PROMIS Computer Adaptive Tests and Their Correlation With Disease Activity in Juvenile Idiopathic Arthritis.

BACKGROUND/OBJECTIVE: The importance of patient-reported outcomes, like the Patient-Reported Outcomes Measurement Information System (PROMIS) measures, is increasingly recognized both in clinical care and in research. While "short forms" have been studied in juvenile idiopathic arthritis (JIA), study of PROMIS computer adaptive tests (CATs) in JIA is limited. This cross-sectional study evaluates whether PROMIS CATs correlate with disease activity in patients with JIA. METHODS: A convenience sample of patients with JIA (N = 44) was recruited from a single center. Patients and parents completed pediatric and parent proxy PROMIS CATs. Disease activity was evaluated using the Juvenile Arthritis Disease Activity Score in 71 joints (JADAS-71) and the Childhood Health Assessment Questionnaire (CHAQ). Correlation of the CAT T scores with disease activity was assessed using Spearman correlation coefficients. RESULTS: Forty-four of 80 eligible subjects (29 patients and 15 parents) completed all or some PROMIS CATs. Pain interference and mobility CATs correlated moderately with JADAS-71. Nearly all correlations with the JADAS-71 were weakened when the patient global was removed. Pain interference, mobility, and fatigue were strongly correlated with the CHAQ. Among parent proxy CATs, only mobility and depressive symptoms correlated strongly with the CHAQ. CONCLUSIONS: Only pain interference and mobility PROMIS CATs showed strong correlation with standard disease activity measures in JIA, and nearly all correlations were weakened when the patient global was removed. Correlations of the CATs with the CHAQ were stronger than correlations with the JADAS-71, indicating that although the CHAQ is no longer routinely used it may be a better measure of health-related quality of life in routine clinical care.

Protein Delivery of an Artificial Transcription Factor Restores Widespread Ube3a Expression in an Angelman Syndrome Mouse Brain.

Angelman syndrome (AS) is a neurological genetic disorder caused by loss of expression of the maternal copy of UBE3A in the brain. Due to brain-specific genetic imprinting at this locus, the paternal UBE3A is silenced by a long antisense transcript. Inhibition of the antisense transcript could lead to unsilencing of paternal UBE3A, thus providing a therapeutic approach for AS. However, widespread delivery of gene regulators to the brain remains challenging. Here, we report an engineered zinc finger-based artificial transcription factor (ATF) that, when injected i.p. or s.c., crossed the blood-brain barrier and increased Ube3a expression in the brain of an adult mouse model of AS. The factor displayed widespread distribution throughout the brain. Immunohistochemistry of both the hippocampus and cerebellum revealed an increase in Ube3a upon treatment. An ATF containing an alternative DNA-binding domain did not activate Ube3a. We believe this to be the first report of an injectable engineered zinc finger protein that can cause widespread activation of an endogenous gene in the brain. These observations have important implications for the study and treatment of AS and other neurological disorders.

Takayasu arteritis presenting in the context of active tuberculosis: a pediatric case.

Takayasu arteritis (TA) is a large-vessel vasculitis, most commonly presenting in young adults and more rarely in pediatric patients. An apparent association between TA and Mycobacterium tuberculosis has been noted previously, although this potential relationship is not yet understood. We present the case of a 16-year-old Haitian girl diagnosed with TA, originally presenting in the context of active tuberculosis. Our patient has been treated with antituberculosis therapy, corticosteroids, methotrexate, and rituximab to control her continued active vasculitis. With this case report, we seek to promote further exploration of the apparent association between TA and tuberculosis, as further clarification of the nature of this relationship may lead to the development of more targeted therapies and better outcomes for TA patients.

"It's Just a Checklist": Examining the Needs of Occupational Health and Safety Training for New Immigrant Workers in Canada.

