Improvement of Refractory Systemic Juvenile Idiopathic Arthritis-Associated Lung Disease with Single-Agent Blockade of IL-1ß and IL-18.

Systemic juvenile idiopathic arthritis associated with interstitial lung disease (SJIA-LD) represents a highly morbid subset of SJIA for which effective therapies are lacking. We report the case of a patient with refractory SJIA-LD who underwent treatment with MAS-825, an investigational bispecific monoclonal antibody targeting IL-1ß and IL-18. MAS-825 treatment was associated with a marked reduction in total IL-18 and free IL-18 in both serum and bronchoalveolar lavage fluid (BAL). Baseline oxygen saturation, exercise tolerance, and quality of life metrics improved after treatment with MAS-825, while pulmonary function testing remained stable. Following treatment, the BAL showed no evidence of pulmonary alveolar proteinosis and inflammatory infiltrates were markedly reduced, reflected by decreased numbers of CD4 T-cells, CD8 T-cells, and macrophages. The patient was able to wean entirely off systemic corticosteroids and other biologics after 10 months of treatment with MAS-825 and experienced no side effects of the drug. This case demonstrates improvement in pulmonary symptoms, lung inflammation, and burden of immunomodulatory therapy after treatment with MAS-825 and suggests that simultaneous targeting of both IL-1ß and IL-18 may be a safe and effective treatment strategy in SJIA-LD.

TNF inhibition in vasculitis management in adenosine deaminase 2 deficiency (DADA2).

BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is a recessively inherited autoinflammatory disorder caused by a loss of functional ADA2 protein. TNF inhibition (TNFi) has proven to be highly effective in treating inflammatory manifestations. OBJECTIVE: We sought to explore the pathophysiology and the underlying mechanisms of TNF-inhibitor response in these patients. METHODS: We performed Sanger sequencing of the ADA2 gene. We used flow cytometry, intracellular cytokine staining, transcriptome analysis, immunohistochemistry, and cell differentiation experiments to define an inflammatory signature in patients with DADA2 and studied their response to TNF-inhibitor treatment. RESULTS: We demonstrated increased inflammatory signals and overproduction of cytokines mediated by IFN and nuclear factor kappa B pathways in patients' primary cells. Treatment with TNFi led to reduction in inflammation, rescued the skewed differentiation toward the proinflammatory M1 macrophage subset, and restored integrity of endothelial cells in blood vessels. We also report 8 novel disease-associated variants in 7 patients with DADA2. CONCLUSIONS: Our data explore the cellular mechanism underlying effective treatment with TNFi therapies in DADA2. DADA2 vasculitis is strongly related to the presence of activated myeloid cells, and the endothelial cell damage is rescued with anti-TNF treatment.

Variation in Preventive Care in Children Receiving Chronic Glucocorticoid Therapy.

OBJECTIVE: To assess preventive care measure prescribing in children exposed to glucocorticoids and identify prescribing variation according to subspecialty and patient characteristics. STUDY DESIGN: Retrospective cohort study of children initiating chronic glucocorticoids in the gastroenterology, nephrology, and rheumatology divisions at a pediatric tertiary care center. Outcomes included 25-hydroxyvitamin D (25OHD) and lipid testing, pneumococcal polysaccharide (PPV) and influenza vaccination, and stress dose hydrocortisone prescriptions. RESULTS: A total of 701 children were followed for a median of 589 days. 25OHD testing was performed in 73%, lipid screening in 29%, and PPV and influenza vaccination in 16% and 78%, respectively. Hydrocortisone was prescribed in 2%. Across specialties, 25OHD, lipid screening, and PPV prescribing varied significantly (all P < .001). Using logistic regression adjusting for specialty, 25OHD testing was associated with older age, female sex, non-Hispanic ethnicity, and lower baseline height and body mass index z-scores (all P < .03). Lipid screening was associated with older age, higher baseline body mass index z-score, and lower baseline height z-score (all P < .01). Vaccinations were associated with lower age (P < .02), and PPV completion was associated with non-White race (P = .04). CONCLUSIONS: Among children chronically exposed to glucocorticoids, 25OHD testing and influenza vaccination were common, but lipid screening, pneumococcal vaccination, and stress dose hydrocortisone prescribing were infrequent. Except for influenza vaccination, preventive care measure use varied significantly across specialties. Quality improvement efforts are needed to optimize preventive care in this high-risk population.

