Expression of myxovirus-resistance protein A: a possible marker of muscle disease activity and autoantibody specificities in juvenile dermatomyositis.

AIMS: To evaluate the relationship between expression of myxovirus-resistance protein A (MxA) protein on muscle biopsies by immunohistochemistry and disease activity in juvenile dermatomyositis (JDM) patients. Also, another aim was to investigate whether the expression of MxA is related with myositis-specific autoantibodies (MSA) status in JDM patients. METHODS: 103 patients (median aged 6.3, interquartile range 0.5-15.9) enrolled in the Juvenile Dermatomyositis Cohort and Biomarker Study (JDCBS). Muscle biopsies were stained with MxA and scored. Clinical data at initial presentation were collected and autoantibodies were analysed. Multiple linear regression analysis was performed to estimate the association between MxA expression on muscle fibres and muscle disease activity, and MSA status. RESULTS: Expression of MxA protein on JDM samples was identified in 61.2%. There was a significant association between MxA scores and Childhood Myositis Assessment Scale (CMAS) (P = 0.002), and Manual Muscle Testing of Eight Muscles (MMT8) (P = 0.026). CMAS and MMT8 scores were significantly lower in the group of patients with strong MxA expression. MxA scores differed according to MSA subgroups (P = 0.002). Patients with positive nuclear matrix protein 2 autoantibodies had strong MxA expression, whereas anti-melanoma differentiation-associated gene 5 positive patients had no or weak MxA expression. CONCLUSIONS: This study reveals the significant association between level of MxA expression on muscle fibres and clinical measures of muscular disease activity in JDM patients and MSA status. This confirms type I interferonopathies in muscle fibres of JDM patients which could help with improving treatment outcome in JDM patients and underscoring the distinct pathophysiological pathways in different MSA status.

Histological heterogeneity in a large clinical cohort of juvenile idiopathic inflammatory myopathy: analysis by myositis autoantibody and pathological features.

AIM: Juvenile idiopathic inflammatory myopathies have been recently reclassified into clinico-serological subgroups. Myopathological correlates of the subgroups are incompletely understood. METHODS: We studied muscle biopsies from 101 children with clinically and serologically defined juvenile idiopathic inflammatory myopathies from the UK JDM Cohort and Biomarker Study by applying the international JDM score tool, myopathological review and C5b-9 complement analysis. RESULTS: Autoantibody data were available for 90/101 cases with 18/90 cases positive for anti-TIF1γ, 15/90 anti-NXP2, 11/90 anti-MDA5, 5/90 anti-Mi2 and 6/90 anti-PmScl. JDM biopsy severity scores were consistently low in the anti-MDA5 group, high in the anti-Mi2 group, and widely distributed in the other groups. Biopsies were classified histologically as perifascicular atrophy (22/101), macrophage-rich necrosis (6/101), scattered necrosis (2/101), clustered necrosis (2/101), inflammatory fibre invasion (2/101), chronic myopathic change (1/101), diffuse endomysial macrophage infiltrates (40/101) and minimal change (24/101). MDA5 cases segregated with the minimal change group and showed no capillary C5b-9-deposition. The Mi2 group displayed high severity scores and a tendency towards sarcolemmal complement deposition. NXP2 and TIF1γ groups showed a variety of pathologies with a high proportion of diffuse endomysial macrophage infiltrates and a high proportion of capillary C5b-9 deposition. CONCLUSION: We have shown that juvenile idiopathic inflammatory myopathies have a spectrum of histopathological phenotypes and show distinct complement attack complex deposition patterns. Both correlate in some cases with the serological subtypes. Most cases do not show typical histological features associated with dermatomyositis (e.g. perifascicular atrophy). In contrast, more than half show relatively mild histopathological changes.

Fine-mapping the MHC locus in juvenile idiopathic arthritis (JIA) reveals genetic heterogeneity corresponding to distinct adult inflammatory arthritic diseases.

