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Non-white people are more likely to develop systemic lupus erythematosus (SLE), yet are underrepresented in SLE clinical trials. The efficacy and safety of drugs may be influenced by ancestry, and ancestrally diverse study populations are necessary to optimize treatments across the full spectrum of patients. However, barriers to entry into clinical trials are amplified in non-white populations. To address these issues, a conference was held in Bethesda, Maryland from October 15th -16th , 2019 entitled "Increasing Ancestral Diversity in Systemic Lupus Erythematosus Clinical Studies: Overcoming the Barriers." Participants included people with lupus, lupus physicians, lupus clinical trialists, treatment developers from biotechnology, social scientists, patient advocacy groups, and United States government representatives (the Office of Minority Health, Centers for Disease Control and Prevention, National Institutes of Health, and the Food and Drug Administration). For all of these groups, the organizers purposefully included people of non-white ancestry. Decreased participation of non-white SLE patients in clinical research was evaluated through historical, societal, experiential, and pragmatic perspectives, and several interventional programs to increase non-white patient participation in SLE and non-SLE research were described and discussed. The presentations and discussions highlighted the need for changes at the societal, institutional, research team, referring physician, and patient education levels to achieve equitable ancestral representation in SLE clinical studies.

ObjectiveAutoantibodies against proteins encoded by human endogenous retrovirus K (HERV-K) have been reported in patients with rheumatoid arthritis (RA), but their relevance, if any, has remained unresolved. We revisited this question and tested if such autoantibodies may react with citrullinated epitopes on the envelope (Env) protein of HERV-K.MethodsImmunoblotting and ELISAs were conducted with unmodified Env protein and with Env citrullinated by protein arginine deiminase 4 (PAD4). Sera from 100 patients with RA, plasma from 32 patients with juvenile idiopathic arthritis (JIA), and healthy adult and pediatric controls were included. Antibody reactivity was evaluated for correlations with clinical and laboratory variables of the patients.ResultsWe replicated and expanded upon published data suggesting that patients with RA or JIA have autoantibodies against HERV-K Env, some with high titers. Anti-HERV-K antibodies correlated with cigarette smoking and with circulating myeloperoxidase-DNA complexes indicative of nonapoptotic neutrophil cell death. Further, most of the patients with RA, but not those with JIA, had autoantibodies that reacted more strongly with Env that was citrullinated by PAD4. These anticitrullinated Env autoantibodies correlated with seropositivity and tended to be higher in patients with erosive disease.ConclusionOur data suggest that anti-HERV-K immunity is elevated in RA and JIA and may have a connection with pathogenic protein citrullination in RA.

IntroductionWe aimed to quantify the DNA of maternal chimeric (MC) cells in the peripheral blood of the BA patients and investigated the impact on the outcome.MethodsPatients with progressive jaundice because of no bile flow, which necessitated liver transplantation, or who showed inadequate bile flow with or without episodes of cholangitis and progressive hepatic fibrosis and portal hypertension were classified into the poor group. Those with adequate bile flow with completely normal liver function tests beyond 2 years were classified into the good group. The qPCR were separately carried out in buffy coat samples and plasma samples, targeting the non-inherited maternal HLA alleles in the DNA samples.ResultsMC-DNA was present in the buffy coat (10–328 gEq per 106 host cells) in seven patients. There was no MC-DNA in the remaining five patients. MC-DNA (214–15,331 gEq per 106 host cells) was observed in the plasma of five patients. The quantity of MC-DNA in the buffy coat showed a significant difference between the two prognostic groups (p = 0.018), whereas there was no significant difference in the quantity of MC-DNA in plasma (p = 0.205). MC-DNA in the buffy coat was significantly associated with the outcome (p = 0.028), whereas MC-DNA in the plasma did not influence the outcome (p = 0.56).ConclusionsPoor outcomes in BA were correlated with circulating maternal chimeric lymphocytes.

Background: Juvenile dermatomyositis (JDM) is a rare immune-mediated disease of childhood that is thought to result from genetic predisposition and environmental drivers, with documented links to microbial exposures. In this multi-center, prospective, observational cohort study, we evaluated whether JDM is associated with discrete oral and gut microbiome signatures.Methods: We generated 16S rRNA sequencing data from fecal, saliva, supragingival, and subgingival plaque samples from JDM probands (n=28, age range 3-18 years, mean age 10 years, 46% female). To control for genetic and environmental determinants of microbiome community structure to the greatest extent possible, we also profiled microbiomes of their unaffected family members (n=27 siblings, n=26 mothers, and n=17 fathers). We performed paired within-family comparisons as well as unpaired analyses of different cohorts. Results: Sample type (oral vs fecal) and nuclear family unit were the two most predominant variables explaining variance in microbiome diversity, more so than having a diagnosis of JDM. The oral and gut microbiomes of JDM probands were more similar to their own unaffected siblings than they were to the microbiomes of other JDM probands. Nonetheless, in a sibling-paired analysis, several potentially immunomodulatory bacterial taxa were differentially abundant in the microbiomes of JDM probands compared to their unaffected siblings, including Faecalibacterium in the gut and Streptococcus in the oral cavity. Further, compared to published microbiome datasets generated from healthy children and adults, fecal microbiomes of both JDM probands and their unaffected family members were markedly different. Conclusions: Family unit (which reflects the confluence of genetic and household effects) has a significant effect on microbiome community structure. Features of the dysbioses seen in oral and fecal microbiomes of JDM probands were shared by their unaffected family members, suggesting familial microbiome signatures. The loss or gain of specific fecal and oral bacteria may potentially play a role in disease pathogenesis and/or be secondary to immune dysfunction in susceptible individuals.

Chronic nonbacterial osteomyelitis (CNO) is a rare autoinflammatory disease that causes bone destruction, soft tissue swelling, and bone pain1. Diagnosis and treatment are hindered by a lack of a reliable laboratory test to assess disease activity. Bone inflammation in CNO is associated with increased osteoclastic activity and bone resorption, causing focal accelerated breakdown of bone collagen. This may be measured through elevated urinary N-terminal telopeptide (NTx). Miettunen, et al reported rapid decline of urinary NTx in children with CNO after pamidronate treatment and subsequent rise of NTx was correlated with disease flare2. The initial NTx from patients with CNO was not different from that of healthy children. Correlation of NTx with disease activity in patients with CNO not treated with pamidronate has not been investigated. We sought to determine if NTx values correlate with CNO disease activity in children treated without a bisphosphonate. Children with a CNO diagnosis made by a pediatric rheumatologist as well as their nonadult healthy siblings were recruited from the rheumatology clinics after written informed consent was obtained (approved by Seattle Children’s Hospital, IRB 14426, and University of Iowa, IRB 200308051). Inclusion criteria consisted of a clinical diagnosis of CNO, … Address correspondence to Dr. Y. Zhao[4][1], 4800 Sand Point Way NE, Seattle, WA 98105, USA. Email: yongdong.zhao{at}seattlechildrens.org. [1]: #ref-4

There exists a standard approach to developing drugs for adults. The process begins with animal studies focused on toxicity, followed by phase I safety and dosage studies in humans, phase II effica...

Objectives: To evaluate the prevalence of special diet adoption in juvenile idiopathic arthritis (JIA) and parental perceptions of efficacy. Design: An online survey was distributed over a...

Abnormal NKG2D ligand expression has been implicated in the initiation and maintenance of various auto-inflammatory disorders including systemic lupus erythematosus (SLE). This study’s goal was to identify the cellular contexts providing NKG2D ligands for stimulation of the immunosuppressive NKG2D+CD4 T cell subset that has been implicated in modulating juvenile-onset SLE disease activity. Although previous observations with NKG2D+CD4 T cells in healthy individuals pointed towards peripheral B cell and myeloid cell compartments as possible sites of enhanced NKG2DL presence, we found no evidence for a disease-associated increase of NKG2DL-positivity among juvenile-onset SLE B cells and monocytes. However, juvenile-onset SLE patient plasma and matched urine samples were positive by ELISA for the soluble form of the NKG2D ligands MICA and MICB, suggesting that kidney and/or peripheral blood may constitute the NKG2DL positive microenvironments driving NKG2D+CD4 T cell population expansions in this disease.

