Anti-Ku antibody-positive systemic sclerosis-polymyositis overlap syndrome in an adolescent.

Systemic sclerosis-polymyositis overlap syndrome is rare in children. Anti-PM/Scl is the most common autoantibody associated with this syndrome. We present a case of systemic sclerosis-polymyositis overlap syndrome in a child with isolated anti-Ku antibodies, an uncommon antibody associated with this rare syndrome.

Risk of Autoimmune Disease in Research-Identified Cases of Autism Spectrum Disorder: A Longitudinal, Population-Based Birth Cohort Study.

OBJECTIVE: Determine the risk of autoimmune disease in research-identified cases of autism spectrum disorder (ASD) compared with referents using a longitudinal, population-based birth cohort. METHODS: ASD incident cases were identified from a population-based birth cohort of 31,220 individuals. Inclusive ASD definition based on DSM-IV-TR autistic disorder, Asperger syndrome, and pervasive developmental disorder, not otherwise specified, was used to determine ASD cases. For each ASD case, 2 age- and sex-matched referents without ASD were identified. Diagnosis codes assigned between birth and December 2017 were electronically obtained. Individuals were classified as having an autoimmune disorder if they had at least 2 diagnosis codes more than 30 days apart. Cox proportional hazards models were fit to estimate the hazard ratio (HR) between ASD status and autoimmune disorder. RESULTS: Of 1014 ASD cases, 747 (73.7%) were male. Fifty ASD cases and 59 of the 1:2 matched referents were diagnosed with first autoimmune disorder at the median age of 14 and 17.1 years, respectively. ASD cases had increased risk of autoimmune disease compared with matched referents (HR 1.74; 95% confidence interval [CI], 1.21-2.52). The increased risk was statistically significant among male patients (HR 2.01; 95% CI, 1.26-3.21) but not among the smaller number of female subjects (HR 1.38; 95% CI, 0.76-2.50). CONCLUSION: This study provides evidence from a longitudinal, population-based birth cohort for co-occurrence of ASD and autoimmune disorders. Thus, children with ASD should be monitored for symptoms of autoimmune disease and appropriate workup initiated.

Practice Analysis and Determining the Knowledge and Skills Expected of a Pediatric Rheumatologist.

OBJECTIVE: The scope of clinical practice of pediatric rheumatology has been difficult to define. The lack of definition prevents an accurate understanding of the knowledge and skills required of practicing pediatric rheumatologists. A practice analysis process was used with the goal of establishing a precise definition of clinical pediatric rheumatology practice. The definition of practice will improve training and the creation of relevant certification examinations. METHODS: A practice analysis approach used meetings with a representative panel of pediatric rheumatologists to create a practice analysis document (PAD) and a test content outline (TCO). Panel experience, entrustable professional activities, and the current TCO were used to guide the process. Surveys were administered to fellowship program directors (PDs) and a broader group of practicing pediatric rheumatologists to revise and validate the content of the documents. RESULTS: A PAD was created, including 14 categories of conditions diagnosed or managed by pediatric rheumatologists and eight domains of practice, with the tasks, knowledge, and skills required to perform these tasks. The survey of PDs (n = 10) indicated that the PAD content is important and useful. A TCO was created and consists of 18 domains used to define content areas to be assessed on certifying examinations. The survey of practicing pediatric rheumatologists (n = 127) indicated that the TCO domains are relevant. CONCLUSION: A practice analysis process produced valuable resources for defining the clinical practice of pediatric rheumatology. The PAD and TCO can be used to develop more specific training curricula and to create relevant certification examinations.

Anxiety and Depressive Symptoms in Juvenile Idiopathic Arthritis Correlate With Pain and Stress Using PROMIS Measures.

