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.

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.

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.

Despite high objective numeracy, lower numeric confidence relates to worse financial and medical outcomes.

People often laugh about being "no good at math." Unrecognized, however, is that about one-third of American adults are likely too innumerate to operate effectively in financial and health environments. Two numeric competencies conceivably matter-objective numeracy (ability to "run the numbers" correctly; like literacy but with numbers) and numeric self-efficacy (confidence that provides engagement and persistence in numeric tasks). We reasoned, however, that attaining objective numeracy's benefits should depend on numeric confidence. Specifically, among the more objectively numerate, having more numeric confidence (vs. less) should lead to better outcomes because they persist in numeric tasks and have the skills to support numeric success. Among the less objectively numerate, however, having more (vs. less) numeric confidence should hurt outcomes, as they also persist, but make unrecognized mistakes. Two studies were designed to test the generalizability of this hypothesized interaction. We report secondary analysis of financial outcomes in a diverse US dataset and primary analysis of disease activity among systemic lupus erythematosus patients. In both domains, best outcomes appeared to require numeric calculation skills and the persistence of numeric confidence. "Mismatched" individuals (high ability/low confidence or low ability/high confidence) experienced the worst outcomes. For example, among the most numerate patients, only 7% of the more numerically confident had predicted disease activity indicative of needing further treatment compared with 31% of high-numeracy/low-confidence patients and 44% of low-numeracy/high-confidence patients. Our work underscores that having 1 of these competencies (objective numeracy or numeric self-efficacy) does not guarantee superior outcomes.

Improving eye screening practice among pediatric rheumatology patients receiving hydroxychloroquine.

OBJECTIVE: Hydroxychloroquine (HCQ) is commonly used in the treatment of various autoimmune diseases related to its many benefits and favorable safety profile. Although HCQ retinopathy was considered to be uncommon, a prevalence of 7.5% was described in a recent study making early detection critical. The most updated screening guidelines by the American Academy of Ophthalmology were published in 2016; however, it lacked pediatric-specific recommendations and the overall compliance with screening guidelines was poor in previous studies. We developed a quality improvement (QI) initiative aiming to create institutional screening recommendations. Additionally, to increase eye screening in pediatric rheumatology clinic for patients receiving HCQ from 65% to 85% in 12 months and to sustain that rate for at least 6 months. METHODS: We formed a multidisciplinary team of pediatric rheumatologists and ophthalmologists, clinical pharmacist, clinic nurses, QI specialist, quality data technician and administrative staff. We included patients receiving HCQ and who were evaluated at Nationwide Children's Hospital rheumatology clinic. A key driver diagram was formulated to identify barriers to compliance and determine possible interventions. Main interventions included summarizing screening guidelines in a step by step algorithm, increasing awareness of these guidelines among patients and providers, improving collaboration and communication with ophthalmologists, and initiating pre-visit planning. RESULTS: Baseline performance data included 164 patients. Fifty-four (33%) of those patients were at high risk for HCQ retinopathy. Of them, 50% were on HCQ dose of >5 mg/kg/day and 31.5% had been taking HCQ for ≥5 years. Two center line shifts were noticed over the course of the project. The target of 85% compliance was reached in February 2019 and was sustained until December 2019. CONCLUSIONS: Our study highlights the importance of interdisciplinary communication to increase awareness of screening guidelines among medical providers and patients. Pre-visit planning played a major role in identifying patients and opportunities for optimizing eye screening in patients at risk for HCQ retinopathy. Collaboration between rheumatologists and ophthalmologists is crucial in managing patients on HCQ. The implementation of same-day eye screening allowed this collaboration to be more efficient. Future efforts are being directed at monitoring and improving utilization of the effective interventions.

Autoimmune thyroid diseases, autoimmune hepatitis, celiac disease and type 1 diabetes mellitus in pediatric systemic lupus erythematosus: Results from the CARRA Legacy Registry.

