An Evidence-Based Guideline Improves Outcomes for Patients With Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome.

OBJECTIVE: To compare clinical outcomes in children with hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) who were managed before and after implementation of an evidence-based guideline (EBG). METHODS: A management algorithm for MAS-HLH was developed at our institution based on literature review, expert opinion, and consensus building across multiple pediatric subspecialties. An electronic medical record search retrospectively identified hospitalized patients with MAS-HLH in the pre-EBG (October 15, 2015, to December 4, 2017) and post-EBG (January 1, 2018, to January 21, 2020) time periods. Predetermined outcome metrics were evaluated in the 2 cohorts. RESULTS: After the EBG launch, 57 children were identified by house staff as potential patients with MAS-HLH, and rheumatology was consulted for management. Ultimately, 17 patients were diagnosed with MAS-HLH by the treating team. Of these, 59% met HLH 2004 criteria, and 94% met 2016 classification criteria for MAS complicating systemic juvenile idiopathic arthritis. There was a statistically significant reduction in mortality from 50% before implementation of the EBG to 6% in the post-EBG cohort (P = 0.02). There was a significant improvement in time to 50% reduction in C-reactive protein level in the post-EBG vs pre-EBG cohorts (log-rank P < 0.01). There were trends toward faster time to MAS-HLH diagnosis, faster initiation of immunosuppressive therapy, shorter length of hospital stay, and more rapid normalization of MAS-HLH-related biomarkers in the patients post-EBG. CONCLUSION: While the observed improvements may be partially attributed to advances in treatment of MAS-HLH that have accumulated over time, this analysis also suggests that a multidisciplinary treatment pathway for MAS-HLH contributed meaningfully to favorable patient outcomes.

Disordered T cell-B cell interactions in autoantibody-positive inflammatory arthritis.

T peripheral helper (Tph) cells, identified in the synovium of adults with seropositive rheumatoid arthritis, drive B cell maturation and antibody production in non-lymphoid tissues. We sought to determine if similarly dysregulated T cell-B cell interactions underlie another form of inflammatory arthritis, juvenile oligoarthritis (oligo JIA). Clonally expanded Tph cells able to promote B cell antibody production preferentially accumulated in the synovial fluid (SF) of oligo JIA patients with antinuclear antibodies (ANA) compared to autoantibody-negative patients. Single-cell transcriptomics enabled further definition of the Tph gene signature in inflamed tissues and showed that Tph cells from ANA-positive patients upregulated genes associated with B cell help to a greater extent than patients without autoantibodies. T cells that co-expressed regulatory T and B cell-help factors were identified. The phenotype of these Tph-like Treg cells suggests an ability to restrain T cell-B cell interactions in tissues. Our findings support the central role of disordered T cell-help to B cells in autoantibody-positive arthritides.

Th1 polarization defines the synovial fluid T cell compartment in oligoarticular juvenile idiopathic arthritis.

Oligoarticular juvenile idiopathic arthritis (oligo JIA) is the most common form of chronic inflammatory arthritis in children, yet the cause of this disease remains unknown. To understand immune responses in oligo JIA, we immunophenotyped synovial fluid T cells with flow cytometry, bulk RNA-Seq, single-cell RNA-Seq (scRNA-Seq), DNA methylation studies, and Treg suppression assays. In synovial fluid, CD4+, CD8+, and γδ T cells expressed Th1-related markers, whereas Th17 cells were not enriched. Th1 skewing was prominent in CD4+ T cells, including Tregs, and was associated with severe disease. Transcriptomic studies confirmed a Th1 signature in CD4+ T cells from synovial fluid. The regulatory gene expression signature was preserved in Tregs, even those exhibiting Th1 polarization. These Th1-like Tregs maintained Treg-specific methylation patterns and suppressive function, supporting the stability of this Treg population in the joint. Although synovial fluid CD4+ T cells displayed an overall Th1 phenotype, scRNA-Seq uncovered heterogeneous effector and regulatory subpopulations, including IFN-induced Tregs, peripheral helper T cells, and cytotoxic CD4+ T cells. In conclusion, oligo JIA is characterized by Th1 polarization that encompasses Tregs but does not compromise their regulatory identity. Targeting Th1-driven inflammation and augmenting Treg function may represent important therapeutic approaches in oligo JIA.

