Nicolino Ruperto1, Angela Pistorio2, Sheila Oliveira3, Francesco Zulian4, Ruben Cuttica5, Angelo Ravelli6, Michel Fischbach7, Bo Magnusson8, Gary Sterba9, Tadej Avcin10, Karine Brochard11, Fabrizia Corona12, Frank Dressler13, Valeria Gerloni14, Maria T Apaz15, Claudia Bracaglia16, Adriana Cespedes-Cruz17, Rolando Cimaz18, Gerard Couillault19, Rik Joos20, Pierre Quartier21, Ricardo Russo22, Marc Tardieu23, Nico Wulffraat24, Blanca Bica25, Pavla Dolezalova26, Virginia Ferriani27, Berit Flato28, Ana G Bernard-Medina29, Troels Herlin30, Maria Trachana31, Antonella Meini32, Emma Allain-Launay33, Clarissa Pilkington34, Veronika Vargova35, Carine Wouters36, Simona Angioloni37, Alberto Martini6. 1. Istituto Giannina Gaslini, Pediatria II, Reumatologia, PRINTO Coordinating Centre, Genoa, Italy. Electronic address: nicolaruperto@gaslini.org. 2. Istituto Giannina Gaslini, Epidemiologia, Biostatistica e Comitati, Genoa, Italy. 3. Instituto de Puericultura e Pediatria Martagao Gesteira, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. 4. Clinica Pediatrica I, Unità di Reumatologia Pediatrica, Padua, Italy. 5. Hospital General de Ninos Pedro de Elizalde, Rheumatology Section, Buenos Aires, Argentina. 6. Istituto Giannina Gaslini, Pediatria II, Reumatologia, PRINTO Coordinating Centre, Genoa, Italy; Università di Genova, Dipartimento di Pediatria, Genoa, Italy. 7. Hôpital Universitaire Hautepierre, Pédiatrie I, Strasbourg, France. 8. Pediatric Rheumatology Unit, Karolinska University Hospital, Stockholm, Sweden. 9. Hospital de Clinicas Caracas, Caracas, Venezuela. 10. University Children's Hospital, University Medical Centre Ljubljana, Department of Allergology, Rheumatology and Clinical Immunology, Ljubljana, Slovenia. 11. Paediatric Nephrology and Internist Medicine, Hôpital des Enfants, Toulouse, France. 12. Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Clinica Pediatrica II De Marchi, Milan, Italy. 13. Medizinische Hochschule Hannover, Kinderklinik, Hannover, Germany. 14. Istituto Gaetano Pini, Divisione di Reumatologia, Milan, Italy. 15. Clínica Universitaria Privada Reina Fabiola, Universidad Católica de Córdoba, Rheumatology, Cordoba, Argentina. 16. Ospedale Pediatrico Bambino Gesù, Reumatologia, Rome, Italy. 17. Centro Medico Nacional La Raza, Reumatologia Pediatrica, Mexico City, Mexico. 18. Azienda Ospedaliero-Universitaria Meyer, Florence, Italy. 19. Hopital d'Enfants, Dijon, France. 20. Universitair Ziekenhuis Gent, Centrum Voor Kinderreumatologie, Gent, Belgium. 21. Unité d'Immunologie, Hématologie et Rhumatologie Pediatrique, Université Paris-Descartes, IMAGINE Institute, Hôpital Necker-Enfants Malades, Paris, France. 22. Hospital de Pediatria Juan P Garrahan, Servicio de Inmunología/Reumatología, Buenos Aires, Argentina. 23. Assistance Publique Hôpitaux de Paris, Hôpitaux Universitaires Paris Sud and Université Paris Sud, Paris, France. 24. Department of Pediatric Immunology and Rheumatology, Wilhelmina Kinderziekenhuis, Utrecht, Netherlands. 25. Hospital Universitário Clementino Fraga Filho, UFRJ, Clinica Medica, Reumatologia, Rio de Janeiro, Brazil. 26. Pediatric Rheumatology Unit, Charles University and General University Hospital, Department of Pediatrics and Adolescent Medicine, Prague, Czech Republic. 27. Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto da Universidade de Sao Paulo, Department of Pediatrics, Division of Immunology, Allergy and Rheumatology, Ribeirao Preto, Brazil. 28. Oslo University Hospital, Rikshospitalet, Department of Rheumatology, Oslo, Norway. 29. Hospital Civil de Guadalajara Fray Antonio Alcalde, Servicio de Reumatología, Guadalajara Jalisco, Mexico. 30. Skejby Sygehus, Aarhus University Hospital, Department of Pediatrics, Aarhus, Denmark. 31. Aristotle University of Thessaloniki, Ippokration General Hospital, First Department of Pediatrics, Ippokration Hospital, Thessaloniki, Greece. 