Juvenile idiopathic inflammatory myositis: an update on pathophysiology and clinical care.

The childhood-onset or juvenile idiopathic inflammatory myopathies (JIIMs) are a heterogenous group of rare and serious autoimmune diseases of children and young people that predominantly affect the muscles and skin but can also involve other organs, including the lungs, gut, joints, heart and central nervous system. Different myositis-specific autoantibodies have been identified that are associated with different muscle biopsy features, as well as with different clinical characteristics, prognoses and treatment responses. Thus, myositis-specific autoantibodies can be used to subset JIIMs into sub-phenotypes; some of these sub-phenotypes parallel disease seen in adults, whereas others are distinct from adult-onset idiopathic inflammatory myopathies. Although treatments and management have much improved over the past decade, evidence is still lacking for many of the current treatments and few validated prognostic biomarkers are available with which to predict response to treatment, comorbidities (such as calcinosis) or outcome. Emerging data on the pathogenesis of the JIIMs are leading to proposals for new trials and tools for monitoring disease.

Role of CD14+ monocyte-derived oxidised mitochondrial DNA in the inflammatory interferon type 1 signature in juvenile dermatomyositis.

OBJECTIVES: To define the host mechanisms contributing to the pathological interferon (IFN) type 1 signature in Juvenile dermatomyositis (JDM). METHODS: RNA-sequencing was performed on CD4+, CD8+, CD14+ and CD19+ cells sorted from pretreatment and on-treatment JDM (pretreatment n=10, on-treatment n=11) and age/sex-matched child healthy-control (CHC n=4) peripheral blood mononuclear cell (PBMC). Mitochondrial morphology and superoxide were assessed by fluorescence microscopy, cellular metabolism by 13C glucose uptake assays, and oxidised mitochondrial DNA (oxmtDNA) content by dot-blot. Healthy-control PBMC and JDM pretreatment PBMC were cultured with IFN-α, oxmtDNA, cGAS-inhibitor, TLR-9 antagonist and/or n-acetyl cysteine (NAC). IFN-stimulated gene (ISGs) expression was measured by qPCR. Total numbers of patient and controls for functional experiments, JDM n=82, total CHC n=35. RESULTS: Dysregulated mitochondrial-associated gene expression correlated with increased ISG expression in JDM CD14+ monocytes. Altered mitochondrial-associated gene expression was paralleled by altered mitochondrial biology, including 'megamitochondria', cellular metabolism and a decrease in gene expression of superoxide dismutase (SOD)1. This was associated with enhanced production of oxidised mitochondrial (oxmt)DNA. OxmtDNA induced ISG expression in healthy PBMC, which was blocked by targeting oxidative stress and intracellular nucleic acid sensing pathways. Complementary experiments showed that, under in vitro experimental conditions, targeting these pathways via the antioxidant drug NAC, TLR9 antagonist and to a lesser extent cGAS-inhibitor, suppressed ISG expression in pretreatment JDM PBMC. CONCLUSIONS: These results describe a novel pathway where altered mitochondrial biology in JDM CD14+ monocytes lead to oxmtDNA production and stimulates ISG expression. Targeting this pathway has therapeutical potential in JDM and other IFN type 1-driven autoimmune diseases.

Juvenile dermatomyositis. Where are we now?

Juvenile onset idiopathic inflammatory myopathy (IIM) has many similarities and distinct differences from adult-onset disease. This review will focus on recent developments in understanding and treatment of juvenile dermatomyositis (JDM), the most common disease sub-type of IIM in childhood. JDM is a systemic immune mediated vasculopathy, increasingly recognised as a group of distinct phenotypes with variable presentation and outlook. This overview will describe long-term outlook and disease course including health-related quality of life and emerging treatments.

Association with HLA-DRß1 position 37 distinguishes juvenile dermatomyositis from adult-onset myositis.

