A hitchhiker's guide through the COVID-19 galaxy.

Numerous reviews have summarized the epidemiology, pathophysiology and the various therapeutic aspects of Coronavirus disease 2019 (COVID-19), but a practical guide on "how to treat whom with what and when" based on an understanding of the immunological background of the disease stages remains missing. This review attempts to combine the current knowledge about the immunopathology of COVID-19 with published evidence of available and emerging treatment options. We recognize that the information about COVID-19 and its treatment is rapidly changing, but hope that this guide offers those on the frontline of this pandemic an understanding of the host response in COVID-19 patients and supports their ongoing efforts to select the best treatments tailored to their patient's clinical status.

Microbiome is not linked to clinical disease severity of familial Mediterranean fever in an international cohort of children.

OBJECTIVES: The severity of familial Mediterranean fever (FMF) may vary in different areas, suggesting a role for environmental factors. We analysed the composition of gut microbiota among children with FMF and healthy controls from Turkey and the USA and determined its effect on disease severity. METHODS: Children with FMF with pathogenic MEFV mutations and healthy controls from Turkey and the USA were enrolled. FMF disease activity was evaluated with the Autoinflammatory Disease Activity Index (AIDAI). Gut bacterial diversity was assessed by sequencing 16S rRNA gene libraries. RESULTS: We included 36 children from Turkey (28 patients with FMF, 8 healthy controls), and 21 patients and 6 controls from the USA. In the Turkish group, 28.6% of patients had severe disease, while 13.3% of US group patients had severe disease. As expected, we observed substantial differences between the gut microbiota of children from the two geographic regions, with Turkish patients and controls exhibiting higher relative abundances of Bacteriodia, while US patients and controls exhibited higher relative abundances of Clostridia. Alpha- and betadiversity did not differ significantly between FMF patients and controls, and neither was predictive of disease severity within each geographic region. We observed differences between FMF patients and controls in the relative abundance of some bacterial taxa at the amplicon sequence variant (ASV) level, but these differences received mixed statistical support. CONCLUSIONS: Among an international cohort of children with FMF, we did not find a strong effect of gut microbiota composition on disease severity. Other environmental or epigenetic factors may be operative.

Subcutaneous golimumab for children with active polyarticular-course juvenile idiopathic arthritis: results of a multicentre, double-blind, randomised-withdrawal trial.

OBJECTIVE: This report aims to determine the safety, pharmacokinetics (PK) and efficacy of subcutaneous golimumab in active polyarticular-course juvenile idiopathic arthritis (polyJIA). METHODS: In this three-part randomised double-blinded placebo-controlled withdrawal trial, all patients received open-label golimumab (30 mg/m2 of body surface area; maximum: 50 mg/dose) every 4 weeks together with weekly methotrexate during Part 1 (weeks 0-16). Patients with at least 30% improvement per American College of Rheumatology Criteria for JIA (JIA ACR30) in Part 1 entered the double-blinded Part 2 (weeks 16-48) after 1:1 randomisation to continue golimumab or start placebo. In Part 3, golimumab was continued or could be restarted as in Part 1. The primary outcome was JIA flares in Part 2; secondary outcomes included JIA ACR50/70/90 responses, clinical remission, PK and safety. RESULTS: Among 173 patients with polyJIA enrolled, 89.0% (154/173) had a JIA ACR30 response and 79.2%/65.9%/36.4% demonstrated JIA ACR50/70/90 responses in Part 1. At week 48, the primary endpoint was not met as treatment groups had comparable JIA flare rates (golimumab vs placebo: 32/78=41% vs 36/76=47%; p=0.41), and rates of clinical remission were comparable (golimumab vs placebo: 10/78=12.8% vs 9/76=11.8%). Adverse event and serious adverse event rates were similar in the treatment groups during Part 2. Injection site reactions occurred with <1% of all injections. PK analysis confirmed adequate golimumab dosing for polyJIA. CONCLUSION: Although the primary endpoint was not met, golimumab resulted in rapid, clinically meaningful, improvement in children with active polyJIA. Golimumab was well tolerated, and no unexpected safety events occurred. CLINICAL TRIAL REGISTRATION: NCT01230827; Results.

