Childhood Myositis Assessment Scale Research Articles

P.042 Anti-HMG Coenzyme A reductase antibody (anti-HMGCR) myopathy: case review of two pediatric patients from a single center

Background: Necrotizing anti-HMGCR myopathy is rare in children. Pediatric cases are not typically associated with statin use or malignancy. Methods: Retrospective chart review (January 2009 to December 2023) identified cases of anti-HMGCR myopathy at our hospital. Results: Two patients were identified. Patient A, presented at 8 yo with a 2 year history of proximal muscle weakness. His CK was 4,840 U/L (normal <205 U/L) with a high anti-HMGCR antibody titre. His Childhood Myositis Assessment Scale (CMAS) score was 33/52. Monthly IVIG was started and his muscle strength and CK improved. Two years later, weekly methotrexate was started for persistent mild CK elevation (602 to 869 U/L). At 11 years old, 3 years after diagnosis, his CMAS score was 47 and he could participate in soccer with mild fatigue. Patient B, presented at 8 yo with acute proximal weakness, rash and CMAS 13/52. His CK was 20,185 U/L with elevated anti-HMGCR antibody titre. He received oral corticosteroids, weekly methotrexate and monthly IVIG. At 10 yo, 2 years after diagnosis, he is asymptomatic with CMAS 51. He is maintained on methotrexate monotherapy. Conclusions: Anti-HMGCR antibody myopathy requires prompt diagnosis to obviate muscle necrosis and long-term complications. Our patients showed clinical and CMAS improvement with treatment.

OA34 Unravelling the role of B cells and interferon dysregulation in juvenile dermatomyositis

Abstract Background/Aims Juvenile dermatomyositis (JDM) is a rare childhood autoimmune disease, characterised by muscle inflammation and skin rash. At present, the exact mechanisms driving JDM pathogenesis remain unclear. Recent investigations have focused on the potential roles of interferon (IFN) dysregulation and B cells. This study aims to explore alterations in B cell populations and their association with disease severity and IFN pathway dysregulation in JDM patients. Methods Transcriptomic, flow cytometry, and clinical data were gathered from a cohort of 61 JDM patients recruited from the UK JDCBS. Clinical demographics and disease variables were extracted from the JDCBS database. Flow cytometry was utilised to examine B cell populations in treatment naïve (‘pre-treatment’ n = 48) and JDM patients on steroids and conventional DMARD treatment, including rituximab (on-treatment n = 24), in parallel with age-matched healthy donors (n = 35). Transcriptomic analysis was performed on the total CD19+ B cells to assess their gene expression profiles in JDM patients. Pathway enrichment analysis was applied to identify the involvement of IFN-related pathways in JDM pathogenesis. Results Flow cytometry analysis revealed a significant expansion of total B cells, (defined as CD19+, p < 0.0001, ANOVA) and immature B cells (defined as CD19+ CD24hi CD38hi, p = 0.0416, Kruskal-Wallis) in pre-treatment JDM patients compared to healthy controls, which returned to levels similar to those in healthy donors in on-treatment JDM patients. An inverse relationship between total B cells and the Childhood Myositis Assessment Scale (CMAS), a measure of muscle strength, was observed in pre-treatment JDM patients, indicating a connection between the expanded B cell population and worse disease. Transcriptomic analysis of B cells illustrated distinctive clustering between pre-treatment JDM patients and healthy controls, based on their type I IFN gene expression profiles. Pathway enrichment analysis confirmed the significant enrichment of IFN-related pathways in B cells of pre-treatment JDM patients. Conclusion This study validates previous observations (Piper et al., 2018) supporting a significant role of B cells in the pathogenesis of JDM and their association with IFN dysregulation. Notably, pre-treatment JDM patients exhibited an expansion of the total B cell population, and of immature B cells, which correlated with disease activity and were restored to normal levels with treatment. Transcriptomic analysis identified distinct IFN-related gene profiles in B cells from pre-treatment JDM patients. These findings offer valuable insights into the complex autoimmune condition of JDM, potentially opening avenues for novel therapeutic strategies. Disclosure A.E.K. Syntakas: None. H.D. Nguyen: None. R. Restuadi: None. B.R. Jebson: None. V. Alexiou: None. L.R. Marshall: None. E. Ralph: None. K. O’Brien: None. D. Cancemi: None. H. Peckham: None. A. Radziszewska: None. N. De Gruijter: None. G.T. Hall: None. S. Castellano: None. C. Ciurtin: None. C.T. Deakin: None. E. Rosser: None. L.R. Wedderburn: None. M. Kartawinata: None. M.G.L. Wilkinson: None.

Longitudinal assessment of disease activity and muscle strength in juvenile dermatomyositis: a multicentre registry study.