OBJECTIVE: Describe anxiety and depressive symptoms in children with juvenile idiopathic arthritis (JIA) using Patient Reported Outcomes Measurement Information System (PROMIS) measures and evaluate potential correlations with disease manifestations. METHODS: We performed a cross-sectional study of children with JIA and a parent proxy who completed PROMIS measures on depression, anxiety, stress, and pain. The Childhood Health Assessment Questionnaire (CHAQ) measured mobility, and the clinical Juvenile Arthritis Disease Activity Score in 10 joints (cJADAS10) measured disease activity. RESULTS: Eighty-four patients completed the study. Demographic median values included age (14 yrs), disease duration (4.73 yrs), CHAQ score (0), total active joint count (0), and cJADAS10 (2). Using cJADAS10, 57 patients (70%) had inactive or low disease activity. Mean PROMIS t-scores for depressive and anxiety symptoms were lower in children with JIA compared to the reference population (P < 0.0001). Nineteen patients (23%) had moderate to severe symptoms of anxiety and/or depression. Age and CHAQ score (mobility) correlated with depressive symptoms (r = 0.36, P =0.0008 and r = 0.32, P = 0.0029, respectively) but not anxiety. Depressive and anxiety symptoms correlated with pain (r = 0.64 and r = 0.47, respectively, P < 0.0001) and stress (r = 0.79 and r = 0.75, respectively, P < 0.0001) but not with sex, JIA subtype, disease duration, or disease activity. CONCLUSION: Approximately one-quarter of children with JIA reported moderate to severe symptoms of anxiety and depression. These symptoms are associated with pain and stress, but they are not associated with other disease manifestations. Understanding how mental health symptoms and JIA affect each other is necessary in order to improve patient outcomes and provide well-rounded care.

Undiagnosed and Rare Diseases in Perinatal Medicine: Lessons in Context and Cognitive Diagnostic Error.

Critically ill neonates experience high rates of morbidity and mortality. Major diagnostic errors are identified in up to 20% of autopsied neonatal intensive care unit deaths. Neonates with undiagnosed or rare congenital disorders may mimic critically ill neonates with more common acquired conditions. The context of the diagnostic evaluation can introduce unique biases that increase the likelihood of diagnostic error. Herein is presented a framework for understanding diagnostic errors in perinatal medicine, and individual, team, and systems-based solutions for improving diagnosis learned through the implementation and administration of an undiagnosed and rare disease program.

Comparison of medical knowledge between pediatric residents who attend continuity clinic at different sites.

OBJECTIVE: The objective of this study is to determine if a difference in medical knowledge exists between pediatric residents attending a private practice continuity clinic and pediatric residents attending an academic continuity clinic, as measured by the American Board of Pediatrics in-training examination. DESIGN: A retrospective evaluation of scores on the American Board of Pediatrics in-training examination was performed, comparing the scores of residents who attend a private practice continuity clinic and those who attend an academic continuity clinic. RESULTS: No significant difference was found in test scores of the 2 groups of residents for each year from 1999 to 2003. There was no significant difference between the mean differences of scores from the PL-1 year to the PL-3 year. Both groups showed improvement in scores betwen the first and last years of residency. CONCLUSION: It is unlikely that there is a significant difference in medical knowledge between pediatric residents attending a continuity clinic in a private practice setting and pediatric residents attending a continuity clinic in an academic setting.

Comparing Board Examination Scores Between Pediatric Residents in Continuity Clinics at Different Sites.

OBJECTIVE: Determine if there is a difference in medical knowledge between pediatric residents attending continuity clinic at a community-based center versus those attending an academic center, as measured by the American Board of Pediatrics In-Training Exam (in-training exam) and the American Board of Pediatrics Certification Exam (certification exam). METHODS: A retrospective evaluation of in-training and certification exam scores of pediatric residents enrolled at the Medical College of Wisconsin and Children's Hospital of Wisconsin was performed. Test scores of the group of residents participating in a community-based continuity clinic were compared to those residents attending an academic center continuity clinic. RESULTS: There were no statistically significant differences in mean test scores for each of the 3 years of residency training on the in-training exam or board certifying exam after graduation. In-training exam scores significantly predicted certification exam scores, and there were significant increases in the in-training exam scores throughout residency, irrespective of clinic location. CONCLUSION: This study shows no difference between residents participating in a communitybased continuity clinic and those participating in an academic center continuity clinic in objective outcomes as measured by scores on the American Board of Pediatrics In-Training Exam and the American Board of Pediatrics Certifying Exam.

Serum S100A8/A9 and S100A12 Levels in Children With Polyarticular Forms of Juvenile Idiopathic Arthritis: Relationship to Maintenance of Clinically Inactive Disease During Anti-Tumor Necrosis Factor Therapy and Occurrence of Disease Flare After Discontinuation of Therapy.

