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Multisystem inflammatory syndrome in children (MIS-C) is a novel disease that was identified during the COVID-19 pandemic and is characterised by systemic inflammation following SARS-CoV-2 infection. Early detection of MIS-C is a challenge given its clinical similarities to Kawasaki disease and other acute febrile childhood illnesses. We aimed to develop and validate an artificial intelligence algorithm that can distinguish among MIS-C, Kawasaki disease, and other similar febrile illnesses and aid in the diagnosis of patients in the emergency department and acute care setting.In this retrospective model development and validation study, we developed a deep-learning algorithm called KIDMATCH (Kawasaki Disease vs Multisystem Inflammatory Syndrome in Children) using patient age, the five classic clinical Kawasaki disease signs, and 17 laboratory measurements. All features were prospectively collected at the time of initial evaluation from patients diagnosed with Kawasaki disease or other febrile illness between Jan 1, 2009, and Dec 31, 2019, at Rady Children's Hospital in San Diego (CA, USA). For patients with MIS-C, the same data were collected from patients between May 7, 2020, and July 20, 2021, at Rady Children's Hospital, Connecticut Children's Medical Center in Hartford (CT, USA), and Children's Hospital Los Angeles (CA, USA). We trained a two-stage model consisting of feedforward neural networks to distinguish between patients with MIS-C and those without and then those with Kawasaki disease and other febrile illnesses. After internally validating the algorithm using stratified tenfold cross-validation, we incorporated a conformal prediction framework to tag patients with erroneous data or distribution shifts. We finally externally validated KIDMATCH on patients with MIS-C enrolled between April 22, 2020, and July 21, 2021, from Boston Children's Hospital (MA, USA), Children's National Hospital (Washington, DC, USA), and the CHARMS Study Group consortium of 14 US hospitals.1517 patients diagnosed at Rady Children's Hospital between Jan 1, 2009, and June 7, 2021, with MIS-C (n=69), Kawasaki disease (n=775), or other febrile illnesses (n=673) were identified for internal validation, with an additional 16 patients with MIS-C included from Connecticut Children's Medical Center and 50 from Children's Hospital Los Angeles between May 7, 2020, and July 20, 2021. KIDMATCH achieved a median area under the receiver operating characteristic curve during internal validation of 98·8% (IQR 98·0-99·3) in the first stage and 96·0% (95·6-97·2) in the second stage. We externally validated KIDMATCH on 175 patients with MIS-C from Boston Children's Hospital (n=50), Children's National Hospital (n=42), and the CHARMS Study Group consortium of 14 US hospitals (n=83). External validation of KIDMATCH on patients with MIS-C correctly classified 76 of 81 patients (94% accuracy, two rejected by conformal prediction) from 14 hospitals in the CHARMS Study Group consortium, 47 of 49 patients (96% accuracy, one rejected by conformal prediction) from Boston Children's Hospital, and 36 of 40 patients (90% accuracy, two rejected by conformal prediction) from Children's National Hospital.KIDMATCH has the potential to aid front-line clinicians to distinguish between MIS-C, Kawasaki disease, and other similar febrile illnesses to allow prompt treatment and prevent severe complications.US Eunice Kennedy Shriver National Institute of Child Health and Human Development, US National Heart, Lung, and Blood Institute, US Patient-Centered Outcomes Research Institute, US National Library of Medicine, the McCance Foundation, and the Gordon and Marilyn Macklin Foundation.

