Does kidney biopsy in pediatric lupus patients "complement" the management and outcomes of silent lupus nephritis? Lessons learned from a pediatric cohort.

BACKGROUND: Silent lupus nephritis (SLN) is systemic lupus erythematosus (SLE) without clinical and laboratory features of kidney involvement but with biopsy-proven nephritis. This study aims to describe and compare the baseline characteristics and outcomes of pediatric SLN with overt LN (OLN) and to identify associated risk factors and biochemical markers. METHODS: In this retrospective, observational study, multivariate logistic regression and receiver operating characteristic (ROC) analyses studied age, sex, race, serum complements, anti-double-stranded-DNA antibody, anti-Smith antibody, eGFR, and proliferative nephritis. RESULTS: In our cohort of 69 patients, 47 were OLN, and 22 were SLN. OLN (OR = 4.9, p = 0.03) and non-African Americans (AA) (OR = 13.0, p < 0.01) had higher odds, and increasing C3 and C4 were associated with lower odds of proliferative nephritis (OR 0.95 and 0.65 per one unit increase in C3 and C4, respectively, p < 0.01). They demonstrated a good discriminative ability to detect proliferative nephritis as assessed by the area under the ROC curve (C3 = 0.78, C4 = 0.78). C3 and C4 in proliferative SLN and OLN were comparable and significantly lower than their non-proliferative counterparts. No association was observed between age, sex, anti-double-stranded-DNA antibody, anti-Smith antibody, eGFR, and proliferative nephritis. Proliferative SLN and OLN patients received similar treatments. Adverse events were identified in the proliferative OLN only. CONCLUSIONS: Lower complement levels are associated with proliferative lesions in pediatric LN-both SLN and OLN. The non-AA population had higher odds of having proliferative nephritis than the AA. Prospective, randomized, long-term follow-up of proliferative SLN patients is needed to ascertain the beneficial effect of early diagnosis and treatment. A higher resolution version of the Graphical abstract is available as Supplementary information.

B-Cell depletion and immunomodulation before initiation of enzyme replacement therapy blocks the immune response to acid alpha-glucosidase in infantile-onset Pompe disease.

OBJECTIVE: To evaluate whether B-cell depletion before enzyme replacement therapy (ERT) initiation can block acid alpha-glucosidase (GAA) antibody responses and improve clinical outcomes. STUDY DESIGN: Six subjects with Pompe disease (including 4 cross-reacting immunologic material-negative infants) aged 2-8 months received rituximab and sirolimus or mycophenolate before ERT. Four subjects continued to receive sirolimus, rituximab every 12 weeks, and intravenous immunoglobulin monthly for the duration of ERT. Sirolimus trough levels, IgG, CD3, CD4, CD8, CD19, CD20, N-terminal pro-brain natriuretic peptide, creatine kinase, creatine kinase-MB, C-reactive protein, platelets, alkaline phosphatase, gamma-glutamyl transferase, aspartate aminotransferase, and alanine aminotransferase were measured regularly. RESULTS: Immunomodulation achieved B-cell depletion without adverse effects. After 17-36 months of rituximab, sirolimus and ERT, all subjects lacked antibodies against GAA, 4 continued to gain motor milestones, yet 2 progressed to require invasive ventilation. The absence of infusion-associated reactions allowed the use of accelerated infusion rates. CONCLUSION: B-cell depletion and T-cell immunomodulation in infants naïve to ERT was accomplished safely and eliminated immune responses against GAA, thereby optimizing clinical outcome; however, this approach did not necessarily influence sustained independent ventilation. Importantly, study outcomes support the initiation of immunomodulation before starting ERT, because the study regimen allowed for prompt initiation of treatment.

Bortezomib is efficacious in the treatment of severe childhood-onset neuropsychiatric systemic lupus erythematosus with psychosis: a case series and mini-review of B-cell immunomodulation in antibody-mediated diseases.

