Multisystem Inflammatory Syndrome in Children and Cardiac Involvement: A Quaternary Center Experience.

We prospectively analyzed clinical and laboratory characteristics associated with cardiac involvement and severe presentation in multisystem inflammatory syndrome in children. Of 146 patients, 66 (45.2%) had cardiac dysfunction and 26 (17.8%) had coronary artery abnormalities. Lower serum albumin levels, absolute lymphocyte and platelet counts, and elevated ferritin, fibrinogen, d-dimer and interleukin-6 levels were associated with cardiac dysfunction. Possible treatment complications were identified.

Atherosclerosis Progression in the APPLE Trial Can Be Predicted in Young People With Juvenile-Onset Systemic Lupus Erythematosus Using a Novel Lipid Metabolomic Signature.

OBJECTIVE: Patients with juvenile-onset systemic lupus erythematosus (JSLE) have increased atherosclerosis risk. This study investigated novel atherosclerosis progression biomarkers in the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial, the largest investigator-led randomized control trial of atorvastatin versus placebo for atherosclerosis progression in JSLE, using carotid intima-media thickness (CIMT) as the primary outcome. METHODS: Unsupervised clustering of baseline CIMT and CIMT progression over 36 months was used to stratify patients with JSLE. Disease characteristics, cardiovascular risk scores, and baseline serum metabolome were investigated in CIMT-stratified patients. Machine learning techniques were used to identify and validate a serum metabolomic signature of CIMT progression. RESULTS: Baseline CIMT stratified patients with JSLE (N = 151) into three groups with distinct high, intermediate, and low CIMT trajectories irrespective of treatment allocation, despite most patients having low cardiovascular disease risk based on recommended assessment criteria. In the placebo group (n = 60), patients with high versus low CIMT progression had higher total (P = 0.001) and low-density lipoprotein (LDL) (P = 0.002) cholesterol levels, although within the reference range. Furthermore, a robust baseline metabolomic signature predictive of high CIMT progression was identified in the placebo arm (area under the curve, 80.7%). Patients treated with atorvastatin (n = 61) had reduced LDL cholesterol levels after 36 months, as expected; however, despite this, 36% still had high atherosclerosis progression, which was not predicted by metabolomic biomarkers, suggesting nonlipid drivers of atherosclerosis in JSLE with management implications for this subset of patients. CONCLUSION: Significant baseline heterogeneity and distinct subclinical atherosclerosis progression trajectories exist in JSLE. Metabolomic signatures can predict atherosclerosis progression in some patients with JSLE with relevance for clinical trial stratification.

Bringing Reproductive Health Guidelines Into Fellowship Training: A National Survey of Adult and Pediatric Rheumatology Fellows and Program Directors.

OBJECTIVE: This study seeks to assess rheumatology fellows' (RFs') and program directors' (PDs') interests in different educational tools and methods and to facilitate curriculum development for reproductive health related to rheumatic disease. METHODS: Constructs were conceptualized in four dimensions: 1) RF and PD confidence in their current curriculum relating to the American College of Rheumatology (ACR) Reproductive Health Guidelines (RHGs), 2) personal interest in this topic, 3) opinions of the importance of this topic, and 4) interest in a range of learning materials and educational experiences. The final survey was distributed to 753 RFs and 179 PDs in the United States using the ACR Committee on Training and Workforce email list. RESULTS: Response rates were 13% (n = 98) for RFs and 25% (n = 44) for PDs. Both groups indicated more interest in the topic than confidence in their curriculum and rated summary sheets, question banks, didactics, and online modules higher than nine other educational tools or methods. Despite interest in the topic, 38% of RF respondents and 24% of PD respondents were unaware of the recently published ACR RHGs. CONCLUSION: RFs and PDs consider reproductive health very important and report high personal interest in this topic. In contrast, both groups indicated lower confidence in current curricula, and substantial proportions of both groups were unaware of recently published guidelines. RFs' and PDs' interests in specific educational modalities are aligned. Curriculum development efforts should prioritize summary sheets, question banks, didactics, and online modules. Efforts are needed to address the educational needs of practicing rheumatologists and other professionals caring for patients with rheumatic disease.

