Childhood Arthritis and Rheumatology Research Alliance Biologic DMARD Consensus Treatment Plans for Refractory Moderately Severe Juvenile Dermatomyositis.

OBJECTIVE: The objective was to develop consensus treatment plans (CTPs) for patients with refractory moderately severe juvenile dermatomyositis (JDM) treated with biologic disease-modifying antirheumatic drugs (bDMARDs). METHODS: The Biologics Workgroup of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) JDM Research Committee used case-based surveys, consensus framework, and nominal group technique to produce bDMARD CTPs for patients with refractory moderately severe JDM. RESULTS: Four bDMARD CTPs were proposed: TNF-alpha inhibitor (adalimumab or infliximab), abatacept, rituximab, and tocilizumab. Each CTP has different options for dosing and/or route. Among 76 respondents, consensus was achieved for the proposed CTPs (93% [67/72]) as well as for patient characteristics, assessments, outcome measures, and follow up. By weighted average, respondents indicated that they would most likely use rituximab followed by abatacept, TNF-alpha inhibitor, and tocilizumab. CONCLUSION: CTPs for the use of bDMARDs in refractory moderately severe JDM were developed using consensus methodology. The implementation of the bDMARD CTPs will lay the groundwork for registry-based prospective comparative effectiveness studies.

Child Health Needs and the Pediatric Rheumatology Workforce: 2020-2040.

The Pediatric Rheumatology (PRH) workforce supply in the United States does not meet the needs of children. Lack of timely access to PRH care is associated with poor outcomes for children with rheumatic diseases. This article is part of a Pediatrics supplement focused on anticipating the future pediatric subspecialty workforce supply. It draws on information in the literature, American Board of Pediatrics data, and findings from a model that estimates the future supply of pediatric subspecialists developed by the Sheps Center for Health Services Research at the University of North Carolina at Chapel Hill, Strategic Modeling and Analysis Ltd., and the American Board of Pediatrics Foundation. PRH has a smaller workforce per capita of children than most other pediatric subspecialties. The model demonstrates that the clinical workforce equivalent of pediatric rheumatologists in 2020 was only 0.27 per 100 000 children, with a predicted increase to 0.47 by 2040. Although the model predicts a 72% increase in providers, this number remains inadequate to provide sufficient care given the number of children with rheumatic diseases, especially in the South and West regions. The likely reasons for the workforce shortage are multifactorial, including lack of awareness of the field, low salaries compared with most other medical specialties, concerns about working solo or in small group practices, and increasing provider retirement. Novel interventions are needed to increase the workforce size. The American College of Rheumatology has recognized the dire consequences of this shortage and has developed a workforce solutions initiative to tackle these problems.

Juvenile dermatomyositis: association between nail fold capillary end row loop- area under the curve- and disease damage indicators.

BACKGROUND: Juvenile Dermatomyositis (JDM) is a rare autoimmune disease characterized by skin and muscle inflammation. The loss of nail fold capillary end row loops (ERL) is evidence of small vessel involvement in JDM. This study aimed to examine the specific association of ERL over the disease course with evidence of JDM disease damage. METHODS: We analyzed data from 68 initially treatment-naïve JDM children who had been observed for at least five years with multiple ERL density assessments. The JDM disease course were categorized into monocyclic short, monocyclic long, polycyclic, and chronic. The ERL capillary count was cumulatively evaluated using the area under the curve (AUC) method. RESULTS: The mean ERL density for the treatment-naive JDM was significantly lower than that of their healthy age-matched controls (4.8 ± 1.6 /mm vs. 7.9 ± 0.9 /mm; p < 0.0001). The ERL AUC was significantly lower in children with a chronic disease course compared to those with a monocyclic short (p = 0.001) or monocyclic long disease course (p = 0.013). JDM patients with lipodystrophy had lower ERL AUC than those without lipodystrophy (p = 0.04). There was no association between ERL AUC and calcifications or fractures. CONCLUSION: Persistently decreased ERL capillary density, reflected by low ERL AUC, is associated with a chronic disease course and lipodystrophy in JDM. Despite medical therapy, the mean ERL count remained below normal even after five years, particularly in polycyclic and chronic cases. It is not clear that restoring normal capillary density is currently feasible in children with JDM.

Nailfold capillary density in 140 untreated children with juvenile dermatomyositis: an indicator of disease activity.