Background The oral microbiota has been implicated in the pathogenesis of rheumatoid arthritis through activation of mucosal immunity. This study tested for associations between oral health, microbial communities and juvenile idiopathic arthritis (JIA). Methods A cross-sectional exploratory study of subjects aged 10–18 years with oligoarticular, extended oligoarticular and polyarticular JIA was conducted. Control groups included pediatric dental clinic patients and healthy volunteers. The primary aim was to test for an association between dental health indices and JIA; the secondary aim was to characterize the microbial profile of supragingival plaque using 16S rRNA gene sequencing. Results The study included 85 patients with JIA, 62 dental patients and 11 healthy child controls. JIA patients overall had significantly more gingival inflammation compared to dental patients, as evidenced by bleeding on probing of the gingiva, the most specific sign of active inflammation (p = 0.02). Overall, however, there was a trend towards better dental hygiene in the JIA patients compared to dental patients, based on indices for plaque, decay, and periodontitis. In the JIA patients, plaque microbiota analysis revealed bacteria belonging to genera Haemophilus or Kingella elevated, and Corynebacterium underrepresented. In poly JIA, bacteria belonging to the genus Porphyromonas was overrepresented and Prevotella was underrepresented. Conclusion Increased gingival inflammation in JIA was independent of general oral health, and thus cannot be attributed to poor dental hygiene secondary to disability. The variation of microbial profile in JIA patients could indicate a possible link between gingivitis and synovial inflammation.

Background Juvenile systemic sclerosis (jSSc) is an orphan disease, associated with high morbidity and mortality. New treatment strategies are much needed. To develop an open label drug trial for the treatment of jSSc patients, it is necessary to clearly define how to evaluate outcomes in this disease, which are currently not existing. A group of experts in jSSc has met annually and worked to develop an index to evaluate outcomes in this disease. Objectives The aim of our third consensus meeting was to establish the domains and the items that should be assessed in a clinical drug trial in jSSc. Methods In the consensus meeting 26 jSSc international experts with various specialties participated (22 voted). In a nominal group technic, moderated by DEF, was used to develop the outcome measures. Agreement was defined if 80% or more of the participants approved an item. Results Domains and items suggested in the 2017 consensus meeting were reconsidered and selected or rejected during the 2018 meeting, as were additional domains/items (Table). Conclusion We reached consensus on domains and items which should be assessed in an open label 1 year clinical jSSc trial. We also listed research items which should be assessed but should not currently be included as an outcome in such a trial. Disclosure of Interests Ivan Foeldvari Consultant for: Chugai, Novartis, Kathryn Torok: None declared, Lusine Ambartsumyan: None declared, Jordi Anton Grant/research support from: Grant/research support, consultant or speakers bureau from AbbVie, Alexion, Bristol-Myers Squibb, ChemoCentryx, Gebro, GlaxoSmithKline, Novartis, Novimmune, Pfizer, Roche, Sanofi and Sobi, Consultant for: Grant/research support, consultant or speakers bureau from AbbVie, Alexion, Bristol-Myers Squibb, ChemoCentryx, Gebro, GlaxoSmithKline, Novartis, Novimmune, Pfizer, Roche, Sanofi and Sobi, Speakers bureau: Grant/research support, consultant or speakers bureau from AbbVie, Alexion, Bristol-Myers Squibb, ChemoCentryx, Gebro, GlaxoSmithKline, Novartis, Novimmune, Pfizer, Roche, Sanofi and Sobi, Christian Beyer: None declared, Michael Blakley: None declared, Tamas Constantin: None declared, Patricia Costa Reis: None declared, Megan Curran: None declared, Maurizio Cutolo: None declared, Francesco Del Galdo: None declared, Christopher Denton Grant/research support from: GlaxoSmithKline, Inventiva, CSF Behring, Consultant for: Roche-Genentech, Actelion, GlaxoSmithKline, Sanofi Aventis, Inventiva, CSL Behring, Boehringer Ingelheim, Bayer, Kim Fligelstone: None declared, Bernd Hinrichs: None declared, Antonia Hoger: None declared, Francesca Ingegnoli: None declared, Ozgur Kasapcopur: None declared, Suzanne Li: None declared, Dana Nemcova: None declared, Catherine Orteu: None declared, Clarissa Pilkington: None declared, Vanessa Smith: None declared, Anne Stevens: None declared, Brandi Stevens: None declared, Allison Zheng: None declared, Dinesh Khanna Shareholder of: Eicos Sciences, Inc, Grant/research support from: Bayer, BMS, Pfizer, Horizon, Consultant for: Actelion Acceleron, Arena, Bayer, BI, BMS, CSL Behring, Corbus, Cytori, GSK, Genentech/Roche, Galapagos, Employee of: Elcos Sciences, Inc, Daniel Furst Grant/research support from: F. Hoffmann-La Roche, Genentech

Localized scleroderma (LS) is a complex disease characterized by a mixture of inflammation and fibrosis of the skin that, especially in the pediatric population, also affects extracutaneous tissues ranging from muscle to the central nervous system. Although developmental origins have been hypothesized, evidence points to LS as a systemic autoimmune disorder, as there is a strong correlation to family history of autoimmune disease, the presence of shared HLA types with rheumatoid arthritis, high frequency of auto-antibodies, and elevated circulating chemokines and cytokines associated with T-helper cell, IFNγ, and other inflammatory pathways. This inflammatory phenotype of the peripheral blood is reflected in the skin via microarray, RNA Sequencing and tissue staining. Research is underway to identify the key players in the pathogenesis of LS, but close approximation of inflammatory lymphocytic and macrophage infiltrate with collagen and fibroblasts deposition supports the notion that LS is a disease of inflammatory driven fibrosis. The immune system is dynamic and undergoes changes during childhood, and we speculate on how the unique features of the immune system in childhood could potentially contribute to some of the differences in LS between children and adults. Interestingly, the immune phenotype in pediatric LS resembles to some extent the healthy adult cellular phenotype, possibly supporting accelerated maturation of the immune system in LS. We discuss future directions in better understanding the pathophysiology of and how to better treat pediatric LS.

Objective To determine the prevalence and clinical characteristics of juvenile idiopathic arthritis (JIA) in Alaska Native children. Methods Potential cases of JIA were identified by querying administrative data from hospitals and clinics in the Alaska Tribal Health System for codes possibly identifying JIA. Medical record abstraction was performed to confirm criteria met for JIA, demographic and clinical characteristics, and treatment patterns. Individuals age ≤18 years with a confirmed diagnosis of JIA were included. The denominator for prevalence was the 2015 Alaska Area Indian Health Service user population age of ≤18 years. Results The unadjusted prevalence of JIA in Alaska Native children was 74.6 per 100,000 (age-adjusted 79.0 per 100,000). JIA was more common in females than males (unadjusted prevalence 105.8 versus 45.0 per 100,000). Oligoarthritis was the most common subtype (31% of cases), but polyarthritis and enthesitis-related arthritis were also common (26% and 24% of cases, respectively), with a notably high prevalence of enthesitis-related arthritis. The median age at diagnosis was 9 years. Of the combined cohort with results available, 56% were antinuclear antibody positive, 23% were rheumatoid factor positive, 19% were anti-cyclic citrullinated peptide antibody positive, and 57% had the presence of HLA-B27. Uveitis had been diagnosed in 16% of cases. Conclusion The prevalence of JIA in Alaska Native children may be higher than the general US population. Enthesitis-related arthritis makes up a higher proportion of cases than in other populations described likely because of the high prevalence of HLA-B27 in this population.