Juvenile dermatomyositis (JDM) is a rare, severe autoimmune disease and the most common idiopathic inflammatory myopathy of children. JDM and adult-onset dermatomyositis (DM) have similar clinical, biological and serological features, although these features differ in prevalence between childhood-onset and adult-onset disease, suggesting that age of disease onset may influence pathogenesis. Therefore, a JDM-focused genetic analysis was performed using the largest collection of JDM samples to date. Caucasian JDM samples (n = 952) obtained via international collaboration were genotyped using the Illumina HumanCoreExome chip. Additional non-assayed human leukocyte antigen (HLA) loci and genome-wide single-nucleotide polymorphisms (SNPs) were imputed. HLA-DRB1*03:01 was confirmed as the classical HLA allele most strongly associated with JDM [odds ratio (OR) 1.66; 95% confidence interval (CI) 1.46, 1.89; P = 1.4 × 10-14], with an independent association at HLA-C*02:02 (OR = 1.74; 95% CI 1.42, 2.13, P = 7.13 × 10-8). Analyses of amino acid positions within HLA-DRB1 indicated that the strongest association was at position 37 (omnibus P = 3.3 × 10-19), with suggestive evidence this association was independent of position 74 (omnibus P = 5.1 × 10-5), the position most strongly associated with adult-onset DM. Conditional analyses also suggested that the association at position 37 of HLA-DRB1 was independent of some alleles of the Caucasian HLA 8.1 ancestral haplotype (AH8.1) such as HLA-DQB1*02:01 (OR = 1.62; 95% CI 1.36, 1.93; P = 8.70 × 10-8), but not HLA-DRB1*03:01 (OR = 1.49; 95% CR 1.24, 1.80; P = 2.24 × 10-5). No associations outside the HLA region were identified. Our findings confirm previous associations with AH8.1 and HLA-DRB1*03:01, HLA-C*02:02 and identify a novel association with amino acid position 37 within HLA-DRB1, which may distinguish JDM from adult DM.

A survey to understand the feelings towards and impact of COVID-19 on the households of juvenile dermato myositis patients from a parent or carer perspective.

OBJECTIVES: This aim of this study was to gain a better understanding of how parents and carers feel about the effects and impact of the coronavirus disease 2019 (COVID-19) pandemic lockdown and how this impacted upon their child/young person with JDM. METHOD: We approached 139 participants from the JDM Cohort Biomarker Study (JDCBS), with specific consent to approach electronically for research studies. A secure electronic questionnaire with study introduction was sent to participants for their parents and carers around the UK to complete. It consisted of 20 questions about the impact of the pandemic on their child or young person's clinical care. Data were analysed quantitatively and qualitatively. RESULTS: There were 76 (55%) responses to the survey. More than 50% of participants were actively being treated for their JDM at the point of survey completion as recorded by their parent or carer. More than 40% attested to disrupted treatment owing to COVID-19. The biggest impact upon clinical care was cancellation of appointments, initiating virtual appointments and extension of time between blood tests. Parents and carers expressed their own feelings of worry, concern and anxiety, but also those of their child or young person. CONCLUSION: Families who have a child or young person with JDM have been affected by COVID-19. Qualitative comments highlight that it has been a very difficult time. Further investigation is required into this area and could be compared with research on the effects of COVID-19 on other patient groups with chronic disease.

JAK inhibitors: a potential treatment for JDM in the context of the role of interferon-driven pathology.

Juvenile Idiopathic Inflammatory Myopathies (IIM) are a group of rare diseases that are heterogeneous in terms of pathology that can include proximal muscle weakness, associated skin changes and systemic involvement. Despite options for treatment, many patients continue to suffer resistant disease and lasting side-effects. Advances in the understanding of the immunopathology and genetics underlying IIM may specify new therapeutic targets, particularly where conventional treatment has not achieved a clinical response. An upregulated type I interferon signature is strongly associated with disease and could be a prime target for developing more specific therapeutics. There are multiple components of the IFN pathway that could be targeted for blockade therapy.Downstream of the cytokine receptor complexes are the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway, which consists of JAK1-3, TYK2, and STAT1-6. Therapeutic inhibitors have been developed to target components of this pathway. Promising results have been observed in case studies reporting the use of the JAK inhibitors, Baricitinib, Tofacitinib and Ruxolitinib in the treatment of refractory Juvenile Dermatomyositis (JDM). There is still the question of safety and efficacy for the use of JAK inhibitors in JDM that need to be addressed by clinical trials. Here we review the future for the use of JAK inhibitors as a treatment for JDM.

