Publications by authors named "Susan Nielsen"

84 Publications

Under detection of interstitial lung disease in juvenile systemic sclerosis (jSSc).

Arthritis Care Res (Hoboken) 2020 Nov 3. Epub 2020 Nov 3.

Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.

Objectives: Utilizing data obtained from a prospective international juvenile systemic sclerosis cohort (jSScC) to determine if pulmonary screening with forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO) is sufficient to assess the presence of interstitial lung disease (ILD) in comparison to high resolution computed tomography (HRCT) in jSSc.

Methods: The jSScC cohort database was queried for patients enrolled from January 2008 to January 2020 with recorded pulmonary function tests (PFT) parameters and HRCT to determine the discriminatory properties of PFTs parameters, FVC and DLCO, in detecting ILD.

Results: Eighty-six jSSc patients had both CT imaging and FVC values for direct comparison. Using findings on HRCT as the standard measure of ILD presence, the sensitivity of FVC in detecting ILD in jSSc was only 40%, the specificity was 77%, and AUC was 0.58. Fifty-eight jSSc patients had both CT imaging and DLCO values for comparison. The sensitivity of DLCO in detecting ILD was 76%, the specificity was 70%, and AUC was 0.73.

Conclusion: The performance of PFTs in jSSc to detect underlying ILD was quite limited. Specifically, the FVC, which is one of the main clinical parameters in adult SSc to detect and monitor ILD, would miss approximately 60% of children that had ILD changes on their accompanying HRCT. The DLCO was more sensitive in detecting potential abnormalities in HRCT, but with less specificity than the FVC. These results support the use of HRCT in tandem with PFTs for the screening of ILD in jSSc.
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http://dx.doi.org/10.1002/acr.24499DOI Listing
November 2020

Uveitis in Juvenile Idiopathic Arthritis: 18-Year Outcome in the Population-based Nordic Cohort Study.

Ophthalmology 2020 Aug 29. Epub 2020 Aug 29.

Department of Pediatrics and Adolescent Medicine, University Hospital of North Norway, Tromsø, Norway; Department of Clinical Medicine, UiT - The Arctic University of Norway, Tromsø, Norway.

Purpose: To assess the long-term outcome of uveitis in juvenile idiopathic arthritis (JIA).

Design: Population-based, multicenter, prospective JIA cohort, with a cross-sectional assessment of JIA-associated uveitis (JIA-U) 18 years after the onset of JIA.

Participants: A total of 434 patients with JIA, of whom 96 had uveitis, from defined geographic areas of Denmark, Finland, Norway, and Sweden.

Methods: Patients with onset of JIA between January 1997 and June 2000 were prospectively followed for 18 years. Pediatric rheumatologists and ophthalmologists collected clinical and laboratory data.

Main Outcome Measures: Cumulative incidence of uveitis and clinical characteristics, JIA and uveitis disease activity, ocular complications, visual outcome, and risk factors associated with the development of uveitis-related complications.

Results: Uveitis developed in 96 (22.1%) of 434 patients with JIA. In 12 patients (2.8%), uveitis was diagnosed between 8 and 18 years of follow-up. Systemic immunosuppressive medication was more common among patients with uveitis (47/96 [49.0%]) compared with patients without uveitis (78/338 [23.1%]). Active uveitis was present in 19 of 78 patients (24.4%) at the 18-year visit. Ocular complications occurred in 31 of 80 patients (38.8%). Short duration between the onset of JIA and the diagnosis of uveitis was a risk factor for developing ocular complications (odds ratio [OR], 1.4; 95% confidence interval [CI], 1.1-1.8). Patients with a diagnosis of uveitis before the onset of JIA all developed cataract and had an OR for development of glaucoma of 31.5 (95% CI, 3.6-274). Presence of antinuclear antibodies (ANAs) was also a risk factor for developing 1 or more ocular complications (OR, 3.0; 95% CI, 1.2-7.7). Decreased visual acuity (VA) <6/12 was found in 12 of 135 eyes (8.9%) with uveitis, and 4 of 80 patients (5.0%) with JIA-U had binocular decreased VA <6/12.

Conclusions: Our results suggest that uveitis screening should start immediately when the diagnosis of JIA is suspected or confirmed and be continued for more than 8 years after the diagnosis of JIA. Timely systemic immunosuppressive treatment in patients with a high risk of developing ocular complications must be considered early in the disease course to gain rapid control of ocular inflammation.
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http://dx.doi.org/10.1016/j.ophtha.2020.08.024DOI Listing
August 2020

[11C]dihydrotetrabenazine Positron Emission Tomography in Manganese-Exposed Workers.

J Occup Environ Med 2020 Oct;62(10):788-794

Department of Neurology (Dr Criswell, Dr Nielsen, Mr Warden, Dr Perlmutter, Mr Lenox-Krug, Dr Racette); Department of Radiology (Dr Perlmutter, Dr Moerlein); Department of Neuroscience (Dr Perlmutter); Program in Physical Therapy (Dr Perlmutter); Program in Occupational Therapy (Dr Perlmutter); Department of Biochemistry and Molecular Biophysics (Dr Moerlein), Washington University School of Medicine, St. Louis, Missouri ; Department of Environmental and Occupational Health Sciences (Dr Sheppard); Department of Biostatistics (Dr Sheppard), School of Public Health, University of Washington, Seattle, Washington; Department of Family Medicine and Public Health (Dr Checkoway); Department of Neurosciences (Dr Checkoway), School of Medicine, University of California, San Diego, La Jolla, California; Faculty of Health Sciences, School of Public Health, University of the Witwatersrand, Parktown, South Africa (Dr Racette).

Objective: To understand the neurotoxic effects of manganese (Mn) exposure on monoaminergic function, utilizing [C]dihydrotetrabenazine (DTBZ) positron emission tomography (PET) to measure vesicular monoamine transporter 2 (VMAT2).

Methods: Basal ganglia and thalamic DTBZ binding potentials (BPND) were calculated on 56 PETs from 41 Mn-exposed workers. Associations between cumulative Mn exposure, regional BPND, and parkinsonism were examined by mixed linear regression.

Results: Thalamic DTBZ BPND was inversely associated with exposure in workers with less than 3 mg Mn/m-yrs, but subsequently remained stable. Pallidal DTBZ binding increased in workers with less than 2 mg Mn/m-yrs of exposure, but decreased thereafter. Thalamic DTBZ binding was inversely associated with parkinsonism (P = 0.003).