Th17 reprogramming of T cells in systemic juvenile idiopathic arthritis.

Systemic juvenile idiopathic arthritis (sJIA) begins with fever, rash, and high-grade systemic inflammation but commonly progresses to a persistent afebrile arthritis. The basis for this transition is unknown. To evaluate a role for lymphocyte polarization, we characterized T cells from patients with acute and chronic sJIA using flow cytometry, mass cytometry, and RNA sequencing. Acute and chronic sJIA each featured an expanded population of activated Tregs uncommon in healthy controls or in children with nonsystemic JIA. In acute sJIA, Tregs expressed IL-17A and a gene expression signature reflecting Th17 polarization. In chronic sJIA, the Th17 transcriptional signature was identified in T effector cells (Teffs), although expression of IL-17A at the protein level remained rare. Th17 polarization was abrogated in patients responding to IL-1 blockade. These findings identify evolving Th17 polarization in sJIA that begins in Tregs and progresses to Teffs, likely reflecting the impact of the cytokine milieu and consistent with a biphasic model of disease pathogenesis. The results support T cells as a potential treatment target in sJIA.

Risk of Diabetes Mellitus in Patients with Juvenile Idiopathic Arthritis.

OBJECTIVE: To examine the risk of type 1 diabetes (T1D) associated with juvenile idiopathic arthritis (JIA). METHODS: Using the IBM MarketScan database, we compared JIA patients with asthma patients and healthy individuals for the risk of incident T1D. RESULTS: We included patients with 15,210 JIA, 76,050 patients with asthma, and 76,050 healthy individuals matched 1:5 on age, sex, and index date. After adjustment for confounders, the multivariable HR of T1D associated with JIA was 1.48 (95% CI 0.86-2.56) versus asthma and 1.81 (95% CI 1.03-3.17) versus healthy individuals. CONCLUSION: JIA appears to be associated with an increased risk of T1D compared to patients with asthma and healthy children.

Pain and Catastrophizing in Patients With Rheumatoid Arthritis: An Observational Cohort Study.

BACKGROUND: The aims of this study were to define changes in catastrophizing that occur with initiation of a new disease-modifying antirheumatic drug (DMARD) and to examine the relationship between changes in Clinical Disease Activity Index (CDAI) and changes in catastrophizing. METHODS: Participants in an ongoing multisite, observational study completed the Pain Catastrophizing Scale (PCS) before and 12 weeks after DMARD initiation. We used multivariable linear regression models to examine the association between changes in CDAI as the exposure and change in pain catastrophizing as the outcome. We also assessed the relationship between changes in each component of CDAI and change in PCS, using multivariable linear regression models. RESULTS: Among the 165 rheumatoid arthritis patients with data on CDAI at both time points, CDAI decreased from 22 to 11.5 on a 76-point scale (p < 0.0001) after 12 weeks. Pain intensity decreased from a median of 5 to 3 on a 10-point numeric rating scale (p < 0.0001), and catastrophizing decreased, from 16.0 to 12.0 on the 52-point PCS (p = 0.0005). Among the 163 with complete data for the regression analysis, changes in CDAI were positively correlated with changes in catastrophizing (standardized ß = 0.19, p = 0.01). Of the components of the CDAI, change in assessor global score was most strongly associated with changes in catastrophizing (standardized ß = 0.24, p = 0.003). CONCLUSIONS: Pain catastrophizing decreases, in conjunction with disease activity, after initiation of a new DMARD. These findings provide support for catastrophizing as a dynamic construct that can be altered with treatment directed at decreasing inflammatory disease activity and pain.

Factors associated with insomnia and complementary medicine use in children: results of a national survey.