OBJECTIVES: New immigrant workers (NIWs) are overrepresented in hazardous workplaces. Sufficient Occupational Health and Safety (OH&S) training could minimize workplace injuries. This study aims to identify the current status of OH&S and training for NIWs in Canada. METHODS: Generic qualitative research was conducted. Seven NIWs and nine service providers were interviewed to understand OH&S issues, perceptions on rules and regulations, and expectations for training. Thematic analysis was used for data analysis. RESULTS: Four themes that affect OH&S for NIWs include attitudes toward safety and training, personal barriers, Canadian workplace culture, and macrolevel interconnected systems. Three needs on OH&S training are increasing accessibility, ensuring full understanding, and building confidence. CONCLUSIONS: Current training does not mitigate safety risks in workplaces, and NIWs do not feel empowered to exercise their rights. New training protocols would be beneficial to equip NIWs to enter the workforce.

In Vivo Applications of Cell-Penetrating Zinc-Finger Transcription Factors.

Artificial transcription factors based on zinc finger, TALE, and CRISPR/Cas9 programmable DNA-binding platforms have been widely used to regulate the expression of specific genes in cultured cells, but their delivery into organs such as the brain represents a critical challenge to apply such tools in live animals. In previous work, we developed a zinc-finger-based artificial transcription factor harboring a cell-penetrating peptide (CPP) that could be injected systemically, cross the blood-brain barrier, and alter expression of a specific gene in the brain of an adult mouse. Importantly, our mode of delivery produced widespread distribution throughout the brain. Here we describe methods for the production and purification of the factor, testing CPP activity in cells, and testing CPP activity in mice.

Pharmacotherapy of lupus nephritis in children: a recommended treatment approach.

Systemic lupus erythematosus (SLE) is a multisystem inflammatory disease of unknown aetiology, which is characterised by recurrent disease flares that may affect any organ system. Renal involvement remains one of the chief causes of morbidity and mortality in children with lupus. Nephritis occurs in approximately two-thirds of patients, ranging from mild glomerulitis to life-threatening occurrences of diffuse proliferative glomerulonephritis. As lupus nephritis is a condition of no single aetiology, there is no single cure. Corticosteroids, although still the first line of treatment, are increasingly being superseded by cytotoxic drugs, in particular cyclophosphamide and corticosteroid-sparing agents. Newer agents such as mycophenolate mofetil, although effective in the treatment of lupus in adults, are less effective in children. Standard of care for highly active lupus nephritis in children remains intravenous cyclophosphamide, although preliminary experience suggests that the addition of rituximab may allow for remission induction with a reduction in cumulative cyclophosphamide dose. Combination therapies and newer agents appear promising for the future as our understanding of the immune system and its dysregulation in SLE improves. In this review, we discuss the current standards of care, newer therapies currently in use, and emerging treatments still undergoing development and investigation. We conclude by discussing our guidelines for treatment at the present time and suggestions for the comprehensive care of children with lupus nephritis.

Anaphylaxis to anakinra in a pediatric patient with systemic juvenile idiopathic arthritis successfully treated with canakinumab: a case-based review.

We present the case of a 2-year-old boy with a history of necrotizing enterocolitis (NEC) with ileostomy diagnosed with systemic juvenile idiopathic arthritis (sJIA) at 10 months of age controlled on anti-interleukin-1 (anti-IL-1) therapy (anakinra). At 17 months of age, ileostomy reversal and bowel re-anastomosis was scheduled with anakinra discontinued 3 days prior to the surgery and steroids initiated in its place. Ten days postoperatively, anakinra was re-started for signs of sJIA flare. Three months later, he developed persistent peripheral eosinophilia and subsequent anaphylactic reaction 6 months postoperatively. The patient safely tolerated an alternative anti-IL-1 agent (canakinumab). Anaphylaxis to anakinra has not been previously reported in the pediatric literature. This case highlights an important issue in a pediatric patient with sJIA: safety of an alternate anti-IL-1 agent, following development of allergy to one initial agent.

A prospective study comparing infection risk and disease activity in children with juvenile idiopathic arthritis treated with and without tumor necrosis factor-alpha inhibitors.