To define disease activity measures, muscle strength and functional assessments in new-onset juvenile dermatomyositis (JDM) patients, at disease onset and follow up. A registry was set up in 18 hospitals, enrolling patients over 3-years (2015-2018). Clinical assessments were performed at baseline, and at 6, 12, 18 and 24 months after diagnosis. Disease Activity Score (DAS20), skin and musculoskeletal DAS sub-scales; Manual Muscle Test (MMT8); Childhood Myositis Assessment Scale (CMAS); Childhood Health Assessment Questionnaire disability index (CHAQ_DI 0-3) and 10 cm Visual Analog Scale (VAS) for overall wellbeing scores were compared by Poisson Model and Wald post-test for repeated measures. Ninety-six cases, being 61 (64%) females, median age 10 years had JDM diagnosis and 12 (13%) onset calcinosis. Mean ±SD scores at diagnosis and 6 months intervals for DAS20 (0-20) were 7.8±5, 6.3 ±4.8, 5±4, 4.9 ±5 and 0.5 ±2.3; with significant difference from baseline (p<0.01). Skin DAS subscales were 2.8±3.3, 1.8±2.9, 1,1±2.2, 0.6±1.8, 0.4±1.5. MMT (0-80) 62.6±20.4, 70.2±13.5, 73.3±11, 75.7±7.9 and 74.8±7.8, with significant difference from baseline up to 6 months (p=0.016); CMAS (0-53) 29.5±11.4, 33.1±8.3, 34.2±5.8, 34±6 and 33.3±5.4. CHAQ-DI (0-3) 1±0.9, 0.6±0.7, 0.8±0.8, 1±0.8 and 1±0.3; parents VAS 4.1±2.5, 2±2.1; 1.3±2.8, 4.1±3.1, 1.7±2.2. There was no significant difference for CMAS, CHAQ-DI and parents VAS from baseline up to 24-month assessment. DAS20 scores improved gradually during follow up, MMT8 improved significantly during the first 6 months and CMAS, CHAQ-DI and parents VAS scores had no significant improvement with persistent functional impairment over 2-years.

The emerging role of Growth Differentiation Factor 15 as a potential disease biomarker in juvenile dermatomyositis.

We aimed to investigate the potential of Growth Differentiation Factor 15 (GDF-15) as a novel biomarker for disease activity in Juvenile Dermatomyositis (JDM). We recruited children with juvenile myositis including juvenile dermatomyositis (n = 77), polymyositis (n = 6), and healthy controls (n = 22). GDF-15 levels in plasma were measured using ELISA. Statistical analyses were performed using non-parametric tests. Levels of GDF-15 were significantly elevated in JDM compared with healthy controls (p< 0.001). GDF-15 levels exhibited strong positive correlations with disease activity scores, including the Disease Activity Score (DAS) total score, DAS skin score, DAS muscle score, and Childhood Myositis Assessment Scale (CMAS). Additionally, GDF-15 levels could differentiate between active disease and remission based on the Physician Global Assessment of muscle score. Positive correlations were observed between levels of GDF-15 and creatine kinase, neopterin, and nailfold end row loops, indicating the potential involvement of GDF-15 in muscle damage, immune activation, and vascular pathology. ROC curve analysis showed GDF-15 to be more effective in assessing disease activity in JDM than creatine kinase (AUC 0.77, p= 0.001 and AUC 0.6369, p= 0.0738, respectively). GDF-15 may serve as a valuable biomarker for assessing disease activity in JDM. It exhibits better sensitivity and specificity than creatine kinase, and the levels correlate with various disease activity scores and functional measures. GDF-15 may provide valuable information for treatment decision-making and monitoring disease progression in JDM.

Janus kinase inhibitor, tofacitinib, in refractory juvenile dermatomyositis: a retrospective multi-central study in China

ObjectivesJuvenile dermatomyositis (JDM) is a chronic autoimmune disease. Some patients remain in an active state even though they were administrated with a combination of corticosteroid and methotrexate. Existing research has suggested that interferon and Janus kinase played an important role in pathogenesis. Existing research has suggested the efficacy of JAK inhibitors (JAKi). Our retrospective study aimed to investigate the efficacy of tofacitinib in refractory JDM patients.MethodsA total of eighty-eight patients in China who had been diagnosed with JDM and subjected to tofacitinib therapy for over 3 months were retrospectively analyzed. Skin and muscle manifestations were assessed using the Cutaneous Assessment Tool-binary method (CAT-BM), Childhood Myositis Assessment Scale (CMAS), and kinase. Pulmonary function was assessed using a high-resolution CT (computerized tomography) scan and pulmonary symptoms. All patients were subjected to regular follow-up, and core measures were assessed every 3 months after initiation. Furthermore, the data were analyzed using the Wilcoxon single test, Mann–Whitney U test, and chi-square test.ResultsCompared with the baseline data, skin and muscle manifestations were found significantly improved during the respective follow-up visit. At the most recent follow-up, nearly 50% of patients achieved a clinical complete response and six patients received tofacitinib monotherapy. Sixty percent of patients suffering from interstitial lung disease well recovered on high-resolution CT. Seventy-five percent of patients showed a reduction in the size or number of calcinosis, and 25% of patients showed completely resolved calcinosis.ConclusionIn this study, the result suggested that tofacitinib therapy exerted a certain effect on skin manifestations, muscle manifestations, interstitial lung disease (ILD), calcinosis, as well as downgrade of medication. In-depth research should be conducted to focus on the correlation between the pathogenesis of JDM and JAKi.

