon (26), Thao Pham (27), Stanislas Pol (28), Xavier Puéchal (29), Pascal Richette (30), Alain Saraux (31), Thierry Schaeverbeke (32), Jérémie Sellam (33), Jacques Blacher (34), Martin Soubrier (35), Anne Sudre (36), Manuelle Viguier (37), Olivier Vittecoq (38), Daniel Wendling (39), Jean Sibilia (40) (1) Service de Dermatologie, CHU Saint-Louis, Paris. (2) Service de Rhumatologie, CHU Hôtel-Dieu, Nantes. (3) Service de Gastro-entérologie, CHU Hôpital Beaujon, Clichy. (4) Service Endocrinologie-Métabolisme, CHU Pitié-Salpétrière, Paris.(5) Service de Rhumatologie, CHU Henri Mondor, Créteil. (6) Service de Rhumatologie, CHU Rangueil, Toulouse. (7) Unité de Rhumatologie, Hôpital Robert Ballanger, Aulnay-sous-Bois. (8) Service de Rhumatologie, CHU Pitié-Salpétrière, Paris. (9) Service de Rhumatologie, CHU Grenoble, Grenoble. (10) Service de Rhumatologie, CHU Edouard Herriot, Lyon. (11) Service de Rhumatologie, CHU Cochin, Paris. (12) Service de Rhumatologie, CHU Hautepierre, Strasbourg. (13) Service de Rhumatologie, CHU Trousseau, Tours. (14) Service de Médecine Interne, CHU Hôpital Claude Huriez, Lille. (15) Service de Pneumologie, CHU Pitié-Salpêtrière, Paris. (16) Service de Dermato-vénérologie, CHU Edouard Herriot, Lyon. (17) Service d’infectiologie, CHU Cochin, Paris. (18) Service d’hépato-Gastro-Entérologie, CHU Saint Louis, Paris. (19) Service de Rhumatologie, CHU de Rouen-Hôpitaux de Rouen, Rouen. (20) Service de Rhumatologie, CHU Dijon, Dijon. (21) Service de Rhumatologie, CHU Bicêtre, Le Kremlin-Bicêtre. (22) Service d’Hématologie, CHU Amiens-Picardie, Amiens. (23) Service de Médecine Interne et Immuno-Rhumatologie, CHU Lapeyronie, Montpellier. (24) Service de Rhumatologie, CHU Angers, Angers. (25) Service d’Immuno-Rhumatologie, CHU Lapeyronie, Montpellier. (26) Service de Médecine Interne, CHU Cochin, Paris. (27) Service de Rhumatologie, CHU Conception, Marseille. (28) Unité d’Hépatologie, CHU Cochin, Paris. (29) Service de Médecine Interne, CHU Cochin, Paris. (30) Service de Rhumatologie, CHU Laboisière, Paris. (31) Service de Rhumatologie, CHU Cavale- Blanche, Brest. (32) Service de Rhumatologie, CHU Pellegrin, Bordeaux. (33) Service de Rhumatologie, Hôpital Saint-Antoine, Paris. (34) Service de Cardiologie, CHU Hôtel-Dieu, Paris. (35) Service de Rhumatologie, CHU Gabriel-Montpied, Clermont-Ferrand. (36) Service de Rhumatologie, CHU Grenoble, Grenoble. (37) Service de Dermatologie, CHU Saint-Louis, Paris. (38) Service de Rhumatologie, CHU Bois-Guillaume, Rouen. (39) Service de Rhumatologie, CHU Jean Minjoz, Besançon. (40) Service de Rhumatologie, CHU Hautepierre, Strasbourg.
The individual who wrote and coordinated these fact sheets didn’t receive fees. Katana Santé ensured the scientific coordination of the project and was in charge of formatting the document. Issue produced with institutional support of Pfizer.