OBJECTIVES: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases, comprising seven categories. Genetic data could potentially be used to help redefine JIA categories and improve the current classification system. The human leucocyte antigen (HLA) region is strongly associated with JIA. Fine-mapping of the region was performed to look for similarities and differences in HLA associations between the JIA categories and define correspondences with adult inflammatory arthritides. METHODS: Dense genotype data from the HLA region, from the Immunochip array for 5043 JIA cases and 14 390 controls, were used to impute single-nucleotide polymorphisms, HLA classical alleles and amino acids. Bivariate analysis was performed to investigate genetic correlation between the JIA categories. Conditional analysis was used to identify additional effects within the region. Comparison of the findings with those in adult inflammatory arthritic diseases was performed. RESULTS: We identified category-specific associations and have demonstrated for the first time that rheumatoid factor (RF)-negative polyarticular JIA and oligoarticular JIA are genetically similar in their HLA associations. We also observe that each JIA category potentially has an adult counterpart. The RF-positive polyarthritis association at HLA-DRB1 amino acid at position 13 mirrors the association in adult seropositive rheumatoid arthritis (RA). Interestingly, the combined oligoarthritis and RF-negative polyarthritis dataset shares the same association with adult seronegative RA. CONCLUSIONS: The findings suggest the value of using genetic data in helping to classify the categories of this heterogeneous disease. Mapping JIA categories to adult counterparts could enable shared knowledge of disease pathogenesis and aetiology and facilitate transition from paediatric to adult services.

Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes.

Autoimmune muscle diseases (myositis) comprise a group of complex phenotypes influenced by genetic and environmental factors. To identify genetic risk factors in patients of European ancestry, we conducted a genome-wide association study (GWAS) of the major myositis phenotypes in a total of 1710 cases, which included 705 adult dermatomyositis, 473 juvenile dermatomyositis, 532 polymyositis and 202 adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl-tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with 4724 controls. Single-nucleotide polymorphisms showing strong associations (P<5×10(-8)) in GWAS were identified in the major histocompatibility complex (MHC) region for all myositis phenotypes together, as well as for the four clinical and autoantibody phenotypes studied separately. Imputation and regression analyses found that alleles comprising the human leukocyte antigen (HLA) 8.1 ancestral haplotype (AH8.1) defined essentially all the genetic risk in the phenotypes studied. Although the HLA DRB1*03:01 allele showed slightly stronger associations with adult and juvenile dermatomyositis, and HLA B*08:01 with polymyositis and anti-Jo-1 autoantibody-positive myositis, multiple alleles of AH8.1 were required for the full risk effects. Our findings establish that alleles of the AH8.1 comprise the primary genetic risk factors associated with the major myositis phenotypes in geographically diverse Caucasian populations.

Genome-wide data reveal novel genes for methotrexate response in a large cohort of juvenile idiopathic arthritis cases.

Clinical response to methotrexate (MTX) treatment for children with juvenile idiopathic arthritis (JIA) displays considerable heterogeneity. Currently, there are no reliable predictors to identify non-responders: earlier identification could lead to a targeted treatment. We genotyped 759 JIA cases from the UK, the Netherlands and Czech Republic. Clinical variables were measured at baseline and 6 months after start of the treatment. In Phase I analysis, samples were analysed for the association with MTX response using ordinal regression of ACR-pedi categories and linear regression of change in clinical variables, and identified 31 genetic regions (P<0.001). Phase II analysis increased SNP density in the most strongly associated regions, identifying 14 regions (P<1 × 10(-5)): three contain genes of particular biological interest (ZMIZ1, TGIF1 and CFTR). These data suggest a role for novel pathways in MTX response and further investigations within associated regions will help to reach our goal of predicting response to MTX in JIA.

Juvenile Dermatomyositis: what comes next? Long-term outcomes in childhood myositis from a patient perspective.