Association of a rare NOTCH4 coding variant with systemic sclerosis: a family-based whole exome sequencing study.

BACKGROUND: Systemic sclerosis (SSc) is a rheumatologic disease with a multifactorial etiology. Genome-wide association studies imply a polygenic, complex mode of inheritance with contributions from variation at the human leukocyte antigen locus and non-coding variation at a locus on chromosome 6p21, among other modestly impactful loci. Here we describe an 8-year-old female proband presenting with diffuse cutaneous SSc/scleroderma and a family history of SSc in a grandfather and maternal aunt. METHODS: We employed whole exome sequencing (WES) of three members of this family. We examined rare missense, nonsense, splice-altering, and coding indels matching an autosomal dominant inheritance model. We selected one missense variant for Sanger sequencing confirmation based on its predicted impact on gene function and location in a known SSc genetic locus. RESULTS: Bioinformatic analysis found eight candidate variants meeting our criteria. We identified a very rare missense variant in the regulatory NODP domain of NOTCH4 located at the 6p21 locus, c.4245G > A:p.Met1415Ile, segregating with the phenotype. This allele has a frequency of 1.83 × 10-5 by the data of the Exome Aggregation Consortium. CONCLUSION: This family suggests a novel mechanism of SSc pathogenesis in which a rare and penetrant coding variation can substantially elevate disease risk in contrast to the more modest non-coding variation typically found at this locus. These results suggest that modulation of the NOTCH4 gene might be responsible for the association signal at chromosome 6p21 in SSc.

Improving Outcomes of Pediatric Lupus Care Delivery With Provider Goal-Setting Activities and Multidisciplinary Care Models.

OBJECTIVE: The present study was undertaken to evaluate high-quality care delivery in the context of provider goal-setting activities and a multidisciplinary care model using an electronic health record (EHR)-enabled pediatric lupus registry. We then determined associations between care quality and prednisone use among youth with systemic lupus erythematosus (SLE). METHODS: We implemented standardized EHR documentation tools to autopopulate a SLE registry. We compared pediatric Lupus Care Index (pLCI) performance (range 0.0-1.0; 1.0 representing perfect metric adherence) and timely follow-up 1) before versus during provider goal-setting activities and population management, and 2) in a multidisciplinary lupus nephritis versus rheumatology clinic. We estimated associations between pLCI and subsequent prednisone use adjusted for time, current medication, disease activity, clinical features, and social determinants of health. RESULTS: We analyzed 830 visits by 110 patients (median 7 visits per patient [interquartile range 4-10]) over 3.5 years. The provider-directed activity was associated with improved pLCI performance (adjusted ß 0.05 [95% confidence interval (95% CI) 0.01, 0.09]; mean 0.74 versus 0.69). Patients with nephritis in multidisciplinary clinic had higher pLCI scores (adjusted ß 0.06 [95% CI 0.02, 0.10]) and likelihood of timely follow-up than those in rheumatology (adjusted relative risk [RR] 1.27 [95% CI 1.02, 1.57]). A pLCI score of ≥0.50 was associated with 0.72-fold lower adjusted risk of subsequent prednisone use (95% CI 0.53, 0.93). Minoritized race, public insurance, and living in areas with greater social vulnerability were not associated with reduced care quality or follow-up, but public insurance was associated with higher risk of prednisone use. CONCLUSION: Greater attention to quality metrics is associated with better outcomes in childhood SLE. Multidisciplinary care models with population management may additionally facilitate equitable care delivery.