Objective Systemic sclerosis (SSc) is a rare disease that is particularly uncommon in children. Specific HLA alleles have been associated with SSc in adults. This study was undertaken to investigate HLA class II alleles in juvenile-onset SSc. Methods DRB1, DQA1, and DQB1 alleles were determined by DNA-based HLA typing. Analyses were conducted comparing Caucasian patients with juvenile-onset SSc (n = 76) to healthy Caucasian controls (n = 581). Results Initial analyses focused on HLA class II associations previously reported in adult Caucasian patients with SSc. The frequency of DRB1*11 was not significantly increased in juvenile-onset SSc (22.4% of patients with juvenile-onset SSc versus 17.6% of controls; odds ratio [OR] 1.35, P = 0.34), nor were the specific DRB1*11:01 or *11:04 alleles. DQA1*05, a risk factor previously identified in adult men with SSc, was increased in patients with juvenile-onset SSc versus controls (57.9% versus 44.1%; OR 1.76, P = 0.027), as was DRB1*03 (34.2% versus 22.5%; OR 1.79, P = 0.031). Secondary analyses of all DRB1 allele groups revealed an association with DRB1*10 (10.5% of patients with juvenile-onset SSc versus 1.5% of controls; OR 7.48, P = 0.0002). As this is a new observation, correction was made for multiple comparisons of 13 different DRB1 allele groups; results nevertheless remained significant (P = 0.003). Also, a lower frequency of DRB1*01 was observed in patients with juvenile-onset SSc who were younger at disease onset (OR 0.06, P = 0.01) and in those with antibodies to topoisomerase (OR 0.14, P = 0.024). Conclusion Associations of HLA alleles with juvenile-onset SSc differed from associations with SSc in women, but were similar to associations with SSc in men. Additionally, a novel association with DRB1*10 was observed in children. The greatest proportion of genetic risk of SSc is contributed by the HLA complex, and the current study reveals the importance of the association of HLA class II genes in juvenile-onset SSc.

Systemic juvenile idiopathic arthritis (sJIA) is characterized by systemic inflammation and arthritis. Monocytes are implicated in sJIA pathogenesis, but their role in disease is unclear. The response of sJIA monocytes to IFN may be dysregulated. We examined intracellular signaling in response to IFN type I (IFNα) and type II (IFNγ) in monocytes during sJIA activity and quiescence, in 2 patient groups. Independent of disease activity, monocytes from Group 1 (collected between 2002 and 2009) showed defective STAT1 phosphorylation downstream of IFNs, and expressed higher transcript levels of SOCS1, an inhibitor of IFN signaling. In the Group 2 (collected between 2011 and 2014), monocytes of patients with recent disease onset were IFNγ hyporesponsive, but in treated, quiescent subjects, monocytes were hyperresponsive to IFNγ. Recent changes in medication in sJIA may alter the IFN hyporesponsiveness. Impaired IFN/pSTAT1 signaling is consistent with skewing of sJIA monocytes away from an M1 phenotype and may contribute to disease pathology.

Circulating maternal cells transfer to the fetus during pregnancy, where they may integrate with the fetal immune and organ systems, creating a state of maternal microchimerism (MMc). MMc can persist throughout the child's life, and it has been implicated in the triggering or perpetuation of chronic inflammatory autoimmune diseases, in the context of specific major histocompatibility genes. Correlative data in humans have now been tested in animal model systems. Results suggest that maternal-fetal tolerance may have health implications far beyond the time of pregnancy and into the child's life.

Juvenile-onset systemic sclerosis (jSSc) is a rare and severe autoimmune disease with associated life-threatening organ inflammation and evidence of fibrosis. The organ manifestations of jSSc resemble adult SSc, but with better outcomes and survival. The etiology of jSSc appears to reflect adult-onset SSc, with similar inflammatory mediators and autoantibodies, but with a significant population of children with uncharacterized anti-nuclear antibodies. The genetics of patients with jSSc differ from women with SSc, resembling instead the genes of adult males with SSc, with additional HLA genes uniquely associated with childhood-onset disease. Current treatments are aimed at inhibiting the inflammatory aspect of disease, but important mechanisms of fibrosis regulated by dermal white adipose tissue dendritic cells may provide an avenue for targeting and potentially reversing the fibrotic stage.

Background Effector memory T lymphocytes (TEM) implicated in the immunopathogenesis of SLE have been detected in the urine of patients with lupus nephritis. As TEM depend on the voltage-gated potassium channel Kv1.3 for activation-induced calcium signalling, activated TEM represents a potential target for the novel Kv1.3 blockade therapy dalazatide. In active SLE nephritis, Kv1.3 is upregulated on peripheral blood CD8+ TEM and cytokine production was inhibited in SLE T lymphocytes. We therefore hypothesized that Kv1.3 is expressed on urinary leukocytes from patients with lupus nephritis. Methods Urinary cells were isolated in 33 samples from patients with SLE ages 15–41 years, (mean 19, IQR 16.2–19.3). Immunofluorescence was performed to quantify and characterize cells expressing Kv1.3. Urinary leukocytes were defined as non-epithelioid cells by morphology. Leukocyte subsets were defined as CD3+ T lymphocytes, CD20+ B lymphocytes, or CD14+ macrophage. Results In the urine, leukocytes expressing Kv1.3 were found in samples from every subject studied. Overall, Kv1.3 expression was detected on a mean of 3.5% of leukocytes (range 0.1%–13.4%; IQR 0.8%–5.1%) with higher levels in patients with active disease (4.8%, IQR 1%–6.7%) compared to patients with inactive disease (2.1%, IQR 0.8%–2.7%, p=0.04). CD3+ lymphocytes expressing Kv1.3 were found in all subjects (mean 52% of CD3+ cells, IQR 33%–100%). In 90% of subjects, Kv1.3 was detected on CD20+ B lymphocytes (mean 68%, IQR 46%–100%), and in 90% of subjects CD14+ macrophages (mean 69%, IQR 46%–100%). Patients with class III or IV nephritis had increased frequencies of leukocytes expressing Kv1.3 (6%) compared to patients with Class V nephritis (2%, p=0.01) or no nephritis (1.8%, p=0.01). Conclusions Kv1.3 is detectable on SLE urinary B lymphocytes, T lymphocytes, and macrophage, implying that inflammatory cells in the kidney may be targeted by this channel. Peripheral blood cell expression and functional data suggest that SLE activated TEM lymphocytes may be susceptible to inhibition by dalazatide. Acknowledgements This work was funded by Seattle Children’s Research Institute and Kineta, Inc.

Background Juvenile systemic scleroderma (jSSc) is an orphan disease with an estimated prevalence of around 3 per 1 000 000 children. There are no studies which evaluated prospectively the patient related outcomes in these patients. We report the data from juvenile scleroderma inception cohort (jSSc) regarding organ involvement and patient related outcomes. Methods The jSSc is a prospective cohort of jSSc patients. Patients were enrolled who were diagnosed with jSSc, had a jSSc onset age under 16 years and were younger as age of 18 years at the time of inclusion. The patients are prospectively assessed every 6 months according to a standardised protocol. Patients with available 12 months follow up data were included in the analyses. Results Currently 100 patients are followed in the jSSc cohort. 51 of them had available 12 months follow up data. Among those patients 37 (72.5%) had diffuse and 14 (27.5%) limited subtype. Mean age of onset of disease was 9.5 (±4.1) years and the mean disease duration at time of inclusion was 3.1 years (±3.2). The proportion of patients treated with DMARD increased from 74.5% to 88% at 12 months follow up. 86% were ANA positive at both assessments. Anti-scl70 positivity increased from 38% to 42%. Anticentromere antibody positivity was 2.4% at both assessments. Mean modified skin score decreased from 17.7 to 14.3 (p=0.151) Raynaud phenomenon occurred in 86% at enrolment and increased up to 88% at 12 months follow up. Nailfold capillary changes occurred around 70% at both assessments, but number of patients with active ulceration decreased from 28% to 16% (p=0.148). The number of patients with decreased FVC (FVC under 80%) decreased from 40.5% to 32% (p=0.497). The number of patients with pulmonary hypertension remained around 10%. No renal crisis or hypertension were reported. The gastrointestinal involvement was around 40% at both assessments. The number of patients with swollen joints decreased from 24% to 10% (p=0.06). The number of patients with muscle weakness decreased significantly from 33% to 9% (p=0.016), parallel to the number of patients with elevated CK values which decreased from 27% to 12% (p=0.074). All patient related outcomes, like global disease activity (p=0.048), global disease damage (p=0.05), Raynaud activity (p=0.003) and ulceration activity (p=0.001) improved significantly over 12 months. Physician assessed global disease activity (p=0.003) and ulceration activity (p=0.001) also improved significantly. Conclusions Our data show, that jSSc patients over a 12 months disease course stayed quite stable or improved regarding organ involvement. But patient and physician related outcomes regarding activity assessment improved significantly. Disclosure of Interest None declared