Conclusion: Mn-dose-dependent associations with thalamic and pallidal DTBZ binding indicate direct effects on monoaminergic VMAT2. Thalamic DTBZ binding was also associated with parkinsonism, suggesting potential as an early biomarker of Mn neurotoxicity.
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http://dx.doi.org/10.1097/JOM.0000000000001915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786890PMC
October 2020

Validation of prediction models of severe disease course and non-achievement of remission in juvenile idiopathic arthritis: part 1-results of the Canadian model in the Nordic cohort.

Arthritis Res Ther 2019 12 5;21(1):270. Epub 2019 Dec 5.

Department of Pediatrics, University Hospital of North Norway, Tromsø, Norway.

Background: Models to predict disease course and long-term outcome based on clinical characteristics at disease onset may guide early treatment strategies in juvenile idiopathic arthritis (JIA). Before a prediction model can be recommended for use in clinical practice, it needs to be validated in a different cohort than the one used for building the model. The aim of the current study was to validate the predictive performance of the Canadian prediction model developed by Guzman et al. and the Nordic model derived from Rypdal et al. to predict severe disease course and non-achievement of remission in Nordic patients with JIA.

Methods: The Canadian and Nordic multivariable logistic regression models were evaluated in the Nordic JIA cohort for prediction of non-achievement of remission, and the data-driven outcome denoted severe disease course. A total of 440 patients in the Nordic cohort with a baseline visit and an 8-year visit were included. The Canadian prediction model was first externally validated exactly as published. Both the Nordic and Canadian models were subsequently evaluated with repeated fine-tuning of model coefficients in training sets and testing in disjoint validation sets. The predictive performances of the models were assessed with receiver operating characteristic curves and C-indices. A model with a C-index above 0.7 was considered useful for clinical prediction.

Results: The Canadian prediction model had excellent predictive ability and was comparable in performance to the Nordic model in predicting severe disease course in the Nordic JIA cohort. The Canadian model yielded a C-index of 0.85 (IQR 0.83-0.87) for prediction of severe disease course and a C-index of 0.66 (0.63-0.68) for prediction of non-achievement of remission when applied directly. The median C-indices after fine-tuning were 0.85 (0.80-0.89) and 0.69 (0.65-0.73), respectively. Internal validation of the Nordic model for prediction of severe disease course resulted in a median C-index of 0.90 (0.86-0.92).

Conclusions: External validation of the Canadian model and internal validation of the Nordic model with severe disease course as outcome confirm their predictive abilities. Our findings suggest that predicting long-term remission is more challenging than predicting severe disease course.
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http://dx.doi.org/10.1186/s13075-019-2060-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896283PMC
December 2019

Manganese exposure, parkinsonian signs, and quality of life in South African mine workers.

Am J Ind Med 2020 01 24;63(1):36-43. Epub 2019 Oct 24.

Occupational Health Division, School of Public Health, University of the Witwatersrand, Johannesburg, South Africa.

Background: Manganese (Mn) neurotoxicity is associated with parkinsonism; the associated motor deficits can affect individuals' quality of life (QoL). We investigated associations between Mn exposure, parkinsonian signs, and QoL in Mn mine workers.

Methods: We assessed parkinsonian signs and QoL in 187 black South African Mn mine workers, using the Unified Parkinson Disease Rating Scale motor subsection 3 (UPDRS3) and the Parkinson Disease Questionnaire (PDQ-39), respectively. We estimated cumulative Mn exposure in mg Mn/m -years using complete occupational histories and a job-exposure matrix. We investigated the cross-sectional association between cumulative Mn exposure and UPDRS3 score, and the UPDRS3 score and PDQ-39, adjusting for age, using linear regression.

Results: Participants' mean age was 41.8 years (range, 21-67 years); 97.3% were male. Estimated mean cumulative Mn exposure at the time of examination was 5.4 mg Mn/m -years, with a mean of 14.0 years working in a Mn mine. The mean UPDRS3 score was 10.1 and 25.7% of the workers had a UPDRS3 score greater than or equal to 15. There was a U-shaped dose-response relation between cumulative Mn exposure and UPDRS3 score, with a positive association up to 15 mg Mn/m -years of exposure and an inverse association thereafter. Greater UPDRS3 scores were associated with poorer self-reported QoL.

Conclusion: In this cohort of employed Mn mine workers, parkinsonian signs were common and were associated with both estimated cumulative Mn exposure and poorer QoL.
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http://dx.doi.org/10.1002/ajim.23060DOI Listing
January 2020

Proposal for a definition for response to treatment, inactive disease and damage for JIA associated uveitis based on the validation of a uveitis related JIA outcome measures from the Multinational Interdisciplinary Working Group for Uveitis in Childhood (MIWGUC).

Pediatr Rheumatol Online J 2019 Oct 1;17(1):66. Epub 2019 Oct 1.

Pediatric Rheumatology Department, Hospital Sant Joan de Déu, Barcelona, Spain.

Background: JIA-associated uveitis (JIAU) is a serious, sight-threatening disease with significant long-term complications and risk of blindness, even with improved contemporary treatments. The MIWGUC was set up in order to propose specific JIAU activity and response items and to validate their applicability for clinical outcome studies.

Methods: The group consists of 8 paediatric rheumatologists and 7 ophthalmologists. A consensus meeting took place on November 2015 in Barcelona (Spain) with the objective of validating the previously proposed measures. The validation process was based on the results of a prospective open, international, multi-centre, cohort study designed to validate the outcome measures proposed by the initial MIWGUC group meeting in 2012. The meeting used the same Delphi and nominal group technique as previously described in the first paper from the MIWGUC group (Arthritis Care Res 64:1365-72, 2012). Patients were included with a diagnosis of JIA, aged less than 18 years, and with active uveitis or an uveitis flare which required treatment with a disease-modifying anti-rheumatic drug. The proposed outcome measures for uveitis were collected by an ophthalmologist and for arthritis by a paediatric rheumatologist. Patient reported outcome measures were also measured.