BACKGROUND: We lack a reliable indicator of disease activity in Juvenile Dermatomyositis (JDM), a rare disease. The goal of this study is to identify the association of nailfold capillary End Row Loop (ERL) loss with disease damage in children with newly diagnosed, untreated JDM. FINDINGS: We enrolled 140 untreated JDM and 46 age, race and sex matched healthy controls, ages 2-17. We selected items from the Juvenile Myositis Registry for analysis. Variables include average ERL density of 8 fingers, average capillary pattern, hemorrhages, and clinical and laboratory correlates. Laboratory data includes Myositis Specific Antibodies (MSA), disease activity scores (DAS), Childhood Myositis Assessment Scale (CMAS), and standard clinical serologic data. The reduced mean ERL density is 5.1 ± 1.5/mm for untreated JDM vs 7.9 ± 0.9/mm for healthy controls, p < 0.0001, and is associated with DAS-skin, r = -0.27 p = 0.014, which did not change within the age range tested. Untreated JDM with MSA Tif-1-γ had the lowest ERL density, (p = 0.037); their ERL patterns were primarily "open" and the presence of hemorrhages in the nailfold matrix was associated with dysphagia (p = 0.004). CONCLUSIONS: Decreased JDM ERL density is associated with increased clinical symptoms; nailfold hemorrhages are associated with dysphagia. Duration of untreated disease symptoms and MSA, modify NFC shape. We speculate nailfold characteristics are useful indicators of disease activity in children with JDM before start of therapy.

Juvenile Dermatomyositis: Association between Nail Fold Capillary End Row Loops Area Under the Curve and Disease Damage Indicators.

Background: Juvenile Dermatomyositis (JDM) is a rare autoimmune disease characterized by skin and muscle inflammation. The loss of nail fold capillary end row loops (ERL) is evidence of small vessel involvement in JDM. This study aimed to examine the association of ERL over the disease course and evidence of disease damage. Methods: We analyzed data from 68 initially treatment-naïve JDM children who had been observed for at least five years with multiple ERL density assessments. The JDM disease courses were categorized into monocyclic short, monocyclic long, polycyclic, and chronic. The ERL capillary count was cumulatively evaluated using the area under the curve (AUC) method. Results: The mean ERL density for the treatment-naive JDM was significantly lower than that of their healthy controls (4.8±1.6 /mm vs. 7.9±0.9 /mm; p <0.0001). The ERL AUC was significantly lower in children with chronic disease course compared to those with monocyclic short (p =0.001) or monocyclic long disease course (p =0.013). JDM patients with lipodystrophy had lower ERL AUC than those without lipodystrophy (p =0.04). There was no association between ERL AUC and calcifications or fractures. Conclusion: Persistently decreased ERL capillary density, evident by low ERL AUC, is associated with chronic disease course and lipodystrophy in JDM. Despite medical therapy, the mean ERL count remained below normal even after five years, particularly in polycyclic and chronic cases. Therefore, the goal of restoring normal capillary density in children with JDM might be challenging and require novel therapeutic strategies targeting their underlying endothelial dysfunction.

Increased Otoferlin Expression in B Cells Is Associated with Muscle Weakness in Untreated Juvenile Dermatomyositis: A Pilot Study.

Otoferlin mRNA expression is increased in JDM patients' PBMCs and muscle compared to healthy controls. This study aims to evaluate the role of otoferlin in JDM disease pathophysiology and its association with disease activity in untreated children with JDM. A total of 26 untreated JDM (88.5% female, 92.3% white, non-Hispanic) and 15 healthy controls were included in this study. Otoferlin mRNA expression was determined by qRT-PCR before and a few months after therapy. Detailed flow cytometry of various cell surface markers and cytoplasmic otoferlin was performed to identify cells expressing otoferlin. In addition, muscle otoferlin expression was evaluated in situ in six untreated JDM patients and three healthy controls. There was a significant increase in otoferlin expression in JDM children compared to controls (Median 67.5 vs. 2.1; p = 0.001). There was a positive correlation between mRNA otoferlin expression and the following disease activity markers: disease activity scores (DAS)-total (rs = 0.62, p < 0.001); childhood myositis assessment scale (CMAS) (rs = -0.61, p = 0.002); neopterin (rs = 0.57, p = 0.004) and von Willebrand factor antigen (vWF: Ag) (rs = 0.60, p = 0.004). Most of the otoferlin-positive cells were unswitched B cells (63-99.4%), with 65-75% of them expressing plasmablast markers (CD19+, IgM+, CD38hi, CD24-). The findings of this pilot study suggest that otoferlin expression is associated with muscle weakness, making it a possible biomarker of disease activity. Additionally, B cells and plasmablasts were the primary cells expressing otoferlin.