Assessing Bleeding Symptoms in Pediatric Patients With Generalized Joint Hypermobility.

OBJECTIVE: To assess bleeding symptoms in patients with generalized/benign joint hypermobility (GJH), compare bleeding scores to healthy historical pediatric controls, and determine whether a correlation exists between Beighton scores and bleeding scores. METHODS: Patients with GJH ages 6-21 years seen by the rheumatology department at Nationwide Children's Hospital in Columbus, Ohio were eligible. Participants/guardians completed the International Society on Thrombosis and Haemostasis Bleeding Assessment Tool, a validated questionnaire defining the presence, severity, and frequency of bleeding symptoms. Scores of ≥3 have been associated with an underlying bleeding disorder in pediatric patients. RESULTS: Eighty-one patients agreed to participate. The median age was 13 years (interquartile range 10-16 years), and the mean Beighton score was 6.3 (range 4-9). Commonly observed bleeding symptoms were oral bleeding (74%), easy bruising (59%), and bleeding with minor wounds (42%). Mean and median bleeding scores were 5.2 and 4, respectively, and were significantly higher than reported bleeding scores in pediatric controls, defined as those without bleeding symptoms or a previously diagnosed bleeding disorder (P < 0.001). Although 75% of patients (95% confidence interval 64-84) had an abnormal bleeding score, only 12.3% were previously assessed by hematology for bleeding symptoms. Among patients with GJH, higher Beighton scores were not associated with higher bleeding scores (Spearman's correlation -0.08). CONCLUSION: In a cohort of pediatric patients with GJH, three-fourths of participants had abnormal bleeding scores, with the mean bleeding score significantly elevated compared to healthy controls. We propose that screening for bleeding symptoms be integrated into routine care for GJH patients, with referral to hematology for patients with bleeding concerns.

The complement system and human autoimmune diseases.

Genetic deficiencies of early components of the classical complement activation pathway (especially C1q, r, s, and C4) are the strongest monogenic causal factors for the prototypic autoimmune disease systemic lupus erythematosus (SLE), but their prevalence is extremely rare. In contrast, isotype genetic deficiency of C4A and acquired deficiency of C1q by autoantibodies are frequent among patients with SLE. Here we review the genetic basis of complement deficiencies in autoimmune disease, discuss the complex genetic diversity seen in complement C4 and its association with autoimmune disease, provide guidance as to when clinicians should suspect and test for complement deficiencies, and outline the current understanding of the mechanisms relating complement deficiencies to autoimmunity. We focus primarily on SLE, as the role of complement in SLE is well-established, but will also discuss other informative diseases such as inflammatory arthritis and myositis.

Preventing Teen Pregnancies on Teratogenic Drugs by Quality Improvement and Behavioral Economics.

BACKGROUND: Adolescents with chronic disease engage in sexual activity similar to their healthy peers, with generally low utilization of contraception. Adolescents with rheumatic diseases prescribed teratogenic medications may be at risk for unplanned pregnancy. METHODS: Using structured quality improvement (QI) methods with behavior economic (BE) principles, a multidisciplinary team aimed to implement pregnancy prevention processes for females on high-risk medications. We leveraged BE-inspired interventions including improved accessibility of consents, utilizing distinctly colored consent forms, real-time reminders, peer comparison, and audit and feedback. Our primary aim was to increase the number of days between pregnancies for postmenarcheal females followed in rheumatology clinics who were taking teratogenic medications. Phase 1 focused on annual consenting of female adolescents prescribed teratogenic drugs. Phase 2 emphasized sexual history screening and pregnancy prevention planning at every clinic visit for females ≥12 years on teratogenic medications. RESULTS: We increased the days between pregnancies for female adolescents prescribed teratogenic medications from 52 days to >900 days by using QI methodology with BE strategies. In phase 1, annual consents for postmenarcheal patients on teratogenic medications improved from 0% in 2017 to 95% in 2021. In phase 2, sexual history screening and pregnancy prevention planning at every clinic visit improved from 2% in 2019 to over 78% in 2021. CONCLUSIONS: A multiphase, multidisciplinary QI project with integration of behavior economic strategies can improve patient and caregiver counseling to prevent unplanned pregnancies for adolescents on teratogenic medications.