Results: A total of 82 patients were enrolled into the validation cohort. Fifty four percent (n = 44) had persistent oligoarthritis followed by rheumatoid factor negative polyarthritis (n = 15, 18%). The mean uveitis disease duration was 3.3 years (SD 3.0). Bilateral eye involvement was reported in 65 (79.3%) patients. The main findings are that the most significant changes, from baseline to 6 months, are found in the AC activity measures of cells and flare. These measures correlate with the presence of pre-existing structural complications and this has implications for the reporting of trials using a single measure as a primary outcome. We also found that visual analogue scales of disease activity showed significant change when reported by the ophthalmologist, rheumatologist and families. The measures formed three relatively distinct groups. The first group of measures comprised uveitis activity, ocular damage and the ophthalmologists' VAS. The second comprised patient reported outcomes including disruption to school attendance. The third group consisted of the rheumatologists' VAS and the joint score.

Conclusions: We propose distinctive and clinically significant measures of disease activity, severity and damage for JIAU. This effort is the initial step for developing a comprehensive outcome measures for JIAU, which incorporates the perspectives of rheumatologists, ophthalmologists, patients and families.
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http://dx.doi.org/10.1186/s12969-019-0345-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774210PMC
October 2019

Longterm Outcomes of Temporomandibular Joints in Juvenile Idiopathic Arthritis: 17 Years of Followup of a Nordic Juvenile Idiopathic Arthritis Cohort.

J Rheumatol 2020 05 15;47(5):730-738. Epub 2019 Sep 15.

From the Department of Pediatrics, Aarhus University Hospital; Section of Orthodontics, Aarhus University; Section of Oral Radiology, Department of Dentistry and Oral Health, Aarhus University, Aarhus, Denmark; Department of Pediatrics, University Hospital of North Norway, Tromsø; Department of Clinical Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø; Department of Otorhinolaryngology and Department and Division of Oral and Maxillofacial Surgery, University Hospital North Norway and Public Dental Service Competence Center of North Norway, Tromsø; Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim; Department of Pediatrics, Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger; Department of Pediatrics, St. Olavs Hospital, Trondheim; Department of Oral and Craniomaxillofacial Surgery, St. Olavs Hospital, Trondheim, Norway; Department of Pediatrics, Ryhov County Hospital, Jönköping; Department of Women's and Children's Health, Uppsala University, Uppsala; Department of Pediatrics, Sahlgrenska Academy, University of Gothenburg, Gothenburg; Department of Oral and Maxillofacial Surgery/Stomatognathic Physiology, The Institute for Postgraduate Dental Education, Jönköping, Sweden; Hospital for Children and Adolescents, University of Helsinki, Helsinki; Orthodontics, Oral and Maxillofacial Diseases, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Pediatrics, Copenhagen University Hospital, Copenhagen; Department of Pediatric Dentistry and Clinical Genetics, University of Copenhagen, Copenhagen; Department of Oral and Maxillofacial Surgery, Aarhus University Hospital, Aarhus, Denmark.

Objective: To determine the prevalence of orofacial symptoms, dysfunctions, and deformities of the temporomandibular joint (TMJ) in juvenile idiopathic arthritis (JIA) 17 years after disease onset.

Methods: Drawn from a prospective, population-based Nordic JIA cohort with disease onset from 1997 to 2000, 420 consecutive cases were eligible for orofacial evaluation of TMJ involvement. The followup visit included demographic data, a standardized clinical orofacial examination, and full-face cone-beam computed tomography (CBCT). For comparison, 200 age-matched healthy controls were used.

Results: Of 420 eligible participants with JIA, 265 (63%) were included (mean age 23.5 ± 4.2 yrs) and completed a standardized clinical orofacial examination. Of these, 245 had a full-face CBCT performed. At least 1 orofacial symptom was reported by 33%. Compared to controls, the JIA group significantly more often reported TMJ pain, TMJ morning stiffness, and limitation on chewing. Further, among participants reporting complaints, the number of symptoms was also higher in JIA. The mean maximal incisal opening was lower in the JIA group (p < 0.001), and TMJ pain on palpation was more frequent. Condylar deformities and/or erosions were observed in 61% as assessed by CBCT, showing bilateral changes in about 70%. Risk factors of condylar deformities were orofacial dysfunction or biologic treatment; enthesitis-related arthritis was protective.

Conclusion: This study of the longterm consequences of TMJ involvement in a population-based JIA cohort reports persistence of comprehensive symptoms, dysfunctions, and damage of the TMJ into adulthood. We suggest interdisciplinary followup of JIA patients also in adulthood.
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http://dx.doi.org/10.3899/jrheum.190231DOI Listing
May 2020

Growth and Puberty in Juvenile Dermatomyositis: A Longitudinal Cohort Study.

Arthritis Care Res (Hoboken) 2020 Feb;72(2):265-273

IRCCS Istituto Giannina Gaslini, Paediatric Rheumatology International Trials Organisation, Genoa, Italy.

Objective: To study growth and puberty in a multinational longitudinal prospective cohort of children with juvenile dermatomyositis (DM).

Methods: Children from 31 countries who were ages <18 years and had juvenile DM in active phase were studied, and analyses of height, weight, and pubertal development were conducted in those who had follow-up visits during a 2-year period and for whom anthropometric data was available.

Results: A total of 196 of 275 children (71%) were included. We found a significant reduction in parent-adjusted height Z score over time in female patients (P < 0.0001) and male patients (P = 0.001), but with catch-up growth at the final study visit. Median body mass index Z score peaked at 6 months (P < 0.0001) and was still significantly above baseline at the final study visit, which was at a median of 26 months after baseline (P = 0.007), with no difference between sexes. Female patients with a disease duration ≥12 months after onset had significantly lower parent-adjusted height Z score (P = 0.002) and no 2-year catch-up growth. At the final study visit, growth failure was seen in 20 of 97 female patients (21%) and in 11 of 73 male patients (15%). Height deflection (∆height Z score less than -0.25/year) was observed in 29 of 116 female patients (25%) and 25 of 80 male patients (31.3%). Delayed puberty was seen in 20 of 55 female patients (36.4%) and in 11 of 31 male patients (35.5%). Children in early pubertal stage at baseline had the highest risk of growth failure.

Conclusion: Juvenile DM in the active phase and/or its treatment has a significant impact on growth and puberty in affected children. Children with recent onset of puberty or previous growth failure have the highest risk of delayed pubertal development and further growth retardation.
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http://dx.doi.org/10.1002/acr.24065DOI Listing
February 2020

Complement lectin pathway protein levels reflect disease activity in juvenile idiopathic arthritis: a longitudinal study of the Nordic JIA cohort.

