Constitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome.

Neutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases; pathomechanisms that regulate extravasation of damaging immune cells into surrounding tissues are poorly understood. Here we identified three unrelated boys with perinatal-onset of neutrophilic cutaneous small vessel vasculitis and systemic inflammation. Two patients developed liver fibrosis in their first year of life. Next-generation sequencing identified two de novo truncating variants in the Src-family tyrosine kinase, LYN, p.Y508*, p.Q507* and a de novo missense variant, p.Y508F, that result in constitutive activation of Lyn kinase. Functional studies revealed increased expression of ICAM-1 on induced patient-derived endothelial cells (iECs) and of ß2-integrins on patient neutrophils that increase neutrophil adhesion and vascular transendothelial migration (TEM). Treatment with TNF inhibition improved systemic inflammation; and liver fibrosis resolved on treatment with the Src kinase inhibitor dasatinib. Our findings reveal a critical role for Lyn kinase in modulating inflammatory signals, regulating microvascular permeability and neutrophil recruitment, and in promoting hepatic fibrosis.

Health disparities in outcomes of pediatric systemic lupus erythematosus.

Healthcare disparities exist throughout the United States, and disparities in healthcare delivery are responsible for a substantial portion of preventable morbidity and mortality. SLE disproportionately affects racial and ethnic minoritized groups, including Blacks, Hispanics, and Asians/Pacific Islanders. Specifically, Black females have a 3 to 4-fold increased risk of developing SLE than White females. Population studies funded through the Centers for Disease Control have examined variations in disease outcomes among the different populations around the United States. For example, studies have shown that lupus nephritis, anti-phospholipid syndrome, and thrombocytopenia are more likely to affect racial and ethnic minorities than Whites. In addition, the Center for Disease Control WONDER (Wide-ranging Online Data for Epidemiologic Research) database found SLE was the seventh leading cause of death for all women aged 15-25 years and the fifth leading cause of death for African American and Hispanic females. From these studies, we know SLE primarily affects racial and ethnic minorities, but we do not know why these groups are at increased risk of developing the disease or have worse outcomes. By examining the underlying mechanisms of health disparities within our patient populations and mitigation strategies, we will further understand and provide better treatment for our patients. This review will discuss current research related to health disparities and health outcomes in childhood-onset SLE (cSLE).

International Consensus for the Dosing of Corticosteroids in Childhood-Onset Systemic Lupus Erythematosus With Proliferative Lupus Nephritis.

OBJECTIVE: To develop a standardized steroid dosing regimen (SSR) for physicians treating childhood-onset systemic lupus erythematosus (SLE) complicated by lupus nephritis (LN), using consensus formation methodology. METHODS: Parameters influencing corticosteroid (CS) dosing were identified (step 1). Data from children with proliferative LN were used to generate patient profiles (step 2). Physicians rated changes in renal and extrarenal childhood-onset SLE activity between 2 consecutive visits and proposed CS dosing (step 3). The SSR was developed using patient profile ratings (step 4), with refinements achieved in a physician focus group (step 5). A second type of patient profile describing the course of childhood-onset SLE for ≥4 months since kidney biopsy was rated to validate the SSR-recommended oral and intravenous (IV) CS dosages (step 6). Patient profile adjudication was based on majority ratings for both renal and extrarenal disease courses, and consensus level was set at 80%. RESULTS: Degree of proteinuria, estimated glomerular filtration rate, changes in renal and extrarenal disease activity, and time since kidney biopsy influenced CS dosing (steps 1 and 2). Considering these parameters in 5,056 patient profile ratings from 103 raters, and renal and extrarenal course definitions, CS dosing rules of the SSR were developed (steps 3-5). Validation of the SSR for up to 6 months post-kidney biopsy was achieved with 1,838 patient profile ratings from 60 raters who achieved consensus for oral and IV CS dosage in accordance with the SSR (step 6). CONCLUSION: The SSR represents an international consensus on CS dosing for use in patients with childhood-onset SLE and proliferative LN. The SSR is anticipated to be used for clinical care and to standardize CS dosage during clinical trials.

Differences in rituximab use between pediatric rheumatologists and nephrologists for the treatment of refractory lupus nephritis and renal flare in childhood-onset SLE.