Postdischarge Glucocorticoid Use and Clinical Outcomes of Multisystem Inflammatory Syndrome in Children.

Importance: Minimal data are available regarding the postdischarge treatment of multisystem inflammatory syndrome in children (MIS-C). Objectives: To evaluate clinical characteristics associated with duration of postdischarge glucocorticoid use and assess postdischarge clinical course, laboratory test result trajectories, and adverse events in a multicenter cohort with MIS-C. Design, Setting, and Participants: This retrospective cohort study included patients with MIS-C hospitalized with severe illness and followed up for 3 months in an ambulatory setting. Patients younger than 21 years who were admitted between May 15, 2020, and May 31, 2021, at 13 US hospitals were included. Inclusion criteria were inpatient treatment comprising intravenous immunoglobulin, diagnosis of cardiovascular dysfunction (vasopressor requirement or left ventricular ejection fraction ≤55%), and availability of complete outpatient data for 3 months. Exposures: Glucocorticoid treatment. Main Outcomes and Measures: Main outcomes were patient characteristics associated with postdischarge glucocorticoid treatment, laboratory test result trajectories, and adverse events. Multivariable regression was used to evaluate factors associated with postdischarge weight gain (≥2 kg in 3 months) and hyperglycemia during illness. Results: Among 186 patients, the median age was 10.4 years (IQR, 6.7-14.2 years); most were male (107 [57.5%]), Black non-Hispanic (60 [32.3%]), and Hispanic or Latino (59 [31.7%]). Most children were critically ill (intensive care unit admission, 163 [87.6%]; vasopressor receipt, 134 [72.0%]) and received inpatient glucocorticoid treatment (178 [95.7%]). Most were discharged with continued glucocorticoid treatment (173 [93.0%]); median discharge dose was 42 mg/d (IQR, 30-60 mg/d) or 1.1 mg/kg/d (IQR, 0.7-1.7 mg/kg/d). Inpatient severity of illness was not associated with duration of postdischarge glucocorticoid treatment. Outpatient treatment duration varied (median, 23 days; IQR, 15-32 days). Time to normalization of C-reactive protein and ferritin levels was similar for glucocorticoid duration of less than 3 weeks vs 3 or more weeks. Readmission occurred in 7 patients (3.8%); none was for cardiovascular dysfunction. Hyperglycemia developed in 14 patients (8.1%). Seventy-five patients (43%) gained 2 kg or more after discharge (median 4.1 kg; IQR, 3.0-6.0 kg). Inpatient high-dose intravenous and oral glucocorticoid therapy was associated with postdischarge weight gain (adjusted odds ratio, 6.91; 95% CI, 1.92-24.91). Conclusions and Relevance: In this multicenter cohort of patients with MIS-C and cardiovascular dysfunction, postdischarge glucocorticoid treatment was often prolonged, but clinical outcomes were similar in patients prescribed shorter courses. Outpatient weight gain was common. Readmission was infrequent, with none for cardiovascular dysfunction. These findings suggest that strategies are needed to optimize postdischarge glucocorticoid courses for patients with MIS-C.

Low copy numbers of complement C4 and C4A deficiency are risk factors for myositis, its subgroups and autoantibodies.