Although intravenous immunoglobulin (IVIG) is effective therapy for Kawasaki disease, 10-20% of patients have recrudescent fever as a sign of persistent inflammation and require additional treatment. We aimed to compare infliximab with a second infusion of IVIG for treatment of resistant Kawasaki disease.In this multicentre comparative effectiveness trial, patients (aged 4 weeks to 17 years) with IVIG resistant Kawasaki disease and fever at least 36 h after completion of their first IVIG infusion were recruited from 30 hospitals across the USA. Patients were randomly assigned (1:1) to second IVIG (2 g/kg over 8-12 h) or intravenous infliximab (10 mg/kg over 2 h without premedication), by using a randomly permuted block randomisation design with block size of two or four. Patients with fever 24 h to 7 days following completion of first study treatment crossed over to receive the other study treatment. The primary outcome measure was resolution of fever at 24 h after initiation of study treatment with no recurrence of fever attributed to Kawasaki disease within 7 days post-discharge. Secondary outcome measures included duration of fever from enrolment, duration of hospitalisation after randomisation, and changes in markers of inflammation and coronary artery Z score. Efficacy was analysed in participants who received treatment and had available outcome values. Safety was analysed in all randomised patients who did not withdraw consent. This clinical trial is registered with ClinicalTrials.gov, NCT03065244.Between March 1, 2017, and Aug 31, 2020, 105 patients were randomly assigned to treatment and 103 were included in the intention-to-treat population (54 in the infliximab group, 49 in the second IVIG group). Two patients randomised to infliximab did not receive allocated treatment. The primary outcome was met by 40 (77%) of 52 patients in the infliximab group and 25 (51%) of 49 patients in the second IVIG infusion group (odds ratio 0·31, 95% CI 0·13-0·73, p=0·0076). 31 patients with fever beyond 24 h received crossover treatment: nine (17%) in the infliximab group received second IVIG and 22 (45%) in second IVIG group received infliximab (p=0·0024). Three patients randomly assigned to infliximab and two to second IVIG with fever beyond 24h did not receive crossover treatment. Mean fever days from enrolment was 1·5 (SD 1·4) for the infliximab group and 2·5 (2·5) for the second IVIG group (p=0·014). Mean hospital stay was 3·2 days (2·1) for the infliximab group and 4·5 days (2·5) for the second IVIG group (p0·001). There was no difference between treatment groups for markers of inflammation or coronary artery outcome. 24 (44%) of 54 patients in the infliximab group and 33 (67%) of 49 in the second IVIG group had at least one adverse event. A drop in haemoglobin concentration of at least 2g/dL was seen in 19 (33%) of 58 patients who received IVIG as either their first or second study treatment (three of whom required transfusion) and in three (7%) of 43 who received only infliximab (none required transfusion; p=0·0028). Haemolytic anaemia was the only serious adverse events deemed definitely or probably related to study treatment, and was reported in nine (15%) of 58 patients who received IVIG as either their first or second study treatment and none who received infliximab only.Infliximab is a safe, well tolerated, and effective treatment for patients with IVIG resistant Kawasaki disease, and results in shorter duration of fever, reduced need for additional therapy, less severe anaemia, and shorter hospitalisation compared with second IVIG infusion.Patient Centered Outcomes Research Institute.

Chronic recurrent multifocal osteomyelitis (CRMO) is a distinct disease entity of unknown etiology primarily affecting children and adolescents. It is an autoinflammatory process that typically affects multiple bones with a waxing and waning course. About one third of the patients diagnosed with CRMO have spinal involvement which can lead to long term morbidity. The clinical presentation and imaging features of CRMO involving the spine are nonspecific and can mimic other disease processes like infection or malignancy. Since imaging plays a very important role in the diagnosis and management of CRMO, we intend to highlight various imaging patterns of spinal CRMO alongside its clinical features and briefly discuss its imitators, management and outcomes.

Background The anti–interleukin-6 receptor-alpha antibody tocilizumab was approved for intravenous (IV) injection in the treatment of patients with systemic juvenile idiopathic arthritis (sJIA) aged 2 to 17 years based on results of a randomized controlled phase 3 trial. Tocilizumab treatment in systemic juvenile idiopathic arthritis (sJIA) patients younger than 2 was investigated in this open-label phase 1 trial and compared with data from the previous trial in patients aged 2 to 17 years. Methods Patients younger than 2 received open-label tocilizumab 12 mg/kg IV every 2 weeks (Q2W) during a 12-week main evaluation period and an optional extension period. The primary end point was comparability of pharmacokinetics during the main evaluation period to that of the previous trial (in patients aged 2–17 years), and the secondary end point was safety; pharmacodynamics and efficacy end points were exploratory. Descriptive comparisons for pharmacokinetics, pharmacodynamics, safety, and efficacy were made with sJIA patients aged 2 to 17 years weighing