Tumor necrosis factor-alpha (TNF-α) inhibitors are effective treatment for juvenile idiopathic arthritis (JIA) but may increase infection rates. However, active JIA may also render patients vulnerable to infection. In this study, we prospectively assessed infection rates in JIA patients treated with and without TNF-α inhibitors and correlated disease activity with infection risk. TNF-α inhibitor-naïve JIA subjects were followed up for 12 months. Subjects initiated on TNF-α inhibitors after enrollment were analyzed in the TNF group. Subjects treated without TNF-α inhibitors were analyzed in the non-TNF group. Questionnaires captured mild or severe infections. JIA disease activity by Childhood Health Assessment Questionnaire (CHAQ) disability index/pain score and physician joint count/global assessment was recorded. Twenty TNF and 36 non-TNF subjects were analyzed. The total infection rate ratio for TNF versus non-TNF group subjects was 1.14 (95% CI, 0.78-1.66; p = 0.51). The average rate of infections per month was 0.29 for TNF and 0.24 for non-TNF subjects. No severe infections or hospitalizations occurred in either group. Secondary infectious outcomes were also similar between groups. Controlling for study group, an increase in CHAQ pain score correlated with an increase in several infectious outcome measures. Our results suggest no difference in infection rates between JIA subjects treated with and without TNF-α inhibitors. Additionally, JIA disease activity may have contributed to infection risk in our cohort, irrespective of immunosuppressive therapy. Future analysis of the relationship between treatment regimens, disease activity, and infection rates may help to further delineate predictors of infection risk in JIA patients.

Unrecognized Celiac Disease in Children Presenting for Rheumatology Evaluation.

BACKGROUND AND OBJECTIVES: Current clinical guidelines do not consider patients with rheumatic conditions to be at high risk for celiac disease (CD) despite numerous reported associations between the two in adults and children. The objective of this study was to evaluate the prevalence of CD among patients presenting for pediatric rheumatology evaluation. METHODS: A total of 2125 patients presenting for initial evaluation by the Division of Pediatric Rheumatology at the Hospital for Special Surgery between June 2006 and December 2013 were screened for CD as a part of the standard initial serologic evaluation. The charts of these patients were evaluated retrospectively at the end of this period. RESULTS: 36 patients (30 girls, 6 boys, mean age 9.4 ± 4.3 years, range 2-16 years) received a diagnosis of CD after serologic testing and evaluation by pediatric gastroenterology. Eight additional patients with known diagnoses of CD presented during this time period. The total prevalence of CD over this 6.5-year period was 2.0%. The most common presenting complaints among patients diagnosed with CD were myalgias, arthralgias, and rash. Less frequently, patients reported gastrointestinal complaints including abdominal pain, nausea, and diarrhea. All patients reported improvement or complete resolution of their musculoskeletal symptoms after initiation of a gluten-free diet. CONCLUSIONS: This study identified 36 new cases of CD among children presenting for rheumatology evaluation, for an overall prevalence rate of 2.0%. The majority of patients who ultimately received a diagnosis of CD presented with extraintestinal manifestations. These results underscore the importance of screening children presenting for rheumatology evaluation for CD.

Incidence and impact of adverse drug events in pediatric inpatients.

OBJECTIVES: To determine the incidence and causes of adverse drug events (ADEs) and potential ADEs in hospitalized children, and to examine the consequences of these events. DESIGN: Prospective review of medical records and staff interviews were performed. The ADEs were defined as injuries from medications or lack of an intended medication, and potential ADEs, as errors with the potential to result in injury. SETTING: A general pediatric unit and a pediatric intensive care unit in a metropolitan medical center. PATIENTS: A total of 1197 consecutive patient admissions were studied from September 15, 2000, to May 10, 2001. The admissions represented a total of 922 patients and 10,164 patient-days. RESULTS: The ADEs (6/100 admissions, 7.5/1000 patient-days) and potential ADEs (8/100 admissions, 9.3/1000 patient-days) were common in hospitalized children. Demographic variables associated with the occurrence of these events were the length of hospital stay, case-mix index, and amount of medication exposure. After adjusting for length of stay, medication exposure continued to have a significant influence on ADEs and potential ADEs. For ADEs, 18 (24%) were judged to be serious or life threatening. Most ADEs were not associated with major or permanent disability. Patients with both ADEs and potential ADEs were less likely to be routinely discharged and more likely to be discharged with home health care or to another institution, suggesting that patient disposition was not related to the adverse event. CONCLUSIONS: Both ADEs and potential ADEs are common among hospitalized children with greater disease burden and medication exposure. These findings suggest that these events were a consequence, rather than a cause, of more severe illness.

