Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome.

BACKGROUND: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. OBJECTIVE: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. METHODS: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. RESULTS: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4-CD8-) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. CONCLUSION: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome.

Comprehensive and reliable sonographic assessment and scoring system for inflammatory lesions of the paediatric ankle.

OBJECTIVE: The clinical decision-making process in paediatric arthritis lacks an objective, reliable bedside imaging tool. The aim of this study was to develop a US scanning protocol and assess the reliability of B-mode and Doppler scoring systems for inflammatory lesions of the paediatric ankle. METHODS: As part of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) US group, 19 paediatric rheumatologists through a comprehensive literature review developed a set of standardized views and scoring systems to assess inflammatory lesions of the synovial recesses as well as tendons of the paediatric ankle. Three rounds of scoring of still images were followed by one practical exercise. Agreement among raters was assessed using two-way single score intraclass correlation coefficients (ICC). RESULTS: Of the 37 initially identified views to assess the presence of ankle synovitis and tenosynovitis, nine views were chosen for each B-mode and Doppler mode semi-quantitative evaluation. Several scoring exercises and iterative modifications resulted in a final highly reliable scoring system: anterior tibiotalar joint ICC: 0.93 (95% CI 0.92, 0.94), talonavicular joint ICC: 0.86 (95% CI 0.81, 0.90), subtalar joint ICC: 0.91 (95% CI 0.88, 0.93) and tendons ICC: 0.96 (95% CI 0.95, 0.97). CONCLUSION: A comprehensive and reliable paediatric ankle US scanning protocol and scoring system for the assessment of synovitis and tenosynovitis were successfully developed. Further validation of this scoring system may allow its use as an outcome measure for both clinical and research applications.

Reliability of the Pediatric Specific Musculoskeletal Ultrasound Scoring Systems for the Elbow, Wrist, and Finger Joints.

OBJECTIVE: Musculoskeletal ultrasound (MSUS) is increasingly being used in the evaluation of pediatric musculoskeletal diseases. In order to provide objective assessments of arthritis, reliable MSUS scoring systems are needed. Recently, joint-specific scoring systems for arthritis of the pediatric elbow, wrist, and finger joints were proposed by the Childhood Arthritis and Rheumatology Research Alliance (CARRA) MSUS workgroup. This study aimed to assess the reliability of these scoring systems when used by sonographers with different levels of expertise. METHODS: Members of the CARRA MSUS workgroup attended training sessions for scoring the elbow, wrist, and finger. Subsequently, scoring exercises of B mode and power Doppler (PD) mode still images for each joint were performed. Interreader reliability was determined using 2-way single-score intraclass correlation coefficients (ICCs) for synovitis and Cohen [Formula: see text] for tenosynovitis. RESULTS: Seventeen pediatric rheumatologists with different levels of MSUS expertise (1-15 yrs) completed a 2-hour training session and calibration exercise for each joint. Excellent reliability (ICC > 0.75) was found after the first scoring exercise for all the finger and elbow views evaluated on B mode and PD mode, and for all of the wrist views on B mode. After a second training session and a scoring exercise, the wrist PD mode views reached excellent reliability as well. CONCLUSION: The preliminary CARRA MSUS scoring systems for assessing arthritis of the pediatric elbow, wrist, and finger joints demonstrate excellent reliability among pediatric MSUS sonographers with different levels of expertise. With further validation, this reliable joint-specific scoring system could serve as a clinical tool and scientific outcome measure.

Childhood Sjögren syndrome: features of an international cohort and application of the 2016 ACR/EULAR classification criteria.