Background Intravenous (IV) tocilizumab (TCZ) was approved in the, US (2011), EU (2013) and other countries for the treatment of systemic juvenile idiopathic arthritis (sJIA) patients (pts)≥2 years of age, based on a phase 3 study WA18221.1 US Food and Drug Administration approval resulted in postmarketing requirement to investigate TCZ in pts with sJIA Objectives Report safety results after completion of the optional extension period (OEP) of NP25737 (until 52 weeks from baseline or 2 years of age, whichever was longer). Methods NP25737 was a multicenter, open-label, single-arm study to evaluate the pharmacokinetics and safety of IV TCZ, 12 mg/kg every 2 weeks, for 12 weeks in pts aged Results Seven of 11 pts enrolled in the MEP continued to the OEP and received ≥1 dose of TCZ. Over the entire study period (n=11), the median number of TCZ doses was 11 (range, 2–26) and the median duration of TCZ exposure was 22 weeks (range, 4–58). Most pts (10/11; 91%) had ≥1 AE; most were mild or moderate in intensity and unrelated to study drug. The most common AEs were upper respiratory tract infection (6/11 pts, 55%), hypersensitivity, neutropenia, rash, viral upper respiratory tract infection, and vomiting (each in 3/11 pts; 27%). Seven serious AEs occurred in 5 of 11 pts (46%): 2 in the OEP (transaminases increased and histiocytosis hematophagic), 3 in the MEP (3 hypersensitivity events), and 2 in the safety follow-up of the MEP (sJIA flare and hand-foot-and-mouth disease). AEs leading to dose modification occurred in 5 of 11 pts (1 in the MEP, 4 in the OEP) mostly because of infections, neutropenia, and elevated liver enzymes, all mild or moderate in intensity. AEs leading to withdrawal occurred in 5 of 11 pts (46%): 1 in the OEP because of serious increased transaminases, 3 in the MEP because of serious hypersensitivity reactions to TCZ, and 1 in the MEP because of thrombocytopenia. No deaths were reported during the study. AE rates per 100 pt-years of exposure are reported in the table 1. Conclusions During the OEP of the study, long-term treatment with TCZ was well tolerated in sJIA pts aged References [1] De Benedetti F, et al. N Engl J Med2012;367:2385–2395. [2] Mallalieu NL, et al. Arthritis Rheumatol2017;69(suppl 10):abstract 2856. Acknowledgements This study was sponsored by F. Hoffmann-La Roche Ltd. Disclosure of Interest S. Wimalasundera Employee of: Roche, I. Calvo Penades: None declared, R. Cuttica Consultant for: Roche, Novartis, Lilly, GlaxoSmithKline, BMS, Janssen, Speakers bureau: Roche, Novartis, Lilly, GlaxoSmithKline, BMS, Janssen, H.-I. Huppertz: None declared, R. Joos: None declared, D. Milojevic: None declared, M. Rosenkranz: None declared, K. Schikler: None declared, T. Constantin: None declared, W. Douglass Employee of: Roche, C. Wells Shareholder of: Roche, Employee of: Roche, Y. Kimura Grant/research support from: Novartis, SOBI, Consultant for: Novartis, SOBI, C. Wouters: None declared

Lyme disease is caused by Borrelia burgdorferi and can lead to dermatologic, neurologic, cardiac, and musculoskeletal manifestations. The arthritis of Lyme disease is typically monoarticular, with the knee being most commonly involved. Lyme arthritis of small joints has not previously been well described. We report 3 children who presented with sternoclavicular joint swelling and who were found to have Lyme disease based on enzyme-linked immunosorbent assay and Western blot. This description of sternoclavicular Lyme arthritis highlights the importance of considering Lyme disease in the differential and diagnostic workup of new onset, small joint arthritis in patients presenting from or with travel to Lyme endemic regions.

Objective: The mechanisms that determine the efficacy or inefficacy of MTX in JIA are ill-defined. The objective of this study was to identify a gene expression transcriptional signature associated with poor response to MTX in patients with JIA. Methods: RNA sequencing was used to measure gene expression in peripheral blood mononuclear cells collected from 47 patients with JIA prior to MTX treatment and 14 age-matched controls. Differentially expressed baseline genes between responders and non-responders were evaluated. Biological differences between all JIA patients and controls were explored by constructing a signature of differentially expressed genes. Unsupervised clustering and pathway analysis was performed. Results: A signature of 99 differentially expressed genes (Bonferroni-corrected P < 0.05) capturing the biological differences between all JIA patients and controls was identified. Unsupervised clustering of samples based on this list of 99 genes produced subgroups enriched for MTX response status. Comparing this gene signature with reference signatures from sorted cell populations revealed high concordance between the expression signatures of monocytes and of MTX non-responders. CXCL8 (IL-8) was the most significantly differentially expressed gene transcript comparing all JIA patients with controls (Bonferroni-corrected P = 4.12 × 10-10). Conclusion: Variability in clinical response to MTX in JIA patients is associated with differences in gene transcripts modulated in monocytes. These gene expression profiles may provide a basis for biomarkers predictive of treatment response.