OBJECTIVE: To determine the relationship between serum levels of S100A8/A9 and S100A12 and the maintenance of clinically inactive disease during anti-tumor necrosis factor (anti-TNF) therapy and the occurrence of disease flare following withdrawal of anti-TNF therapy in patients with polyarticular forms of juvenile idiopathic arthritis (JIA). METHODS: In this prospective, multicenter study, 137 patients with polyarticular-course JIA whose disease was clinically inactive while receiving anti-TNF therapy were enrolled. Patients were observed for an initial 6-month phase during which anti-TNF treatment was continued. For those patients who maintained clinically inactive disease over the 6 months, anti-TNF was withdrawn and they were followed up for 8 months to assess for the occurrence of flare. Serum S100 levels were measured at baseline and at the time of anti-TNF withdrawal. Spearman's rank correlation test, Mann-Whitney U test, Kruskal-Wallis test, receiver operating characteristic (ROC) curve, and Kaplan-Meier survival analyses were used to assess the relationship between serum S100 levels and maintenance of clinically inactive disease and occurrence of disease flare after anti-TNF withdrawal. RESULTS: Over the 6-month initial phase with anti-TNF therapy, the disease state reverted from clinically inactive to clinically active in 24 (18%) of the 130 evaluable patients with polyarticular-course JIA; following anti-TNF withdrawal, 39 (37%) of the 106 evaluable patients experienced a flare. Serum levels of S100A8/A9 and S100A12 were elevated in up to 45% of patients. Results of the ROC analysis revealed that serum S100 levels did not predict maintenance of clinically inactive disease during anti-TNF therapy nor did they predict disease flare after treatment withdrawal. Elevated levels of S100A8/A9 were not predictive of the occurrence of a disease flare within 30 days, 60 days, 90 days, or 8 months following anti-TNF withdrawal, and elevated S100A12 levels had a modest predictive ability for determining the risk of flare within 30, 60, and 90 days after treatment withdrawal. Serum S100A12 levels at the time of anti-TNF withdrawal were inversely correlated with the time to disease flare (r = -0.36). CONCLUSION: Serum S100 levels did not predict maintenance of clinically inactive disease or occurrence of disease flare in patients with polyarticular-course JIA, and S100A12 levels were only moderately, and inversely, correlated with the time to disease flare.

Risk, Timing, and Predictors of Disease Flare After Discontinuation of Anti-Tumor Necrosis Factor Therapy in Children With Polyarticular Forms of Juvenile Idiopathic Arthritis With Clinically Inactive Disease.

OBJECTIVE: To determine the frequency, time to flare, and predictors of disease flare upon withdrawal of anti-tumor necrosis factor (anti-TNF) therapy in children with polyarticular forms of juvenile idiopathic arthritis (JIA) who demonstrated ≥6 months of continuous clinically inactive disease. METHODS: In 16 centers 137 patients with clinically inactive JIA who were receiving anti-TNF therapy (42% of whom were also receiving methotrexate [MTX]) were prospectively followed up. If the disease remained clinically inactive for the initial 6 months of the study, anti-TNF was stopped and patients were assessed for flare at 1, 2, 3, 4, 6, and 8 months. Life-table analysis, t-tests, chi-square test, and Cox regression analysis were used to identify independent variables that could significantly predict flare by 8 months or time to flare. RESULTS: Of 137 patients, 106 (77%) maintained clinically inactive disease while receiving anti-TNF therapy for the initial 6 months and were included in the phase of the study in which anti-TNF therapy was stopped. Stopping anti-TNF resulted in disease flare in 39 (37%) of 106 patients by 8 months. The mean/median ± SEM time to flare was 212/250 ± 9.77 days. Patients with shorter disease duration at enrollment, older age at onset and diagnosis, shorter disease duration prior to experiencing clinically inactive disease, and shorter time from onset of clinically inactive disease to enrollment were found to have significantly lower hazard ratios for likelihood of flare by 8 months (P < 0.05). CONCLUSION: Over one-third of patients with polyarticular JIA with sustained clinically inactive disease will experience a flare by 8 months after discontinuation of anti-TNF therapy. Several predictors of lower likelihood of flare were identified.

Usual and Unusual Manifestations of Systemic and Central Nervous System Vasculitis.

