Dosing Variation at Initiation of Adalimumab and Etanercept and Clinical Outcomes in Juvenile Idiopathic Arthritis: A Childhood Arthritis and Rheumatology Research Alliance Registry Study.

OBJECTIVE: To determine the dose-response relationship of tumor necrosis factor (TNF) inhibition in the treatment of juvenile idiopathic arthritis (JIA). METHODS: Participants of the Childhood Arthritis and Rheumatology Research Alliance Registry were eligible for inclusion in the analyses if they started TNF inhibition treatment for JIA. The primary treatment response was determined 3 to 7 months after the start of treatment, based on the JIA American College of Rheumatology Pediatric criteria for improvement, clinical Juvenile Arthritis Disease Activity Score, and persistence of treatment after 6 months. Subsequently, pooled logistic regression models were performed to include long-term follow-up data. The models were adjusted for risk factors associated with poor treatment response. Dosing was expressed by body weight, body surface area, ideal body weight, fat free mass, and lean body mass. RESULTS: Participants treated with adalimumab (n = 328) and etanercept (n = 437) were included in the analyses (median dose 0.82 mg/kg body weight [interquartile range (IQR) 0.66-1.04] and 0.83 mg/kg body weight [IQR 0.75-0.95], respectively). The majority of analyses did not show a relationship between dose and outcome. Where associations were found, results were conflicting. Alternative dosing characteristics based on ideal body weight, fat free mass, and lean body mass did not result in stronger or more consistent associations. CONCLUSION: This study was not able to confirm our hypothesis that increased dosing of TNF inhibitors results in improved treatment outcomes. Although adjustment was performed for risk factors of impaired treatment response, residual confounding by indication likely explains the negative associations found in this study.

Early Abnormal Nailfold Capillary Changes Are Predictive of Calcinosis Development in Juvenile Dermatomyositis.

OBJECTIVE: The long-term outcomes of juvenile dermatomyositis (JDM) are more favorable in recent years. However, calcinosis is still among the complications that can cause serious functional impairment. Little is known about the pathogenesis and risk factors of calcinosis. The aim of this study is to determine risk factors for the development of calcinosis in JDM. METHODS: This was a single-center, retrospective cohort study. All patients were diagnosed and followed at the multidisciplinary JDM clinic of The Hospital for Sick Children, from January 1, 1989, until May 31, 2018. To investigate predictors of incident calcinosis, Cox regression analysis was performed. RESULTS: A total of 172 patients met inclusion criteria, with a median age at diagnosis of 7.7 years (IQR 4.9-12.1), and a median follow-up of 8.5 years (IQR 3.4-12.6, range 0.1-28.3). The only risk factor significantly associated with the development of calcinosis in the univariate analysis was nailfold abnormality at baseline (hazard ratio [HR] 4.86, P = 0.03). In multivariable analysis, including nailfold abnormality, age of diagnosis, sex, and duration from onset to diagnosis, the only statistically significant risk factor for calcinosis was the presence of nailfold abnormalities (HR 4.98, P = 0.03). Further, calcinosis was significantly increased in patients with a chronic course (chi-square 25.8, P < 0.001). CONCLUSION: The presence of abnormal nailfold capillary changes at baseline is predictive for the development of calcinosis in children with idiopathic inflammatory myopathies.

Management of Calcinosis Cutis in Rheumatic Diseases.

Calcinosis (hydroxyapatite and calcium phosphate crystal deposition) within the extracellular matrix of the dermis and subcutaneous tissue is a frequent manifestation of adult and pediatric systemic autoimmune rheumatic diseases, specifically systemic sclerosis, dermatomyositis, mixed connective tissue disease, and systemic lupus erythematosus. In this article, we review classification of calcinosis, highlight mechanisms that may contribute to the pathogenesis of calcinosis, and summarize the evidence evaluating nonpharmacologic and pharmacologic interventions for the treatment of calcinosis.