Background Tocilizumab (TCZ) is approved for the treatment of systemic juvenile idiopathic arthritis (sJIA) based on clinical trials in patients (pts) ≥2 years of age. This study (NP25737) is the first for a biologic in sJIA pts Objectives To evaluate the pharmacokinetics (PK), pharmacodynamics (PD), efficacy, and safety of TCZ in sJIA pts Methods Pts with uncontrolled sJIA and symptoms for ≥1 month prescreening who failed treatment with corticosteroids and NSAIDs and had no history of allergy to TCZ or other biologics received open-label TCZ 12 mg/kg intravenously (IV) every 2 weeks (dose calculated at each visit based on body weight). Pts were treated up to week 12 and could continue until the age of 2 years or were treated for 1 year from baseline. End points included PK (primary) at week 12, PD and efficacy (exploratory), and safety. Comparison was made to exposures from a previous trial in sJIA pts ≥2 years of age (WA18221) that was the basis for approval of TCZ in sJIA. Results Eleven pts were enrolled; median (range) age was 16 (10–22) months and weight was 10.40 (6.8–11.5) kg. Serum TCZ concentrations, estimated using population PK analysis, peaked immediately after infusion; median (range) maximum concentration was 282 (195–347) μg/mL (steady state reached by week 12), and median (range) trough concentration was 34.3 (19.2–59.7) μg/mL. Peak and trough exposures were within the exposure range in older children (244 [109–382] to 54.3 [10.9–117] μg/mL; Figure). Observed mean±SD soluble IL-6 receptor levels were 47.65±16.40 ng/mL at baseline and 927.83±148.07 ng/mL at day 71. CRP levels were 250.81±425.11 mg/L and 2.80±3.56 mg/L, respectively. ESR levels were 59.40±27.47 mm/h and 2.00±1.00 mm/h, respectively. Mean±SD Juvenile Arthritis Disease Activity Score-71 improved from 22.27±10.09 at baseline to 3.66±4.66 at day 71. By week 12, 10 pts had 32 adverse events (AEs) and 4 withdrew due to AEs. Infections or infestations were the most frequently reported AEs (10 events, 9 pts). Five serious AEs (SAEs) occurred; 3 pts had SAEs of hypersensitivity that led to withdrawal; 1 of these pts then experienced SAEs of foot and mouth disease and sJIA flare after study withdrawal. No actual cases of MAS were reported, but 2 pts had laboratory abnormalities indicative of MAS according to 2016 criteria.1 No deaths occurred during the study. Conclusions TCZ exposures achieved in this study fell within the range of the previous trial in sJIA pts ≥2 years of age. This study provides evidence that TCZ is effective in sJIA pts References Ravelli A et al. Ann Rheum Dis. 2016;75:481–9. Disclosure of Interest N. Mallalieu Shareholder of: Roche, Employee of: Roche, J. Hsu Employee of: Roche, K. Wang Employee of: Roche, S. Wimalasundera Employee of: Roche Products Ltd., C. Wells Employee of: Roche Products Ltd., I. Calvo Penades: None declared, R. Cuttica Consultant for: Roche, Novartis, Lilly, GlaxoSmithKline, Bristol-Myers Squibb, Janssen, Speakers bureau: Roche, Novartis, Lilly, GlaxoSmithKline, Bristol-Myers Squibb, Janssen, H. Huppertz: None declared, R. Joos: None declared, Y. Kimura Consultant for: Novartis, SOBI, D. Milojevic: None declared, M. Rosenkranz: None declared, K. Schikler: None declared, T. Constantin: None declared, C. Wouters: None declared

Objective CD8+ T cells lacking CD28 were originally reported to be a characteristic feature of juvenile idiopathic arthritis (JIA), but the relevance of these unusual cells to this disease remains to be elucidated. Because of recent evidence that loss of CD28 cells is typical of terminally differentiated lymphocytes, the aim of this study was to examine functional subsets of CD8+ T cells in patients with JIA. Methods Blood and/or waste synovial fluid samples were collected from children with a definite diagnosis of JIA (n = 98). Deidentified peripheral blood (n = 33) and cord blood (n = 13) samples from healthy donors were also collected. CD8+ and CD4+ T cells were screened for novel receptors, and where indicated, bioassays were performed to determine the functional relevance of the identified receptor. Results JIA patients had a naive T cell compartment with shortened telomeres, and their entire T cell pool had reduced proliferative capacity. They had an overabundance of CD31+CD28nullCD8+ T cells, which was a significant feature of oligoarticular JIA (n = 62) as compared to polyarticular JIA (n = 36). CD31+ CD28nullCD8+ T cells had limited mitotic capacity and expressed high levels of the senescence antigens histone γH2AX and/or p16. Ligation of CD31, which was independent of the T cell receptor (TCR), sufficiently induced tyrosine phosphorylation, vesicle exocytosis, and production of interferon-γ and interleukin-10. Conclusion These data provide the first evidence of cell senescence, as represented by CD31+CD28null CD8+ T cells, in the pathophysiology of JIA. Activation of these unusual cells in a TCR-independent manner suggests that they are maladaptive and could be potential targets for immunotherapy.

