Race, ethnicity and patient-reported outcomes in childhood-onset systemic lupus erythematosus.

OBJECTIVES: This study assesses the association of race/ethnicity with the Patient-Reported Outcomes Measurement Information System (PROMIS®) in childhood-onset systemic lupus erythematosus (cSLE) patients from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry. METHODS: cSLE patients enrolled in the CARRA Registry within two years of cSLE diagnosis who met ACR and/or SLICC classification criteria for lupus were included. Baseline demographics, laboratory, and disease features as well as patient-reported outcomes were obtained. Multivariable linear regression analysis was used to examine the association of race and ethnicity with PROMIS scores at registry enrolment. RESULTS: 425 cSLE patients met inclusion criteria: 83.8% were female, 30.6% non-Hispanic White, 29.7% Black, 22.1% Hispanic. The mean age at diagnosis was 13.9 years (SD 2.5). Household income and highest parental education varied by race/ethnic group, as did frequency of rash, leukopenia, and anti-Smith antibodies. The cohort had low-moderate baseline disease activity (SLEDAI mean: 6.0 [SD 6.7]). The overall PROMIS Global Health mean T-score was 38.6 (SD 6.5), more than one standard deviation below the general population mean of 50. There was no association between race/ethnicity and PROMIS scores in multivariable linear regression analysis. CONCLUSIONS: In this multiethnic paediatric lupus cohort, PROMIS global health was lower when compared with the general paediatric US population. Moreover, PROMIS global health, pain interference, and physical function mobility did not vary across races/ethnicities.

Heterozygous FOXN1 Variants Cause Low TRECs and Severe T Cell Lymphopenia, Revealing a Crucial Role of FOXN1 in Supporting Early Thymopoiesis.

FOXN1 is the master regulatory gene of thymic epithelium development. FOXN1 deficiency leads to thymic aplasia, alopecia, and nail dystrophy, accounting for the nude/severe combined immunodeficiency (nu/SCID) phenotype in humans and mice. We identified several newborns with low levels of T cell receptor excision circles (TRECs) and T cell lymphopenia at birth, who carried heterozygous loss-of-function FOXN1 variants. Longitudinal analysis showed persistent T cell lymphopenia during infancy, often associated with nail dystrophy. Adult individuals with heterozygous FOXN1 variants had in most cases normal CD4+ but lower than normal CD8+ cell counts. We hypothesized a FOXN1 gene dosage effect on the function of thymic epithelial cells (TECs) and thymopoiesis and postulated that these effects would be more prominent early in life. To test this hypothesis, we analyzed TEC subset frequency and phenotype, early thymic progenitor (ETP) cell count, and expression of FOXN1 target genes (Ccl25, Cxcl12, Dll4, Scf, Psmb11, Prss16, and Cd83) in Foxn1nu/+ (nu/+) mice and age-matched wild-type (+/+) littermate controls. Both the frequency and the absolute count of ETP were significantly reduced in nu/+ mice up to 3 weeks of age. Analysis of the TEC compartment showed reduced expression of FOXN1 target genes and delayed maturation of the medullary TEC compartment in nu/+ mice. These observations establish a FOXN1 gene dosage effect on thymic function and identify FOXN1 haploinsufficiency as an important genetic determinant of T cell lymphopenia at birth.

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.

Thrombotic microangiopathy following systemic AAV administration is dependent on anti-capsid antibodies.

BACKGROUNDSystemic administration of adeno-associated virus (AAV) can trigger life-threatening inflammatory responses, including thrombotic microangiopathy (TMA), acute kidney injury due to atypical hemolytic uremic syndrome-like complement activation, immune-mediated myocardial inflammation, and hepatic toxicity.METHODSWe describe the kinetics of immune activation following systemic AAV serotype 9 (AAV9) administration in 38 individuals following 2 distinct prophylactic immunomodulation regimens. Group 1 received corticosteroids and Group 2 received rituximab plus sirolimus in addition to steroids to prevent anti-AAV antibody formation.RESULTSGroup 1 participants had a rapid increase in immunoglobulin M (IgM) and IgG. Increase in D-dimer, decline in platelet count, and complement activation are indicative of TMA. All Group 1 participants demonstrated activation of both classical and alternative complement pathways, as indicated by depleted C4 and elevated soluble C5b-9, Ba, and Bb antigens. Group 2 patients did not have a significant change in IgM or IgG and had minimal complement activation.CONCLUSIONSThis study demonstrates that TMA in the setting of AAV gene therapy is antibody dependent (classical pathway) and amplified by the alternative complement pathway. Critical time points and interventions are identified to allow for management of immune-mediated events that impact the safety and efficacy of systemic gene therapy.