BACKGROUND: Consensus treatment plans have been developed for induction therapy of newly diagnosed proliferative lupus nephritis (LN) in childhood-onset systemic lupus erythematosus. However, patients who do not respond to initial therapy, or who develop renal flare after remission, warrant escalation of treatment. Our objective was to assess current practices of pediatric nephrologists and rheumatologists in North America in treatment of refractory proliferative LN and flare. METHODS: Members of Childhood Arthritis and Rheumatology Research Alliance (CARRA) and the American Society for Pediatric Nephrology (ASPN) were surveyed in November 2015 to assess therapy choices (other than modifying steroid dosing) and level of agreement between rheumatologists and nephrologists for proliferative LN patients. Two cases were presented: (1) refractory disease after induction treatment with corticosteroid and cyclophosphamide (CYC) and (2) nephritis flare after initial response to treatment. Survey respondents chose treatments for three follow up scenarios for each case that varied by severity of presentation. Treatment options included CYC, mycophenolate mofetil (MMF), rituximab (RTX), and others, alone or in combination. RESULTS: Seventy-six respondents from ASPN and foty-one respondents from CARRA represented approximately 15 % of the eligible members from each organization. Treatment choices between nephrologists and rheumatologists were highly variable and received greater than 50 % agreement for an individual treatment choice in only the following 2 of 6 follow up scenarios: 59 % of nephrologists, but only 38 % of rheumatologists, chose increasing dose of MMF in the case of LN refractory to induction therapy with proteinuria, hematuria, and improved serum creatinine. In a follow up scenario showing severe renal flare after achieving remission with induction therapy, 58 % of rheumatologists chose CYC and RTX combination therapy, whereas the top choice for nephrologists (43 %) was CYC alone. Rheumatologists in comparison to nephrologists chose more therapy options that contained RTX in all follow up scenarios except one (p < 0.05). CONCLUSIONS: Therapy choices for pediatric rheumatologists and nephrologists in the treatment of refractory LN or LN flare were highly variable with rheumatologists more often choosing rituximab. Further investigation is necessary to delineate the reasons behind this finding. This study highlights the importance of collaborative efforts in developing consensus treatment plans for pediatric LN.

FROSTED BRANCH ANGIITIS IN METHIMAZOLE-INDUCED ANTINEUTROPHIL CYTOPLASMIC ANTIBODY-POSITIVE VASCULITIS.

PURPOSE: To describe an unusual case of frosted branch angiitis that developed in a patient with acute onset systemic vasculitis possibly triggered by the antithyroid medication methimazole. METHODS: We conducted a thorough review of the medical records of a 16-year-old female patient who presented with frosted branch angiitis. During the initial hospital admission, the patient underwent an extensive systemic workup to determine the etiology of her disease and ophthalmologic testing including fundus photographs and fluorescein angiography. RESULTS: Our patient presented with a unilateral acute onset loss of vision, whose fundus examination revealed the pathognomonic features of frosted branch angiitis. Extensive systemic workup revealed an antineutrophilic cytoplasmic antibody-positive vasculitis, possibly triggered by methimazole. CONCLUSION: This case is the first reported frosted branch angiitis associated with a drug-induced antineutrophilic cytoplasmic antibody-positive vasculitis triggered by methimazole.

Advances in the care of children with lupus nephritis.

The care of children with lupus nephritis (LN) has changed dramatically over the past 50 y. The majority of patients with childhood-onset systemic lupus erythematosus (cSLE) develop LN. In the 1960's, prognosis in children was worse than in adults; therapies were limited and toxic. Nearly half of cases resulted in death within 2 y. Since this time, several diagnostic recommendations and disease-specific indices have been developed to assist physicians caring for patients with LN. Pediatric researchers are validating and adapting these indices and guidelines for the treatment of LN in cSLE. Classification systems, activity, and chronicity indices for kidney biopsy have been validated in pediatric cohorts in several countries. Implementation of contemporary immunosuppressive agents has reduced treatment toxicity and improved outcomes. Biomarkers sensitive to LN in children have been identified in the kidney, urine, and blood. Multi-institutional collaborative networks have formed to address the challenges of pediatric LN research. Considerable variation in evaluation and treatment has been addressed for proliferative forms of LN by development of consensus treatment practices. Patient survival at 5 y is now 95-97% and renal survival exceeds 90%. Moreover, international consensus exists for quality indicators for cSLE that consider the unique aspects of chronic disease in childhood.

Practice patterns and approach to kidney biopsy in lupus: a collaboration of the Midwest Pediatric Nephrology Consortium and the Childhood Arthritis and Rheumatology Research Alliance.

