Innovative Research Design to Meet the Challenges of Clinical Trials for Juvenile Dermatomyositis
Purpose of Review
This paper aims to provide a summary of the recent therapeutic advances and the latest research on outcome measures for clinical trials in juvenile dermatomyositis (JDM).
Recent randomized controlled trials (RCTs) have demonstrated the superiority of the combination of prednisone with methotrexate over other conventional therapies and the potential effectiveness of rituximab in refractory cases. A multinational project has led to develop new criteria for the definition of minimal, moderate, and major improvement in future JDM clinical trials. This effort has been paralleled by the establishment of criteria for clinically inactive disease. The validation of the first composite disease activity score for JDM is in progress.
The new outcome measures will increase the reliability of assessment of clinical response in JDM clinical trials and foster future multinational RCTs aimed to investigate novel treatment strategies for refractory forms of JDM.
KeywordsJuvenile dermatomyositis Idiopathic inflammatory myopathies Outcome measures Randomized clinical trials Disease remission
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 3.Mendez EP, Lipton R, Ramsey-Goldman R, Roettcher P, Bowyer S, Dyer A, et al. For the NIAMS juvenile DM registry physician referral group. US incidence of juvenile dermatomyositis, 1995–1998: results from the National Institute of Arthritis and Musculoskeletal and Skin Diseases registry. Arthritis Rheum. 2003;49:300–5.CrossRefPubMedGoogle Scholar
- 7.Tollisen A, Sanner H, Flatø B, Wahl AK. Quality of life in adults with juvenile-onset dermatomyositis: a case-control study. Arthritis Care Res (Hoboken). 2012;64:1020–7.Google Scholar
- 9.Ruperto N, Pistorio A, Ravelli A, Rider LG, Pilkington C, Oliveira S, et al. Paediatric rheumatology international trials organisation (PRINTO); pediatric rheumatology collaborative study group (PRCSG). The Paediatric Rheumatology International Trials Organisation provisional criteria for the evaluation of response to therapy in juvenile dermatomyositis. Arthritis Care Res (Hoboken). 2010;62:1533–41.CrossRefGoogle Scholar
- 11.Hasija R, Pistorio A, Ravelli A, Demirkaya E, Khubchandani R, Guseinova D, et al. Pediatric rheumatology international trials organization. Therapeutic approaches in the treatment of juvenile dermatomyositis in patients with recent-onset disease and in those experiencing disease flare: an international multicenter PRINTO study. Arthritis Rheum. 2011;63:3142–52.CrossRefPubMedGoogle Scholar
- 12.Oddis CV, Reed AM, Aggarwal R, Rider LG, Ascherman DP, Levesque MC, et al. RIM study group. Rituximab in the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis: a randomized, placebo-phase trial. Arthritis Rheum. 2013;65:314–24.CrossRefPubMedPubMedCentralGoogle Scholar
- 13.•• Ruperto N, Pistorio A, Oliveira S, Zulian F, Cuttica R, Ravelli A, et al. Prednisone versus prednisone plus ciclosporin versus prednisone plus methotrexate in new-onset juvenile dermatomyositis: a randomised trial. Lancet. 2016;387:671–8. A randomized controlled trial showing the superiority of prednisone plus methotrexate over prednisone alone or prednisone plus cyclosporine. CrossRefPubMedGoogle Scholar
- 14.Huber AM, Giannini EH, Bowyer SL, Kim S, Lang B, Lindsley CB, et al. Protocols for the initial treatment of moderately severe juvenile dermatomyositis: results of a children’s arthritis and rheumatology research alliance consensus conference. Arthritis Care Res (Hoboken). 2010;62:219–25.CrossRefGoogle Scholar
- 15.Huber AM, Robinson AB, Reed AM, Abramson L, Bout-Tabaku S, Carrasco R, et al. Juvenile Dermatomyositis Subcommittee of the Childhood Arthritis and Rheumatology Research Alliance. Consensus treatments for moderate juvenile dermatomyositis: beyond the first two months. Results of the second childhood arthritis and rheumatology research alliance consensus conference. Arthritis Care Res (Hoboken). 2012;64:546–53.CrossRefGoogle Scholar
- 16.• Huber AM, Kim S, Reed AM, Carrasco R, Feldman BM, Hong SJ, et al. Childhood Arthritis and Rheumatology Research Alliance Consensus Clinical Treatment Plans for Juvenile Dermatomyositis with Persistent Skin Rash. J Rheumatol. 2017;44:110–6. This study presents consensus clinical treatment plans (CTP) for patients with JDM with persistent skin rash despite complete resolution of muscle disease developed by the Childhood Arthritis and Rheumatology Research Alliance. CrossRefPubMedGoogle Scholar
- 17.• Kim S, Kahn P, Robinson AB, Lang B, Shulman A, Oberle EJ, et al. Childhood Arthritis and Rheumatology Research Alliance consensus clinical treatment plans for juvenile dermatomyositis with skin predominant disease. Pediatr Rheumatol Online J. 2017;15:1. Another proposal of consensus clinical treatment plans for children with JDM who have active skin rashes without significant muscle involvement made by the Childhood Arthritis and Rheumatology Research Alliance (CARRA). CrossRefPubMedPubMedCentralGoogle Scholar