Nailfold capillary density in 140 untreated children with juvenile dermatomyositis: an indicator of disease activity

BackgroundWe lack a reliable indicator of disease activity in Juvenile Dermatomyositis (JDM), a rare disease. The goal of this study is to identify the association of nailfold capillary End Row Loop (ERL) loss with disease damage in children with newly diagnosed, untreated JDM.FindingsWe enrolled 140 untreated JDM and 46 age, race and sex matched healthy controls, ages 2–17. We selected items from the Juvenile Myositis Registry for analysis. Variables include average ERL density of 8 fingers, average capillary pattern, hemorrhages, and clinical and laboratory correlates. Laboratory data includes Myositis Specific Antibodies (MSA), disease activity scores (DAS), Childhood Myositis Assessment Scale (CMAS), and standard clinical serologic data. The reduced mean ERL density is 5.1 ± 1.5/mm for untreated JDM vs 7.9 ± 0.9/mm for healthy controls, p < 0.0001, and is associated with DAS-skin, r = -0.27 p = 0.014, which did not change within the age range tested. Untreated JDM with MSA Tif-1-γ had the lowest ERL density, (p = 0.037); their ERL patterns were primarily “open” and the presence of hemorrhages in the nailfold matrix was associated with dysphagia (p = 0.004).ConclusionsDecreased JDM ERL density is associated with increased clinical symptoms; nailfold hemorrhages are associated with dysphagia. Duration of untreated disease symptoms and MSA, modify NFC shape. We speculate nailfold characteristics are useful indicators of disease activity in children with JDM before start of therapy.

E58 The rheumatologic masquerader: a case report on SLE-dermatomyositis-systemic scleroderma overlap syndrome

Abstract Introduction Juvenile dermatomyositis is an autoimmune connective tissue disorder characterized by idiopathic inflammatory myopathy primarily affecting the skin and muscles(1, 2). It may occur alone or in overlap syndromes usually with systemic scleroderma, systemic lupus erythematosus (SLE) and mixed connective tissue disease(3, 4). There is need to further describe and characterize cases encountered in different set ups. Objective To describe a case of dermatomyositis-scleroderma overlap in an African male adolescent. Methods We carried out a retrospective chart review to ascertain clinical features and management strategies. Results We present a case of a 17- year old African male patient who presented with a diagnosis of systemic lupus erythematosus made at a peripheral facility in February 2021, and started on azathioprine 50 mg daily, hydroxychloroquine 200 mg daily and prednisolone 5 mg twice daily. He presented on 30th November 2022 with a 2-year history of bilateral elbow, knee, ankle pain and swelling with an 8-month history of bilateral proximal upper and lower limb muscle weakness. Review of systems revealed alopecia, occasional fever and hyperpigmentation over his proximal interphalangeal and metacarpophalangeal joints that has since evolved to hypopigmentation. Positive examination findings included fine sparse hair, heliotrope rash, Gottron's papule, salt and pepper skin rash, hardening of the skin over the arm and thighs with a rodnan score 3/3 over the phalanges, nodular non tender lesions in the abdominal subcutaneous tissue and dactylitis with fixed flexion deformities of both elbows. He had bilateral flexion contractures of both elbows and knees with dactylitic fingers. Laboratory investigations showed an elevated CRP 94 mg/l, elevated lactate dehydrogenase 458 U/l, elevated creatine kinase 492U/l, positive antinuclear antibodies (1:640 titres) with a nuclear coarse and large speckled pattern, positive double stranded DNA antibodies and weak positive anti SM, anti RNP and PCNA antibodies. Myositis panel was positive for MDA5 and OJ. Pelvic MRI showed features of proximal inflammatory myositis. The childhood myositis assessment scale revealed a score of 25/52. ECHO and chest radiograph were normal. Pulmonary function test showed a low FEV 1 and FVC in keeping with a restrictive lung picture. Gastroenterology review revealed gastritis with no other stigmata of autoimmune disease. Management has consisted of monthly therapy with intravenous immunoglobulin. Azathioprine therapy was switched with mycophenolate mofetil 1 gram twelve hourly. He was advised on sunscreen protection. Physiotherapy and occupational therapy has been ongoing. Three months of follow up has led to the resolution of the flexion knee contractures, improved functionality in activities of daily living and a rodnan score of 2/3 over the phalanges. Conclusion SLE-juvenile dermatomyositis and systemic scleroderma can occur as an overlap syndrome and a definitive diagnosis remains elusive to many clinicians. A thorough history and comprehensive physical examination remains key to establishing a correct diagnosis. Early patient referral to paediatric rheumatologist for prompt appropriate treatment can avert debilitating morbidity and mortality.

