Publications by authors named "Timothy Beukelman"

103 Publications

Juvenile Spondyloarthritis in the CARRA Registry: High Biologic Use, Low Prevalence of HLA-B27, and Equal Sex Representation in Sacroiliitis.

Arthritis Care Res (Hoboken) 2020 Dec 16. Epub 2020 Dec 16.

University of Alabama at Birmingham, Birmingham, United States.

Objective: To describe characteristics of children with enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (JPsA) enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry.

Methods: All children with ERA and JPsA were identified. Demographics, clinical characteristics, and treatments were described. Those with and without sacroiliitis were compared. In those with sacroiliitis, the first visit with clinically active sacroiliitis (which came first in 72% of cases) was compared to the first visit without.

Results: Nine hundred two children with ERA or JPsA were identified. Children with ERA were older at diagnosis (10.8 vs. 8.2 years, p<0.01) and more likely male (56% vs. 38%, p<0.01). Polyarticular involvement was reported in 57% and 72% of those with ERA and JPsA. HLA-B27 was positive in 38% and 12% of those tested with ERA and JPsA. At least one biologic was taken by 72% and 64% of those with ERA and JPsA. Sacroiliitis (diagnosed clinically and/or by imaging) was reported in 28% (40% ERA and 12% JPsA). Of these, 54% were female, 36% were HLA-B27 positive, and 81% took at least one biologic. In children with sacroiliitis, the physician global, parent/patient global, and cJADAS 10 were all significantly worse at the first visit with clinically active sacroiliitis versus the first visit without active sacroiliitis.

Conclusion: In this registry, there are over 900 children with ERA or JPsA. There was high biologic use in this population, especially in those with sacroiliitis. Further, there was equal sex representation in those with sacroiliitis.
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http://dx.doi.org/10.1002/acr.24537DOI Listing
December 2020

Biologic Switching among Non-Systemic Juvenile Idiopathic Arthritis Patients: A Cohort Study in the Childhood Arthritis and Rheumatology Research Alliance Registry.

J Rheumatol 2020 Sep 15. Epub 2020 Sep 15.

Division of Pediatric Rheumatology, University of Alabama at Birmingham, Birmingham, AL, USA; Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Pediatrics, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA; Rutgers Center for Pharmacoepidemiology and Treatment Science, Institute for Health, Health Care Policy and Aging Research, New Brunswick, NJ, USA; Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, NJ, USA; Division of Pediatric Rheumatology, Seattle Children's Hospital, Seattle, WA, USA; Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA; Duke Clinical Research Institute, Duke University, Durham, NC, USA. Grants: This project was supported by funding from the Childhood Arthritis and Rheumatology Research Alliance. Address correspondence to Melissa L Mannion, 1600 7th Ave South, CPPN G10, Birmingham, AL 35233. E-mail:

Objective: Biologic medications have significantly improved disease control and outcomes of patients with juvenile idiopathic arthritis (JIA). Current treatment recommendations suggest escalating therapy; including changing biologics if needed, when inactive or low disease activity is not attained. The patterns and reasons for switching biologics in clinical practice in North America are not well described.

Methods: We used the Childhood Arthritis and Rheumatology Research Alliance Registry and included individuals with JIA if they newly started a biologic after January 1, 2008 and had at least 12 months of subsequent observable time. Subjects with systemic JIA were excluded. We compared characteristics of switchers and non-switchers using chi-square for categorical variables and Wilcoxon rank sum testing for continuous variables and used linear regression for time analysis.

Results: 1361 eligible children with JIA in the registry started a biologic (94% tumor necrosis factor TNF inhibitors [TNFi]). Median follow-up time was 30 months, and 349 (26%) switched biologics. Among biologic switchers, ineffectiveness/disease flare was the most common reason for switch (202, 58%). The most common documented switch was from etanercept to another TNFi (221, 63%). The median time to switch to a second biologic decreased substantially from 55.2 months in 2008 to 7.2 months in 2016.

Conclusion: In a multicenter cohort of patients with JIA starting a biologic, one-quarter switched to a second biologic, and the time to switching decreased in recent years. Additional studies should evaluate the outcomes and optimal timing of switching and preferred sequence of biologic use.
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http://dx.doi.org/10.3899/jrheum.200437DOI Listing
September 2020

Oral Glucocorticoids and Incident Treatment of Diabetes Mellitus, Hypertension, and Venous Thromboembolism in Children.

Am J Epidemiol 2020 Sep 9. Epub 2020 Sep 9.

Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama.

This study quantified rates of incident treatment for diabetes mellitus, hypertension, and venous thromboembolism (VTE) associated with oral glucocorticoid exposure in children ages 1-18. The retrospective cohort included >930,000 children diagnosed with autoimmune diseases (inflammatory bowel disease, juvenile idiopathic arthritis, or psoriasis) or a non-immune comparator condition (attention-deficit/hyperactivity disorder) identified using US Medicaid claims (2000-2010). Associations of glucocorticoid dose per age-/sex-imputed weight with incident treated diabetes, hypertension, and VTE were estimated using Cox regression models. Crude rates were lowest for VTE (unexposed: 0.5/million person-days [95% CI 0.4, 0.6]; currently exposed: 15.6/million person-days [95% CI 11.8, 20.1]) and highest for hypertension (unexposed: 6.7/million person-days [95% CI 6.5, 7.0]; currently exposed: 74.4/million person-days [95% CI 65.7, 83.9]). Absolute rates for all outcomes were higher in unexposed and exposed children with autoimmune diseases compared to those with attention-deficit/hyperactivity disorder. Strong dose-dependent relationships were found between current glucocorticoid exposure and all outcomes (adjusted hazard ratios for high-dose glucocorticoids: diabetes mellitus 5.93 [95% confidence intervals (CI) 3.94, 8.91]; hypertension 19.13 [95% CI 15.43, 23.73]; VTE 16.16 [95% CI 8.94, 29.22]). These results suggest strong relative risks, but low absolute risks, of newly treated VTE, diabetes, and especially hypertension in children taking high-dose oral glucocorticoids.
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http://dx.doi.org/10.1093/aje/kwaa197DOI Listing
September 2020

New Medications Are Needed for Children With Juvenile Idiopathic Arthritis.