Lupus-associated causal mutation in neutrophil cytosolic factor 2 (NCF2) brings unique insights to the structure and function of NADPH oxidase.

Systemic lupus erythematosus (SLE), the prototypic systemic autoimmune disease, is a debilitating multisystem autoimmune disorder characterized by chronic inflammation and extensive immune dysregulation in multiple organ systems, resulting in significant morbidity and mortality. Here, we present a multidisciplinary approach resulting in the identification of neutrophil cytosolic factor 2 (NCF2) as an important risk factor for SLE and the detailed characterization of its causal variant. We show that NCF2 is strongly associated with increased SLE risk in two independent populations: childhood-onset SLE and adult-onset SLE. The association between NCF2 and SLE can be attributed to a single nonsynonymous coding mutation in exon 12, the effect of which is the substitution of histidine-389 with glutamine (H389Q) in the PB1 domain of the NCF2 protein, with glutamine being the risk allele. Computational modeling suggests that the NCF2 H389Q mutation reduces the binding efficiency of NCF2 with the guanine nucleotide exchange factor Vav1. The model predicts that NCF2/H389 residue interacts with Vav1 residues E509, N510, E556, and G559 in the ZF domain of Vav1. Furthermore, replacing H389 with Q results in 1.5 kcal/mol weaker binding. To examine the effect of the NCF2 H389Q mutation on NADPH oxidase function, site-specific mutations at the 389 position in NCF2 were tested. Results show that an H389Q mutation causes a twofold decrease in reactive oxygen species production induced by the activation of the Vav-dependent Fcγ receptor-elicited NADPH oxidase activity. Our study completes the chain of evidence from genetic association to specific molecular function.

Long-term safety and efficacy of rilonacept in patients with systemic juvenile idiopathic arthritis.

OBJECTIVE: To determine the long-term safety and efficacy of rilonacept, an anti-interleukin-1 fusion protein, in patients with active systemic juvenile idiopathic arthritis (JIA). METHODS: In patients with systemic JIA, ages 4-20 years, the efficacy of rilonacept was evaluated using 30%, 50%, and 70% levels of improvement according to the adapted American College of Rheumatology (ACR) Pediatric 30, 50, and 70 response criteria, respectively. Efficacy and safety were evaluated during 23 months of open-label treatment (3 phases) after a 4-week, double-blind, placebo-controlled phase. Following double-blind treatment with 2.2 mg/kg or 4.4 mg/kg of rilonacept, patients were eligible to receive open-label treatment at their prior dose, with adjustments. Reductions in the median daily dose of oral prednisone and improvements in laboratory parameters of disease activity (i.e., decreased levels of D-dimer and myeloid-related proteins [MRPs]) were also evaluated. RESULTS: Twenty-four patients entered the double-blind study and 23 entered the open-label period. Patients were predominantly white and female, and had a median age of 14.0 years at baseline. No significant differences in efficacy were observed between the rilonacept- and placebo-treated patients during the double-blind phase, but fever and rash completely resolved by month 3 in all patients during the open-label treatment period and did not recur. Adapted ACR Pediatric 30, 50, and 70 response rates at 3 months from the start of the study were 78.3%, 60.9%, and 34.8%, respectively; these responses were generally maintained over the study duration. Levels of D-dimer and MRP-8/MRP-14 dramatically improved during the study, and in 22 of 23 patients, the prednisone dose was decreased or prednisone therapy was discontinued. No serious treatment-related adverse events were observed. CONCLUSION: Sustained improvements in clinical and laboratory measures of the articular and systemic manifestations of systemic JIA were achieved in >50% of rilonacept-treated patients over 2 years. Treatment with rilonacept had a substantial steroid-sparing effect and was generally well-tolerated.