Towards therapeutic drug monitoring of TNF inhibitors for children with juvenile idiopathic arthritis: a scoping review.

OBJECTIVES: Before a clinician decides whether treatment with TNF inhibition in children with JIA has failed, one should ensure adequate systemic exposure has been achieved. Therapeutic drug monitoring might allow for improved treatment outcome with lower treatment-associated costs. However, this requires understanding of the pharmacokinetic (PK) characteristics, and the pharmacokinetic/pharmacodynamic (PK/PD) relationship for children with JIA. We performed a scoping review to summarize the available literature and identify areas for future research. METHODS: A systematic search was conducted of the Medline, EMBASE, Web of Science and Cochrane databases as well as the clinicaltrials.gov registry. In total, 3959 records were screened and 130 publications were selected for full text assessment. RESULTS: Twenty publications were included and divided into three categories: PK (n = 9), PK/PD (n = 3) and anti-drug antibodies (n = 13). Industry involvement was significant in 14 publications. Although data are limited, systemic exposure to TNF inhibitors is generally lower in younger children but meta-analysis is not possible. The PK/PD relationship has had limited study but there is partial evidence for infliximab. Anti-drug antibodies are common, and are related to impaired clinical outcome with adalimumab and infliximab therapy. CONCLUSION: The current knowledge about the PK and PK/PD of TNF inhibitors in the treatment of children with JIA is limited, which prevents the introduction of TDM. Re-analysis of available data from previous trials, incorporation of pharmacologic assessments into existing biorepository studies as well as new prospective PK and PK/PD trials are required to obtain this knowledge.

2019 American College of Rheumatology/Arthritis Foundation Guideline for the Screening, Monitoring, and Treatment of Juvenile Idiopathic Arthritis-Associated Uveitis.

OBJECTIVE: To develop recommendations for the screening, monitoring, and treatment of uveitis in children with juvenile idiopathic arthritis (JIA). METHODS: Pediatric rheumatologists, ophthalmologists with expertise in uveitis, patient representatives, and methodologists generated key clinical questions to be addressed by this guideline. This was followed by a systematic literature review and rating of the available evidence according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. A group consensus process was used to compose the final recommendations and grade their strength as conditional or strong. RESULTS: Due to a lack of literature with good quality of evidence, recommendations were formulated on the basis of available evidence and a consensus expert opinion. Regular ophthalmic screening of children with JIA is recommended because of the risk of uveitis, and the frequency of screening should be based on individual risk factors. Regular ophthalmic monitoring of children with uveitis is recommended, and intervals should be based on ocular examination findings and treatment regimen. Ophthalmic monitoring recommendations were strong primarily because of concerns of vision-threatening complications of uveitis with infrequent monitoring. Topical glucocorticoids should be used as initial treatment to achieve control of inflammation. Methotrexate and the monoclonal antibody tumor necrosis factor inhibitors adalimumab and infliximab are recommended when systemic treatment is needed for the management of uveitis. The timely addition of nonbiologic and biologic drugs is recommended to maintain uveitis control in children who are at continued risk of vision loss. CONCLUSION: This guideline provides direction for clinicians and patients/parents making decisions on the screening, monitoring, and management of children with JIA and uveitis, using GRADE methodology and informed by a consensus process with input from rheumatology and ophthalmology experts, current literature, and patient/parent preferences and values.

2019 American College of Rheumatology/Arthritis Foundation Guideline for the Treatment of Juvenile Idiopathic Arthritis: Therapeutic Approaches for Non-Systemic Polyarthritis, Sacroiliitis, and Enthesitis.