Pompe disease gene therapy.

Pompe disease is an autosomal recessive metabolic myopathy caused by the deficiency of the lysosomal enzyme acid alpha-glucosidase and results in cellular lysosomal and cytoplasmic glycogen accumulation. A wide spectrum of disease exists from hypotonia and severe cardiac hypertrophy in the first few months of life due to severe mutations to a milder form with the onset of symptoms in adulthood. In either condition, the involvement of several systems leads to progressive weakness and disability. In early-onset severe cases, the natural history is characteristically cardiorespiratory failure and death in the first year of life. Since the advent of enzyme replacement therapy (ERT), the clinical outcomes have improved. However, it has become apparent that a new natural history is being defined in which some patients have substantial improvement following ERT, while others develop chronic disability reminiscent of the late-onset disease. In order to improve on the current clinical outcomes in Pompe patients with diminished clinical response to ERT, we sought to address the cause and potential for the treatment of disease manifestations which are not amenable to ERT. In this review, we will focus on the preclinical studies that are relevant to the development of a gene therapy strategy for Pompe disease, and have led to the first clinical trial of recombinant adeno-associated virus-mediated gene-based therapy for Pompe disease. We will cover the preliminary laboratory studies and rationale for a clinical trial, which is based on the treatment of the high rate of respiratory failure in the early-onset patients receiving ERT.

B-Cell depletion and immunomodulation before initiation of enzyme replacement therapy blocks the immune response to acid alpha-glucosidase in infantile-onset Pompe disease.

OBJECTIVE: To evaluate whether B-cell depletion before enzyme replacement therapy (ERT) initiation can block acid alpha-glucosidase (GAA) antibody responses and improve clinical outcomes. STUDY DESIGN: Six subjects with Pompe disease (including 4 cross-reacting immunologic material-negative infants) aged 2-8 months received rituximab and sirolimus or mycophenolate before ERT. Four subjects continued to receive sirolimus, rituximab every 12 weeks, and intravenous immunoglobulin monthly for the duration of ERT. Sirolimus trough levels, IgG, CD3, CD4, CD8, CD19, CD20, N-terminal pro-brain natriuretic peptide, creatine kinase, creatine kinase-MB, C-reactive protein, platelets, alkaline phosphatase, gamma-glutamyl transferase, aspartate aminotransferase, and alanine aminotransferase were measured regularly. RESULTS: Immunomodulation achieved B-cell depletion without adverse effects. After 17-36 months of rituximab, sirolimus and ERT, all subjects lacked antibodies against GAA, 4 continued to gain motor milestones, yet 2 progressed to require invasive ventilation. The absence of infusion-associated reactions allowed the use of accelerated infusion rates. CONCLUSION: B-cell depletion and T-cell immunomodulation in infants naïve to ERT was accomplished safely and eliminated immune responses against GAA, thereby optimizing clinical outcome; however, this approach did not necessarily influence sustained independent ventilation. Importantly, study outcomes support the initiation of immunomodulation before starting ERT, because the study regimen allowed for prompt initiation of treatment.

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.

Case Report: Refractory macrophage activation syndrome requiring high-dose anakinra, emapalumab, and etoposide therapy in early-onset systemic juvenile idiopathic arthritis associated with adenoviremia.

