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.

Disseminated Ureaplasma polyarthritis in a renal transplant recipient.

BACKGROUND: The risk of infection following kidney transplant increases substantially in the setting of hypogammaglobulinemia and T-cell-depleting therapy. Ureaplasma has been described to cause invasive disease in immunocompromised hosts with humoral immunodeficiency. We describe a kidney transplant recipient with history of antineutrophil cytoplasmic autoantibody (ANCA) vasculitis remotely treated with rituximab who developed Ureaplasma polyarthritis following transplant. The purpose of this report is to highlight the unique risks that kidney transplant patients face particularly if hypogammaglobulinemic. CASE REPORT: Patient is a 16-year-old female with history of granulomatosis with polyangiitis (GPA) treated with maintenance dose of rituximab 13 months prior to transplant. Patient underwent deceased donor kidney transplant with thymoglobulin induction. IgG was 332 mg/dL and CD20 was zero at the time of transplant. One month posttransplant, the patient developed polyarticular arthritis without fever, pyuria, or evidence of GPA reactivation. MRI had diffuse tenosynovitis, myositis, fasciitis, cellulitis, and effusions of three involved joints. Bacterial, fungal, and AFB cultures remained negative, but 16 s ribosomal PCR testing from joint aspirates detected Ureaplasma parvum. The patient was treated with levofloxacin for 12 weeks with the resolution of symptoms. CONCLUSIONS: Ureaplasma infection is an under-recognized pathogen in kidney transplant patients. A high index of clinical suspicion should be employed to identify Ureaplasma infection, especially in those with secondary hypogammaglobulinemia, as this is often missed due to its lack of growth on standard media and the need for molecular testing. In patients with prior B-cell depletion, routine monitoring for B-cell recovery to identify risk factors for opportunistic infections is indicated.

Non-pharmacologic therapies in treatment of childhood-onset systemic lupus erythematosus: A systematic review.

BACKGROUND: Childhood-onset systemic lupus erythematosus (cSLE) is a complex multisystem autoimmune disease often associated with pain, fatigue, and mood-related disturbances. cSLE is associated with increased disease severity and higher rates of mortality as compared to adult onset SLE. Therefore, a multi-faceted approach to care, including the use of non-pharmacologic therapies, is essential to ensure optimal patient outcomes. The use of non-pharmacologic therapies as adjunctive treatments has been shown to be beneficial in adults with SLE, yet, their use and effect is less well understood in cSLE. This is the first systematic review to explore the use and quality of evidence of non-pharmacologic approaches to treat cSLE. METHODS: A literature review was performed using PRISMA guidelines. Studies until March 2021 with participants diagnosed with cSLE were included. The quality of the evidence was graded via OCEBM levels of evidence guidelines and bias assessed using Cochrane guidelines. Completed clinical trials (via clinicaltrials.gov) were also searched to identify unpublished results. RESULTS: Eleven published studies consisting of 1152 patients met inclusion criteria for this review, as well as three additional studies with unpublished data on clinicaltrial.gov. Of the published trials, four studies used patient education/support, three studies used dietary supplementation, three used forms of psychotherapy (e.g., Cognitive behavioral therapy), and 1 used aerobic exercise to target the following issues: treatment adherence (n = 3), quality of life (n = 3), fatigue (n = 2), pain (n = 2), depressive symptoms (n = 1), anxiety (n = 1), and health-related outcomes including disease severity (n = 3), cardiovascular disease risk (Cardiovascular disease; n = 3), and muscle function (n = 1). Across investigations, the quality of the evidence based on study design was moderate/low. In terms of potential outcomes, dietary supplementation methods were successful in 2 of 3 studies and were associated with improvements in disease activity and fatigue. Aerobic exercise was effective in decreasing resting heart rate and increasing cardiorespiratory capacity. Patient education/support was related to significantly increased treatment adherence and decreased cardiovascular risk markers. Two of the three studies examining the impact of psychotherapy showed improvements (e.g., in treatment adherence, depression and fatigue). CONCLUSION: This review identifies several promising non-pharmacologic therapies to use as adjunctive treatments to traditional pharmacologic regimens in health and mental health-related outcomes in patients with cSLE. Future well controlled clinical trials would be beneficial to more rigorously evaluate the effects of non-pharmacologic therapies in pediatric populations.

A descriptive study on multisystem inflammatory syndrome in children in a single center in West Michigan.

