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Background Diagnosis of systemic autoimmune rheumatic diseases (SARD) relies on the presence of hallmark anti-nuclear antibodies (ANA), many of which can be detected years before clinical manifestations. However, ANAs are also seen in healthy individuals, most of whom will not develop SARD. Here, we examined a unique cohort of asymptomatic ANA+ individuals to determine whether they share any of the cellular immunologic features seen in SARD. Methods Healthy ANA− controls and ANA+ (ANA ≥1:160 by immunofluorescence) participants with no SARD criteria, with at least one criterion (undifferentiated connective tissue disease (UCTD)), or meeting SARD classification criteria were recruited. Peripheral blood cellular immunological changes were assessed by flow cytometry and transcript levels of BAFF, interferon (IFN)-induced and plasma cell-expressed genes were quantified by NanoString. Results A number of the immunologic abnormalities seen in SARD, including changes in peripheral B (switched memory) and T (iNKT, T regulatory, activated memory T follicular helper) subsets and B cell activation, were also seen in asymptomatic ANA+ subjects and those with UCTD. The extent of these immunologic changes correlated with ANA titer or the number of different specific ANAs produced. Principal component analysis of the cellular data indicated that a significant proportion of asymptomatic ANA+ subjects and subjects with UCTD clustered with patients with early SARD, rather than ANA− healthy controls. Conclusions ANA production is associated with altered T and B cell activation even in asymptomatic individuals. Some of the currently accepted cellular features of SARD may be associated with ANA production rather than the immunologic events that cause symptoms in SARD. Electronic supplementary material The online version of this article (10.1186/s13075-018-1752-3) contains supplementary material, which is available to authorized users.

Background Anti-TNF (Tumor necrosis factor) therapy is effective in treating pediatric patients with refractory rheumatic disease. There is however a concern that anti-TNF usage may increase the risk of malignancy. Reports on specific types of malignancy in this patient population have been emerging over the past decade, but there is a need for additional malignancy reports, as these events are rare. Therefore, a retrospective chart review was performed on the biologic database of pediatric rheumatology patients at The Hospital for Sick Children (SickKids) from 1997 to 2013 for neoplasms, patient demographic information and rheumatologic treatment course. Findings 6/357 (1.68%) rheumatology patients treated with anti-TNF therapy between 1997 and 2013 developed neoplasms. One patient had two malignancies. One patient had a benign neoplasm. Cases were exposed to etanercept, infliximab or both. Neoplasms developed late after anti-TNF exposure (median 5.0 years) and infliximab treatment was associated with a shorter time to malignancy. The neoplasms identified were as follows: 2 renal clear cell carcinoma, 1 pilomatricoma, 1 nasopharyngeal carcinoma, 1 Ewing’s sarcoma, 1 hepatic T-cell lymphoma, 1 lymphoproliferative disease. Conclusions The malignancy rate at our centre is low, however more than half of the neoplasms identified were rare and unusual in the pediatric population. The 5-year malignancy-free probability for patients with juvenile idiopathic arthritis (JIA) treated with biologic therapy was 97% from our database. Long-term screening for rare neoplasms is important as part of the safety monitoring for any pediatric rheumatology patient receiving anti-TNF therapy.

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that affects various organs. Lupus nephritis is one of the most common, and most important, serious manifestations of SLE. Antimalarial agents are part of the immunomodulatory regimen used to treat patients with SLE; however, their role in the treatment of patients with lupus nephritis in particular is less well recognized, especially by nephrologists. Not all antimalarial agents have been used in the treatment of lupus; this Review will focus on studies using chloroquine and hydroxychloroquine. In addition, this Review will briefly describe the history of antimalarial drug use in patients with SLE, the theorized mechanisms of action of the agents chloroquine and hydroxychloroquine, their efficacy in patients with SLE and those with lupus nephritis, their use in pregnancy, and potential adverse effects. The Review will also cover the latest recommendations regarding monitoring for hydroxychloroquine-associated or chloroquine-associated retinopathy. Overall, antimalarial drugs have numerous beneficial effects in patients with SLE and lupus nephritis, and have a good safety profile.

Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disease with a highly variable clinical course. Pediatric-onset SLE (pSLE) represents 10-20% of all SLE cases, and is associated with higher disease severity, including more-rapid damage accrual, than adult-onset SLE. As in adults, pSLE disease expression varies according to ethnicity, with a milder disease course in white patients. The majority of pSLE patients will have developed damage within 5-10 years of disease onset, most frequently involving the musculoskeletal, ocular, renal and neuropsychiatric systems. Owing to improvements in disease management and recognition over the past 20-30 years, patients now live longer, but as a result have increased disease damage. Premature atherosclerosis and osteoporosis have become increasingly prevalent morbidities in pSLE patients. Early atherosclerosis leads to a considerable rise in cardiovascular and cerebrovascular events, and failure to develop adequate peak bone mass during adolescence-a crucial period of bone accrual-is likely to lead to early osteoporosis and fractures. Patients with pSLE have an incurable, potentially devastating disease that occurs during a vulnerable period of psychosocial development, leading to specific and unique psychosocial stressors. Additional large, long-term follow-up studies in pSLE are needed to better understand the disease prognosis and to facilitate development of tailored treatments.

The pathogenesis of congenital heart block (CHB) remains unclear. The occurrence rate of neonatal CHB is low, even in murine models of lupus erythematosus. The assessment of heart block in murine maternal lupus models by measuring atrioventricular conduction in neonatal offspring is potentially confounded by fetal wastage. We therefore sought to develop a murine CHB model with a superior immune response and to use embryonic Doppler echocardiography to observe conduction system damage in the fetus. Mature 8-wk-old female C3H/HeJ mice (n=43) were immunized with 60 kD Ro, 48 kD La, or recombinant calreticulin autoantigens. ELISA confirmed that significant serum autoantibodies developed in all three immunized groups when compared with controls. Starting at 13 d of gestation, a significantly lower fetal heart rate (HR) and a higher percentage of fetal bradycardia/atrioventricular block (AVB, nonadvanced second degree) were observed in all immunized groups, compared with controls. There was 9-18% nonadvanced second-degree AVB in immunized groups and 0% in controls at18 d of gestation. Neonatal electrocardiograms demonstrated only 1 degrees AVB in immunized groups. Maternal immunization with 60 kD Ro, 48 kD La, or recombinant calreticulin autoantigens resulted in AVB in a significant percentage of fetuses, however, lesser degrees of AVB were seen at birth. Significant fetal bradycardia and AVB may be missed by assessment only at birth in murine models of CHB due to fetal wastage.

> Copublished with permission in Rheumatology, The Journal of Rheumatology, Clinical and Experimental Rheumatology, Clinical Rheumatology, Rheumatology International, Modern Rheumatology, Zeitschrift fur Rheumatologie and Reumatologia clinica. All rights reserved in respect of Rheumatology, ©The Authors 2016. For The Journal of Rheumatology, ©The Journal of Rheumatology 2016. For Clinical Rheumatology, ©Clinical Rheumatology 2016. For Clinical and Experimental Rheumatology, ©Clinical and Experimental Rheumatology 2016. For Rheumatology International and Zeitschrift fur Rheumatologie, © Springer-Verlag GmbH Berlin Heidelberg 2016. For Modern Rheumatology, ©Japan College of Rheumatology 2016. For Reumatologia clinica,© Elsevier Espana, S.L.U. Barcelona, 2016. Ghost authorship, defined as when an individual has made a substantial contribution to writing, research, or editing of a manuscript, but is neither listed as an author nor appropriately acknowledged in the paper, is a cause for concern in biomedical publishing. A reader needs to be confident that the paper they are reading is the work of those prepared to take responsibility for it. The question of ghost authorship examines the criteria of what qualifies a person to be an author of a paper. Where does contribution end and authorship begin? … Address correspondence to K. Wilson; E-mail: editorial{at}rheumatology.org.uk

The objective of this study was to determine predictive factors in children with Kawasaki disease (KD) with which we could distinguish the patients with KD who are either at very low risk or at very high risk for coronary artery inflammation (i.e., either patients who do not need intravenous immunoglobulin treatment or patients in whom more aggressive or even experimental therapies should be considered). Prospectively collected demographic, clinical, and laboratory data on 344 patients treated for KD were correlated with the patients' echocardiographic findings. The parameters studied were age, sex, duration of the fever, erythrocyte sedimentation rate, hemoglobin, white blood cell count, platelet count, and serum albumin. These were examined both in bivariable comparisons and in multiple logistic regression models. Low serum albumin, age