Childhood-onset neuropsychiatric systemic lupus erythematosus (cNPSLE) with psychosis is a challenging manifestation of SLE. Pathogenic long-lived plasma cells (LLPCs) are not specifically targeted by standard immunosuppression and their persistence contributes to chronic autoimmunity. Bortezomib is approved for the treatment of multiple myeloma and has shown benefits in a variety of other antibody-mediated diseases. Bortezomib may be efficacious for severe or treatment-refractory cNPSLE through eradication of LLPCs, decreasing autoantibody production. We describe the first pediatric case series of five patients with unrelenting cNPSLE with psychosis who were treated safely and effectively with bortezomib between 2011 and 2017. Most patients had persistent cNPSLE with psychosis despite aggressive immunosuppression with methylprednisolone, cyclophosphamide, rituximab, and usually plasmapheresis. All patients demonstrated rapid clinical improvement in their psychotic manifestations with the ability to quickly taper immunosuppression after the introduction of bortezomib. No patient had a recurrence of overt psychosis during a follow-up period of 1-10 years. Secondary hypogammaglobulinemia developed in all five patients and required immunoglobulin replacement. No other severe side effects or adverse events were observed. Bortezomib-mediated LLPC depletion is a promising therapy for severe recalcitrant cNPSLE with psychosis when used as adjunctive therapy to conventional immunosuppression, B-cell, and antibody-depleting therapies. After initiation of bortezomib, patients had rapid, demonstrable improvement in psychosis as well as reduction in glucocorticoids and antipsychotics. Further investigation is needed to determine the therapeutic role of bortezomib in severe cNPSLE and cSLE. We present a mini-review of the rationale for bortezomib use and novel B-cell immunomodulation in rheumatic disease.

Do United States Medical Licensing Examination (USMLE) scores predict in-training test performance for emergency medicine residents?

BACKGROUND: Residency selection committees commonly utilize USMLE scores as criteria to screen residency applicants. OBJECTIVES: The purpose of this study is to evaluate the relationship between United States Medical Licensing Examination (USMLE) and American Board of Emergency Medicine (ABEM) in-training examination scores (ITEs). METHODS: In an Accreditation Council for Graduate Medical Education-accredited emergency medicine residency program, data were collected for this retrospective cohort study for the classes of 2002-2006. USMLE Step 1 and 2 scores and the ABEM ITEs were recorded for each post-graduate year (PGY) within the aforementioned time frame. Step 1 and 2 scores were compared to consecutive PGY ABEM ITEs to evaluate for an association. RESULTS: There were 51 USMLE Step 1 and 39 Step 2 scores available for comparison with 153 ABEM ITEs. The mean USMLE Step 1 and Step 2 scores were 228.9 (range 197-252) and 228.4 (range 168-259), respectively. The mean in-training percentiles for the PGY 1, 2, and 3 years were 40.4, 68.3, and 81.7, respectively. The R-squared values for the Step 1 scores compared to the PGY 1, 2, and 3 years' ITEs were 0.25, 0.18, and 0.16, respectively. The R-squared values for Step 2 scores as compared to the ABEM ITEs for the PGY 1, 2, and 3 years were 0.43, 0.44, and 0.38, respectively. Residents who scored below 200 on either USMLE Step 1 or Step 2 had significantly lower mean ABEM ITEs than residents who scored above 200 (p < 0.05) and were 10-fold more likely than residents who scored above 220 to score below the 70th percentile in their PGY3 ABEM ITE. CONCLUSIONS: USMLE Step 1 scores are mildly correlated and Step 2 scores are moderately correlated with ABEM ITEs. Scoring below 200 on either test is associated with significantly lower ABEM ITEs.

Trimming the fat: identification of risk factors associated with obesity in a pediatric emergency department.