Increased Otoferlin Expression in B Cells Is Associated with Muscle Weakness in Untreated Juvenile Dermatomyositis: A Pilot Study.

Otoferlin mRNA expression is increased in JDM patients' PBMCs and muscle compared to healthy controls. This study aims to evaluate the role of otoferlin in JDM disease pathophysiology and its association with disease activity in untreated children with JDM. A total of 26 untreated JDM (88.5% female, 92.3% white, non-Hispanic) and 15 healthy controls were included in this study. Otoferlin mRNA expression was determined by qRT-PCR before and a few months after therapy. Detailed flow cytometry of various cell surface markers and cytoplasmic otoferlin was performed to identify cells expressing otoferlin. In addition, muscle otoferlin expression was evaluated in situ in six untreated JDM patients and three healthy controls. There was a significant increase in otoferlin expression in JDM children compared to controls (Median 67.5 vs. 2.1; p = 0.001). There was a positive correlation between mRNA otoferlin expression and the following disease activity markers: disease activity scores (DAS)-total (rs = 0.62, p < 0.001); childhood myositis assessment scale (CMAS) (rs = -0.61, p = 0.002); neopterin (rs = 0.57, p = 0.004) and von Willebrand factor antigen (vWF: Ag) (rs = 0.60, p = 0.004). Most of the otoferlin-positive cells were unswitched B cells (63-99.4%), with 65-75% of them expressing plasmablast markers (CD19+, IgM+, CD38hi, CD24-). The findings of this pilot study suggest that otoferlin expression is associated with muscle weakness, making it a possible biomarker of disease activity. Additionally, B cells and plasmablasts were the primary cells expressing otoferlin.

Association of Juvenile Dermatomyositis Disease Activity With the Expansion of Blood Memory B and T Cell Subsets Lacking Follicular Markers.

This study was undertaken to identify blood markers of juvenile dermatomyositis (DM) disease activity (DA), which are needed to improve disease management. The study comprised a total of 123 juvenile DM patients and 53 healthy controls. Results of laboratory tests (aldolase, creatinine kinase, lactate dehydrogenase [LDH], aspartate aminotransferase) and clinical measures of DA in patients with juvenile DM, including the Manual Muscle Testing in 8 muscles (MMT-8), Childhood Myositis Assessment Scale (CMAS), and disease activity scores (DAS) (total DAS for juvenile DM, the muscle DAS, and the skin DAS), were recorded when available. Surface phenotype of peripheral blood mononuclear cells was assessed using flow cytometry. Whole blood transcriptional profiles were studied using either RNA-sequencing or microarrays. Differential gene expression was determined using DESeq and compared by pathway and gene ontology analyses. Conventional memory (CD27+IgD-) B cells expressing low CXCR5 levels (CXCR5low/- CM B cells) were significantly increased in frequency and absolute numbers in 2 independent cohorts of juvenile DM patients compared with healthy controls. The frequency of CD4+ Th2 memory cells (CD45RA-CXCR5-CCR6-CXCR3-) was also increased in juvenile DM, especially in patients who were within <1 year from diagnosis. The frequency of CXCR5low/- CM B cells correlated with serum aldolase levels and with a blood interferon-stimulated gene transcriptional signature. Furthermore, both the frequency and absolute numbers of CXCR5low/- CM B cells correlated with clinical and laboratory measures of muscle DA (MMT-8, CMAS, aldolase, and LDH). These findings suggest that both CM B cells lacking the CXCR5 follicular marker and CXCR5- Th2 cells represent potential biomarkers of DA in juvenile DM and may contribute to its pathogenesis.

A Video-Based Augmented Reality System for Human-in-the-Loop Muscle Strength Assessment of Juvenile Dermatomyositis.

As the most common idiopathic inflammatory myopathy in children, juvenile dermatomyositis (JDM) is characterized by skin rashes and muscle weakness. The childhood myositis assessment scale (CMAS) is commonly used to measure the degree of muscle involvement for diagnosis or rehabilitation monitoring. On the one hand, human diagnosis is not scalable and may be subject to personal bias. On the other hand, automatic action quality assessment (AQA) algorithms cannot guarantee 100% accuracy, making them not suitable for biomedical applications. As a solution, we propose a video-based augmented reality system for human-in-the-loop muscle strength assessment of children with JDM. We first propose an AQA algorithm for muscle strength assessment of JDM using contrastive regression trained by a JDM dataset. Our core insight is to visualize the AQA results as a virtual character facilitated by a 3D animation dataset, so that users can compare the real-world patient and the virtual character to understand and verify the AQA results. To allow effective comparisons, we propose a video-based augmented reality system. Given a feed, we adapt computer vision algorithms for scene understanding, evaluate the optimal way of augmenting the virtual character into the scene, and highlight important parts for effective human verification. The experimental results confirm the effectiveness of our AQA algorithm, and the results of the user study demonstrate that humans can more accurately and quickly assess the muscle strength of children using our system.