Arthritis Rheumatol 2020 11 8;72(11):1945-1951. Epub 2020 Oct 8.

University of Alabama at Birmingham.

Objective: To document the need for additional Food and Drug Administration (FDA)-approved medications for the treatment of juvenile idiopathic arthritis (JIA).

Methods: The electronic medical records of JIA patients treated at Cincinnati Children's Hospital Medical Center (CCHMC) and data from JIA patients enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry were included in this study. Unmet medication need was defined in 2 ways: (a) the presence of chronically uncontrolled JIA, defined as a physician global assessment of JIA activity ≥3 (on a 0-10 scale, where 0 = inactive) OR ≥3 joints with active arthritis OR a patient global assessment of well-being ≥3 (on a 0-10 scale, where 0 = very well), despite sequential use of ≥2 biologic disease-modifying antirheumatic drugs (bDMARDs); and (b) the use of ≥1 bDMARD not approved for any JIA category.

Results: At CCHMC, 829 of 1,599 JIA patients (52%) were treated with ≥1 bDMARD, and 304 (19%) had been exposed to ≥1 unapproved bDMARD. In the CARRA Registry, 4,766 of 7,379 children (65%) had received ≥1 bDMARD, and 1,122 (15%) had been prescribed ≥1 unapproved bDMARD. Of those children treated with ≥2 bDMARDs for whom complete data were available, 52% (255 of 487) at CCHMC and 45% (527 of 1,159) in the CARRA Registry had chronically uncontrolled JIA despite the use of ≥2 bDMARDs.

Conclusion: Despite the availability of bDMARDs currently approved for JIA, there is persistent need for additional therapies to control JIA signs and symptoms. Since FDA approval is critical to ensure access to bDMARDs, the study and licensing of new medications is critical to address the unmet medication need and to further improve JIA outcomes.
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http://dx.doi.org/10.1002/art.41390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722045PMC
November 2020

Reply.

Arthritis Rheumatol 2020 06 16;72(6):1040-1041. Epub 2020 Apr 16.

Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH.

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http://dx.doi.org/10.1002/art.41238DOI Listing
June 2020

Making Decisions About Stopping Medicines for Well-Controlled Juvenile Idiopathic Arthritis: A Mixed-Methods Study of Patients and Caregivers.

Arthritis Care Res (Hoboken) 2021 Mar;73(3):374-385

Institute for Health, Health Care Policy and Aging Research, New Brunswick, New Jersey.

Objective: Improved treatments for juvenile idiopathic arthritis (JIA) have increased remission rates. We conducted this study to investigate how patients and caregivers make decisions about stopping medications when JIA is inactive.

Methods: We performed a mixed-methods study of caregivers and patients affected by JIA, recruited through social media and flyers, and selected by purposive sampling. Participants discussed their experiences with JIA, medications, and decision-making through recorded telephone interviews. Of 44 interviewees, 20 were patients (50% ages <18 years), and 24 were caregivers (50% caring for children ages ≤10 years). We evaluated characteristics associated with high levels of reported concerns about JIA or medicines using Fisher's exact testing.

Results: Decisions about stopping medicines were informed by competing risks between disease activity and treatment. Participants who expressed more concerns about JIA were more likely to report disease-related complications (P = 0.002) and more motivated to continue treatment. However, participants expressing more concern about medicines were more likely to report treatment-related complications (P = 0.04) and felt more compelled to stop treatment. Additionally, participants considered how JIA or treatments facilitated or interfered with their sense of normalcy and safety, expressed feelings of guilt and regret about previous or potential adverse events, and reflected on uncertainty and unpredictability of future harms. Decision-making was also informed by trust in rheumatologists and other information sources (e.g., family and online support groups).

Conclusion: When deciding whether to stop medicines whenever JIA is inactive, patients and caregivers weigh competing risks between disease activity and treatment. Based on our results, we suggest specific approaches for clinicians to perform shared decision-making regarding stopping medicines for JIA.
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http://dx.doi.org/10.1002/acr.24129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319899PMC
March 2021

Ferritin to Erythrocyte Sedimentation Rate Ratio: Simple Measure to Identify Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis.

ACR Open Rheumatol 2019 Aug 13;1(6):345-349. Epub 2019 Jul 13.

University of Alabama at Birmingham.

Objective: Macrophage activation syndrome (MAS) is a life-threatening complication of systemic juvenile idiopathic arthritis (sJIA). Early diagnosis is critical. Classification criteria for MAS in sJIA perform less well in the setting of cytokine-directed therapies. The goal herein was to explore a simple ratio of serum ferritin to the erythrocyte sedimentation rate (ESR) for diagnosis of MAS in the setting of sJIA, and to assess ferritin alone as a screening tool for identifying MAS of multiple etiologies.

Methods: Data from a large international cohort of sJIA patients with and without MAS, and from hospitalized patients with systemic infection (SI), were assessed for the ferritin:ESR ratio and ferritin alone to identify MAS among sJIA patients. Moreover, data from a smaller cohort of MAS patients associated with multiple etiologies and febrile hospitalized controls were explored. For both cohorts and controls, receiver operating characteristic curves (ROCs) for the ferritin:ESR ratio and ferritin alone were constructed, and areas under the curves (AUCs) were calculated. The Youden index was used to determine the optimal ferritin:ESR ratio and ferritin alone cut points for diagnosis.

