Opsonization of red blood cells that retain mitochondria (Mito+ RBCs), a feature of systemic lupus erythematosus (SLE), triggers type I interferon (IFN) production in macrophages. We report that monocytes (Mos) co-produce IFN and mature interleukin-1β (mIL-1β) upon Mito+ RBC opsonization. IFN expression depended on cyclic GMP-AMP synthase (cGAS) and RIG-I-like receptors' (RLRs) sensing of Mito+ RBC-derived mitochondrial DNA (mtDNA) and mtRNA, respectively. Interleukin-1β (IL-1β) production was initiated by the RLR antiviral signaling adaptor (MAVS) pathway recognition of Mito+ RBC-derived mtRNA. This led to the cytosolic release of Mo mtDNA, which activated the inflammasome. Importantly, mIL-1β secretion was independent of gasdermin D (GSDMD) and pyroptosis but relied on IFN-inducible myxovirus-resistant protein 1 (MxA), which facilitated the incorporation of mIL-1β into a trans-Golgi network (TGN)-mediated secretory pathway. RBC internalization identified a subset of blood Mo expressing IFN-stimulated genes (ISGs) that released mIL-1β and expanded in SLE patients with active disease.

Our study aimed to evaluate the presence, clinical associations, and potential mechanistic roles of non-criteria antiphospholipid antibodies (aPL) and circulating calprotectin, a highly stable marker of neutrophil extracellular trap release (NETosis), in pediatric APS patients. We found that 79% of pediatric APS patients had at least one non-criteria aPL at moderate-to-high titer. Univariate logistic regression demonstrated that positive anti-beta-2 glycoprotein I domain 1 (anti-D1) IgG (p = 0.008), anti-phosphatidylserine/prothrombin (aPS/PT) IgG (p < 0.001), and aPS/PT IgM (p < 0.001) were significantly associated with venous thrombosis. Positive anti-D1 IgG (p < 0.001), aPS/PT IgG (p < 0.001), and aPS/PT IgM (p = 0.001) were also associated with non-thrombotic manifestations of APS, such as thrombocytopenia. Increased levels of calprotectin were detected in children with APS. Calprotectin correlated positively with absolute neutrophil count (r = 0.63, p = 0.008) and negatively with platelet count (r = -0.59, p = 0.015). Mechanistically, plasma from pediatric APS patients with high calprotectin levels impaired platelet viability in a dose-dependent manner.

OBJECTIVE:This study was undertaken to identify blood markers of juvenile dermatomyositis (DM) disease activity (DA), which are needed to improve disease management.METHODS:The study comprised a total of 123 juvenile DM patients and 53 healthy controls. Results of laboratory tests (aldolase, creatinine kinase, lactate dehydrogenase [LDH], aspartate aminotransferase) and clinical measures of DA in patients with juvenile DM, including the Manual Muscle Testing in 8 muscles (MMT-8), Childhood Myositis Assessment Scale (CMAS), and disease activity scores (DAS) (total DAS for juvenile DM, the muscle DAS, and the skin DAS), were recorded when available. Surface phenotype of peripheral blood mononuclear cells was assessed using flow cytometry. Whole blood transcriptional profiles were studied using either RNA-sequencing or microarrays. Differential gene expression was determined using DESeq and compared by pathway and gene ontology analyses.RESULTS:Conventional memory (CD27+IgD-) B cells expressing low CXCR5 levels (CXCR5low/- CM B cells) were significantly increased in frequency and absolute numbers in 2 independent cohorts of juvenile DM patients compared with healthy controls. The frequency of CD4+ Th2 memory cells (CD45RA-CXCR5-CCR6-CXCR3-) was also increased in juvenile DM, especially in patients who were within <1 year from diagnosis. The frequency of CXCR5low/- CM B cells correlated with serum aldolase levels and with a blood interferon-stimulated gene transcriptional signature. Furthermore, both the frequency and absolute numbers of CXCR5low/- CM B cells correlated with clinical and laboratory measures of muscle DA (MMT-8, CMAS, aldolase, and LDH).CONCLUSION:These findings suggest that both CM B cells lacking the CXCR5 follicular marker and CXCR5- Th2 cells represent potential biomarkers of DA in juvenile DM and may contribute to its pathogenesis.