Pediatric Rheumatology Care and Outcomes Improvement Network's Quality Measure Set to Improve Care of Children With Juvenile Idiopathic Arthritis.

OBJECTIVE: To describe the selection, development, and implementation of quality measures (QMs) for juvenile idiopathic arthritis (JIA) by the Pediatric Rheumatology Care and Outcomes Improvement Network (PR-COIN), a multihospital learning health network using quality improvement methods and leveraging QMs to drive improved outcomes across a JIA population since 2011. METHODS: An American College of Rheumatology-endorsed multistakeholder process previously selected initial process QMs. Clinicians in PR-COIN and parents of children with JIA collaboratively selected outcome QMs. A committee of rheumatologists and data analysts developed operational definitions. QMs were programmed and validated using patient data. Measures are populated by registry data, and performance is displayed on automated statistical process control charts. PR-COIN centers use rapid-cycle quality improvement approaches to improve performance metrics. The QMs are revised for usefulness, to reflect best practices, and to support network initiatives. RESULTS: The initial QM set included 13 process measures concerning standardized measurement of disease activity, collection of patient-reported outcome assessments, and clinical performance measures. Initial outcome measures were clinical inactive disease, low pain score, and optimal physical functioning. The revised QM set has 20 measures and includes additional measures of disease activity, data quality, and a balancing measure. CONCLUSION: PR-COIN has developed and tested JIA QMs to assess clinical performance and patient outcomes. The implementation of robust QMs is important to improve quality of care. PR-COIN's set of JIA QMs is the first comprehensive set of QMs used at the point-of-care for a large cohort of JIA patients in a variety of pediatric rheumatology practice settings.

Inflammatory diseases and bone health in children.

PURPOSE OF REVIEW: Chronic pediatric inflammatory diseases are associated with low bone mass and fractures during childhood, and may hasten the onset of osteoporosis later in life. Proinflammatory cytokines and glucocorticoid therapy are likely key factors that impair bone accrual, along with downstream effects including malnutrition, pubertal delay, low muscle mass and physical inactivity. RECENT FINDINGS: Studies have used advanced imaging to characterize deficits in trabecular and cortical bone and have evaluated the 'functional muscle-bone unit'. In general, bone strength in the appendicular skeleton is compromised because of thinner cortical bone, with a low periosteal circumference and a normal or expanded endosteal circumference. Low muscle mass likely contributes to, but does not fully account for bone deficits. Systematic efforts to define the incidence and prevalence of bone fragility in children with inflammatory conditions demonstrated that vertebral fractures occur in a significant minority of patients in association with high disease activity, glucocorticoid use, and weight gain. Lumbar spine dual X-ray absorptiometry does not consistently distinguish children with and without vertebral fractures. SUMMARY: In children with inflammatory diseases, the documented elevated fracture risk and bone structural abnormalities highlight the need for additional research to better define methods for the assessment and prevention of bone fragility.

Consensus Approach to a Treat-to-target Strategy in Juvenile Idiopathic Arthritis Care: Report From the 2020 PR-COIN Consensus Conference.

OBJECTIVE: Treat to target (T2T) is a strategy of adjusting treatment until a target is reached. An international task force recommended T2T for juvenile idiopathic arthritis (JIA) treatment. Implementing T2T in a standard and reliable way in clinical practice requires agreement on critical elements of (1) target setting, (2) T2T strategy, (3) identifying barriers to implementation, and (4) patient eligibility. A consensus conference was held among Pediatric Rheumatology Care and Outcomes Improvement Network (PR-COIN) stakeholders to inform a statement of understanding regarding the PR-COIN approach to T2T. METHODS: PR-COIN stakeholders including 16 healthcare providers and 4 parents were invited to form a voting panel. Using the nominal group technique, 2 rounds of voting were held to address the above 4 areas to select the top 10 responses by rank order. RESULTS: Incorporation of patient goals ranked most important when setting a treatment target. Shared decision making (SDM), tracking measurable outcomes, and adjusting treatment to achieve goals were voted as the top elements of a T2T strategy. Workflow considerations, and provider buy-in were identified as key barriers to T2T implementation. Patients with JIA who had poor prognostic factors and were at risk for high disease burden were leading candidates for a T2T approach. CONCLUSION: This consensus conference identified the importance of incorporating patient goals as part of target setting and of the influence of patient stakeholder involvement in drafting treatment recommendations. The network approach to T2T will be modified to address the above findings, including solicitation of patient goals, optimizing SDM, and better workflow integration.