Pediatr Rheumatol Online J 2019 Sep 9;17(1):63. Epub 2019 Sep 9.

Department of Pediatrics, Aarhus University Hospital, Palle Juul-Jensens Blvd. 99, 8200, Aarhus N, Denmark.

Background: To determine the serum levels of the lectin pathway proteins early in the disease course and 17 years after disease onset and to correlate the protein levels to markers of disease activity in participants from a population-based Nordic juvenile idiopathic arthritis (JIA) cohort. Additionally, to assess the predictive value of lectin pathway proteins with respect to remission status.

Methods: A population-based cohort study of consecutive cases of JIA with a disease onset from 1997 to 2000 from defined geographical areas of Finland, Sweden, Norway and Denmark with 17 years of follow-up was performed. Clinical characteristics were registered and H-ficolin, M-ficolin, MASP-1, MASP-3, MBL and CL-K1 levels in serum were analyzed.

Results: In total, 293 patients with JIA were included (mean age 23.7 ± 4.4 years; mean follow-up 17.2 ± 1.7 years). Concentrations of the lectin protein levels in serum were higher at baseline compared to the levels 17 years after disease onset (p ≤ 0.006, n = 164). At baseline, the highest level of M-ficolin was observed in systemic JIA. Further, high M-ficolin levels at baseline and at 17-year follow-up were correlated to high levels of ESR. In contrast, high MASP-1 and MASP-3 tended to correlate to low ESR. CL-K1 showed a negative correlation to JADAS71 at baseline. None of the protein levels had prognostic abilities for remission status 17 years after disease onset.

Conclusion: We hypothesize that increased serum M-ficolin levels are associated with higher disease activity in JIA and further, the results indicate that MASP-1, MASP-3 and CL-K1 are markers of inflammation.
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http://dx.doi.org/10.1186/s12969-019-0367-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734250PMC
September 2019

MRI Signal Intensity and Parkinsonism in Manganese-Exposed Workers.

J Occup Environ Med 2019 08;61(8):641-645

Department of Neurology, Washington University School of Medicine, St. Louis, Missouri (Dr Criswell, Dr Nielsen, Mr Warden, Mr Flores, Mr Lenox-Krug, Ms Racette, and Dr Racette); Department of Environmental and Occupational Health Sciences, University of Washington, School of Public Health, Seattle, Washington (Dr Sheppard); Department of Biostatistics, University of Washington, School of Public Health, Seattle, Washington (Dr Sheppard); Department of Family Medicine and Public Health, UC San Diego School of Medicine, La Jolla, California (Dr Checkoway); Department of Neurosciences, UC San Diego School of Medicine, La Jolla, California (Dr Checkoway); School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Parktown, South Africa (Dr Racette).

Objective: T1-weighted brain magnetic resonance imaging (MRI) of the basal ganglia provides a noninvasive measure of manganese (Mn) exposure, and may also represent a biomarker for clinical neurotoxicity.

Methods: We acquired T1-weighted MRI scans in 27 Mn-exposed welders, 12 other Mn-exposed workers, and 29 nonexposed participants. T1-weighted intensity indices were calculated for four basal ganglia regions. Cumulative Mn exposure was estimated from work history data. Participants were examined using the Unified Parkinson's Disease Rating Scale motor subsection 3 (UPDRS3).

Results: We observed a positive dose-response association between cumulative Mn exposure and the pallidal index (PI) (β = 2.33; 95% confidence interval [CI], 0.93 to 3.74). There was a positive relationship between the PI and UPDRS3 (β = 0.15; 95% CI, 0.03 to 0.27).

Conclusion: The T1-weighted pallidal signal is associated with occupational Mn exposure and severity of parkinsonism.
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http://dx.doi.org/10.1097/JOM.0000000000001634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098806PMC
August 2019

Participation in school and physical education in juvenile idiopathic arthritis in a Nordic long-term cohort study.

Pediatr Rheumatol Online J 2019 Jul 15;17(1):44. Epub 2019 Jul 15.

Department of Clinical and Molecular Medicine, NTNU - Norwegian University of Science and Technology, Trondheim, Norway.

Background: The aim of the study was to describe school attendance and participation in physical education in school among children with juvenile idiopathic arthritis (JIA).

Methods: Consecutive cases of JIA from defined geographical areas of Finland, Sweden and Norway with disease onset in 1997 to 2000 were followed for 8 years in a multi-center cohort study, aimed to be as close to population-based as possible. Clinical characteristics and information on school attendance and participation in physical education (PE) were registered.

Results: Participation in school and in PE was lowest initially and increased during the disease course. Eight years after disease onset 228/274 (83.2%) of the children reported no school absence due to JIA, while 16.8% reported absence during the last 2 months due to JIA. Full participation in PE was reported by 194/242 (80.2%), partly by 16.9%, and none by 2.9%. Lowest participation in PE was found among children with ERA and the undifferentiated categories. Absence in school and PE was associated with higher disease activity measures at the 8-year visit. School absence > 1 day at baseline predicted use of disease-modifying anti-rheumatic drugs, including biologics (DMARDs) (OR 1.2 (1.1-1.5)), and non-remission off medication (OR 1.4 (1.1-1.7) 8 years after disease onset.

Conclusion: School absence at baseline predicted adverse long-term outcome. In children and adolescents with JIA participation in school activities is mostly high after 8 years of disease. For the minority with low participation, special attention is warranted to promote their full potential of social interaction and improve long-term outcome.
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http://dx.doi.org/10.1186/s12969-019-0341-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6631827PMC
July 2019

Clinical characteristics and genetic analyses of 187 patients with undefined autoinflammatory diseases.

Ann Rheum Dis 2019 10 5;78(10):1405-1411. Epub 2019 Jul 5.

Center for Autoinflammatory Diseases and Immunodeficiency, IRCCS Instituto Giannina Gaslini, Genoa, Italy

Objectives: To describe the clinical characteristics, treatment response and genetic findings in a large cohort of patients with undefined systemic autoinflammatory diseases (SAIDs).