Systemic Lupus Erythematosus (SLE) is characterized by autoreactive B cell activation, upregulation of Type I Interferon (IFN) and widespread inflammation. Mitochondrial nucleic acids (NAs) are increasingly recognized as triggers of IFN 1 . Thus, defective removal of mitochondria from mature red blood cells (Mito + RBCs), a feature of SLE, contributes to IFN production by myeloid cells 2 . Here we identify blood monocytes (Mo) that have internalized RBCs and co-express IFN-stimulated genes (ISGs) and interleukin-1β (IL-1β) in SLE patients with active disease. We show that ISG expression requires the interaction between Mito + RBC-derived mitochondrial DNA (mtDNA) and cGAS, while IL-1β production entails Mito + RBC-derived mitochondrial RNA (mtRNA) triggering of RIG-I-like receptors (RLRs). This leads to the cytosolic release of Mo-derived mtDNA that activates the NLRP3 inflammasome. Importantly, IL-1β release depends on the IFN-inducible myxovirus resistant protein 1 (MxA), which enables the translocation of this cytokine into a trans-Golgi network (TGN)-mediated unconventional secretory pathway. Our study highlights a novel and synergistic pathway involving IFN and the NLRP3 inflammasome in SLE.

OBJECTIVE:To identify perceived health literacy (HL) and patient activation (PA) needs during the transition from pediatric to adult rheumatology among patients with childhood-onset systemic lupus erythematosus (cSLE).METHODS:Semistructured interviews of patients and health care professionals were conducted from November 2019 through May 2020, until thematic saturation was achieved. Interviews were audio-recorded, transcribed, coded, and analyzed using thematic analysis.RESULTS:Thirteen post-transition adult female participants with cSLE were recruited from a public safety-net hospital system or from private practice. Thirteen health care team members were recruited from two pediatric and four adult rheumatology clinical sites serving patients in the same metropolitan area. Patients and health care team members acknowledged numerous HL components as important to transition, including language fluency, education, SLE-specific knowledge, self-efficacy, and accurate knowledge of personal medical history. Our interviews found PA to be an important component of the transition process, driven by internalization of the implications of cSLE diagnosis, self-education, autonomy, introspection, and trustworthy doctor-patient relationships. Patients valued access to their online electronic medical record, recommended multimodal SLE-specific education materials, and desired increased access to social workers. Health care team members stressed the importance of early preparation for transition and use of mobile medical applications and endorsed interventions such as lupus camp and increased partnership with psychologists and social workers.CONCLUSION:HL and PA are perceived by patients and health care team members as substantially influencing transition success. Further research is needed to evaluate whether interventions to improve HL and PA positively influence cSLE transition outcomes.

Multiple studies have shown the microbiota to be abnormal in patients with spondyloarthritis (SpA). The purpose of this study was to explore the genetic contributions of these microbiota abnormalities. We analyzed the impact of HLA-B27 on the microbiota of children at risk for SpA and compared the microbiota of HLA-B27+ pediatric offspring of ankylosing spondylitis (AS) patients with that of HLA-B27+ children with SpA. Human DNA was obtained from the offspring for determination of HLA-B27 status and polygenic risk score (PRS). Fecal specimens were collected from both groups for sequencing of the V4 region of the 16S ribosomal RNA gene. Among the offspring of AS patients, there was slight clustering by HLA-B27 status. After adjusting for multiple comparisons, five operational taxonomic units (OTUs) representing three unique taxa distinguished the HLA-B27+ from negative children: Blautia and Coprococcus were lower in the HLA-B27+ offspring, while Faecalibacterium prausnitzii was higher. HLA-B27+ offspring without arthritis were compared to children with treatment-naïve HLA-B27+ SpA. After adjustments, clustering by diagnosis was present. A total of 21 OTUs were significantly associated with diagnosis state, including Bacteroides (higher in SpA patients) and F. prausnitzii (higher in controls). Thus, our data confirmed associations with B. fragilis and F. prausnitzii with juvenile SpA, and also suggest that the mechanism by which HLA-B27 is associated with SpA may not involve alterations of the microbiota.

The authors wish to make the following correction to this paper [...]