OBJECTIVE: To develop treatment recommendations for children with juvenile idiopathic arthritis manifesting as non-systemic polyarthritis, sacroiliitis, or enthesitis. METHODS: The Patient/Population, Intervention, Comparison, and Outcomes (PICO) questions were developed and refined by members of the guideline development teams. A systematic review was conducted to compile evidence for the benefits and harms associated with treatments for these conditions. GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology was used to rate the quality of evidence. A group consensus process was conducted among the Voting Panel to generate the final recommendations and grade their strength. A Parent and Patient Panel used a similar consensus approach to provide patient/caregiver preferences for key questions. RESULTS: Thirty-nine recommendations were developed (8 strong and 31 conditional). The quality of supporting evidence was very low or low for 90% of the recommendations. Recommendations are provided for the use of nonsteroidal antiinflammatory drugs, disease-modifying antirheumatic drugs, biologics, and intraarticular and oral glucocorticoids. Recommendations for the use of physical and occupational therapy are also provided. Specific recommendations for polyarthritis address general medication use, initial and subsequent treatment, and adjunctive therapies. Good disease control, with therapeutic escalation to achieve low disease activity, was recommended. The sacroiliitis and enthesitis recommendations primarily address initial therapy and adjunctive therapies. CONCLUSION: This guideline provides direction for clinicians, caregivers, and patients making treatment decisions. Clinicians, caregivers, and patients should use a shared decision-making process that accounts for patients' values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.

2019 American College of Rheumatology/Arthritis Foundation Guideline for the Screening, Monitoring, and Treatment of Juvenile Idiopathic Arthritis-Associated Uveitis.

OBJECTIVE: To develop recommendations for the screening, monitoring, and treatment of uveitis in children with juvenile idiopathic arthritis (JIA). METHODS: Pediatric rheumatologists, ophthalmologists with expertise in uveitis, patient representatives, and methodologists generated key clinical questions to be addressed by this guideline. This was followed by a systematic literature review and rating of the available evidence according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. A group consensus process was used to compose the final recommendations and grade their strength as conditional or strong. RESULTS: Due to a lack of literature with good quality of evidence, recommendations were formulated on the basis of available evidence and a consensus expert opinion. Regular ophthalmic screening of children with JIA is recommended because of the risk of uveitis, and the frequency of screening should be based on individual risk factors. Regular ophthalmic monitoring of children with uveitis is recommended, and intervals should be based on ocular examination findings and treatment regimen. Ophthalmic monitoring recommendations were strong primarily because of concerns of vision-threatening complications of uveitis with infrequent monitoring. Topical glucocorticoids should be used as initial treatment to achieve control of inflammation. Methotrexate and the monoclonal antibody tumor necrosis factor inhibitors adalimumab and infliximab are recommended when systemic treatment is needed for the management of uveitis. The timely addition of nonbiologic and biologic drugs is recommended to maintain uveitis control in children who are at continued risk of vision loss. CONCLUSION: This guideline provides direction for clinicians and patients/parents making decisions on the screening, monitoring, and management of children with JIA and uveitis, using GRADE methodology and informed by a consensus process with input from rheumatology and ophthalmology experts, current literature, and patient/parent preferences and values.

European consensus-based recommendations for diagnosis and treatment of immunoglobulin A vasculitis-the SHARE initiative.

OBJECTIVES: IgA vasculitis (IgAV, formerly known as Henoch-Schönlein purpura) is the most common cause of systemic vasculitis in childhood. To date, there are no internationally agreed, evidence-based guidelines concerning the appropriate diagnosis and treatment of IgAV in children. Accordingly, treatment regimens differ widely. The European initiative SHARE (Single Hub and Access point for paediatric Rheumatology in Europe) aims to optimize care for children with rheumatic diseases. The aim therefore was to provide internationally agreed consensus recommendations for diagnosis and treatment for children with IgAV. METHODS: Recommendations were developed by a consensus process in accordance with the EULAR standard operating procedures. An extensive systematic literature review was performed, and evidence-based recommendations were extrapolated from the included papers. These were evaluated by a panel of 16 international experts via online surveys and subsequent consensus meeting, using nominal group technique. Recommendations were accepted when ⩾80% of experts agreed. RESULTS: In total, 7 recommendations for diagnosis and 19 for treatment of paediatric IgAV were accepted. Diagnostic recommendations included: appropriate use of skin and renal biopsy, renal work-up and imaging. Treatment recommendations included: the importance of appropriate analgesia and angiotensin-converting enzyme inhibitor use and non-renal indications for CS use, as well as a structured approach to treating IgAV nephritis, including appropriate use of CS and second-line agents in mild, moderate and severe disease along with use of angiotensin-converting enzyme inhibitors and maintenance therapy. CONCLUSION: The SHARE initiative provides international, evidence-based recommendations for the diagnosis and treatment of IgAV that will facilitate improvement and uniformity of care.