Results: A ferritin:ESR ratio of 21.5 was 82% sensitive and 78% specific for diagnosing sJIA-MAS versus active sJIA without MAS. Ferritin alone with a set sensitivity of 95% (screening tool) had an 89.3% specificity of identifying all-cause MAS versus febrile hospitalized children.

Conclusion: The ferritin:ESR ratio is a practical tool for diagnosing MAS among sJIA patients, and serum ferritin alone is a remarkable screening tool for identifying MAS among febrile hospitalized children.
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http://dx.doi.org/10.1002/acr2.11048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857981PMC
August 2019

Comparison of second-line therapy in IVIg-refractory Kawasaki disease: a systematic review.

Pediatr Rheumatol Online J 2019 Nov 27;17(1):77. Epub 2019 Nov 27.

Division of Pediatric Rheumatology, University of Alabama, 1600 7th Avenue S, CPPN G10, Birmingham, AL, 35233, USA.

Background: Evidence remains contradictory regarding second-line therapy in patients with Kawasaki disease (KD) refractory to initial intravenous immunoglobulin (IVIg). The objective of this study aims to evaluate the efficacy and safety of three treatments [i.e. a second IVIg infusion, methylprednisolone (IVMP), and infliximab (IFX)] in patients with refractory KD.

Methods: A systematic search of PubMed, Embase, Cochrane, and ClinicalTrials.gov using predefined MeSH terms was performed from 1990 through 2017. Relevance screening was performed by two independent reviewers. Inclusion criteria included English-only, original clinical data. Eight studies met the inclusion criteria. Fever resolution, coronary lesions, and adverse event outcomes were extracted and pooled for analysis.

Results: Of the 388 patients included from the 8 studies analyzed, a majority received a second IVIg dose (n = 263, 68%). Fever resolution was comparable between IVIg (72%) and IVMP (73%). IFX (88%) significantly increased fever resolution by approximately 20% compared to IVIg re-dose (RR 1.2; [95% CI: 1.1-1.4]; p = 0.03) and IVMP (RR 1.2; [95% CI: 1.0-1.5]; p = 0.04). Clinical significance of differences in coronary outcomes remains unclear.

Conclusions: This combined analysis was limited due to variability in design and data reporting methods between the studies and risk of bias. In the absence of a clinical trial, IFX monotherapy as second-line treatment should be considered in patients who fail to respond to initial IVIg. This conclusion is based on a systematic review of the literature with pooled outcome data analysis suggesting IFX is more effective in fever resolution compared to a second IVIg dose and IVMP.
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http://dx.doi.org/10.1186/s12969-019-0380-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882052PMC
November 2019

Benefit of Anakinra in Treating Pediatric Secondary Hemophagocytic Lymphohistiocytosis.

Arthritis Rheumatol 2020 02 26;72(2):326-334. Epub 2019 Dec 26.

University of Alabama at Birmingham School of Medicine.

Objective: To assess the benefit of the recombinant human interleukin-1 receptor antagonist anakinra in treating pediatric patients with secondary hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) associated with rheumatic and nonrheumatic conditions.

Methods: A retrospective chart review of all anakinra-treated patients with secondary HLH/MAS was performed at Children's of Alabama from January 2008 through December 2016. Demographic, clinical, laboratory, and genetic characteristics, outcomes data, and information on concurrent treatments were collected from the records and analyzed using appropriate univariate statistical approaches to assess changes following treatment and associations between patient variables and outcomes.

Results: Forty-four patients with secondary HLH/MAS being treated with anakinra were identified in the electronic medical records. The median duration of hospitalization was 15 days. The mean pretreatment serum ferritin level was 33,316 ng/ml and dropped to 14,435 ng/ml (57% decrease) within 15 days of the start of anakinra treatment. The overall mortality rate in the cohort was 27%. Earlier initiation of anakinra (within 5 days of hospitalization) was associated with reduced mortality (P = 0.046), whereas thrombocytopenia (platelet count <100,000/μl) and STXBP2 mutations were both associated with increased mortality (P = 0.008 and P = 0.012, respectively). In considering patients according to their underlying diagnosis, those with systemic juvenile idiopathic arthritis (JIA) had the lowest mortality rate, with no deaths among the 13 systemic JIA patients included in the study (P = 0.006). In contrast, those with an underlying hematologic malignancy had the highest mortality rate, at 100% (n = 3).

Conclusion: These findings suggest that anakinra appears to be effective in treating pediatric patients with non-malignancy-associated secondary HLH/MAS, especially when it is given early in the disease course and when administered to patients who have an underlying rheumatic disease.
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http://dx.doi.org/10.1002/art.41103DOI Listing
February 2020

Toward Accelerated Authorization and Access to New Medicines for Juvenile Idiopathic Arthritis.

Arthritis Rheumatol 2019 12 1;71(12):1976-1984. Epub 2019 Nov 1.

Hackensack University Medical Center, Hackensack, New Jersey.

A meeting was organized to bring together multiple stakeholders involved in the testing and authorization of new medications for juvenile idiopathic arthritis (JIA) to discuss current issues surrounding clinical trials and access to new medications for children and adolescents with JIA. The Childhood Arthritis and Rheumatology Research Alliance invited representatives of regulatory agencies (Food and Drug Administration and European Medicines Agency), and major pharmaceutical companies with JIA-approved products or products in development, patient and parent representatives, representatives of an advocacy organization (Arthritis Foundation), and pediatric rheumatology clinicians/investigators to a 1-day meeting in April 2018. The participants engaged in discussion regarding issues in clinical trials. As the pharmacologic options to treat inflammatory arthritis rapidly expand, registration trial designs to test medications in JIA patients must adapt. Many methodologies successfully used in the recent past are no longer feasible. The pool of patients meeting entry criteria who are willing to participate is shrinking while the number of medications to be tested is growing. Suggested solutions included proposing innovative clinical trial methods to regulatory agencies, as well as open discussions among stakeholders. Ensuring that new medications are authorized in a timely manner to meet the needs of JIA patients worldwide is critical. Approaches should include open dialog between regulatory agencies, pharmaceutical companies, and other stakeholders to develop and implement novel study designs, including patient and clinician perspectives to define meaningful trial outcomes, and changing existing study plans.
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http://dx.doi.org/10.1002/art.41043DOI Listing
December 2019

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

Arthritis Care Res (Hoboken) 2019 06 25;71(6):703-716. Epub 2019 Apr 25.