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

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.

Objective.There are no validated tools for measuring disease activity in pediatric vasculitis. The Birmingham Vasculitis Activity Score (BVAS) is a valid disease activity tool in adult vasculitis. Version 3 (BVAS v.3) correlates well with physician’s global assessment (PGA), treatment decision, and C-reactive protein in adults. The utility of BVAS v.3 in pediatric vasculitis is not known. We assessed the association of BVAS v.3 scores with PGA, treatment decision, and erythrocyte sedimentation rate (ESR) at diagnosis in pediatric antineutrophil cytoplasmic antibody-associated vasculitis (AAV).Methods.Children with AAV diagnosed between 2004 and 2010 at all ARChiVe centers were eligible. BVAS v.3 scores were calculated with a standardized online tool (www.vasculitis.org). Spearman’s rank correlation coefficient (rs) was used to test the strength of association between BVAS v.3 and PGA, treatment decision, and ESR.Results.A total of 152 patients were included. The physician diagnosis of these patients was predominantly granulomatosis with polyangiitis (n = 99). The median BVAS v.3 score was 18.0 (range 0–40). The BVAS v.3 correlations were rs = 0.379 (95% CI 0.233 to 0.509) with PGA, rs = 0.521 (95% CI 0.393 to 0.629) with treatment decision, and rs = 0.403 (95% CI 0.253 to 0.533) with ESR.Conclusion.Applied to children with AAV, BVAS v.3 had a weak correlation with PGA and moderate correlation with both ESR and treatment decision. Prospective evaluation of BVAS v.3 and/or pediatric-specific modifications to BVAS v.3 may be required before it can be formalized as a disease activity assessment tool in pediatric AAV.

Objective Juvenile idiopathic arthritis (JIA) is a heterogeneous group of inflammatory diseases, and no clinically useful prognostic markers to predict disease outcome in children with JIA are currently available. Synovial fluid likely reflects the proteins present in the inflamed synovium. The purpose of this study was to delineate the synovial fluid proteome and determine whether protein expression differs in the different subtypes of JIA. Methods Synovial fluid samples obtained from children with oligoarticular JIA, polyarticular JIA, or systemic JIA were compared. Two-dimensional gel electrophoresis for protein separation and matrix-assisted laser desorption ionization−time-of-flight mass spectrometry and quadripole time-of-flight mass spectrometry for protein identification were used for this study. Synovial fluid cells were analyzed by polymerase chain reaction (PCR) for the presence of haptoglobin messenger RNA (mRNA). Results The synovial fluid proteome of the samples was delineated. The majority of proteins showed overexpression in JIA synovial fluid as compared with noninflammatory control samples. There were 24 statistically significantly differentially expressed spots (>2-fold change; P < 0.05) between the subtypes of JIA. PCR analysis revealed haptoglobin mRNA, suggesting that haptoglobin is locally produced in an inflamed joint in JIA. Conclusion Despite the similar histologic appearance of inflamed joints in patients with different subtypes of JIA, there are differences in protein expression according to the subtype of JIA. Haptoglobin is differentially expressed between the subtypes of JIA and is locally produced in an inflamed joint in JIA. Haptoglobin and other differentially expressed proteins may be potential biomarkers in JIA.

Objective.To develop and evaluate a Localized Scleroderma (LS) Skin Severity Index (LoSSI) and global assessments’ clinimetric property and effect on quality of life (QOL).Methods.A 3-phase study was conducted. The first phase involved 15 patients with LS and 14 examiners who assessed LoSSI [surface area (SA), erythema (ER), skin thickness (ST), and new lesion/extension (N/E)] twice for inter/intrarater reliability. Patient global assessment of disease severity (PtGA-S) and Children’s Dermatology Life Quality Index (CDLQI) were collected for intrarater reliability evaluation. The second phase was aimed to develop clinical determinants for physician global assessment of disease activity (PhysGA-A) and to assess its content validity. The third phase involved 2 examiners assessing LoSSI and PhysGA-A on 27 patients. Effect of training on improving reliability/validity and sensitivity to change of the LoSSI and PhysGA-A was determined.Results.Interrater reliability was excellent for ER [intraclass correlation coefficient (ICC) 0.71], ST (ICC 0.70), LoSSI (ICC 0.80), and PhysGA-A (ICC 0.90) but poor for SA (ICC 0.35); thus, LoSSI was modified to mLoSSI. Examiners’ experience did not affect the scores, but training/practice improved reliability. Intrarater reliability was excellent for ER, ST, and LoSSI (Spearman’s rho = 0.71–0.89) and moderate for SA. PtGA-S and CDLQI showed good intrarater agreement (ICC 0.63 and 0.80). mLoSSI correlated moderately with PhysGA-A and PtGA-S. Both mLoSSI and PhysGA-A were sensitive to change following therapy.Conclusion.mLoSSI and PhysGA-A are reliable and valid tools for assessing LS disease severity and show high sensitivity to detect change over time. These tools are feasible for use in routine clinical practice. They should be considered for inclusion in a core set of LS outcome measures for clinical trials.