BACKGROUND: Multisystem Inflammatory Syndrome in Children (MIS-C) is a rare hyperinflammatory condition that occurs following SARS-CoV-2 infection. There is a paucity of research describing risk factors, optimal management, and outcomes of this life-threatening condition. METHODS: This is a case series of 26 patients diagnosed with MIS-C in a West Michigan pediatric tertiary care center from April 2020 to February 2021. We describe the clinical, imaging, and laboratory characteristics of these patients and detail their treatments and outcomes with comparisons between Pediatric Intensive Care Unit (PICU) and non-PICU patients. Categorical testing utilized Chi-square and Fisher's Exact tests. Comparison between groups used T-tests or Kruskal-Wallis. RESULTS: Fifteen patients (57%) required intensive care. There was no statistically significant difference in demographics between PICU and non-PICU patients, however all Black patients required intensive care. Gastrointestinal symptoms were present in 22 patients (84%). Seventeen patients (65%) had Kawasaki-like features and 12 (46%) developed coronary artery dilation. Patients requiring intensive care were less likely to have a reported history of COVID-19 disease or exposure (p = 0.0362). Statistically significant differences were also noted in peak ferritin (p = 0.0075), procalcitonin, and BNP in those who required intensive care. CONCLUSIONS: Although overlap exists with other hyperinflammatory conditions, our study provides further evidence that MIS-C is a distinct, albeit heterogenous, disorder with various degrees of cardiac involvement. Anakinra, in conjunction with steroid use, appears to be effective and safe in the treatment of MIS-C. This report identifies procalcitonin, peak ferritin, and BNP as potentially useful biomarkers for severity of disease.

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 to Predict Response to Lupus Nephritis Therapy in Children and Young Adults.

OBJECTIVE: To delineate urine biomarkers that forecast response to therapy of lupus nephritis (LN). METHODS: Starting from the time of kidney biopsy, patients with childhood-onset systemic lupus erythematosus who were diagnosed with LN were studied serially. Levels of 15 biomarkers were measured in random spot urine samples, including adiponectin, α-1-acid glycoprotein (AGP), ceruloplasmin, hemopexin, hepcidin, kidney injury molecule 1, monocyte chemotactic protein-1, lipocalin-like prostaglandin D synthase (LPGDS), transforming growth factor-ß (TGF-ß), transferrin, and vitamin D binding protein (VDBP). RESULTS: Among 87 patients (mean age 15.6 yrs) with LN, there were 37 treatment responders and 50 nonresponders based on the American College of Rheumatology criteria. At the time of kidney biopsy, levels of TGF-ß (p < 0.0001) and ceruloplasmin (p = 0.006) were significantly lower among responders than nonresponders; less pronounced differences were present for AGP, hepcidin, LPGDS, transferrin, and VDBP (all p < 0.05). By Month 3, responders experienced marked decreases of adiponectin, AGP, transferrin, and VDBP (all p < 0.01) and mean levels of these biomarkers were all outstanding (area under the receiver-operating characteristic curve ≥ 0.9) for discriminating responders from nonresponders. Patient demographics and extrarenal disease did not influence differences in biomarker levels between response groups. CONCLUSION: Low urine levels of TGF-ß and ceruloplasmin at baseline and marked reduction of AGP, LPGDS, transferrin, or VDBP and combinations of other select biomarkers by Month 3 are outstanding predictors for achieving remission of LN. If confirmed, these results can be used to help personalize LN therapy.

Relationship of cell-free urine MicroRNA with lupus nephritis in children.

BACKGROUND: MicroRNAs (miRNAs) are involved in the post-transcriptional regulation of genes. The objective of this study was to investigate whether select urinary cell-free microRNA's may serve as biomarkers in children with active lupus nephritis (LN) and to assess their relationship to the recently identified combinatorial urine biomarkers, a.k.a. the LN-Panel (neutrophil gelatinase associated lipocalin, monocyte chemotactic protein 1, transferrin, and beta-trace protein). METHODS: miRNAs (125a, 127, 146a, 150 and 155) were measured using real-time polymerase chain reaction in the urine pellet (PEL) and supernatant (SUP) in 14 patients with active LN, 10 patients with active extra-renal lupus, and 10 controls. The concentrations of the LN-Panel biomarkers (neutrophil gelatinase associated lipocalin, monocyte chemotactic protein-1, transferrin, beta-trace protein) was assayed. Traditional laboratory and clinical measures of LN and lupus (complements, protein to creatinine ratio; Systemic Lupus Erythematosus Disease Activity Index) were also measured. RESULTS: All tested miRNAs in the SUP, but not the PEL, were associated with the LN-Panel biomarkers (0.3 < |r Pearson| < 0.73; p < 0.05), miRNA125a, miRNA127,miRNA146a also with C3 and dsDNA antibody levels (|r Pearson| > 0.24; p < 0.05), and miRNA146a with the renal domain of the SLEDAI (|r Pearson| = 0.32; p < 0.05). Mean miRNA levels of patients with active LN did not statistically (P > 0.05) differ from those of SLE patients without LN or controls. CONCLUSION: Levels of cell-free miR-125a, miR-150, and miR-155 in the urine supernatant are associated with the expression of LN-Panel biomarkers and some LN measures. These miRNA's may complement, but are unlikely superior to the LN-Panel for estimating concurrent LN activity.