European consensus-based recommendations for the diagnosis and treatment of rare paediatric vasculitides - the SHARE initiative.

OBJECTIVES: The European initiative Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) aimed to optimize care for children with rheumatic diseases. Systemic vasculitides are very rare in children. Consequently, despite recent advances, paediatric-specific information is sparse. The lack of evidence-based recommendations is an important, unmet need. This study aimed to provide recommendations for diagnosing and treating children with rare forms of childhood systemic vasculitis. METHODS: Recommendations were developed by a consensus process in accordance with the European League Against Rheumatism standard operating procedures. A systematic literature review informed the recommendations, which were devised and evaluated by a panel of experts via an online survey, and two consensus meetings using nominal group technique. Recommendations were accepted when ⩾ 80% of experts agreed. RESULTS: Ninety-three relevant articles were found, and 78 recommendations were accepted in the two consensus meetings. General, cross-cutting recommendations and disease-specific statements regarding the diagnosis and treatment of childhood-onset PAN, granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, and Takayasu arteritis are provided. CONCLUSION: These Single Hub and Access point for paediatric Rheumatology in Europe recommendations were formulated through an evidence-based consensus process to support uniform, high-quality standard of care for children with rare forms of paediatric systemic vasculitis.

Development of neoplasms in pediatric patients with rheumatic disease exposed to anti-tumor necrosis factor therapies: a single Centre retrospective study.

BACKGROUND: Anti-TNF (Tumor necrosis factor) therapy is effective in treating pediatric patients with refractory rheumatic disease. There is however a concern that anti-TNF usage may increase the risk of malignancy. Reports on specific types of malignancy in this patient population have been emerging over the past decade, but there is a need for additional malignancy reports, as these events are rare. Therefore, a retrospective chart review was performed on the biologic database of pediatric rheumatology patients at The Hospital for Sick Children (SickKids) from 1997 to 2013 for neoplasms, patient demographic information and rheumatologic treatment course. FINDINGS: 6/357 (1.68%) rheumatology patients treated with anti-TNF therapy between 1997 and 2013 developed neoplasms. One patient had two malignancies. One patient had a benign neoplasm. Cases were exposed to etanercept, infliximab or both. Neoplasms developed late after anti-TNF exposure (median 5.0 years) and infliximab treatment was associated with a shorter time to malignancy. The neoplasms identified were as follows: 2 renal clear cell carcinoma, 1 pilomatricoma, 1 nasopharyngeal carcinoma, 1 Ewing's sarcoma, 1 hepatic T-cell lymphoma, 1 lymphoproliferative disease. CONCLUSIONS: The malignancy rate at our centre is low, however more than half of the neoplasms identified were rare and unusual in the pediatric population. The 5-year malignancy-free probability for patients with juvenile idiopathic arthritis (JIA) treated with biologic therapy was 97% from our database. Long-term screening for rare neoplasms is important as part of the safety monitoring for any pediatric rheumatology patient receiving anti-TNF therapy.

2017 European League Against Rheumatism/American College of Rheumatology Classification Criteria for Adult and Juvenile Idiopathic Inflammatory Myopathies and Their Major Subgroups.