Urinary HER2, TWEAK and VCAM-1 levels are associated with new-onset proteinuria in paediatric lupus nephritis.

OBJECTIVE: Lupus nephritis is a key driver of morbidity and mortality in SLE. Detecting active nephritis on a background of pre-existing renal damage is difficult, leading to potential undertreatment and accumulating injury. An unmet need is a biomarker that distinguishes active lupus nephritis, particularly important in paediatrics where minimising invasive procedures is desirable. METHODS: This was a multicentre, prospective study of 113 paediatric patients with biopsy-proven lupus nephritis. Clinical data and urine were obtained every 3-4 months and patients averaged 2 years on study with seven time points. Urine was analysed for human epidermal growth factor receptor 2 (HER2), tumour necrosis factor-like weak inducer of apoptosis and vascular cell adhesion molecule-1 (VCAM-1) by ELISA. We defined active disease as either a rise in serum creatinine ≥0.3 mg/dL from baseline or a rise in renal Systemic Lupus Erythematosus Disease Activity Index score from the previous visit. These markers were also studied in patients with acute kidney injury, juvenile idiopathic arthritis (JIA), amplified pain syndrome and healthy controls. RESULTS: The rate of active disease was 56% over an average of 2 years of follow-up. HER2 and VCAM-1 were significantly elevated at time points with active disease defined by increased serum creatinine compared with time points with inactive disease or patients who never flared. All three biomarkers were associated with new-onset proteinuria and VCAM-1 was elevated at time points preceding new-onset proteinuria. These biomarkers were not increased in acute kidney injury or JIA. CONCLUSION: All three biomarkers were associated with new onset proteinuria and increased VCAM-1 may predict impending proteinuria. These biomarkers provide potential non-invasive measures for monitoring that may be more sensitive to impending flare than conventional measures.

2015 American College of Rheumatology Workforce Study and Demand Projections of Pediatric Rheumatology Workforce, 2015-2030.

OBJECTIVE: To describe the character and composition of the 2015 pediatric rheumatology workforce in the US, evaluate current workforce trends, and project future supply and demand of the pediatric rheumatology workforce through 2030. METHODS: The American College of Rheumatology created the workforce study group to study the rheumatology workforce. The workforce study group used primary and secondary data to create a representative workforce model. Pediatric rheumatology supply and demand was projected through 2030 using an integrated data-driven framework to capture a more realistic clinical full-time equivalent (FTE) and produce a better picture of access to care issues in pediatric rheumatology. RESULTS: The 2015 pediatric rheumatology workforce was estimated at 287 FTEs (300 providers), while the estimated excess demand was 95 (33%). The projected demand will continue to increase to almost 100% (n = 230) by 2030 if no changes occur in succession planning, new graduate entrants into the profession, and other factors associated with the workforce. CONCLUSION: This study projects that the pediatric rheumatology workforce gap will continue to worsen significantly from the 2015 baseline, and by 2030 the demand for pediatric rheumatologists will be twice the supply. Innovative strategies are needed to increase the workforce supply and to improve access to care.

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.

Impact of Psychiatric Diagnosis and Treatment on Medication Adherence in Youth With Systemic Lupus Erythematosus.

OBJECTIVE: Youth with systemic lupus erythematosus (SLE) experience high rates of psychiatric comorbidities, which may affect medication adherence. We undertook this study to examine the association between psychiatric disorders and hydroxychloroquine adherence and to determine whether psychiatric treatment modifies this association. METHODS: We identified incident hydroxychloroquine users among youth with SLE (ages 10-24 years) using de-identified US commercial insurance claims in Optum Clinformatics Data Mart (2000-2016). Adherence was estimated using medication possession ratios (MPRs) over a 365-day time period. Multivariable linear regression models were used to estimate the effect of having any psychiatric disorder on MPRs, as well as the independent effects of depression, anxiety, adjustment, and other psychiatric disorders. We tested for interactions between psychiatric diagnoses and treatment with psychotropic medications or psychotherapy. RESULTS: Among 873 subjects, 20% had a psychiatric diagnosis, most commonly depression. Only adjustment disorders were independently associated with decreased MPRs (ß -0.12, P = 0.05). We observed significant crossover interactions, in which psychiatric disorders had opposite effects on adherence depending on the receipt of psychiatric treatment. Among youth with any psychiatric diagnosis, psychotropic medication use was associated with a 0.15 increase in the MPR compared with no psychotropic medication use (P = 0.02 for interaction). Among youth with depression or anxiety, psychotherapy was also associated with a higher MPR compared with no psychotherapy (P = 0.05 and P < 0.01 for interaction, respectively). CONCLUSION: The impact of psychiatric disorders on medication adherence differed by whether youth had received psychiatric treatment. Improving recognition and treatment of psychiatric conditions may increase medication adherence in youth with SLE.