Development of a Novel Renal Activity Index of Lupus Nephritis in Children and Young Adults.

OBJECTIVE: Noninvasive estimation of the degree of inflammation seen on kidney biopsy with lupus nephritis (LN) remains difficult. The objective of this study was to develop a Renal Activity Index for Lupus (RAIL) that, based solely on laboratory measures, accurately reflects histologic LN activity. METHODS: We assayed traditional LN laboratory tests and 16 urine biomarkers (UBMs) in children (n = 47) at the time of kidney biopsy. Histologic LN activity was measured by the National Institutes of Health activity index (NIH-AI) and the tubulointerstitial activity index (TIAI). High LN-activity status (versus moderate/low) was defined as NIH-AI scores >10 (versus ≤10) or TIAI scores >5 (versus ≤5). RAIL algorithms that predicted LN-activity status for both NIH-AI and TIAI were derived by stepwise multivariate logistic regression, considering traditional biomarkers and UBMs as candidate components. The accuracy of the RAIL for discriminating by LN-activity status was determined. RESULTS: The differential excretion of 6 UBMs (neutrophil gelatinase-associated lipocalin, monocyte chemotactic protein 1, ceruloplasmin, adiponectin, hemopexin, and kidney injury molecule 1) standardized by urine creatinine was considered in the RAIL. These UBMs predicted LN-activity (NIH-AI) status with >92% accuracy and LN-activity (TIAI) status with >80% accuracy. RAIL accuracy was minimally influenced by concomitant LN damage. Accuracies between 71% and 85% were achieved without standardization of the UBMs. The strength of these UBMs to reflect LN-activity status was confirmed by principal component and linear discriminant analyses. CONCLUSION: The RAIL is a robust and highly accurate noninvasive measure of LN activity. The measurement properties of the RAIL, which reflect the degree of inflammatory changes as seen on kidney biopsy, will require independent validation.

Validation of the Lupus Nephritis Clinical Indices in Childhood-Onset Systemic Lupus Erythematosus.

OBJECTIVE: To validate clinical indices of lupus nephritis activity and damage when used in children against the criterion standard of kidney biopsy findings. METHODS: In 83 children requiring kidney biopsy, the Systemic Lupus Erythematosus Disease Activity Index renal domain (SLEDAI-R), British Isles Lupus Assessment Group index renal domain (BILAG-R), Systemic Lupus International Collaborating Clinics (SLICC) renal activity score (SLICC-RAS), and SLICC Damage Index renal domain (SDI-R) were measured. Fixed effects and logistic models were calculated to predict International Society of Nephrology/Renal Pathology Society (ISN/RPS) class; low-to-moderate versus high lupus nephritis activity (National Institutes of Health [NIH] activity index [AI]) score: ≤10 versus >10; tubulointerstitial activity index (TIAI) score: ≤5 versus >5; or the absence versus presence of lupus nephritis chronicity (NIH chronicity index) score: 0 versus ≥1. RESULTS: There were 10, 50, and 23 patients with ISN/RPS class I/II, III/IV, and V, respectively. Scores of the clinical indices did not differentiate among patients by ISN/RPS class. The SLEDAI-R and SLICC-RAS but not the BILAG-R differed with lupus nephritis activity status defined by NIH-AI scores, while only the SLEDAI-R scores differed between lupus nephritis activity status based on TIAI scores. The sensitivity and specificity of the SDI-R to capture lupus nephritis chronicity was 23.5% and 91.7%, respectively. Despite being designed to measure lupus nephritis activity, SLICC-RAS and SLEDAI-R scores significantly differed with lupus nephritis chronicity status. CONCLUSION: Current clinical indices of lupus nephritis fail to discriminate ISN/RPS class in children. Despite its shortcomings, the SLEDAI-R appears best for measuring lupus nephritis activity in a clinical setting. The SDI-R is a poor correlate of lupus nephritis chronicity.

Biomarkers for childhood-onset systemic lupus erythematosus.

Childhood-onset systemic lupus erythematosus (cSLE) is a systemic autoimmune disease characterized by the presence of autoantibodies. cSLE often affects multiple organs in the body and is known to have a poorer prognosis than adult-onset disease (Azevedo et al. 2014). Current laboratory tests are clearly insufficient for identifying and monitoring the disease. Recent studies have yielded novel biomarkers for cSLE which can be used for monitoring disease activity and response to treatment. The most encouraging biomarkers will be discussed herein and include cell-bound complement activation products, some genomic profiles, and urinary proteins such as neutrophil gelatinase-associated lipocalin, monocyte chemoattractant protein-1, and others. Previous studies suggested that a combination of the novel biomarkers might help to enhance sensitivity and specificity for early diagnosis, disease monitoring, and prediction of cSLE flares.