REVIEW

CURRENT OPINION Recent advances in juvenile idiopathic inflammatory

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 and Research Alliance registry, are conducting trials to enhance our understanding of JIIMs. Ultraviolet radiation exposure 1 month prior to juvenile (JDM) may trigger the onset of disease. -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 , tory muscle disorders characterized by muscle weak- Gottron’s papules, heliotrope , 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 gastrointestinal (i.e. 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

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[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 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 , 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 erythematosus (SLE), major serologic subsets in JIIM patients, the anti- juvenile idiopathic arthritis (JIA), , 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

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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 , 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, JCTM 23–35% [1,9&&,10&&,14] photosensitive dermatomyositis rashes, lower creatine kinase, chronic course, not associated with cancer Anti-MJ (NXP-2) [1,10&&,14] Dysphonia, muscle cramps, increased JDM 23–25% calcinosis, monocyclic course Anti-U1-RNP [1,10&&] Raynaud’s phenomenon, sclerodactyly, JCTM (more common), JPM 5–10% arthritis Anti-PM-Scl [1,10&&] Raynaud’s phenomenon, arthritis, ILD, JPM, JCTM 1–4% dysphagia

ILD, interstitial lung disease; JCTM, juvenile connective tissue disease (overlap) myositis; JDM, juvenile dermatomyositis; JIIMs, juvenile idiopathic inflammatory myopathies; JPM, juvenile polymyositis; MAAs, myositis-associated autoantibodies; MSAs, myositis-specific autoantibodies; NXP-2, nuclear matrix protein 2; SRP, signal recognition particle; TIF1-g, transcriptional intermediary factor 1g. Data from Rider et al. [1]. aAnti-Jo1, anti-PL7, anti-PL12, anti-EJ, anti-OJ, anti-KS, anti-Ha, and anti-Zo.

‘shawl-sign’, lower creatine kinase levels, and a active in JDM [17], and Malattia chronic course. In contrast to adults, children with et al. [18&] have expanded the use of MRIs for track- anti-p155/140 antibodies do not have an increased ing disease activity in JDM by comparing whole- association with cancer-associated myositis [1]. In body MRI to the clinical examination. Whole-body the anti-MJ antibody subgroup, children have dys- MRI revealed muscle inflammation such as distal leg phonia, muscle cramps, and a monocyclic course. In and forearm inflammation that was not detected the anti-SRP subgroup, patients are often Blacks during the clinical examination, suggesting that a with JPM and severe proximal and distal muscle significant amount of disease activity remains weakness, falling episodes, higher creatine kinase clinically underrecognized. levels, and frequent hospitalizations. Conversely, the anti-Mi2 subgroup is more common in His- panics and is characterized by JDM with a low GENETICS mortality rate [9&&,10&&]. Furthermore, several JIIMs, in particular JDM, exhibit complex genetic patients in this group had a co-existence of more associations [19]. The TNFa-308A polymorphism (A than one MSA or MAA [9&&]. to G polymorphism in the promoter region) has been associated with a prolonged disease course in JDM, dystrophic calcinosis and ulcerations, and increased MRI production of TNF-a in muscle fibers and peripheral According to the CARRA registry, MRI is replacing blood mononuclear cells (PBMCs) [20,21]. Recently, EMG and muscle biopsy as the principal means for there have been additional genetic factors identified diagnosing JDM: 90% of the enrolled 483 individ- to be significantly associated with JIIM disease course uals had an MRI prior to enrollment [4&&]. Indeed, an and features. Habers et al. [22&] found that HLA alleles MRI (91%) was more likely than an EMG (50%) or a are significantly associated with disease course in muscle biopsy (76%) to reveal abnormalities specific Caucasian JIIM patients in the USA and Canada. to JDM; the false-negative rate was higher with HLA-DRB11501 was present more frequently in EMGs (50%), and half of the children who had an 22% of patients exhibiting a monocyclic course com- EMG required an additional diagnostic study [4&&]to pared with 5% of patients with a polycyclic course confirm JDM. Regarding disease assessment, an MRI and 7% of patients with a chronic course. Addition- scoring system based on short tau inversion recov- ally, the F25-peptide-binding motif was found less ery (STIR) sequences of the gluteal and thigh muscle frequently in patients with a monocyclic course com- groups has been developed for the detection of pared with polycyclic and chronic courses.