Methods: Clinical and genetic data from patients with undefined SAIDs were extracted from the Eurofever registry, an international web-based registry that retrospectively collects clinical information on patients with autoinflammatory diseases.

Results: This study included 187 patients. Seven patients had a chronic disease course, 180 patients had a recurrent disease course. The median age at disease onset was 4.3 years. Patients had a median of 12 episodes per year, with a median duration of 4 days. Most commonly reported symptoms were arthralgia (n=113), myalgia (n=86), abdominal pain (n=89), fatigue (n=111), malaise (n=104) and mucocutaneous manifestations (n=128). In 24 patients, relatives were affected as well. In 15 patients, genetic variants were found in autoinflammatory genes. Patients with genetic variants more often had affected relatives compared with patients without genetic variants (p=0.005). Most patients responded well to non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, colchicine and anakinra. Complete remission was rarely achieved with NSAIDs alone. Notable patterns were found in patients with distinctive symptoms. Patients with pericarditis (n=11) were older at disease onset (33.8 years) and had fewer episodes per year (3.0/year) compared with other patients. Patients with an intellectual impairment (n=8) were younger at disease onset (2.2 years) and often had relatives affected (28.6%).

Conclusion: This study describes the clinical characteristics of a large cohort of patients with undefined SAIDs. Among these, patients with pericarditis and intellectual impairment appear to comprise distinct subsets.
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http://dx.doi.org/10.1136/annrheumdis-2018-214472DOI Listing
October 2019

Phenotypic variability and disparities in treatment and outcomes of childhood arthritis throughout the world: an observational cohort study.

Lancet Child Adolesc Health 2019 04 26;3(4):255-263. Epub 2019 Feb 26.

Clinic of Paediatrics and Rheumatology, IRCCS Istituto Giannina Gaslini, University of Genoa, Genoa, Italy; Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Sciences, University of Genoa, Genoa, Italy. Electronic address:

Background: To our knowledge, the characteristics and burden of childhood arthritis have never been studied on a worldwide basis. We aimed to investigate, with a cross-sectional study, the prevalence of disease categories, treatment methods, and disease status in patients from across different geographical areas and from countries with diverse wealth status.

Methods: In this multinational, cross-sectional, observational cohort study, we asked international paediatric rheumatologists from specialised centres to enrol children with a diagnosis of juvenile idiopathic arthritis, according to International League of Associations for Rheumatology criteria, who were seen consecutively for a period of 6 months. Each patient underwent retrospective and cross-sectional assessments, including measures of disease activity and damage and questionnaires on the wellbeing and quality of life of the children. We qualitatively compared the collected data across eight geographical areas, and we explored an association between disease activity and damage and a country's gross domestic product (GDP) with a multiple logistic regression analysis.

Findings: Between April 4, 2011, and Nov 21, 2016, 9081 patients were enrolled at 130 centres in 49 countries, grouped into eight geographical areas. Systemic arthritis (125 [33·0%] of 379 patients) and enthesitis-related arthritis (113 [29·8%] of 379) were more common in southeast Asia, whereas oligoarthritis was more prevalent in southern Europe (1360 [56·7%] of 2400) and rheumatoid factor-negative polyarthritis was more frequent in North America (165 [31·5%] of 523) than in the other areas. Prevalence of uveitis was highest in northern Europe (161 [19·1%] of 845 patients) and southern Europe (450 [18·8%] of 2400) and lowest in Latin America (54 [6·4%] of 849), Africa and Middle East (71 [5·9%] of 1209), and southeast Asia (19 [5·0%] of 379). Median age at disease onset was lower in southern Europe (3·5 years, IQR 1·9-7·3) than in other regions. Biological, disease-modifying antirheumatic drugs were prescribed more frequently in northern Europe and North America than in other geographical settings. Patients living in countries with lower GDP had greater disease activity and damage than those living in wealthier countries. Damage was associated with referral delay.

Interpretation: Our study documents a variability in prevalence of disease phenotypes and disparities in therapeutic choices and outcomes across geographical areas and wealth status of countries. The greater disease burden in lower-resource settings highlights the need for public health efforts aimed at improving equity in access to effective treatments and care for juvenile idiopathic arthritis.

Funding: IRCCS Istituto Giannina Gaslini.
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http://dx.doi.org/10.1016/S2352-4642(19)30027-6DOI Listing
April 2019

Long-Term Outcomes in Juvenile Idiopathic Arthritis: Eighteen Years of Follow-Up in the Population-Based Nordic Juvenile Idiopathic Arthritis Cohort.

Arthritis Care Res (Hoboken) 2020 04;72(4):507-516

Aarhus University Hospital, Aarhus, Denmark.

Objective: The present study was undertaken to assess the long-term course, remission rate, and disease burden in juvenile idiopathic arthritis (JIA) 18 years after disease onset in a population-based setting from the early biologic era.

Methods: A total of 510 consecutive cases of JIA with disease onset between 1997 and 2000 from defined geographic regions in Denmark, Norway, Sweden, and Finland were prospectively included in this 18-year cohort study. At the follow-up visit, patient-reported demographic and clinical data were collected.

Results: The study included 434 (85%) of the 510 eligible JIA participants. The mean ± SD age was 24.0 ± 4.4 years. The median juvenile arthritis disease activity score in 71 joints (JADAS-71) was 1.5 (interquartile range [IQR] 0-5), with the enthesitis-related arthritis (ERA) category of JIA having the highest median score (4.5 [IQR 1.5-8.5], P = 0.003). In this cohort, 46% of patients still had active disease, and 66 (15%) were treated with synthetic disease-modifying antirheumatic drugs and 84 (19%) with biologics. Inactive disease indicated by a JADAS-71 score of <1 was seen in 48% of participants. Clinical remission off medication (CR) was documented in 33% of the participants with high variability among the JIA categories. CR was most often seen in persistent oligoarticular and systemic arthritis and least often in ERA (P < 0.001).

Conclusion: A substantial proportion of the JIA cohort did not achieve CR despite new treatment options during the study period. The ERA category showed the worst outcomes, and in general there is still a high burden of disease in adulthood for JIA.
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http://dx.doi.org/10.1002/acr.23853DOI Listing
April 2020

Pharmacovigilance in juvenile idiopathic arthritis patients treated with biologic or synthetic drugs: combined data of more than 15,000 patients from Pharmachild and national registries.