Objective.To determine whether adult disease severity subclassification systems for antineutrophil cytoplasmic antibody-associated vasculitis (AAV) are concordant with the decision to treat pediatric patients with cyclophosphamide (CYC).Methods.We applied the European Vasculitis Study (EUVAS) and Wegener’s Granulomatosis Etanercept Trial (WGET) disease severity subclassification systems to pediatric patients with AAV in A Registry for Childhood Vasculitis (ARChiVe). Modifications were made to the EUVAS and WGET systems to enable their application to this cohort of children. Treatment was categorized into 2 groups, “cyclophosphamide” and “no cyclophosphamide.” Pearson’s chi-square and Kendall’s rank correlation coefficient statistical analyses were used to determine the relationship between disease severity subgroup and treatment at the time of diagnosis.Results.In total, 125 children with AAV were studied. Severity subgroup was associated with treatment group in both the EUVAS (chi-square 45.14, p < 0.001, Kendall’s tau-b 0.601, p < 0.001) and WGET (chi-square 59.33, p < 0.001, Kendall’s tau-b 0.689, p < 0.001) systems; however, 7 children classified by both systems as having less severe disease received CYC, and 6 children classified as having severe disease by both systems did not receive CYC.Conclusion.In this pediatric AAV cohort, the EUVAS and WGET adult severity subclassification systems had strong correlation with physician choice of treatment. However, a proportion of patients received treatment that was not concordant with their assigned severity subclass.

Background Orbital myositis (or idiopathic orbital myositis) is an inflammatory process affecting extraocular muscles.It is essential to distinguish it from other inflammatory conditions affecting the orbit including (but not limited to) Thyroid associated ophthalmopathy, vasculitides including GPA, Sjogrens syndrome, sarcoidosis.At intial presentation it might be confused with other disease processes including infections, malignancies, congenital lesions (eg hemangioma), foreign body etc. For optimal management it is essential to differentiate it from these entities. We aim to help in understanding this disease by sharing our experience in diagnosis and management of patients presenting with this condition. Objectives We aim to describe the salient features including clinical presentation, laboratory, imaging and histopathologic findings and treatment in patients seen in a tertiary care pediatric rheumatology center with a diagnosis of orbital myositis. Methods Retrospective chart review was performed in this series of patients presenting with inflammatory lesions of the orbit/s involving extraocular muscles, between December 2004 and August 2014 Results 9 patients with median age of 14 years (with range 6yrs – 16yrs) at the time of initial diagnosis were identified. Duration of symptoms at the time of presentation ranged from a few weeks (2 weeks) to several years (2 years). Most common presenting symptom was orbital pain in all the patients followed by headache and diplopia in 78% and 56% patients respectively. Motility restriction was fairly common on exam seen in 67% patients. Increased intraocular pressure was seen in 3 patients. Bilaterality was seen in 8 cases (89%). Decreased visual acuity was seen in 1 patient due to optic nerve involvement. Laboratory workup did not reveal any specific characteristics and only 1 patient had positive anti thyroid antibodies in absence of any clinical signs/symptoms suggestive for thyroid disease along with normal thyroid function tests. One patient over course of first year after initial presentation developed inflammatory bowel disease. Imaging was obtained in all patients with orbital MRI (n=7), orbital CT scan (n=4), both MRI and CT scan (n=2). Biopsy of extra ocular muscles was obtained in one patient with evidence of mild chronic inflammatory infiltrate. All cases were steroid responsive, although majority required the addition of a steroid sparing agent due disease recurrence or steroid dependence. Methotrexate was the most commonly used initial DMARD in these cases with good response. One patient had recalcitrant disease despite therapy with corticosteroids, methotrexate and Infliximab and is currently being treated with Rituximab with good initial response to therapy. Conclusions Idiopathic orbital myositis is a rare inflammatory disorder in the pediatric population. What makes the diagnosis even more difficult is the vast differential diagnosis. Our case series is one of the largest series of patients diagnosed and followed over time with this condition. It is fairly steroid responsive, although recurrence is common and warrants further treatment. First line treatment with methotrexate is appropriate with good response in majority. Further biologic therapy is needed in resistant cases, although there are no set guidelines to direct management. References Semin Arthritis Rheum 2008 Feb;37(4):207-22. Epub 2007 Sep 4.Orbital inflammatory disease. Lutt JR, Lim LL, Phal PM, Rosenbaum JT. Disclosure of Interest None declared