Treatment of Pediatric Takayasu arteritis with infliximab and cyclophosphamide: experience from an American-Brazilian cohort study.

BACKGROUND: Pediatric Takayasu arteritis (pTA) is difficult to treat and can lead to significant morbidity and mortality. OBJECTIVES: The objective of this study was to describe clinical characteristics for pTA and determine the safety and efficacy of cyclophosphamide (CYC) and infliximab (IFX) in pTA. METHODS: This was a retrospective analysis of 23 pTA patients seen at Children's Hospital Los Angeles and Universidade Federal de São Paulo-Brazil from 1990 to 2011. All patients fulfilled the 1990 American College of Rheumatology criteria for Takayasu arteritis. Disease activity was assessed using a modified National Institutes of Health score. RESULTS: Twenty-three patients (14 female and 9 male patients), mean age of 15.7 ± 6.0 years, were included. Cyclophosphamide was used before IFX treatment in 17 of 23 and IFX before CYC in 2 of 23 patients. The average time from disease onset to treatment initiation was 2.6 ± 2.4 years for CYC and 4.1 ± 2.4 years for IFX. Nine (60%) of 15 patients failed CYC, and of these 6 were changed to IFX with subsequent clinical stabilization in 5 (83%) of 6. Two patients initially treated with IFX were switched to CYC because of lack of appropriate response: 1 patient later worsened, and the other was lost to follow-up. Five opportunistic infections requiring hospitalization occurred in the CYC group, whereas none were observed in the IFX group. Patients in the IFX group were more likely to decrease or stop their corticosteroids when compared with the CYC patients. CONCLUSIONS: Cyclophosphamide is often used as initial treatment but has many adverse effects. In this retrospective case series, IFX was equivalent to CYC with fewer adverse effects, making IFX an alternative therapeutic option for pTA.

T lymphocyte abnormalities in juvenile systemic sclerosis patients.

Multi-center evaluations of pediatric patients with juvenile systemic sclerosis (jSSc) have suggested that the pathogenesis of jSSc may differ from that of systemic sclerosis (SSc) in adult patients. Therefore, we undertook to identify abnormalities in the T lymphocytes of jSSc patients and to determine if they differed from the abnormalities reported in the T lymphocytes of adult SSc patients. We identified decreases in the frequency of resting regulatory T lymphocytes and an increased frequency of CD45RA expressing effector memory (EMRA) CD4 T lymphocytes, which were characterized by an increased frequency of CCR7 protein expressing cells. Neither the increases in the EMRA subpopulation nor the increased CCR7 protein expression have been reported in adult SSc patients. The decrease in resting regulatory T lymphocytes in jSSc patients may permit the expansion of the disease initiating CD4 T lymphocytes present in the CCR7 expressing EMRA CD4 T lymphocyte subpopulation.

Exome sequencing reveals RAG1 mutations in a child with autoimmunity and sterile chronic multifocal osteomyelitis evolving into disseminated granulomatous disease.

We describe a boy who developed autoinflammatory (chronic sterile multifocal osteomyelitis) and autoimmune (autoimmune cytopenias; vitiligo) phenotypes who subsequently developed disseminated granulomatous disease. Whole exome sequencing revealed homozygous RAG1 mutations thus expanding the spectrum of combined immunodeficiency with autoimmunity and granuloma that can occur with RAG deficiency.

Rilonacept for colchicine-resistant or -intolerant familial Mediterranean fever: a randomized trial.