32. Clinica Pediatrica dell'Università di Brescia, Spedali Civili, Unità di Immunologia e Reumatologia Pediatrica, Brescia, Italy. 33. CHU Clinique Médicale Pédiatrique, Nantes, France. 34. Great Ormond Street Hospital for Sick Children, Centre of Paediatric and Adolescent Rheumatology, University College London, London, UK. 35. Detska Fakultna Nemocnica, First Pediatric Department, Kosice, Slovakia. 36. University Hospital Gasthuisberg, Department of Pediatrics, Division of Pediatric Rheumatology, Leuven, Belgium. 37. Istituto Giannina Gaslini, Pediatria II, Reumatologia, PRINTO Coordinating Centre, Genoa, Italy.
Abstract
BACKGROUND: Most data for treatment of dermatomyositis and juvenile dermatomyositis are from anecdotal, non-randomised case series. We aimed to compare, in a randomised trial, the efficacy and safety of prednisone alone with that of prednisone plus either methotrexate or ciclosporin in children with new-onset juvenile dermatomyositis. METHODS: We did a randomised trial at 54 centres in 22 countries. We enrolled patients aged 18 years or younger with new-onset juvenile dermatomyositis who had received no previous treatment and did not have cutaneous or gastrointestinal ulceration. We randomly allocated 139 patients via acomputer-based system to prednisone alone or in combination with either ciclosporin or methotrexate. We did not mask patients or investigators to treatment assignments. Our primary outcomes were the proportion of patients achieving a juvenile dermatomyositis PRINTO 20 level of improvement (20% improvement in three of six core set variables at 6 months), time to clinical remission, and time to treatment failure. We compared the three treatment groups with the Kruskal-Wallis test and Friedman's test, and we analysed survival with Kaplan-Meier curves and the log-rank test. Analysis was by intention to treat. Here, we present results after at least 2 years of treatment (induction and maintenance phases). This trial is registered with ClinicalTrials.gov, number NCT00323960. FINDINGS:Between May 31, 2006, and Nov 12, 2010, 47 patients were randomly assignedprednisone alone, 46 were allocated prednisone plus ciclosporin, and 46 were randomised prednisone plus methotrexate. Median duration of follow-up was 35.5 months. At month 6, 24 (51%) of 47 patients assigned prednisone, 32 (70%) of 46 allocated prednisone plus ciclosporin, and 33 (72%) of 46 administered prednisone plus methotrexate achieved a juvenile dermatomyositis PRINTO 20 improvement (p=0.0228). Median time to clinical remission was 41.9 months in patients assigned prednisone plus methotrexate but was not observable in the other two treatment groups (2.45 fold [95% CI 1.2-5.0] increase with prednisone plus methotrexate; p=0.012). Median time to treatment failure was 16.7 months in patients allocated prednisone, 53.3 months in those assigned prednisone plus ciclosporin, but was not observable in patients randomised to prednisone plus methotrexate (1.95 fold [95% CI 1.20-3.15] increase with prednisone; p=0.009). Median time to prednisone discontinuation was 35.8 months with prednisone alone compared with 29.4-29.7 months in the combination groups (p=0.002). A significantly greater proportion of patients assigned prednisone plus ciclosporin had adverse events, affecting the skin and subcutaneous tissues, gastrointestinal system, and general disorders. Infections and infestations were significantly increased in patients assigned prednisone plus ciclosporin and prednisone plus methotrexate. No patients died during the study. INTERPRETATION: Combined treatment with prednisone and either ciclosporin or methotrexate was more effective than prednisone alone. The safety profile and steroid-sparing effect favoured the combination of prednisone plus methotrexate. FUNDING: Italian Agency of Drug Evaluation, Istituto Giannina Gaslini (Genoa, Italy), Myositis Association (USA).