Background JIA is a heterogenous group of rheumatic conditions characterized by local inflammation and destruction of the joint space. Pro-inflammatory cytokines derived from T cells are considered culprits of disease. We have recently shown that some of these cytokines directly come from a distinct subset of T cells expressing CD31, an adhesion molecule normally expressed by granulocytes and endothelial cells. Objectives In the present work, we examined whether the array of cytokines in blood and synovial fluid of patients are the same array produced by CD8+ T cells activation through CD31 ligation independent of the TCR. We propose that CD31-driven cytokine production by T cells is a self-perpetuating mechanism of local and systemic inflammation in JIA. Methods Following informed consent/assent, blood and/or synovial fluid were collected from children with oligoarticular and polyarticular JIA. Similar blood samples were also collected from healthy subjects. Cytokine composition of the plasma and/or fluid was determined by multiplex analysis. Phenotypes of mononuclear cells in blood and synovial fluid were examined by multicolor flow cytometry. Drawing from the results of the multiplex assay, receptor crosslinking bioassays for cytokine production were performed using CD31+ primary T cells, and T lymphoid cell lines. Results As expected, the overall cytokine signature of JIA is characterized by the dominance of IL-6, IL-10 and TNFα. Patients with oligoarticular disease showed higher levels of IFNγ and IL-17 family cytokines than those with polyarticular disease. Both types of patients however showed a similar cellular signature characterized by T cells deficient in CD4, CD8, and CD28, but expressing CD31. Results of CD31 cross-linking bioassays, using either specific antibody or its recombinant ligand CD38, showed high levels of induction of IL-2, IL-17, and IFNγ. Specificity of CD31-driven, TCR-independent cytokine production was verified by similar bioassays using somatic T cell line mutants deficient in TCR or in TCR/CD3 complex, but are both CD31+. The observed cytokine production was associated with phosphorylation of classical T cell-signaling substrates indicating CD31 ligation effectively pass the TCR-driven route of activation. Conclusions Our data show that the cytokine profile of oligoarticular JIA is distinct with the dominance of IFNγ and IL17. CD31-driven induction of these cytokines in a TCR-independent manner indicates maladaptive T cell function in JIA. Further investigation on the relevance of IFNγ and IL-17 to disease activity/clinical outcomes, and the CD31 signaling cascade will pave way to innovations in immunotherapy in JIA. Acknowledgements This work is supported by grants from the Nancy Taylor Foundation for Chronic Diseases, and the National Institutes of Health (T32 AR052282). Authors have no financial conflicts of interest. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5501

Pro-inflammatory cytokines in the blood and synovium are key actors in JIA pathology. We recently reported that JIA patients have an over abundance of prematurely senescent CD8+ T cells expressing CD31, an adhesion molecule expressed by granulocytes and endothelial cells. CD31 triggering alone is sufficient to activate such senescent T cells. This study examined whether cytokine profile in JIA may be derived from T cell activation through CD31 ligation independent of the TCR. Results showed a cytokine signature of JIA characterized by dominance of IL-6, IL-10 and TNFα. Notably, patients with oligoarticular JIA showed higher levels of IFNγ and IL-17 family cytokines than those with polyarticular JIA. All patients also had a novel subset of T cells deficient in CD4, CD8, and CD28, but expressing CD31. Cross-linking bioassays, using anti-CD31 or its ligand CD38, show high levels of induction of IL-2, IL-17, and IFNγ. This CD31-driven, TCR-independent cytokine production was also verified by using somatic T cell line mutants that lack TCR and TCR/CD3, respectively, but both are CD31+. The observed cytokine production was associated with the phosphorylation of the signaling substrates ZAP70, cAbl, and p65-NFΚB. TCR independent, CD31-driven induction of these cytokines suggests maladaptive T cell function in JIA. Further investigation on the relevance of IFNγ and IL-17 to disease activity, and the CD31 signaling pathway may allow for innovations in immunotherapy.