BACKGROUND: Currently, there is no proven alternative therapy for patients with familial Mediterranean fever (FMF) that is resistant to or intolerant of colchicine. Interleukin-1 is a key proinflammatory cytokine in FMF. OBJECTIVE: To assess the efficacy and safety of rilonacept, an interleukin-1 decoy receptor, in treating patients with colchicine-resistant or -intolerant FMF. DESIGN: Randomized, double-blind, single-participant alternating treatment study. (ClinicalTrials.gov number: NCT00582907). SETTING: 6 U.S. sites. PATIENTS: Patients with FMF aged 4 years or older with 1 or more attacks per month. INTERVENTION: One of 4 treatment sequences that each included two 3-month courses of rilonacept, 2.2 mg/kg (maximum, 160 mg) by weekly subcutaneous injection, and two 3-month courses of placebo. MEASUREMENTS: Differences in the frequency of FMF attacks and adverse events between rilonacept and placebo. RESULTS: 8 males and 6 females with a mean age of 24.4 years (SD, 11.8) were randomly assigned. Among 12 participants who completed 2 or more treatment courses, the rilonacept-placebo attack risk ratio was 0.59 (SD, 0.12) (equal-tail 95% credible interval, 0.39 to 0.85). The median number of attacks per month was 0.77 (0.18 and 1.20 attacks in the first and third quartiles, respectively) with rilonacept versus 2.00 (0.90 and 2.40, respectively) with placebo (median difference, -1.74 [95% CI, -3.4 to -0.1]; P = 0.027). There were more treatment courses of rilonacept without attacks (29% vs. 0%; P = 0.004) and with a decrease in attacks of greater than 50% compared with the baseline rate during screening (75% vs. 35%; P = 0.006) than with placebo. However, the duration of attacks did not differ between placebo and rilonacept (median difference, 1.2 days [-0.5 and 2.4 days in the first and third quartiles, respectively]; P = 0.32). Injection site reactions were more frequent with rilonacept (median difference, 0 events per patient treatment month [medians of -4 and 0 in the first and third quartiles, respectively]; P = 0.047), but no differences were seen in other adverse events. LIMITATION: Small sample size, heterogeneity of FMF mutations, age, and participant indication (colchicine resistance or intolerance) were study limitations. CONCLUSION: Rilonacept reduces the frequency of FMF attacks and seems to be a treatment option for patients with colchicine-resistant or -intolerant FMF. PRIMARY FUNDING SOURCE: U.S. Food and Drug Administration, Office of Orphan Products Development.

Acanthamoeba meningoencephalitis presenting as neuropsychiatric lupus in a pediatric patient.

We present the case of a 16-year-old patient with systemic lupus erythematosus who presented with altered mental status and regressive behaviour. She was worked up and empirically treated for common and opportunistic infectious agents. All work-up was negative and after an extensive course of antibiotics she was treated for neuropsychiatric lupus with cytoxan. She initially responded, but this was short-lived and she eventually became comatose and passed away. On brain biopsy she was found to have numerous trophozoites with round nucleus, prominent nucleolus and thin nuclear membrane. Methenamine silver stain showed encysted amoeba, corresponding with a diagnosis of acanthamoeba meningoencephalitis. Making the diagnosis of acanthamoeba meningoencephalitis requires a high degree of suspicion. Specific serum antibodies may not be a reliable measure in immunocompromised patients and trophozoites in CSF can be confused with monocytes. Brain biopsy may be required to make a definitive diagnosis. It is important for clinicians treating immunocompromised patients to keep this agent in mind in an immunocompromised patient with neurological manifestations. Acanthamoeba infections have only been reported in a small handful of patients and, to our knowledge, this is the first reported case in the United States.

Pediatric rheumatic disease in the intensive care unit: lessons learned from 15 years of experience in a tertiary care pediatric hospital.