OBJECTIVE: The purpose of this study was to assess which knowledge deficits and dietary habits in an urban pediatric emergency department (ED) population are risk factors for obesity. METHODS: This cross-sectional study in an urban pediatric ED used a modified version of the Diet and Health Knowledge Survey, an in-person interview questionnaire, to collect data on demographics, dietary knowledge, and practices. All patients aged 2 to 17 years were enrolled in the study over a 4-month period. Subjects were excluded if they were in extremis, pregnant, incarcerated, institutionalized, considered an emancipated minor, or consumed only a modified consistency diet. RESULTS: One hundred seventy-nine subjects were enrolled in this study. Based on body mass index, the prevalence of obesity in our study population was 24%. Parents with obese children answered a mean of 62.9% (95% confidence interval, 60.4%-65.5%) of knowledge questions correctly, whereas all others scored 60.3% (95% confidence interval, 58.3%-62.3%) correctly. Based on the univariate analysis, 10 predictors met inclusion criteria into logistic regression analysis: screen time (P = 0.03), race (P = 0.08), sex (P = 0.04), parental education (P = 0.08), parental estimation that child is overweight (P < 0.0001), parental estimation that child is underweight (P = 0.003), trimming fat from meat (P = 0.06), soft-drink consumption (P = 0.03), exercise (P = 0.07), and chip consumption (P = 0.04). In a multivariate analysis, only male sex, regularly trimming fat from meat, and parental assessment of obesity were independently associated with obesity. CONCLUSIONS: Knowledge deficiencies regarding healthy nutrition among parents in an urban pediatric ED population were not significantly associated with having obese children; however, specific habits were. Emergency physicians may provide a valuable role in identification and brief behavioral intervention in high-risk populations during the current epidemic of childhood obesity.

Impact of systemic juvenile idiopathic arthritis/Still's disease on adolescents as evidenced through social media posts.

PURPOSE: To understand the experience of adolescent systemic juvenile idiopathic arthritis (SJIA) patients and those of their parents based on their social media posts. METHODS: English language posts related to SJIA, Still's disease, or juvenile arthritis were collected and analyzed. RESULTS: In total, 71 posts created between 2009 and 2015 on 15 websites were identified in November 2015. Of the 32 unique authors, 17 were SJIA patients aged 13-20 years (40 posts), 7 were mothers of SJIA patients (12 posts), and 8 patients had unspecified forms of juvenile arthritis (19 posts). Many patients posted about similar diagnostic experiences marked by 5 phases: 1) early prediagnosis: pain and fatigue overlooked until crisis occurred, 2) first misdiagnosis: doctors talked about "growing pains" and psychosocial problems ("fake pains" to avoid school), 3) second misdiagnosis: severity acknowledged, but diagnosed as leukemia or another cancer, 4) tests: tests leading to diagnosis and treatment conducted, and 5) cognitive identity: patient accepted the diagnosis and its implications. Many adolescent patients, looking back at disease onset in their childhood, described themselves as a "sleeping child" rather than the typical active child. Several patients tried to hide their illness from friends, but expressed concerns openly online. Many patients described SJIA as a powerful external enemy, using terms like "bulldozer," "dragon," and "monster." Many posts from patients and their mothers used superhero language/imagery to help "fight" SJIA. Some patients also posted about the risk of death. CONCLUSION: Although most adolescent SJIA patients openly posted about the difficulties of their disease online, they made efforts to hide their disease in the real world. They frequently used superhero words and images in describing their fight for better health. Physicians can use these insights when counseling SJIA patients to provide a narrative that meshes with the patients' worldview and perhaps to improve physician-patient communication to increase treatment adherence.

BK viruria and viremia in children with systemic lupus erythematosus.