Clinical approach to the diagnosis of autoimmune encephalitis in the pediatric patient.

OBJECTIVE: Autoimmune encephalitis (AE) is an important and treatable cause of acute encephalitis. Diagnosis of AE in a developing child is challenging because of overlap in clinical presentations with other diseases and complexity of normal behavior changes. Existing diagnostic criteria for adult AE require modification to be applied to children, who differ from adults in their clinical presentations, paraclinical findings, autoantibody profiles, treatment response, and long-term outcomes. METHODS: A subcommittee of the Autoimmune Encephalitis International Working Group collaborated through conference calls and email correspondence to consider the pediatric-specific approach to AE. The subcommittee reviewed the literature of relevant AE studies and sought additional input from other expert clinicians and researchers. RESULTS: Existing consensus criteria for adult AE were refined for use in children. Provisional pediatric AE classification criteria and an algorithm to facilitate early diagnosis are proposed. There is also discussion about how to distinguish pediatric AE from conditions within the differential diagnosis. CONCLUSIONS: Diagnosing AE is based on the combination of a clinical history consistent with pediatric AE and supportive diagnostic testing, which includes but is not dependent on antibody testing. The proposed criteria and algorithm require validation in prospective pediatric cohorts.

Rituximab-associated Hypogammaglobulinemia in pediatric patients with autoimmune diseases.

BACKGROUND: Despite the increased use of rituximab in treating pediatric patients with autoimmune diseases in the last decade, there are limited data on rituximab safety in those subjects who have a developing immune system. The objective of this study is to determine the prevalence of hypogammaglobulinemia in children with autoimmune disease receiving rituximab within the first three years of treatment in the pediatric rheumatology clinic at a tertiary care center. METHODS: We conducted a retrospective chart review of 63 pediatric subjects who received rituximab for the treatment of their autoimmune disease. Immunoglobulin gamma (IgG) levels, immunosuppressive medication and the need for immunoglobulin replacement therapy were evaluated. Hypogammaglobulinemia was defined as a serum IgG level less than two standard deviations below the mean for age-matched healthy controls. RESULTS: Twenty-eight patients (44%) were found to have hypogammaglobulinemia. Hypogammaglobulinemia occurred within the first six months of rituximab treatment in the majority of patients (22 out of 28). The occurrence of hypogammaglobulinemia varied based on the rituximab indication: 46% pediatric Systemic Lupus Erythematosus (SLE), 71% autoimmune CNS disease, 60% ANCA vasculitis, and 12% in the miscellaneous group. Autoimmune CNS disease had more severe hypogammaglobulinemia, more persistent and was associated with more frequent or severe infections. Three patients with autoimmune CNS disease and one with SLE were given IgG replacement therapy to prevent recurrent or severe infections. CONCLUSIONS: The prevalence of hypogammaglobulinemia in rituximab treated children with autoimmune disease seems to be higher than published data for adults, especially for children with autoimmune CNS disease. The onset of hypogammaglobulinemia is usually within six months of initiation of rituximab therapy. We recommend: 1) obtaining an IgG level prior to starting rituximab; 2) close monitoring for hypogammaglobulinemia after the use of rituximab in pediatric patients and 3) early institution of immunoglobulin replacement therapy if patients develop recurrent infections.

American College of Rheumatology Provisional Criteria for Clinically Relevant Improvement in Children and Adolescents With Childhood-Onset Systemic Lupus Erythematosus.