BACKGROUND: There is no clear consensus regarding optimal indications or timing of initial or repeat kidney biopsy in the management of pediatric systemic lupus erythematosus (pSLE). METHODS: A web-based survey was designed to assess current practice patterns among pediatric nephrologists and pediatric rheumatologists and distributed to members of Midwest Pediatric Nephrology Consortium (MWPNC) and Childhood Arthritis and Rheumatology Research Alliance (CARRA). RESULTS: Respondents included 111 rheumatologists and 71 nephrologists from 65 and 34 centers, respectively. Numbers of years in sub-specialty practice were comparable. Rheumatologists and nephrologists frequently collaborate in the care of children with lupus nephritis (LN). More than 90% of respondents refer patients to each either other after diagnosing LN. Over 60% describe shared decision making regarding when to perform kidney biopsy and how to interpret biopsy findings. Many pediatric nephrologists consider biopsy to be of higher risk for complication in pSLE and alter their standard pre-or post-biopsy management. CONCLUSIONS: It is uncommon for pediatric nephrologists to manage LN without input from pediatric rheumatologists and vice versa. Consensus exists between specialties in general, and practice differences that exist occur between individual physicians rather than between specialties. A systematic approach to biopsy may result in improved health related outcomes in pSLE.

Cognitive Performance Scores for the Pediatric Automated Neuropsychological Assessment Metrics in Childhood-Onset Systemic Lupus Erythematosus.

OBJECTIVE: To develop and initially validate a global cognitive performance score (CPS) for the Pediatric Automated Neuropsychological Assessment Metrics (PedANAM) to serve as a screening tool of cognition in childhood lupus. METHODS: Patients (n = 166) completed the 9 subtests of the PedANAM battery, each of which provides 3 principal performance parameters (accuracy, mean reaction time for correct responses, and throughput). Cognitive ability was measured by formal neurocognitive testing or estimated by the Pediatric Perceived Cognitive Function Questionnaire-43 to determine the presence or absence of neurocognitive dysfunction (NCD). A subset of the data was used to develop 4 candidate PedANAM-CPS indices with supervised or unsupervised statistical approaches: PedANAM-CPSUWA , i.e., unweighted averages of the accuracy scores of all PedANAM subtests; PedANAM-CPSPCA , i.e., accuracy scores of all PedANAM subtests weighted through principal components analysis; PedANAM-CPSlogit , i.e., algorithm derived from logistic models to estimate NCD status based on the accuracy scores of all of the PedANAM subtests; and PedANAM-CPSmultiscore , i.e., algorithm derived from logistic models to estimate NCD status based on select PedANAM performance parameters. PedANAM-CPS candidates were validated using the remaining data. RESULTS: PedANAM-CPS indices were moderately correlated with each other (|r| > 0.65). All of the PedANAM-CPS indices discriminated children by NCD status across data sets (P < 0.036). The PedANAM-CPSmultiscore had the highest area under the receiver operating characteristic curve (AUC) across all data sets for identifying NCD status (AUC >0.74), followed by the PedANAM-CPSlogit , the PedANAM-CPSPCA , and the PedANAM-CPSUWA , respectively. CONCLUSION: Based on preliminary validation and considering ease of use, the PedANAM-CPSmultiscore and the PedANAM-CPSPCA appear to be best suited as global measures of PedANAM performance.

Randomized, double-blind, placebo-controlled trial of the efficacy and safety of rilonacept in the treatment of systemic juvenile idiopathic arthritis.

OBJECTIVE: To assess the efficacy and safety of rilonacept, an interleukin-1 inhibitor, in a randomized, double-blind, placebo-controlled trial. METHODS: An initial 4-week double-blind placebo phase was incorporated into a 24-week randomized multicenter design, followed by an open-label phase. Seventy-one children who had active arthritis in ≥2 joints were randomized (1:1) to the 2 arms of the study. Patients in the rilonacept arm received rilonacept (loading dose 4.4 mg/kg followed by 2.2 mg/kg weekly, subcutaneously) beginning on day 0. Patients in the placebo arm received placebo for 4 weeks followed by a loading dose of rilonacept at week 4 followed by weekly maintenance doses. The primary end point was time to response, using the adapted American College of Rheumatology Pediatric 30 criteria coupled with the absence of fever and taper of the dosage of systemic corticosteroids, using prespecified criteria. RESULTS: The time to response was shorter in the rilonacept arm than in the placebo arm (χ(2) = 7.235, P = 0.007). The secondary analysis, which used the same response criteria, showed that 20 (57%) of 35 patients in the rilonacept arm had a response at week 4 compared with 9 (27%) of 33 patients in the placebo arm (P = 0.016). Exacerbation of systemic juvenile idiopathic arthritis (JIA) was the most common severe adverse event. More patients in the rilonacept arm had elevated liver transaminase levels (including levels more than 3 times the upper limit of normal) compared with those in the placebo arm. Adverse events were similar in the 2 arms of the study. CONCLUSION: Rilonacept was generally well tolerated and demonstrated efficacy in active systemic JIA.

Juvenile idiopathic arthritis: management and therapeutic options.