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ENVIRONMENT IFN-a activity correlated with specific nucleic-acid- Environmental factors such as ultraviolet (UV) light associated autoantibodies, such as the Ro/La and and preceding upper respiratory or gastrointestinal Sm/RNP; therefore, sera from patients with JDM, have long been observed as possible trig- in particular the RNA-containing autoantigens Ro, gers for JIIM onset and exacerbations, in particular La, Smith, and RNP, have the ability to induce type 1 JDM [23]. These environmental factors may also IFN-a activity and therefore may play a significant play a role in determining the disease course and role in stimulating JDM pathogenesis. features. Habers et al. [22&] suggested that infections, Sanner et al. [36&] measured the cytokine profiles usually respiratory, 6 months prior to disease onset in 54 JDM patients from Norway with a median 16.8 in JIIMs were more common in patients with a years after disease onset and compared these profiles polycyclic course than a monocyclic or chronic to 54 age-matched and sex-matched controls. The course. Similarly, UV light exposure 1 month prior JDM patients had higher levels of eotaxin [an ago- to diagnosis was higher in girls with a polycyclic nist of chemokine receptor 3 (CCR3) and partial course than in a monocyclic or chronic course. Shah agonist of chemokine receptor 2 (CCR2)], monocyte et al. [24&] also found that intense UV light exposure chemoattractant protein (MCP-1), and interferon- 1 month prior to disease onset increased the risk for inducible protein 10 (IP-10) compared with con- JDM, especially among girls, compared with JPM trols, and these levels correlated with disease patients; the highest UV indices were associated duration and age. Patients with active disease had with the development of anti-p155/140 MAA in a higher level of MCP-1, and these levels were White boys. Clinical and autoantibody phenotypes associated with early organ damage at follow-up. may vary according to the U.S. geoclimactic regions In addition to attracting and activating monocytes and latitude locations: in the southern latitudes, and T cells, MCP-1 is important in promoting there was a higher prevalence of JDM and anti- inflammation, angiogenesis, and atherosclerosis p155/140 autoantibodies than anti-MJ autoanti- [37]. Hence, eotaxin and MCP-1 may play a role bodies, which had a higher prevalence in the in sustaining prolonged inflammation leading to northern latitudes. organ damage and may be useful biomarkers of disease outcomes in JDM. Similarly, Nistala et al. [38&] identified the proinflammatory myeloid- IMMUNOPATHOGENESIS related protein (MRP) 8/14 to be overexpressed by Humoral and cell-mediated pathways play a role in CD68þ macrophages in JDM muscle, which leads to the immunopathogenesis of JIIMs. Cytokines and downstream proinflammatory effect with secretion chemokines are important in regulating the innate of MCP-1 and IL-6, the proinflammatory mediators. and adaptive immune systems and are involved in a MRP induces apoptosis of skeletal muscle via Toll- wide range of activities such as B-and T-cell growth, like receptor 4 [39]. By significantly correlating differentiation, recruitment, and activation [25,26]. serum MRP8/14 to clinical disease assessments, Over the last decade, research using gene-expression serum MRP8/14 may potentially be a sensitive bio- transcript profiling and immunohistochemistry marker for disease activity in JDM [38&]. analysis of PBMCs, skin, and muscle tissue show that Type 1 interferon (IFN) a genes and related proteins are upregulated in JDM, and they may serve CYTOKINE STORM as biomarkers for JDM disease activity and organ Hemophagocytic lymphohistiocytosis (HLH) is a damage [27–30]. Type 1 IFN is important in the rare, life-threatening disorder characterized by antiviral response to microbial invasion [29]. systemic inflammation and activation of proliferat- Type 1 IFN is produced by plasmacytoid dendritic ing histiocytes in the reticuloendothelial system. cells (pDCs) in skin and muscle tissue in active JDM; Among the juvenile rheumatic diseases, HLH or they are important in upregulating major histocom- macrophage activation syndrome (MAS) has been patibility complex class I expression and promoting described in association with systemic-onset juven- T-cell survival, dendritic cell maturation, and ile arthritis (sJIA), SLE, Kawasaki’s disease, and enhancing the transcription of related cytokines rheumatoid arthritis with a few reports of JDM and chemokines [30,31]. Several investigators have patients [40–44]. examined the usefulness of measuring type 1 IFN- Aberrant overproduction of proinflammatory related cytokine and chemokine expression as cytokines, such as TNF-a, IFN-gamma, macrophage indicators of JDM disease activity by correlating colony-stimulating factor, and IL-6, driven from a the levels to clinical disease assessments [32–34]. defect (acquired or congenital) of the killing activity In a small pilot study, Balboni et al. [35] evaluated of natural killer (NK) cells and cytotoxic T cells, the sera of 36 JDM patients and found that type 1 impairs the clearance of infected cells and leads to