Background Juvenile systemic scleroderma (jSSc) is an orphan disease, with an estimated prevalence of 3 per 1000 000 children. Most jSSc patients primarily present with Raynaud phenomenon (RP). We investigated in our patient of the juvenile scleroderma inception cohort, how fare patients with (RP+) and without (RP-) RP differed in their clinical presentation at enrolment. Methods The jSSc is a prospective cohort of jSSc patients. Patients were enrolled who were diagnosed with jSSc, had a jSSc onset age under 16 years and were younger as age of 18 years at the time of inclusion. The patients are prospectively assessed every 6 months according to a standardised protocol. We reviewed the organ involvement pattern of our patients currently followed in the cohort. Results 100 patients are currently followed in the cohort and 89 (89%) of them had RP. The female/male ratio was lower in the RP +group, 3.7:1 compared to 4.5:1(p=0.808). Diffuse subtype was more common in the RP +group, 72% compared to 63%. Mean age of onset of first non- Raynaud symptomatic was 10.4 years in both groups. Mean disease duration was slightly higher in the RP +group, 3.4 compared to 2.2 years. ANA positivity was higher in the RP +group, 88% compared to 70% (p=0.48). Anti-Scl70 was 34% in the RP +and 20% in the RP-group (p=0.34). Interestingly 7% of RP +but none of the RP +were anti-centromere positive. The mean modified skin score was lower in RP +group (mean of 14.8 compared to 17.0). There were significantly more nailfold capillary changes (70% compared to 18%, p=0.001) and a higher rate of history of ulceration in the RP +group (49% compared to 20%, p=0.083). Decreased DLCO and FVC Conclusions The RP– group differed from RP +group in the clinical presentation at enrolment. The absence of Raynaud phenomenon was associated with a decreased rate of history of ulceration, no occurrence of pulmonary hypertension. Interestingly higher rate of urinary sedimentary changes and no anticentromere positivity was observed in RP- patients. Disclosure of Interest None declared

OBJECTIVE Juvenile systemic sclerosis (SSc) is a disabling autoimmune condition that affects multiple organs in addition to skin, notably the gastrointestinal and pulmonary systems. The relationship between esophageal abnormalities and pulmonary disease in juvenile SSc is not well understood. We describe associations between radiologic esophageal abnormalities and pulmonary function. METHODS Clinical and radiographic data of children ages >18 years who fulfilled the 2007 Pediatric Rheumatology Provisional Classification Criteria for juvenile SSc between 1994 and 2016 were reviewed. Fluoroscopic upper gastrointestinal (UGI) studies, high-resolution computed tomography (HRCT), and pulmonary function tests (PFTs) within 12 months of presentation to Seattle Children's Hospital were extracted. RESULTS Twenty-one children with juvenile SSc (67% female, ages 8-17 years) were studied. Esophageal abnormalities, defined as abnormal esophageal peristalsis and/or bolus clearance, were found in 12 patients. Abnormal esophagus on UGI tests was not associated with gastrointestinal or pulmonary symptoms, disease duration, use of medications (proton pump inhibitor or immunosuppressant), or specific autoantibodies. Compared with patients with a normal esophagus on UGI tests, children with an abnormal esophagus had decreased PFTs: mean forced expiratory volume in 1 second 96% versus 78% (P = 0.03), forced vital capacity 94% versus 76% (P = 0.02), and vital capacity 95% versus 76% (P = 0.02). Children with an abnormal esophagus on UGI tests had a larger mean esophageal diameter on HRCT (14.6 mm compared to 8.5 mm; P < 0.01). CONCLUSION There was an association between esophageal and pulmonary disease in children with juvenile SSc. Esophageal findings on UGI tests or HRCT, despite lack of symptoms, should raise concern for esophageal dysfunction and prompt heightened surveillance for concurrent lung disease.

Leptin is abnormally elevated in the plasma of patients with systemic lupus erythematosus (SLE), where it is thought to promote and/or sustain pro-inflammatory responses. Whether this association could reflect an increased genetic susceptibility to develop SLE is not known, and studies of genetic associations with leptin-related polymorphisms in SLE patients have been so far inconclusive. Here we genotyped DNA samples from 15,706 SLE patients and healthy matched controls from four different ancestral groups, to correlate polymorphisms of genes of the leptin pathway to risk for SLE. It was found that although several SNPs showed weak associations, those associations did not remain significant after correction for multiple testing. These data do not support associations between defined leptin-related polymorphisms and increased susceptibility to develop SLE. © 2015 Elsevier Inc.

In our recent case report, the finding of lupus erythematosus (LE) cells in a bone marrow aspirate led to the diagnosis of systemic lupus erythematosus (SLE) and appropriate treatment, although the patient was not clinically suspected to have SLE. To determine whether LE cells are present in the bone marrow aspirates of SLE patients, but overlooked in routine bone marrow morphology review, bone marrow aspirates from 30 pediatric patients (15 with SLE and 15 with other diagnoses) evaluated by rheumatologists were reviewed. LE cells were found in the bone marrow aspirates of only 1 SLE patient and none in non-SLE patients. However, hematoxylin bodies were identified in 53% (8/15) of SLE patients. Neither hematoxylin bodies nor LE cells were found in the aspirates from patients with other disorders. Three additional pediatric patients identified prospectively were found to have hematoxylin bodies in the bone marrow aspirates. Although the diagnosis was not initially suspected, 2 of the 3 patients were subsequently diagnosed with SLE. All patients with hematoxylin bodies and SLE had antinuclear antibody titers ≥1:640 with a homogeneous staining pattern. In addition, bone marrow aspirates of 9 adult patients were reviewed, and neither LE cells nor hematoxylin bodies were identified. In summary, hematoxylin bodies were present in the bone marrow aspirates of many pediatric SLE patients, while LE cells were rare. The finding of hematoxylin bodies in pediatric bone marrow aspirates is a helpful and specific diagnostic clue that may lead to the diagnosis of SLE when other clinical features are nonspecific.

Objective To investigate clinical manifestations of juvenile systemic sclerosis (SSc; scleroderma), including disease characteristics and patient quality of life, using the multinational Childhood Arthritis and Rheumatology Research Alliance (CARRA) Legacy Registry. Methods Patients with juvenile SSc were prospectively enrolled between 2010 and 2013. The diagnosis of juvenile SSc was determined by the enrolling pediatric rheumatologist, with the requirement for disease onset prior to age 18 years. Collected data included demographics, disease characteristics, medication exposure, and quality of life metrics. Results In total, 64 patients with juvenile SSc were enrolled a median of 3.6 years after disease onset, which occurred at a median age of 10.3 years. The most common organ manifestations were dermatologic and vascular, followed by musculoskeletal, gastrointestinal, and pulmonary; in 38% of patients, ≥4 organ systems were affected. Patients with juvenile SSc had significantly more disability at enrollment compared with CARRA Legacy Registry patients with juvenile idiopathic arthritis, dermatomyositis, or systemic lupus erythematosus. Although physician-reported measures correlated most closely with arthritis, dermatologic manifestations, and pulmonary manifestations, poor patient-reported measures were associated with gastrointestinal involvement. During >50 person-years of follow-up, most organ manifestations remained stable, and no mortality or development of new solid organ involvement after enrollment was reported. Conclusion In the first multicenter prospective cohort of patients with juvenile SSc in North America, the disease burden was high: multiorgan manifestations were common, and functional disability was greater than that observed in patients with other childhood-onset rheumatic diseases. Gastrointestinal involvement had the greatest impact on quality of life.