OBJECTIVES: Sleep difficulties are a serious health problem in children, and interest in using complementary and alternative medicine (CAM) therapies to treat sleep is growing. In this study, we aimed to identify: the prevalence of sleep difficulties in children, and the prevalence and patterns of CAM use among children with trouble sleeping. METHODS: We used the 2012 National Health Interview Survey (NHIS) dataset to estimate the prevalence of sleep difficulties and CAM use in children ages 6-17 years. Prevalence estimates were weighted to reflect the survey's sampling design. We used logistic regression to explore associations between sleep difficulties, psychosocial factors, comorbidities and CAM use. RESULTS: 6.4% of children in the 2012 NHIS dataset reported regular difficulty sleeping in the last year, corresponding to an estimated 1.5 million children in the US. Older age, poorer health status, more missed school days, and multiple comorbidities were all associated with sleep difficulties (p ≤ 0.001). Among children with sleep difficulties, 29% used at least one CAM therapy. Of the CAM therapies surveyed, non-vitamin, non-mineral supplements were the most commonly used (14.6%), followed by manipulation therapies (9.2%) and mind-body techniques (8.8%). Parental education and CAM use were most strongly associated with child CAM use (p ≤ 0.001). CONCLUSIONS: CAM therapies, particularly non-vitamin, non-mineral supplements, are commonly used among children with sleeping problems. More research is needed to characterize the safety and efficacy of CAM therapies for sleep in this population.

Integrative Medicine for Gastrointestinal Disease.

Gastrointestinal conditions are prevalent in the population and account for significant morbidity and health care costs. Patients with gastrointestinal conditions use integrative medicine. There is growing evidence that integrative medicine approaches can improve symptoms and affect physiology and disease course. This article reviews data on some common and well-studied approaches, including mind-body therapies, acupuncture, diet, probiotics, and dietary supplements and herbs. Although clear recommendations can be made for some conditions, in others there are challenges in translating these findings owing to small study size, lack of standardization, and trial heterogeneity.

Factors associated with complementary medicine use in pediatric musculoskeletal conditions: Results from a national survey.

OBJECTIVES: Complementary and alternative medicine (CAM) use is common in children, but its use has only been investigated in children with musculoskeletal conditions (MSK) to a limited extent. We aimed to characterize factors associated with CAM use in children with MSK conditions. METHODS: Within the 2012 National Health Interview Survey dataset (including its child CAM supplement), we examined factors associated with CAM use in children with MSK conditions and performed an analysis examining the perceived usefulness of CAM therapies for MSK conditions. RESULTS: Overall, there were 10,218 children in the dataset. 28.0% of children with MSK conditions used CAM, compared to 8.8% of children without MSK conditions. Gender (p=0.003), region (p=0.001), race (p=0.001), parental CAM use (p<0.001), education (<0.001), and having anxiety, stress or depression (p=0.030) were correlated with CAM use. Among 90 children who reported on CAM use, 89.7% said that CAM helped some or a great deal for their MSK condition. CONCLUSIONS: Several factors, particularly parental education and parental CAM use, were associated with CAM use, and self-reported improvement rates were high. Interventional trials are needed to determine the efficacy of specific CAM therapies for treating different MSK conditions in children.

A systematic review of psychosocial therapies for children with rheumatic diseases.

BACKGROUND: To assess the quality of evidence for the effects of psychosocial therapies on pain and function in children with rheumatic diseases. METHODS: We conducted a literature search of MEDLINE and PsycINFO for randomized clinical trials of psychosocial interventions for pain and disability in children with rheumatic diseases from January 1969 to September 2015. Studies with a sample size less than 10 subjects were excluded. Study quality was assessed using the Jadad score. RESULTS: Five articles met inclusion criteria, for a total of 229 patients, aged 5 to 18 years. Two studies included children with fibromyalgia. Three studies included children with juvenile arthritis. Neither study in fibromyalgia reported the statistical significance of immediate between-group pre-post changes in functioning or pain. One study examining the effects of an internet-based psychosocial intervention in children with juvenile arthritis reported significant differences in post-intervention pain scores (p = 0.03). However, 2 studies did not show improvements in pain scores among children with juvenile arthritis treated with psychosocial interventions vs. a wait-list control or vs. an active control (massage). No studies reported significant between-group differences for functional outcomes in children with juvenile arthritis. CONCLUSIONS: The available data were limited by the scarcity of randomized trials. Definite conclusions about the immediate effect of psychosocial interventions on pain and function in children with fibromyalgia could not be made because between-group comparisons of post-treatment change scores were not reported. For children with juvenile inflammatory arthritis, results of between-group comparisons for pain differed across studies, and analyses examining disability revealed no significant differences between groups.