Single cell spatial transcriptomic profiling of childhood-onset lupus nephritis reveals complex interactions between kidney stroma and infiltrating immune cells.

Children with systemic lupus erythematosus (SLE) are at increased risk of developing kidney disease, termed childhood-onset lupus nephritis (cLN). Single cell transcriptomics of dissociated kidney tissue has advanced our understanding of LN pathogenesis, but loss of spatial resolution prevents interrogation of in situ cellular interactions. Using a technical advance in spatial transcriptomics, we generated a spatially resolved, single cell resolution atlas of kidney tissue (>400,000 cells) from eight cLN patients and two controls. Annotated cells were assigned to 35 reference cell types, including major kidney subsets and infiltrating immune cells. Analysis of spatial distribution demonstrated that individual immune lineages localize to specific regions in cLN kidneys, including myeloid cells trafficking to inflamed glomeruli and B cells clustering within tubulointerstitial immune hotspots. Notably, gene expression varied as a function of tissue location, demonstrating how incorporation of spatial data can provide new insights into the immunopathogenesis of SLE. Alterations in immune phenotypes were accompanied by parallel changes in gene expression by resident kidney stromal cells. However, there was little correlation between histologic scoring of cLN disease activity and glomerular cell transcriptional signatures at the level of individual glomeruli. Finally, we identified modules of spatially-correlated gene expression with predicted roles in induction of inflammation and the development of tubulointerstitial fibrosis. In summary, single cell spatial transcriptomics allows unprecedented insights into the molecular heterogeneity of cLN, paving the way towards more targeted and personalized treatment approaches.

Subdural hemorrhage, macrocephaly, rash, and developmental delay in an infant: A pathogenic variant in NLRP3 causes CINCA/NOMID.

Subdural hemorrhages (SDHs) in children are most often observed in abusive head trauma (AHT), a distinct form of traumatic brain injury, but they may occur in other conditions as well, typically with clear signs and symptoms of an alternative diagnosis. We present a case of an infant whose SDH initially raised the question of AHT, but multidisciplinary evaluation identified multiple abnormalities, including rash, macrocephaly, growth failure, and elevated inflammatory markers, which were all atypical for trauma. These, along with significant cerebral atrophy, ventriculomegaly, and an absence of other injuries, raised concerns for a genetic disorder, prompting genetic consultation. Clinical trio exome sequencing identified a de novo likely pathogenic variant in NLRP3, which is associated with chronic infantile neurological, cutaneous, and articular (CINCA) syndrome, also known as neonatal-onset multisystem inflammatory disease (NOMID). He was successfully treated with interleukin-1 blockade, highlighting the importance of prompt treatment in CINCA/NOMID patients. This case also illustrates how atraumatic cases of SDH can be readily distinguished from AHT with multidisciplinary collaboration and careful consideration of the clinical history and exam findings.

Feasibility of Conducting Comparative Effectiveness Research and Validation of a Clinical Disease Activity Score for Chronic Nonbacterial Osteomyelitis.

OBJECTIVE: Prospective comparative effectiveness research (CER) in chronic nonbacterial osteomyelitis (CNO) is lacking. Our objectives were to (1) determine the use and safety of each consensus treatment plan (CTP) regimen for CNO, (2) assess the feasibility of using the Chronic Nonbacterial Osteomyelitis International Registry (CHOIR) data for CER, and (3) develop and validate a CNO clinical disease activity score (CDAS) using CHOIR. METHODS: Consenting children or young adults with CNO were enrolled into CHOIR. Demographic, clinical, and imaging data were prospectively collected. The CNO CDAS was developed through a Delphi survey and nominal group technique. External validation surveys were administered to CHOIR participants. RESULTS: One hundred forty (78.2%) CHOIR participants enrolled between August 2018 and September 2020 received at least 1 CTP regimen. Baseline characteristics from different CTP groups were well matched. Patient pain, patient global assessment, and clinical CNO lesion count were key variables included in the CNO CDAS. The CDAS showed a strong correlation with patient/parent report of difficulty using a limb, back, or jaw and patient/parent report of disease severity, but a weak correlation with patient/parent report of fatigue, sadness, and worry. The change in CDAS was significant in patients reporting disease worsening or improvement (P < 0.001). The CDAS significantly decreased after initiating second-line treatments from median 12.0 (IQR 8.0-15.5) to 5.0 (IQR 3.0-12.0; P = 0.002). Although second-line treatments were well tolerated, psoriasis was the most common adverse event. CONCLUSION: The CNO CDAS was developed and validated for disease monitoring and assessment of treatment effectiveness. CHOIR provided a comprehensive framework for future CER.