OBJECTIVE: To develop and validate new classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIM) and their major subgroups. METHODS: Candidate variables were assembled from published criteria and expert opinion using consensus methodology. Data were collected from 47 rheumatology, dermatology, neurology, and pediatric clinics worldwide. Several statistical methods were utilized to derive the classification criteria. RESULTS: Based on data from 976 IIM patients (74% adults; 26% children) and 624 non-IIM patients with mimicking conditions (82% adults; 18% children), new criteria were derived. Each item is assigned a weighted score. The total score corresponds to a probability of having IIM. Subclassification is performed using a classification tree. A probability cutoff of 55%, corresponding to a score of 5.5 (6.7 with muscle biopsy) "probable IIM," had best sensitivity/specificity (87%/82% without biopsies, 93%/88% with biopsies) and is recommended as a minimum to classify a patient as having IIM. A probability of ≥90%, corresponding to a score of ≥7.5 (≥8.7 with muscle biopsy), corresponds to "definite IIM." A probability of <50%, corresponding to a score of <5.3 (<6.5 with muscle biopsy), rules out IIM, leaving a probability of ≥50-<55% as "possible IIM." CONCLUSION: The European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for IIM have been endorsed by international rheumatology, dermatology, neurology, and pediatric groups. They employ easily accessible and operationally defined elements, and have been partially validated. They allow classification of "definite," "probable," and "possible" IIM, in addition to the major subgroups of IIM, including juvenile IIM. They generally perform better than existing criteria.

2017 European League Against Rheumatism/American College of Rheumatology classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups.

OBJECTIVE: To develop and validate new classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIM) and their major subgroups. METHODS: Candidate variables were assembled from published criteria and expert opinion using consensus methodology. Data were collected from 47 rheumatology, dermatology, neurology and paediatric clinics worldwide. Several statistical methods were used to derive the classification criteria. RESULTS: Based on data from 976 IIM patients (74% adults; 26% children) and 624 non-IIM patients with mimicking conditions (82% adults; 18% children), new criteria were derived. Each item is assigned a weighted score. The total score corresponds to a probability of having IIM. Subclassification is performed using a classification tree. A probability cut-off of 55%, corresponding to a score of 5.5 (6.7 with muscle biopsy) 'probable IIM', had best sensitivity/specificity (87%/82% without biopsies, 93%/88% with biopsies) and is recommended as a minimum to classify a patient as having IIM. A probability of ≥90%, corresponding to a score of ≥7.5 (≥8.7 with muscle biopsy), corresponds to 'definite IIM'. A probability of <50%, corresponding to a score of <5.3 (<6.5 with muscle biopsy), rules out IIM, leaving a probability of ≥50 to <55% as 'possible IIM'. CONCLUSIONS: The European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for IIM have been endorsed by international rheumatology, dermatology, neurology and paediatric groups. They employ easily accessible and operationally defined elements, and have been partially validated. They allow classification of 'definite', 'probable' and 'possible' IIM, in addition to the major subgroups of IIM, including juvenile IIM. They generally perform better than existing criteria.

Cardiac findings in children with juvenile Dermatomyositis at disease presentation.

BACKGROUND: Juvenile Dermatomyositis (JDM) is a pediatric vasculopathy characterized primarily by skin and muscle involvement. Cardiac findings have been reported in children with JDM but have rarely been investigated in detail. METHODS: We aimed to describe the relevant clinical and laboratory cardiac findings of a cohort of patients with JDM, followed at one centre, at disease diagnosis. RESULTS: We performed a retrospective review of 105 patients with JDM, followed from 1991 to 2007. Six of 70 patients (9%, 6% of the entire cohort) had abnormal electrocardiographic (ECG) findings, while 26 of 54 patients (48%, 25% of the entire cohort) had abnormal echocardiographic (echo) findings. Many of these findings were either mild or unlikely to be a result of JDM. CONCLUSIONS: Our findings suggest that cardiac abnormalities at JDM disease onset are frequently seen, but are rarely significant findings due to disease; however, JDM patients should be considered for screening for cardiac disease as late cardiac complications are well recognized.