BACKGROUND: To describe long-term outcomes in JDM using patient questionnaires and link to longitudinal, prospectively collected data for each patient within the Juvenile Dermatomyositis Cohort and Biomarker Study, UK and Ireland (JDCBS) to determine outcome predictors.  METHODS: JDCBS participants aged ≥ 16y completed the SF36, HAQ and a questionnaire regarding current disease features, medications, education and employment. Data collected from the JDCBS included disease subtype, demographics, clinical and laboratory features. Intensity indices were calculated for physician VAS, modified skin DAS, CMAS and MMT8 by dividing area under the curve (AUC) from longitudinal score trajectories by duration of study follow-up (y). Relationships between questionnaire and JDCBS clinical / laboratory data were investigated fitting statistical models appropriate for cross sectional and longitudinal data. RESULTS: Of 190 questionnaires sent, 84 (44%) were returned. Average age of respondents was 20.6 years (SD 3.9), time since diagnosis was 12.4 years (SD 5.0), age at onset was 9.2 years (SD 4.3), female to male ratio 4.25:1. Forty-nine (59%) self-reported persistently active disease, 54 (65%) were still taking immunosuppressive medication. 14/32 at school/higher education reported myositis adversely affecting academic results. 18-24 year-olds were twice as likely to be unemployed compared the UK population (OR = 0.456, 95% CI 0.24, 0.84, p = 0.001). Participants ≥ 18 years were three times as likely to be living with a parent/guardian (OR = 3.39, p < 0.001). SF36 MCS and MMT8 intensity index scores were significantly correlated (ρ = 0.328, p = 0.007). CONCLUSIONS: After 12.4 years, questionnaire responders reported self-perceived high rates of persistently active disease and medication use, reduced rates of employment and were more likely to live with a parent/guardian. Perceived persistently active muscle disease appeared to affect quality of life in these patients and was the most significant contributor to long-term outcomes. Our findings highlight the importance of including the patient perspective in the assessment of long term outcomes, so that that we can start to target initial management strategies more effectively based on a combination of clinical and patient-reported data.

Age-dependent inhibition of ectopic calcification: a possible role for fetuin-A and osteopontin in patients with juvenile dermatomyositis with calcinosis.

OBJECTIVES: To assess if age and/or age-dependent variations in the levels of two major calcification regulatory proteins, fetuin-A and osteopontin, could be associated with an increased risk of calcinosis in children with juvenile dermatomyositis (JDM). METHODS: The frequency of calcinosis was derived from a national UK database of 212 cases of JDM. Serum fetuin-A and plasma osteopontin levels were determined using ELISA in 15 JDM patients with calcinosis and 15 JDM patients without calcinosis. Healthy controls were 19 age-matched children, 24 adolescents and 13 adults. Sixteen patients with juvenile idiopathic arthritis (JIA) were additional paediatric disease controls. RESULTS: Of the 212 JDM cases 10% had calcinosis. Calcinosis patients had younger age of disease onset than those without calcinosis (mean age of 5.3 yrs vs 7.1 yrs, respectively, P = 0.016). No significant difference in fetuin-A or osteopontin could be detected between the two JDM groups. Fetuin-A levels in all groups of children and the adolescent group were much lower than described previously in adults, and there was a significant positive correlation between age and fetuin-A level, and also between osteopontin levels in plasma and serum fetuin-A. CONCLUSIONS: Children who develop JDM at an younger age may have increased risk of developing calcinosis. Physiologically low levels of fetuin-A in young children combined with an additional negative acute-phase effect on fetuin-A due to chronic inflammation could explain in part the propensity to develop ectopic calcification observed in JDM patients, and why calcinosis is less frequent in adults with dermatomyositis.

Clinical associations of autoantibodies to a p155/140 kDa doublet protein in juvenile dermatomyositis.

OBJECTIVES: Myositis-specific autoantibodies (MSAs) may define homogeneous clinical subsets of adult patients with dermatomyositis (DM). Recently, there have been descriptions of novel autoantibodies in DM. This study was conducted to establish the clinical significance of anti-p155/140 autoantibodies in juvenile DM (JDM). METHODS: The first 116 children recruited to the JDM National Registry and Repository (UK and Ireland) were studied. Comprehensive clinical features were recorded and sera screened for anti-p155/140 autoantibodies using radio-immunoprecipitation. Sera from adults with DM (n = 20), PM (n = 25), SSc (n = 150), SLE (n = 40) and healthy subjects (n = 50) were used for comparison. Immunodepletion experiments were used to establish whether the p155/140 kDa targets recognized by JDM sera were the same as adult DM sera. RESULTS: Twenty-seven out of 116 (23%) JDM cases were positive for anti-p155/140 in comparison with 6/20 (30%) adults with DM. Immunodepletion confirmed that the 155/140 kDa proteins recognized by JDM and adult DM sera were the same targets. All other adult control sera were negative for anti-p155/140 autoantibodies. There was a higher frequency of males in the anti-p155/140-positive JDM group (P = 0.02). JDM patients with anti-p155/140 autoantibodies had significantly more cutaneous involvement including Gottron's papules (P = 0.003), ulceration (P = 0.005) and oedema (P = 0.013). The distribution of skin lesions was more extensive particularly periorbitally (P = 0.014) and over the small (P < 0.001) and large joints (P = 0.003). CONCLUSIONS: Anti-p155/140 autoantibodies are clinically significant in JDM and may define a clinical subset in terms of disease severity and outcome. The same autoantigen target is detected in adult DM patients.