Golimumab in Children with Chronic Recurrent Multifocal Osteomyelitis: A Case Series and Review of the Literature.

BACKGROUND: Chronic recurrent multifocal osteomyelitis (CRMO) is a rare autoinflammatory bone disease requiring immunosuppressive treatment in half of patients. Monoclonal tumor necrosis factor inhibitors (TNFi) are often used as effective second-line off-label therapies. However, paradoxical psoriasis can occur in a subset of patients exposed to monoclonal TNFi and can prompt conversion to alternate therapy if severe. OBJECTIVE: The aim of this study was to determine the efficacy and safety of golimumab, a fully humanized TNFi, in children with CRMO, including those who develop paradoxical psoriasis after exposure to other monoclonal TNFi. METHODS: A retrospective chart review was conducted of patients with CRMO who received golimumab in a single center between 01 June, 2018 and 31 December, 2020. Patients who were diagnosed before 21 years of age and followed up for CRMO at least once after receiving ≥ 3 months of golimumab were included. Extracted data included patient demographics, whole-body MRI lesion counts, clinically relevant data, laboratory results, patient-reported outcomes, and psoriasis burden. Linear mixed models with log-transformed outcomes were used to assess changes in the outcomes over time. The random effect is included in the model to account for the within-subject correlation of repeated measures. p-values and 95% confidence intervals were reported. RESULTS: Eighteen patients were included. Patients were observed for a median of 9.95 months [interquartile range 3.84-15.64]. The median age at the initiation of golimumab was 10.95 years [9.86-13.77] and the median duration of disease between the disease onset and the initiation of golimumab was 2.60 years [1.66-3.62]. Ten patients received golimumab via intravenous route and eight patients received golimumab via subcutaneous route. The median dose was 1.64 mg/kg/month [1.46, 2]. Fourteen patients were previously treated with disease-modifying antirheumatic drugs and 17 with other TNFi. Patients treated with golimumab showed significant improvement in median physician global assessment for CRMO from 2.00 [1.00-3.00] to 0.00 [0.00-0.25] by the fourth visit (p < 0.001), with median erythrocyte sedimentation rate (ESR) decreasing significantly from 12.00 [6.75-23.75] to 5.00 [3.00-10.00] by the fourth visit (p < 0.05). The median number of lesions on MRI decreased significantly from 3.50 [2.00-5.50] to 0.50 [0.00-4.25] lesions per patient (p < 0.01). Nine out of 12 patients who had previous paradoxical psoriasis associated with adalimumab or infliximab had persistent active psoriasis at study baseline. For patients with psoriasis at study baseline, the prevalence of psoriasis had decreased from 100% to approximately 50-57% at the following visits. Of the 18 patients initiated on golimumab in this study, there was only one new case of mild psoriasis in a patient with previously resolved infliximab-associated paradoxical psoriasis. No serious infections or adverse events were noted during the study. Two patients in the study showed clinical improvement with concomitant golimumab and ustekinumab with no reported adverse side effects or increased effects in these patients over a 16-month interval, showing that this combination can be safe and effective for children with CRMO. CONCLUSION: In our experience, golimumab has been shown to be a safe and effective therapy for CRMO and demonstrated improvement in paradoxical psoriasis in many patients. Longer follow-up periods would be helpful to develop longer term outcomes data for patients with CRMO and overall paradoxical psoriasis risk.

A multi-site pilot randomized clinical trial of the Treatment and Education Approach for Childhood-onset Lupus (TEACH) program: study design and COVID-19 adaptations.