Arthritis Res Ther 2018 12 27;20(1):285. Epub 2018 Dec 27.

IRCCS Istituto Giannina Gaslini, Clinica Pediatrica e Reumatologia, PRINTO, Via Gaslini, 5, 16147, Genoa, Italy.

Background: The availability of methotrexate and the introduction of multiple biological agents have revolutionized the treatment of juvenile idiopathic arthritis (JIA). Several international and national drug registries have been implemented to accurately monitor the long-term safety/efficacy of these agents. This report aims to present the combined data coming from Pharmachild/PRINTO registry and the national registries from Germany (BiKeR) and Sweden.

Methods: Descriptive statistics was used for demographic, clinical data, drug exposure, adverse events (AEs) and events of special interest (ESIs). For the Swedish register, AE data were not available.

Results: Data from a total of 15,284 patients were reported: 8274 (54%) from the Pharmachild registry and 3990 (26%) and 3020 (20%) from the German and the Swedish registries, respectively. Pharmachild children showed a younger age (median of 5.4 versus 7.6 years) at JIA onset and shorter disease duration at last available visit (5.3 versus 6.1-6.8) when compared with the other registries. The most frequent JIA category was the rheumatoid factor-negative polyarthritis (range of 24.6-29.9%). Methotrexate (61-84%) and etanercept (24%-61.8%) were the most frequently used synthetic and biologic disease-modifying anti-rheumatic drugs (DMARDs), respectively. There was a wide variability in glucocorticoid use (16.7-42.1%). Serious AEs were present in 572 (6.9%) patients in Pharmachild versus 297 (7.4%) in BiKeR. Infection and infestations were the most frequent AEs (29.4-30.1%) followed by gastrointestinal disorders (11.5-19.6%). The most frequent ESIs were infections (75.3-89%).

Conclusions: This article is the first attempt to present a very large sample of data on JIA patients from different national and international registries and represents the first proposal for data merging as the most powerful tool for future analysis of safety and effectiveness of immunosuppressive therapies in JIA.

Registry Registration: The Pharmachild registry is registered at ClinicalTrials.gov ( NCT01399281 ) and at the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) ( http://www.encepp.eu/encepp/viewResource.htm?id=19362 ). The BiKeR registry is registered at ENCePP ( http://www.encepp.eu/encepp/viewResource.htm?id=20591 ).
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http://dx.doi.org/10.1186/s13075-018-1780-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307151PMC
December 2018

Occupational exposures and parkinsonism among Shanghai women textile workers.

Am J Ind Med 2018 11 9;61(11):886-892. Epub 2018 Sep 9.

Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Epidemiology Division, Seattle, Washington.

Background: Endotoxin, a contaminant of cotton dust, is an experimental model for parkinsonism (PS).

Methods: We investigated associations between exposures to endotoxin, solvents, magnetic fields, and night shift work, and neurologist-determined PS among Shanghai women textile workers, including 537 retired cotton factory workers ages ≥50 years and an age-matched reference group of 286 retired textile workers not exposed to cotton dust. Repeat exams were conducted 2.5 years after enrollment among 467 cotton workers and 229 reference workers.

Results: We identified 39 prevalent PS cases and 784 non-cases. No consistent or statistically significant associations were observed for endotoxin, solvents, magnetic fields, or shift work with PS risk, severity, or progression.

Conclusions: Despite the null findings, additional studies of endotoxin exposure and risk of PS in other well-characterized occupational cohorts are warranted in view of toxicological evidence that endotoxin is a pathogenic agent and its widespread occurrence in multiple industries worldwide.
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http://dx.doi.org/10.1002/ajim.22906DOI Listing
November 2018

In silico validation of the Autoinflammatory Disease Damage Index.

Ann Rheum Dis 2018 11 4;77(11):1599-1605. Epub 2018 Aug 4.

Department of Paediatrics, Universitair Medisch Centrum Utrecht-Locatie Wilhelmina Kinderziekenhuis, Utrecht, The Netherlands.

Introduction: Autoinflammatory diseases can cause irreversible tissue damage due to systemic inflammation. Recently, the Autoinflammatory Disease Damage Index (ADDI) was developed. The ADDI is the first instrument to quantify damage in familial Mediterranean fever, cryopyrin-associated periodic syndromes, mevalonate kinase deficiency and tumour necrosis factor receptor-associated periodic syndrome. The aim of this study was to validate this tool for its intended use in a clinical/research setting.

Methods: The ADDI was scored on paper clinical cases by at least three physicians per case, independently of each other. Face and content validity were assessed by requesting comments on the ADDI. Reliability was tested by calculating the intraclass correlation coefficient (ICC) using an 'observer-nested-within-subject' design. Construct validity was determined by correlating the ADDI score to the Physician Global Assessment (PGA) of damage and disease activity. Redundancy of individual items was determined with Cronbach's alpha.

Results: The ADDI was validated on a total of 110 paper clinical cases by 37 experts in autoinflammatory diseases. This yielded an ICC of 0.84 (95% CI 0.78 to 0.89). The ADDI score correlated strongly with PGA-damage (r=0.92, 95% CI 0.88 to 0.95) and was not strongly influenced by disease activity (r=0.395, 95% CI 0.21 to 0.55). After comments from disease experts, some item definitions were refined. The interitem correlation in all different categories was lower than 0.7, indicating that there was no redundancy between individual damage items.

Conclusion: The ADDI is a reliable and valid instrument to quantify damage in individual patients and can be used to compare disease outcomes in clinical studies.
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http://dx.doi.org/10.1136/annrheumdis-2018-213725DOI Listing
November 2018

Early Self-Reported Pain in Juvenile Idiopathic Arthritis as Related to Long-Term Outcomes: Results From the Nordic Juvenile Idiopathic Arthritis Cohort Study.

Arthritis Care Res (Hoboken) 2019 07 12;71(7):961-969. Epub 2019 Jun 12.

Norwegian University of Science and Technology and St. Olavs Hospital, Trondheim, Norway.

Objective: To study self-reported pain early in the disease course of juvenile idiopathic arthritis (JIA) as a predictor of long-term disease outcomes.