ECRI Institute, Plymouth Meeting, Pennsylvania.

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.
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http://dx.doi.org/10.1002/acr.23871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777949PMC
June 2019

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

Arthritis Rheumatol 2019 06 25;71(6):846-863. Epub 2019 Apr 25.

ECRI Institute, Plymouth Meeting, Pennsylvania.

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.
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http://dx.doi.org/10.1002/art.40884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561114PMC
June 2019

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

Arthritis Care Res (Hoboken) 2019 06 25;71(6):717-734. Epub 2019 Apr 25.

ECRI Institute, Plymouth Meeting, Pennsylvania.

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.
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http://dx.doi.org/10.1002/acr.23870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561125PMC
June 2019

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

Arthritis Rheumatol 2019 06 25;71(6):864-877. Epub 2019 Apr 25.

ECRI Institute, Plymouth Meeting, Pennsylvania.

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.
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http://dx.doi.org/10.1002/art.40885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788287PMC
June 2019

Primary Oral Presentation of Sarcoidosis in a Pediatric Patient.

J Oral Maxillofac Surg 2019 Jun 23;77(6):1180-1186. Epub 2019 Jan 23.

Associate Professor, Department of Pediatric Rheumatology, Children's of Alabama, Birmingham, AL.

Sarcoidosis is a multisystem granulomatous disease of unknown etiology that commonly affects the lungs, lymph nodes, and skin. The disease often presents in patients between the third and sixth decade and its pathology is defined by the presence of noncaseating granulomas within organs throughout the body. Oral and neurologic involvement of sarcoid is extremely rare and occurs in approximately 1% and 5% of patients with the disease, respectively. A case of sarcoidosis involving the gingiva and submandibular lymph nodes is described in a 14-year-old girl. Further neural involvement of the disease was recognized after initial biopsy examinations and systemic evaluation. This presentation is especially rare given the patient's lack of symptoms, age at diagnosis, and initial oral manifestations.
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http://dx.doi.org/10.1016/j.joms.2019.01.018DOI Listing
June 2019

Juvenile Idiopathic Arthritis: An Idea Whose Time Has Gone?

J Rheumatol 2019 02;46(2):124-126

Brigham and Women's Hospital, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

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http://dx.doi.org/10.3899/jrheum.180922DOI Listing
February 2019

Rituximab treatment for chronic steroid-dependent Henoch-Schonlein purpura: 8 cases and a review of the literature.

Pediatr Rheumatol Online J 2018 Nov 14;16(1):71. Epub 2018 Nov 14.

Department of Pediatrics, Division of Rheumatology, University of Alabama at Birmingham, 1600 7th Ave S, CPPN G10, Birmingham, AL, 35233, USA.

Background: Henoch-Schonlein purpura (HSP) is a small vessel vasculitis that is characterized by non-thrombocytopenic purpura, abdominal pain, arthritis, and glomerulonephritis. Typically, HSP is self-limited requiring only supportive care, but more severe cases may require corticosteroid (CS) treatment. Rarely, a subset of these patients has persistent rash, arthritis, abdominal involvement, or renal disease despite treatment with CS, or has disease recurrence on CS tapering. Refractory HSP has been effectively treated with a variety of CS sparing therapies. For life-threatening refractory HSP, the B cell depleting agent, rituximab (RTX), has been reported as beneficial for children with substantial renal or central nervous system involvement. However, RTX use for children with less severe HSP, but chronic CS dependent disease refractory to CS sparing immunomodulatory agents, has been less well explored. Herein, we describe 8 children treated with RTX for chronic refractory HSP and report a reduction in recurrent hospitalizations and eventual CS discontinuation.

Methods: This is a retrospective analysis of eight children who were treated with RTX for chronic CS dependent HSP during the years 2006-2014 at a single institution. A chart review of the electronic medical record was performed to determine the presenting symptoms, the type and duration of treatment received, and the number of hospitalizations prior to and after RTX. The number of hospitalizations and oral corticosteroid burden were analyzed using the Wilcoxon signed rank test.

Results: Prior to receiving RTX, seven patients had at least one hospitalization for HSP (median 1.5, range 0-3). Following RTX, only two patients were hospitalized, each a single time for recurrent abdominal pain. The median oral CS burden was 0.345 mg/kg/day before RTX and 0 mg/kg/day at 6 months (p = 0.078), 1 year (p = 0.0625), and 2 years (p = 0.03) following RTX infusion. Seven out of eight children met remission criteria, defined as no active rash, arthritis, nephritis (hematuria and proteinuria), or gastrointestinal distress following RTX. No serious adverse events were noted.

Conclusion: Overall, RTX effectively reduced the number of hospital admissions and oral CS burden. RTX also helped most all children achieve clinical remission. RTX appears to be an effective and safe alternative for chronic CS dependent and immunomodulatory refractory childhood HSP.
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http://dx.doi.org/10.1186/s12969-018-0285-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6236882PMC
November 2018

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.

Arthritis Rheumatol 2019 03 24;71(3):451-459. Epub 2019 Jan 24.

Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

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.
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http://dx.doi.org/10.1002/art.40727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393224PMC
March 2019

Association of Statin Exposure With Histologically Confirmed Idiopathic Inflammatory Myositis in an Australian Population.