OBJECTIVE: Sjögren syndrome in children is a poorly understood autoimmune disease. We aimed to describe the clinical and diagnostic features of children diagnosed with Sjögren syndrome and explore how the 2016 ACR/EULAR classification criteria apply to this population. METHODS: An international workgroup retrospectively collected cases of Sjögren syndrome diagnosed under 18 years of age from 23 centres across eight nations. We analysed patterns of symptoms, diagnostic workup, and applied the 2016 ACR/EULAR classification criteria. RESULTS: We identified 300 children with Sjögren syndrome. The majority of patients n = 232 (77%) did not meet 2016 ACR/EULAR classification criteria, but n = 110 (37%) did not have sufficient testing done to even possibly achieve the score necessary to meet criteria. Even among those children with all criteria items tested, only 36% met criteria. The most common non-sicca symptoms were arthralgia [n = 161 (54%)] and parotitis [n = 140 (47%)] with parotitis inversely correlating with age. CONCLUSION: Sjögren syndrome in children can present at any age. Recurrent or persistent parotitis and arthralgias are common symptoms that should prompt clinicians to consider the possibility of Sjögren syndrome. The majority of children diagnosed with Sjögren syndromes did not meet 2016 ACR/EULAR classification criteria. Comprehensive diagnostic testing from the 2016 ACR/EULAR criteria are not universally performed. This may lead to under-recognition and emphasizes a need for further research including creation of paediatric-specific classification criteria.

Pulmonary Histopathology Findings in Patients With STAT3 Gain of Function Syndrome.

INTRODUCTION AND AIM: Multiorgan autoimmunity and interstitial lung disease (ILD) are reported in patients with STAT3 GOF syndrome. RESULTS: We present lung histopathology findings in 3 such children, two of whom underwent wedge biopsies with adequate diagnostic material. Wedge biopsies showed interstitial cellular expansion with linear and nodular aggregates of CD8 positive T lymphocytes, plasma cells, and histiocytes; consistent with lymphocytic interstitial pneumonia pattern (LIP). CD4+ T cells and CD20+ B cells were present but infrequent in the interstitium. FOXP3 cells ranged from 0-5%. Focal interstitial and intraalveolar histiocytes were also seen. Neutrophils and eosinophils were rare/absent. Non-occlusive peribronchial lymphoid aggregates showed equal T and B cells; likely reactive in nature. Pulmonary vessels appeared normal without vasculitis or hypertensive change. There was no interstitial or subepithelial fibrosis or organizing pneumonia. Interlobular septa and visceral pleura were unremarkable. CONCLUSION: Children with multi-system autoimmune disorders with ILD should be investigated for STAT3 GOF syndrome. Lung wedge biopsies are more informative than transbronchial biopsies, if a tissue sampling is indicated. CD8 dominant T cell inflammation seems to be a key driver of ILD. Although interstitial fibrosis was not seen in our small sample, longer follow up is needed to understand the natural history.

Takayasu's arteritis presenting as acute myocardial infarction: case series and review of literature.

This series describes three adolescent females who presented with chest pain and ventricular dysfunction related to acute coronary ischemia secondary to Takayasu's arteritis with varied courses of disease progression leading to a diverse range of therapies including cardiac transplantation. While Takayasu's arteritis is rare in childhood, it should be strongly considered in any adolescent female presenting with systemic inflammation and chest pain consistent with myocardial infarction. A high index of suspicion can lead to early detection and aggressive management of the underlying vasculitis reducing associated morbidity and mortality. The purpose of this report is to describe the challenges in the clinical diagnosis and management of Takayasu's arteritis with myocardial infarction. We also seek to enhance awareness about unique presentations of Takayasu's arteritis within the paediatric community.

S100A12 and S100A8/9 proteins are biomarkers of articular disease activity in Blau syndrome.