Macrophage activation syndrome (MAS) is a life-threatening condition characterized by the excessive stimulation of macrophages and T lymphocytes, provoked by infections, malignancy, and autoimmune or autoinflammatory conditions such as systemic juvenile idiopathic arthritis (sJIA). Clinical signs of sJIA may include high-spiking, quotidian fevers, lymphadenopathy, hepatosplenomegaly, and a salmon-colored migratory, evanescent rash. By contrast, MAS is characterized by unremitting fevers and diffuse, fixed, maculopapular rashes. In addition to hepatosplenomegaly and lymphadenopathy, patients with MAS may also have clinical signs of coagulopathy, as well as cardiac, lung, renal, and central nervous system dysfunction. The empiric treatment for MAS is initially high-dose IV corticosteroids, but usually requires addition of immunomodulators such as tacrolimus or a biologic such as Anakinra to control. The addition of immunotherapies for MAS has improved patient outcomes. We present a 2-year-old male patient with a history of early-onset sJIA, who presented with MAS refractory to corticosteroids and anakinra triggered by adenoviremia that required addition of emapalumab to control. We believe this is the first reported case of a combination of immunosuppressive therapy of emapalumab, etoposide, anakinra, tacrolimus, and corticosteroids used in the successful treatment of infection-induced MAS in early-onset sJIA. Given the lack of treatment guidelines and approved therapies for MAS, alternative strategies should be considered for patients with an intractable course.

Adeno-associated virus-mediated gene therapy in a patient with Canavan disease using dual routes of administration and immune modulation.

Gene replacement therapy is a rational therapeutic strategy and clinical intervention for neurodegenerative disorders like Canavan disease, a leukodystrophy caused by biallelic mutations in the aspartoacylase (ASPA) gene. We aimed to investigate whether simultaneous intravenous (i.v.) and intracerebroventricular (i.c.v.) administration of rAAV9-CB6-ASPA provides a safe and effective therapeutic strategy in an open-label, individual-patient, expanded-access trial for Canavan disease. Immunomodulation was given prophylactically prior to adeno-associated virus (AAV) treatment to prevent an immune response to ASPA or the vector capsid. The patient served as his own control, and change from baseline was assessed by clinical pathology tests, vector genomes in the blood, antibodies against ASPA and AAV capsids, levels of cerebrospinal fluid (CSF) N-acetylaspartate (NAA), brain water content and morphology, clinical status, and motor function tests. Two years post treatment, the patient's white matter myelination had increased, motor function was improved, and he remained free of typical severe epilepsy. NAA level was reduced at 3 months and remained stable up to 4 years post treatment. Immunomodulation prior to AAV exposure enables repeat dosing and has prevented an anti-transgene immune response. Dual-route administration of gene therapy may improve treatment outcomes.

Acute-onset opioid-induced hyperalgesia in a child with juvenile idiopathic arthritis.

We describe a child with polyarticular juvenile idiopathic arthritis (JIA) presenting with severe diffuse pain refractory to nonsteroidal anti-inflammatory agents and high-dose opioids. Her JIA involved her knees and ankles and was mildly active on etanercept and nonsteroidal anti-inflammatory agents. At presentation, she complained of hip pain progressing to severe diffuse pain and allodynia involving her extremities. No abnormalities were seen in her laboratory parameters and imaging of her lower extremities. After appreciating no substantial benefit by increasing her opioids, her opioids were tapered and discontinued, and this was followed by significant alleviation in her pain, and a diagnosis of opioid-induced hyperalgesia (OIH) was made. Despite reports in adults, the phenomenon of OIH has been reported infrequently in children. To our knowledge, OIH has not been described in children with rheumatologic conditions. We recommend investigating the possibility of OIH when treating a child with JIA and severe refractory pain.

Clonality analysis after retroviral-mediated gene transfer to CD34+ cells from the cord blood of ADA-deficient SCID neonates.