JAMA Intern Med 2018 09;178(9):1224-1229

Department of Medicine, University of Adelaide, Adelaide, Australia.

Importance: Statin medications are widely prescribed for cardiovascular risk reduction. Myalgia and rhabdomyolysis are well-recognized adverse effects of statins, and they resolve with the cessation of statin therapy. Idiopathic inflammatory myositis (IIM) is a heterogeneous group of autoimmune myopathies that may also be associated with statin use. Recently, statin-associated autoimmune myopathy has been recognized as a distinct entity with the presence of specific autoantibodies against hydroxymethylglutaryl-coenzyme A reductase, which results in a necrotizing myositis that does not resolve with cessation of statin therapy and requires treatment with immunosuppressive agents.

Objective: To examine the association between histologically confirmed IIM and current exposure to statin medications.

Design, Setting, And Participants: Population-based case-control study using the South Australian Myositis Database of all histologically confirmed cases of IIM diagnosed between 1990 and 2014 in patients 40 years or older (n = 221) and population-based controls from the North West Adelaide Health Study (n = 662), matched by age and sex in a 3:1 ratio of controls to cases. Data analysis using conditional logistic regression was performed from June 1, 2016, to July 14, 2017.

Exposures: Current statin medication use.

Main Outcomes And Measures: Unadjusted and adjusted (for diabetes and cardiovascular disease) odds ratios and 95% CIs for likelihood of inflammatory myositis.

Results: A total of 221 IIM cases met the inclusion criteria with a mean (SD) age of 62.2 (10.8) years, and 132 (59.7%) were female. Statin exposure at the time of IIM diagnosis was 68 of 221 patients (30.8%) and 142 of 662 matched controls (21.5%) (P = .005). There was an almost 2-fold increased likelihood of statin exposure in patients with IIM compared with controls (adjusted odds ratio, 1.79; 95% CI, 1.23-2.60; P = .001). Similar results were observed when patients with necrotizing myositis were excluded from the analysis (adjusted odds ratio, 1.92; 95% CI, 1.29-2.86; P = .001).

Conclusions And Relevance: In this large population-based study, statin exposure was significantly associated with histologically confirmed IIM. Given the increased use of statins worldwide and the severity of IIM, increased awareness and recognition of this potentially rare adverse effect of statin exposure is needed.
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http://dx.doi.org/10.1001/jamainternmed.2018.2859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142971PMC
September 2018

Juvenile Idiopathic Arthritis: Oligoarthritis and Polyarthritis.

Pediatr Clin North Am 2018 08;65(4):657-674

Department of Pediatrics, Division of Rheumatology, University of Alabama at Birmingham, 1600 7th Avenue South, CPPN G10, Birmingham, AL 35233, USA. Electronic address:

Juvenile idiopathic arthritis (JIA) comprises a group of heterogeneous diseases further divided into various categories based on shared clinical presentation, laboratory markers, and disease prognosis. Extra-articular complications include uveitis and growth abnormalities. Disease course and prognosis vary with respect to each JIA category and subsequently guide respective treatment. Over the past few decades, considerable treatment advances have significantly reduced the morbidity associated with childhood arthritis. Nevertheless, the treatments are not curative; many children continue to have active disease into adulthood. Emphasis is placed on the initiation of early aggressive therapy in hopes of delaying disease progression and inducing remission.
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http://dx.doi.org/10.1016/j.pcl.2018.03.005DOI Listing
August 2018

Childhood Arthritis and Rheumatology Research Alliance Consensus Treatment Plans for Juvenile Idiopathic Arthritis-Associated and Idiopathic Chronic Anterior Uveitis.

Arthritis Care Res (Hoboken) 2019 04;71(4):482-491

Duke University Medical Center, Durham, North Carolina.

Objective: Systemic immunosuppressive treatment of pediatric chronic anterior uveitis (CAU), both juvenile idiopathic arthritis-associated and idiopathic anterior uveitis, varies, making it difficult to identify best treatments. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) developed consensus treatment plans (CTPs) for CAU for the purpose of reducing practice variability and allowing future comparison of treatments using comparative effectiveness analysis techniques.

Methods: A core group of pediatric rheumatologists, ophthalmologists with uveitis expertise, and a lay advisor comprised the CARRA uveitis workgroup that performed a literature review on pharmacologic treatments, held teleconferences, and developed a case-based survey administered to the CARRA membership to delineate treatment practices. We held 3 face-to-face consensus meetings using nominal group technique to develop CTPs.

Results: The survey identified areas of treatment practice variability. We developed 2 CTPs for the treatment of CAU, case definitions, and monitoring parameters. The first CTP is directed at children who are naive to steroid-sparing medication, and the second at children initiating biologic therapy, with options for methotrexate, adalimumab, and infliximab. We defined a core data set and outcome measures, with data collection at 3 and 6 months after therapy initiation. The CARRA membership voted to accept the CTPs with a >95% approval (n = 233).

Conclusion: Using consensus methodology, 2 standardized CTPs were developed for systemic immunosuppressive treatment of CAU. These CTPs are not meant as treatment guidelines, but are designed for further pragmatic research within the CARRA research network. Use of these CTPs in a prospective comparison effectiveness study should improve outcomes by identifying best practice options.
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http://dx.doi.org/10.1002/acr.23610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6261704PMC
April 2019

Risk Factors for Intraarticular Heterotopic Bone Formation in the Temporomandibular Joint in Juvenile Idiopathic Arthritis.

J Rheumatol 2018 08 15;45(9):1301-1307. Epub 2018 May 15.

From the Department of Pediatrics at the University of Alabama at Birmingham, Birmingham, Alabama, USA.