OBJECTIVE: To identify biomarkers of articular and ocular disease activity in patients with Blau syndrome (BS). METHODS: Multiplex plasma protein arrays were performed in five BS patients and eight normal healthy volunteers (NHVs). Plasma S100A12 and S100A8/9 were subsequently measured by ELISA at baseline and 1-year follow-up in all patients from a prospective multicentre cohort study. CRP was measured using Meso Scale Discovery immunoassay. Active joint counts, standardization uveitis nomenclature for anterior uveitis cells and vitreous haze by Nussenblatt scale were the clinical parameters. RESULTS: Multiplex Luminex arrays identified S100A12 as the most significantly elevated protein in five selected BS vs eight NHVs and this was confirmed by ELISA on additional samples from the same five BS patients. In the patient cohort, S100A12 (n = 39) and S100A8/9 (n = 33) were significantly higher compared with NHVs (n = 44 for S100A12, n = 40 for S100A8/9) (P = 0.0000004 and P = 0.0003, respectively). Positive correlations between active joint counts and S100 levels were significant for S100A12 (P = 0.0008) and S100A8/9 (P = 0.015). CRP levels did not correlate with active joint count. Subgroup analysis showed significant association of S100 proteins with active arthritis (S100A12 P = 0.01, S100A8/9 P = 0.008). Active uveitis was not associated with increased S100 levels. CONCLUSION: S100 proteins are biomarkers of articular disease activity in BS and potential outcome measures in future clinical trials. As secreted neutrophil and macrophage products, S100 proteins may reflect the burden of granulomatous tissue in BS.

Single-cell transcriptomics unveil profiles and interplay of immune subsets in rare autoimmune childhood Sjögren's disease.

Childhood Sjögren's disease represents critically unmet medical needs due to a complete lack of immunological and molecular characterizations. This study presents key immune cell subsets and their interactions in the periphery in childhood Sjögren's disease. Here we show that single-cell RNA sequencing identifies the subsets of IFN gene-enriched monocytes, CD4+ T effector memory, and XCL1+ NK cells as potential key players in childhood Sjögren's disease, and especially in those with recurrent parotitis, which is the chief symptom prompting clinical visits from young children. A unique cluster of monocytes with type I and II IFN-related genes is identified in childhood Sjögren's disease, compared to the age-matched control. In vitro regulatory T cell functional assay demonstrates intact functionality in childhood Sjögren's disease in contrast to reduced suppression in adult Sjögren's disease. Mapping this transcriptomic landscape and interplay of immune cell subsets will expedite the understanding of childhood Sjögren's disease pathogenesis and set the foundation for precision medicine.

The Florida Scoring System for stratifying children with suspected Sjögren's disease: a cross-sectional machine learning study.

BACKGROUND: Childhood Sjögren's disease is a rare, underdiagnosed, and poorly-understood condition. By integrating machine learning models on a paediatric cohort in the USA, we aimed to develop a novel system (the Florida Scoring System) for stratifying symptomatic paediatric patients with suspected Sjögren's disease. METHODS: This cross-sectional study was done in symptomatic patients who visited the Department of Pediatric Rheumatology at the University of Florida, FL, USA. Eligible patients were younger than 18 years or had symptom onset before 18 years of age. Patients with confirmed diagnosis of another autoimmune condition or infection with a clear aetiological microorganism were excluded. Eligible patients underwent comprehensive examinations to rule out or diagnose childhood Sjögren's disease. We used latent class analysis with clinical and laboratory variables to detect heterogeneous patient classes. Machine learning models, including random forest, gradient-boosted decision tree, partial least square discriminatory analysis, least absolute shrinkage and selection operator-penalised ordinal regression, artificial neural network, and super learner were used to predict patient classes and rank the importance of variables. Causal graph learning selected key features to build the final Florida Scoring System. The predictors for all models were the clinical and laboratory variables and the outcome was the definition of patient classes. FINDINGS: Between Jan 16, 2018, and April 28, 2022, we screened 448 patients for inclusion. After excluding 205 patients due to symptom onset later than 18 years of age, we recruited 243 patients into our cohort. 26 patients were excluded because of confirmed diagnosis of a disorder other than Sjögren's disease, and 217 patients were included in the final analysis. Median age at diagnosis was 15 years (IQR 11-17). 155 (72%) of 216 patients were female and 61 (28%) were male, 167 (79%) of 212 were White, and 20 (9%) of 213 were Hispanic, Latino, or Spanish. The latent class analysis identified three distinct patient classes: class I (dryness dominant with positive tests, n=27), class II (high symptoms with negative tests, n=98), and class III (low symptoms with negative tests, n=92). Machine learning models accurately predicted patient class and ranked variable importance consistently. The causal graphical model discovered key features for constructing the Florida Scoring System. INTERPRETATION: The Florida Scoring System is a paediatrician-friendly tool that can be used to assist classification and long-term monitoring of suspected childhood Sjögren's disease. The resulting stratification has important implications for clinical management, trial design, and pathobiological research. We found a highly symptomatic patient group with negative serology and diagnostic profiles, which warrants clinical attention. We further revealed that salivary gland ultrasonography can be a non-invasive alternative to minor salivary gland biopsy in children. The Florida Scoring System requires validation in larger prospective paediatric cohorts. FUNDING: National Institute of Dental and Craniofacial Research, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Heart, Lung, and Blood Institute, and Sjögren's Foundation.