OBJECTIVE: This study describes the 15-yr experience of a large urban tertiary care children's hospital in treating critically ill patients with pediatric rheumatic diseases. DESIGN: Retrospective case series. SETTING: Children's Hospital Los Angeles, a large urban tertiary care children's hospital. PATIENTS: All patients with pediatric rheumatic diseases admitted to the Children's Hospital Los Angeles pediatric intensive care unit from January 1995 to July 2009. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: An internal database and medical records were reviewed for demographics, diagnoses, treatments, organ dysfunction, interventions, infections, and outcomes. Standardized mortality ratio was calculated based on Pediatric Risk of Mortality III estimated mortality. Factors associated with mortality were identified by univariate analyses.Ninety patients with 122 total admissions were identified. The majority of patients were Hispanic (63%), female (73%), and had systemic lupus erythematosus (62%). Pediatric rheumatic disease-related complications (50%) were the most common reason for admission; 32% of admissions involved multiorgan dysfunction. Eighteen admissions (15%) resulted in mortality. Deaths were most commonly attributed to combined infection and active rheumatic disease (50%), infection only (22%), rheumatic disease only (11%), or other causes (17%). In 30 (25%) admissions, a new rheumatologic diagnosis was established. Standardized mortality ratio was 0.72 (95% confidence interval 0.38-1.25) for pediatric rheumatic disease patients compared to 0.87 (95% confidence interval 0.79-0.96) for all pediatric intensive care unit patients. Factors associated with mortality included use of mechanical ventilation, vasopressors, and renal replacement (continuous venovenous hemodialysis) (all p < .05). CONCLUSIONS: Pediatric rheumatic disease-related complications were the principal cause of pediatric intensive care unit admission. Deaths occurred most often from severe infections in patients with active rheumatic disease. Pediatric rheumatology patients admitted to the pediatric intensive care unit had outcomes similar to the global pediatric intensive care unit population when adjusted for severity of illness.

Identification of IRAK1 as a risk gene with critical role in the pathogenesis of systemic lupus erythematosus.

A combined forward and reverse genetic approach was undertaken to test the candidacy of IRAK1 (interleukin-1 receptor associated kinase-1) as an X chromosome-encoded risk factor for systemic lupus erythematosus (SLE). In studying approximately 5,000 subjects and healthy controls, 5 SNPs spanning the IRAK1 gene showed disease association (P values reaching 10(-10), odds ratio >1.5) in both adult- and childhood-onset SLE, in 4 different ethnic groups, with a 4 SNP haplotype (GGGG) being strongly associated with the disease. The functional role of IRAK1 was next examined by using congenic mouse models bearing the disease loci: Sle1 or Sle3. IRAK1 deficiency abrogated all lupus-associated phenotypes, including IgM and IgG autoantibodies, lymphocytic activation, and renal disease in both models. In addition, the absence of IRAK1 reversed the dendritic cell "hyperactivity" associated with Sle3. Collectively, the forward genetic studies in human SLE and the mechanistic studies in mouse models establish IRAK1 as a disease gene in lupus, capable of modulating at least 2 key checkpoints in disease development. This demonstration of an X chromosome gene as a disease susceptibility factor in human SLE raises the possibility that the gender difference in SLE may in part be attributed to sex chromosome genes.

Anti-CD52 antibody-mediated immune ablation with autologous immune recovery for the treatment of refractory juvenile polymyositis.

Autologous hematopoietic stem cell transplantation (HSCT) has been used for the treatment of both adult and pediatric autoimmune diseases. However, HSCT has significant side effects (neutropenia, thrombocytopenia, infertility, cardiotoxicity) and costs (HSC collection/harvesting, blood product support). In an attempt to avoid the toxicities and costs associated with HSCT, we investigated whether immune ablation similar to that achieved following myeloablative HSCT could be achieved by the intensive administration of an anti-CD52 antibody (Campath-1H antibody). The first patient treated with the treatment regime, who had refractory juvenile polymyositis, achieved immune ablation (the elimination of pre-therapy antigen-specific T lymphocyte immunity) and has had stable clinical improvement for more than 6 years.

Adalimumab with or without methotrexate in juvenile rheumatoid arthritis.