Objective: Intraarticular corticosteroid (IAC) injections are often used to treat temporomandibular joint (TMJ) arthritis associated with juvenile idiopathic arthritis (JIA). One potential complication of IA therapy is heterotopic bone formation (HBF). The purpose of our study was to evaluate risk factors for HBF development in children with JIA who received IA therapy for TMJ arthritis.

Methods: This was a retrospective study of children with JIA who had received ≥ 1 IAC injection into the TMJ. Survival regression analysis was performed to identify risk factors for the development of HBF.

Results: There were 238 children included, of whom 33 (14%) developed HBF. No cases of HBF were diagnosed prior to the initial injection. Univariate analysis revealed that the risk factors for development of HBF were the total number of injections received into the TMJ and age at diagnosis of JIA, while the length of time from diagnosis of JIA to the first injection was inversely associated with the risk of HBF formation. The total number of injections was no longer significant following adjusted survival models. Children with HBF had increased physical examination evidence of acute or chronic changes, namely decreased maximal incisal opening and increased likelihood of jaw deviation.

Conclusion: HBF within the TMJ is relatively common in patients with JIA receiving IAC injections for TMJ arthritis. Future prospective studies are required to delineate the risks posed by the injections themselves as opposed to the underlying disease activity, as well as to evaluate alternative forms of local therapy to the TMJ.
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http://dx.doi.org/10.3899/jrheum.171306DOI Listing
August 2018

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.

Arthritis Rheumatol 2018 09 25;70(9):1508-1518. Epub 2018 Jul 25.

Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

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.
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http://dx.doi.org/10.1002/art.40509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115300PMC
September 2018

Bayesian comparative effectiveness study of four consensus treatment plans for initial management of systemic juvenile idiopathic arthritis: FiRst-Line Options for Systemic juvenile idiopathic arthritis Treatment (FROST).

Clin Trials 2018 06 15;15(3):268-277. Epub 2018 Mar 15.

7 Division of Pediatric Rheumatology, Joseph M. Sanzari Children's Hospital, Hackensack University Medical Center, Hackensack, NJ, USA.

Background: Systemic juvenile idiopathic arthritis is a rare febrile arthritis of childhood characterized by a potentially severe course, including prolonged glucocorticoid exposure, growth failure, destructive arthritis, and life-threatening macrophage activation syndrome. Early cytokine-blocking biologic therapy may improve long-term outcomes, although some systemic juvenile idiopathic arthritis patients respond well to non-biologic treatment, leaving optimal management undefined. Consequently, treatment of new-onset systemic juvenile idiopathic arthritis by expert clinicians varies widely.

Purpose: To describe a pragmatic, observational comparative effectiveness study that takes advantage of diversity in the management of a rare disease: FiRst-Line Options for Systemic juvenile idiopathic arthritis Treatment (FROST), comparing non-biologic and biologic consensus treatment plans for new-onset systemic juvenile idiopathic arthritis within the 60-center Childhood Arthritis and Rheumatology Research Alliance Registry (CARRA).

Methods: FiRst-Line Options for Systemic juvenile idiopathic arthritis Treatment (FROST) is a multicenter, prospective, non-randomized study that compares four Childhood Arthritis and Rheumatology Research Alliance (CARRA) consensus treatment plans for new-onset systemic juvenile idiopathic arthritis: (1) glucocorticoids alone, (2) methotrexate, (3) interleukin-1 blockade, and (4) interleukin-6 blockade. Patients consenting to participation in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry are started on one of four Consensus Treatment Plans at the discretion of the treating physician. The outcome of primary interest is clinically inactive disease off glucocorticoids at 9 months, comparing non-biologic (Consensus Treatment Plans 1 + 2) versus biologic (Consensus Treatment Plans 3 + 4) strategies. Bayesian analytic methods will be employed to evaluate response rates, using propensity scoring to balance treatment groups for potential confounding. With 200 patients in a 2:1 ratio of biologic to non-biologic, there is a >90% probability of finding biologic consensus treatment plans more effective if the rate of clinically inactive disease is 30% higher than for non-biologic therapy. Additional outcomes include Patient-Reported Outcomes Measurement Information System measures and other parent-/patient-reported outcomes reported in real time using smartphone technology. Routine operation of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry will allow assessment of outcomes over at least 10 years.

Results: FiRst-Line Options for Systemic juvenile idiopathic arthritis Treatment (FROST) began enrollment in November 2016.

Limitations: The observational design may not provide balance in measured and unmeasured confounders. Use of consensus treatment plan (CTP) strategies at frequencies more unbalanced than predicted could reduce the chance of finding differences in efficacy.

Conclusion: FiRst-Line Options for Systemic juvenile idiopathic arthritis Treatment (FROST) will provide the first prospective comparison of Childhood Arthritis and Rheumatology Research Alliance's (CARRA's) consensus-derived non-biologic versus biologic management strategies in systemic juvenile idiopathic arthritis, performed in a real-world setting wherein each patient receives standard-of-care treatment selected by the treating physician. Outcomes include clinician- and patient-/family-reported outcomes, empowering both physician and patient decision making in new-onset systemic juvenile idiopathic arthritis.
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http://dx.doi.org/10.1177/1740774518761367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5990441PMC
June 2018

Risk of malignancy associated with paediatric use of tumour necrosis factor inhibitors.

Ann Rheum Dis 2018 07 9;77(7):1012-1016. Epub 2018 Feb 9.

Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Objective: To determine whether tumour necrosis factor inhibitor (TNFi) use is associated with an increased rate of incident malignancy compared with no TNFi use in the treatment of juvenile idiopathic arthritis (JIA), paediatric inflammatory bowel disease (pIBD) and paediatric plaque psoriasis (pPsO).