Systemic Lupus Erythematosus (SLE) is a chronic, multisystem autoimmune disease that is the result of the interaction between genetic and environmental factors. Specific genes have been found to be related to the development of SLE and also single nucleotide polymorphisms (SNPs) have been associated to this condition. Although patients with pediatric-onset SLE (pSLE) and adult-onset SLE (aSLE) differ in disease presentation, activity, and outcomes, all studies to date have not found any specific or unique set of genes in pSLE compared to aSLE. Moreover, it has been shown that the frequency of genes in these two SLE populations is the same. However, is possible that an increased genetic load may explain the earlier onset and more severe disease seen in pSLE as compared to aSLE patients.

Cardiovascular morbidity and mortality are becoming major health concerns for adults with inflammatory rheumatic diseases. The enhanced atherogenesis in this patient population is promoted by the exposure to traditional risk factors as well as nontraditional cardiovascular insults, such as corticosteroid therapy, chronic inflammation and autoantibodies. Despite definite differences between many adult-onset and pediatric-onset rheumatologic diseases, it is extremely likely that atherosclerosis will become the leading cause of morbidity and mortality in this pediatric patient population. Because cardiovascular events are rare at this young age, surrogate measures of atherosclerosis must be used. The three major noninvasive vascular measures of early atherosclerosis - namely, flow-mediated dilatation, carotid intima-media thickness and pulse wave velocity - can be performed easily on children. Few studies have explored the prevalence of cardiovascular risk factors and even fewer have used the surrogate vascular measures to document signs of early atherosclerosis in children with pediatric-onset rheumatic diseases. The objective of this review is to provide an overview on cardiovascular risk and early atherosclerosis in pediatric-onset systemic lupus erythematosus, juvenile idiopathic arthritis and juvenile dermatomyositis patients, and to review cardiovascular preventive strategies that should be considered in this population.

Background Following the introduction of the ILAR criteria for juvenile idiopathic arthritis, juvenile psoriatic arthritis (JPsA) has become a better recognized category within the inflammatory arthritides of childhood. There are fewer reports describing the characteristics and long-term outcome of patients with JPsA than other subtypes of JIA. The aim of our study was to determine the long-term outcome and clinical course of patients with juvenile psoriatic arthritis (JPsA) and to define subgroups of JPsA. Methods Clinical records of all patients meeting criteria for JPsA were reviewed and divided into 4 groups depending on their clinical features and onset type. Patient characteristics and clinical features at onset and during follow-up were determined. Results The cohort consisted of 119 patients: 65 with oligoarticular-onset (55%; persistent 44 and extended 21), 34 (29%) with RF(-) and 4 (3%) RF(+) polyarticular and 16 (13%) enthesitis-related arthritis (ERA). At diagnosis patients with ERA were oldest and more commonly male (p=0.001 and =0.01 respectively). Patients with a polyarticular course had more involvement of small joints of the hands and wrist when compared to patients with persistent oligoarticular and ERA (p Outcome: Time to first inactive disease on, but not off, therapy was significantly longer among patients with polyarticular course when compared to oligoarticular and ERA (p=0.016 and p=0.48 respectively). Patients with polyarticular course more frequently had contractures during follow-up than other groups (p=0.01). Conclusion The long-term outcome of with JPsA was generally good. Patients with JPsA did not appear to form distinct sub-group of patients but rather resembled JIA patients with onset types without psoriasis.

Methods Childhood-onset SLE (

Fatigue was related to prednisone and methotrexate use as reported by patients and parents. Conclusion Sleep disturbance and fatigue are prevalent among children with different rheumatic diseases. Sleep disturbance and fatigue are strongly related to increases in pain and decreases in quality of life. Strategies aimed at improving sleep should be studied as possible ways of improving quality of life for children with rheumatic illness. from 15th Paediatric Rheumatology European Society (PreS) Congress London, UK. 14–17 September 2008

A Superantigen in Lactobacillus casei Cell Wall Extract Induces Coronary Arteritis: An Animal Model for Kawasaki Diseasee