OBJECTIVE: To develop a Childhood Lupus Improvement Index (CHILI) as a tool to measure response to therapy in childhood-onset systemic lupus erythematosus (cSLE), with a focus on clinically relevant improvement (CRIc SLE ). METHODS: Pediatric nephrology and rheumatology subspecialists (n = 213) experienced in cSLE management were invited to define CRIc SLE and rate a total of 433 unique patient profiles for the presence/absence of CRIc SLE . Patient profiles included the following cSLE core response variables (CRVs): global assessment of patient well-being (patient-global), physician assessment of cSLE activity (MD-global), disease activity index score (here, we used the Systemic Lupus Erythematosus Disease Activity Index), urine protein-to-creatinine ratio, and Child Health Questionnaire physical summary score. Percentage and absolute changes in these cSLE-CRVs (baseline versus follow-up) were considered in order to develop candidate algorithms and validate their performance (sensitivity, specificity, area under the receiver operating characteristic curve [AUC]; range 0-1). RESULTS: During an international consensus conference, unanimous agreement on a definition of CRIc SLE was achieved; cSLE experts (n = 13) concurred (100%) that the preferred CHILI algorithm considers absolute changes in the cSLE-CRVs. After transformation to a range of 0-100, a CHILI score of ≥54 had outstanding accuracy for identifying CRIc SLE (AUC 0.93, sensitivity 81.1%, and specificity 84.2%). CHILI scores also reflect minor, moderate, and major improvement for values exceeding 15, 68, and 92, respectively (all AUC ≥0.92, sensitivity ≥93.1%, and specificity ≥73.4%). CONCLUSION: The CHILI is a new, seemingly highly accurate index for measuring CRI in cSLE over time. This index is useful to categorize the degree of response to therapy in children and adolescents with cSLE.

Multisite Randomized Clinical Trial Evaluating an Online Self-Management Program for Adolescents With Juvenile Idiopathic Arthritis.

OBJECTIVE: To determine the efficacy in improving pain and health-related quality of life (HRQOL) of an online self-management program for adolescents with juvenile idiopathic arthritis (JIA). METHODS: Youth ages 12-18 years with JIA were recruited from 10 rheumatology clinics across the United States and randomized to complete an online self-management program (n = 144) or an online disease education program (n = 145). Participants in the self-management group worked through multimedia-based modules comprising psychoeducation, training in cognitive-behavioral coping skills and stress management, and other self-management topics over a 12-week period. Participants in the control group viewed a series of preselected quality educational websites about JIA over the same interval. Online content for both groups was made available in English and Spanish to facilitate inclusion of Hispanic participants. Blinded assessment of main outcomes (pain intensity, pain interference, and HRQOL) and process outcomes (disease knowledge, self-efficacy, pain coping, and emotional adjustment) occurred at baseline, posttreatment, and at 6- and 12-month postrandomization follow-up visits. RESULTS: Participants on average demonstrated significant improvements over the study period in the main outcomes, with no significant group differences in the degree of improvement. Effect sizes for these improvements were small. The amount of improvement in self-efficacy, emotional avoidance coping, disease knowledge, and emotional functioning in part predicted improvement in pain and HRQOL outcomes. CONCLUSIONS: Primarily self-directed online self-management training and online disease education comparably and modestly improve pain and HRQOL in youth with JIA.

Urine biomarkers of chronic kidney damage and renal functional decline in childhood-onset systemic lupus erythematosus.

OBJECTIVES: To delineate urine biomarkers that reflect kidney structural damage and predict renal functional decline in pediatric lupus nephritis (LN). METHODS: In this prospective study, we evaluated kidney biopsies and urine samples of 89 patients with pediatric LN. Urinary levels of 10 biomarkers [adiponectin, ceruloplasmin, kidney injury molecule-1, monocyte chemotactic protein-1, neutrophil gelatinase-associated lipocalin, osteopontin, transforming growth factor-ß (TGFß), vitamin-D binding protein, liver fatty acid binding protein (LFABP), and transferrin] were measured. Regression analysis was used to identify individual and combinations of biomarkers that determine LN damage status [NIH-chronicity index (NIH-CI) score ≤ 1 vs. ≥ 2] both individually and in combination, and biomarker levels were compared for patients with vs. without renal functional decline, i.e., a 20% reduction of the glomerular filtration rate (GFR) within 12 months of a kidney biopsy. RESULTS: Adiponectin, LFABP, and osteopontin levels differed significantly with select histological damage features considered in the NIH-CI. The GFR was associated with NIH-CI scores [Pearson correlation coefficient (r) = - 0.49; p < 0.0001] but not proteinuria (r = 0.20; p > 0.05). Similar to the GFR [area under the ROC curve (AUC) = 0.72; p < 0.01], combinations of osteopontin and adiponectin levels showed moderate accuracy [AUC = 0.75; p = 0.003] in discriminating patients by LN damage status. Renal functional decline occurred more commonly with continuously higher levels of the biomarkers, especially of TGFß, transferrin, and LFABP. CONCLUSION: In combination, urinary levels of adiponectin and osteopontin predict chronic LN damage with similar accuracy as the GFR. Ongoing LN activity as reflected by high levels of LN activity biomarkers heralds renal functional decline. KEY MESSAGES: • Levels of osteopontin and adiponectin measured at the time of kidney biopsy are good predictors of histological damage with lupus nephritis. • Only about 20% of children with substantial kidney damage from lupus nephritis will have an abnormally low urine creatinine clearance. • Continuously high levels of biomarkers reflecting lupus nephritis activity are risk factors of declining renal function.

