Decreased Peripheral Blood Natural Killer Cell Count in Untreated Juvenile Dermatomyositis Is Associated with Muscle Weakness.

Juvenile Dermatomyositis (JDM) is the most common inflammatory myopathy in pediatrics. This study evaluates the role of Natural Killer (NK) cells in Juvenile Dermatomyositis (JDM) pathophysiology. The study included 133 untreated JDM children with an NK cell count evaluation before treatment. NK cell subsets (CD56low/dim vs. CD 56bright) were examined in 9 untreated children. CD56 and perforin were evaluated in situ in six untreated JDM and three orthopedic, pediatric controls. 56% of treatment-naive JDM had reduced circulating NK cell counts, designated "low NK cell". This low NK group had more active muscle disease compared to the normal NK cell group. The percentage of circulating CD56low/dim NK cells was significantly lower in the NK low group than in controls (0.55% vs. 4.6% p < 0.001). Examination of the untreated JDM diagnostic muscle biopsy documented an increased infiltration of CD56 and perforin-positive cells (p = 0.023, p = 0.038, respectively). Treatment-naive JDM with reduced circulating NK cell counts exhibited more muscle weakness and higher levels of serum muscle enzymes. Muscle biopsies from treatment-naive JDM displayed increased NK cell infiltration, with increased CD56 and perforin-positive cells.

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.

Wide variation in glucocorticoid dosing in paediatric ANCA-associated vasculitis with renal disease: a paediatric vasculitis initiative study.

OBJECTIVES: High-dose glucocorticoids for remission-induction of ANCA-associated vasculitis are recommended and commonly used in adults, but recent studies suggest lower glucocorticoid doses can reduce toxicity without reducing efficacy. No paediatric-specific data exists to inform optimal glucocorticoid dosing in paediatric ANCA-associated vasculitis (pAAV). Our objectives were to describe glucocorticoid use in pAAV-related renal disease, and to explore associations between glucocorticoid dose, baseline patient characteristics and 12-month outcomes. METHODS: Youth <18 years with pAAV, biopsy-confirmed pauci-immune glomerulonephritis and 12-month follow-up data were included from an international paediatric vasculitis registry. Presenting features and 12-month outcomes (eGFR, glucocorticoid-related adverse effects), were compared between patients receiving no, low-moderate (≤90mg/kg) and high (>90mg/kg) cumulative intravenous methylprednisolone (IVMP), and low (<0.5mg/kg/day prednisone equivalent), moderate (0.5-1.5mg/kg/day) and high (>1.5mg/kg/day) starting doses of oral glucocorticoids. RESULTS: Among 131 patients (101 granulomatosis with polyangiitis, 30 microscopic polyangiitis), 27 (21%) received no IVMP, 64 (49%) low-moderate and 29 (22%) high-dose IVMP, while 9 (7%) received low, 75 (57%) moderate and 47 (36%) high initial doses of oral glucocorticoids. Renal failure at diagnosis (p=0.022) and plasmapheresis use (p=0.0001) were associated with high-dose IVMP. Rates of glucocorticoid-related adverse effects ranged from 15-31% across dose levels, and glucocorticoid dosing did not associate with 12-month outcomes. CONCLUSIONS: Glucocorticoid dosing for pAAV-related renal disease was highly variable, and rates of adverse effects were high across all dosing groups. A significant proportion of patients received oral glucocorticoid or IVMP doses that were discordant with current adult guidelines. Higher glucocorticoid doses did not associate with improved outcomes.

Multi-pronged approach to enhance education of children and adolescents with lupus, caregivers, and healthcare providers in New Jersey: Needs assessment, evaluation, and development of educational materials.

BACKGROUND: Childhood Systemic Lupus Erythematosus (cSLE) patients are younger at diagnosis and have a more severe disease course compared to adult onset SLE patients and develop significant complications related to disease and or immunosuppression. Moreover, female and minority populations experience higher rates of cSLE, with African American, Afro-Caribbean, and Hispanic populations being at greatest risk and having poor prognosis. METHODS: The Pediatric Alliance for Lupus initiative addressed the dearth in education and resources in a multi-stage process. First, we conducted a need assessment identifying knowledge gaps among healthcare providers (HCPs), and resources needed to care for cSLE patients and their families. Second, we educated HCPs about the diagnosis and treatment of cSLE by Continuing Medical Education (CME) sessions/webinars (presented here). Third, HCPs participated in a Quality Improvement (QI) program on cSLE approved by the American Board of Pediatrics Maintenance of Certification Part 4. Finally, patients and caregivers were educated through the development of appropriate, culturally and linguistically sensitive cSLE resources. PAL disseminated materials among HCPs and the community to improve the awareness of the availability of these materials. RESULTS: According to results from the statewide needs assessment (representative of every county throughout NJ), HCPs face significant challenges in providing care to cSLE patients and their families, in part due to the multi-systemic nature of the autoimmune disease. CONCLUSION: Based on this need, we developed educational sessions, with pre-post comparison data showing a significant increase in knowledge after HCP education. The 15 different materials developed as part of the endeavor is a major contribution to the cSLE community, HCPs and pediatric rheumatologists. Resources are available in multiple formats (PDF and web pages), and are accessible on the National Resource Center on Lupus, the latest web site of the Lupus Foundation of American that houses materials for SLE patients, their families, schools, HCPs, and the community at large.Improving cSLE knowledge will empower the children and adolescents and families by increasing their self-efficacy; and positively impact key health outcomes (transition readiness and HRQOL) that are not optimally addressed with current medical treatment alone.