Methods: Consecutive cases of JIA with disease onset from 1997 to 2000 from defined geographical areas of Norway, Sweden, Finland, and Denmark were prospectively enrolled in this population-based cohort study. Self-reported, disease-related pain was measured on a 10-cm visual analog scale (VAS pain). Inclusion criteria were a baseline visit with a pain score 6 months after disease onset, followed by an 8-year study visit. Remission was defined according to Wallace et al (2004) preliminary criteria. Functional disability was measured by the Childhood Health Assessment Questionnaire and the Child Health Questionnaire Parent Form if the child was age <18 years and by the Health Assessment Questionnaire if age ≥18 years. Damage was scored using the Juvenile Arthritis Damage Index.

Results: The final study cohort consisted of 243 participants, and 120 participants (49%) had oligoarticular onset. At baseline, 76% reported a VAS pain score >0 compared to 57% reporting at 8 years. Half of those who reported baseline pain also reported pain at 8 years but at a lower intensity. Compared to no pain, higher pain intensity at baseline predicted more pain at 8 years, more functional disability, more damage, and less remission without medication. Baseline pain predicted more use of disease-modifying antirheumatic drugs/biologics during the disease course. Participants with oligoarticular JIA reporting pain at baseline were more likely to develop extended oligoarticular JIA or other JIA categories with an unfavorable prognosis.

Conclusion: Early self-reported, disease-related pain among children and adolescents with JIA is common and seems to predict persistent pain and unfavorable long-term disease outcomes.
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http://dx.doi.org/10.1002/acr.23715DOI Listing
July 2019

[Affected liver biochemistry in children with rheumatic diseases].

Ugeskr Laeger 2018 May;180(22)

Children with rheumatic diseases often have elevated liver biochemistry. This can be triggered by medical treatment, e.g. methotrexate can induce liver injury ranging from mild to severe. Autoimmune hepatitis and sclerosing cholangitis are also seen in conjunction with rheumatic diseases, and early diagnosis and treatment is crucial to prevent development of cirrhosis and liver transplantation. Macrophage activation syndrome is a rare but important differential diagnosis as it is a potentially fatal complication to systemic rheumatic diseases, causing liver dysfunction and multi-organ failure.
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May 2018

Predicting unfavorable long-term outcome in juvenile idiopathic arthritis: results from the Nordic cohort study.

Arthritis Res Ther 2018 05 3;20(1):91. Epub 2018 May 3.

Department of Pediatrics, University Hospital of North Norway, Tromsø, Norway.

Background: The aim was to develop prediction rules that may guide early treatment decisions based on baseline clinical predictors of long-term unfavorable outcome in juvenile idiopathic arthritis (JIA).

Methods: In the Nordic JIA cohort, we assessed baseline disease characteristics as predictors of the following outcomes 8 years after disease onset. Non-achievement of remission off medication according to the preliminary Wallace criteria, functional disability assessed by Childhood Health Assessment Questionnaire (CHAQ) and Physical Summary Score (PhS) of the Child Health Questionnaire, and articular damage assessed by the Juvenile Arthritis Damage Index-Articular (JADI-A). Multivariable models were constructed, and cross-validations were performed by repeated partitioning of the cohort into training sets for developing prediction models and validation sets to test predictive ability.

Results: The total cohort constituted 423 children. Remission status was available in 410 children: 244 (59.5%) of these did not achieve remission off medication at the final study visit. Functional disability was present in 111/340 (32.7%) children assessed by CHAQ and 40/199 (20.1%) by PhS, and joint damage was found in 29/216 (13.4%). Model performance was acceptable for making predictions of long-term outcome. In validation sets, the area under the curves (AUCs) in the receiver operating characteristic (ROC) curves were 0.78 (IQR 0.72-0.82) for non-achievement of remission off medication, 0.73 (IQR 0.67-0.76) for functional disability assessed by CHAQ, 0.74 (IQR 0.65-0.80) for functional disability assessed by PhS, and 0.73 (IQR 0.63-0.76) for joint damage using JADI-A.

Conclusion: The feasibility of making long-term predictions of JIA outcome based on early clinical assessment is demonstrated. The prediction models have acceptable precision and require only readily available baseline variables. Further testing in other cohorts is warranted.
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http://dx.doi.org/10.1186/s13075-018-1571-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5934822PMC
May 2018

The Danish version of the Juvenile Arthritis Multidimensional Assessment Report (JAMAR).

Rheumatol Int 2018 Apr 7;38(Suppl 1):131-138. Epub 2018 Apr 7.

Clinica Pediatrica e Reumatologia, Paediatric Rheumatology International Trials Organisation (PRINTO), Istituto Giannina Gaslini, Via Gaslini 5, 16147, Genoa, Italy.

The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) is a new parent/patient-reported outcome measure that enables a thorough assessment of the disease status in children with juvenile idiopathic arthritis (JIA). We report the results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the Danish language. The reading comprehension of the questionnaire was tested in ten JIA parents and patients. Each participating centre was asked to collect demographic, clinical data and the JAMAR in 100 consecutive JIA patients or all consecutive patients seen in a 6-month period and to administer the JAMAR to 100 healthy children and their parents. The statistical validation phase explored descriptive statistics and the psychometric issues of the JAMAR: the three Likert assumptions, floor/ceiling effects, internal consistency, Cronbach's alpha, interscale correlations, test-retest reliability and construct validity (convergent and discriminant validity). A total of 303 JIA patients (7.9% systemic, 35% oligoarticular, 22.1% RF negative polyarthritis, 35% other categories) and 99 healthy children, were enrolled in three centres. The JAMAR components discriminated well healthy subjects from JIA patients. All JAMAR components revealed good psychometric performances. In conclusion, the Danish version of the JAMAR is a valid tool for the assessment of children with JIA and is suitable for use both in routine clinical practice and clinical research.
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http://dx.doi.org/10.1007/s00296-018-3946-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5893706PMC
April 2018

The multifaceted presentation of chronic recurrent multifocal osteomyelitis: a series of 486 cases from the Eurofever international registry.

Rheumatology (Oxford) 2018 Jul;57(7):1203-1211

Istituto Giannina Gaslini, Pediatria II, Reumatologia, Genoa.

Objectives: Chronic non-bacterial osteomyelitis (CNO) or chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory disorder characterized by sterile bone osteolytic lesions. The aim of this study was to evaluate the demographic data and clinical, instrumental and therapeutic features at baseline in a large series of CNO/CRMO patients enrolled in the Eurofever registry.