Background Juvenile systemic sclerosis (jSSc) is an orphan autoimmune disease. It was rarely looked at the differences between the clinical presentations of patients at different paediatric age groups. The juvenile scleroderma inception cohort (www.juvenile-scleroderma.com)is a prospective standardized register for patients with jSSc. Objectives Comparison of clinical characteristics of patients with different age range at the time of inclusion in the registry. Methods Patients with jSSc were included worldwide to the juvenile scleroderma inception cohort. We compared the demographics and clinical characteristics of the patients at different age ranges. We created 3 cohorts with different age ranges at onset of disease. Patents aged less than 5 years (Group1), 5–10 years (Group2) and over 10 years (Group3) at the time of diagnosis of the first non-Raynaud involvement of jSSc. Results Up till now 88 patients were enrolled,14 patients (15%) in Group1, 22 (25%) in Group2 and 52 (59%) in Group3. Diffuse subtype occurred in 71% in Group1, in 82% in Group2 and in 65% in Group3. Most patients were Caucasian. Disease duration at time of inclusion into the cohort was 3.9 years in Group1, 4.9 years in Group2 and 2.2 years in Group3. ANA positivity was 57% in Group1, 77% in Group2 and 86% in Group3. Anti-scl 70 was around 30% in all groups. Anti-Centromere positivity was 7 to 10%. Mean modified skin score was 12.4 in Group1, 16.5 in Group2 and 15.9 in Group3. Raynaud Phenomenon occurred in 85 to 95% of the patients. History of active or inactive ulceration occurred in 57% in Group1, 62% in Group2 and 43% in Group3. Decreased FVC under 80% occurred in 43% in Group1, 32% in Group2 and 30% in Group3. Pulmonary hypertension occurred in 7% in Group1 and in 10% in Group3. No renal hypertension was observed. Urinary sedimentary changes occurred in 7% in Group1 and in 10% in Group3. Gastrointestinal involvement occurred in 21% in Group1, 45% in Group2 and 27% in Group3. Musculoskeletal involvement occurred in 58 to 64%. Patient global disease activity (VAS 0–100) was 42.8 to 47.9. Patient global disease damage (VAS 0–100) was 39.6- to 45.0. Physician global disease activity (VAS 0–100) was 35.4–40.0. Physician global disease damage (VAS 0–100) was 37.1 in Group1, 41.3 in Group2 and 27.7 in Group3. Conclusions It seems to be that patients, with onset of the disease in younger age have more severe disease as patients with disease onset after the age of 10 years. We need more patients in our cohort to gain more sufficient data to prove our preliminary observation. Disclosure of Interest None declared

Background Juvenile idiopathic arthritis (JIA) is the most common pediatric rheumatologic illness and can lead to significant disability. Complementary and alternative treatments are commonly practiced by families of patients with JIA, and >40% of patients with chronic arthritis seek dietary changes after their diagnosis. Dietary intervention studies in adults with rheumatoid arthritis showed moderate improvement in joint symptoms. Dietary supplements of omega-3 fatty acids have been tested in children with chronic arthritis and found to be associated with less NSAID use and lower serum IL-1 and TNF levels. There is an increasing need to understand if there is a role for dietary therapy in chronic arthritis. Objectives We aimed to evaluate the prevalence of special diets and the perception of the effectiveness of these diets on arthritis in JIA. We also assessed the interest of dietary interventions and perceived barriers. Methods An online survey was designed through a REDCap database capturing demographic information, self- or parent-initiated special dietary interventions and self- or parent-observing effects on joint symptoms, willingness to participate in a dietary intervention study. The survey link was posted on social media websites and distributed by the Arthritis Foundation. Descriptive statistical analyses were performed. Results A total of 265 responses were received from adult patients who had JIA and parents of children with JIA. We excluded 14 patients with inflammatory bowel disease or celiac disease-related arthritis and 24 responders with incomplete answers. Demographic and JIA characteristics of adult and pediatric patients are listed in Table 1. Ninety patients (63 children with JIA, 27 adults with history of JIA) had tried a special diet for arthritis. The top three special diets reported by parents included a gluten-free diet (62%), an anti-inflammatory diet (53%), and a lactose-free diet (26%). There were similar clinical responses among the three diets (Figure 1). Twenty-five to thirty percent reported no change in joint symptoms whereas 20–30% reported improved pain or joint swelling. Sixty-one (34%) parents were willing to participate in a 3-month dietary intervention study and 78 (44%) parents answered “it depends”. Conclusions This is the first report of the family/patient perspective of the role of dietary intervention on JIA. Almost half of the affected patients attempted special diets, and many reported improvement in symptoms. Future interventional studies with objective outcome measurements are needed to validate these reports. Acknowledgements The authors would like to thank all the patients and families who have taken the survey. Arthritis Foundation and Facebook JA groups have helped distribute the survey. Disclosure of Interest E. Little: None declared, S. Grevich Grant/research support from: supported by Pfizer Medical and Academic partnership program, J. Huber: None declared, D. Suskind: None declared, M. Bradford: None declared, A. Stevens Grant/research support from: funded by Kineta Inc and Seattle Genetics. She has a license agreement with Quest Diagnostics., Y. Zhao: None declared

The ovary is not an immunologically privileged organ, but a breakdown in tolerogenic mechanisms for ovary-specific antigens has disastrous consequences on fertility in women, and this is replicated in murine models of autoimmune disease. Isolated ovarian autoimmune disease is rare in women, likely due to the severity of the disease and the inability to transmit genetic information conferring the ovarian disease across generations. Nonetheless, autoimmune oophoritis is often observed in association with other autoimmune diseases, particularly autoimmune adrenal disease, and takes a toll on both society and individual health. Studies in mice have revealed at least two mechanisms that protect the ovary from autoimmune attack. These mechanisms include control of autoreactive T cells by thymus-derived regulatory T cells, as well as a role for the autoimmune regulator (AIRE), a transcriptional regulator that induces expression of tissue-restricted antigens in medullary thymic epithelial cells during development of T cells. Although the latter mechanism is incompletely defined, it is well established that failure of either results in autoimmune-mediated targeting and depletion of ovarian follicles. In this review, we will address the clinical features and consequences of autoimmune-mediated ovarian infertility in women, as well as the possible mechanisms of disease as revealed by animal models.

Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5-TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5-TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-valuemeta = 6 × 10-49; OR = 1.38-1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3(P-valuesEU = 10-27-10-32, OR = 1.7-1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credibleset of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjögren's syndrome and systemic sclerosis whereas only the IRF5-TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5-TNPO3. © The Author 2014.

Systemic lupus erythematosis (SLE) can affect the lungs and pleura, usually manifesting with pleural effusions or diffuse parenchymal disease. A rare manifestation of SLE is shrinking lung syndrome, a severe restrictive respiratory disorder. While pleuropulmonary complications of pediatric SLE are common, shrinking lung syndrome is exceedingly rare in children. We present a case of a 13-year-old girl previously diagnosed with lupus, who developed severe dyspnea on exertion and restrictive pulmonary physiology. Her chest radiographs on presentation demonstrated low lung volumes, and CT showed neither pleural nor parenchymal disease. Fluoroscopy demonstrated poor diaphragmatic excursion. While shrinking lung syndrome is described and studied in adults, there is only sparse reference to shrinking lung syndrome in children.

The optimal combination of galactomannan index (GMI) testing for the diagnosis of invasive pulmonary aspergillosis (IPA) remains unclear. For diagnostic approaches that are triggered by clinical signs and symptoms in high-risk patients, institutional variation remains, with some centers routinely relying on only serum GMI or bronchoalveolar lavage (BAL) GMI testing. In addition, use of mold-active agents before diagnosis of IPA is becoming increasingly common, and understanding the effect of these drugs on test yield is important when making time-critical treatment decisions. In a single-center cohort of 210 allogeneic hematopoietic cell transplant (HCT) recipients, we found that serum and BAL GMI testing contributed independently to IPA diagnosis, supporting the practice of sending both tests simultaneously to ensure a timely diagnosis of IPA. BAL GMI sensitivity was not affected by receipt of mold-active therapy in our cohort.

The genetic factors underlying the pathogenesis of lupus nephritis associated with systemic lupus erythematosus are largely unknown, although animal studies indicate that nuclear factor (NF)-?B is involved. We reported previously that aknockin mouse expressinganin active form of ABIN1 (ABIN1[D485N]) develops lupus-like autoimmune disease and demonstrates enhanced activation of NF-?B and mitogen-activated protein kinases in immune cells after toll-like receptor stimulation. In the current study, we show that ABIN1[D485N] mice develop progressive GN similar to class III and IV lupus nephritis in humans. To investigate the clinical relevance of ABIN1 dysfunction, we genotyped five single-nucleotide polymorphisms in the gene encoding ABIN1, TNIP1, in samples from European-American, African American, Asian, Gullah, and Hispanic participants in the Large Lupus Association Study 2. Comparing cases of systemic lupus erythematosus with nephritis and cases ofsystemic lupus erythematosus without nephritis revealed strong associations with lupus nephritis at rs7708392 in European Americans and rs4958881 in African Americans. Comparing cases of systemic lupus erythematosus with nephritis and healthy controls revealed a stronger association at rs7708392 in European Americans but not at rs4958881 in African Americans. Our data suggest that variants in the TNIP1 gene are associated with the risk for lupus nephritis and could be mechanistically involved in disease development via aberrant regulation of NF-?B and mitogen-activated protein kinase activity. Copyright © 2013 by the American Society of Nephrology.