Translating research into practice-implementation recommendations for pediatric rheumatology; Proceedings of the childhood arthritis and rheumatology research alliance 2020 implementation science retreat.

The translation of research findings into clinical practice is challenging, especially fields like in pediatric rheumatology, where the evidence base is limited, there are few clinical trials, and the conditions are rare and heterogeneous. Implementation science methodologies have been shown to reduce the research- to- practice gap in other clinical settings may have similar utility in pediatric rheumatology. This paper describes the key discussion points from the inaugural Childhood Arthritis and Rheumatology Research Alliance Implementation Science retreat held in February 2020. The aim of this report is to synthesize those findings into an Implementation Science Roadmap for pediatric rheumatology research. This roadmap is based on three foundational principles: fostering curiosity and ensuring discovery, integration of research and quality improvement, and patient-centeredness. We include six key steps anchored in the principles of implementation science. Applying this roadmap will enable researchers to evaluate the full range of research activities, from the initial clinical design and evidence acquisition to the application of those findings in pediatric rheumatology clinics and direct patient care.

Determinants of changes in linear growth and body composition in incident pediatric Crohn's disease.

BACKGROUND & AIMS: Pediatric Crohn's disease (CD) is associated with growth, lean mass (LM), and fat mass (FM) deficits. This study assessed and identified determinants of changes in height and body composition in children with CD following. METHODS: Whole-body LM and FM were assessed using dual-energy x-ray absorptiometry in 78 CD subjects at diagnosis, 6, 12, and a median of 43 months (range, 24-63) later. Race- and sex-specific Z scores for lean mass (LM-ht-Z) and fat mass (FM-ht-Z) relative to height were derived using reference data in >900 controls. Serum cytokines and growth factors were measured, and quasi-least squares regression was used to identify determinants of changes in height and body composition. RESULTS: LM-ht-Z and FM-ht-Z (both P<.005) improved significantly after diagnosis; however, female patients had persistent LM deficits vs controls (-0.50+/-1.02, P<.05). Serum interleukin-6, tumor necrosis factor-alpha, and lipopolysaccharide binding protein decreased significantly (all P<.001). Greater increases in LM-ht-Z were associated with infliximab therapy (P<.05), increases in albumin (P<.001) and decreases in erythrocyte sedimentation rate (P<.05), interleukin-6 (P<.005), and lipopolysaccharide binding protein (P<.05). Greater increases in FM-ht-Z were associated with glucocorticoid, methotrexate, and infliximab therapy, and increases in albumin (P<.05) and growth hormone binding protein (P<.05). Overall, height-Z did not improve; however, greater increases in insulin-like growth factor-1 (P<.05) and decreases in tumor necrosis factor-alpha (P<.05), interleukin-6 (P<.05), and lipopolysaccharide binding protein (P<.05) levels were associated with increases in height-Z. CONCLUSIONS: Immune-mediated mechanisms contribute to growth and body composition deficits in CD. Therapies should target these deficits.

Vitamin D supplementation in the pediatric rheumatology clinic.

Vitamin D is capturing the attention of healthy and chronically ill populations for its potential skeletal and nonskeletal benefits. New information suggesting a role in immune modulation has led to a surge of interest among rheumatologists. Although the epidemiologic data are limited, it appears that many children with rheumatic conditions are at risk of vitamin D deficiency. However, understanding this phenomenon requires an appreciation for how vitamin D status is assessed, and options for supplementation. Although a "more-is-better" attitude is tempting when considering the medicinal effects of a nutritional supplement, we suggest a cautious approach and suggest that further studies are needed to clarify the potential benefits and risks among children with rheumatic conditions.