OBJECTIVE: Polyautoimmunity (PA) with systemic lupus erythematosus (SLE) is reported as a poor prognostic factor, but little is known about its effect in childhood-onset SLE (cSLE). We describe PA in cSLE within the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Legacy Registry and evaluate its association to lupus disease outcomes. METHODS: CARRA Legacy Registry is the largest pediatric rheumatology registry that collected data at enrollment and every 6 months thereafter. We describe the co-occurrence of selected autoimmune disorders (autoimmune thyroid diseases, autoimmune hepatitis, celiac disease and type 1 diabetes mellitus) in cSLE. To assess outcomes, we studied measures of lupus disease activity, complications, and patient's quality of life (QoL). Comparisons by PA status were made using chi-square, Fisher's exact test, two-sample t-tests, Wilcoxon rank sum tests, and mixed effects models as appropriate. RESULTS: 1285 patients met the American College of Rheumatology criteria for SLE. Of those, 388 (30%) had data on comorbidity. The prevalence of PA was 8.8%. Patients with PA reported more hospitalizations and aggressive immunotherapy use. SLEDAI and PGA scores improved over time, but did not differ by PA status. No significant differences were found in QoL measures or their trajectory over time by PA status. CONCLUSION: In cSLE, PA is associated with more hospitalizations and aggressive immunotherapy use. Although lupus disease activity improved over time, patients' QoL neither improved over time nor differed by having other autoimmune disease. Prospective, case-control, long-term follow-up studies on cSLE are needed to validate our results. MESH KEY INDEXING TERMS: Pediatric systemic lupus erythematosus; Autoimmune diseases; Outcome assessment.

Pathological manifestation of autoimmune myocarditis is detected prior to glomerulonephritis in a murine model of lupus nephritis.

OBJECTIVE: Since enhanced cardiac magnetic resonance imaging (cMRI) signals have been associated with lupus disease activity in humans prior to renal failure and novel, cardiac-focused therapeutic strategies could be investigated with an associated animal model, autoimmune myocarditis was characterized in murine lupus nephritis (NZM2410). METHODS: Weekly blood urea nitrogen (BUN) levels and weights were recorded. Cardiac function was assessed by echocardiogram. Myocardial edema was measured with quantitative T2 cMRI mapping. Endpoint serum and cardiac tissue were collected for histopathological analysis and cytokine measurements. RESULTS: Despite showing no signs of significant renal disease, mice displayed evidence of myocarditis and fibrosis histologically at 30-35 weeks. Moreover, T2 cMRI mapping displayed robust signals and analysis of sagittal heart sections showed significant myocardium thickening. Cytokine expression levels of IL-2, IL-10, TNF-α, CXCL1, and IL-6 were significantly enhanced in serum. Echocardiograms demonstrated significantly increased ventricular diameters and reduced ejection fractions, while immunohistochemical staining identified CD4+ and CD8+ T cells, and IL-17 in cardiac infiltrates. Human lupus cardiac tissue showed similar histopathology with enhanced infiltrates by H&E, fibrosis, and CD4+ detection. CONCLUSIONS: Histopathology, functional abnormalities, and enhanced cMRI signals indicative of myocarditis are detected in NZM2410 mice without glomerulonephritis, which supports the primary pathological role of autoimmune-mediated, cardiac-targeted inflammation in lupus.

Healthcare Use Patterns and Economic Burden of Chronic Musculoskeletal Pain in Children before Diagnosis.

OBJECTIVES: To evaluate the healthcare use and costs of amplified musculoskeletal pain syndrome (AMPS) in children before diagnosis. STUDY DESIGN: We performed a retrospective study in children with AMPS at a pediatric rheumatology clinic between 2010 and 2014. Data were abstracted on 80 patients after primary rheumatic diseases were excluded. Healthcare visits, medications and diagnostic testing that occurred in the years before diagnosis were collected. The Medical Expenditure Panel Survey was used to estimate visit costs. RESULTS: Patients were adolescent females (89%) and white (86%). The median time to diagnosis was 10.2 months. The median pain score was 6.5 and the median Childhood Health Assessment Questionnaire score was 1.1. In this cohort, 29% had at least 1 ED visit and 5% were hospitalized. All patients saw a rheumatologist and 41% had visited another specialist, typically orthopedics and sports medicine. More than one-half had at least 1 radiographic study and 21% had at least 1 magnetic resonance imaging. The total cost for office, emergency department, and hospital visits for AMPS in all 80 patients was $152 853. The mean cost per patient over the entire study period (2008-2014) was $1911 ± $3808, and 43% of costs were outpatient visits. CONCLUSIONS: Children with AMPS have high levels of disability and take a long time to be diagnosed. As a result, even before diagnosis, they have high levels of healthcare use, diagnostic testing, and medical costs. Early recognition of disability and quicker referral to trained subspecialists may improve the prognosis, reduce unnecessary testing, and reduce the overall costs of healthcare.