BACKGROUND: Childhood-onset Systemic Lupus Erythematosus (cSLE) is an autoimmune disease associated with fatigue, mood symptoms, and pain. Fortunately, these symptoms are potentially modifiable with psychological intervention such as cognitive-behavioral therapy (CBT). The Treatment and Education Approach for Childhood-onset Lupus (TEACH) program is a CBT intervention developed to target these symptoms for adolescents and young adults with cSLE. This pilot randomized controlled trial (RCT) aims to determine the feasibility and effect of TEACH for youth with cSLE. Adjustments to the study protocol following the COVID-19 pandemic are also described. METHODS: This two-arm multisite RCT will explore the feasibility (primary outcome) and effect (secondary outcome) of a remotely delivered TEACH protocol. Participants will be randomized to a six-week remotely delivered TEACH program plus medical treatment as usual (TAU) or TAU alone. We will include patients ages 12-22 years presenting to rheumatology clinics from six sites. Validated measures of fatigue, depressive symptoms, and pain will be obtained at baseline and approximately eight and 20 weeks later. Protocol adjustments were also made due to the COVID-19 pandemic, in collaboration with the investigative team, which included patients and caregivers. CONCLUSIONS: Findings from this multi-site RCT aim to document the feasibility of TEACH and provide an estimate of effect of a remotely delivered TEACH protocol on fatigue, depression, and pain symptoms in youth with cSLE as compared to standard medical treatment alone. This findings may positively impact clinical care for patients with cSLE. CLINICAL TRIALS: gov registration: NCT04335643.

Whole-body MRI at initial presentation of pediatric chronic recurrent multifocal osteomyelitis and correlation with clinical assessment.

BACKGROUND: Chronic recurrent multifocal osteomyelitis (CRMO) is a diagnosis of exclusion, relying heavily on whole-body magnetic resonance imaging (WB-MRI) for diagnosing and evaluating response to therapy. Information with respect to disease distribution and imaging correlation with clinical disease severity at initial presentation is lacking. OBJECTIVE: To retrospectively characterize distribution of disease on WB-MRI and to correlate imaging findings with disease severity at initial rheumatology presentation. MATERIALS AND METHODS: Using a modified version of a recently devised imaging-based scoring system, we evaluated disease distribution and correlation between findings on WB-MRI and clinical disease severity in 54 patients presenting for initial evaluation of CRMO. Symptomatic lesion sites were extracted from chart review and physician global assessment was determined by the consensus of two rheumatologists. RESULTS: Sites of CRMO involvement evident on imaging at initial presentation had a strong predilection for the pelvis and lower extremities. There was significant correlation between the number of lesions detected on WB-MRI and total clinical severity score at initial rheumatology presentation (P<0.01). However, no other imaging parameter correlated with disease severity. CONCLUSION: While the overall number of lesions identified on MRI correlates with clinical severity scores at initial imaging, other MR parameters of CRMO lesions may not be reliable indicators of disease severity at initial presentation. Further research is needed to assess whether these parameters are implicated in longitudinal disease severity or overall response to therapy.

International Consensus for the Dosing of Corticosteroids in Childhood-Onset Systemic Lupus Erythematosus With Proliferative Lupus Nephritis.

OBJECTIVE: To develop a standardized steroid dosing regimen (SSR) for physicians treating childhood-onset systemic lupus erythematosus (SLE) complicated by lupus nephritis (LN), using consensus formation methodology. METHODS: Parameters influencing corticosteroid (CS) dosing were identified (step 1). Data from children with proliferative LN were used to generate patient profiles (step 2). Physicians rated changes in renal and extrarenal childhood-onset SLE activity between 2 consecutive visits and proposed CS dosing (step 3). The SSR was developed using patient profile ratings (step 4), with refinements achieved in a physician focus group (step 5). A second type of patient profile describing the course of childhood-onset SLE for ≥4 months since kidney biopsy was rated to validate the SSR-recommended oral and intravenous (IV) CS dosages (step 6). Patient profile adjudication was based on majority ratings for both renal and extrarenal disease courses, and consensus level was set at 80%. RESULTS: Degree of proteinuria, estimated glomerular filtration rate, changes in renal and extrarenal disease activity, and time since kidney biopsy influenced CS dosing (steps 1 and 2). Considering these parameters in 5,056 patient profile ratings from 103 raters, and renal and extrarenal course definitions, CS dosing rules of the SSR were developed (steps 3-5). Validation of the SSR for up to 6 months post-kidney biopsy was achieved with 1,838 patient profile ratings from 60 raters who achieved consensus for oral and IV CS dosage in accordance with the SSR (step 6). CONCLUSION: The SSR represents an international consensus on CS dosing for use in patients with childhood-onset SLE and proliferative LN. The SSR is anticipated to be used for clinical care and to standardize CS dosage during clinical trials.