BACKGROUND: BK virus (BKV) is a ubiquitous polyoma virus that lies dormant in the genitourinary tract once acquired in early childhood. In states of cellular immunodeficiency, the virus can reactivate to cause hemorrhagic cystitis and nephritis. Children with systemic lupus erythematosus (SLE) have an increased risk of developing infectious complications secondary to their immunocompromised state from the administration of several immuno-modulatory drugs. Currently, there are no data regarding the prevalence of BK viruria or viremia in children with SLE. METHODS: We conducted a prospective cohort study involving children with SLE of 18 years and younger. We obtained urine and blood samples at baseline and every 3 months up to 1 year for BK virus detection by real-time, quantitative polymerase chain reaction analysis. A comprehensive review of demographic information, clinical characteristics and medication history was also obtained. RESULTS: Thirty-two pediatric patients (26 females and 6 males) with SLE were enrolled. Median age at the time of SLE diagnosis and enrollment into study was 13.6 years and 16.0 years old, respectively. The prevalence at enrollment was 3.1% (1/32) for BK viruria and 6.2% (2/32) for BK viremia. During the study period, 3 patients had viruria, 5 had viremia and 4 had both viruria and viremia. Of the 12 patients with BKV reactivation, only one was positive for microscopic hematuria, all others were asymptomatic. A total of nine of 97(9.2%) urine samples and 10 of 96(10.4%) blood samples were positive for BK virus. The most commonly utilized biologics in this cohort group were Rituximab (90.6%), Abatacept (12.5%), and Belimumab (9.3%). The type of medication exposure and clinical characteristics did not statistically differ between the groups that did or did not have BK viruria and/or viremia. CONCLUSIONS: Our study suggests that pediatric patients with SLE have BK viremia and/or viruria at a higher rate than the general healthy population, although the significance of the reactivation and viral level is unclear. The influence of immune-modulatory drugs on BKV reactivation is still uncertain. To understand the interplay amongst BK virus, immunosuppression and dysregulated immune system in children with SLE, ongoing research in a larger population is still warranted, which may help establish proper surveillance, diagnosis and treatment for BKV infection.

A Case of Polyarteritis Nodosa Associated with Vertebral Artery Vasculitis Treated Successfully with Tocilizumab and Cyclophosphamide.

Pediatric polyarteritis nodosa is rare systemic necrotizing arteritis involving small- and medium-sized muscular arteries characterized by aneurysmal dilatations involving the vessel wall. Aneurysms associated with polyarteritis nodosa are common in visceral arteries; however intracranial aneurysms have also been reported and can be associated with central nervous system symptoms, significant morbidity, and mortality. To our knowledge extracranial involvement of the vertebral arteries has not been reported but has the potential to be deleterious due to fact that they supply the central nervous system vasculature. We present a case of a 3-year-old Haitian boy with polyarteritis nodosa that presented with extracranial vessel involvement of his vertebral arteries. After thorough diagnostic imaging, including a bone scan, ultrasound, Magnetic Resonance Imaging/Angiography, and Computed Tomography Angiography, he was noted to have vertebral artery vasculitis, periostitis, subacute epididymoorchitis, arthritis, and myositis. He met diagnostic criteria for polyarteritis nodosa and was treated with cyclophosphamide, methylprednisolone, and tocilizumab, which resulted in improvement of his inflammatory markers, radiographic findings, and physical symptoms after treatment. To the authors' knowledge, this is the first report of vertebral artery vasculitis in polyarteritis nodosa as well as successful treatment of the condition using the combination cyclophosphamide and tocilizumab for this condition.

The family journey-to-diagnosis with systemic juvenile idiopathic arthritis: a cross-sectional study of the changing social media presence.