HLA class II haplotype and autoantibody associations in children with juvenile dermatomyositis and juvenile dermatomyositis-scleroderma overlap.

OBJECTIVES: To investigate a large cohort of children with juvenile dermatomyositis (JDM), and those with JDM-scleroderma (JDM-SSc) overlap, using detailed serological analysis, HLA class II genotyping and clinical characterization. METHODS: Children (114) with JDM were recruited, and clinical data collected, through the JDM National Registry and Repository (UK and Ireland). Sera were assayed for ANA using standard immunofluorescence techniques and specific antibodies characterized using ELISA, immunodiffusion and radioimmunoprecipitation. Patients and controls (n = 537) were genotyped at the HLA-DRB1 and DQB1 loci, and then the DQA1 locus data was derived. RESULTS: Over 70% of the patients were ANA-positive. Clear differences in serological and genetic data were demonstrated between JDM and JDM-SSc overlap groups. Strong associations were seen for HLA-DRB1*03 (all cases vs controls, P(corr) = 0.02; JDM-SSc vs controls, P(corr) = 0.001) and HLA-DQA1*05 (all cases vs controls, P(corr) = 0.01; JDM-SSc vs controls, P(corr) = 0.005). The frequency of the HLA-DRB1*03-DQA1*05-DQB1*02 haplotype was significantly increased in the JDM-SSc (P = 0.003) and anti-PM-Scl antibody (P = 0.002) positive groups. All anti-U1-RNP antibody-positive patients had at least one copy of HLA-DRB1*04-DQA1*03-DQB1*03 haplotype. Associations were observed between serology and specific clinical features. CONCLUSIONS: We present clinical data, HLA genotyping and serological profiling on a large cohort of JDM patients and a carefully characterized subset of patients with JDM-SSc overlap. The results confirm known HLA associations and extend the knowledge by stratification of data in serological and clinical subgroups. In the future, a combination of serological and genetic typing may allow for better prediction of clinical course and disease subtype in JDM.

Failure to over express MHC-CLASS-1 on muscle biopsy in a case of amyopathic juvenile dermatomyositis.

The concept of amyopathic dermatomyositis or dermatomyositis sine myositis, is contentious, particularly within paediatrics. We report an 8-year-old girl presenting with dermatological dermatomyositis without muscle weakness. Muscle biopsy changes are described, in particular, the absence of MHC class 1 over expression. This supports the concept of amyopathic dermatomyositis as a subgroup of juvenile dermatomyositis (JDM) and suggests that immunohistological analysis may be a valuable in excluding a myositic element in such cases.

Effective induction therapy for anti-SRP associated myositis in childhood: A small case series and review of the literature.