Pilot study comparing the childhood arthritis and rheumatology research alliance consensus treatment plans for induction therapy of juvenile proliferative lupus nephritis.

BACKGROUND: To reduce treatment variability and facilitate comparative effectiveness studies, the Childhood Arthritis and Rheumatology Research Alliance (CARRA) published consensus treatment plans (CTPs) including one for juvenile proliferative lupus nephritis (LN). Induction immunosuppression CTPs outline treatment with either monthly intravenous (IV) cyclophosphamide (CYC) or mycophenolate mofetil (MMF) in conjunction with one of three corticosteroid (steroid) CTPs: primarily oral, primarily IV or mixed oral/IV. The acceptability and in-practice use of these CTPs are unknown. Therefore, the primary aims of the pilot study were to demonstrate feasibility of adhering to the LN CTPs and delineate barriers to implementation in clinical care in the US. Further, we aimed to explore the safety and effectiveness of the treatments for induction therapy. METHODS: Forty-one patients were enrolled from 10 CARRA sites. Patients had new-onset biopsy proven ISN/RPS class III or IV proliferative LN, were starting induction therapy with MMF or IV CYC and high-dose steroids and were followed for up to 24 months. Routine clinical data were collected at each visit. Provider reasons for CTP selection were assessed at baseline. Adherence to the CTPs was evaluated by provider survey and medication logs. Complete and partial renal responses were reported at 6 months. RESULTS: The majority of patients were female (83%) with a mean age of 14.7 years, SD 2.8. CYC was used more commonly than MMF for patients with ISN/RPS class IV LN (vs. class III), those who had hematuria, and those with adherence concerns. Overall adherence to the immunosuppression induction CTPs was acceptable with a majority of patients receiving the target MMF (86%) or CYC (63%) dose. However, adherence to the steroid CTPs was poor (37%) with large variability in dosing. Renal response endpoints were exploratory and did not show a significant difference between CYC and MMF. CONCLUSIONS: Overall, the immunosuppression CTPs were followed as intended in the majority of patients however, adherence to the steroid CTPs was poor indicating revision is necessary. In addition, our pilot study revealed several sources of treatment selection bias that will need to be addressed in for future comparative effectiveness research.

American College of Rheumatology Provisional Criteria for Global Flares in Childhood-Onset Systemic Lupus Erythematosus.

OBJECTIVE: To validate the preliminary criteria of global flare for childhood-onset SLE (cSLE). METHODS: Pediatricians experienced in cSLE care (n = 268) rated unique patient profiles; results of standard cSLE laboratory testing and information about the cSLE flare descriptors were presented as follows: global assessment of patient well-being, physician global assessment of disease activity (MD-global), Disease Activity Index score, protein/creatinine ratio (PCR), and erythrocyte sedimentation rate (ESR). Using rater interpretation of the course of cSLE (baseline versus followup as the gold standard), performance (sensitivity, specificity, area under the receiver operating characteristic curve [AUC]) of the preliminary flare criteria was tested. An international consensus conference was held to rank the preliminary flare criteria as per the American College of Rheumatology recommendations and delineate threshold scores for minor, moderate, and major flares. RESULTS: The accuracy of the 2 highest-ranked candidate criteria that consider absolute changes (∆) of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) or British Isles Lupus Assessment Group (BILAG) (numeric scoring: A = 12, B = 8, C = 1, and D/E = 0), MD-global, PCR, and ESR were confirmed (both AUC >0.93). For the SLEDAI-based criteria (0.5 × ∆SLEDAI + 0.45 × ∆PCR + 0.5 × ∆MD-global + 0.02 × ∆ESR) flare scores ≥6.4/3.0/0.6 constituted major/moderate/minor flares, respectively. For the BILAG-based algorithm (0.4 × ∆BILAG + 0.65 × ∆PCR + 0.5 × ∆MD-global + 0.02 × ∆ESR) flare scores ≥7.4/3.7/2.2 delineated major/moderator/minor flares, respectively. These threshold values (SLEDAI, BILAG) were all >82% sensitive and specific for capturing flare severity. CONCLUSION: Provisional criteria for global flares in cSLE are available to identify patients who experienced a flare. These criteria also allow for discrimination of the severity of cSLE exacerbations.