Objective To obtain international consensus around processes that support the delivery of high-quality care to patients with childhood-onset systemic lupus erythematosus (SLE) based on current recommendations and scientific evidence. Methods To identify process quality indicators (QIs) for the medical care of children and adolescents with childhood-onset SLE, we sent 2 Delphi questionnaires internationally to 340 physicians who treat these patients. We set consensus at 80% of completed responses. Results Two hundred ninety-seven physicians (87%) responded to the first Delphi questionnaire and 265 physicians (76%) responded to the second questionnaire. The group achieved consensus for 26 QIs addressing laboratory testing at diagnosis, health maintenance measures, diagnosis and therapy of lupus nephritis, general preventive strategies, surveillance for medication safety, counseling and evaluation of cardiovascular risk factors, as well as transition planning. Of the 26 process QIs for use in childhood-onset SLE, 11 matched those established for adults with SLE, 9 required modification, and consensus was reached for an additional 6 QIs specific to children. Conclusion An international consensus for a set of process QIs for childhood-onset SLE was reached that considers unique aspects of children with childhood-onset SLE. The presented set of QIs for children and adolescents with childhood-onset SLE defines agreed-upon standards of medical care.

Objective.Little is known about the genetic etiology of systemic lupus erythematosus (SLE) in individuals of African ancestry, despite its higher prevalence and greater disease severity. Overproduction of nitric oxide (NO) and reactive oxygen species are implicated in the pathogenesis and severity of SLE, making NO synthases and other reactive intermediate-related genes biological candidates for disease susceptibility. We analyzed variation in reactive intermediate genes for association with SLE in 2 populations with African ancestry.Methods.A total of 244 single-nucleotide polymorphisms (SNP) from 53 regions were analyzed in non-Gullah African Americans (AA; 1432 cases and 1687 controls) and the genetically more homogeneous Gullah of the Sea Islands of South Carolina (133 cases and 112 controls). Single-marker, haplotype, and 2-locus interaction tests were computed for these populations.Results.The glutathione reductase geneGSR(rs2253409; p = 0.0014, OR 1.26, 95% CI 1.09–1.44) was the most significant single SNP association in AA. In the Gullah, the NADH dehydrogenaseNDUFS4(rs381575; p = 0.0065, OR 2.10, 95% CI 1.23–3.59) and NO synthase geneNOS1(rs561712; p = 0.0072, OR 0.62, 95% CI 0.44–0.88) were most strongly associated with SLE. When both populations were analyzed together,GSRremained the most significant effect (rs2253409; p = 0.00072, OR 1.26, 95% CI 1.10–1.44). Haplotype and 2-locus interaction analyses also uncovered different loci in each population.Conclusion.These results suggest distinct patterns of association with SLE in African-derived populations; specific loci may be more strongly associated within select population groups.

Author(s): Fotis, Lampros; Shaikh, Nur; Baszis, Kevin; French, Anthony; Tarr, Phillip; Grevich, Sriharsha; Lee, Peggy; Ringold, Sarah; Leroux, Brian; Leahey, Hannah; Yuasa, Megan; Foster, Jessica; Sokolove, Jeremy; Lahey, Lauren; Robinson, William; Newsom, Joshua; Stevens, Anne; Karasawa, Rie; Tamaki, Mayumi; Tanaka, Megumi; Sato, Toshiko; Yudoh, Kazuo; Jarvis, James N; Moncrieffe, Halima; Bennett, Mark F; Tsoras, Monica; Luyrink, Lorie; Xu, Huan; Prahalad, Sampath; Morris, Paula; Dare, Jason; Nigrovic, Peter A; Rosenkranz, Margalit; Becker, Mara; O’Neil, Kathleen M; Griffin, Thomas; Lovell, Daniel J; Grom, Alexei A; Medvedovic, Mario; Thompson, Susan D; Zhu, Lisha; Jiang, Kaiyu; Wong, Laiping; Buck, Michael J; Chen, Yanmin; Moncrieffe, Halima; Brungs, Laura; Liu, Tao; Wang, Ting; Jarvis, James N; Alsaeid, Khaled; Alfailakawi, Jasim; Alenezi, Hamid; Alsaeed, Hazim; Beukelman, Tim; Natter, Marc; Ilowite, Norm; Mieszkalski, Kelly; Burrell, Grendel; Best, Brian; Bristow, Helen; Carr, Shannon; Dennos, Anne; Kaufmann, Rachel; Kimura, Yukiko; Schanberg, Laura; Blier, Peter R; Boneparth, Alexis; Wenderfer, Scott E; Moorthy, L Nandini; Radhakrishna, Suhas M; Sagcal-Gironella, Anna Carmela P; von Scheven, Emily; Gedik, Kader Cetin; Siddique, Salma; Aguiar, Cassyanne L; Erkan, Doruk; Cohen, Ezra; Lee, Yvonne; Dossett, Michelle; Mehta, Darshan; Davis, Roger; Gilbert, Mileka; Goilav, Beatrice; Meidan, Esra

Bullous eruptions in patients with underlying systemic lupus erythematosus (LE) can mimic toxic-epidermal necrolysis (TEN), a rapidly progressive mucocutaneous reaction usually associated with medication use. Differentiating between classic drug-induced TEN and TEN-like cutaneous LE is important but difficult. We report a series of 3 patients with pediatric systemic LE who were admitted with severe worsening of skin disease resembling TEN. However, the initial photo-distribution of the eruption, subacute progression, limited mucosal involvement, mild systemic symptoms, supportive biopsy and laboratory results, and lack of culprit drugs was more suggestive of a TEN-like cutaneous LE. These patients recovered with various systemic immunosuppressive medications including methylprednisolone, intravenous immunoglobulin, and plasmapheresis. Our cases are rare and demonstrate key clinical and histologic features of TEN-like cutaneous LE in young patients and the importance of differentiating this entity from drug-induced TEN.

Objective.Granulomatosis with polyangiitis (Wegener’s; GPA) and other antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are rare in childhood and are sometimes difficult to discriminate. We compared use of adult-derived classification schemes for GPA against validated pediatric criteria in the ARChiVe (A Registry for Childhood Vasculitis e-entry) cohort, a Childhood Arthritis and Rheumatology Research Alliance initiative.Methods.Time-of-diagnosis data for children with physician (MD) diagnosis of AAV and unclassified vasculitis (UCV) from 33 US/Canadian centers were analyzed. The European Medicines Agency (EMA) classification algorithm and European League Against Rheumatism/Paediatric Rheumatology International Trials Organisation/Paediatric Rheumatology European Society (EULAR/PRINTO/PRES) and American College of Rheumatology (ACR) criteria for GPA were applied to all patients. Sensitivity and specificity were calculated (MD-diagnosis as reference).Results.MD-diagnoses for 155 children were 100 GPA, 25 microscopic polyangiitis (MPA), 6 ANCA-positive pauciimmune glomerulonephritis, 3 Churg-Strauss syndrome, and 21 UCV. Of these, 114 had GPA as defined by EMA, 98 by EULAR/PRINTO/PRES, and 87 by ACR. Fourteen patients were identified as GPA by EULAR/PRINTO/PRES but not by ACR; 3 were identified as GPA by ACR but not EULAR/PRINTO/PRES. Using the EMA algorithm, 135 (87%) children were classifiable. The sensitivity of the EMA algorithm, the EULAR/PRINTO/PRES, and ACR criteria for classifying GPA was 90%, 77%, and 69%, respectively, with specificities of 56%, 62%, and 67%. The relatively poor sensitivity of the 2 criteria related to their inability to discriminate patients with MPA.Conclusion.EULAR/PRINTO/PRES was more sensitive than ACR criteria in classifying pediatric GPA. Neither classification system has criteria for MPA; therefore usefulness in discriminating patients in ARChiVe was limited. Even when using the most sensitive EMA algorithm, many children remained unclassified.