Favorable antibody responses to human coronaviruses in children and adolescents with autoimmune rheumatic diseases.

BACKGROUND: Differences in humoral immunity to coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), between children and adults remain unexplained, and the effect of underlying immune dysfunction or suppression is unknown. Here, we sought to examine the antibody immune competence of children and adolescents with prevalent inflammatory rheumatic diseases, juvenile idiopathic arthritis (JIA), juvenile dermatomyositis (JDM), and juvenile systemic lupus erythematosus (JSLE) against the seasonal human coronavirus (HCoV)-OC43 that frequently infects this age group. METHODS: Sera were collected from JIA (n = 118), JDM (n = 49), and JSLE (n = 30) patients and from healthy control (n = 54) children and adolescents prior to the coronavirus disease 19 (COVID-19) pandemic. We used sensitive flow-cytometry-based assays to determine titers of antibodies that reacted with the spike and nucleoprotein of HCoV-OC43 and cross-reacted with the spike and nucleoprotein of SARS-CoV-2, and we compared them with respective titers in sera from patients with multisystem inflammatory syndrome in children and adolescents (MIS-C). FINDINGS: Despite immune dysfunction and immunosuppressive treatment, JIA, JDM, and JSLE patients maintained comparable or stronger humoral responses than healthier peers, which was dominated by immunoglobulin G (IgG) antibodies to HCoV-OC43 spike, and harbored IgG antibodies that cross-reacted with SARS-CoV-2 spike. In contrast, responses to HCoV-OC43 and SARS-CoV-2 nucleoproteins exhibited delayed age-dependent class-switching and were not elevated in JIA, JDM, and JSLE patients, which argues against increased exposure. CONCLUSIONS: Consequently, autoimmune rheumatic diseases and their treatment were associated with a favorable ratio of spike to nucleoprotein antibodies. FUNDING: This work was supported by a Centre of Excellence Centre for Adolescent Rheumatology Versus Arthritis grant, 21593, UKRI funding reference MR/R013926/1, the Great Ormond Street Children's Charity, Cure JM Foundation, Myositis UK, Lupus UK, and the NIHR Biomedical Research Centres at GOSH and UCLH. This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK, the UK Medical Research Council, and the Wellcome Trust.

The Role of Immunometabolism in the Pathogenesis of Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder in which pathogenic abnormalities within both the innate and adaptive immune response have been described. In order to activated, proliferate and maintain this immunological response a drastic upregulation in energy metabolism is required. Recently, a greater understanding of these changes in cellular bioenergetics have provided new insight into the links between immune response and the pathogenesis of a number of diseases, ranging from cancer to diabetes and multiple sclerosis. In this review, we highlight the latest understanding of the role of immunometabolism in SLE with particular focus on the role of abnormal mitochondrial function, lipid metabolism, and mTOR signaling in the immunological phenomenon observed in the SLE. We also consider what implications this has for future therapeutic options in the management of the disease in future.

Preexisting and de novo humoral immunity to SARS-CoV-2 in humans.

Zoonotic introduction of novel coronaviruses may encounter preexisting immunity in humans. Using diverse assays for antibodies recognizing SARS-CoV-2 proteins, we detected preexisting humoral immunity. SARS-CoV-2 spike glycoprotein (S)-reactive antibodies were detectable using a flow cytometry-based method in SARS-CoV-2-uninfected individuals and were particularly prevalent in children and adolescents. They were predominantly of the immunoglobulin G (IgG) class and targeted the S2 subunit. By contrast, SARS-CoV-2 infection induced higher titers of SARS-CoV-2 S-reactive IgG antibodies targeting both the S1 and S2 subunits, and concomitant IgM and IgA antibodies, lasting throughout the observation period. SARS-CoV-2-uninfected donor sera exhibited specific neutralizing activity against SARS-CoV-2 and SARS-CoV-2 S pseudotypes. Distinguishing preexisting and de novo immunity will be critical for our understanding of susceptibility to and the natural course of SARS-CoV-2 infection.

Using peripheral blood immune signatures to stratify patients with adult and juvenile inflammatory myopathies.