BACKGROUND: Idiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases characterised by myositis-related autoantibodies plus infiltration of leucocytes into muscles and/or the skin, leading to the destruction of blood vessels and muscle fibres, chronic weakness and fatigue. While complement-mediated destruction of capillary endothelia is implicated in paediatric and adult dermatomyositis, the complex diversity of complement C4 in IIM pathology was unknown. METHODS: We elucidated the gene copy number (GCN) variations of total C4, C4A and C4B, long and short genes in 1644 Caucasian patients with IIM, plus 3526 matched healthy controls using real-time PCR or Southern blot analyses. Plasma complement levels were determined by single radial immunodiffusion. RESULTS: The large study populations helped establish the distribution patterns of various C4 GCN groups. Low GCNs of C4T (C4T=2+3) and C4A deficiency (C4A=0+1) were strongly correlated with increased risk of IIM with OR equalled to 2.58 (2.28-2.91), p=5.0×10-53 for C4T, and 2.82 (2.48-3.21), p=7.0×10-57 for C4A deficiency. Contingency and regression analyses showed that among patients with C4A deficiency, the presence of HLA-DR3 became insignificant as a risk factor in IIM except for inclusion body myositis (IBM), by which 98.2% had HLA-DR3 with an OR of 11.02 (1.44-84.4). Intragroup analyses of patients with IIM for C4 protein levels and IIM-related autoantibodies showed that those with anti-Jo-1 or with anti-PM/Scl had significantly lower C4 plasma concentrations than those without these autoantibodies. CONCLUSIONS: C4A deficiency is relevant in dermatomyositis, HLA-DRB1*03 is important in IBM and both C4A deficiency and HLA-DRB1*03 contribute interactively to risk of polymyositis.

Age-Stratified 30-day Rehospitalization and Mortality and Predictors of Rehospitalization Among Patients With Systemic Lupus Erythematosus: A Medicare Cohort Study.

OBJECTIVE: Recent studies suggest young adults with systemic lupus erythematosus (SLE) have high 30-day readmission rates, which may necessitate tailored readmission reduction strategies. To aid in risk stratification for future strategies, we measured 30-day rehospitalization and mortality rates among Medicare beneficiaries with SLE and determined rehospitalization predictors by age. METHODS: In a 2014 20% national Medicare sample of hospitalizations, rehospitalization risk and mortality within 30 days of discharge were calculated for young (aged 18-35 yrs), middle-aged (aged 36-64 yrs), and older (aged 65+ yrs) beneficiaries with and without SLE. Multivariable generalized estimating equation models were used to predict rehospitalization rates among patients with SLE by age group using patient, hospital, and geographic factors. RESULTS: Among 1.39 million Medicare hospitalizations, 10,868 involved beneficiaries with SLE. Hospitalized young adult beneficiaries with SLE were more racially diverse, were living in more disadvantaged areas, and had more comorbidities than older beneficiaries with SLE and those without SLE. Thirty-day rehospitalization was 36% among young adult beneficiaries with SLE-40% higher than peers without SLE and 85% higher than older beneficiaries with SLE. Longer length of stay and higher comorbidity risk score increased odds of rehospitalization in all age groups, whereas specific comorbid condition predictors and their effect varied. Our models, which incorporated neighborhood-level socioeconomic disadvantage, had moderate-to-good predictive value (C statistics 0.67-0.77), outperforming administrative data models lacking comprehensive social determinants in other conditions. CONCLUSION: Young adults with SLE on Medicare had very high 30-day rehospitalization at 36%. Considering socioeconomic disadvantage and comorbidities provided good prediction of rehospitalization risk, particularly in young adults. Young beneficiaries with SLE with comorbidities should be a focus of programs aimed at reducing rehospitalizations.

The pediatric glucocorticoid toxicity index.