Neuroinflammatory Disease as an Isolated Manifestation of Hemophagocytic Lymphohistiocytosis.

Isolated neuroinflammatory disease has been described in case reports of familial hemophagocytic lymphohistiocytosis (FHL), but the clinical spectrum of disease manifestations, response to therapy and prognosis remain poorly defined. We combined an international survey with a literature search to identify FHL patients with (i) initial presentation with isolated neurological symptoms; (ii) absence of cytopenia and splenomegaly at presentation; and (iii) systemic HLH features no earlier than 3 months after neurological presentation. Thirty-eight (20 unreported) patients were identified with initial diagnoses including acute demyelinating encephalopathy, leukoencephalopathy, CNS vasculitis, multiple sclerosis, and encephalitis. Median age at presentation was 6.5 years, most commonly with ataxia/gait disturbance (75%) and seizures (53%). Diffuse multifocal white matter changes (79%) and cerebellar involvement (61%) were common MRI findings. CSF cell count and protein were increased in 22/29 and 15/29 patients, respectively. Fourteen patients progressed to systemic inflammatory disease fulfilling HLH-2004 criteria at a mean of 36.9 months after initial neurological presentation. Mutations were detected in PRF1 in 23 patients (61%), RAB27A in 10 (26%), UNC13D in 3 (8%), LYST in 1 (3%), and STXBP2 in 1 (3%) with a mean interval to diagnosis of 28.3 months. Among 19 patients who underwent HSCT, 11 neurologically improved, 4 were stable, one relapsed, and 3 died. Among 14 non-transplanted patients, only 3 improved or had stable disease, one relapsed, and 10 died. Isolated CNS-HLH is a rare and often overlooked cause of inflammatory brain disease. HLH-directed therapy followed by HSCT seems to improve survival and outcome.

Hypergammaglobulinemic purpura of Waldenström in children.

BACKGROUND: Hypergammaglobulinemic purpura of Waldenström (HGPW), a rare cutaneous eruption characterized by the triad of recurrent episodes of lower extremity petechiae, symptoms of stinging and burning, and lower extremity edema, is poorly described in children. Some children have been reported to follow a benign course, while others are eventually diagnosed with fulminant rheumatologic disease. OBJECTIVES: To determine the distinguishing features of HGPW including the spectrum of disease manifestations and clinical outcomes. METHODS: This is a multicenter, retrospective case series of six children with HGPW combined with a literature review of 45 previously published pediatric cases. RESULTS: Most children were eventually diagnosed with systemic disease (63%) or developed autoantibody accumulation suggestive of evolving disease (71%). The most common diagnoses were Sjogren's syndrome and systemic lupus erythematosus. The mean duration between onset of cutaneous eruption and diagnosis of systemic disease was 5.6 years, underscoring that HPGW patients often present with a rash that precedes the development of systemic symptoms. CONCLUSIONS: Diagnosis of HGPW should prompt initial screening for rheumatologic disease with long-term rheumatology follow-up, as the majority of patients present with evolving manifestations of systemic disease.

Cutaneous manifestations of pediatric lupus.

PURPOSE OF REVIEW: To review recent evidence on cutaneous manifestations of lupus, with a focus on evidence for pediatric patients. RECENT FINDINGS: Cutaneous manifestations of SLE are common and may precede signs or symptoms of systemic disease. Early recognition and initiation of therapy improves quality of life by reducing cutaneous disease activity. Antimalarials are first line for moderate-to-severe disease. Photo protection is a critical component of therapy and perhaps the only modifiable risk factor for SLE. Recognition of cutaneous vasculopathy may reduce mortality from vascular occlusion. SUMMARY: There is a critical need for better understanding of pathogenesis, risk factors and outcomes in cutaneous lupus to determine optimal treatment and surveillance strategies. Correlation of clinical phenotypes with biomarkers may help to stratify patients, optimize targeted interventions, and influence prognosis.