Methods: We performed a retrospective cohort study of administrative claims data from the USA from 2000 to 2014. Exposure to TNFi was considered permanent from the first observed exposure onward. The malignancy outcome was defined by diagnosis codes with evidence of cancer treatment. We calculated standardised incidence ratios (SIRs) comparing the observed number of malignancies to the expected numbers according to cancer surveillance data. We used multivariable Cox proportional hazards models to estimate adjusted HRs (aHRs) for incident malignancy.

Results: We identified 15 598 children with TNFi use and 73 839 children with no TNFi use (30 703 and 121 801 person-years of follow-up, respectively). We identified 15 malignancies among children with TNFi use (SIR 2.9 (1.6 to 4.9)) and 42 malignancies among children without TNFi use (SIR 2.1 (1.5 to 2.9)). The aHR was 1.58 (0.88 to 2.85) for TNFi use versus no TNFi use. In pIBD, TNFi use with thiopurine use was associated with a higher SIR (6.0 (1.2 to 17.5)) compared with TNFi use without thiopurine use (2.5 (0.7 to 6.4)).

Conclusion: Children diagnosed with JIA, pIBD and pPsO had an increased rate of malignancy compared with the general population, but treatment with TNFi did not appear to significantly further increase the risk compared with no TNFi use. More data are needed about the long-term risks of TNFi use.
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http://dx.doi.org/10.1136/annrheumdis-2017-212613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6094159PMC
July 2018

High Levels of DEK Autoantibodies in Sera of Patients With Polyarticular Juvenile Idiopathic Arthritis and With Early Disease Flares Following Cessation of Anti-Tumor Necrosis Factor Therapy.

Arthritis Rheumatol 2018 04 22;70(4):594-605. Epub 2018 Feb 22.

University of Michigan, Ann Arbor.

Objective: The nuclear oncoprotein DEK is an autoantigen associated with juvenile idiopathic arthritis (JIA), especially the oligoarticular subtype. DEK is a secreted chemotactic factor. Abundant levels of DEK and DEK autoantibodies are found in inflamed synovium in JIA. We undertook this study to further characterize the nature of DEK autoantibodies in screening serum samples from 2 different cohorts that consisted mostly of patients with JIA.

Methods: DEK autoantibody levels were analyzed in sera from 33 JIA patients, 13 patients with other inflammatory conditions, and 11 healthy controls, as well as in 89 serum samples from JIA patients receiving anti-tumor necrosis factor (anti-TNF) therapy. Recombinant His-tagged full-length DEK protein (1-375 amino acids [aa]) and the 187-375-aa and 1-350-aa His-tagged DEK fragments made in a baculovirus system were used for enzyme-linked immunosorbent assay (ELISA) and immunoblotting. The C-terminal 25-aa fragment of DEK was expressed in a glutathione S-transferase-tagged vector. ELISA results were calculated as area under the curve by the trapezoidal rule.

Results: DEK autoantibody levels were significantly higher in patients with polyarticular JIA than in those with oligoarticular JIA, and were higher in patients with polyarticular JIA who had more active disease after cessation of anti-TNF therapy. Immunoblotting against the C-terminal 25-aa fragment of DEK confirmed that this section of the DEK molecule is the most immunogenic domain.

Conclusion: DEK autoantibody levels are higher in patients with polyarticular JIA than in those with oligoarticular JIA, and higher in patients who have disease flares after cessation of anti-TNF therapy. The C-terminal 25-aa fragment is the most immunogenic portion of DEK. These findings are significant with respect to the nature of DEK autoantibodies, their contribution to JIA pathogenesis, and their implications for JIA management.
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http://dx.doi.org/10.1002/art.40404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5876119PMC
April 2018

Risk of tuberculosis among Alabama children and adolescents treated with tumor necrosis factor inhibitors: a retrospective study.

Pediatr Rheumatol Online J 2017 Nov 9;15(1):79. Epub 2017 Nov 9.

Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA.

Background: Tumor Necrosis Factor inhibitors (TNFi) have dramatically improved the outlook for patients with inflammatory arthritides and bowel disease (IBD), but are associated with increased infection risks, including tuberculosis (TB). Pediatric inflammatory diseases are uncommon, and the risk of TB in children taking TNFi remains unclear. The objective of this study was to report the incidence of TB disease among TNFi recipients at a single pediatric medical center serving most of Alabama compared to that of the general population of Alabama children.

Methods: Instances of TNFi usage among patients under age 20 years from July 1, 2007 through April 17, 2015 were captured from electronic health records at Children's of Alabama (CoA), which has the only pediatric rheumatology clinic in Alabama, and where a substantial number of children in Alabama with inflammatory bowel disease receive care., and reports of TB cases were obtained from the Alabama Department of Public Health (ADPH). Incidence was expressed as TB cases/10,000 person-years, using population estimates from the Alabama Center for Health Statistics.

Results: 1033 Alabama patients at CoA who were residents of Alabama were identified who received TNFi for a total of 1564 person-years. One adolescent on TNFi developed severe extrapulmonary TB (incidence density = 6.4 per 10,000; 95% CI 0.9-45.4 per 10,000). Sixty-three cases occurred in persons not on TNFi (incidence density = 0.064 per 10,000; 95% CI 0.050-0.082 per 10,000).

Conclusions: One case of TB disease among TNFi-exposed children was identified for 1564 person-years in Alabama residents. Although rare, this is higher than expected relative to the general rate of TB in Alabama. Thus, continued diagnostic vigilance for TB in children taking TNFi is required.

Trial Registration Number: Not applicable.
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http://dx.doi.org/10.1186/s12969-017-0207-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5679346PMC
November 2017

Comparative Effectiveness of Tumor Necrosis Factor Agents and Disease-modifying Antirheumatic Therapy in Children with Enthesitis-related Arthritis: The First Year after Diagnosis.

J Rheumatol 2018 01 15;45(1):107-114. Epub 2017 Sep 15.