BACKGROUND: Tumor necrosis factor (TNF) has a pathogenic role in juvenile rheumatoid arthritis. We evaluated the efficacy and safety of adalimumab, a fully human monoclonal anti-TNF antibody, in children with polyarticular-course juvenile rheumatoid arthritis. METHODS: Patients 4 to 17 years of age with active juvenile rheumatoid arthritis who had previously received treatment with nonsteroidal antiinflammatory drugs underwent stratification according to methotrexate use and received 24 mg of adalimumab per square meter of body-surface area (maximum dose, 40 mg) subcutaneously every other week for 16 weeks. We randomly assigned patients with an American College of Rheumatology Pediatric 30% (ACR Pedi 30) response at week 16 to receive adalimumab or placebo in a double-blind fashion every other week for up to 32 weeks. RESULTS: Seventy-four percent of patients not receiving methotrexate (64 of 86) and 94% of those receiving methotrexate (80 of 85) had an ACR Pedi 30 response at week 16 and were eligible for double-blind treatment. Among patients not receiving methotrexate, disease flares (the primary outcome) occurred in 43% of those receiving adalimumab and 71% of those receiving placebo (P=0.03). Among patients receiving methotrexate, flares occurred in 37% of those receiving adalimumab and 65% of those receiving placebo (P=0.02). At 48 weeks, the percentages of patients treated with methotrexate who had ACR Pedi 30, 50, 70, or 90 responses were significantly greater for those receiving adalimumab than for those receiving placebo; the differences between patients not treated with methotrexate who received adalimumab and those who received placebo were not significant. Response rates were sustained after 104 weeks of treatment. Serious adverse events possibly related to adalimumab occurred in 14 patients. CONCLUSIONS: Adalimumab therapy seems to be an efficacious option for the treatment of children with juvenile rheumatoid arthritis. (ClinicalTrials.gov number, NCT00048542.)

Effects of long-term etanercept treatment on growth in children with selected categories of juvenile idiopathic arthritis.

OBJECTIVE: To evaluate the effects of long-term etanercept treatment, with or without methotrexate, on growth in children with selected categories of juvenile idiopathic arthritis (JIA). METHODS: We conducted a 3-year, open-label, nonrandomized registry of 594 patients with polyarticular or systemic JIA treated with etanercept only, etanercept plus methotrexate, or methotrexate only. Height, weight, and body mass index (BMI) were assessed at baseline and at years 1, 2, and 3, using percentiles derived from US Centers for Disease Control and Prevention standardized growth charts. RESULTS: Statistically significant increases in the mean height percentiles from baseline were observed in etanercept-treated patients at year 3 (4.8 percentile points) and in patients treated with etanercept plus methotrexate at years 1, 2, and 3 (2.4, 3.3, and 5.6 percentile points, respectively). Statistically significant increases from baseline in the mean weight percentiles were observed at years 1, 2, and 3 in both the etanercept group (7.4, 10.0, and 13.0 percentile points) and the etanercept-plus-methotrexate group (2.9, 6.9, and 8.4 percentile points, respectively). Statistically significant increases from baseline in the mean BMI percentiles were observed in both the etanercept group (range 9.6-13.8 percentile points) and the etanercept-plus-methotrexate group (range 2.1-5.2 percentile points). The mean height, weight, and BMI percentiles did not change significantly in patients in the methotrexate-only group. CONCLUSION: Etanercept treatment, with or without methotrexate, may contribute to the restoration of normal growth in children with JIA.

Prevalence and significance of serum 14-3-3η in juvenile idiopathic arthritis.