Urine S100 proteins as potential biomarkers of lupus nephritis activity.

BACKGROUND: Improved, noninvasive biomarkers are needed to accurately detect lupus nephritis (LN) activity. The purpose of this study was to evaluate five S100 proteins (S100A4, S100A6, S100A8/9, and S100A12) in both serum and urine as potential biomarkers of global and renal system-specific disease activity in childhood-onset systemic lupus erythematosus (cSLE). METHODS: In this multicenter study, S100 proteins were measured in the serum and urine of four cSLE cohorts and healthy control subjects using commercial enzyme-linked immunosorbent assays. Patients were divided into cohorts on the basis of biospecimen availability: (1) longitudinal serum, (2) longitudinal urine, (3) cross-sectional serum, and (4) cross-sectional urine. Global and renal disease activity were defined using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and the SLEDAI-2K renal domain score. Nonparametric testing was used for statistical analysis, including the Wilcoxon signed-rank test, Kruskal-Wallis test, Mann-Whitney U test, and Spearman's rank correlation coefficient. RESULTS: All urine S100 proteins were elevated in patients with active LN compared with patients with active extrarenal disease and healthy control subjects. All urine S100 protein levels decreased with LN improvement, with S100A4 demonstrating the most significant decrease. Urine S100A4 levels were also higher with proliferative LN than with membranous LN. S100A4 staining in the kidney localized to mononuclear cells, podocytes, and distal tubular epithelial cells. Regardless of the S100 protein tested, serum levels did not change with cSLE improvement. CONCLUSIONS: Higher urine S100 levels are associated with increased LN activity in cSLE, whereas serum S100 levels do not correlate with disease activity. Urine S100A4 shows the most promise as an LN activity biomarker, given its pronounced decrease with LN improvement, isolated elevation in urine, and positive staining in resident renal cells.

Urine Biomarkers to Predict Response to Lupus Nephritis Therapy in Children and Young Adults.

OBJECTIVE: To delineate urine biomarkers that forecast response to therapy of lupus nephritis (LN). METHODS: Starting from the time of kidney biopsy, patients with childhood-onset systemic lupus erythematosus who were diagnosed with LN were studied serially. Levels of 15 biomarkers were measured in random spot urine samples, including adiponectin, α-1-acid glycoprotein (AGP), ceruloplasmin, hemopexin, hepcidin, kidney injury molecule 1, monocyte chemotactic protein-1, lipocalin-like prostaglandin D synthase (LPGDS), transforming growth factor-ß (TGF-ß), transferrin, and vitamin D binding protein (VDBP). RESULTS: Among 87 patients (mean age 15.6 yrs) with LN, there were 37 treatment responders and 50 nonresponders based on the American College of Rheumatology criteria. At the time of kidney biopsy, levels of TGF-ß (p < 0.0001) and ceruloplasmin (p = 0.006) were significantly lower among responders than nonresponders; less pronounced differences were present for AGP, hepcidin, LPGDS, transferrin, and VDBP (all p < 0.05). By Month 3, responders experienced marked decreases of adiponectin, AGP, transferrin, and VDBP (all p < 0.01) and mean levels of these biomarkers were all outstanding (area under the receiver-operating characteristic curve ≥ 0.9) for discriminating responders from nonresponders. Patient demographics and extrarenal disease did not influence differences in biomarker levels between response groups. CONCLUSION: Low urine levels of TGF-ß and ceruloplasmin at baseline and marked reduction of AGP, LPGDS, transferrin, or VDBP and combinations of other select biomarkers by Month 3 are outstanding predictors for achieving remission of LN. If confirmed, these results can be used to help personalize LN therapy.