Factors Associated With Variation in Pediatric Systemic Lupus Erythematosus Care Delivery.

OBJECTIVE: Patients with pediatric systemic lupus erythematosus (pSLE) and mixed connective tissue disease (MCTD) receive only a fraction of recommended care. Using published quality indicators and guidelines, we developed a 13-item pediatric lupus care index (p-LuCI) to quantify the proportion of recommended clinical evaluations and comorbidity prevention interventions completed and the timeliness of follow-up. Our objective was to assess baseline index performance and identify sources of p-LuCI variation. METHODS: We performed a cross-sectional study in patients with pSLE or MCTD and analyzed the performance of individual p-LuCI process metrics and calculated the overall p-LuCI score. We identified factors associated with the p-LuCI using multivariable linear regression with clustering by provider. RESULTS: For 110 patients (99 with pSLE and 11 with MCTD), the median p-LuCI was 65.2% (interquartile range: 9.1-92.3%). Component performance ranged from 27.3% (on-time scheduling) to 95.4% (steroid-sparing treatment). Patients with p-LuCI scores above the median had higher scores across all 13 components. Higher p-LuCI scores were independently associated with disease-modifying antirheumatic drug use (ß = 14.3 [95% confidence interval (CI), 1.5-27.2]), nephritis (ß = 10.4 [95% CI, 5.1-15.8]), higher provider pSLE/MCTD volume (ß = 3.1 [95% CI, 1.9-4.2] per patient), assignment to rheumatology fellow trainee (ß = 36.3 [95% CI, 17.3-55.2]), and disease duration of less than 1 year (ß = 12.6 [95% CI, 0.7-24.5]). Differences by race, ethnicity, and/or insurance were not observed. CONCLUSION: Using an index of recommended pSLE care metrics, we identified significant variation in performance by disease, treatment, and provider characteristics. The p-LuCI may be useful to assess care quality at the patient, provider, and practice levels and to identify areas in need of greater standardization.

Evaluation of pediatric rheumatology telehealth satisfaction during the COVID-19 pandemic.

BACKGROUND: During the Coronavirus disease 2019 pandemic, ambulatory pediatric rheumatology healthcare rapidly transformed to a mainly telehealth model. However, pediatric patient and caregiver satisfaction with broadly deployed telehealth programs remains largely unknown. This study aimed to evaluate patient/caregiver satisfaction with telehealth and identify the factors associated with satisfaction in a generalizable sample of pediatric rheumatology patients. METHODS: Patients with an initial telehealth video visit with a rheumatology provider between April and June 2020 were eligible. All patients/caregivers were sent a post-visit survey to assess a modified version of the Telehealth Usability Questionnaire (TUQ) and demographic and clinical characteristics. TUQ total and sub-scale (usefulness, ease of use, effectiveness, satisfaction) scores were calculated and classified as "positive" based on responses of "agree" or "strongly agree" on a 5-point Likert scale. Results were analyzed using standard descriptive statistics and Wilcoxon signed rank testing. The association between demographic and clinical characteristics with TUQ scores was assessed using univariate linear regression. RESULTS: 597 patients/caregivers met inclusion criteria, and the survey response rate was 42% (n = 248). Juvenile idiopathic arthritis was the most common diagnosis (33.5%). The majority of patients were diagnosed greater than 6 months previously (72.6%) and were prescribed chronic medications (59.7%). The median total TUQ score was 4 (IQR: 4-5) with positive responses in 81% of items. Of the subscales, usefulness scores were lowest (median: 4, p < 0.001). Telehealth saves time traveling was the highest median item score (median = 5, IQR: 4-5). Within subscales, items that scored significantly lower included convenience, providing for needs, seeing rheumatologist as well as in person, and being an acceptable way to receive rheumatology services (all p < 0.001). There were no significant demographic or clinical features associated with TUQ scores. CONCLUSIONS: Our results suggest telehealth is a promising mode of healthcare delivery for pediatric rheumatic diseases but also identifies opportunities for improvement. Innovation and research are needed to design a telehealth system that delivers high quality and safe care that improves healthcare outcomes. Since telehealth is a rapidly emerging form of pediatric rheumatology care, improved engagement and training of patients, caregivers, and providers may help improve the patient experience in the future.