RCT Entities:
BACKGROUND: Most data for treatment of dermatomyositis and juvenile dermatomyositis are from anecdotal, non-randomised case series. We aimed to compare, in a randomised trial, the efficacy and safety of prednisone alone with that of prednisone plus either methotrexate or ciclosporin in children with new-onset juvenile dermatomyositis. METHODS: We did a randomised trial at 54 centres in 22 countries. We enrolled patients aged 18 years or younger with new-onset juvenile dermatomyositis who had received no previous treatment and did not have cutaneous or gastrointestinal ulceration. We randomly allocated 139 patients via a computer-based system to prednisone alone or in combination with either ciclosporin or methotrexate. We did not mask patients or investigators to treatment assignments. Our primary outcomes were the proportion of patients achieving a juvenile dermatomyositis PRINTO 20 level of improvement (20% improvement in three of six core set variables at 6 months), time to clinical remission, and time to treatment failure. We compared the three treatment groups with the Kruskal-Wallis test and Friedman's test, and we analysed survival with Kaplan-Meier curves and the log-rank test. Analysis was by intention to treat. Here, we present results after at least 2 years of treatment (induction and maintenance phases). This trial is registered with ClinicalTrials.gov, number NCT00323960. FINDINGS: Between May 31, 2006, and Nov 12, 2010, 47 patients were randomly assigned prednisone alone, 46 were allocated prednisone plus ciclosporin, and 46 were randomised prednisone plus methotrexate. Median duration of follow-up was 35.5 months. At month 6, 24 (51%) of 47 patients assigned prednisone, 32 (70%) of 46 allocated prednisone plus ciclosporin, and 33 (72%) of 46 administered prednisone plus methotrexate achieved a juvenile dermatomyositis PRINTO 20 improvement (p=0.0228). Median time to clinical remission was 41.9 months in patients assigned prednisone plus methotrexate but was not observable in the other two treatment groups (2.45 fold [95% CI 1.2-5.0] increase with prednisone plus methotrexate; p=0.012). Median time to treatment failure was 16.7 months in patients allocated prednisone, 53.3 months in those assigned prednisone plus ciclosporin, but was not observable in patients randomised to prednisone plus methotrexate (1.95 fold [95% CI 1.20-3.15] increase with prednisone; p=0.009). Median time to prednisone discontinuation was 35.8 months with prednisone alone compared with 29.4-29.7 months in the combination groups (p=0.002). A significantly greater proportion of patients assigned prednisone plus ciclosporin had adverse events, affecting the skin and subcutaneous tissues, gastrointestinal system, and general disorders. Infections and infestations were significantly increased in patients assigned prednisone plus ciclosporin and prednisone plus methotrexate. No patients died during the study. INTERPRETATION: Combined treatment with prednisone and either ciclosporin or methotrexate was more effective than prednisone alone. The safety profile and steroid-sparing effect favoured the combination of prednisone plus methotrexate. FUNDING: Italian Agency of Drug Evaluation, Istituto Giannina Gaslini (Genoa, Italy), Myositis Association (USA).
Authors: Lisa G Rider; Rohit Aggarwal; Pedro M Machado; Jean-Yves Hogrel; Ann M Reed; Lisa Christopher-Stine; Nicolino Ruperto Journal: Nat Rev Rheumatol Date: 2018-04-12 Impact factor: 20.543
Authors: Takayuki Kishi; William Warren-Hicks; Nastaran Bayat; Ira N Targoff; Adam M Huber; Michael M Ward; Lisa G Rider Journal: Rheumatology (Oxford) Date: 2021-05-14 Impact factor: 7.580