Objective. To develop a provisional definition for the evaluation of response to therapy in juvenile dermatomyositis (DM) based on the Paediatric Rheumatology International Trials Organisation juvenile DM core set of variables. Methods. Thirty-seven experienced pediatric rheumatologists from 27 countries achieved consensus on 128 difficult patient profiles as clinically improved or not improved using a stepwise approach (patient's rating, statistical analysis, definition selection). Using the physicians' consensus ratings as the "gold standard measure," chi-square, sensitivity, specificity, false-positive and-negative rates, area under the receiver operating characteristic curve, and kappa agreement for candidate definitions of improvement were calculated. Definitions with kappa values >0.8 were multiplied by the face validity score to select the top definitions. Results. The top definition of improvement was at least 20% improvement from baseline in 3 of 6 core set variables with no more than 1 of the remaining worsening by more than 30%, which cannot be muscle strength. The second-highest scoring definition was at least 20% improvement from baseline in 3 of 6 core set variables with no more than 2 of the remaining worsening by more than 25%, which cannot be muscle strength (definition P1 selected by the International Myositis Assessment and Clinical Studies group). The third is similar to the second with the maximum amount of worsening set to 30%. This indicates convergent validity of the process. Conclusion. We propose a provisional data-driven definition of improvement that reflects well the consensus rating of experienced clinicians, which incorporates clinically meaningful change in core set variables in a composite end point for the evaluation of global response to therapy in juvenile DM.

Purpose of review To identify clues to disease activity and discuss therapy options. Recent findings The diagnostic evaluation includes documenting symmetrical proximal muscle damage by exam and MRI, as well as elevated muscle enzymes—aldolase, creatine phosphokinase, LDH, and SGOT—which often normalize with a longer duration of untreated disease. Ultrasound identifies persistent, occult muscle inflammation. The myositis-specific antibodies (MSA) and myositis-associated antibodies (MAA) are associated with specific disease course variations. Anti-NXP-2 is found in younger children and is associated with calcinosis; anti-TIF-1γ+ juvenile dermatomyositis has a longer disease course. The diagnostic rash—involving the eyelids, hands, knees, face, and upper chest—is the most persistent symptom and is associated with microvascular compromise, reflected by loss of nailfold (periungual) end row capillaries. This loss is associated with decreased bioavailability of oral prednisone; the bioavailability of other orally administered medications should also be considered. At diagnosis, at least 3 days of intravenous methyl prednisolone may help control the HLA-restricted and type 1/2 interferon–driven inflammatory process. The requirement for avoidance of ultraviolet light exposure mandates vitamin D supplementation. Summary This often chronic illness targets the cardiovascular system; mortality has decreased from 30 to 1–2% with corticosteroids. New serological biomarkers indicate occult inflammation: ↑CXCL-10 predicts a longer disease course. Some biologic therapies appear promising.

Summary: Serum was obtained from 155 children at the time of admission to hospital for elective surgery. The concentration of serum keratan sulphate was determined by an ELISA which uses an antibody specific for keratan sulphate, a molecule found predominantly in cartilage. Concentrations of keratan sulphate rise progressively during the first four years of life (0-2: mean = 357 μg/l; 2-4: mean = 422 μg/l) and then remain high until 12 years of age (mean = approx. 500 μg/l). At this time, concentrations drop markedly (13-year olds: mean = 3?7μ §^1; 14-year olds: mean = 318μg/l). After age 15, concentrations continue to fall toward the concentrations found in normal adults. Serum concentrations did not show significant differences with respect to disease category, sex or race but were found to vary, sometimes markedly, from child to child at any one age. The results suggest human cartilage undergoes significant changes in metabolic activities during maturation. Measurements of keratan sulphate concentration in serum may prove useful in studying the biochemical and physiological bases of these changes and in monitoring growth or endochondral ossification during maturation.

In juvenile dermatomyositis (JDM), the most common pediatric inflammatory myopathy, weakness is accompanied by a characteristic rash that often becomes chronic and is associated with vascular damage. We hoped to understand the molecular underpinnings of JDM, particularly when untreated, which would facilitate the identification of novel mechanisms and clinical targets that might disrupt disease progression. We studied the RNA-Seq data from untreated JDM peripheral blood mononuclear cells (PBMCs; n = 11), PBMCs from a subset of the same patients when clinically inactive (n = 8/11), and separate samples of untreated JDM skin and muscle (n = 4 each). All JDM samples were compared to non-inflammatory control tissues. The untreated JDM PBMCs showed a strong signature for type1 interferon response, along with IL-1, IL-10, and NF-κB. Surprisingly, PBMCs from clinically inactive JDM individuals had persistent immune activation that was enriched for IL-1 signaling. JDM skin and muscle both showed evidence for type 1 interferon activation and genes related to antigen presentation and decreased expression of cellular respiration genes. Additionally, we found that PBMC gene expression correlates with disease activity scores (DAS; skin, muscle, and total domains) and with nailfold capillary end row loop number (an indicator of microvascular damage). This included otoferlin, which was significantly increased in untreated JDM PBMCs and correlated with all 3 DAS domains. Overall, these data demonstrate that PBMC transcriptomes are informative of molecular disruptions in JDM and provide transcriptional evidence of chronic inflammation despite clinical quiescence.