Urine proteomics by mass spectrometry identifies proteins involved in key pathogenic pathways in patients with juvenile dermatomyositis.

To identify and validate biomarkers in JDM patients using a multiplexing tandem mass tag urine proteome profiling approach. First morning void urine samples were collected from JDM patients (n = 20) and healthy control subjects (n = 21) and processed for analysis using a standardized liquid chromatography-tandem mass spectrometry approach. Biomarkers with significantly altered levels were correlated with clinical measures of myositis disease activity and damage. A subset of candidate biomarkers was validated using commercially available ELISA kits. In total, 2348 proteins were detected in the samples, with 275 proteins quantified across all samples. Among the differentially altered proteins, cathepsin D and galectin-3 binding protein were significantly increased in the urine of JDM patients (adjusted P < 0.05), supporting previous findings in myositis patients. These two candidate biomarkers were confirmed with ELISAs. Cathepsin D positively correlated with Myositis Damage Index (r = 0.57, P < 0.05) and negatively correlated with the Childhood Myositis Assessment Scale (r = -0.54, P < 0.05). We also identified novel JDM candidate biomarkers involved with key features of myositis, including extracellular matrix remodelling proteins. This study confirmed the presence of several proteins in the urine of JDM patients that were previously found to be elevated in the blood of myositis patients and identified novel candidate biomarkers that require validation. These results support the use of urine as a source for biomarker development in JDM.

48 Juvenile dermatomyositis: the experience of Military Pediatrics Department of Tunis

BackgroundJuvenile dermatomyositis (JD) is a rare autoimmune disorder characterized by a non-infectious inflammatory state affecting of the muscles and skin associated with a vasculopathy which represents the essential of its physiopathogenesis.ObjectivesTo review the clinical and biological diagnosis of DMJ as well as its evolution under treatment based on the cases of two patients at the Military Pediatrics Department of Tunis.ObservationsCase 1: This was a three-and-a-half-year-old child with a history of a simple febrile seizure, admitted for a skin rash and myalgia that had been evolving for eight months. Skin examination revealed an erythematous rash of the face and upper eyelids with erythematous papular lesions in front of the proximal interphalangeal joint recalling Gottron's papules. Muscle testing was in favor of a proximal deficiency and the electromyogram (EMG) revealed a diffuse myogenic process more pronounced on the proximal muscles without signs of myositic activity. Biology analysis did not reveal a biological inflammatory syndrome but rather increased muscle enzymes levels up to 3- and 4-times normal values. On the immune status report, there was no evidence of DMJ-specific autoantibodies (ASM), but the anti-SRP antibodies associated with myositis were present. The diagnosis of DMJ was established in view of the association of typical cutaneous signs and 3 muscular signs (proximal deficit, elevation of muscle enzymes, myogenic tracing) and an evaluation of the activity of the disease according to a standardized scale by the Childhood Myositis Assessment Scale (CMAS) was required (which was at 7/52). Treatment with corticosteroids and methotrexate was started after a pretherapeutic evaluation and regular check-ups of the child showed a clear improvement of clinical and muscular signs (CMAS became at 41/52). Case 2: A 7-year-old boy, with no previous pathological history, admitted to our department to explore his gait disorder associated to erythematosquamous lesions. At the dermatological inspection, a localized erythema was noted on the upper eyelids, the nose, the cheeks and the chin area, as well as erythematosquamous lesions on the interphalangeal joints, metacarpophalangeal joints, elbows and knees (Gottron papules). The gait was waddling, the EMG was in favor of myogenic disorder and the muscular testing revealed a proximal muscular affection. The biology results showed an elevation of CPK and LDH to 1.5 times the normal values and a sedimentation rate at 40 mm/h. The antibodies determination showed the existence of anti-NXP2 antibodies specific to myositis. The progression under treatment (corticosteroids, methotrexate and adjuvant treatment) was favorable with a CMAS score of 39 (CMAS was 11 when admitted). The persistence of squamous lesions recalling calcinosis on the dorsal surfaces of the forearms was well correlated with the presence of anti-NXP2 antibodies.ConclusionThe positive diagnosis of DMJ in a child must be based on clinical and biological arguments. The immunological characterization of DMJ should be an important element in the disease management because it can explain the lesions associated with certain myositis specific antibodies as well as their evolution, which implies a particular follow-up depending on the detected antibodies (risk of cancer in anti-NXP2 AC positive patients)

P11 An unusual case of Systemic Sclerosis/JDM overlap in a child with PAX8-related congenital hypothyroidism