Welcoming Healthcare Into Our Virtual Meeting Rooms: Perspective and Perseverance in Pediatric Rheumatology.

Purpose of Review: We highlight practice changes adopted to increased use of telemedicine, look at precision, and accuracy in using a virtual visit to evaluate and treat rheumatic disease, and describe our shift in engaging patients and their families in supporting our research aims. Recent Findings: Telemedicine visits increased substantially with the start of the SARS-CoV-2 pandemic. With this change came the need for significant advances to our telemedicine practices to allow for quality patient visits and continued research collection. Summary: Telemedicine will continue to be an area of increasing importance and has been found to be especially useful for regions like ours which cover many patients in remote areas across Washington, Wyoming, Idaho, Montana, and Alaska. Through the development of new techniques and the use of new technologies, we have been able to improve both the visit quality for patients and our ability to collect research data.

Paradoxical Psoriasis in Children Receiving Anti-TNFα Treatment for Inflammatory/autoimmune Disease.

Tumor necrosis factor alpha inhibitors (TNFi) are widely used in children with autoimmune and autoinflammatory conditions. Although TNFi are approved to treat psoriasis, they have also been shown to paradoxically induce psoriasiform lesions. In this review, we aim to focus on the clinical presentation and management of paradoxical psoriasis after exposure to TNFi in children with juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), or chronic nonbacterial osteomyelitis (CNO). A narrative review of the literature was performed given the limited number of publications on this topic. Children with IBD, CNO, and JIA have a higher risk of developing psoriasis at baseline, which increases after TNFi use in those with JIA and IBD. Risk factors for paradoxical psoriasis remain incompletely defined, and patients with IBD and/or CNO develop paradoxical psoriasis more commonly than those with JIA. Sex, race, and family history were not significantly associated with paradoxical psoriasis. The most commonly implicated TNFi include infliximab and adalimumab. Paradoxical psoriasis occurs in a similar distribution on the body to isolated psoriatic lesions and is morphologically indistinguishable. In many instances, topical therapies are effective in treating psoriasis and children can continue on TNFi for their primary disease. If lesions are severe or unacceptable to patients, TNFi may be switched or discontinued. Further research is needed to better characterize risk factors and understand the mechanism of disease pathogenesis. Pediatric health care providers who prescribe TNFi should counsel families regarding the risk of paradoxical psoriasis prior to starting the medication and monitor for new cutaneous eruptions.

Scurvy Due to Selective Diet in a Seemingly Healthy 4-Year-Old Boy.

Scurvy is a rare disease in developed nations. In the field of pediatrics, it primarily is seen in children with developmental and behavioral issues, malabsorptive processes, or diseases involving dysphagia. We present the case of an otherwise developmentally appropriate 4-year-old boy who developed scurvy after gradual self-restriction of his diet. He initially presented with a limp and a rash and was subsequently found to have anemia and hematuria. A serum vitamin C level was undetectable, and after review of the MRI of his lower extremities, the clinical findings supported a diagnosis of scurvy. Although scurvy is rare in developed nations, this diagnosis should be considered in a patient with the clinical constellation of lower-extremity pain or arthralgias, a nonblanching rash, easy bleeding or bruising, fatigue, and anemia. This case highlights the importance of carefully assessing a child's dietary and developmental status at well-child visits, which can help avoid a more invasive workup.