Emergent high fatality lung disease in systemic juvenile arthritis.

OBJECTIVE: To investigate the characteristics and risk factors of a novel parenchymal lung disease (LD), increasingly detected in systemic juvenile idiopathic arthritis (sJIA). METHODS: In a multicentre retrospective study, 61 cases were investigated using physician-reported clinical information and centralised analyses of radiological, pathological and genetic data. RESULTS: LD was associated with distinctive features, including acute erythematous clubbing and a high frequency of anaphylactic reactions to the interleukin (IL)-6 inhibitor, tocilizumab. Serum ferritin elevation and/or significant lymphopaenia preceded LD detection. The most prevalent chest CT pattern was septal thickening, involving the periphery of multiple lobes ± ground-glass opacities. The predominant pathology (23 of 36) was pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia (PAP/ELP), with atypical features including regional involvement and concomitant vascular changes. Apparent severe delayed drug hypersensitivity occurred in some cases. The 5-year survival was 42%. Whole exome sequencing (20 of 61) did not identify a novel monogenic defect or likely causal PAP-related or macrophage activation syndrome (MAS)-related mutations. Trisomy 21 and young sJIA onset increased LD risk. Exposure to IL-1 and IL-6 inhibitors (46 of 61) was associated with multiple LD features. By several indicators, severity of sJIA was comparable in drug-exposed subjects and published sJIA cohorts. MAS at sJIA onset was increased in the drug-exposed, but was not associated with LD features. CONCLUSIONS: A rare, life-threatening lung disease in sJIA is defined by a constellation of unusual clinical characteristics. The pathology, a PAP/ELP variant, suggests macrophage dysfunction. Inhibitor exposure may promote LD, independent of sJIA severity, in a small subset of treated patients. Treatment/prevention strategies are needed.

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.

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.

Neonatal Lupus: What We Have Learned and Current Approaches to Care.

Neonatal lupus results from the passive transfer of autoantibodies; however, this transfer is not sufficient to cause disease. This article reviews clinical presentation with a focus on autoimmune-mediated congenital heart disease. Recent data looking for additional disease mechanisms and biomarkers as well as latest information on interventions will be reviewed. Our understanding of this rare disease is often dependent on patient participation in disease registries and biorepositories. Future participation in registries including descriptive as well as biophysical data is critical to our knowledge.

The natural history of pediatric-onset discoid lupus erythematosus.

BACKGROUND: Pediatric discoid lupus erythematosus (DLE) is rare. The risk of progression to systemic lupus erythematosus (SLE) is uncertain. OBJECTIVE: We sought to determine the risk of progression of pediatric DLE to SLE and to characterize its phenotype. METHODS: This was a retrospective review of 40 patients with DLE. RESULTS: Six (15%) of 40 patients presented with DLE as a manifestation of concurrent SLE. Of the remaining 34, 9 (26%) eventually met SLE criteria and 15 (44%) developed laboratory abnormalities without meeting SLE criteria. Only 10 (29%) maintained skin-limited disease. The average age at progression to SLE was 11 years, with greatest risk in the first year after DLE diagnosis. Most (89%) patients with SLE met diagnostic criteria with mucocutaneous disease (discoid lesions, malar rash, oral and nasal ulcers, photosensitivity), positive antibodies, and/or cytopenia without developing end-organ damage over 5 years of median follow-up. LIMITATIONS: The study was retrospective. CONCLUSIONS: In pediatric patients, DLE carries a significant risk of progression to SLE but may predict a milder phenotype of systemic disease. All patients require careful monitoring for SLE, particularly within the first year of diagnosis.

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.

Validation of the systemic lupus erythematosus responder index for use in juvenile-onset systemic lupus erythematosus.