Magnetic resonance enterography has good inter-rater agreement and diagnostic accuracy for detecting inflammation in pediatric Crohn disease.

BACKGROUND: Magnetic resonance enterography (MRE) is increasingly relied upon for noninvasive assessment of intestinal inflammation in Crohn disease. However very few studies have examined the diagnostic accuracy of individual MRE signs in children. OBJECTIVE: We have created an MR-based multi-item measure of intestinal inflammation in children with Crohn disease - the Pediatric Inflammatory Crohn's MRE Index (PICMI). To inform item selection for this instrument, we explored the inter-rater agreement and diagnostic accuracy of individual MRE signs of inflammation in pediatric Crohn disease and compared our findings with the reference standards of the weighted Pediatric Crohn's Disease Activity Index (wPCDAI) and C-reactive protein (CRP). MATERIALS AND METHODS: In this cross-sectional single-center study, MRE studies in 48 children with diagnosed Crohn disease (66% male, median age 15.5 years) were reviewed by two independent radiologists for the presence of 15 MRE signs of inflammation. Using kappa statistics we explored inter-rater agreement for each MRE sign across 10 anatomical segments of the gastrointestinal tract. We correlated MRE signs with the reference standards using correlation coefficients. Radiologists measured the length of inflamed bowel in each segment of the gastrointestinal tract. In each segment, MRE signs were scored as either binary (0-absent, 1-present), or ordinal (0-absent, 1-mild, 2-marked). These segmental scores were weighted by the length of involved bowel and were summed to produce a weighted score per patient for each MRE sign. Using a combination of wPCDAI≥12.5 and CRP≥5 to define active inflammation, we calculated area under the receiver operating characteristic curve (AUC) for each weighted MRE sign. RESULTS: Bowel wall enhancement, wall T2 hyperintensity, wall thickening and wall diffusion-weighted imaging (DWI) hyperintensity were most commonly identified. Inter-rater agreement was best for decreased motility and wall DWI hyperintensity (kappa≥0.64). Correlation between MRE signs and wPCDAI was higher than with CRP. AUC was highest (≥0.75) for ulcers, wall enhancement, wall thickening, wall T2 hyperintensity and wall DWI hyperintensity. CONCLUSION: Some MRE signs had good inter-rater agreement and AUC for detection of inflammation in children with Crohn disease.

Validity of the Stage of Exercise Scale in Children with Rheumatologic Conditions.

OBJECTIVE: To determine the face, content, and construct validity of the Stages of Exercise Scale (SOES) in children with rheumatologic conditions [juvenile idiopathic arthritis (JIA) and juvenile dermatomyositis (JDM)], and if the validity of the SOES differs by disease type by comparing it with a disease control with a chronic respiratory illness [cystic fibrosis (CF)]. METHODS: Sixty-seven children and adolescents (43 female) ages 11 to 18 years with a diagnosis of either JDM (n = 15), JIA (n = 39), or CF (n = 13) completed the SOES; scales of sensibility, process of change, decisional balance, and self-efficacy; the Child Health Assessment Questionnaire; and patient/physician ratings of disease severity. Physical activity was measured by an accelerometer. Relationships among SOES and measured constructs were determined by ANOVA and with logistical modeling. RESULTS: SOES, decisional balance, and self-efficacy as well as behavioral and cognitive processes from the process of change demonstrated significant differences across the staging subgroups. Disease groups did not significantly differ on the scoring across the SOES. Children and adolescents in higher stages participated in more minutes of vigorous physical activity compared with those in the lower stages. CONCLUSION: The SOES demonstrated good face, content, and construct validity in children and adolescents with rheumatic disease.

Cost-Effectiveness Analysis of First-Line Treatment With Biologic Agents in Polyarticular Juvenile Idiopathic Arthritis.