OBJECTIVE: The inflammatory idiopathic myopathies (IIM) are a group of rare autoimmune diseases defined by muscle weakness and characterized by pro-inflammatory infiltrates in muscle. Little is known about the immunological profile in peripheral blood of these patients and how this relates to IIM subtypes. This study aimed to stratify adult and juvenile-onset IIM patients according to immune cell profile. METHODS: Peripheral blood mononuclear cells from 44 patients with adult myositis (AM), 15 adolescent-onset juvenile dermatomyositis (a-JDM), and 40 age-matched healthy controls were analysed by flow cytometry to quantify 33 immune cell subsets. Adult myositis patients were grouped according to myositis subtype; DM and polymyositis; and also autoantibody specificity. Disease activity was determined by the myositis disease activity assessment tool and clinicians' decision on treatment. RESULTS: Unique immune signatures were identified for DM, polymyositis and a-JDM compared with healthy controls. DM patients had a T-cell signature comprising increased CD4+ and TH17 cell frequencies and increased immune cell expression of IL-6. Polymyositis patients had a B-cell signature with reduced memory B cells. A-JDM had decreased naïve B cells and increased CD4+T cells. All patient groups had decreased CD8+central memory T-cell frequencies. The distinct immune signatures were also seen when adult myositis patients were stratified according to auto-antibody expression; patients with anti-synthetase-antibodies had reduced memory B cells and patients with autoimmune rheumatic disease overlap had an elevated Th17 profile. CONCLUSION: Unique immune signatures were associated with adult vs juvenile disease. The Th17 signature in DM patients supports the potential use of IL-17 inhibitors in treatment of IIMs.

B Cells as a Therapeutic Target in Paediatric Rheumatic Disease.

B cells carry out a central role in the pathogenesis of autoimmune disease. In addition to the production of autoantibodies, B cells can contribute to disease development by presenting autoantigens to autoreactive T cells and by secreting pro-inflammatory cytokines and chemokines which leads to the amplification of the inflammatory response. Targeting both the antibody-dependent and antibody-independent function of B cells in adult rheumatic disease has led to the advent of B cell targeted therapies in clinical practice. To date, whether B cell depletion could also be utilized for the treatment of pediatric disease is relatively under explored. In this review, we will discuss the role of B cells in the pathogenesis of the pediatric rheumatic diseases Juvenile Idiopathic Arthritis (JIA), Juvenile Systemic Lupus Erythematosus (JSLE) and Juvenile Dermatomyositis (JDM). We will also explore the rationale behind the use of B cell-targeted therapies in pediatric rheumatic disease by highlighting new case studies that points to their efficacy in JIA, JSLE, and JDM.

CD19+CD24hiCD38hi B Cells Are Expanded in Juvenile Dermatomyositis and Exhibit a Pro-Inflammatory Phenotype After Activation Through Toll-Like Receptor 7 and Interferon-α.

Juvenile dermatomyositis (JDM) is a rare form of childhood autoimmune myositis that presents with proximal muscle weakness and skin rash. B cells are strongly implicated in the pathogenesis of the disease, but the underlying mechanisms are unknown. Therefore, the main objective of our study was to investigate mechanisms driving B cell lymphocytosis and define pathological features of B cells in JDM patients. Patients were recruited through the UK JDM Cohort and Biomarker study. Peripheral blood B cell subpopulations were immunophenotyped by flow cytometry. The results identified that immature transitional B cells were significantly expanded in active JDM, actively dividing, and correlated positively with disease activity. Protein and RNAseq analysis revealed high interferon alpha (IFNα) and TLR7-pathway signatures pre-treatment. Stimulation of B cells through TLR7/8 promoted both IL-10 and IL-6 production in controls but failed to induce IL-10 in JDM patient cells. Interrogation of the CD40-CD40L pathway (known to induce B cell IL-10 and IL-6) revealed similar expression of IL-10 and IL-6 in B cells cultured with CD40L from both JDM patients and controls. In conclusion, JDM patients with active disease have a significantly expanded immature transitional B cell population which correlated with the type I IFN signature. Activation through TLR7 and IFNα may drive the expansion of immature transitional B cells in JDM and skew the cells toward a pro-inflammatory phenotype.