3
Biologic targeted therapies in pediatric rheumatology
Use of TNFα antagonists in juvenile idiopathic arthritis Evidence Based Medicine
Official Recommendations
Expert opinion
TNFα antagonists have been tested not only in adults with RA or AS, but also in international studies of patients with juvenile idiopathic arthritis (JIA). These new medications have radically changed the management of our patients. Trials were conducted thanks to the 1999 FDA Pediatric Rule requiring pharmaceutical companies to test biological agents in children with JIA simultaneously with the trials in adults. The first TNFα antagonist licensed for use in patients with polyarticular-course JIA refractory to methotrexate therapy was etanercept in 2000 in Europe and the USA, a fusion protein composed of human IgG1 and the human soluble TNFα receptor p75. The monoclonal antibodies adalimumab and infliximab have also been evaluated in patients with polyarticular-course JIA. Adalimumab was licensed for use in this indication in 2008. The primary objective of the infliximab trial in JIA was not achieved, and this drug is not licensed for use in paediatric joint disease. Finally, the most recent TNFα antagonists golimumab and certolizumab, have not yet been evaluated in paediatric patients with joint disease. Indications in JIA Etanercept and adalimumab are currently indicated in polyarticular-course JIA, that is, polyarticular disease, extended oligoarticular disease, and systemic disease with progression to polyarthritis. TNFα antagonist therapy has been used successfully in openlabel trials in patients with juvenile spondyloarthropathies (jSpA) refractory to conventional treatment (NSAIDs, and DMARDS in peripheral forms) (1, 2) and approved in Europe in 2012 for children with jSpA or juvenile psoriatic arthritis (jPsA). The use of TNFα antagonist therapy for refractory chronic uveitis (white eye) in oligoarticular or polyarticular JIA or refractory acute uveitis (red eye) in jSpA is hotly debated and is not approved to date in paediatric patients [see the relevant paragraphs]. Infliximab is licensed for use in severe Crohn’s disease in children older than 6 years of age, based on an open-label trial showing a significant therapeutic effect in this situation (3). Published openlabel studies suggest that adalimumab may be effective also (4). Finally, etanercept has been licensed for use in severe chronic plaque psoriasis refractory to conventional therapies including phototherapy, in children older than 8 and more recently 6 years of age, based on a randomised controlled trial showing beneficial effects (5). Proof of efficacy in the different forms of JIA
Etanercept 1- In refractory polyarticular-course JIA
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Biologic targeted therapies in pediatric rheumatology
1a- In a randomised placebo-controlled trial, etanercept was effective in polyarticularcourse JIA unresponsive to methotrexate (>10 mg/m2/week). This trial comprised a 3-month lead-in period during which all patients took etanercept, followed by random allocation of the ACR Pedi30 responders to placebo or etanercept for 4 months or until the first relapse and, finally, by an open extension phase (6). The assessment of the efficacy of etanercept therapy in JIA was based on the six ACR Pedi criteria (global VAS score by the physician, global VAS score by the patient or parent, C-HAQ, number of joints with active arthritis, number of joints with limited motion, and ESR). An ACR Pedi30 response is defined as a greater than 30% improvement in at least three of the six criteria with a greater than 30% worsening of no more than one of the six criteria (7). The trial included 69 patients with severe polyarticular-course JIA (mean disease duration, 6 years). Previous DMARD therapy was stopped. The 51 (74%) patients with an ACR Pedi30 response were randomised. Relapses occurred in 21 (81%) of the 26 placebo patients and 7 (28%) of the 25 etanercept patients (p=0.003). The time to relapse was 28 days in the placebo group and more than 116 days in the etanercept group (p 80%) than in systemic JIA (ACR Pedi30, 40%) (5, 12, 1719). In some patients with systemic JIA, the initial benefits provided by etanercept therapy may be transient (20, 21). Other treatment options are being evaluated for systemic JIA, which, according to some studies, may respond better to biological agents that target interleukin-1 (IL-1) or interleukin-6 (IL-6) (22-28). It should be borne in mind that systemic JIA is a heterogeneous disease and that among recurrent forms some will continue to produce systemic manifestations (e.g., fever, rash, lymphadenopathy, and/or splenomegaly), whereas others will become strictly articular. The role for TNFα antagonists, as well as for IL-1 or IL-6 antagonists, in the various facets of systemic JIA remains to be determined. TNFα antagonists are not recommended for the first-line treatment of systemic JIA but remain a therapeutic option in patients who do not respond to IL-1 or IL-6 antagonists. 