THE GOALS OF TREATMENT FOR JUVENILE IDIOPATHIC ARTHRITIS (JIA) INCLUDE: suppression of inflammation, achievement of remission, relief of pain, maintenance of function and doing so with minimal toxicity. Important discoveries over the past 10-15 years have led to more targeted treatments for children with JIA. The International League of Associations for Rheumatology (ILAR) classification system for childhood arthritides, better assessment tools for clinical response, improved definitions of remission, new imaging techniques and evidence in gene expression profiling have all contributed to the development of more targeted treatments. Nonsteroidal anti-inflammatory agents still have a role in mild disease and intra-articular steroid injections continue to be used most commonly in patients with oligoarticular JIA. Disease-modifying agents such as methotrexate have demonstrated efficacy and safety; however, in many patients, the disease remains active despite this treatment. These children now receive more targeted treatment including the tumor necrosis factor alpha (TNFα) inhibitors, interleukin-1 blockade, interleukin-6 blockade, selective costimulation modulators and selective B-cell blockade. The biologic targeted therapies have changed the strategy in which we treat our children with JIA; however, there remains much to be learned about the long-term effects and safety of these medicines.

Initial validation of the Pediatric Automated Neuropsychological Assessment Metrics for childhood-onset systemic lupus erythematosus.

OBJECTIVE: To evaluate the concurrent validity and diagnostic accuracy of the pediatric Automated Neuropsychological Assessment Metrics (Ped-ANAM) when used in childhood-onset systemic lupus erythematosus (SLE). METHODS: Formal neuropsychological testing and the Ped-ANAM were performed on 27 children with SLE who had not been previously diagnosed with neuropsychiatric SLE. Performance when completing the 10 Ped-ANAM tests was based on accuracy (AC), mean time to correct response, coefficient of variation of the time required for a correct response (CVc), and throughput. Formal neuropsychological testing was used as a criterion standard for diagnosing neurocognitive dysfunction (NCD; yes/no). RESULTS: NCD was common and present in 16 (59%) of 27 participants. Ped-ANAM performance parameters were often moderately correlated with the Z scores on formal neuropsychological testing. The NCD group differed significantly (P < 0.05) from the normal cognition group in 3 Ped-ANAM tests: CVc with mathematical processing (MTH-CVc), AC with continuous performance test (CPT-AC), and CVc with spatial processing (SPD-CVc). Areas under the receiver operating curves (AUCs) ranged between 0.75 and 0.84 when each of these parameters (CPT-AC, MTH-CVc, SPD-CVc) was used to identify NCD independently. The AUC was improved to 0.96 for the combined assessment. CONCLUSION: The Ped-ANAM has concurrent validity when used in children with SLE. Initial validation suggests that the Ped-ANAM could be a useful screening tool for NCD in children with SLE.

Pediatric clinical research.

PURPOSE OF REVIEW: This review will focus on childhood-onset systemic lupus erythematosus, juvenile idiopathic arthritis, and juvenile dermatomyositis, with special interest on strategies to improve the health-related quality of life in these conditions. RECENT FINDINGS: The contribution of plasma insulin levels, lipoproteins, markers of oxidized state (including nitric oxide metabolites, isoprostanes) and autoantibodies to oxidized low-density lipoprotein to risk for atherosclerosis has been studied in childhood-onset systemic lupus erythematosus. Elevated serum levels of myeloid-related protein-8 (also called S100A8) and myeloid-related protein-14 (S100A9) in children with juvenile idiopathic arthritis can indicate clinically occult disease activity. Serum levels of S100A12 correlate with disease activity in juvenile idiopathic arthritis. Magnetic resonance imaging T2 relaxation times in weight-bearing cartilage in patients with juvenile idiopathic arthritis may help with early detection of cartilage changes. Quantitative computed tomography commonly shows decreased muscle mass and abnormal bone geometry in juvenile idiopathic arthritis patients. In patients with juvenile idiopathic arthritis who do not respond to oral methotrexate, subcutaneous methotrexate dosing was frequently successful. Duration of inactive disease while a patient is receiving methotrexate does not decrease the frequency of flaring of disease once methotrexate is discontinued. Residual synovial inflammation seems to be a stronger influence on the rate of relapse. In juvenile dermatomyositis, the quantitative magnetic resonance imaging T2 relaxation time and overexpression of Class I major histocompatibility complex in early juvenile dermatomyositis are reported. Intravenous cyclophosphamide in refractory juvenile dermatomyositis and tacrolimus ointment for the dermatologic manifestations of juvenile dermatomyositis seem promising. SUMMARY: Progress has been made in the diagnosis and treatment of childhood-onset systemic lupus erythematosus, juvenile idiopathic arthritis, and juvenile dermatomyositis.