A clinical trial of retroviral-mediated transfer of the adenosine deaminase (ADA) gene into umbilical cord blood CD34(+) cells was started in 1993. ADA-containing peripheral blood mononuclear cells (PBMCs) have persisted in patients from this trial, with T lymphocytes showing the highest prevalence of gene marking. To gain a greater understanding of the nature and number of the transduced cells that were engrafted, we used linear amplification-mediated PCR (LAM-PCR) to identify clonal vector proviral integrants. In one patient, a single vector integrant was predominant in T lymphocytes at a stable level over most of the eight-year time span analyzed and was also detected in some myeloid samples. T-cell clones with the predominant integrant, isolated after eight years, showed multiple patterns of T-cell receptor (TCR) gene rearrangement, indicating that a single pre-thymic stem or progenitor cell served as the source of the majority of the gene-marked cells over an extended period of time. It is important to distinguish the stable pattern of monoclonal gene marking that we observed here from the progressive increase of a T-cell clone with monoclonal gene marking that results from leukemic transformation, as observed in two subjects in a clinical trial of gene therapy for X-linked severe combined immunodeficiency (SCID).

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.

Rituximab as Adjunct Maintenance Therapy for Refractory Juvenile Myasthenia Gravis.

BACKGROUND: Juvenile myasthenia gravis is a pediatric autoimmune disorder of the neuromuscular junction associated with substantial morbidity, for which standard therapies are not always efficacious. The objective of our study was to assess the tolerability and efficacy of rituximab use in children with refractory juvenile myasthenia gravis. METHODS: We conduced a retrospective cohort study at a single tertiary care referral center to evaluate children with juvenile myasthenia gravis who were treated with rituximab. The clinical status of these participants before and after initiation of rituximab therapy was measured, focusing on numbers of hospital admissions, numbers of immunomodulatory or immunosuppressive medications needed, and Myasthenia Gravis Foundation of America severity class. RESULTS: Five children with juvenile myasthenia gravis were ascertained who received rituximab as part of their regimen, four of whom had elevated acetylcholine receptor antibodies and one of whom had elevated muscle-specific kinase antibodies. After initiation of rituximab therapy, all participants experienced reduced numbers of immunomodulatory medications during the follow-up period (mean 11.6 months). Four of the five subjects experienced fewer juvenile myasthenia gravis-related hospital admissions and reduced (improved) Myasthenia Gravis Foundation of America classes, with no subjects having moderate or severe symptoms following treatment with rituximab. No significant adverse events were recorded for any of the participants. CONCLUSION: Rituximab was well-tolerated and efficacious in this juvenile myasthenia gravis cohort. The beneficial effect of rituximab was most pronounced in the one participant with muscle-specific kinase antibodies.

End-stage renal disease secondary to anti-glomerular basement membrane disease in a child with common variable immunodeficiency.

BACKGROUND: Anti-glomerular basement membrane (GBM) disease is caused by autoantibodies against the α3-chain of type IV collagen in the GBM. Common variable immunodeficiency (CVID) is a primary immunodeficiency manifested by hypogammaglobulinemia, inability to make functional antibody, and recurrent infections. This report extends the phenotype of CVID-associated autoimmune diseases to include anti-GBM disease. CASE PRESENTATION: A 15-year-old Caucasian female with prior normal renal function presented with nephrotic proteinuria, pedal edema, oliguria, acute kidney injury, and was found to have positive serum anti-GBM antibody. She had been diagnosed with CVID at 3 years of age. Her renal biopsy showed crescentic glomerulonephritis (50%), and immunofluorescence showed linear staining for IgG along the glomerular capillary wall. There was no clinical or imaging evidence of pulmonary hemorrhage. She was treated with pulse IV steroids, cyclophosphamide, rituximab, and several sessions of plasmapheresis. Her serum anti-GBM antibody level decreased from 194 U/mL at presentation to 0 U/mL after therapy. However, she progressed to end-stage renal disease (ESRD) within weeks, despite aggressive therapy, and required chronic renal replacement therapy in the form of dialysis. Her clinical course was also complicated by hypertensive encephalopathy, CMV viremia and meningoencephalitis, status epilepticus, and she passed away a few months later from lower respiratory tract complications. CONCLUSION: Anti-GBM disease is a rare autoimmune condition that has not been reported in association with a primary immunodeficiency syndrome. ESRD secondary to anti-GBM disease in a patient with CVID is an interesting association and supports the role of immune dysregulation in systemic autoimmune disease.

BK viruria and viremia in children with systemic lupus erythematosus.