Introduction/BackgroundJuvenile dermatomyositis is a rare inflammatory disease with a reported incidence of 0.8–4.1 per million children per year. It presents with a constellation of symptoms and signs of inflammation of skin and muscle, and is associated with significant morbidity if untreated. Juvenile systemic sclerosis (JSSc) is an even rarer rheumatological condition of childhood with significant risk of internal organ involvement, especially cardiopulmonary disease. We herewith present the case of a 7-year-old boy with history of hypothyroidism associated with a PAX8 gene variant who presented with clinical features of an overlap of Systemic Sclerosis with JDM with supportive autoantibody profile.Description/MethodA 7-year-old boy presented with a history of restricted range of movements in his hands – noted due to difficulties with pen grip – and calcinosis. He reported symptoms of fatigue, intolerance to cold with colour changes to hands and feet, stiffness of movements particularly in the morning, and infrequent episodes of choking. His past medical history was significant for hypothyroidism secondary to a paternally inherited PAX8 missense mutation, and there is a family history of Raynaud’s and hypothyroidism. A detailed examination identified diffusely swollen hands with sclerodactyly, calcinosis of his elbows and fingertips, and limited flexion of his fingers and wrists. He also had telangiectasia of his upper eyelids, Gottron’s papules over his knees and elbows, and sluggish circulation in his hands and feet. He had evidence of mild proximal muscle weakness.His investigations revealed mild elevation of muscle enzymes with normal inflammatory markers. His autoantibody profile showed a moderately positive ANA titre of 1600 with a nucleolar pattern, and was positive for anti-NXP2 and anti-SCL-100 antibodies MRI scan of the pelvis showed no evidence of myositis, echocardiogram was normal and a high-resolution CT scan of chest was normal with no features of interstitial lung disease.The overall picture was one of Systemic Sclerosis/JDM overlap with CREST syndrome. He was commenced on induction therapy with IV Methylprednisolone and Cyclophosphamide in view of the calcinosis. After three cycles of Cyclophosphamide and weaning course of oral corticosteroids, his energy levels are significantly improved and he has better overall mobility with no significant proximal muscle weakness (Childhood Myositis Assessment Scale score 49/53). However, flexion of his fingers remains limited albeit better; he has ongoing fingertip calcinosis but fewer lesions over his elbows. He has been commenced on weekly subcutaneous Methotrexate as he completes Cyclophosphamide.Discussion/ResultsThis patient had an unusual medical history of early onset thyroid dysfunction, the genetic testing for which revealed a missense PAX8 gene variant [c.49G>Ap.(Gly17Arg)] (also present in his father, who is euthyroid). This was classified as being of uncertain significance, although felt to clinically be the most likely cause for his hypothyroidism. There was no evidence to suggest that PAX8 gene mutations increased the risk of autoimmune conditions. There is evidence that PAX8 gene mutations, when expressed on malignant cells, may confer resistance to chemotherapy, which made us rethink the plan to commence him on Cyclophosphamide. However, we were reassured that in constitutional variants, there is no increased risk of cancer, and no known history of resistance to Cyclophosphamide.This patient also demonstrated an interesting antibody pattern, as he was positive for anti-NXP2 antibodies (indicating high risk for calcinosis) and anti-SCL-100 antibodies, which are associated with a clinical subset of patients with overlap of Systemic Sclerosis and JDM and associated with extensive extra-muscular features. He had two distinct clinical phenotypes of calcinosis, which is probably explained by the presence of two autoantibodies that increase the risk of calcinosis.Key learning points/ConclusionAlthough JDM has bimodal age group for presentation in childhood, only 3% of systemic sclerosis are seen in childhood, which makes this an extremely unusual presentation, given the age, gender and the overlap features (clinical and immunological).We explored whether this rare presentation could be linked to the underlying PAX8 gene mutations, but we could not find any association.With the clinical diagnosis of systemic sclerosis, it was important to rule out cardiopulmonary complications.The other consideration was regarding the choice of therapeutic agent - whether the germline PAX8 gene variants could increase the risk of malignancies or cause resistance to chemotherapeutic agents like Cyclophosphamide, for neither of which we could find any evidence.Extensive calcinosis cutis in this patient could be explained by the presence of two risk factors (CREST syndrome and JDM with NXP2 antibodies).

Short-term effectiveness of baricitinib in children with refractory and/or severe juvenile dermatomyositis.

ObjectiveTo determine the short-term effectiveness safety of baricitinib in children with refractory and/or severe juvenile dermatomyositis (rsJDM) in a real-world setting.MethodsThis was a single-center retrospective study, including 20 children with rsJDM. They were all treated using baricitinib combined with steroids and other immunosuppressive agents. The childhood myositis assessment scale (CMAS) and PRINTO remission criteria were used to evaluate the disease severity and treatment outcome at 0, 4, 12, and 24 weeks after initiation of baricitinib.ResultsThe skin rash improved in 95% of patients (19/20) at week 24, with a significant decrease of skin-DAS at weeks 12 (6.0 vs. 2.0, p < 0.05] and week 24 [6.0 vs. 1.0, p < 0.05) by median statistics. The CMAS score increased significantly at week 12 (41.0 [29.0, 44.0] vs. 46.0 [42.0, 52.0], p < 0.05) and week 24 (41.0 [29.0, 44.0] vs. 50.0 [45.0, 52.0], p < 0.05), as did the manual muscle testing (MMT)-8 score at week 24 (73.0 [610, 76.0] vs. 79.0 [77.0, 80.0], p < 0.05). At 24 weeks, the complete response (CR) and partial response (PR) were achieved in 75% (15/20) and 15% (3/20), respectively. The dose of corticosteroids (CS) decreased by 37% from the baseline (0.53 [0.42, 1.00] mg/kg) to week 12 (0.33 [0.18, 0.40] mg/kg) (p < 0.05), and by 49% at week 24 (p < 0.05). No serious side effects were observed.ConclusionBaricitinib combined with traditional immunosuppressants treatment was efficacious in rsJDM. Add-on therapy of baricitinib was helpful for tapering CS dose. No serious side effects were observed in this study.