Exploring Pediatric Tele-Rheumatology Practices During COVID-19: A Survey of the PRCOIN Network.

Healthcare providers were rapidly forced to modify the way they practiced medicine during the coronavirus disease 2019 (COVID-19) pandemic. Many providers transitioned from seeing their patients in person to virtually using telemedicine platforms with limited training and experience using this medium. In pediatric rheumatology, this was further complicated as musculoskeletal exams typically require hands-on assessment of patients. The objective of this study was to examine the adoption of telemedicine into pediatric rheumatology practices, to assess its benefits and challenges, and to gather opinions on its continued use. A survey was sent to the lead representatives of each Pediatric Rheumatology Care and Outcomes Improvement Network (PR-COIN) site to collect data about their center's experience with telemedicine during the COVID-19 pandemic. Quantitative data were analyzed using descriptive statistics, and qualitative data were thematically analyzed. Responses were received from the majority [19/21 (90%)] of PR-COIN sites. All respondents reported transitioning from in-person to primarily virtual patient visits during the COVID-19 pandemic. All centers reported seeing both new consultations and follow-up patients over telemedicine. Most centers reported using both audio and video conferencing systems to conduct their telemedicine visits. The majority of respondents [13/19 (68%)] indicated that at least 50% of their site's providers consistently used pediatric Gait Arms Legs and Spine (pGALS) to perform active joint count assessments over telemedicine. Over half of the centers [11/19 (58%)] reported collecting patient-reported outcomes (PROs), but the rate of reliably documenting clinical components varied. A few sites [7/19 (37%)] reported performing research-related activity during telemedicine visits. All centers thought that telemedicine visits were able to meet providers' needs and support their continued use when the pandemic ends. Benefits reported with telemedicine visits included convenience and continuity of care for families. Conversely, challenges included limited ability to perform physical exams and varying access to technology. Pediatric rheumatology providers were able to transition to conducting virtual visits during the COVID-19 pandemic. Healthcare providers recognize how telemedicine can enhance their practice, but challenges need to be overcome in order to ensure equitable, sustainable delivery of quality and patient-centered care.

Longitudinal assessment of bone density and structure in an incident cohort of children with Crohn's disease.

BACKGROUND & AIMS: The impact of childhood Crohn's disease (CD) on volumetric bone mineral density (vBMD), bone structure, and muscle mass have not been established. The objective of this longitudinal study was to assess musculoskeletal outcomes in an incident cohort of children with CD using peripheral quantitative computed tomography (pQCT). METHODS: Tibia pQCT was performed in 78 CD subjects (ages, 5-18 years) at diagnosis and in 67 over the subsequent year. pQCT outcomes were converted to sex- and race-specific z scores based on reference data in over 650 controls. Multivariable linear regression models identified factors associated with changes in bone outcomes. RESULTS: At diagnosis, CD subjects had significant deficits in trabecular vBMD (z score, -1.32+/-1.32; P< .001), cortical section modulus (a measure of bone geometry and strength) (z score, -0.44+/-1.11; P< .01), and muscle (z score, -0.96+/-1.02; P< .001) compared with controls. Over the first 6 months, trabecular vBMD and muscle z scores improved significantly (both, P< .001); however, section modulus worsened (P= .0001), and all 3 parameters remained low after 1 year. Increases in muscle z scores were associated with less severe declines in cortical section modulus z scores. Improvements in trabecular vBMD z scores were greater in prepubertal subjects. Glucocorticoids were associated with increases in cortical vBMD. CONCLUSIONS: Substantial deficits in trabecular vBMD, cortical bone geometry, and muscle were observed at CD diagnosis. Trabecular vBMD improved incompletely; however, cortical deficits progressed despite improvements in muscle. Glucocorticoids were not associated with bone loss. Therapies to improve bone accrual in childhood CD are needed.