674 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 an uncontrolled immune response and a cytokine STANDARDIZED GUIDELINES FOR storm [40–42]. To make a diagnosis, five of the TREATMENT following 2004 diagnostic criteria for HLH need to Consensus statements have been developed by the be met [43]: fever; splenomegaly; cytopenias CARRA registry to standardize the guidelines for the (hemoglobin <9 g/dl, platelets <100 000/ml, and treatment of moderately active JDM patients and neutrophils <1000 ml); hypertriglyceridemia; hypo- corticosteroid dose reduction [49,50]. Three consen- fibrinogenemia; hemophagocytosis in the bone sus treatment protocols (CTPs) have been proposed marrow, spleen, or lymph nodes; hyperferritinemia that involve combinations of therapies from the (>500 ng/ml); low or absent NK cell activity; and time of diagnosis, such as steroids (2 mg/kg/day) elevated soluble CD25 (sIL-2R; >2400 U/l). Early and (15 mg/m2) and intravenous recognition of HLH is paramount toward making (IVMP) or IVMP with intrave- a prompt diagnosis and instituting therapy as it can nous immune globulin (IVIG) [1,49,50]. Currently, rapidly progress to multiorgan failure and death. prospective studies examining these three CTPs are Therapy often entails high-dose corticosteroids in underway [1]. Corticosteroids in combination with conjunction with the intravenous immunoglobu- a Disease-modifying antirheumatic drug, most com- lin, cyclosporine, and etoposide [41]. monly methotrexate, still remain the mainstays of treatment for JDM among pediatric rheumatologists in the USA and Canada. Other common treatments CLINICAL ASSESSMENT include , pulse methylpredni- Disease assessment in JDM may be difficult as solone, IVIG, and cyclosporine [1,51]. muscle enzyme levels often normalize during treat- ment and may not be reflective of the subtle changes in disease activity; moreover, chronic muscle BIOLOGIC THERAPY atrophy, deconditioning, and scarring may occur So far, open-label studies have highlighted the use of impacting accurate muscle strength testing and biologics for JDM treatment. For example, a small, overall clinical assessment. The International Myo- open-label, prospective, pilot study by Rouster- sitis Assessment and Clinical Studies Group (IMACS) Stevens et al. [52] used etanercept in nine patients and Paediatric Rheumatology International Trials with refractory JDM, six of whom completed all Organization (PRINTO) have developed preliminary follow-up visits, and found mixed results at weeks definitions of improvement and validated core set 12 and 24; some patients demonstrated mild measures of disease activity and damage such as the improvement, but a few patients worsened in nail- Childhood Myositis Assessment Scale (CMAS) and fold capillaroscopy and Disease Activity Scores the Child Health Assessment Questionnaire (CHAQ) (DAS). The authors concluded that there were no that will be used as outcome assessments in the improvements at the end of the 6-month trial and clinical trials [45,46]. Recently, criteria for determin- advised caution when using TNF-alpha inhibitors ing clinically inactive disease in JDM have been because of concern for suppression of type 1 IFN proposed by PRINTO [47&]. By prospectively analyz- pathway which is upregulated in JDM. ing the data from 275 JDM patients for 24 months, The large, multicentered Rituximab in Myositis the group has rigorously defined inactive disease as (RIM) trial published in 2013 by Oddis et al. [53&] fulfilling at least three of the four criteria in patients used rituximab in 200 refractory myositis patients, on or off therapy: manual muscle test (MMT-8) of at including 48 patients with JDM, but failed to reach least 78 (0–80), physician global assessment of its primary endpoint which was detecting a signifi- muscle disease activity (PhyGloVAS) of 0.2 or less, cant difference between two treatment groups (sep- CMAS of at least 48, and creatine kinase of 150 or arated by an 8-week delay in receiving rituximab) in less. These criteria are thought to have practical achieving the IMACS definition of improvement applicability in clinical practice and research trials. (DOI), that is, at least 20% improvement in three Sanner et al. [48&] applied the new PRINTO criteria or six core set disease activity measures, at two con- for inactive disease in a cross-sectional study of an secutive time points. The study was not adequately inception cohort of 59 Norwegian JDM patients powered to detect a significant effect based on an diagnosed between 1970 and 2006, and found that error in predicting the onset of therapeutic action of use of the PRINTO criteria identified 51% of patients rituximab: it was a cross-over design based on the with active disease after a median of 16.8 years, premise that more than 50% of patients would whereas use of the Myositis Disease Activity Assess- respond to rituximab by 8 weeks when in actuality ment Tool (MDAAT) identified 73% of patients with 50% responded by week 20, suggesting a slower onset active disease, most commonly manifested in the of action and potency. Yet, 83% of adult and JDM skin and skeletal systems. patients did reach DOI by trial end. Of interest,