The idiopathic vasculitides are a group of inflammatory and immune-mediated conditions associated with inflammation of blood vessels. They affect multiple organ and body systems, and vary in their clinical manifestations, severity, prognosis, and pathology. They frequently present a diagnostic challenge for clinicians because of their complexity, overlapping features, and similar findings to other noninflammatory, genetic, or infectious conditions. This article summarizes some of the common pediatric vasculitides, emphasizing both the characteristic and unusual clinical manifestations of these diseases.

How Doctors Think: Common Diagnostic Errors in Clinical Judgment-Lessons from an Undiagnosed and Rare Disease Program.

The scientific process of analysis and deduction is frequently, often subconsciously, used by physicians to develop a differential diagnosis based on patients' symptoms. Common disorders are most frequently diagnosed in general practice. Rare diseases are uncommon and frequently remain undiagnosed for many years. Cognitive errors in clinical judgment delay definitive diagnosis. Whole-exome sequencing has helped identify the cause of undiagnosed or rare diseases in up to 40% of children. This article provides experiences with an undiagnosed or rare disease program, where detailed data accumulation and a multifaceted analytical approach assisted in diagnosing atypical presentations of common disorders.

Toxic Epidermal Necrolysis-Like Cutaneous Lupus in Pediatric Patients: A Case Series and Review.

Bullous eruptions in patients with underlying systemic lupus erythematosus (LE) can mimic toxic-epidermal necrolysis (TEN), a rapidly progressive mucocutaneous reaction usually associated with medication use. Differentiating between classic drug-induced TEN and TEN-like cutaneous LE is important but difficult. We report a series of 3 patients with pediatric systemic LE who were admitted with severe worsening of skin disease resembling TEN. However, the initial photo-distribution of the eruption, subacute progression, limited mucosal involvement, mild systemic symptoms, supportive biopsy and laboratory results, and lack of culprit drugs was more suggestive of a TEN-like cutaneous LE. These patients recovered with various systemic immunosuppressive medications including methylprednisolone, intravenous immunoglobulin, and plasmapheresis. Our cases are rare and demonstrate key clinical and histologic features of TEN-like cutaneous LE in young patients and the importance of differentiating this entity from drug-induced TEN.

An evaluation of the utility of routine laboratory monitoring of juvenile idiopathic arthritis (JIA) patients using non-steroidal anti-inflammatory drugs (NSAIDs): a retrospective review.

BACKGROUND: No consensus evidence-based guidelines for the routine laboratory monitoring of children with JIA receiving non-steroidal anti-inflammatory drugs (NSAIDs) exist. The purpose of this study is to evaluate the clinical utility of routine laboratory monitoring of hemoglobin, transaminases, blood urea nitrogen, serum creatinine, and urinalysis in patients with juvenile idiopathic arthritis (JIA) receiving NSAIDs. METHODS: The medical records of 91 children with JIA followed between 1996 and 2006 were retrospectively reviewed for laboratory results and clinically significant adverse effects attributed to NSAID use. Laboratory abnormalities were documented, with potential adverse clinical sequelae, including if NSAID use was discontinued. RESULTS: Abnormal laboratory results were recorded for 24 of 91 patients. Nearly all abnormalities were mild and not associated with adverse clinical sequelae. All patients but one continued to receive NSAID therapy after the abnormality was detected. CONCLUSIONS: Although detection of abnormal laboratory values occurred while on NSAIDs, these abnormalities did not correlate with adverse clinical signs and symptoms. The routine monitoring of laboratory tests in asymptomatic children treated with NSAIDs is of questionable utility.

High-density genotyping of STAT4 reveals multiple haplotypic associations with systemic lupus erythematosus in different racial groups.