BACKGROUND: Anti-Signal Recognition Particle associated myopathy is a clinically and histopathologically distinct subgroup of Juvenile Idiopathic Inflammatory Myositis, which is under-recognised in children and fails to respond to conventional first line therapies. We present three cases where remission was successfully induced using combination therapy with intensive rehabilitation. CASE PRESENTATIONS: Three new patients are reported. All 3 cases presented with profound, rapid-onset, proximal myopathy and markedly raised CK, but no rash. Histology revealed a destructive myopathy characterized by scattered atrophic and necrotic fibres with little or no inflammatory infiltrate. All 3 patients responded to induction with cyclophosphamide, IVIG and rituximab, in conjunction with intensive physiotherapy and methotrexate as the maintenance agent. Our patients regained near-normal strength (MMT > 70/80), in contrast with the current literature where >50% of cases reported severe residual weakness. A literature search on paediatric anti-SRP myositis was performed to June 2016; PubMed was screened using a combination of the following terms: signal recognition particle, autoantibodies, antibodies, myositis, muscular diseases, skeletal muscle, childhood, paediatric, juvenile. Articles in a foreign language were excluded. Nine case studies were found. CONCLUSION: This paper supports the hypothesis that anti-SRP myositis is distinct from other JIIM. It is an important differential to JDM and should be considered where there is severe weakness without rash or if highly elevated muscle enzymes (CK > 10,000 U/l) are found. Early identification is essential to initiate aggressive medical and physical therapy. Greater international collaboration and long-term follow-up data is needed to establish the most effective treatment strategy for this rare group of patients.

The lived experience of juvenile idiopathic arthritis in young people receiving etanercept.

BACKGROUND: This study explores young people's daily experiences of living with Juvenile Idiopathic Arthritis (JIA) and their thoughts, beliefs and feelings related to the biological drug Etanercept, prescribed as part of their treatment. METHODS: An Interpretive Phenomenological approach was used to allow in-depth examinations of the young people's personal accounts of their lived experiences. Data were obtained from 6 young people between the ages of 10-13 years, from one tertiary institution's Paediatric Rheumatology department using audio-taped open-ended interviews. RESULTS: The transcripts yielded seven thousand words of data and two hundred significant statements, which were reduced to five themes; 1) Who understands me, 2) Medicines and injections, 3) Challenges of schooling and friendships, 4) Being different, and 5) Exclusion from sports. There were marked similarities between the young people's statements; however, there were also some striking differences. The theme 'Who understands me' yielded the biggest section of data, but also produced the biggest disparity between the young people. Two patients were very clear that they thought everyone 'understands', whilst two other patients held the belief that 'no one understood'. This paper explores these statements in further detail. CONCLUSIONS: The findings from this study can give healthcare professionals novel insight into the likely reactions to treatment for JIA and, through this, enable them to offer improved support, education and early intervention before these issues become a concern. This study also provides insight into the emotional resilience of young people with JIA.

Concurrence of sarcoidosis and systemic lupus erythematosus in three patients.

We present three cases of patients with systemic lupus erythematosus and sarcoidosis. Although both of these conditions are thought to involve autoimmune mechanisms they occur together only rarely. Our cases suggest that their concurrence may be more common than previously thought, and raise issues regarding the management of patients with SLE. We discuss the possibility that these two diseases are either causally or mechanistically related.

Comparison of children with onset of juvenile dermatomyositis symptoms before or after their fifth birthday in a UK and Ireland juvenile dermatomyositis cohort study.

OBJECTIVE: To compare 2 groups of children with juvenile dermatomyositis (DM), those with onset of symptoms before their fifth birthday versus those whose disease begins either on or after their fifth birthday, and to assess whether age at onset is associated with differences in disease presentation, treatments received, or outcomes 2 years after diagnosis. METHODS: Data were analyzed on children recruited to a UK juvenile DM cohort study with a diagnosis of probable or definite juvenile DM and less than 12 months between diagnosis and recruitment. RESULTS: Fifty-five (35%) of 157 children had onset of symptoms before their fifth birthday. At diagnosis, cutaneous ulceration was found in 32.7% of the younger group versus 11.8% of the older group (P = 0.003). Facial or body swelling was reported more often in the younger group, whereas headaches, alopecia, and Raynaud's phenomenon were all more frequently reported in the older group. At followup 2 years later, there were no important differences in outcomes between the groups. More than 90% of patients in both groups received both methotrexate and steroids. Twenty-three percent of both groups remained on steroids 2 years after diagnosis. CONCLUSION: Our study showed that children with juvenile DM with disease onset at age <5 years are more likely to present with ulcerative skin disease and edema. There were no clinically significant differences in outcomes between the 2 groups.

Autoantibodies to a 140-kd protein in juvenile dermatomyositis are associated with calcinosis.