Prolonged improvement of childhood onset systemic lupus erythematosus following systematic administration of rituximab and cyclophosphamide.

BACKGROUND: Although the combination of cyclophosphamide and rituximab has been utilized in case reports, there are no previous reports of the long term outcome of SLE treated systematically with this regimen. We report a pilot study to evaluate the efficacy of a systematically administered course of rituximab and cyclophosphamide over an eighteen month period to provide sustained improvement in childhood onset systemic lupus erythematosus (SLE). FINDINGS: Twelve patients with childhood onset lupus nephritis or corticosteroid resistant SLE received systematic treatment with a combination of rituximab (750 mg/M2 up to 1 gram) and cyclophosphamide (750 mg/M2: no patient exceeded 1.8 M2). Two administrations of rituximab and cyclophosphamide, two weeks apart, were administered at the start of study, six months later, and eighteen months later. Clinical data were collected and analyzed after sixty months of follow up. There was sustained improvement in all clinical parameters with a dramatic reduction in both mean SLEDAI score (10.1 to 1 at one year and 0 at five years p<0.005) and mean daily prednisone dosage (29.7 mg/day to 12.7 by one year and 7.0 mg/day at five years p<0.005), with sustained improvement in mean C3 (55.5 mg/ml to 113 at one year and 107.5 at five years p<0.001) which was maintained through sixty months of follow up. Serum immunoglobulin levels were transiently depressed but mean values were within the normal range for both IgG and IgM at one and five years. Few complications were observed (two episodes of febrile neutropenia during the first year of treatment were the only serious adverse events) and patients routinely reported sustained wellbeing. CONCLUSIONS: This pilot study demonstrates that a systematically administered course of rituximab and cyclophosphamide over an eighteen month period provided sustained relief for patients with childhood onset SLE which was maintained over a sixty month period, while minimizing the need for corticosteroids, without excessive toxicity.

Update on the pathogenesis and treatment of systemic onset juvenile rheumatoid arthritis.

PURPOSE OF REVIEW: Although systemic onset juvenile rheumatoid arthritis accounts for only about 20% of most reported series, children with systemic onset juvenile rheumatoid arthritis are often the most difficult to treat. Many children with persistent systemic onset juvenile rheumatoid arthritis have marked physical and emotional disability as a result of both disease and treatment-related morbidities. This review highlights recent studies that better elucidate the etiopathogenesis of systemic onset juvenile rheumatoid arthritis. New therapies derived from better understanding of cytokines, cytokine gene expression, and their complex interactions, which result in inflammation, are improving our ability to control active disease while reducing or reliance on corticosteroids. RECENT FINDINGS: Recent advances in our understanding of the etiopathogenesis of systemic onset juvenile rheumatoid arthritis have led to therapies that specifically target the cytokines found in abnormal quantities in children with active disease. Biologic agents that directly target interleukin-1a, interleukin-6, and tumor necrosis factor alpha are currently in use, and additional agents that modulate interleukin-18, myeloid-related proteins 8 and 14, natural killer cell function, and macrophage migration inhibitory factor production are under investigation. SUMMARY: Anakinra, monoclonal antibody to interleukin-6 receptor, and thalidomide each have led to significant clinical improvement with fewer side effects than resulted when corticosteroids were the mainstay of therapy.

Treatment of orbital myositis with adalimumab (Humira).

Adalimumab is a fully humanized IgG1 monoclonal antibody to tumor necrosis factor-a. We describe 2 patients (17 and 13 years of age) with refractory, steroid-dependent, recurrent nonspecific orbital myositis not controlled with standard immunosuppressive medications. Both improved with adalimumab treatment, allowing reduction in corticosteroid dosage without disease flare.