OBJECTIVES: This study tested the concurrent validity of the systemic lupus erythematosus responder index (SRI) in assessing improvement in juvenile-onset systemic lupus erythematosus (jSLE). METHODS: The SRI considers changes in the SELENA-SLEDAI, BILAG and a 3-cm visual analogue scale of physician-rated disease activity (PGA) to determine patient improvement. Using prospectively collected data from 760 unique follow-up visit intervals of 274 jSLE patients, we assessed the sensitivity and specificity of the SRI using these external standards: physician-rated improvement (MD-change), patient/parent-rated major improvement of wellbeing (patient-change) and decrease in prescribed systemic corticosteroids (steroid-change). Modifications of the SRI that considered different thresholds for the SELENA-SLEDAI, BILAG and 10-cm PGA were explored and agreement with the American College of Rheumatology/PRINTO provisional criteria for improvement of jSLE (PCI) was examined. RESULTS: The sensitivity/specificity in capturing major improvement by the MD-change were 78%/76% for the SRI and 83%/78% for the PCI, respectively. There was fair agreement between the SRI and PCI (kappa=0.35, 95% CI 0.02 to 0.73) in capturing major improvement by the MD-change. Select modified versions of the SRI had improved accuracy overall. All improvement criteria tested had lower sensitivity when considering patient-change and steroid-change as external standards compared to MD-change. CONCLUSIONS: The SRI and its modified versions based on meaningful changes in jSLE have high specificity but at most modest sensitivity for capturing jSLE improvement. When used as an endpoint of clinical trials in jSLE, the SRI will provide a conservative estimate regarding the efficacy of the therapeutic agent under investigation.

Brain morphometric changes associated with childhood-onset systemic lupus erythematosus and neurocognitive deficit.

OBJECTIVE: To use structural magnetic resonance imaging (MRI) to characterize changes in gray matter and white matter volumes between patients with childhood-onset systemic lupus erythematosus (SLE) and matched controls, between patients with childhood-onset SLE with and those without neurocognitive deficit, and in relation to disease duration and treatment with steroids. METHODS: Twenty-two patients with childhood-onset SLE and 19 healthy controls underwent high-resolution structural MRI. Probability density maps for gray matter and white matter were compared between groups. RESULTS: Neuropsychological testing confirmed the presence of neurocognitive deficit in 8 patients with childhood-onset SLE. Multiple brain regions had reduced gray matter volume in the patients with childhood- onset SLE with neurocognitive deficit versus controls or patients with childhood-onset SLE without neurocognitive deficit. Neither disease duration nor cumulative oral or intravenous steroid doses accounted for decreases in gray matter. White matter volume was also reduced in patients with childhood-onset SLE with neurocognitive deficit, and the reduction was positively associated with both disease duration and cumulative oral steroid dose. Conversely, higher cumulative intravenous steroid doses were associated with higher white matter volumes. CONCLUSION: Neurocognitive deficit in patients with childhood-onset SLE is associated with multifocal decreases in both gray and white matter volumes. Since only white matter volume changes are related to disease duration and cumulative oral steroid use, this may suggest that gray and white matter alterations relate to different underlying mechanisms. Further work is needed to understand the relationship between gray and white matter alterations in childhood-onset SLE, whether the underlying mechanisms relate to immunologic, vascular, or other causes, and whether the changes are reversible or preventable. Likewise, the protective properties of intravenous steroids in maintaining white matter volumes require confirmation in larger cohorts.

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.

Implementation of the Lupus Low Disease Activity State in Pediatric Rheumatology Care: The Role of the Visual Analog Scale.

OBJECTIVE: We compared the measurement properties of a traditional physician global assessment of disease activity (PhGA) 10-cm visual analog scale (PhGA0-10) with that of the three-point numeric scale (PhGA0-3) in childhood-onset systemic lupus erythematosus (cSLE) as part of the childhood Lupus Low Disease Activity State (cLLDAS). METHODS: We used a secondary data analysis from a convenience sample of 100 patients with cSLE followed every three months for up to seven visits. Ratings of PhGA0-10, PhGA0-3, parent assessment of patient well-being (ParGA) (range: 0= very poorly, 10 = very well), disease activity as measured by the SLE disease activity index 2000 (SLEDAI-2k), Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI, and the British Isles International Lupus Activity Group index (BILAG; A = 9, B = 3, C = 1, D/E = 0) were compared. After linear transformation of PhGA0-10 to a 0 to 3 range (tPhGA0-10), the frequency of PhGA0-3 ≤1 was assessed to estimate the impact of scale type on the scoring of the cLLDAS. RESULTS: In 600 visits, the median (range) scores of PhGA0-10, PhGA0-3, SLEDAI-2k, SELENA-SLEDAI, and BILAG were 2 (0-10), 1(0-3), 4 (0-28), 4 (0-32), and 2 (0-28), respectively. PhGA0-10 and PhGA0-3 ratings were strong to moderately correlated with (r = 0.73; P < 0.0001) and with more variability for PhGA0-3 ≥2. SELENA-SLEDAI and SLEDAI-2k scores were moderately correlated with PhGA0-10 (r = 0.56/0.54; P < 0.0001). ParGA values were weakly correlated with all other measures considered (all r = -0.19 to -0.34). There were 490 of 600 visits with PhGA0-3 ≤1 and 497 of 600 visits with tPhGA0-10 ≤1 (κ (SE) =0.59 (0.04), McNemar P = 0.4). CONCLUSION: PhGA0-3 and PhGA0-10 have comparable measurement properties and yield almost identical cLLDAS rates when used in cSLE.