Feasibility of the wingate anaerobic exercise test as a clinical measure in patients with juvenile dermatomyositis

BackgroundCore sets, while widely adopted for clinical assessment in juvenile dermatomyositis (JDM), have some drawbacks – they are time consuming, were developed primarily for research, and require an experienced multidisciplinary team. We propose the Wingate Anaerobic Test, a 30-s all out test performed on a cycle ergometer, as a potential alternative; it is valid and reliable in this patient population. We aimed to determine the feasibility of performing the Wingate test as part of a typical clinic visit, and to determine if it is correlated to current measures of disease activity.MethodsPatients 5–18 years of age, with JDM, were recruited from the JDM clinic at a large Canadian academic children’s hospital. Participants underwent a standard clinic assessment, then completed a Wingate test at the end of the visit.ResultsTwenty-six patients participated in the study, representing a recruitment rate of 81%; of those, 88% were able to complete the Wingate test. Patients liked the Wingate test and felt it should be included as a regular clinic test. Absolute peak power (watts) on the Wingate test was strongly correlated to the manual muscle test (MMT-8) and the timed squat test. Relative peak power (watts/kg) on the Wingate test was strongly correlated to the timed squat test and the Childhood Myositis Assessment Scale (CMAS). Exploratory principal components analysis revealed that Wingate relative average power explained almost 2/3 of the variance of the CMAS, MMT and timed squats combined.ConclusionThe Wingate test is a feasible test for children with JDM and correlates well with standard clinical assessments. Given its brevity, it has the potential to replace more standard measures of physical function currently used in clinical assessments for children with JDM. Future work should focus on how best to operationalize Wingate testing in clinic without the use of dedicated personnel.

SIGLEC1 enables straightforward assessment of type I interferon activity in idiopathic inflammatory myopathies

ObjectiveTo evaluate sialic acid binding Ig-like lectin 1 (SIGLEC1) expression on monocytes by flow cytometry as a type I interferon biomarker in idiopathic inflammatory myopathies (IIM).MethodsWe performed a retrospective analysis...

Preliminary validation of muscle ultrasound in juvenile dermatomyositis (JDM).

To compare muscle ultrasound (MUS) parameters in patients with juvenile JDM and healthy controls, and examine their association with JDM disease activity measures and MRI. MUS of the right mid-rectus femoris was performed in 21 patients with JDM meeting probable or definite Bohan and Peter criteria and 28 demographically matched healthy control subjects. MUS parameters were quantitated by digital image processing and correlated with JDM disease activity measures and semi-quantitative thigh MRI short tau inversion recovery (STIR) and T1 scores. Rectus femoris MUS echogenicity was increased (median 47.8 vs 38.5, P = 0.002) in patients with JDM compared with controls. Rectus femoris MUS echogenicity correlated with Physician Global Activity (PGA), Manual Muscle Testing (MMT), and Childhood Myositis Assessment Scale (CMAS) (rs 0.4-0.54). Some MUS parameters correlated with functional quantitative measures of muscle strength: resting RF area on MUS strongly correlated with knee extension quantitative muscle testing (rs 0.76), and contracted area correlated with proximal MMT, knee extension quantitative muscle testing, and CMAS (rs 0.71-0.80). MUS echogenicity correlated with both STIR and T1 MRI (rs 0.43), and T1 MRI correlated inversely with RF contracted area (rs -0.49) on MUS. There were differences in pre- and post-exercise vascular power and colour Doppler on MUS in patients with JDM vs controls, with the percentage change of post-exercise vascular power Doppler lower in JDM compared with controls (7.1% vs 100.0%). These data suggest MUS may be a valuable imaging modality to assess JDM disease activity and damage.