3- In juvenile spondyloarthropathies (jSpAs) Two pilot studies evaluated the efficacy of etanercept on enthesitis and arthritis (1, 2). Data from the German and Dutch registries indicate a nearly 80% ACR Pedi30 response rate with etanercept therapy in 11 and 8 patients, respectively (12, 18). Etanercept is being evaluated in an open-label phase lllb trial in a large international cohort of patients with jSpA or jPsA (29). In our experience, TNFα antagonists in patients with jSpA or jPsA refractory to NSAIDs with or without DMARDs are as effective as in adults with inflammatory joint disease. TNFα antagonists constitute a therapeutic option when other treatments fail. 4- The role for etanercept therapy in refractory chronic anterior uveitis associated with JIA, is extremely controversial (30-35). In a pilot randomised placebo-controlled trial, etanercept was evaluated for 6 months in 12 patients with JIA (without jSpA or jPsA). No benefits were found in the etanercept group compared to the placebo group (36). An open-label trial compared etanercept and infliximab in the same indication in 45 patients with JIA (including 3 with jSpA), for 24 months (37). Infliximab was more effective than etanercept. Retrospective studies done in Hamburg and Toronto produced similar findings (32, 38). The role for etanercept in recurrences of acute uveitis associated with jSpA has not been assessed. However, data obtained in adults indicate that etanercept fails to prevent recurrences of acute uveitis associated with SpA and may even induce the development of uveitis flares (34, 39) (see the section on safety and paradoxical reactions).
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Biologic targeted therapies in pediatric rheumatology
In sum, etanercept is not recommended for the treatment of chronic uveitis or acute uveitis.
Adalimumab 1- In a randomised placebo-controlled trial, adalimumab was proven effective in patients with polyarticular-course JIA, aged 4 years or older, with or without concomitant methotrexate therapy (10-15 mg/m2/week). During the 4-month open-label lead-in phase, all patients received adalimumab (24 mg/m2/2 weeks). ACR Pedi30 responders were then allocated at random to placebo or adalimumab therapy, for 32 months or until the first relapse. Finally, during the open-label extension phase patients received adalimumab every 2 weeks in a dosage of 20 mg or 40 mg depending on whether they weighed less than 30 kg or at least 30 kg (40). Of the 171 patients with JIA included in this study, 144 achieved an ACR Pedi30 response during the lead-in phase and were randomised to adalimumab or placebo therapy. An ACR Pedi30 response was achieved in 74% of patients not on concomitant methotrexate therapy and 94% of those on methotrexate therapy. Among the patients not on methotrexate therapy, 71% of those allocated to the placebo group experienced relapses, compared to 43% of those in the adalimumab group. Among patients on methotrexate, the relapse rate was 65% in the placebo group and 37% in the adalimumab group (p1 year) requiring replacement therapy with intravenous immunoglobulins (40%) (102); in a case-series study by Jansson et al. of children taking rituximab, the serum IgG, IgM, and IgA levels 6 months after the rituximab infusion were decreased by 7%, 38%, and 15%, respectively, compared to normal values for age; it should be noted that only 30 children were included in this study (73). The risk of persistent hypogammaglobulinemia, chiefly affecting IgM and IgA levels and requiring intravenous immunoglobulin replacement therapy, increases with the number of rituximab infusion cycles (73). Prolonged CD20+ B-cell depletion (>1 year); in the pediatric case-series study by Jansson et al., 59% of the patients had a differential lymphocyte count lower than 2% 6 months after the rituximab cycle. In 9% of patients, no reconstitution of the CD20+ B-cell population was noted after 13 to 87 months (73). Administration modalities: age, dosage, dosing interval, and route Age Rituximab is not licensed for use in pediatric patients with autoimmune diseases. Rituximab has been used to treat refractory forms of various autoimmune diseases starting at 7 months of age, usually concomitantly with a maintenance drug such as methotrexate (103).