Childhood Arthritis and Rheumatology Research Alliance Biologic Disease-Modifying Antirheumatic Drug 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 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: tumor necrosis factor α (TNFα) 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 of 72]) as well as for patient characteristics, assessments, outcome measures, and follow-up. By weighted average, respondents indicated that they would most likely administer rituximab, followed by abatacept, TNFα inhibitor, and tocilizumab. CONCLUSION: CTPs for the administration 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.

Classification Criteria for Axial Disease in Youth with Juvenile Spondyloarthritis.

OBJECTIVES: To develop and validate classification criteria for axial disease in youth with juvenile spondyloarthritis (SpA; AxJSpA). METHODS: This international initiative consisted of four phases: 1) Item generation; 2) Item reduction; 3) Criteria development; and 4) Validation of the AxJSpA criteria by an independent team of experts in an internationally representative Validation cohort. RESULTS: These criteria are intended to be used on youth with a physician diagnosis of juvenile SpA and for whom axial disease is suspected. Item generation consisted of a systematic literature review and a free-listing exercise using input from international physicians and collectively resulted in 108 items. After the item reduction exercise and expert panel input, 37 items remained for further consideration. The final AxJSpA criteria domains included: imaging: active inflammation, imaging: structural lesions, pain chronicity, pain pattern, pain location, stiffness, and genetics. The most heavily weighted domains were active inflammation and structural lesions on imaging. Imaging typical of sacroiliitis was deemed necessary, but not sufficient, to classify a youth with AxJSpA. The threshold for classification of AxJSpA was a score of ≥55 (out of 100). When tested in the validation data set, the final criteria had a specificity of 97.5% (95% CI: 91.4-99.7), sensitivity of 64.3% (95% CI: 54.9-73.1) and Area Under the Receiver Operating Characteristic (AUROC) curve of 0.81 (95% CI: 0.76-0.86). CONCLUSIONS: The new AxJSpA classification criteria require an entry criterion, physician diagnosis of juvenile SpA, and include seven weighted domains. The AxJSpA classification criteria are validated and designed to identify participants for research studies.

Interleukin (IL)-1/IL-6-Inhibitor-Associated Drug Reaction With Eosinophilia and Systemic Symptoms (DReSS) in Systemic Inflammatory Illnesses.

BACKGROUND: After introducing IL-1/IL-6 inhibitors, some patients with Still and Still-like disease developed unusual, often fatal, pulmonary disease. This complication was associated with scoring as DReSS (drug reaction with eosinophilia and systemic symptoms) implicating these inhibitors, although DReSS can be difficult to recognize in the setting of systemic inflammatory disease. OBJECTIVE: To facilitate recognition of IL-1/IL-6 inhibitor-DReSS in systemic inflammatory illnesses (Still/Still-like) by looking at timing and reaction-associated features. We evaluated outcomes of stopping or not stopping IL-1/IL-6 inhibitors after DReSS reaction began. METHODS: In an international study collaborating primarily with pediatric specialists, we characterized features of 89 drug-reaction cases versus 773 drug-exposed controls and compared outcomes of 52 cases stopping IL-1/IL-6 inhibitors with 37 cases not stopping these drugs. RESULTS: Before the reaction began, drug-reaction cases and controls were clinically comparable, except for younger disease-onset age for reaction cases with preexisting cardiothoracic comorbidities. After the reaction began, increased rates of pulmonary complications and macrophage activation syndrome differentiated drug-reaction cases from drug-tolerant controls (P = 4.7 × 10-35 and P = 1.1 × 10-24, respectively). The initial DReSS feature was typically reported 2 to 8 weeks after initiating IL-1/IL-6 inhibition. In drug-reaction cases stopping versus not stopping IL-1/IL-6-inhibitor treatment, reaction-related features were indistinguishable, including pulmonary complication rates (75% [39 of 52] vs 76% [28 of 37]). Those stopping subsequently required fewer medications for treatment of systemic inflammation, had decreased rates of macrophage activation syndrome, and improved survival (P = .005, multivariate regression). Resolution of pulmonary complications occurred in 67% (26 of 39) of drug-reaction cases who stopped and in none who continued inhibitors. CONCLUSIONS: In systemic inflammatory illnesses, recognition of IL-1/IL-6-inhibitor-associated reactions followed by avoidance of IL-1/IL-6 inhibitors significantly improved outcomes.