REVIEW CURRENT OPINION Recent advances in juvenile idiopathic inflammatory myopathies Floranne C. Ernstea and Ann M. Reedb Purpose of review Ongoing research continues to advance our understanding of the juvenile idiopathic inflammatory myopathies (JIIMs). We review the recent contributions from the published literature about the classification, pathogenesis, assessment, and treatment of JIIMs in basic and translational science and clinical research in 2013 through early 2014. Recent findings Large registries, such as the Childhood Arthritis and Rheumatology Research Alliance registry, are conducting trials to enhance our understanding of JIIMs. Ultraviolet radiation exposure 1 month prior to juvenile dermatomyositis (JDM) may trigger the onset of disease. Myositis-specific autoantibodies define clinical phenotypes in JIIMs. MRI is useful in diagnosing JDM and may be used as a disease assessment tool. Type 1 interferon genes and proteins are increasing in use as disease assessment tools, but larger, prospective, validation studies are needed. Moderate-to-intense physical activity is effective in increasing the aerobic capacity of JDM patients in remission. New criteria developed by the Paediatric Rheumatology International Trials Organization for classifying inactive disease in JDM have practical applicability to the current clinical practice and clinical trials as even after 16.8 years of symptom onset, over half of JDM patients still have active disease. Summary There has been significant progress in understanding the clinical characteristics, diagnostic workup, treatment, disease assessment, and prognosis of JIIM patients, but more prospective treatment trials are needed, especially in light of the paucity of the current biologic treatment agents available. Keywords clinical characteristics, immunopathogenesis, juvenile dermatomyositis, prognosis, therapy INTRODUCTION common myositis is JDM, comprising approxi- The juvenile idiopathic inflammatory myopathies mately 85% of JIIM patients. JDM is characterized (JIIMs) are a group of rare, autoimmune inflamma- by symmetrical proximal muscle weakness, tory muscle disorders characterized by muscle weak- Gottron’s papules, heliotrope rash, and periungual telangiectasias, signifying an immune-mediated ness and multisystem involvement. The main && clinical phenotypes of JIIMs are classified as juvenile vasculopathy [1–3,4 ,5]. Other organs also are dermatomyositis (JDM), juvenile connective tissue affected such as the joints (inflammatory arthritis), disease myositis (JCTM), and juvenile polymyositis gastrointestinal (i.e. dysphagia or gastrointestinal ulceration), pulmonary (interstitial lung disease), (JPM) [1]. In this review, we discuss the recent && developments in understanding the classification, and cardiac systems [1,4 ]. The Childhood Arthritis clinical characteristics, diagnostic workup, immuno- and Rheumatology Research Alliance (CARRA) pathogenesis, and standardization of treatment plans and prognosis from the recent clinical and aDivision of Rheumatology, Department of Internal Medicine and translational research trials over the last year and bDepartment of Pediatrics, Mayo Clinic College of Medicine, Rochester, a half. Minnesota, USA Correspondence to Floranne C. Ernste, MD, 200 First Street SW, Rochester, MN 55905, USA. Tel: +1 507 284 2060; fax: +1 507 CLASSIFICATION 284 0564; e-mail: [email protected] Large registry studies have helped to clarify the Curr Opin Rheumatol 2014, 26:671–678 common clinical phenotypes of JIIMs [1]. The most DOI:10.1097/BOR.0000000000000103 1040-8711 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-rheumatology.com Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Myositis and myopathies [9&&,10&&]. Clinical characteristics include proximal KEY POINTS and distal muscle weakness, higher muscle enzymes, and more frequent falling episodes and cardiac events The Childhood Arthritis and Rheumatology Research && Alliance (CARRA) registry is conducting ongoing trials [10 ]. Amyopathic or hypomyopathic dermatomyo- for understanding the clinical characteristics, prognosis, sitis occurs with a frequency of 1%. Manifestations and standardizing treatment guidelines for JDM. include inflammatory rashes without muscle weak- ness or subclinical muscle weakness. Approximately Ultraviolet radiation exposure 1 month prior to JIIM disease onset plays a role in determining the disease 25% of children with amyopathic dermatomyositis course and serologic autoantibody expression. may eventually develop JDM [1]. Myositis-specific autoantibodies, such as anti-p155/ 140 and anti-MJ, define two major serologic subgroups DIAGNOSIS in JIIMs. Historically, the diagnosis of JIIMs has