- 18.•• Enders FB, Bader-Meunier B, Baildam E, et al. Consensus-based recommendations for the management of juvenile dermatomyositis. Ann Rheum Dis. 2017;76:329–40. This paper reports the evidence-based recommendations for the diagnosis and treatment of JDM developed in the context of a European initiative called Single Hub and Access point for pediatric Rheumatology in Europe (SHARE). CrossRefPubMedGoogle Scholar
- 19.• McCann LJ, Pilkington CA, Huber AM, Ravelli A, Appelbe D, Kirkham JJ, et al. Development of a consensus core dataset in juvenile dermatomyositis for clinical use to inform research. Ann Rheum Dis. 2018;77(2):241–250. This study introduces an internationally agreed dataset for JDM that is designed to capture disease activity and damage over time and is aimed to enhance collaborative research and allow integration of data between centers. Google Scholar
- 24.Ruperto N, Ravelli A, Pistorio A, Ferriani V, Calvo I, Ganser G, et al. The provisional pediatric rheumatology international trial organization/American College of Rheumatology/European league against rheumatism disease activity core set for the evaluation of response to therapy in juvenile dermatomyositis: a prospective validation study. Arthritis Rheum. 2008;59:4–13.CrossRefPubMedGoogle Scholar
- 27.Lovell DJ, Lindsley CB, Rennebohm RM, Ballinger SH, Bowyer SL, Giannini EH, et al. Development of validated disease activity and damage indices for the juvenile idiopathic inflammatory myopathies. II. The childhood myositis assessment scale (CMAS): a quantitative tool for the evaluation of muscle function. Arthritis Rheum. 1999;42:2213–9.CrossRefPubMedGoogle Scholar
- 30.•• Rider LG, Aggarwal R, Pistorio A, et al. 2016 American College of Rheumatology/European League Against Rheumatism Criteria for Minimal, Moderate, and Major Clinical Response in Juvenile Dermatomyositis: An International Myositis Assessment and Clinical Studies Group/Paediatric Rheumatology International Trials Organisation Collaborative Initiative. Ann Rheum Dis. 2017;76:782–91. This report presents the new response criteria for JDM, with thresholds for minimal, moderate and major improvement. CrossRefPubMedGoogle Scholar
- 33.Pincus T, Sokka T, Kavanaugh A. Relative versus absolute goals of therapies for RA: ACR 20 or ACR 50 responses versus target values for “near remission” of DAS or single measures. Clin Exp Rheumatol. 2004;(Suppl 35):S50–6.Google Scholar
- 37.• Almeida B, Campanilho-Marques R, Arnold K, et al. Analysis of published criteria for clinically inactive disease in a large juvenile dermatomyositis cohort shows that skin disease is underestimated. Arthritis Rheumatol. 2015;67:2495–502. This study highlights the potential shortcomings of the definition of clinically inactive disease in JDM patients with active skin disease. CrossRefPubMedPubMedCentralGoogle Scholar
- 39.Consolaro A, Bracciolini G, Ruperto N, Pistorio A, Magni-Manzoni S, Malattia C, et al. Remission, minimal disease activity, and acceptable symptom state in juvenile idiopathic arthritis. Defining criteria based on the juvenile arthritis disease activity score. Arthritis Rheum. 2012;64:2366–74.CrossRefPubMedGoogle Scholar
- 42.Rosina S, Consolaro A, van Dijkhuizen P, et al. Development and validation of a composite disease activity score for juvenile dermatomyositis [abstract]. In: 23rd Paediatric rheumatology European society congress; 28th Sept - 1st Oct 2016; genoa, Italy. Pediatric Rheumatology. 2017;15(Suppl 1):P358.Google Scholar
- 49.Huber AM, Lachenbruch PA, Dugan EM, Miller FW, Rider LG, For the Juvenile Dermatomyositis Disease Activity Collaborative Study Group. For the juvenile dermatomyositis disease activity collaborative study group. Alternative scoring of the cutaneous assessment tool in juvenile dermatomyositis: results using abbreviated formats. Arthritis Rheum. 2008;59:352–6.CrossRefPubMedPubMedCentralGoogle Scholar
- 50.Isenberg DA, Allen E, Farewell V, Ehrenstein MR, Hanna MG, Lundberg IE, et al. International consensus outcome measures for patients with idiopathic inflammatory myopathies: development and initial validation of myositis activity and damage indices in patients with adult onset disease. Rheumatology (Oxford). 2004;43:49–54.CrossRefGoogle Scholar
- 52.• Campanilho-Marques R, Almeida B, Claire D, et al. Comparison of the utility and validity of three scoring tools to measure skin involvement in patients with juvenile dermatomyositis. Arthritis Care Res (Hoboken). 2016;68:1514–21. An analysis of the advantages and limitations of the most popular skin tools for JDM. CrossRefGoogle Scholar
- 58.• Deakin CT, Yasin SA, Simou S, et al. Muscle biopsy findings in combination with myositis-specific autoantibodies aid prediction of outcomes in juvenile dermatomyositis. Arthritis Rheumatol. 2016;68:2806–16. A demonstration of the potential prognostic role of severity of histopathologic findings on muscle biopsy and presence of myositis-specific autoantibodies. CrossRefPubMedPubMedCentralGoogle Scholar
- 59.Varnier GC, Rosina S, Ferrari C, Pistorio A, Consolaro A, Bovis F, et al. Development and testing of a hybrid measure of muscle strength in juvenile dermatomyositis for use in routine care. Arthritis Care Res (Hoboken). 2017. https://doi.org/10.1002/acr.23491