BACKGROUND: Prompt diagnosis of juvenile idiopathic arthritis (JIA) is important to avoid long term complications. Elevated serum 14-3-3η levels improve the diagnostic sensitivity of rheumatoid factor (RF) and cyclic citrullinated peptide (CCP) antibody in adult rheumatoid arthritis (RA), and have been associated with more severe phenotype. We investigated the prevalence and clinical significance of serum 14-3-3η in different types of JIA. METHODS: JIA patients (n = 151) followed by the Pediatric Rheumatology Core at Children's Hospital of Los Angeles were categorized into 5 groups: polyarticular JIA RF+ (PJIA RF+; n = 39), PJIA RF- (n = 39), psoriatic arthritis (PsA; n = 19), enthesitis-related arthritis (ERA; n = 18), and oligoarticular JIA (OJIA [control group]; n = 36). RF, CCP antibody, and 14-3-3η were measured for all patients. 14-3-3η serum levels > 0.2 ng/mL were considered positive. Disease activity was assessed by the Juvenile Arthritis Disease Activity Score-71 (JADAS-71). RESULTS: Elevated 14-3-3η levels were detected in 34/151 (23%) patients, and across all groups tested. Most patients with 14-3-3η had titers ≥4 times above the cutoff value. The majority (22, 65%) of 14-3-3η-positive patients were also positive for RF or CCP antibodies, 16 (47%) were positive for all 3, and 12 (35%) were single-positive for 14-3-3η. The highest prevalence of 14-3-3η was in PJIA RF+ patients (49%), followed by OJIA (22%). Positivity for 14-3-3η was not significantly associated with disease activity or age at diagnosis. CONCLUSION: Serum 14-3-3η can be detected in all forms of JIA tested but appears to be most common in PJIA RF+. 14-3-3η does not appear to correlate with disease activity in JIA.

Clinical Presentation, Management, and Long-Term Outcome of Pars Planitis, Panuveitis, and Vogt-Koyanagi-Harada Disease in Children and Adolescents.

OBJECTIVE: Chronic uveitis is a common manifestation of pediatric rheumatologic conditions and may result in irreversible blindness and long-term disability. While chronic anterior uveitis is the most commonly encountered ocular manifestation of rheumatic disease, little is known about the clinical presentation, management, and long-term outcome of more complex eye conditions such as pars planitis (PP), panuveitis (PU), and Vogt-Koyanagi-Harada disease (VKH). The present study was undertaken to comprehensively assess the long-term safety and efficacy of disease-modifying antirheumatic drugs (DMARDs) and biologics for the treatment of pediatric and adolescent patients with PP, PU, and VKH. METHODS: We retrospectively reviewed a cohort of 75 children and adolescents with idiopathic PP (n = 50), PU (n = 12), and VKH (n = 14) followed by the Pediatric Rheumatology Core at Children's Hospital Los Angeles and evaluated referral patterns, clinical presentation, treatment response, and long-term clinical outcome. RESULTS: Patients were followed for an average of 52 months. Their mean age at disease onset was 10 years. Bilateral eye involvement was seen in 87% of the patients. At first presentation to an ophthalmologist, glaucoma was noted in 21% of patients and vision loss (<20/40) in 87% of patients, while legal blindness (≤20/200 in the better-seeing eye) was diagnosed in 18 of 75 (24%) of patients (PP 22%, PU 36%, and VKH 21%). The average referral time to a pediatric rheumatologist was 13 months (range 1-96 months). Topical steroids were used in all patients, but 98% of patients required additional DMARDs, and 73% required therapy with biologics. After a mean of 52 months, 35% of patients across all disease groups had significant vision loss or were blind, and only 28% were in clinical remission without medications. The worst outcome was observed in children with PU. Regression analysis, young age at onset, delayed referral to a pediatric rheumatologist, and chronic disease were strong predictors for the risk of long-term blindness. CONCLUSION: PP, PU, and VKH involve a high risk of permanent vision loss and should be managed by a skilled rheumatologist as early and as aggressively as possible.

Long-term outcomes in patients with polyarticular juvenile idiopathic arthritis receiving adalimumab with or without methotrexate.