Background: Severe myocarditis leading to heart failure is a specific entity complicating the acute phase of Kawasaki disease (KD) in children. Clinical course and response to therapy appear to differ in those children with myocarditis requiring inotropic treatment. Objective: To characterize specific clinical, laboratory and imaging findings in patients with severe myocarditis and delineate their response to therapeutic intervention. Methods: A 3 year retrospective chart review of all patients seen at the HSC (1998-2001) with the diagnosis of KD plus severe myocarditis was performed. The demographic features, clinical, lab and imaging findings and response to treatment were analyzed. Results: 5 patients (3female/ 2male) with a mean age at onset of 3.4years (range 1.5 to 4.4yrs) met diagnostic criteria for KD. In addition all children had significant fatigue, severe tachycardia (mean HR161/min) and hypotension (5/5

Fetal and Neonatal Manifestations in a Murine Model of Congenital Heart Block, Including Fetal Echocardiographic Assessment

Pathologic reports and animal models of congenital complete AV block(CCAVB) suggest that the sinus node may be affected in this disease. Assessment of chronotropic competence of the sinus node has not been performed in large numbers of patients with CCAVB. Demonstration of chronotropic competence of the sinus node in these patients would influence the choice of pacing device, application and mode (VDD vs DDDR). METHODS: To assess the chronotropic competence of the sinus node, we evaluated the intrinsic atrial rate at peak exercise during Bruce treadmill exercise tests in 27 CCAVB patients (59% female) age 12.2±3.3 years and compared them to published normal data. RESULTS: The data summarised below indicate that normal atrial rate response to exercise testing was present in 24/27 patients (89%), but 3/27 (11%) demonstrated atrial chronotropic incompetence. CONCLUSION: Although the majority of patients with CCAVB show an appropriate atrial rate response to exercise, it remains important to evaluate the chronotropic competence of the sinus node prior to deciding on the specific pacemaker therapy they require. In the majority a VDD system would suffice. Figure

ARE PATIENTS AT EXTREMES OF AGE AT INCREASED RISK FOR CORONARY ARTERY INVOLVEMENT IN KAWASAKI DISEASE? † 805

Quantitative assays for C3 and C4 activation were carried out simultaneously on blood from children with varied types of juvenile arthritis. Factor VIII-related antigen was also measured as an indicator of vascular damage. In active systemic juvenile arthritis, the C4d/C4 ratio was frequently elevated and was usually associated with elevated C3d/C3 ratios and elevated concentrations of factor VIII-related antigen. Children with chronic polyarticular arthritis, no matter which forms of onset they had had, also had increased levels of the C4d/C4 ratio, C3d/C3 ratio, and factor VIII-related antigen, but these were less consistent and were not associated with each other. In contrast, in pauciarticular arthritis there was a uniquely isolated increase in the C3d/C3 ratio. This work implies that there are different mechanisms responsible for complement activation in the different types and at different stages of juvenile arthritis.

Systemic onset juvenile arthritis (SJA) has been associated with growth failure in children treated with or without steroids. Growth hormone secretion in SJA is reported to be normal; however, insulin-like growth factor (IGF) has not been examined. To assess the possible role of IGF's in growth failure in SJA, we measured concentrations of IGF-I and II at different stages of activity in patients receiving either steroid or non-steroid therapy. IGF-I and II concentrations were determined in 2 samples from 10 patients who had not received steroids for at least 6 months and 5 patients receiving prednisone. Mean IGF-I and II concentrations in patients receiving steroids were 53% and 61% of normal mean for age.In patients receiving non-steroid therapy; mean IGF-I and II concentrations were 46% and 64% of normal mean for age. Growth failure during periods of active disease was observed in both groups as only 3/11 pre-pubertal patients had growth ≥ 4.5 cm/year. Erythrocyte sedimentation rate (ESR) was compared with concentrations of IGF-I and II in both groups. A statistically significant correlation of IGF-I and II with ESR was observed in those patients receiving non-steroid therapy Rs=.56 and .59 (p=.02, ≤ .01). In the group of patients receiving prednisone at greater than 5 mg/m2/day, ESR showed a statistically significant correlation with IGF-I (Rs=.68, p< .05) but not IGF-II. Thus, low concentrations of IGF-I and II may contribute to growth failure in children with SJA whether or not they receive steroids.