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Biologic targeted therapies in pediatric rheumatology
Dosage and dosing interval The dosage and dosing interval used for the first rituximab cycle were either 375 mg/m2 once a week for 4 weeks or 750 mg/m2 every 2 weeks for 4 weeks. Depending on the authors, the second rituximab cycle should be given upon reconstitution of the B-cell population, which usually coincides with a relapse of the autoimmune disease; or when evidence of activity of the treated autoimmune disease reappears. There is general agreement that the minimum interval between rituximab cycles is 6 months. The infusions should be given after intravenous premedication with acetaminophen, methylprednisolone, and dexchlorpheniramine (see next paragraph). The hemodynamic parameters should be monitored during the infusion. The initial infusion rate of 25 mg/h is increased gradually by doubling the rate every 30 minutes as long as the drug is well tolerated, up to 100 mg/h. The infusion rate is then increased further, by 50 to 100 mg/h every 30 minutes, to a maximum of 400 mg/h (diluted in 5% glucose solution or saline to a final concentration of 1 to 4 mg/mL). Equipment allowing prompt resuscitation if needed should be kept at hand (72). The incidence of infusion-related reactions is lower at the second treatment cycle then diminishes further as the number of cycles increases. These reactions usually resolve after a decrease in the infusion rate or discontinuation of the infusion combined with the administration of drugs appropriate to the intensity of the reaction (acetaminophen, antihistamines, methylprednisolone). In mild-to-moderate infusion-related reactions, halving the infusion rate and injecting acetaminophen and an antihistamine if needed often results in resolution of the symptoms. Persistence of the symptoms requires discontinuation of the infusion. The infusion can be restarted at a low rate after full resolution of all symptoms. After the end of the infusion, the patient should be monitored for at least 2 hours before being allowed to return home. Any type of severe infusion-related reaction (e.g., shock or bronchospasm) requires immediate and permanent discontinuation of rituximab therapy and the administration on an emergency basis of appropriate symptomatic treatment (injection of an antihistamine, epinephrine, and glucocorticoids in the event of anaphylaxis) (72). The half-life of rituximab is 21 days in adults. No data are available in pediatric patients. Route of administration Intravenous Routine premedication with an antipyretic agent, an antihistamine, and methylprednisolone unless the child is already receiving systemic glucocorticoid therapy (72). Pretreatment workup Thorough clinical evaluation including the items listed below. 1. Contraindications and drug-drug interactions - Latent infections (tuberculosis, contact with a varicella patient...), chronic infections, recurrent infections, severe infections, acute active infections (ENT, lower respiratory tract, urinary tract, or dental infections); the parents should be informed of the risk of infection after the rituximab infusions. - History of demyelinating disease in the patient - Deleterious drug-drug interactions
Biologic targeted therapies in pediatric rheumatology
- Severe immune deficiency (increased risk of infection and PML) - History of neutropenia 10 mm in a patient with a previous history of BCG vaccination and a mild degree of immune deficiency; whenever the test result is in doubt, particularly in a patient previously vaccinated with the BCG, a Quantiferon®or T-Spot TB® test should be obtained (but may not be reimbursed by the statutory health insurance system in France). Interpretation of these tests for children under 5 years of age should be cautious, since guidelines are not available for this population.
6. In sexually active female adolescents, effective contraception is mandatory, particularly as some of these patients also receive methotrexate, which is known to be teratogenic. 7. Radiographs of the affected joints and an posteroanterior chest radiograph must be obtained. 8. Additional investigations as required by each specific autoimmune disease. In general, the use of immunosuppressant drugs concomitantly with or shortly after rituximab therapy is associated with a risk of severe infection and mandates close follow-up. Evaluating treatment response - Follow-up The follow-up should include both clinical evaluations and investigations, depending on the characteristics of each autoimmune disease. The most common schedule is a visit 3 months after the end of the first rituximab cycle then a visit every 6 months depending on the interval between cycles and on whether any adverse events develop. Routine investigations consist of absolute and differential blood cell counts 3 and 6 months after the cycle then before each new cycle; IgG, IgA, and IgM assays and B-cell phenotype determination (CD19 et CD20) 6 months after the cycle then before each new cycle (72). In every case, the effect of rituximab is gradual and should be assessed at a distance from each cycle; time to effectiveness depends on the type of autoimmune disease (e.g., 4 to 6 months in polyarthritis). The safety evaluation should include a search for adverse events during treatment, with particular attention to infections. In the event of a fever or patent infection, or of neuropsychiatric disorders, an emergency room visit is mandatory. In patients with persistent hypogammaglobulinemia, B-cell depletion, or recurrent infections, as well as in infants and very young children, continued monitoring of the IgG levels and B-cell phenotype is in order. - Prophylactic measures Intravenous immunoglobulin replacement therapy is not given routinely throughout the period of B-cell depletion. This treatment can be considered in patients with hypogammaglobulinemia and IgG levels 10 mm in children vaccinated with the BCG and having only mild immunodepression; if the result is doubtful, particularly in BCGvaccinated children, perform a QuantiFERON® or T-Spot TB®. 6. In adolescents, birth control must be discussed, particularly as concomitant methotrexate therapy is common. 7. An ophthalmologic evaluation must be performed before starting abatacept therapy. 8. Radiographs of involved joints and an anteroposterior chest radiograph must be obtained. Evaluating the treatment response in pediatric patients - The effectiveness of drugs for JIA should be evaluated using the ACR Pedi30, 50, 70, 90, and 100 criteria (7). - Monitoring of drug safety includes evaluations for adverse events during treatment, most notably infections and malignancies. - In most cases, visits are scheduled once a month at the beginning of abatacept therapy then every 3 months and later on every 6 months depending on whether a remission is obtained.