OBJECTIVES: To develop a Pediatric glucocorticoid toxicity index (pGTI), a standardized, weighted clinical outcome assessment that measures change in glucocorticoid (GC) toxicity over time. METHODS: Fourteen physician experts from 7 subspecialties participated. The physician experts represented multiple subspecialties in which GCs play a major role in the treatment of inflammatory disease: nephrology, rheumatology, oncology, endocrinology, genetics, psychiatry, and maternal-fetal medicine. Nine investigators were from Canada, Europe, or New Zealand, and 5 were from the United States. Group consensus methods and multi-criteria decision analysis were used. The pGTI is an aggregate assessment of GC toxicities that are common, important, and dynamic. These toxicities are organized into health domains graded as minor, moderate, or major and are weighted according to severity. The relative weights were derived by group consensus and multi-criteria decision analysis using the 1000MindsTM software platform. Two quantitative scores comprise the overall toxicity profile derived from pGTI data: (1) the Cumulative Worsening Score; and (2) the Aggregate Improvement Score. The pGTI also includes a qualitative, unweighted record of GC side-effects known as the Damage Checklist, which documents less common toxicities that, although potentially severe, are unlikely to change with varying GC dosing. RESULTS: One hundred and seven (107) toxicity items were included in the pGTI and thirty-two (32) in the Damage Checklist. To assess the degree to which the pGTI corresponds to expert clinical judgement, the investigators ranked 15 cases by clinical judgement from highest to lowest GC toxicity. Expert rankings were then compared to case ranking by the pGTI, yielding excellent agreement (weighted kappa 0.86). The pGTI was migrated to a digital environment following its development and initial validation. The digital platform is designed to ensure ease-of-use in the clinic, rigor in application, and accuracy of scoring. Clinic staff enter vital signs, laboratory results, and medication changes relevant to pGTI scoring. Clinicians record findings for GC myopathy, skin toxicity, mood dysfunction, and infection. The pGTI algorithms then apply the weights to these raw data and calculate scores. Embedded logic accounts for the impact of age- and sex-related reference ranges on several health domains: blood pressure, lipid metabolism, and bone mineral density. Other algorithms account for anticipated changes in the height Z-scores used in the growth domain, thereby addressing a concern unique to GC toxicity in children. The Damage Checklist ensures comprehensive measurement of GC toxicity but does not contribute to pGTI scoring, because the scored domains emphasize manifestations of GC toxicity that are likely to change over the course of a trial. CONCLUSIONS: We describe the development and initial evaluation of a weighted, composite toxicity index for the assessment of morbidity related to GC use in children and adolescents. Developing the pGTI digital platform was essential for performing the nuanced calculations necessary to ensure rigor, accuracy, and ease-of-use in both clinic and research settings.

Adolescents' and Young Adults' Recommendations for Implementing Healthcare Transition in Rheumatology: A Mixed Methods Study.

OBJECTIVE: The goal was to elicit adolescents' and young adults' (AYAs) perspectives about how to implement the Six Core Elements of Healthcare Transition within rheumatology care. METHODS: AYAs (ages 16-28 years old) with self-reported rheumatic conditions were recruited through patient organizations and social media. In Phase One (qualitative [QUAL]), 90-minute focus groups were facilitated to elicit AYAs' reactions to Six Core Elements content. In Phase Two (quantitative; QUAN), a national survey was conducted to determine generalizability of recommendations extracted from Phase One. Mixed methods analyses were conducted by a multidisciplinary team of social science researchers, pediatric rheumatologists, and patients. RESULTS: Although focus group participants (n = 39) were previously unfamiliar with the Six Core Elements, they reacted favorably to its format and content. Participants provided suggestions for how to logistically execute each component in the clinic. Additionally, 3 overarching recommendations emerged that focused on motivating AYAs to engage: 1) frame health care transition as an opportunity for empowerment; 2) implement a structured education plan; and 3) consider the role of parents. In line with qualitative findings, survey participants (n = 137) reported that they would prefer to learn most transitional skills from and discuss developmentally specific topics with their rheumatology team. Participants reported they would likely complete programs to learn transitional skills from allied professionals, via patient portals, or in group settings. CONCLUSION: Incorporating patient perspectives into research and clinical practice is an opportunity to strengthen educational programs. AYAs emphasized the importance of gaining independence and becoming empowered through the health care transition process with structured support from their rheumatology teams.

Storming the castle: A case report of multi-system dysregulation in a child with Castleman disease.

Castleman disease is a non-clonal, lymphoproliferative disorder rarely seen in children. Presented is a 12-year-old male with progressive abdominal pain, vomiting, and fever. Diagnostic testing revealed multi-organ system involvement and the diagnosis was ultimately made with tissue biopsy. Marked disease regression occurred after high-dose steroids and continued interleukin-6 inhibition.

Use of EuroLupus Cyclophosphamide Dosing for the Treatment of Lupus Nephritis in Childhood-onset Systemic Lupus Erythematosus in North America.