Bortezomib is efficacious in the treatment of severe childhood-onset neuropsychiatric systemic lupus erythematosus with psychosis: a case series and mini-review of B-cell immunomodulation in antibody-mediated diseases.

Childhood-onset neuropsychiatric systemic lupus erythematosus (cNPSLE) with psychosis is a challenging manifestation of SLE. Pathogenic long-lived plasma cells (LLPCs) are not specifically targeted by standard immunosuppression and their persistence contributes to chronic autoimmunity. Bortezomib is approved for the treatment of multiple myeloma and has shown benefits in a variety of other antibody-mediated diseases. Bortezomib may be efficacious for severe or treatment-refractory cNPSLE through eradication of LLPCs, decreasing autoantibody production. We describe the first pediatric case series of five patients with unrelenting cNPSLE with psychosis who were treated safely and effectively with bortezomib between 2011 and 2017. Most patients had persistent cNPSLE with psychosis despite aggressive immunosuppression with methylprednisolone, cyclophosphamide, rituximab, and usually plasmapheresis. All patients demonstrated rapid clinical improvement in their psychotic manifestations with the ability to quickly taper immunosuppression after the introduction of bortezomib. No patient had a recurrence of overt psychosis during a follow-up period of 1-10 years. Secondary hypogammaglobulinemia developed in all five patients and required immunoglobulin replacement. No other severe side effects or adverse events were observed. Bortezomib-mediated LLPC depletion is a promising therapy for severe recalcitrant cNPSLE with psychosis when used as adjunctive therapy to conventional immunosuppression, B-cell, and antibody-depleting therapies. After initiation of bortezomib, patients had rapid, demonstrable improvement in psychosis as well as reduction in glucocorticoids and antipsychotics. Further investigation is needed to determine the therapeutic role of bortezomib in severe cNPSLE and cSLE. We present a mini-review of the rationale for bortezomib use and novel B-cell immunomodulation in rheumatic disease.

Long-term efficacy of sialendoscopy in treating childhood Sjögren's disease with chronological monitoring by salivary gland ultrasonography: A novel approach.

BACKGROUND: Childhood Sjögren's Disease (cSjD) is an underdiagnosed phenomenon with clinical and pathophysiological nuances in contrast to Sjögren's Disease (SjD) in the adult population. While adults typically experience sicca symptoms, children with cSjD often present with recurrent parotitis, diverse autoantibody profiles, and renal and neurological manifestations. Diagnosis and classification in pediatric rheumatology remain controversial due to the reliance on adult-focused diagnostic criteria and the lack of standardized treatment and understanding of outcomes. The purpose of the paper is to propose a multimodal treatment plan and demonstrate the effectiveness of sialendoscopy in the management of cSjD. CASE PRESENTATION: We present the case of a twelve-year-old female diagnosed with cSjD using the 2016 American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) diagnostic criteria for SjD. In addition to medical management, she underwent sialendoscopy with triamcinolone irrigation under sedation and was monitored for progress via salivary gland ultrasonography (SGUS). Over the course of one year, she demonstrated significant improvement in symptoms, with serial SGUS scores gradually decreasing by five points. CONCLUSIONS: This paper proposes a multimodal treatment plan involving sialendoscopy and medical management as a non-invasive and potentially more effective approach for cSjD. Standardized monitoring through SGUS scoring allows objective and quantifiable measurement of treatment progress, enabling better assessment of glandular tissue status. Recurrence is possible, and each cSjD patient may present differently. Nevertheless, our year-long observation of a patient with cSjD demonstrates that sialendoscopy, as seen in adults, can promote remission of recurrent parotitis in children as well.