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Biologic targeted therapies in pediatric rheumatology
Use of tocilizumab in juvenile idiopathic arthritis Evidence Based Medicine
Official Recommendations
Expert opinion
In 2011, tocilizumab gained official recognition as a treatment for active, moderateto-severe, systemic forms of juvenile idiopathic arthritis (sJIA) in pediatric patients aged at least 2 years and having had an inadequate response to a previous treatment regimen with a nonsteroidal antiinflammatory drug and a systemic glucocorticoid. Tocilizumab can be given either as single-drug therapy (in patients unable to tolerate methotrexate or when methotrexate therapy is inappropriate) or in combination with methotrexate. These official positions are important, since the results of trials of tocilizumab in adults with rheumatoid arthritis (RA) or Still’s disease are not fully applicable to the pediatric population. 1- Some forms of JIA have no equivalent in adults (oligoarticular form with chronic anterior uveitis); others exist in adults but with different initial clinical manifestations (psoriatic arthritis, arthritis with enthesitis); and the frequency distribution of JIA types differs from that of chronic inflammatory joint disease in adults (juvenile RA 30 Kg and 12 mg/Kg/15 days if body weight is 30 Kg and 10 mg/Kg in those weighing 30% improvement in at least three of the six variables of the ACRPedi score, with no more than one of the six variables worsening by >30% (7). In the various studies of sJIA, the ACRPedi score was modified to take the systemic manifestations into account; in some studies, the CRP level had to remain below a predefined cutoff, which varied across studies; and in others, more comprehensive
Biologic targeted therapies in pediatric rheumatology
tools were used, such as the systemic score developed by Woo et al. and based on the fever, peripheral lymphadenopathy, liver and spleen enlargement, seritis (pericardium, pleura, and peritoneum), and skin rash (140). To date, no systemic score has been validated. The glucocorticoid-sparing effect of the study treatment has also been suggested as a useful efficacy measure. Results of therapeutic trials of tocilizumab in sJIA:
Two phase III trials have been published, one conducted in Japan and the other in the West (25, 124), as well as a nearly 3-year extension of the Japanese study (123). Tocilizumab proved effective on both the systemic and the articular manifestations of sJIA refractory to conventional maintenance drugs or to TNFα antagonists or IL-1 antagonists. - The Japanese trial included 56 patients with refractory sJIA inadequately controlled by glucocorticoid therapy (25). No maintenance drugs were allowed during the trial. The trial involved three phases: a 6-week lead-in phase during which all patients received tocilizumab (8 mg/Kg/2 weeks), a double-blind randomized phase in which patients with an ACRPedi 30 response and CRP15 mg/L] under placebo therapy during the double-blind phase were automatically entered into the third phase). At completion of the lead-in phase, the ACRPedi 30, 50, and 70 response rates were 91%, 86%, and 68%, respectively. Of the 43 patients randomized during the second phase, 17% (4/23) in the placebo group and 80% (16/20) in the tocilizumab group maintained the ACRPedi 30 response and CRP