BACKGROUND: BK virus (BKV) is a ubiquitous polyoma virus that lies dormant in the genitourinary tract once acquired in early childhood. In states of cellular immunodeficiency, the virus can reactivate to cause hemorrhagic cystitis and nephritis. Children with systemic lupus erythematosus (SLE) have an increased risk of developing infectious complications secondary to their immunocompromised state from the administration of several immuno-modulatory drugs. Currently, there are no data regarding the prevalence of BK viruria or viremia in children with SLE. METHODS: We conducted a prospective cohort study involving children with SLE of 18 years and younger. We obtained urine and blood samples at baseline and every 3 months up to 1 year for BK virus detection by real-time, quantitative polymerase chain reaction analysis. A comprehensive review of demographic information, clinical characteristics and medication history was also obtained. RESULTS: Thirty-two pediatric patients (26 females and 6 males) with SLE were enrolled. Median age at the time of SLE diagnosis and enrollment into study was 13.6 years and 16.0 years old, respectively. The prevalence at enrollment was 3.1% (1/32) for BK viruria and 6.2% (2/32) for BK viremia. During the study period, 3 patients had viruria, 5 had viremia and 4 had both viruria and viremia. Of the 12 patients with BKV reactivation, only one was positive for microscopic hematuria, all others were asymptomatic. A total of nine of 97(9.2%) urine samples and 10 of 96(10.4%) blood samples were positive for BK virus. The most commonly utilized biologics in this cohort group were Rituximab (90.6%), Abatacept (12.5%), and Belimumab (9.3%). The type of medication exposure and clinical characteristics did not statistically differ between the groups that did or did not have BK viruria and/or viremia. CONCLUSIONS: Our study suggests that pediatric patients with SLE have BK viremia and/or viruria at a higher rate than the general healthy population, although the significance of the reactivation and viral level is unclear. The influence of immune-modulatory drugs on BKV reactivation is still uncertain. To understand the interplay amongst BK virus, immunosuppression and dysregulated immune system in children with SLE, ongoing research in a larger population is still warranted, which may help establish proper surveillance, diagnosis and treatment for BKV infection.

Early Outcomes in Children With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

OBJECTIVE: To characterize the early disease course in childhood-onset antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and the 12-month outcomes in children with AAV. METHODS: Eligible subjects were children entered into the Pediatric Vasculitis Initiative study who were diagnosed before their eighteenth birthday as having granulomatosis with polyangiitis (Wegener's), microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis (Churg-Strauss), or ANCA-positive pauci-immune glomerulonephritis. The primary outcome measure was achievement of disease remission (Pediatric Vasculitis Activity Score [PVAS] of 0) at 12 months with a corticosteroid dosage of <0.2 mg/kg/day. Secondary outcome measures included the rates of inactive disease (PVAS of 0, with any corticosteroid dosage) and rates of improvement at postinduction (4-6 months after diagnosis) and at 12 months, presence of damage at 12 months (measured by a modified Pediatric Vasculitis Damage Index [PVDI]; score 0 = no damage, score 1 = one damage item present), and relapse rates at 12 months. RESULTS: In total, 105 children with AAV were included in the study. The median age at diagnosis was 13.8 years (interquartile range 10.9-15.8 years). Among the study cohort, 42% of patients achieved remission at 12 months, 49% had inactive disease at postinduction (4-6 months), and 61% had inactive disease at 12 months. The majority of patients improved, even if they did not achieve inactive disease. An improvement in the PVAS score of at least 50% from time of diagnosis to postinduction was seen in 92% of patients. Minor relapses occurred in 12 (24%) of 51 patients after inactive disease had been achieved postinduction. The median PVDI damage score at 12 months was 1 (range 0-6), and 63% of patients had ≥1 PVDI damage item scored as present at 12 months. CONCLUSION: This is the largest study to date to assess disease outcomes in pediatric AAV. Although the study showed that a significant proportion of patients did not achieve remission, the majority of patients responded to treatment. Unfortunately, more than one-half of this patient cohort experienced damage to various organ systems early in their disease course.