Longitudinal assessment of racial disparities in juvenile idiopathic arthritis disease activity in a treat-to-target intervention.

BACKGROUND: We sought to evaluate racial disparities in disease outcomes among children with polyarticular juvenile idiopathic arthritis (JIA) during a treat-to-target (TTT) intervention with clinical decision support (CDS). METHODS: This was a retrospective analysis of a TTT-CDS strategy integrated into clinical practice for children with polyarticular JIA at a single center from 2016 to 2019. The primary outcome was the clinical Juvenile Arthritis Disease Activity Score (cJADAS-10). We used multivariable linear regression to assess racial differences in disease outcomes at the index visit (first visit after implementation). The effect of race on disease outcomes over time was estimated using linear mixed-effects models, stratified by incident or prevalent disease. RESULTS: We included 159 children with polyarticular JIA, of which 74, 13 and 13% were white, black, and Asian/other, respectively. cJADAS-10 improved significantly over time for all race categories, while the rates of improvement did not differ by race in incident (p = 0.53) or prevalent cases (p = 0.58). cJADAS-10 over time remained higher among black children compared to white children (ß 2.5, p < 0.01 and ß 1.2, p = 0.08 for incident and prevalent cases, respectively). Provider attestation to CDS use at ≥50% of encounters was associated with a 3.9 greater reduction in cJADAS-10 among black children compared to white children (p = 0.02). CONCLUSION: Despite similar rates of improvement over time by race, disparities in JIA outcomes persisted throughout implementation of a TTT-CDS approach. More consistent CDS use may have a greater benefit among black children and needs to be explored further.

Outcome Monitoring and Clinical Decision Support in Polyarticular Juvenile Idiopathic Arthritis.

OBJECTIVE: Inconsistent assessment and treatment may impair juvenile idiopathic arthritis (JIA) outcomes. We aimed to improve polyarticular JIA (rheumatoid factor-positive and -negative) outcomes by standardizing point-of-care disease activity monitoring and implementing clinical decision support (CDS) to reduce treatment variation. METHODS: We performed a quality improvement initiative in an outpatient pediatric rheumatology practice. The interventions, implemented from April to November 2016, included standardized disease activity measurement, disease activity target review, and phased introduction of polyarticular JIA CDS to guide medication selection, dosing, treatment duration, and tapering. Process measures included visit-level target attestation (goal: 50%) and CDS use (goal: 15%). Our goal was to reduce the polyarticular JIA clinical Juvenile Arthritis Disease Activity Score (cJADAS-10) by at least 10%. Included patients had at least 2 visits from April 2016 through July 2017, and were classified as having early (≤ 6 mos) or established disease (> 6 mos). RESULTS: Patients with polyarticular JIA (n = 97; 81% established disease) were observed for 10.3 months (interquartile range: 6.4-12.3). Target attestation and CDS use occurred in a mean of 77% and 45% of polyarticular JIA visits, respectively. The median cJADAS-10 decreased significantly in both early (16.5 to 2.7, p < 0.001) and established polyarticular JIA (2.1 to 1.0, p = 0.01). A high proportion of patients with early disease received biologic therapy (73.7%). In established disease, although prescription of nonbiologic and biologic disease-modifying antirheumatic drugs remained similar overall, adalimumab prescribing increased (12.8% to 23.1%, p = 0.008). CONCLUSION: Implementation of structured disease activity monitoring and CDS in polyarticular JIA was associated with significant reductions in disease activity scores in both early and established disease.

Determinants of disease activity change over time in Enthesitis related arthritis: effect of structured outcome monitoring and clinical decision support.