Objectives: Systemic lupus erythematosus (SLE) is a sexually dimorphic autoimmune disease which is more common in women, but affected men often experience a more severe disease. The genetic basis of sexual dimorphism in SLE is not clearly defined. A study was undertaken to examine sex-specific genetic effects among SLE susceptibility loci. Methods: A total of 18 autosomal genetic susceptibility loci for SLE were genotyped in a large set of patients with SLE and controls of European descent, consisting of 5932 female and 1495 male samples. Sex-specific genetic association analyses were performed. The sex-gene interaction was further validated using parametric and non-parametric methods. Aggregate differences in sex-specific genetic risk were examined by calculating a cumulative genetic risk score for SLE in each individual and comparing the average genetic risk between male and female patients. Results: A significantly higher cumulative genetic risk for SLE was observed in men than in women. (P=4.52x10 -8) A significant sex-gene interaction was seen primarily in the human leucocyte antigen (HLA) region but also in IRF5, whereby men with SLE possess a significantly higher frequency of risk alleles than women. The genetic effect observed in KIAA1542 is specific to women with SLE and does not seem to have a role in men. Conclusions: The data indicate that men require a higher cumulative genetic load than women to develop SLE. These observations suggest that sex bias in autoimmunity could be influenced by autosomal genetic susceptibility loci.

Inflammatory bowel disease (IBD) shares many immunologic and clinical characteristics with graft versus host disease caused by allogeneic T lymphocytes after hematopoietic cell transplantation. Since maternal cells are known to enter the fetal circulation in a high proportion of pregnancies, we hypothesized that maternal engraftment in the fetus results in immune sequelae that can lead to IBD.The presence and extent of maternal microchimerism in tissues and blood samples from patients with Crohn's, Ulcerative colitis (UC), and control groups were determined using kinetic Polymerase Chain Reaction (kPCR) to detect maternal- and patient-specific HLA types. In addition, fluorescent in situ hybridization (FISH) was employed to detect maternal cells in biopsies from patients with IBD.Using kPCR, maternal microchimerism was observed in 9 of the 16 (56%) patients with IBD and 6 out of 15 of the control group (40%) (P=NS). Five of 10 Crohn's patients had evidence of maternal microchimerism (50%) (P=NS). Four of six UC patients had evidence of maternal microchimerism in gut tissues (67%) (P=NS). There was no correlation between maternal michrochimerism and disease activity, disease location or granulomas in patients with IBD. Using FISH, five male Crohn's and five male UC patient's intestinal biopsies were analyzed for maternal microchimerism. No maternal cells were identified.There is nothing in the data to suggest that patients with IBD differ from disease controls in their frequency of maternal microchimerism in either blood or gut mucosal tissues. These data suggest that maternal microchimerism in blood and biopsies is a relatively common phenomenon that has neither positive nor negative impact on IBD.

Systemic lupus erythematosus (SLE) is considered to be the prototypic autoimmune disease, with a complex genetic architecture influenced by environmental factors. We sought to replicate a putative association at 11p13 not yet exceeding genome-wide significance (p < 5 × 10-8) identified in a genome-wide association study (GWAS). Our GWA scan identified two intergenic SNPs located between PDHX and CD44 showing suggestive evidence of association with SLE in cases of European descent (rs2732552, p = 0.004, odds ratio [OR] = 0.78; rs387619, p = 0.003, OR = 0.78). The replication cohort consisted of >15,000 subjects, including 3562 SLE cases and 3491 controls of European ancestry, 1527 cases and 1811 controls of African American (AA) descent, and 1265 cases and 1260 controls of Asian origin. We observed robust association at both rs2732552 (p = 9.03 × 10-8, OR = 0.83) and rs387619 (p = 7.7 × 10-7, OR = 0.83) in the European samples with pmeta = 1.82 × 10-9 for rs2732552. The AA and Asian SLE cases also demonstrated association at rs2732552 (p = 5 × 10-3, OR = 0.81 and p = 4.3 × 10-4, OR = 0.80, respectively). A meta-analysis of rs2732552 for all racial and ethnic groups studied produced pmeta = 2.36 × 10-13. This locus contains multiple regulatory sites that could potentially affect expression and functions of CD44, a cell-surface glycoprotein influencing immunologic, inflammatory, and oncologic phenotypes, or PDHX, a subunit of the pyruvate dehydrogenase complex. © 2011 The American Society of Human Genetics.

Objective To compare the criteria for Wegener's granulomatosis (WG) of the American College of Rheumatology (ACR) with those of the European League Against Rheumatism/Pediatric Rheumatology European Society (EULAR/PRES) in a cohort of children with WG and other antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides (AAVs), and to describe the interval to diagnosis, presenting features, and initial treatment for WG. Methods Eligible patients had been diagnosed by site rheumatologists (termed the “MD diagnosis”) since 2004. This diagnosis was used as a reference standard for sensitivity and specificity testing of the 2 WG classification criteria. Descriptive analyses were confined to ACR-classified WG patients. Results MD diagnoses of 117 patients (82 of whom were female) were WG (n = 76), microscopic polyangiitis (n = 17), ANCA-positive pauci-immune glomerulonephritis (n = 5), Churg-Strauss syndrome (n = 2), and unclassified vasculitis (n = 17). The sensitivities of the ACR and EULAR/PRES classification criteria for WG among the spectrum of AAVs were 68.4% and 73.6%, respectively, and the specificities were 68.3% and 73.2%, respectively. Two more children were identified as having WG by the EULAR/PRES criteria than by the ACR criteria. For the 65 ACR-classified WG patients, the median age at diagnosis was 14.2 years (range 4–17 years), and the median interval from symptom onset to diagnosis was 2.7 months (range 0–49 months). The most frequent presenting features by organ system were constitutional (89.2%), pulmonary (80.0%), ear, nose, and throat (80.0%), and renal (75.4%). Fifty-four patients (83.1%) commenced treatment with the combination of corticosteroids and cyclophosphamide, with widely varying regimens; the remainder received methotrexate alone (n = 1), corticosteroids alone (n = 4), or a combination (n = 6). Conclusion The EULAR/PRES criteria minimally improved diagnostic sensitivity and specificity for WG among a narrow spectrum of children with AAVs. Diagnostic delays may result from poor characterization of childhood WG. Initial therapy varied considerably among participating centers.

Maternal microchimerism (MMc) has been purported to play a role in the pathogenesis of autoimmunity, but how a small number of foreign cells could contribute to chronic, systemic inflammation has not been explained. Reports of peripheral blood cells differentiating into tissue-specific cell types may shed light on the problem in that chimeric maternal cells could act as target cells within tissues. We investigated MMc in tissues from 7 male infants. Female cells, presumed maternal, were characterized by simultaneous immunohistochemistry and fluorescence in situ hybridization for X- and Y-chromosomes. Maternal cells constituted 0.017% to 1.9% of parenchymal cells and were found in all infants in liver, pancreas, lung, kidney, bladder, skin, and spleen. Maternal cells were differentiated: maternal hepatocytes in liver, renal tubular cells in kidney, and β-islet cells in pancreas. Maternal cells were not found in areas of tissue injury or inflammatory infiltrate. Maternal hematopoietic cells were found only in hearts from patients with neonatal lupus. Thus, differentiated maternal cells are present in multiple tissue types and occur independently of inflammation or tissue injury. Loss of tolerance to maternal parenchymal cells could lead to organ-specific “auto” inflammatory disease and elimination of maternal cells in areas of inflammation.

The NKG2D receptor stimulates natural killer cell and T cell responses upon engagement of ligands associated with malignancies and certain autoimmune diseases. However, conditions of persistent NKG2D ligand expression can lead to immunosuppression. In cancer patients, tumor expression and shedding of the MHC class I-related chain A (MICA) ligand of NKG2D drives proliferative expansions of NKG2D(+)CD4(+) T cells that produce interleukin-10 (IL-10) and transforming growth factor-beta, as well as Fas ligand, which inhibits bystander T cell proliferation in vitro. Here, we show that increased frequencies of functionally equivalent NKG2D(+)CD4(+) T cells are inversely correlated with disease activity in juvenile-onset systemic lupus erythematosus (SLE), suggesting that these T cells may have regulatory effects. The NKG2D(+)CD4(+) T cells correspond to a normally occurring small CD4 T cell subset that is autoreactive, primed to produce IL-10, and clearly distinct from proinflammatory and cytolytic CD4 T cells with cytokine-induced NKG2D expression that occur in rheumatoid arthritis and Crohn's disease. As classical regulatory T cell functions are typically impaired in SLE, it may be clinically significant that the immunosuppressive NKG2D(+)CD4(+) T cells appear functionally uncompromised in this disease.