OBJECTIVE: Childhood-onset systemic lupus erythematosus (cSLE) has higher rates of lupus nephritis (LN) than adult-onset SLE, often requiring intensive immunosuppression. This study examined North American practices and preferences for the low-dose EuroLupus cyclophosphamide (CYC) protocol, as compared to the high-dose National Institutes of Health (NIH) CYC protocol, to treat LN in cSLE. METHODS: A 35-item Web-based survey was distributed to Childhood Arthritis and Rheumatology Research Alliance (CARRA) and Pediatric Nephrology Research Consortium (PNRC) providers. The survey assessed participant demographics, CYC prescribing practices, perceptions of EuroLupus protocol, and LN vignette treatment decisions; 1 vignette was taken from a 2009 CARRA survey and responses were compared. Multivariable logistic regression analyzed provider factors associated with use of low- vs high-dose CYC. RESULTS: Responses were provided by 185/421 (44%) pediatric rheumatologists (CARRA) and 40/354 (11%) pediatric nephrologists (PNRC). Among respondents who prescribed CYC for pediatric LN over the past year (n = 135), half reported using EuroLupus. When presented with the same vignette about an adolescent with class IV LN, 32% of pediatric rheumatologists chose EuroLupus dosing in 2020, vs 6% in 2009. Provider factors associated with choosing the low-dose regimen were familiarity with the protocol (OR 4.2, P = 0.006) and greater perceived benefit (OR 1.6, P < 0.0001). Pediatric nephrologists had similar responses to the pediatric rheumatology providers. Overall, 78% of respondents perceived EuroLupus protocol efficacy to be equivalent to the high-dose protocol in cSLE LN. CONCLUSION: Pediatric specialists are currently more likely to use low-dose CYC to treat cSLE LN than they were a decade ago. Nevertheless, familiarity with EuroLupus dosing remains low.

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.

Human Complement C4B Allotypes and Deficiencies in Selected Cases With Autoimmune Diseases.

Human complement C4 is one of the most diverse but heritable effectors for humoral immunity. To help understand the roles of C4 in the defense and pathogenesis of autoimmune and inflammatory diseases, we determined the bases of polymorphisms including the frequent genetic deficiency of C4A and/or C4B isotypes. We demonstrated the diversities of C4A and C4B proteins and their gene copy number variations (CNVs) in healthy subjects and patients with autoimmune disease, such as type 1 diabetes, systemic lupus erythematosus (SLE) and encephalitis. We identified subjects with (a) the fastest migrating C4B allotype, B7, or (b) a deficiency of C4B protein caused by genetic mutation in addition to gene copy-number variation. Those variants and mutants were characterized, sequenced and specific techniques for detection developed. Novel findings were made in four case series. First, the amino acid sequence determinant for C4B7 was likely the R729Q variation at the anaphylatoxin-like region. Second, in healthy White subject MS630, a C-nucleotide deletion at codon-755 led to frameshift mutations in his single C4B gene, which was a private mutation. Third, in European family E94 with multiplex lupus-related mortality and low serum C4 levels, the culprit was a recurrent haplotype with HLA-A30, B18 and DR7 that segregated with two defective C4B genes and identical mutations at the donor splice site of intron-28. Fourth, in East-Asian subject E133P with anti-NMDA receptor encephalitis, the C4B gene had a mutation that changed tryptophan-660 to a stop-codon (W660x), which was present in a haplotype with HLA-DRB1*04:06 and B*15:27. The W660x mutation is recurrent among East-Asians with a frequency of 1.5% but not detectable among patients with SLE. A meticulous annotation of C4 sequences revealed clusters of variations proximal to sites for protein processing, activation and inactivation, and binding of interacting molecules.

Outcome Measures in Pediatric Rheumatic Disease.

Reliable and responsive outcome measures that accurately detect changes in disease state, activity, and damage are crucial to conducting observational and interventional trials that can directly transform care for children with rheumatic disease. A combination of consensus-based and direct measurement approaches has led to the development of several validated, composite outcome measures in juvenile idiopathic arthritis, juvenile dermatomyositis, childhood-onset systemic lupus erythematosus, and pediatric vasculitis. This review outlines clinician-reported, disease-specific outcome measures developed for these conditions.