BACKGROUND: We aimed to test if standardized point-of-care outcome monitoring and clinical decision support (CDS), as compared to standard care, improves disease activity and patient-reported pain in children with enthesitis-related arthritis (ERA). METHODS: This was a retrospective cohort study of outcomes of children with ERA after phased implementation of I) standardized outcome monitoring with CDS for polyarticular JIA, and II) CDS for ERA, compared to a pre-intervention group of historical controls. We used multivariable mixed-effects models for repeated measures to test whether implementation phase or other disease characteristics were associated with change over time in disease activity, as measured by the clinical juvenile arthritis disease activity score (cJADAS), and pain. RESULTS: One hundred fifty-two ERA patients (41% incident cases) were included with a median age of 14.9 years. Implementation of standardized outcome monitoring or ERA-specific CDS did not result in significant differences in cJADAS or pain over time compared to the pre-intervention cohort. Higher cJADAS at the index visit, pain and more tender entheses were significantly associated with higher cJADAS scores over time (all p < 0.01), while biologic use was associated with lower cJADAS (p = 0.02). Regardless of intervention period, incident ERA cases had a greater rate of cJADAS improvement over time compared to prevalent cases (p < 0.01), but pain persisted over time among both incident and prevalent cases. CONCLUSIONS: There was no significant effect of point-of-care outcome monitoring or CDS interventions on disease activity or pain over time in children with ERA in this single center study. Future efforts to improve disease outcomes using standardized outcome monitoring and CDS will need to consider the importance of addressing pain as a target in addition to spondyloarthritis-specific disease activity metrics.

Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases.

BACKGROUNDUndifferentiated systemic autoinflammatory diseases (USAIDs) present diagnostic and therapeutic challenges. Chronic interferon (IFN) signaling and cytokine dysregulation may identify diseases with available targeted treatments.METHODSSixty-six consecutively referred USAID patients underwent underwent screening for the presence of an interferon signature using a standardized type-I IFN-response-gene score (IRG-S), cytokine profiling, and genetic evaluation by next-generation sequencing.RESULTSThirty-six USAID patients (55%) had elevated IRG-S. Neutrophilic panniculitis (40% vs. 0%), basal ganglia calcifications (46% vs. 0%), interstitial lung disease (47% vs. 5%), and myositis (60% vs. 10%) were more prevalent in patients with elevated IRG-S. Moderate IRG-S elevation and highly elevated serum IL-18 distinguished 8 patients with pulmonary alveolar proteinosis (PAP) and recurrent macrophage activation syndrome (MAS). Among patients with panniculitis and progressive cytopenias, 2 patients were compound heterozygous for potentially novel LRBA mutations, 4 patients harbored potentially novel splice variants in IKBKG (which encodes NF-κB essential modulator [NEMO]), and 6 patients had de novo frameshift mutations in SAMD9L. Of additional 12 patients with elevated IRG-S and CANDLE-, SAVI- or Aicardi-Goutières syndrome-like (AGS-like) phenotypes, 5 patients carried mutations in either SAMHD1, TREX1, PSMB8, or PSMG2. Two patients had anti-MDA5 autoantibody-positive juvenile dermatomyositis, and 7 could not be classified. Patients with LRBA, IKBKG, and SAMD9L mutations showed a pattern of IRG elevation that suggests prominent NF-κB activation different from the canonical interferonopathies CANDLE, SAVI, and AGS.CONCLUSIONSIn patients with elevated IRG-S, we identified characteristic clinical features and 3 additional autoinflammatory diseases: IL-18-mediated PAP and recurrent MAS (IL-18PAP-MAS), NEMO deleted exon 5-autoinflammatory syndrome (NEMO-NDAS), and SAMD9L-associated autoinflammatory disease (SAMD9L-SAAD). The IRG-S expands the diagnostic armamentarium in evaluating USAIDs and points to different pathways regulating IRG expression.TRIAL REGISTRATIONClinicalTrials.gov NCT02974595.FUNDINGThe Intramural Research Program of the NIH, NIAID, NIAMS, and the Clinical Center.