OBJECTIVE: The identification of novel autoantibodies in juvenile dermatomyositis (DM) may have etiologic and clinical implications. The aim of this study was to describe autoantibodies to a 140-kd protein in children recruited to the Juvenile DM National Registry and Repository for UK and Ireland. METHODS: Clinical data and sera were collected from children with juvenile myositis. Sera that recognized a 140-kd protein by immunoprecipitation were identified. The identity of the p140 autoantigen was investigated by immunoprecipitation/immunodepletion, using commercial monoclonal antibodies to NXP-2, reference anti-p140, and anti-p155/140, the other autoantibody recently described in juvenile DM. DNA samples from 100 Caucasian children with myositis were genotyped for HLA class II haplotype associations and compared with those from 864 randomly selected UK Caucasian control subjects. RESULTS: Sera from 37 (23%) of 162 patients with juvenile myositis were positive for anti-p140 autoantibodies, which were detected exclusively in patients with juvenile DM and not in patients with juvenile DM-overlap syndrome or control subjects. No anti-p140 antibody-positive patients were positive for other recognized autoantibodies. Immunodepletion suggested that the identity of p140 was consistent with NXP-2 (the previously identified MJ autoantigen). In children with anti-p140 antibodies, the association with calcinosis was significant compared with the rest of the cohort (corrected P < 0.005, odds ratio 7.0, 95% confidence interval 3.0-16.1). The clinical features of patients with anti-p140 autoantibodies were different from those of children with anti-p155/140 autoantibodies. The presence of HLA-DRB1*08 was a possible risk factor for anti-p140 autoantibody positivity. CONCLUSION: This study has established that anti-p140 autoantibodies represent a major autoantibody subset in juvenile DM. This specificity may identify a further immunogenetic and clinical phenotype within the juvenile myositis spectrum that includes an association with calcinosis.

The protein tyrosine phosphatase N22 gene is associated with juvenile and adult idiopathic inflammatory myopathy independent of the HLA 8.1 haplotype in British Caucasian patients.

OBJECTIVE: To examine single-nucleotide polymorphisms (SNPs) of the protein tyrosine phosphatase N22 gene (PTPN22) and to study the relationship between PTPN22 and the HLA region in patients with idiopathic inflammatory myopathies (IIMs). METHODS: PTPN22 SNPs were assessed in a large, cross-sectional, case-control study from the UK involving patients with adult or juvenile IIM, comprising patients with polymyositis (PM) (n=114), dermatomyositis (DM) (n=102), myositis associated with another connective tissue disease (myositis-CTD overlap syndrome) (n=64), or juvenile DM (n=101), in comparison with 748 control subjects. Seventeen PTPN22 SNPs were genotyped using the Sequenom MassArray iPLEX platform. Serotyping for myositis-specific/myositis-associated autoantibodies (MSAs/MAAs) was performed by radioimmunoprecipitation. RESULTS: A significant association was noted between the R620W variant (rs2476601) and IIM (corrected P [Pcorr]=0.0009 versus controls), and specifically with the clinical subgroup of PM (Pcorr=0.003 versus controls). A weaker association was noted with juvenile DM (Pcorr=0.009 versus controls). No significant associations were noted after stratification by serologic subgroups. The association with the R620W variant was independent of alleles forming the HLA 8.1 haplotype. No other PTPN22 SNPs were associated with IIM. The PTPN22 haplotype containing the R620W T allele was the only haplotype significantly associated with IIM. CONCLUSION: The R620W variant is a significant risk factor for IIM, independent of the HLA 8.1 haplotype. Unlike that in the HLA region, risk is not increased in individuals possessing MSAs/MAAs. These results are further evidence that the PTPN22 gene confers autoimmune susceptibility.

The Juvenile Dermatomyositis National Registry and Repository (UK and Ireland)--clinical characteristics of children recruited within the first 5 yr.