Secondary analysis of APPLE study suggests atorvastatin may reduce atherosclerosis progression in pubertal lupus patients with higher C reactive protein.

OBJECTIVE: Participants in the Atherosclerosis Prevention in Paediatric Lupus Erythematosus (APPLE) trial were randomised to placebo or atorvastatin for 36 months. The primary endpoint, reduced carotid intima medial thickness (CIMT) progression, was not met but atorvastatin-treated participants showed a trend of slower CIMT progression. Post-hoc analyses were performed to assess subgroup benefit from atorvastatin therapy. METHODS: Subgroups were prespecified and defined by age (> or ≤15.5 years), systemic lupus erythematosus (SLE) duration (> or ≤24 months), pubertal status (Tanner score≥4 as post-pubertal or <4 as pre-pubertal), low density lipoprotein cholesterol (LDL) (≥ or <110 mg/dl) and high-sensitivity C reactive protein (hsCRP) (≥ or <1.5 mg/l). A combined subgroup (post-pubertal and hsCRP≥1.5 mg/l) was compared to all others. Longitudinal linear mixed-effects models were developed using 12 CIMT and other secondary APPLE outcomes (lipids, hsCRP, disease activity and damage, and quality of life). Three way interaction effects were assessed for models. RESULTS: Significant interaction effects with trends of less CIMT progression in atorvastatin-treated participants were observed in pubertal (3 CIMT segments), high hsCRP (2 CIMT segments), and the combined high hsCRP and pubertal group (5 CIMT segments). No significant treatment effect trends were observed across subgroups defined by age, SLE duration, LDL for CIMT or other outcome measures. CONCLUSIONS: Pubertal status and higher hsCRP were linked to lower CIMT progression in atorvastatin-treated subjects, with most consistent decreases in CIMT progression in the combined pubertal and high hsCRP group. While secondary analyses must be interpreted cautiously, results suggest further research is needed to determine whether pubertal lupus patients with high CRP benefit from statin therapy. TRIAL REGISTRATION: Clinical Trials.gov Identifier: NCT00065806.

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.

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.

Autoantibodies in chronic idiopathic urticaria and nonurticarial systemic autoimmune disorders.

BACKGROUND: Chronic idiopathic urticaria (CU) has been associated with other autoimmune diseases and basophil-activating autoantibodies to FcεRI or IgE. It is unknown whether patients with systemicautoimmune diseases have a similar prevalence of these autoantibodies. OBJECTIVE: To compare the prevalences of basophil-activating autoantibodies (elevated CU Index) in patients with CU, rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). Clinical characteristics and laboratory studies were examined for an association with the CU Index. METHODS: Adult patients, 27 with CU, 27 with RA, and 26 with SLE, and 20 healthy controls were compared on the basis of the CU Index panel, anti-IgE, and antithyroid antibodies. RESULTS: The CU Index values were significantly higher in the CU group when compared with the RA group but not when compared with the SLE group. 33% of CU, 23% of SLE, 3.7% of RA, and 15% of controls had apositive CU Index. Elevated antithyroid antibody levels did not correlate with a positive CU Index in any of the groups. An elevated CU Index in the SLE group was not associated with age, sex, ethnicity, disease severity, or history of atopy. CONCLUSION: The CU Index values were elevated in patients with CU and SLE. The presence of these autoantibodies did not correlate with disease activity or presence of thyroid antibodies. Functional autoantibodies may not be specific for chronic idiopathic urticaria, and their role in nonurticarial systemic autoimmune diseases requires further investigation.

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.

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.

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.

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.

An update on stem cell transplantation in autoimmune rheumatologic disorders.

Stem cell transplant (SCT) has long been the standard of care for several hematologic, immunodeficient, and oncologic disorders. Recently, SCT has become an increasingly utilized therapy for refractory autoimmune rheumatologic disorders (ARDs). The efficacy of SCT in ARDs has been attributed to resetting an aberrant immune system either through direct immune replacement with hematopoietic stem cells or through immunomodulation with mesenchymal stem cells. Among ARDs, refractory systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are the most common indications for SCT. SCT has also been used in refractory rheumatoid arthritis, inflammatory myopathies, antiphospholipid syndrome, granulomatosis with polyangiitis, and pediatric ARDs. Complete responses have been reported in approximately 30 % of patients in all disease categories. Transplant-related mortality, however, remains a concern. Future large multi-center prospective randomized clinical trials will help to better define the specific role of SCT in the treatment of patients with ARDs.

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.