OBJECTIVE: Systemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disorder, with complex etiology and a strong genetic component. Recently, gene products involved in the interferon pathway have been under intense investigation in terms of the pathogenesis of SLE. STAT-1 and STAT-4 are transcription factors that play key roles in the interferon and Th1 signaling pathways, making them attractive candidates for involvement in SLE susceptibility. METHODS: Fifty-six single-nucleotide polymorphisms (SNPs) across STAT1 and STAT4 on chromosome 2 were genotyped using the Illumina platform, as part of an extensive association study in a large collection of 9,923 lupus patients and control subjects from different racial groups. DNA samples were obtained from the peripheral blood of patients with SLE and control subjects. Principal components analyses and population-based case-control association analyses were performed, and the P values, false discovery rate q values, and odds ratios with 95% confidence intervals were calculated. RESULTS: We observed strong genetic associations with SLE and multiple SNPs located within STAT4 in different ethnic groups (Fisher's combined P = 7.02 x 10(-25)). In addition to strongly confirming the previously reported association in the third intronic region of this gene, we identified additional haplotypic association across STAT4 and, in particular, a common risk haplotype that is found in multiple racial groups. In contrast, only a relatively weak suggestive association was observed with STAT1, probably due to its proximity to STAT4. CONCLUSION: Our findings indicate that STAT4 is likely to be a crucial component in SLE pathogenesis in multiple racial groups. Knowledge of the functional effects of this association, when they are revealed, might improve our understanding of the disease and provide new therapeutic targets.

Identification of novel susceptibility genes in childhood-onset systemic lupus erythematosus using a uniquely designed candidate gene pathway platform.

OBJECTIVE: Childhood-onset systemic lupus erythematosus (SLE) presents a unique subgroup of patients for genetic study. The present study was undertaken to identify susceptibility genes contributing to SLE, using a novel candidate gene pathway microarray platform to investigate gene expression in patients with childhood-onset SLE and both of their parents. METHODS: Utilizing bioinformatic tools, a platform of 9,412 single-nucleotide polymorphisms (SNPs) from 1,204 genes was designed and validated. Molecular inversion probes and high-throughput SNP technologies were used for assay development. Seven hundred fifty three subjects, corresponding to 251 full trios of childhood-onset SLE families, were genotyped and analyzed using transmission disequilibrium testing (TDT) and multitest corrections. RESULTS: Family-based TDT showed a significant association of SLE with a N673S polymorphism in the P-selectin gene (SELP) (P = 5.74 x 10(-6)) and a C203S polymorphism in the interleukin-1 receptor-associated kinase 1 gene (IRAK1) (P = 9.58 x 10(-6)). These 2 SNPs had a false discovery rate for multitest correction of <0.05, and therefore a >95% probability of being considered as proven. Furthermore, 7 additional SNPs showed q values of <0.5, suggesting association with SLE and providing a direction for followup studies. These additional genes notably included TNFRSF6 (Fas) and IRF5, supporting previous findings of their association with SLE pathogenesis. CONCLUSION: SELP and IRAK1 were identified as novel SLE-associated genes with a high degree of significance, suggesting new directions in understanding the pathogenesis of SLE. The overall design and results of this study demonstrate that the candidate gene pathway microarray platform used provides a novel and powerful approach that is generally applicable in identifying genetic foundations of complex diseases.

Linear scleroderma en coup de sabre with associated neurologic abnormalities.

Linear scleroderma represents a unique form of localized scleroderma that primarily affects the pediatric population, with 67% of patients diagnosed before 18 years of age. When linear scleroderma occurs on the head, it is referred to as linear scleroderma en coup de sabre, given the resemblance of the skin lesions to the stroke of a sabre. Here we describe 3 pediatric patients with linear scleroderma en coup de sabre who presented with neurologic abnormalities before or concurrent with the diagnosis of their skin disease. Our patients' cases highlight the underrecognized relationship between neurologic complications and linear scleroderma en coup de sabre and illustrate the importance of a thorough skin examination in patients with unexplained neurologic disease.

Necrotic facial papules in an adolescent: C2 deficiency with eventual development of lupus erythematosus.

A 14-year-old girl was admitted to the hospital because of persistent throat pain, fever, fatigue, 25 pound weight loss, and leukopenia. On physical examination she was thin, ill-appearing, and had necrotic papules on the face and palpable cervical lymph nodes. Presumptive differential diagnosis included occult malignancy and infection. Numerous investigative procedures failed to elucidate a source. Vasculitis was eventually appreciated after repeat skin biopsy. Numerous serologic studies were performed and were notable for a very low level of the second component of complement without direct evidence of lupus erythematosus (LE) or other autoimmune conditions. A diagnosis of C2 deficiency-associated vasculitis was made. She was treated with high-dose prednisone and cyclophosphamide with resolution of her symptoms. Two years later she returned with marked malar erythema. Antinuclear and Smith antibodies were then detected and a diagnosis of LE was made. She was treated with hydroxychloroquine and sun-avoidance measures with clearance of the malar rash.