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Aggarwal et al. [54&&] performed a multivariate counterparts, aerobic fitness is significantly analysis of clinical predictors for improvement in decreased even among patients who have recovered patients from the RIM trial, and identified the pres- from JDM [55&,56]. As recently described by Sanner ence of autoantibodies, such as the antisynthetase et al. [36&], up to 73% of JDM patients may have antibodies (anti-Jo-1) and anti-Mi2 antibodies, to be active disease a median of 16 years after diagnosis. the strongest predictors for the shortest time to JPM patients have more frequent hospitalizations, achieving improvement. wheelchair use, and have a higher mortality rate (6.3%) than JDM patients [9&&,10&&]. Recently, there have been efforts to utilize multidimensional survey EXERCISE THERAPY tools for the assessment of parent-reported and Despite the controversy about the role of exercise in child-reported outcomes for pediatric rheumatic the rehabilitation of JIIM patients historically, diseases such as JDM in busy clinical practices [60]. recent trials suggest that aerobic training may be well tolerated and effective for improving physical fitness of JDM patients in remission [55&,56,57&]. CONCLUSION JDM patients are less physically fit because of muscle In conclusion, there has been considerable work damage compared with healthy children; indeed, over the last year that has contributed to a better decreased maximal oxygen uptake (VO2 max) has understanding about the classification, clinical been found to be directly related to the duration of characteristics, diagnostic workup, immunopatho- active disease [55&]. A study of eight JDM patients by genesis, and standardization of treatment plans and Riisager et al. [57&] found that 12 weeks of moderate- prognosis of JIIM patients. However, more work is to-intense physical activity consisting of riding a needed to validate the existing tools for disease cycle ergometer at 65% of VO2 max (42 training assessment and identify new targets for biologic sessions) increased oxidative capacity and cardio- therapy, especially for patients with chronic disease vascular fitness as indicated by a lower heart rate at activity who are refractory to standard medical man- study end; creatine kinase did not change before agement. or after the training period, suggesting no muscle damage. Hence, although JDM patients in remission Acknowledgements (median of 7 years) may be less physically fit than None. their healthy counterparts, their low oxidative capacity can be reversed and improved with a dedi- Conflicts of interest cated aerobic exercise program. Caution must still There are no conflicts of interest. be taken when recommending an exercise routine to JDM patients; Habers et al. [58] demonstrated that REFERENCES AND RECOMMENDED 11 children with JDM had impaired blood flow in READING the muscle microvasculature as detected by near- Papers of particular interest, published within the annual period of review, have been highlighted as: infrared spectroscopy during strenuous exercise & of special interest compared with 13 normal controls. && of outstanding interest

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