been based New criteria developed by the Paediatric on the Bohan and Peter [11,12] criteria, that is, Rheumatology International Trials Organization classic rash and at least three of the following: (PRINTO) for classifying clinically inactive disease in muscle weakness, elevated muscle enzymes, charac- JDM have practical applicability to the current clinical teristic electromyography (EMG) findings sugges- practice and clinical trials. tive of inflammatory myopathy, and typical Over half of JDM patients still have clinically active histopathological features on a muscle biopsy. How- disease even after a median of 16.8 years after ever, a major limitation to the criteria is that symptom onset. pediatric patients often do not undergo EMG and muscle biopsies. Rather, it has become a common practice to forego muscle biopsies and utilize non- registry, a multicenter national registry established invasive diagnostic methods such as myositis auto- in the United States in 2010, recently conducted a antibodies and MRI of affected muscles to secure a cross-sectional analysis of data about the clinical diagnosis [4&&,13,14]. characteristics, treatments, and functional out- comes of 384 children with JDM from 2010 to 2012 [4&&]. The median age of onset is 7.5–10.8 years MYOSITIS-SPECIFIC AND MYOSITIS- with a female and White predominance [1,4&&]; ASSOCIATED AUTOANTIBODIES there are three disease patterns described: a mono- The presence of myositis-specific autoantibodies cyclic course in a third of patients with resolution (MSAs) or myositis-associated autoantibodies within 2 years; a polycyclic course defined by (MAAs) provide a useful noninvasive means to sero- periods of remission and disease recurrence; and a logically classify JIIM patients. They provide defined chronic continuous course occurring in over 50% of subsets of JIIM patients who share similar clinical JDM patients, characterized by persistent capillary features and help predict prognosis [1,15,16] nailfold changes and active inflammatory rashes (Table 1). The earliest studied MSAs were the anti- [1,4&&,6,7]. Subcutaneous and intramuscular calci- aminoacyl-tRNA synthetase autoantibodies such as nosis, refractory to medical management, may be a anti-Jo-1 and the anti-Mi2 and antisignal recog- dominant feature among 15–50% of JDM patients nition particle (SRP) autoantibodies, although they [1,6,7]. Recently, a retrospective review of sub- are found in less than 10% of JDM patients Saharan African children with JDM found a cumu- [1,9&&,10&&,15,16]. Shah et al. [10&&] found that lative frequency of calcinosis in 71%, of whom a JDM patients frequently had more anti-p155/140 third had calcinosis at presentation, whereas 38% (reactive to transcriptional intermediary factor developed calcinosis during follow-up [8]. 1g), anti-MJ (NXP-2), and anti-Mi2 autoantibodies, Less common clinical phenotypes include JCTM, whereas anti-SRP and anti-Jo-1 antibodies occurred JPM, and amyopathic or hypomyopathic dermato- more frequently in JPM patients, and anti-U1-RNP myositis [1,9&&,10&&]. JCTM occurs in 6–11% of JIIMs and anti-PM-Scl antibodies were seen mostly in in conjunction with another connective tissue dis- JCTM. Rider et al. [9&&] reported that there are two ease such as systemic lupus erythematosus (SLE), major serologic subsets in JIIM patients, the anti- juvenile idiopathic arthritis (JIA), scleroderma, p155/140 antibody and the anti-MJ antibody, and and Sjo¨gren’s syndrome [1]. JCTM patients have they have a prevalence of 35 and 23%, respectively; Raynaud’s phenomenon, inflammatory arthritis, children with these MSAs share similar clinical malar rashes, and interstitial lung disease characteristics. For example, in the anti-p155/140 [1,9&&,10&&]. JPM occurs in approximately 4–8% of antibody subgroup, there are severe skin abnormal- patients. It is often seen in Black adolescent patients ities such as Gottron papules, malar rash, V-sign and 672 www.co-rheumatology.com Volume 26 Number 6 November 2014 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Juvenile idiopathic inflammatory myopathies Ernste and Reed Table 1. Clinical associations of MSAs and MAAs in JIIM subsets Autoantibody Clinical associations JIIM subgroup Frequency (%) Antisynthetasesa (e.g. anti-Jo1) Fever, Raynaud’s phenomenon, arthritis, JPM (more common), JDM, JCTM 2–4% [1,10&&,14,16] mechanic’s hands, myositis, ILD Anti-Mi2 [1,14,16] Classic dermatomyositis rash, mild JDM, JCTM 2–13% disease, seen more often in Hispanics Anti-SRP [1] Severe muscle weakness, high creatine JPM (more common) 1% kinase, frequent falls, chronic course, seen more often in African-American girls anti-p155/140 (TIF1-g) Cutaneous ulceration and edema, severe JDM,