OBJECTIVE: The optimal timing of biologic agent treatment in polyarticular juvenile idiopathic arthritis (JIA) is unknown. This study evaluated the costs and outcomes of first-line treatment with etanercept (ETN), an anti-tumor necrosis factor (anti-TNF) agent, compared with step-wise therapy in JIA. METHODS: We compared 2 strategies: methotrexate (MTX) plus ETN as first-line therapy (ETN-first) and MTX monotherapy followed by ETN (ETN-second), using a cohort state-transition model of newly diagnosed JIA patients. The model's time horizon was 5 years, and the perspective was that of the Canadian health care system. The base case patient was 11 years old, weighed 40 kg, and had 5 or more active joints. Direct costs were calculated and discounted at a rate of 3% per year. Outcomes were expressed as quality-adjusted life years (QALYs). Scenario analyses varied multiple parameters simultaneously to model more severely and more mildly affected patients. RESULTS: ETN-first, compared to ETN-second, yielded a discounted incremental cost of $16,893 (95% confidence interval [95% CI] 9,348-25,310), incremental QALY of 0.19 (95% CI 0.08-0.32), and an incremental cost-effectiveness ratio of $88,815 per QALY gained. The results were sensitive to the cost of ETN, the time horizon of the model, and estimates of the efficacy of the first-line therapies. The cost per QALY for treating patients with severe JIA was $33,960. CONCLUSION: First-line therapy of ETN and MTX is relatively expensive compared to MTX alone, but may be economically attractive for more severely affected patients. More research is needed regarding the efficacy of first-line anti-TNF agents.

Abnormal Liver Biochemistry Is Common in Pediatric Inflammatory Bowel Disease: Prevalence and Associations.

BACKGROUND: Liver enzymes (LEs) abnormalities associated with pediatric inflammatory bowel diseases (IBD) are understudied. We undertook to describe the development and associations of abnormal LEs in pediatric IBD. METHODS: We ascertained a cohort of 300 children with IBD and collected retrospective data. A Kaplan-Meier analysis determined the time to development of different thresholds of abnormal LEs. Associations between clinical variables and the development of abnormal LEs were determined. RESULTS: The probability of developing the first episode of abnormal LEs above the upper limit of normal (ULN) within 150 months was 58.1% (16.3% by 1 mo post-IBD diagnosis). There was a 6% prevalence of primary sclerosing cholangitis (PSC) or autoimmune sclerosing cholangitis (ASC) in this cohort. Of those diagnosed with PSC/ASC, 93% had persistent LE elevations at a threshold of >2× ULN, while those without PSC/ASC had a 4% probability of this abnormality. Elevated gamma glutamyltranspeptidase levels of 252 U/L had a 99% sensitivity and 71% specificity for PSC/ASC in IBD. After exclusion of patients with PSC/ASC, corticosteroids, antibiotics, and exclusive enteral nutrition demonstrated strongly positive associations with the first development of abnormal LEs >ULN (hazard ratio 2.1 [95% confidence interval, 1.3-3.3], hazard ratio 5.6 [95% confidence interval, 3.6-8.9], hazard ratio 4.2 [95% confidence interval, 1.6-11.3], respectively). CONCLUSIONS: Abnormal LEs are common in pediatric IBD and occur early. PSC/ASC is associated with persistently high LEs and gamma glutamyltranspeptidase levels >252 U/L. Children with IBD are at risk of elevated LEs if they require medications other than 5-ASA to induce IBD remission.

Recommendations for the management of autoinflammatory diseases.