Objective. Skin inflammation heralds systemic disease in juvenile myositis, yet we lack an understanding of pathogenic mechanisms driving skin inflammation in this disease. We undertook this study to define cutaneous gene expression signatures in juvenile myositis and identify key genes and pathways that differentiate skin disease in juvenile myositis from childhood-onset systemic lupus erythematosus (SLE).Methods. We used formalin-fixed paraffin-embedded skin biopsy samples from 15 patients with juvenile myositis (9 lesional, 6 nonlesional), 5 patients with childhood-onset SLE, and 8 controls to perform transcriptomic analysis and identify significantly differentially expressed genes (DEGs; q ≤ 5%) between patient groups. We used Ingenuity Pathway Analysis (IPA) to highlight enriched biologic pathways and validated DEGs by immunohistochemistry and quantitative real-time polymerase chain reaction.Results. Comparison of lesional juvenile myositis to control samples revealed 221 DEGs, with the majority of upregulated genes representing interferon (IFN)-stimulated genes. CXCL10, CXCL9, and IFI44L represented the top 3 DEGs (fold change 23.2, 13.3, and 13.0, respectively; q < 0.0001). IPA revealed IFN signaling as the top canonical pathway. When compared to childhood-onset SLE, lesional juvenile myositis skin shared a similar gene expression pattern, with only 28 unique DEGs, including FBLN2, CHKA, and SLURP1. Notably, patients with juvenile myositis who were positive for nuclear matrix protein 2 (NXP-2) autoantibodies exhibited the strongest IFN signature and also demonstrated the most extensive Mx-1 immunostaining, both in keratinocytes and perivascular regions.Conclusion. Lesional juvenile myositis skin demonstrates a striking IFN signature similar to that previously reported in juvenile myositis muscle and peripheral blood. Further investigation into the association of a higher IFN score with NXP-2 autoantibodies may provide insight into disease endotypes and pathogenesis.

The child who develops the symptoms of the specific rash, proximal muscle weakness, and fatigue should seek medical care promptly. With the advances in physical and medical therapy, many of the consequences of the disease can now be ameliorated. There are suggestive data that JDMS and PM may each have a different pathophysiology, but more evidence is needed. The next few years should be exciting as there is increased effort to determine if there is, in fact, a causal relationship between Coxsackievirus B or other enterovirus and genetic factors that alter the susceptibility to or severity of the course of the disease.

Objective Myositis‐specific antibodies (MSAs) facilitate grouping children with juvenile dermatomyositis (DM) into distinct phenotypes. The first aim of this study was to investigate the link between anti‐p155/140 and lipodystrophy as determined by dual x‐ray absorptiometry (DXA) assessment of fat distribution. The second aim was to examine the relationship between anti‐p155/140 and damage to the nailfold capillary system. Methods Children with juvenile DM followed for a minimum of 5 years were included. The study population was divided into 3 groups (anti‐p155/140, other MSA, and MSA negative). Lipodystrophy was assessed by physician assessment and DXA fat distribution (trunk‐to‐leg fat ratio). Documentation of nailfold capillary end row loops (ERLs) was obtained at diagnosis. Results A total of 96 subjects (44% anti‐p155/140, 23% other MSA, 33% MSA negative) were included. There was no significant difference in age, disease activity scores, or lipodystrophy between the 3 groups. The trunk‐to‐leg fat ratios were similar among the 3 groups at different time points. However, the anti‐p155/140 group had significantly decreased ERL counts (P = 0.006) at baseline as well as a prolonged duration of untreated disease at diagnosis (P = 0.027). Also, the anti‐p155/140 group had fewer patients with a monophasic disease course than the other 2 groups (P = 0.008). Conclusion Generalized lipodystrophy frequency was equivalent in all 3 groups based on physician assessments and trunk‐to‐leg fat ratios. The anti‐p155/140 group had a greater loss of ERLs, suggesting that this MSA may impact the vascular component of juvenile DM.

Background Blood accessible biomarkers to assess disease activity and their response to therapies in Juvenile Dermatomyositis (JDM) are urgently needed. This pilot study aims to identify serum protein biomarkers associated with clinical disease activity in untreated JDM and their response to medical therapy. Methods SomaScan® technology screened JDM patients for 1305 proteins at three points: 1) before start of treatment, 2) while on therapy, and 3) after treatment tapering when patients were clinically inactive. To define disease associated biomarkers, SomaScan® data from untreated JDM patients (n = 8) were compared to SomaScan® data from an independent age-matched healthy control group (n = 12). Longitudinal analysis defined treatment responsive proteins at three time points: untreated (7 samples), treated (7 samples), and clinically inactive (6 samples). To confirm the SomaScan® data, a subset of nine candidate proteins (CXCL11, IL-17B, IL-17D, IL-22, CXCL10, MCP-1, ANGPT2, MIF, IL-23) were tested by ELISA after adding 2 JDM (one untreated, one clinically inactive) serum samples to the same group of JDM girls (8 untreated, 7 treated; 7 clinically inactive) as well as with 17 age, gender, matched healthy controls. Results Comparison of untreated JDM versus healthy controls identified 202 elevated and 49 decreased serum proteins in JDM patients with an adjusted p-value < 0.001. Only 82 out of 251 identified biomarker candidates responded to treatment while 12 out of these 82 proteins returned to their original untreated disease levels upon therapy tapering. The ELISA testing of the untreated samples for nine candidate proteins confirmed previously known biomarkers (CXCL10 or IP-10, CXCL11 or I-TAC and MCP-1) and identified novel biomarkers including IL-22, Angiopoetin-2, and IL-17B in a cross-sectional analysis comparing 8 untreated JDM and 17 age/gender matched controls. The subsequent longitudinal data by ELISA were not concordant for some biomarkers (IL-22 and IL-17B), but the other biomarkers either normalized or rebounded concordantly. Conclusions Blood accessible protein biomarkers reflecting JDM pathophysiology were identified; some of them rebounded after therapy was tapered. Further studies bridging these biomarkers to specific clinical features of JDM are required to confirm the clinical utility of these serum protein biomarkers.