Recommendations for the management of secondary hypogammaglobulinaemia due to B cell targeted therapies in autoimmune rheumatic diseases.

OBJECTIVES: The association of B cell targeted therapies with development of hypogammaglobulinaemia and infection is increasingly recognized. Our aim was to develop consensus recommendations for immunoglobulin replacement therapy for management of hypogammaglobulinaemia following B cell targeted therapies in autoimmune rheumatic diseases. METHODS: A modified Delphi exercise involved a 17-member Taskforce committee, consisting of immunologists, rheumatologists, nephrologists, haematologists, a gastroenterologist, an immunology specialist nurse and a patient representative. The first round identified the most pertinent topics to address in the recommendations. A search string was agreed upon for the identification of publications in PubMed focusing on these areas, for a systematic literature review. Original data was presented from this review to the Taskforce committee. Recommendations from the British Society for Rheumatology, the UK Department of Health, EULAR, the ACR, and the American Academy of Allergy, Asthma, and Immunology were also reviewed. The evidence was discussed in a face-to-face meeting to formulate recommendation statements. The levels of evidence and statements were graded according to Scottish Intercollegiate Guidelines Network methodology. RESULTS: Three overarching principles, eight recommendation statements and a research agenda were formulated. The Taskforce committee voted on these statements, achieving 82-100% agreement for each recommendation. The strength of the recommendations was restricted by the low quality of the available evidence, with no randomized controlled trial data. The recommendations cover risk factors, monitoring, referral for hypogammaglobulinaemia; indications, dosage and discontinuation of immunoglobulin replacement therapy. CONCLUSION: These are the first recommendations specifically formulated for B cell targeted therapies related to hypogammaglobulinaemia in autoimmune rheumatic diseases. The recommendations are to aid health-care professionals with clinical decision making for patients with hypogammaglobulinaemia.

Validation of a score tool for measurement of histological severity in juvenile dermatomyositis and association with clinical severity of disease.

OBJECTIVES: To study muscle biopsy tissue from patients with juvenile dermatomyositis (JDM) in order to test the reliability of a score tool designed to quantify the severity of histological abnormalities when applied to biceps humeri in addition to quadriceps femoris. Additionally, to evaluate whether elements of the tool correlate with clinical measures of disease severity. METHODS: 55 patients with JDM with muscle biopsy tissue and clinical data available were included. Biopsy samples (33 quadriceps, 22 biceps) were prepared and stained using standardised protocols. A Latin square design was used by the International Juvenile Dermatomyositis Biopsy Consensus Group to score cases using our previously published score tool. Reliability was assessed by intraclass correlation coefficient (ICC) and scorer agreement (α) by assessing variation in scorers' ratings. Scores from the most reliable tool items correlated with clinical measures of disease activity at the time of biopsy. RESULTS: Inter- and intraobserver agreement was good or high for many tool items, including overall assessment of severity using a Visual Analogue Scale. The tool functioned equally well on biceps and quadriceps samples. A modified tool using the most reliable score items showed good correlation with measures of disease activity. CONCLUSIONS: The JDM biopsy score tool has high inter- and intraobserver agreement and can be used on both biceps and quadriceps muscle tissue. Importantly, the modified tool correlates well with clinical measures of disease activity. We propose that standardised assessment of muscle biopsy tissue should be considered in diagnostic investigation and clinical trials in JDM.

Juvenile dermatomyositis: new insights and new treatment strategies.

Juvenile dermatomyositis (JDM) is a rare but complex and potentially life-threatening autoimmune disease of childhood, primarily affecting proximal muscles and skin. Although the cause of JDM remains unknown it is clear that genetic and environmental influences play a role in the aetiology. In contrast to adults with dermatomyositis, children with JDM are more likely to have complications that are thought to indicate a vasculopathic process, such as severe skin disease, with ulceration or calcinosis, gut vasculopathy or central nervous system disease. New treatments are much needed and are becoming available and being tested through international multicentre trials. This review will focus on recent insights into pathogenesis, the assessment of the disease in children and the modern approach to its treatment.

Genetic association study of NF-κB genes in UK Caucasian adult and juvenile onset idiopathic inflammatory myopathy.

OBJECTIVE: Treatment-resistant muscle wasting is an increasingly recognized problem in idiopathic inflammatory myopathy (IIM). TNF-α is thought to induce muscle catabolism via activation of nuclear factor-kappa B (NF-κB). Several genes share homology with the NF-κB family of proteins. This study investigated the role of NF-κB-related genes in disease susceptibility in UK Caucasian IIM. METHODS: Data from 362 IIM cases [274 adults, 49 (±14.0) years, 72% female; 88 juveniles, 6 (±3.6) years, 73% female) were compared with 307 randomly selected Caucasian controls. DNA was genotyped for 63 single nucleotide polymorphisms (SNPs) from NF-κB-related genes. Data were stratified by IIM subgroup/serotype. RESULTS: A significant allele association was observed in the overall IIM group vs controls for the IKBL-62T allele (rs2071592, odds ratio 1.5, 95% CI 1.21, 1.89, corrected P = 0.0086), which strengthened after stratification by anti-Jo-1 or -PM-Scl antibodies. Genotype analysis revealed an increase for the AT genotype in cases under a dominant model. No other SNP was associated in the overall IIM group. Strong pairwise linkage disequilibrium was noted between IKBL-62T, TNF-308A and HLA-B*08 (D' = 1). Using multivariate regression, the IKBL-62T IIM association was lost after adjustment for TNF-308A or HLA-B*08. CONCLUSION: An association was noted between IKBL-62T and IIM, with increased risk noted in anti-Jo-1- and -PM-Scl antibody-positive patients. However, the IKBL-62T association is dependent on TNF-308A and HLA-B*08, due to strong shared linkage disequilibrium between these alleles. After adjustment of the 8.1 HLA haplotype, NF-κB genes therefore do not independently confer susceptibility in IIM.