Long-term outcome in patients with juvenile dermatomyositis: A case series

BackgroundFollow-up of juvenile dermatomyositis (JDM) patients has demonstrated the impact of the disease on several organs in the long term. ObjectiveAs there is little information on the long-term outcome of JDM, we aimed to assess long-term outcomes in a series of JDM patients. MethodsAfter selection of JDM patients, a consultation with a dermatologist and a rheumatologist was held for each patient. Cutaneous, muscle, and disease damage was assessed using different validated scores including the abbreviated Cutaneous Assessment Tool (aCAT), 8-muscle Manual Muscle Testing (MMT8), Childhood Myositis Assessment Scale (CMAS), Myositis Damage Index (MDI), Childhood Health Assessment Questionnaire (CHAQ), and Health Assessment Questionnaire (HAQ). Long-term disease outcomes were recorded including growth and pubertal development, educational and vocational achievement, and development of comorbidities. ResultsSeven patients were included in the study. After a mean follow-up of 14.9±8.8 years, the mean aCAT score was 0.57±1.4 and only one patient had a positive aCAT activity score. The mean aCAT damage score was 1.4±1.3 and five (71%) patients had a score of ≥1. Five (71.4%) patients had normal muscle strength with an MMT8 score of >72, and none had severe muscle weakness (MMT8 ≤32, and CMAS<35). The mean total extent of damage according to the MDI was ≥1 in five (71%) patients and mainly involved the skin. Two (29%) patients had mild disability according to the CHAQ/HAQ disability index. In terms of quality of life, no patient had a score of<40 (1 SD below the mean for healthy controls). ConclusionsBased on validated cutaneous and musculoskeletal scores, our study demonstrated the good functional outcomes of JDM at long-term follow-up.

From Diagnosis to Prognosis: Revisiting the Meaning of Muscle ISG15 Overexpression in Juvenile Inflammatory Myopathies

ObjectiveJuvenile idiopathic inflammatory/immune myopathies (IIMs) constitute a highly heterogeneous group of disorders with diagnostic difficulties and prognostic uncertainties. Circulating myositis‐specific autoantibodies (MSAs) have been recognized as reliable tools for patient substratification. Considering the key role of type I interferon (IFN) up‐regulation in juvenile IIM, we undertook the present study to investigate whether IFN‐induced 15‐kd protein (ISG‐15) could be a reliable biomarker for stratification and diagnosis and to better elucidate its role in juvenile IIM pathophysiology.MethodsThe study included 56 patients: 24 with juvenile dermatomyositis (DM), 12 with juvenile overlap myositis (OM), 10 with Duchenne muscular dystrophy, and 10 with congenital myopathies. Muscle biopsy samples were assessed by immunohistochemistry, immunoblotting, and real‐time quantitative polymerase chain reaction. Negative regulators of type I IFN (ISG15 and USP18) and positive regulators of type I IFN (DDX58 and IFIH1) were analyzed.ResultsISG15 expression discriminated patients with juvenile IIM from those with nonimmune myopathies and, among patients with juvenile IIM, discriminated those with DM from those with OM. Among patients with juvenile DM, up‐regulation of the type I IFN positive regulators DDX58 and IFIH1 was similar regardless of MSA status. In contrast, the highest levels of the type I IFN negative regulator ISG15 were observed in patients who were positive for melanoma differentiation–associated gene 5 (MDA‐5). Finally, ISG15 levels were inversely correlated with the severity of muscle histologic abnormalities and positively correlated with motor performance as evaluated by the Childhood Myositis Assessment Scale and by manual muscle strength testing.ConclusionMuscle ISG15 expression is strongly associated with juvenile DM, with patients exhibiting a different ISG‐15 muscle signature according to their MSA class. Patients with juvenile DM who are positive for MDA‐5 have higher expression of ISG15 in both gene form and protein form compared to the other subgroups. Moreover, our data show that negative regulation of type I IFN correlates with milder muscle involvement.

Myositis-specific autoantibodies and their associated phenotypes in juvenile dermatomyositis: data from a German cohort.

To describe a German cohort of patients with juvenile dermatomyositis (JDM) and to evaluate clinical manifestations, disease course and prognosis in JDM patients with a certain myositis-specific autoantibody. Cross-sectional data on patients with JDM documented in the National Paediatric Rheumatologic Database in Germany between 2014 and 2016 were analysed. In a subgroup of the cohort, MSAs were determined with a commercial multiplex array, and a retrospective chart review was conducted to specify the clinical phenotype and patient outcome. The total cohort consisted of 196 patients with JDM (mean age 12.2±4.0 years, mean disease duration 5.1±3.8 years, 70% female). Apart from typical skin changes and muscle weakness, 41% of patients also had arthritis and/or contractures, 27% had calcinosis and approximately 10% had interstitial lung disease. Immunoblot testing was performed on the sera of 91 (46%) patients, detecting MSAs in 44% of patients. Patient groups with specific MSAs differed in clinical characteristics such as calcinosis, dysphagia, and lung and joint involvement. The extent of muscle weakness evaluated by the Childhood Myositis Assessment Scale was significantly associated with an increased level of creatine kinase. Patients with anti-MDA5 were particularly affected by polyarthritis of the small joints. After 5 years, 51 patients of the MSA cohort (56.0%) achieved an inactive disease state, 12/51 (23.5%) were off therapy. Patients with JDM in Germany show a broad spectrum of clinical manifestations that can be grouped into homogeneous groups using MSA, which also helps to predict the course and prognosis of the disease.