BACKGROUND: Children with systemic juvenile idiopathic arthritis (SJIA) often encounter a delay between symptom onset and disease diagnosis, partly due to the broad differential of fever and lack of symptom recognition by providers. Families often seek multiple medical opinions and post on social media about their frustrations. This linguistic analysis observed the changing language patterns and social media posting behaviors of parents in the time leading to, during, and after SJIA diagnosis. METHODS: Public social media sites were manually reviewed by a linguistic team to evaluate posts about SJIA from US-based parents. RESULTS: A total of 3,979 posts between July 2001 and January 2015 were reviewed from 108 sites. Pre-SJIA diagnosis parents sought answers and shared status updates on social media, focusing primarily on the following three site types: alternative/natural lifestyle forums (39%), Facebook (27%), and disease-specific forums (17%). Posts during early prediagnosis phases were characterized by expressive language showing confidence in health care providers and trust in parental instincts. At later prediagnosis stages, parents continued to use social media, but the posts demonstrated increased frustration with delays in diagnosis and gaps in communication with providers. More objective symptom descriptions and a greatly reduced child-centered emotional focus were observed as parents shifted into caregiving roles. Once the diagnosis of SJIA was confirmed, parents used straightforward, less expressive language, and Facebook (47%) to make "announcement" posts and increased their use of SJIA websites (30%). With treatment initiation, the posts demonstrated a slow return of expressive language and an increased parental understanding of the "new normal". CONCLUSION: Parents use different language styles, frames of reference, and websites before and after SJIA diagnosis. Gaps in parent-provider communication, especially before diagnosis, and their new roles as caregivers lead to parental use of social media to express frustration with the health care process. Providers should tailor their discussions with parents to address these issues.

Review article: BK virus in systemic lupus erythematosus.

BK virus (BKV) is a human polyomavirus with a seroprevalence of 60-80 % in the general population. In renal transplant patients, it is known to cause renal failure, ureteric stenosis and hemorrhagic cystitis. In bone marrow transplant patients, it is evident that BKV can also cause hemorrhagic cystitis along with BK virus nephropathy (BKVN) in the native kidneys, with subsequent renal failure. However, little is known about BVKN in non-transplanted immune-compromised patients, such as systemic lupus erythematosus (SLE) who may have underlying nephritis and have a compromised immune system due to therapy and/or systemic illness. Thus, this article will focus on the clinical aspects of BKV and its association in patients with SLE.

Teaching musculoskeletal physical diagnosis using a web-based tutorial and pathophysiology-focused cases.

OBJECTIVE: To assess the effectiveness of an experimental curriculum on teaching first-year medical students the musculoskeletal exam as compared to a traditional curriculum. BACKGROUND: Musculoskeletal complaints are common in the primary care setting. Practitioners are often deficient in examination skills and knowledge regarding musculoskeletal diseases. There is a lack of uniformity regarding how to teach the musculoskeletal examination among sub-specialists. We propose a novel web-based approach to teaching the musculoskeletal exam that is enhanced by peer practice with pathophysiology-focused cases. We sought to assess the effectiveness of an innovative musculoskeletal curriculum on the knowledge and skills of first-year medical students related to musculoskeletal physical diagnosis as compared to a traditional curriculum. The secondary purpose of this study was to assess satisfaction of students and preceptors exposed to this teaching method. METHODS: This quasi-experimental study was conducted at a single LCME-accredited medical school and included a convenience sample from 2 consecutive classes of medical students during the musculoskeletal portion of their physical diagnosis class. We conducted a needs assessment of the traditional curriculum used to teach musculoskeletal examination. The needs assessment informed the development of an experimental curriculum. One class (control group) received the traditional curriculum while the second class (experimental group) received the experimental curriculum, consisting of a web-based musculoskeletal tutorial, pathophysiology-focused cases, and facilitator preparation. We used multiple-choice questions and musculoskeletal OSCE scores to assess differences between knowledge and skills in the 2 groups. RESULTS: The sample consisted of 140 students in each medical school class. There were no statistically significant differences between the 2 groups. One hundred seven students from the control group and 120 students from the experimental group took the multiple-choice examination. The average score was 66% (95% CI= 59.7-72.3) for the control group and 66% (95% CI = 60.5-71.5) for the experimental group. There was no difference between the median musculoskeletal OSCE scores between the 2 groups. The experimental group was satisfied with the new teaching method and gained the additional benefit of a persistent resource. CONCLUSIONS: This web-based experimental curriculum was as effective as the traditional curriculum for teaching the musculoskeletal exam. Additionally, users were satisfied with the web-based training and benefited from a persistent resource.