Background The psychosocial burden of having a chronic disease can be substantial for adolescents with childhood-onset systemic lupus erythematosus (cSLE). Current literature is scarce on interventions that can improve psychosocial outcomes for this population. Therapeutic recreation camps have been proposed as a beneficial experience for chronically ill pediatric populations. However, their effective components have not been well characterized in patients with cSLE. In this study, we sought to understand the various components of the camp experience for adolescents with cSLE from both the patient and parent perspective. Methods We recruited patients with cSLE who had participated in one or more annual, weekend-long recreational lupus camp(s) near Dallas, Texas. Semi-structured in-depth telephone interviews were conducted from March-June 2020 with both the patients and parents. Questions focused on overall patient experience, psychosocial impact of camp participation, coping skills gained, and opportunities to prepare for the transition from pediatric to adult care. Interviews were coded and analyzed using inductive thematic analysis. Results We interviewed 9 current and former campers (ages 16–24), including a current camp counselor, and 3 of their parents separately. Reported benefits included a positive impact on social support through peer bonding, opportunities to develop coping mechanisms through structured activities and peer/medical staff interactions, opportunities for education about the cSLE disease experience, improved adherence through peer modeling, overall increase in self-efficacy, and better parental insight into the patient experience. Participants also provided suggestions for expansion and improvement in program development to optimize educational opportunities for both campers and parents. In addition, they advocated for longitudinal social support and community building. Conclusions In this qualitative study, in which cSLE patients and their parents reflected on their experiences with therapeutic recreation camps, we found several perceived benefits impacting the patient and parent experience. Participants expressed a desire for more educational opportunities that could contribute to their successful transition from pediatric to adult care. Further studies are needed to demonstrate the effects of therapeutic recreation camps on the psychosocial health of this population.

Purpose of review Childhood Sjogren's syndrome (cSS) is a rare, chronic autoimmune disease characterized by inflammation of the exocrine glands. cSS is underrecognized because of differences in clinical presentation compared with adults. Until recently, publications describing clinical manifestations in cSS were limited to case reports and case series with small numbers of patients. Diagnostic studies to assess glandular symptoms in adults, are less commonly obtained in children. Recent findings Recent cohort studies describe presenting diagnostic clinical features in large populations of cSS and demonstrate how current classification criteria, used in adults, are not applicable to children. Recurrent parotitis is the consistent predominant manifestation that is inversely correlated with age. Novel salivary biomarkers and salivary gland ultrasonography are important objective measure, which may improve diagnosis and disease monitoring. Standardized treatment recommendations are needed. Summary Findings from large cohort studies provide a framework for the future development of diagnostic criteria for cSS. Such criteria should incorporate objective measures that are easily obtained in children. Future research to improve understanding of the application of novel biomarkers and imaging and developing consensus on treatment recommendations is needed.

ObjectiveOur objective was to develop and validate a composite disease flare definition for juvenile spondyloarthritis (SpA) that would closely approximate the clinical decision made to reinitiate or not reinitiate systemic therapy after therapy de‐escalation.MethodsRetrospective chart reviews of children with SpA who underwent systemic therapy de‐escalation of biologic or conventional disease‐modifying antirheumatic drugs were used to develop and validate the flare outcome. Data on independent cohorts for development (1 center) and validation (4 centers) were collected from large tertiary health care systems. Core measure thresholds and candidate disease flare outcomes were assessed using sensitivity, specificity, positive predictive values (PPVs) and negative predictive values (NPVs), and the receiver operating characteristic (ROC) area under the curve (AUC), with physician assessment of active disease plus re‐initiation of standard dose of systemic therapy as the reference standard.ResultsOf the candidate definitions, clinically meaningful worsening in ≥3 of the following 5 core measures performed best: caregiver/patient assessment of well‐being; physician assessment of disease activity; caregiver/patient assessment of pain, physical function, and active joint count. The ROC AUC was 0.91, PPV 87.5%, NPV 98.1%, sensitivity 82.4%, and specificity 98.7%. Cronbach's α was 0.81, signifying internal consistency, and factor analysis demonstrated that the outcome measured 1 construct. The Juvenile SpA Flare measure had face validity according to 21 surveyed pediatric rheumatologists. Juvenile SpA Flare had an ROC AUC of 0.85, a PPV of 92.3%, and an NPV of 96.8% in the validation cohort.ConclusionThere is initial support for the validity of the Juvenile SpA Flare measure as a tool to identify disease flare in juvenile SpA patients de‐escalating therapy, and the measure is potentially applicable in clinical practice, observational studies, and therapeutic trials.