Recurrent cardiac tamponade in a child with newly diagnosed systemic-onset juvenile idiopathic arthritis.

A previously healthy 5-year-old boy presented with prolonged fever, evanescent rash, and arthralgias. Diagnostic tests were significant for marked systemic inflammation. He rapidly developed pleural and pericardial effusions with cardiac tamponade, requiring placement of a pericardial drain. He briefly responded to nonsteroidal anti-inflammatory drugs and pulse methylprednisolone, but tamponade recurred shortly thereafter. Subsequently, he required high-dose intravenous immunoglobulin, infliximab, and anakinra. Thus, we report a patient with severe serositis and recurrent cardiac tamponade as the initial presentation of systemic juvenile idiopathic arthritis (sJIA) and review the literature regarding pericarditis and tamponade in sJIA. This potentially fatal complication of sJIA requires timely recognition and therapy to avoid significant morbidity and mortality.

A human STAT3 gain-of-function variant confers T cell dysregulation without predominant Treg dysfunction in mice.

Primary immune regulatory disorders (PIRD) represent a group of disorders characterized by immune dysregulation, presenting with a wide range of clinical disease, including autoimmunity, autoinflammation, or lymphoproliferation. Autosomal dominant germline gain-of-function (GOF) variants in STAT3 result in a PIRD with a broad clinical spectrum. Studies in patients have documented a decreased frequency of FOXP3+ Tregs and an increased frequency of Th17 cells in some patients with active disease. However, the mechanisms of disease pathogenesis in STAT3 GOF syndrome remain largely unknown, and treatment is challenging. We developed a knock-in mouse model harboring a de novo pathogenic human STAT3 variant (p.G421R) and found these mice developed T cell dysregulation, lymphoproliferation, and CD4+ Th1 cell skewing. Surprisingly, Treg numbers, phenotype, and function remained largely intact; however, mice had a selective deficiency in the generation of iTregs. In parallel, we performed single-cell RNA-Seq on T cells from STAT3 GOF patients. We demonstrate only minor changes in the Treg transcriptional signature and an expanded, effector CD8+ T cell population. Together, these findings suggest that Tregs are not the primary driver of disease and highlight the importance of preclinical models in the study of disease mechanisms in rare PIRD.

An ELF4 hypomorphic variant results in NK cell deficiency.

NK cell deficiencies (NKD) are a type of primary immune deficiency in which the major immunologic abnormality affects NK cell number, maturity, or function. Since NK cells contribute to immune defense against virally infected cells, patients with NKD experience higher susceptibility to chronic, recurrent, and fatal viral infections. An individual with recurrent viral infections and mild hypogammaglobulinemia was identified to have an X-linked damaging variant in the transcription factor gene ELF4. The variant does not decrease expression but disrupts ELF4 protein interactions and DNA binding, reducing transcriptional activation of target genes and selectively impairing ELF4 function. Corroborating previous murine models of ELF4 deficiency (Elf4-/-) and using a knockdown human NK cell line, we determined that ELF4 is necessary for normal NK cell development, terminal maturation, and function. Through characterization of the NK cells of the proband, expression of the proband's variant in Elf4-/- mouse hematopoietic precursor cells, and a human in vitro NK cell maturation model, we established this ELF4 variant as a potentially novel cause of NKD.

The Diagnostic Performance of Early Sjögren's Syndrome Autoantibodies in Juvenile Sjögren's Syndrome: The University of Florida Pediatric Cohort Study.