Differences in rituximab use between pediatric rheumatologists and nephrologists for the treatment of refractory lupus nephritis and renal flare in childhood-onset SLE.

BACKGROUND: Consensus treatment plans have been developed for induction therapy of newly diagnosed proliferative lupus nephritis (LN) in childhood-onset systemic lupus erythematosus. However, patients who do not respond to initial therapy, or who develop renal flare after remission, warrant escalation of treatment. Our objective was to assess current practices of pediatric nephrologists and rheumatologists in North America in treatment of refractory proliferative LN and flare. METHODS: Members of Childhood Arthritis and Rheumatology Research Alliance (CARRA) and the American Society for Pediatric Nephrology (ASPN) were surveyed in November 2015 to assess therapy choices (other than modifying steroid dosing) and level of agreement between rheumatologists and nephrologists for proliferative LN patients. Two cases were presented: (1) refractory disease after induction treatment with corticosteroid and cyclophosphamide (CYC) and (2) nephritis flare after initial response to treatment. Survey respondents chose treatments for three follow up scenarios for each case that varied by severity of presentation. Treatment options included CYC, mycophenolate mofetil (MMF), rituximab (RTX), and others, alone or in combination. RESULTS: Seventy-six respondents from ASPN and foty-one respondents from CARRA represented approximately 15 % of the eligible members from each organization. Treatment choices between nephrologists and rheumatologists were highly variable and received greater than 50 % agreement for an individual treatment choice in only the following 2 of 6 follow up scenarios: 59 % of nephrologists, but only 38 % of rheumatologists, chose increasing dose of MMF in the case of LN refractory to induction therapy with proteinuria, hematuria, and improved serum creatinine. In a follow up scenario showing severe renal flare after achieving remission with induction therapy, 58 % of rheumatologists chose CYC and RTX combination therapy, whereas the top choice for nephrologists (43 %) was CYC alone. Rheumatologists in comparison to nephrologists chose more therapy options that contained RTX in all follow up scenarios except one (p < 0.05). CONCLUSIONS: Therapy choices for pediatric rheumatologists and nephrologists in the treatment of refractory LN or LN flare were highly variable with rheumatologists more often choosing rituximab. Further investigation is necessary to delineate the reasons behind this finding. This study highlights the importance of collaborative efforts in developing consensus treatment plans for pediatric LN.

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.

American College of Rheumatology Guidance for the Management of Pediatric Rheumatic Disease During the COVID-19 Pandemic: Version 2.

OBJECTIVE: To provide clinical guidance to rheumatology providers who treat children with pediatric rheumatic disease (PRD) in the context of the coronavirus disease 2019 (COVID-19) pandemic. METHODS: The task force, consisting of 7 pediatric rheumatologists, 2 pediatric infectious disease physicians, 1 adult rheumatologist, and 1 pediatric nurse practitioner, was convened on May 21, 2020. Clinical questions and subsequent guidance statements were drafted based on a review of the queries posed by the patients as well as the families and healthcare providers of children with PRD. An evidence report was generated and disseminated to task force members to assist with 3 rounds of asynchronous, anonymous voting by email using a modified Delphi approach. Voting was completed using a 9-point numeric scoring system with predefined levels of agreement (categorized as disagreement, uncertainty, or agreement, with median scores of 1-3, 4-6, and 7-9, respectively) and consensus (categorized as low, moderate, or high). To be approved as a guidance statement, median vote ratings were required to fall into the highest tertile for agreement, with either moderate or high levels of consensus. RESULTS: To date, 39 guidance statements have been approved by the task force. Those with similar recommendations were combined to form a total of 33 final guidance statements, all of which received median vote ratings within the highest tertile of agreement and were associated with either moderate consensus (n = 5) or high consensus (n = 28). CONCLUSION: These guidance statements have been generated based on review of the available literature, indicating that children with PRD do not appear to be at increased risk for susceptibility to SARS-CoV-2 infection. This guidance is presented as a "living document," recognizing that the literature on COVID-19 is rapidly evolving, with future updates anticipated.