OBJECTIVES: Long-term safety and efficacy of adalimumab among patients with juvenile idiopathic arthritis (JIA) was evaluated through 6 years of treatment. METHODS: Children aged 4-17 years with polyarticular JIA were enrolled in a phase III, randomised-withdrawal, double-blind, placebo-controlled trial consisting of a 16-week open-label lead-in period, 32-week randomised double-blind period and 360-week long-term extension. Patients were stratified by baseline methotrexate use. Adverse events (AEs) were monitored, and efficacy assessments included JIA American College of Rheumatology (JIA ACR) 30%, 50%, 70% or 90% responses and the proportions of patients achieving 27-joint Juvenile Arthritis Disease Activity Score (JADAS27) low disease activity (LDA, ≤3.8) and inactive disease (ID, ≤1). RESULTS: Of 171 patients enrolled, 62 (36%) completed the long-term extension. Twelve serious infections in 11 patients were reported through 592.8 patient-years of exposure. No cases of congestive heart failure-related AEs, demyelinating disease, lupus-like syndrome, malignancies, tuberculosis or deaths were reported. JIA ACR 30/50/70/90 responses and JADAS27 LDA were achieved in 66% to 96% of patients at week 104, and 63 (37%) patients achieved clinical remission (JADAS27 ID sustained for ≥6 continuous months) during the study. Attainment of JIA ACR 50 or higher and JADAS27 LDA or ID in the initial weeks were the best predictors of clinical remission. Mean JADAS27 decreased from baseline, 22.5 (n=170), to 2.5 (n=30) at week 312 (observed analysis). CONCLUSIONS: Through 6 years of exposure, adalimumab was well tolerated with significant clinical response (up to clinical remission) and a relatively low retention rate.

Ocular complications of childhood rheumatic diseases: nonuveitic inflammatory eye diseases.

Ocular involvement is common in pediatric rheumatologic diseases, supporting the concept that these conditions do not manifest in isolation but are components of a multisystem inflammatory process. It remains unclear why the eye and its adjacent tissues become a target during paninflammatory disease. Pediatric rheumatologists must recognize ocular disorders, as these conditions significantly concern the treatment team managing serious cases of inflammatory eye disease. Close collaboration between the treating rheumatologist and ophthalmologist is required to prevent potentially devastating outcomes. Therapeutic interventions, such as topical steroids, systemic immunosuppressants, and biologics, must balance the necessity of controlling ocular inflammation and treatment-related adverse effects. This article-the second in a series on ocular complications of childhood rheumatic diseases-reviews the presentation and management of the more common nonuveitic inflammatory ocular manifestations of childhood rheumatologic disease.

Translation and validation of the Transition Readiness Assessment Questionnaire (TRAQ).

OBJECTIVE: To translate and validate the Brazilian Portuguese version of the Transition Readiness Assessment Questionnaire in a population of adolescents and young adults with chronic rheumatologic disorders. This questionnaire evaluates the patient's readiness for making the transition from the pediatric health service to adult care. METHODS: The four-phase methodology for the translation and validation of generic questionnaires was followed, including translation, back-translation, pilot testing and clinical validation of the final tool. The confirmatory factor analysis was used for clinical validation and the Cronbach's alpha coefficient was used to assess the overall internal consistency of the final tool. RESULTS: A total of 150 patients with a mean age of 17.0 years (SD=2.2 years, range 14-21 years) were enrolled for the final tool validation. Of those, 71 patients had juvenile systemic lupus erythematosus (47.3%), 64 had juvenile idiopathic arthritis (42.7%), and 15 had juvenile dermatomyositis (10%). During the confirmatory factor analysis, the dimension "Talking with providers" consisting of two questions, was considered as not fitting the translated questionnaire due to a very high ceiling effect and was therefore excluded. All other translated items favorably contributed to the overall consistency of the final tool; removing that dimension did not result in a substantial increase in Cronbach's alpha, which was 0.776. CONCLUSIONS: The Brazilian Portuguese version of the Transition Readiness Assessment Questionnaire was validated in a population of transitional patients with chronic rheumatologic disorders, after one dimension from the original questionnaire was excluded. It is a non-specific disease questionnaire; thus, it can be used to evaluate the transition readiness of Brazilian patients with other chronic diseases.