Objectives: The aim of this study was to evaluate the clinical validity of early Sjögren's syndrome (SS) autoantibodies (eSjA), which were originally marketed for early diagnosis of SS, for juvenile SS (JSS) in a recently identified pediatric cohort. Methods: A total of 105 symptomatic subjects with eSjA results available were evaluated at the Center for Orphaned Autoimmune Disorders at the University of Florida and enrolled for this study. JSS diagnosis was based on the 2016 ACR/EULAR SS criteria. Demographic/clinical/laboratory parameters were compared between JSS (n = 27) and non-JSS (n = 78) for % positivity, sensitivity, and specificity of eSjA (SP1, anti-salivary protein; CA6, anti-carbonic anhydrase VI; PSP, anti-parotid secretory protein) and classic SS-autoantibodies (cSjA; ANA, SSA/SSB, RF, and others) either alone or in combination. Associations between eSjA and diagnostic/glandular parameters were also determined by Fisher's exact test. Results: Compared to non-JSS, JSS patients exhibited sicca symptoms demonstrating reduced unstimulated salivary flow rate (USFR) and abnormal glandular features revealed by salivary gland ultrasound (SGUS). Among cSjA, ANA demonstrated the highest sensitivity of 69.2%, while SSA, SSB, and RF showed around 95% specificities for JSS diagnosis. The % positive-SSA was notably higher in JSS than non-JSS (56% vs. 5%). Of eSjA, anti-CA6 IgG was the most prevalent without differentiating JSS (37%) from non-JSS (32%). Sensitivity and specificity of eSjA were 55.6 and 26.9%, respectively. Autoantibodies with potentially applicable specificity/sensitivity for JSS were seen only in cSjA without a single eSjA included. There were no associations detected between eSjA and focus score (FS), USFR, SSA, SGUS, and parotitis/glandular swelling analyzed in the entire cohort, JSS, and non-JSS. However, a negative association between anti-PSP and parotitis/glandular swelling was found in a small group of positive-SSA (n = 19, p = 0.02) whereas no such association was found between anti-PSP-positive compared to anti-PSP-negative. JSS and non-JSS groups differed in FS, USFR, and EULAR SS Patient Reported Index Dryness/Mean in CA6/PSP/ANA, SP1, and SSA-positive groups, respectively. Additionally, a higher FS was found in RF-positive than RF-negative individuals. Conclusions: eSjA underperformed cSjS in differentiating JSS from non-JSS. The discovery of clinical impact of eSjA on early diagnosis of JSS necessitates a longitudinal study.

Juvenile Sjögren's Syndrome: Clinical Characteristics With Focus on Salivary Gland Ultrasonography.

OBJECTIVE: Juvenile Sjögren's syndrome (SS) is a rare, poorly defined, and possibly underdiagnosed condition affecting children and adolescents. The aim of this study was to characterize symptoms and clinical findings of juvenile SS and to explore the clinical application of major salivary gland ultrasonography (SGUS) in patients with juvenile SS. METHODS: A cross-sectional multicenter study recruited patients with disease onset until age 18 years (n = 67). Disease characteristics were recorded, and unstimulated whole sialometry and SGUS examination of the parotid and submandibular salivary glands were performed. RESULTS: The female:male ratio was 58:9. The mean age at first symptom was 10.2 years and 12.1 years at diagnosis. Ocular and oral symptoms were noted in 42 of 67 patients (63%) and 53 of 66 patients (80%), respectively. The American-European Consensus Group or American College of Rheumatology/European League Against Rheumatism classification criteria for primary SS were fulfilled by 42 of 67 patients (63%). Pathologic SGUS findings were observed in 41 of 67 patients (61%); 26 of 41 SGUS+ patients (63%) fulfilled primary SS criteria. Salivary gland enlargements/parotitis were noted in 37 of 58 patients and were nonsignificantly associated with SGUS+ status (P = 0.066). The mean levels of saliva were 5.6 ml/15 minutes in SGUS- patients compared to 3.3 ml/15 minutes in the SGUS+ patients (P = 0.049). A total of 36 of 41 SGUS+ patients (88%) were anti-Ro/La+ compared to 14 of 26 SGUS- patients (54%) (P = 0.001). In addition, 24 of 39 SGUS+ patients (62%) were positive for rheumatoid factor (RF), whereas only 5 of 25 SGUS- patients (20%) were RF+ (P = 0.001). CONCLUSION: Juvenile SS is characterized by a large spectrum of clinical symptoms and findings. Several glandular and extraglandular parameters such as hyposalivation, swollen salivary glands, and autoantibodies are associated with pathologic SGUS findings.

