title: Prednisone versus prednisone plus ciclosporin versus prednisone plus methotrexate in new-onset juvenile dermatomyositis: a randomised trial.
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 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Italian Agency of Drug Evaluation, Istituto Giannina Gaslini (Genoa, Italy), Myositis Association (USA).
authors.affiliation: Istituto Giannina Gaslini, Pediatria II, Reumatologia, PRINTO Coordinating Centre, Genoa, Italy. Electronic address: nicolaruperto@gaslini.org.
authors.forename: Nicolino
authors.initials: N
authors.lastname: Ruperto
authors.affiliation: Istituto Giannina Gaslini, Epidemiologia, Biostatistica e Comitati, Genoa, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Pistorio
authors.affiliation: Instituto de Puericultura e Pediatria Martagao Gesteira, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Sheila
authors.initials: S
authors.lastname: Oliveira
authors.affiliation: Clinica Pediatrica I, Unità di Reumatologia Pediatrica, Padua, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Zulian
authors.affiliation: Hospital General de Ninos Pedro de Elizalde, Rheumatology Section, Buenos Aires, Argentina.
authors.forename: Ruben
authors.initials: R
authors.lastname: Cuttica
authors.affiliation: Istituto Giannina Gaslini, Pediatria II, Reumatologia, PRINTO Coordinating Centre, Genoa, Italy; Università di Genova, Dipartimento di Pediatria, Genoa, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Ravelli
authors.affiliation: Hôpital Universitaire Hautepierre, Pédiatrie I, Strasbourg, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Fischbach
authors.affiliation: Pediatric Rheumatology Unit, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Bo
authors.initials: B
authors.lastname: Magnusson
authors.affiliation: Hospital de Clinicas Caracas, Caracas, Venezuela.
authors.forename: Gary
authors.initials: G
authors.lastname: Sterba
authors.affiliation: University Children's Hospital, University Medical Centre Ljubljana, Department of Allergology, Rheumatology and Clinical Immunology, Ljubljana, Slovenia.
authors.forename: Tadej
authors.initials: T
authors.lastname: Avcin
authors.affiliation: Paediatric Nephrology and Internist Medicine, Hôpital des Enfants, Toulouse, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Brochard
authors.affiliation: Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Clinica Pediatrica II De Marchi, Milan, Italy.
authors.forename: Fabrizia
authors.initials: F
authors.lastname: Corona
authors.affiliation: Medizinische Hochschule Hannover, Kinderklinik, Hannover, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Dressler
authors.affiliation: Istituto Gaetano Pini, Divisione di Reumatologia, Milan, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Gerloni
authors.affiliation: Clínica Universitaria Privada Reina Fabiola, Universidad Católica de Córdoba, Rheumatology, Cordoba, Argentina.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Apaz
authors.affiliation: Ospedale Pediatrico Bambino Gesù, Reumatologia, Rome, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Bracaglia
authors.affiliation: Centro Medico Nacional La Raza, Reumatologia Pediatrica, Mexico City, Mexico.
authors.forename: Adriana
authors.initials: A
authors.lastname: Cespedes-Cruz
authors.affiliation: Azienda Ospedaliero-Universitaria Meyer, Florence, Italy.
authors.forename: Rolando
authors.initials: R
authors.lastname: Cimaz
authors.affiliation: Hopital d'Enfants, Dijon, France.
authors.forename: Gerard
authors.initials: G
authors.lastname: Couillault
authors.affiliation: Universitair Ziekenhuis Gent, Centrum Voor Kinderreumatologie, Gent, Belgium.
authors.forename: Rik
authors.initials: R
authors.lastname: Joos
authors.affiliation: Unité d'Immunologie, Hématologie et Rhumatologie Pediatrique, Université Paris-Descartes, IMAGINE Institute, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Quartier
authors.affiliation: Hospital de Pediatria Juan P Garrahan, Servicio de Inmunología/Reumatología, Buenos Aires, Argentina.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Russo
authors.affiliation: Assistance Publique Hôpitaux de Paris, Hôpitaux Universitaires Paris Sud and Université Paris Sud, Paris, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Tardieu
authors.affiliation: Department of Pediatric Immunology and Rheumatology, Wilhelmina Kinderziekenhuis, Utrecht, Netherlands.
authors.forename: Nico
authors.initials: N
authors.lastname: Wulffraat
authors.affiliation: Hospital Universitário Clementino Fraga Filho, UFRJ, Clinica Medica, Reumatologia, Rio de Janeiro, Brazil.
authors.forename: Blanca
authors.initials: B
authors.lastname: Bica
authors.affiliation: Pediatric Rheumatology Unit, Charles University and General University Hospital, Department of Pediatrics and Adolescent Medicine, Prague, Czech Republic.
authors.forename: Pavla
authors.initials: P
authors.lastname: Dolezalova
authors.affiliation: 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.
authors.forename: Virginia
authors.initials: V
authors.lastname: Ferriani
authors.affiliation: Oslo University Hospital, Rikshospitalet, Department of Rheumatology, Oslo, Norway.
authors.forename: Berit
authors.initials: B
authors.lastname: Flato
authors.affiliation: Hospital Civil de Guadalajara Fray Antonio Alcalde, Servicio de Reumatología, Guadalajara Jalisco, Mexico.
authors.forename: Ana G
authors.initials: AG
authors.lastname: Bernard-Medina
authors.affiliation: Skejby Sygehus, Aarhus University Hospital, Department of Pediatrics, Aarhus, Denmark.
authors.forename: Troels
authors.initials: T
authors.lastname: Herlin
authors.affiliation: Aristotle University of Thessaloniki, Ippokration General Hospital, First Department of Pediatrics, Ippokration Hospital, Thessaloniki, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Trachana
authors.affiliation: Clinica Pediatrica dell'Università di Brescia, Spedali Civili, Unità di Immunologia e Reumatologia Pediatrica, Brescia, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Meini
authors.affiliation: CHU Clinique Médicale Pédiatrique, Nantes, France.
authors.forename: Emma
authors.initials: E
authors.lastname: Allain-Launay
authors.affiliation: Great Ormond Street Hospital for Sick Children, Centre of Paediatric and Adolescent Rheumatology, University College London, London, UK.
authors.forename: Clarissa
authors.initials: C
authors.lastname: Pilkington
authors.affiliation: Detska Fakultna Nemocnica, First Pediatric Department, Kosice, Slovakia.
authors.forename: Veronika
authors.initials: V
authors.lastname: Vargova
authors.affiliation: University Hospital Gasthuisberg, Department of Pediatrics, Division of Pediatric Rheumatology, Leuven, Belgium.
authors.forename: Carine
authors.initials: C
authors.lastname: Wouters
authors.affiliation: Istituto Giannina Gaslini, Pediatria II, Reumatologia, PRINTO Coordinating Centre, Genoa, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Angioloni
authors.affiliation: Istituto Giannina Gaslini, Pediatria II, Reumatologia, PRINTO Coordinating Centre, Genoa, Italy; Università di Genova, Dipartimento di Pediatria, Genoa, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Martini
mesh_terms: D000293:Adolescent; D000704:Analysis of Variance; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000009:adverse effects; D002648:Child; D002675:Child, Preschool; D016572:Cyclosporine / Q000008:administration & dosage* / Q000009:adverse effects; D003879:Dermatologic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D003882:Dermatomyositis / Q000188:drug therapy*; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage* / Q000009:adverse effects; D011241:Prednisone / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D000893:Anti-Inflammatory Agents; D003879:Dermatologic Agents; D016572:Cyclosporine; D011241:Prednisone; D008727:Methotrexate