: Autoinflammatory diseases are characterised by fever and systemic inflammation, with potentially serious complications. Owing to the rarity of these diseases, evidence-based guidelines are lacking. In 2012, the European project Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) was launched to optimise and disseminate regimens for the management of children and young adults with rheumatic diseases, facilitating the clinical practice of paediatricians and (paediatric) rheumatologists. One of the aims of SHARE was to provide evidence-based recommendations for the management of the autoinflammatory diseases cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) and mevalonate kinase deficiency (MKD). These recommendations were developed using the European League Against Rheumatism standard operating procedure. An expert committee of paediatric and adult rheumatologists was convened. Recommendations derived from the systematic literature review were evaluated by an online survey and subsequently discussed at a consensus meeting using Nominal Group Technique. Recommendations were accepted if more than 80% agreement was reached. In total, four overarching principles, 20 recommendations on therapy and 14 recommendations on monitoring were accepted with ≥80% agreement among the experts. Topics included (but were not limited to) validated disease activity scores, therapy and items to assess in monitoring of a patient. By developing these recommendations, we aim to optimise the management of patients with CAPS, TRAPS and MKD.

Trying to improve care: the Morbidity and Mortality Conference in a division of rheumatology.

OBJECTIVE: To describe the frequency and types of reported adverse events and system improvement recommendations in the Morbidity and Mortality Conference (M&MC) within the Division of Rheumatology at The Hospital for Sick Children, Toronto, Ontario, Canada (SickKids). METHODS: A 5-year retrospective review of the M&MC within the Division of Rheumatology at SickKids was completed. Descriptive data including the number and types of events reported were collected. Events were categorized using an adaptation of the National Coordinating Council for Medication Error Reporting and Prevention Index. Recommendations were classified according to the Institute for Safe Medication Practices Canada. RESULTS: Between January 2007 and December 2011, 30 regularly scheduled M&MC were held. Eighty-three cases were reviewed. The most common types of reported events were related to "miscommunication" (34.9%), "treatment/test/procedure" (22.9%), "adverse drug reactions" (12.0%), and "medication errors" (8.4%). Category A events ("an event that has the capacity to cause error") were the most common with 39.8% of the cases, followed by Category C events ("an event occurred that reached the patient, but did not cause harm") with 28.9%. Eighty-nine recommendations were made. Over half of these were classified as "information" (58.4%), followed by 11 "rules and policies" recommendations (12.4%). Of the 36 action items generated from these recommendations, most are either complete or ongoing. CONCLUSION: The M&MC within the Division of Rheumatology reviews a variety of events. Increased reporting of adverse events can lead to system improvements, and has the potential to improve and promote safer healthcare.

Non-biologic remission maintenance therapy in adult patients with ANCA-associated vasculitis: a systematic review and network meta-analysis.

OBJECTIVE: To determine the comparative efficacy of non-biologic treatments for remission maintenance in ANCA-associated vasculitis. METHODS: We identified all randomized trials comparing leflunomide, azathioprine, methotrexate or mycophenolate mofetil in adult patients with granulomatosis with polyangiitis or microscopic polyangiitis. Relapse-free survival was compared through hazard ratios (HR) using a Bayesian fixed-effects network meta-analysis. Multiple sensitivity analyses were performed to explore biases identified in one trial using original trial data. RESULTS: Three trials were available (leflunomide-methotrexate, methotrexate- azathioprine, azathioprine-mycophenolate). Mycophenolate was inferior to all treatments, although the 95% credible interval (CrI) of the HR relative to methotrexate crossed 1. Leflunomide was superior to azathioprine (HR 0.43 [95% CrI: 0.14-1.3]) and methotrexate (HR 0.47 [95% CrI: 0.18-1.2]), although the 95% CrI also crossed 1. There was a 90% probability that leflunomide was the best treatment. After down weighting the effect of leflunomide vs. methotrexate for early trial termination and slow MTX dose escalation, there remained a 55% probability leflunomide was best. CONCLUSION: Based on indirect evidence, leflunomide is effective in maintaining remission in granulomatosis with polyangiitis or microscopic polyangiitis relative to other non-biologic treatments. Further randomized trials of leflunomide are needed for confirmation.