Consensus treatment plans for periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome (PFAPA): a framework to evaluate treatment responses from the childhood arthritis and rheumatology research alliance (CARRA) PFAPA work group.

BACKGROUND: Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome in children. There is considerable heterogeneity in management strategies and a lack of evidence-based treatment guidelines. Consensus treatment plans (CTPs) are standardized treatment regimens that are derived based upon best available evidence and current treatment practices that are a way to enable comparative effectiveness studies to identify optimal therapy and are less costly to execute than randomized, double blind placebo controlled trials. The purpose of this project was to develop CTPs and response criteria for PFAPA. METHODS: The CARRA PFAPA Working Group is composed of pediatric rheumatologists, infectious disease specialists, allergists/immunologists and otolaryngologists. An extensive literature review was conducted followed by a survey to assess physician practice patterns. This was followed by virtual and in-person meetings between 2014 and 2018. Nominal group technique (NGT) was employed to develop CTPs, as well as inclusion criteria for entry into future treatment studies, and response criteria. Consensus required 80% agreement. RESULTS: The PFAPA working group developed CTPs resulting in 4 different treatment arms: 1. Antipyretic, 2. Abortive (corticosteroids), 3. Prophylaxis (colchicine or cimetidine) and 4. Surgical (tonsillectomy). Consensus was obtained among CARRA members for those defining patient characteristics who qualify for participation in the CTP PFAPA study. CONCLUSION: The goal is for the CTPs developed by our group to lead to future comparative effectiveness studies that will generate evidence-driven therapeutic guidelines for this periodic inflammatory disease.

Novel Ultrasound Image Acquisition Protocol and Scoring System for the Pediatric Knee.

OBJECTIVE: The use of musculoskeletal ultrasound is increasing among pediatric rheumatologists. Reliable scoring systems are needed for the objective assessment of synovitis. The aims of this study were to create a standardized and reproducible image acquisition protocol for B-mode and Doppler ultrasound of the pediatric knee, and to develop a standardized scoring system and determine its reliability for pediatric knee synovitis. METHODS: Six pediatric rheumatologists developed a set of standard views for knee assessment in children with juvenile arthritis. Subsequently, a comprehensive literature review, practical exercises, and a consensus process were performed. A scoring system for both B-mode and Doppler was then developed and assessed for reliability. Interreader reliability or agreement among a total of 16 raters was determined using 2-way single-score intraclass correlation coefficient (ICC) analysis. RESULTS: Twenty-one views to assess knee arthritis were initially identified. Following completion of practical exercises and subsequent consensus processes, 3 views in both B-mode and Doppler were selected: suprapatellar longitudinal and medial/lateral parapatellar transverse views. Several rounds of scoring and modifications resulted in a final ICC of suprapatellar view B-mode 0.89 (95% confidence interval [95% CI] 0.86-0.92) and Doppler 0.55 (95% CI 0.41-0.69), medial parapatellar view B-mode 0.76 (95% CI 0.68-0.83) and Doppler 0.75 (95% CI 0.66-0.83), and lateral parapatellar view B-mode 0.82 (95% CI 0.75-0.88) and Doppler 0.76 (95% CI 0.66-0.84). CONCLUSION: A novel B-mode and Doppler image acquisition and scoring system for assessing synovitis in the pediatric knee was successfully developed through practical exercises and a consensus process. Study results demonstrate overall good-to-excellent reliability.