From the Department of Pediatric Rheumatology, Department of Pediatrics, and Center for Pediatric Clinical Effectiveness, The Children's Hospital of Philadelphia; Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; University of Texas Southwestern, Texas Scottish Rite Hospital for Children, Dallas, Texas; University of Alabama, Birmingham, Alabama; Cincinnati Children's Hospital, Cincinnati, Ohio, USA; University of Florence and Anna Meyer Children's Hospital, Florence, Italy.

Objective: To characterize the effect of anti-tumor necrosis factor (TNF) therapy compared to conventional synthetic disease-modifying antirheumatic drugs (csDMARD) in children with enthesitis-related arthritis (ERA) over the first year after diagnosis.

Methods: We conducted a multicenter retrospective comparative effectiveness study of children diagnosed with ERA. We estimated the effect of anti-TNF therapy on clinical variables (active joint count, tender entheses count) and patient-reported pain and global assessment of disease activity over the first year after diagnosis using state-of-the-art comparative effectiveness analytic methods.

Results: During the study period, 217 patients newly diagnosed with ERA had a total of 965 clinic visits the first year after disease diagnosis. Children [median age 11.6 yrs, interquartile range 10-14] were treated with anti-TNF monotherapy (n = 33, 15.2%), csDMARD monotherapy (n = 73, 33.6%), or both (n = 52, 23.9%) in the first year after disease diagnosis. There was a statistically significant improvement in the primary outcome, active joint count, over time in children who received an anti-TNF drug versus those who did not (p = 0.03). Additionally, use of anti-TNF therapy versus no anti-TNF therapy was associated with less patient-reported pain (p < 0.01) and improved disease activity over time as assessed by the clinical Juvenile Arthritis Disease Activity Score (p < 0.01). The magnitude of estimated effect on clinical outcomes was uniformly greater, with the exception of tender entheses count, in children treated with an anti-TNF drug versus a csDMARD.

Conclusion: During the first year after diagnosis, anti-TNF exposure was associated with benefits for several clinically meaningful outcomes in children with enthesitis-related arthritis.
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http://dx.doi.org/10.3899/jrheum.170251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5750113PMC
January 2018

Evidence for Updating the Core Domain Set of Outcome Measures for Juvenile Idiopathic Arthritis: Report from a Special Interest Group at OMERACT 2016.

J Rheumatol 2017 Dec 15;44(12):1884-1888. Epub 2017 Aug 15.

Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Pediatric Rheumatology and Pediatric Health Services Research, University of Michigan CS Mott Children's Hospital, Ann Arbor, Michigan; Office of Research, Division of Rheumatology, Columbia University Medical Center, New York; Division of Rheumatology, University of Rochester, Golisano Children's Hospital, Rochester, New York; Thornhill Associates, Hermosa Beach; Division of Immunology/Rheumatology, Stanford University, Stanford, California; Division of Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama; Arthritis Foundation, Atlanta, Georgia; Division of Rheumatology, Children's Mercy, Kansas City, Missouri; Division of Pediatric Rheumatology, Rutgers Robert Wood Johnson Medical School, Institute for Health, Health Care Policy and Aging Research, New Brunswick, New Jersey; Medical College of Wisconsin, Milwaukee, Wisconsin; Division of Rheumatology, Seattle Children's Hospital, Seattle, Washington; Johns Hopkins Arthritis Center, Johns Hopkins University, Baltimore, Maryland, USA; Division of Rheumatology, Istituto Giannina Gaslini; University of Genoa, Genoa, Italy; Rheumatology, Royal Children's Hospital; Murdoch Children's Research Institute, Melbourne, Australia; The Hospital for Sick Children, and Lawrence S. Bloomberg Faculty of Nursing, University of Toronto, Toronto; Children's Hospital of Eastern Ontario Research Institute, Department of Pediatrics and School of Rehabilitation Sciences, University of Ottawa, Ottawa, Ontario, Canada.

Objective: The current Juvenile Idiopathic Arthritis (JIA) Core Set was developed in 1997 to identify the outcome measures to be used in JIA clinical trials using statistical and consensus-based techniques, but without patient involvement. The importance of patient/parent input into the research process has increasingly been recognized over the years. An Outcome Measures in Rheumatology (OMERACT) JIA Core Set Working Group was formed to determine whether the outcome domains of the current core set are relevant to those involved or whether the core set domains should be revised.

Methods: Twenty-four people from the United States, Canada, Australia, and Europe, including patient partners, formed the working group. Guided by the OMERACT Filter 2.0 process, we performed (1) a systematic literature review of outcome domains, (2) a Web-based survey (142 patients, 343 parents), (3) an idea-generation study (120 parents), (4) 4 online discussion boards (24 patients, 20 parents), and (5) a Special Interest Group (SIG) activity at the OMERACT 13 (2016) meeting.

Results: A MEDLINE search of outcome domains used in studies of JIA yielded 5956 citations, of which 729 citations underwent full-text review, and identified additional domains to those included in the current JIA Core Set. Qualitative studies on the effect of JIA identified multiple additional domains, including pain and participation. Twenty-one participants in the SIG achieved consensus on the need to revise the entire JIA Core Set.

Conclusion: The results of qualitative studies and literature review support the need to expand the JIA Core Set, considering, among other things, additional patient/parent-centered outcomes, clinical data, and imaging data.
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http://dx.doi.org/10.3899/jrheum.161389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5914507PMC
December 2017

Biologic Agents in the Treatment of Childhood-Onset Rheumatic Disease.

J Pediatr 2017 10 13;189:31-39. Epub 2017 Jul 13.

Department of Pediatrics, Division of Rheumatology, University of Alabama at Birmingham, Birmingham, AL. Electronic address:

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http://dx.doi.org/10.1016/j.jpeds.2017.06.041DOI Listing
October 2017