OBJECTIVES: To identify epidemiological, clinical and laboratory characteristics of juvenile dermatomyositis (JDM) in a national multi-centre cohort of patients, and to review recent changes in the understanding of management and prognosis in the light of these data. METHODS: All children with idiopathic inflammatory myositis recruited to the Juvenile Dermatomyositis National Registry and Repository (UK and Ireland) were included. Features at presentation, and later in disease, were assessed and evaluated. A total of 63 out of 175 children with a new diagnosis of myositis were recruited at the time of diagnosis and followed prospectively. Out of the 175 children, 122 diagnosed prior to 2000 were recruited retrospectively, with subsequent data collected prospectively. RESULTS: One patient died (0.7%), which is equivalent to one death per 465 patient years. Data were available at the time of analysis on 151 registered patients. The most common presenting features were characteristic rash, weakness, tiredness, Gottron's patches and myalgia. Muscle biopsy, magnetic resonance imaging and muscle enzymes were frequently, but not always, abnormal. Muscle enzymes and erythrocyte sedimentation rate were not useful markers of disease activity. CONCLUSIONS: The JDM National Registry and Repository captures data on a significant cohort of children with inflammatory myositis. The current study reports the largest European cohort of children with dermatomyositis to date. This powerful resource will help improve our understanding of this rare disease. Prospective data collection will allow a fuller analysis of poor prognostic features, impact of therapy, and variable outcome of childhood myositis.

Expansion and enhanced survival of natural killer cells expressing the killer immunoglobulin-like receptor KIR3DL2 in spondylarthritis.

OBJECTIVE: The spondylarthritides (SpA) are strongly associated with possession of HLA-B27. We hypothesized that the expression of abnormal forms of HLA-B27 in SpA may have a pathogenic role through interaction with cells bearing natural killer (NK) receptors, in particular, killer immunoglobulin-like receptor (KIR) KIR3DL2, a receptor for HLA-B27 homodimer (B27(2)). We therefore undertook the present study to determine the number and function of NK and T cells bearing KIR3DL2 in SpA. METHODS: Expression of KIR3DL2 on NK and T cells was quantified in peripheral blood (PB) from 35 patients with SpA and 5 patients with juvenile enthesitis-related arthritis (juvenile ERA); samples were compared with samples from healthy and rheumatoid arthritis (RA) controls. Paired synovial fluid (SF) was studied where available. Expression of other KIRs as well as activation, memory, and homing markers on KIR3DL2+ NK and T cells was quantified. NK cell survival was assessed using the apoptotic markers annexin V and 7-aminoactinomycin D, and cytotoxicity by (51)Cr release assay. RESULTS: In SpA, an increased number of PB and SF NK and CD4+ T cells expressed the KIR3DL2 receptor compared with controls. In ERA, KIR3DL2 expression was increased in PB and SF CD4 T cells (and SF NK cells) compared with RA controls. KIR3DL2+ NK cells had an activated phenotype, and were protected from apoptosis by culture with a cell line expressing B27(2). SpA PB mononuclear NK cells from SpA patients showed greater cytotoxicity than those from controls. CONCLUSION: KIR3DL2 expression on NK cells and CD4 lymphocytes is increased in SpA and ERA. These cells are activated and may have a pathogenic role.

Divergence in the degree of clonal expansions in inflammatory T cell subpopulations mirrors HLA-associated risk alleles in genetically and clinically distinct subtypes of childhood arthritis.

Clinically distinct forms of childhood arthritis are associated with different risk alleles of polymorphic loci within the MHC, which code for the antigen-presenting class I or class II molecules. We have compared the TCR diversity of synovial T cells from children with enthesitis-related (HLA-B27(+)) arthritis and oligoarticular arthritis (with class II MHC risk allele associations) in parallel with peripheral blood T cells from each child, using a high-resolution heteroduplex TCR analysis. We demonstrate that multiple clonal T cell expansions are present and persistent within the joint in both groups, but that there is disease-specific divergence in the dominant T cell subset containing these expansions. Thus, the largest clonotypes within the inflamed joints of children with class II-associated arthritis are within the CD4(+) synovial T cell population, while the dominant clones from children with enthesitis-related arthritis (associated with a class I allele) are within the CD8(+) synovial T cell population. These data provide powerful data to support the concept that recognition of MHC-peptide complexes by T cells plays a role in the pathogenesis of juvenile arthritis.