Background/Purpose: JIA is the banner diagnosis for a heterogenous group of rheumatic conditions characterized by local inflammation and destruction of the joint space and systemic manifestations. Pro-inflammatory cytokines derived from T cells are considered effectors of disease. Recent data has shown that some of these cytokines come directly from a distinct subset of T cells expressing CD31, an adhesion molecule expressed by granulocytes and endothelial cells. In the present work, we examined whether the array of cytokines in blood and synovial fluid of patients are the same array produced by T cells activation through CD31 ligation independent of the TCR. We propose that CD31-driven cytokine production by T cells is a self-perpetuating mechanism of local and systemic inflammation in JIA. Methods: Following informed consent/assent, blood and/or synovial fluid were collected from patients with oligoarticular and polyarticular JIA. Similar blood samples were also collected from healthy subjects. Cytokine composition of the plasma and/or fluid were subjected to multiplex analysis using the Luminex platform. Phenotypes of mononuclear cells in blood and synovial fluid were examined by multicolor flow cytometry. Drawing from the results of the Luminex assay, receptor crosslinking bioassays using primary CD31+ T cells (in blood and/or synovial fluid) and CD31+ T cell lines were conducted. Cytokine production by these cells were assessed by flow cytometry and/or by Luminex. Results: The overall cytokine signature of JIA characterized by the dominance of IL-6, IL-10 and TNFα. Unexpectedly, patients with oligoarticular disease showed higher levels of IFNγ and IL-17 family cytokines than those with polyarticular disease. Both types of patients however showed a similar cellular signature characterized by the preponderance of T cells deficient in CD4, CD8, and CD28, but expressing CD31. Results of CD31 cross-linking bioassays, using either specific antibody or its recombinant ligand CD38, showed high levels of induction of IL-2, IL-17 and IFNγ. Specificity of CD31-driven, TCR-dependent cytokine production was verified by similar bioassays using somatic somatic T cell line mutants Loucy and JRT3 that lack TCR and TCR/CD3, respectively, but are both CD31+. The observed cytokine production was associated with the phosphorylation of the signaling substrates ZAP70, cAbl, and p65-NFKB. Conclusion: Our data show that the cytokine signature of oligoarticular JIA appears distinct with the dominance of IFNγ and IL17. TCR independent, CD31-driven induction of these cytokines suggests maladaptive T cell function in JIA. Further investigation on the relevance of IFNγ and IL-17 to disease activity/clinical outcomes, and the CD31 signaling pathway will pave way to innovations in immunotherapy in JIA.

An SAR model for inhibition of metabolic cooperation (iMC) was developed. The structural and physicochemical features associated with the ability to cause iMC are primarily lipophilic moieties consistent with the possibility that they represent receptor-binding ligands. There are also significant parallels between the structural descriptors associated with iMC and those associated with tumor promotion and with carcinogenesis in rodents. Overall, the present study provides structural evidence that iMC is a feature associated with the carcinogenic process.

Pervasive T cell clonality is a feature of Juvenile Idiopathic Arthritis (JIA), but the role of oligoclonal T cells in this chronic disease of childhood is poorly understood. We propose that T cell clonality in JIA is indicative of replicative pressure leading to accumulation of terminally differentiated cells. Hence, we examined the T cell repertoire of children with confirmed diagnosis of JIA and their age-matched healthy counterparts. Results showed that naive T cells of children with JIA had significantly lower telomere-FISH fluorescence indicating a long replicative history. Multicolor cytometry analyses also showed that patients had over abundance of CD8+CD31+CD28null T cells in blood and synovial fluid irrespective of disease duration and medication. Frequency of these unusual T cells was significantly higher among patients with the more severe, polyarticular form of JIA disease than those with oligoarticular disease. Furthermore, these T cells expressed high levels of γH2AX and pRB suggesting senescence. In proliferation assays using CFSE, these T cells remained CFSEhi but were CD69hiCD25lo/neg, results consistent with senescence and not quiescence. In receptor crosslinking assays, ligation of CD31 alone sufficiently induced tyrosine phosphorylation, cytolysis, and production of IFNγ, TNFα, and IL-10. These data indicate premature immune senescence in JIA, with CD8+CD31+CD28nullH2AX+ T cells as maladaptive effectors, and are potential targets for therapy.

Objectives We have reported recently that JIA patients carry high numbers of unusual senescent CD8 T cells bearing CD31, a molecule known mediate leukocyte diapedesis into sites of injury. In the present work, we re-surveyed the T cell populations of patients for other CD31 senescent T cell subsets. We hypothesized that CD31 signaling in these senescent cells is a self-perpetuating mechanism for the upregulation of inflammatory cytokines in JIA.