Purpose of review Powerful new methods are allowing identification of genetic risk factors in large populations of adults with autoimmune diseases. In this review, we describe the advantages and limitations of genetic methodologies, and how these methods have been used to discover candidate genes in smaller populations of pediatric patients. We also introduce novel concepts for nontraditional modes of genetic inheritance that may be important in the pathogenesis of autoimmunity. Recent findings Candidate genes identified by linkage analyses and genome-wide association scans in adult populations have led to focused genetic studies in pediatric populations. Some genes are associated with subsets of both adult and pediatric patients; others appear to be age specific. Novel concepts in genetics have uncovered potential contributions of maternal compared with paternal transmission, noninherited maternal alleles that may work through maternal microchimerism, and sex-specific epigenetic mechanisms of immunoregulation. Summary Advancing methods are leading to the discovery of genes associated with childhood autoimmune diseases. However, the genetic contribution to disease risk for any one gene remains less than 30% for most diseases, suggesting that pediatric autoimmunity is not primarily genetic in a classical sense. A combinatorial approach considering the contributions of multiple genes, mode of inheritance, and environmental influences will be required to fully understand the mechanisms of pathogenesis in pediatric autoimmune disease.

Objective. Antigen-presenting cells (APC) play critical roles in establishing and maintaining peripheral tolerance. This is accomplished in part via expression of negative co-stimulatory molecules such as programmed death ligand-1 (PD-L1) on tolerogenic APC, such as immature myeloid dendritic cells (mDC). Several studies have strongly linked dysfunction of APC, including mDC, to the pathogenesis of SLE. The objective of this study was to determine whether APC expressed PD-L1 protein at normal levels during active lupus. Methods. Peripheral blood mononuclear cells (PBMC) were isolated from 19 paediatric patients with SLE and from 17 healthy age-matched controls. PBMC from both cohorts were cultured in the absence of exogenously added stimuli, and leucocyte PD-L1 expression was measured by flow cytometry. Results. Immature mDC and monocytes (Mo) from healthy children expressed little PD-L1 at initial isolation, but spontaneously up-regulated PD-L1 by 24 h. In contrast, both mDC and Mo from patients with active SLE failed to up-regulate PD-L1 over a 5 day time course, expressing this protein only during disease remissions. Conclusions. These data are the first to link active lupus with reversibly decreased PD-L1 expression on professional APC, suggesting a novel mechanism for loss of peripheral tolerance in SLE.

Objective.Autoantibodies to the dense fine speckled 70 kDa antigen (DFS70) are reported to be more common in individuals who do not have an antinuclear antibody (ANA)-associated rheumatic disease (AARD) than in patients with AARD. The frequency of anti-DFS70 antibodies has been thoroughly studied in adult but not in pediatric populations. The primary objective of this observational study was to determine the frequency of anti-DFS70 in pediatric AARD and reference cohorts.Methods.Sera from 743 children with AARD and related conditions, and 345 samples from reference cohorts (healthy children and those being investigated for AARD) were studied for anti-DFS70 autoantibodies as measured by a chemiluminescence immunoassay. A de-identified administrative database was used to retrieve demographic, serologic, and clinical data.Results.Anti-DFS70 antibodies were seen in 2.1% of healthy children and in 4.5% of sera from pediatric individuals referred for ANA testing. The frequency of anti-DFS70 was highest in juvenile localized scleroderma (LS; 4/29, 13.8%), juvenile dermatomyositis (JDM; 2/11, 18.2%), childhood systemic lupus erythematosus (cSLE; 19/331, 5.7%), diffuse cutaneous systemic sclerosis (1/22, 4.5%), celiac disease (2/49, 4.1%), and juvenile idiopathic arthritis (JIA; 5/202, 2.5%). Of note, anti-DFS70 antibodies were observed in 3/26 children (11.5%) with uveitis and JIA-associated uveitis.Conclusion.The frequency of anti-DFS70 autoantibodies in healthy pediatric subjects is within the lower range of that reported in adults. Anti-DFS70 antibodies can be found in childhood SSc and cSLE, but has a remarkably high frequency in children with LS, JDM, and uveitis.

OBJECTIVE. Systemic sclerosis (SSc) is a rare disease that is particularly uncommon in children. Specific HLA alleles have been associated with SSc in adults. This study was undertaken to investigate HLA class II alleles in juvenile-onset SSc. METHODS. DRB1, DQA1, and DQB1 alleles were determined by DNA-based HLA typing. Analyses were conducted comparing Caucasian patients with juvenileonset SSc (n = 76) to healthy Caucasian controls (n = 581). RESULTS. Initial analyses focused on HLA class II associations previously reported in adult Caucasian patients with SSc. The frequency of DRB1*11 was not significantly increased in juvenile-onset SSc (22.4% of patients with juvenile-onset SSc versus 17.6% of controls; odds ratio [OR] 1.35, P = 0.34), nor were the specific DRB1*11:01 or *11:04 alleles. DQA1*05, a risk factor previously identified in adult men with SSc, was increased in patients with juvenile-onset SSc versus controls (57.9% versus 44.1%; OR 1.76, P = 0.027), as was DRB1*03 (34.2% versus 22.5%; OR 1.79, P = 0.031). Secondary analyses of all DRB1 allele groups revealed an association with DRB1*10 (10.5% of patients with juvenile-onset SSc versus 1.5% of controls; OR 7.48, P = 0.0002). As this is a new observation, correction was made for multiple comparisons of 13 different DRB1 allele groups; results nevertheless remained significant (P = 0.003). Also, a lower frequency of DRB1*01 was observed in patients with juvenile-onset SSc who were younger at disease onset (OR 0.06, P = 0.01) and in those with antibodies to topoisomerase (OR 0.14, P = 0.024). CONCLUSION. Associations of HLA alleles with juvenile-onset SSc differed from associations with SSc in women, but were similar to associations with SSc in men. Additionally, a novel association with DRB1*10 was observed in children. The greatest proportion of genetic risk of SSc is contributed by the HLA complex, and the current study reveals the importance of the association of HLA class II genes in juvenile-onset SSc.

OBJECTIVE. Juvenile systemic sclerosis is a rare multisystem autoimmune disorder characterized by vasculopathy and multiorgan fibrosis. Cardiopulmonary complications are the leading cause of morbidity and mortality. Although pulmonary fibrosis is the complication that is most common and well described, cardiovascular and esophageal involvement may also be observed. In this article, common thoracic findings in juvenile systemic sclerosis will be discussed. We will focus on chest CT, including CT findings of pulmonary fibrosis and associated grading methods, as well as cardiac MRI and esophageal imaging. CONCLUSION. Radiologists play a pivotal role in the initial diagnosis and follow-up evaluation of pediatric patients with systemic sclerosis. Treatment decisions and prognostic assessment are directly related to imaging findings along with clinical evaluation.

Long-term persistence of fetal cells in parous women (fetal microchimerism, FM) as well as maternal cells in their offspring (maternal microchimerism, MM) have been reported. Systemic sclerosis (SSc), primary biliary cirrhosis (PBC), and Sjögren's syndrome (SS) share similar epidemiology with a predilection for females following childbearing years, with clinical similarities to chronic graft-versus-host disease, a known condition of chimerism. This led to the hypothesis that FM could be involved in the pathogenesis of autoimmune diseases. Initial investigations were conducted in SSc, where the hypothesis was supported by the more frequent occurrence and, quantitatively, a greater degree of FM in women with SSc compared to matched healthy women. Long-term persistence, however, of fetal cells in healthy women indicates that FM per se is not sufficient for causing SSc, but may be important in the context of other risk factors, such as genetic susceptibility and HLA relationship among host and nonhost cells. Contradictory results have recently been published for both PBC and SS and cause difficulty in drawing any conclusions about the role of FM in their pathogenesis. On the other hand, MM has been investigated as a risk factor in patients with systemic lupus (SLE) and juvenile dermatomyositis (JDM). A potential role of MM has been suggested in the pathogenesis of SLE. Recent publications also support the hypothesis that MM might lead to increased risks for JDM. In conclusion, contradictory results have been observed. This reflects a need for standardization of protocols and the selection of control populations. Detection of microchimerism has to be quantitatively studied in the context of genetic factors in order to study its relationship to the pathogenesis of autoimmune diseases.