Quantification of normal range of inflammatory changes in morphologically normal pediatric muscle.

The aim of this study was to define normal ranges of histological features in pediatric muscle in comparison with muscle demonstrating inflammatory changes. Sixteen pediatric muscle biopsy samples, considered normal by standard histology, were analyzed for the presence of inflammatory cells, and the expression of neonatal myosin and major histocompatibility complex (MHC) Class 1. Normal findings were defined for each feature. These data will facilitate quantitative analysis of inflammatory changes in pediatric muscle biopsy.

International consensus on a proposed score system for muscle biopsy evaluation in patients with juvenile dermatomyositis: a tool for potential use in clinical trials.

OBJECTIVE: To devise and test a system with which to evaluate abnormalities on muscle biopsy samples obtained from children diagnosed with juvenile dermatomyositis (DM). METHODS: We established an International Consensus Group on Juvenile DM Biopsy and carried out 2 phases of consensus process and scoring workshops. Biopsy sections (n = 33) were stained by standard methods. The scoring tool was based on 4 domains of change: inflammatory, vascular, muscle fiber, and connective tissue. Using a Latin square design, biopsy samples were scored by 11 experts for items in each domain, and for a global abnormality measure using a 10-cm visual analog score (VAS 0-10). The tool's reliability was assessed using an intraclass correlation coefficient (ICC) and scorer agreement (alpha) by determining variation in scorers' ratings. RESULTS: There was good agreement in many items of the tool, and several items refined between the meetings improved in reliability and/or agreement. The inflammatory and muscle fiber domains had the highest reliability and agreement. The overall VAS score for abnormality had high agreement and reliability, reaching an ICC of 0.863 at the second consensus meeting. CONCLUSION: We propose a provisional scoring system to measure abnormalities on muscle biopsy samples obtained from children with juvenile DM. This system needs to be validated, and then could be used in prospective studies to test which features of muscle pathology are prognostic of disease course or outcome. We suggest that the process we used could be a template for developing similar systems in other forms of myositis.

Paediatric idiopathic inflammatory muscle disease.

The paediatric idiopathic inflammatory myopathies (IIMs) are a group of rare but serious systemic autoimmune conditions of childhood. The most common of the paediatric IIMs is juvenile dermatomyositis (JDM), while polymyositis and inclusion body myositis are rare in children. JDM has a significantly different spectrum of disease from adult dermatomyositis. Juvenile myositis can also occur as part of other systemic autoimmune diseases such as scleroderma and systemic lupus erythematosus. There has recently been significant progress towards the development and validation of tools to measure disease activity and damage in the paediatric IIMs. In addition, several new therapeutic avenues have been used to treat JDM. This review will discuss developments in the diagnostic criteria for JDM, the clinical types and course of these conditions, recent progress in disease assessment, treatment options and new developments in research into the pathogenesis of paediatric IIM.

MHC Class I overexpression on muscles in early juvenile dermatomyositis.

OBJECTIVE: To assess muscle expression of MHC Class I complexes (heavy chain and beta2-microglobulin) and to analyze the composition of infiltrating mononuclear cells, specifically cells that bear receptors for class I MHC molecules, in the muscles of children with early juvenile dermatomyositis (JDM). METHODS: Light microscopic and immunohistochemical analysis of muscle biopsies from 10 patients with JDM and 3 controls. The mean duration from initial weakness was 2.8 months. At the time of biopsy, 9 patients had not received steroid treatment or immunomodulatory drugs. RESULTS: MHC Class I over-expression was evident on muscle fibers in all 10 JDM samples, even in a biopsy reported as normal by conventional histology. MHC class I heavy chain and beta2-microglobulin were over-expressed in an identical distribution. Variable infiltration of T cells and macrophages was seen in the JDM biopsies, with minimal lymphocytic and monocytic infiltration in 4 cases, and none in one. Only very occasional natural killer lymphocytes were identified. Neuronal cell adhesion molecule (NCAM, CD56) staining of regenerating muscle fibers was seen in all samples and these cells were confirmed as being of muscle origin by co-staining for dystrophin. CONCLUSION: MHC Class I over-expression is an early event in JDM, and may occur in the absence of lymphocytic infiltration and muscle damage. Immunostaining for MHC Class I could be used routinely in the assessment of muscle histology in juvenile dermatomyositis.