Methods: A web-based registry collected retrospective data on patients affected by CRMO/CNO. Both paediatric and adult centres were involved.

Results: Complete baseline information on 486 patients was available (176 male, 310 female). The mean age of onset was 9.9 years. Adult onset (>18 years of age) was observed in 31 (6.3%) patients. The mean time from disease onset to final diagnosis was 1 year (range 0-15). MRI was performed at baseline in 426 patients (88%), revealing a mean number of 4.1 lesions. More frequent manifestations not directly related to bone involvement were myalgia (12%), mucocutaneous manifestations (5% acne, 5% palmoplantar pustulosis, 4% psoriasis, 3% papulopustular lesions, 2% urticarial rash) and gastrointestinal symptoms (8%). A total of 361 patients have been treated with NSAIDs, 112 with glucocorticoids, 61 with bisphosphonates, 58 with MTX, 47 with SSZ, 26 with anti-TNF and 4 with anakinra, with a variable response.

Conclusion: This is the largest reported case series of CNO patients, showing that the range of associated clinical manifestations is rather heterogeneous. The study confirms that the disease usually presents with an early teenage onset, but it may also occur in adults, even in the absence of mucocutaneous manifestations.
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http://dx.doi.org/10.1093/rheumatology/key058DOI Listing
July 2018

Incidence and predictors of Uveitis in juvenile idiopathic arthritis in a Nordic long-term cohort study.

Pediatr Rheumatol Online J 2017 Aug 18;15(1):66. Epub 2017 Aug 18.

Department of Clinical and Molecular Medicine, NTNU - Norwegian University of Science and Technology, and Department of Pediatrics, St. Olavs Hospital, Trondheim, Norway.

Background: The incidence of uveitis associated with juvenile idiopathic arthritis (JIA) varies around the world. Our aim was to investigate the incidence and predictors of uveitis in a Nordic population-based cohort.

Methods: Consecutive JIA cases from defined geographical areas in Denmark, Finland, Sweden and Norway with disease onset between January 1997 to June 2000 were followed for median 98 months in this prospective longitudinal cohort study. Potential clinical and immunological predictors of uveitis were identified with logistic regression analysis.

Results: Uveitis occurred in 89 (20.5%) of the 435 children with regular ophtalmologic follow-up among the 500 included. Chronic asymptomatic uveitis developed in 80 and acute symptomatic uveitis in 9 children. Uveitis developed at a median interval of 0.8 (range - 4.7 to 9.4) years after onset of arthritis. Predictors of uveitis were age < 7 years at JIA onset (Odds ratio (OR) 2.1, 95% confidence interval (CI) 1.3 to 3.5), presence of antihistone antibodies (AHA) > 15 U/ml (OR 4.8 (1.8 to 13.4)) and antinuclear antibodies (ANA) (OR 2.4 (1.5 to 4.0)). Mean combined IgM/IgG AHA was significantly higher in the uveitis group (19.2 U/ml) than in the non-uveitis group (10.2 U/ml) (p = 0.002). Young age at JIA onset predicted uveitis in girls (p < 0.001), but not in boys (p = 0.390).

Conclusion: Early-onset arthritis and presence of AHA in girls, as well as presence of ANA in both genders, were significant predictors of chronic uveitis. The high incidence of uveitis in this long-term Nordic JIA cohort may have severe implications in a lifelong perspective.
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http://dx.doi.org/10.1186/s12969-017-0195-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5562983PMC
August 2017

[F]FDOPA positron emission tomography in manganese-exposed workers.

Neurotoxicology 2018 01 8;64:43-49. Epub 2017 Jul 8.

Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA; School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Parktown, South Africa.

Occupational manganese (Mn) exposure is associated with the development of parkinsonism; however, the mechanism of neurotoxicity is unknown. Brain positron emission tomography (PET) imaging provides a non-invasive method of assessing dopamineric neuronal function. 6-[F]fluoro-L-DOPA (FDOPA) PET reflects in-vivo nigrostriatal function, but results in Mn exposure are conflicting. The objective of this study was to investigate the association between Mn exposure secondary to occupational welding, FDOPA striatal uptake, and clinical parkinsonism as measured by Unified Parkinson Disease Rating Scale motor subscore 3 (UPDRS3) scores. FDOPA PET scans were acquired on 72 subjects (27 Mn-exposed welders, 14 other Mn-exposed workers, and 31 non-exposed subjects). We estimated cumulative welding exposure from detailed work histories, and a movement disorders specialist examined all subjects. Striatal volumes of interest were identified on aligned magnetic resonance imaging (MRI) for each subject. Specific striatal FDOPA uptake was calculated with a graphical analysis method. We used linear regression while adjusting for age to assess the association between welding exposure and FDOPA uptake in the caudate, anterior putamen, and posterior putamen. Compared to the non-exposed subjects, mean caudate FDOPA uptake was 0.0014min (95% confidence interval [CI] 0.0008, 0.0020) lower in Mn-exposed welders and 0.0012min (95% CI 0.0005, 0.0019) lower in other Mn-exposed workers (both p≤0.001). There was no clear dose-response association between caudate FDOPA uptake and Mn exposure or UPDRS3 scores. Mn-exposed welders and workers demonstrated lower caudate FDOPA uptake, indicating pre-synaptic dopaminergic dysfunction in Mn-exposed subjects that was not associated with clinical parkinsonism.
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http://dx.doi.org/10.1016/j.neuro.2017.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5758438PMC
January 2018

Early Outcomes in Children With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

Arthritis Rheumatol 2017 07 9;69(7):1470-1479. Epub 2017 Jun 9.

Kimberly A. Morishita, MD, MHSc, David A. Cabral, MBBS: British Columbia Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.

Objective: To characterize the early disease course in childhood-onset antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and the 12-month outcomes in children with AAV.

Methods: Eligible subjects were children entered into the Pediatric Vasculitis Initiative study who were diagnosed before their eighteenth birthday as having granulomatosis with polyangiitis (Wegener's), microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis (Churg-Strauss), or ANCA-positive pauci-immune glomerulonephritis. The primary outcome measure was achievement of disease remission (Pediatric Vasculitis Activity Score [PVAS] of 0) at 12 months with a corticosteroid dosage of <0.2 mg/kg/day. Secondary outcome measures included the rates of inactive disease (PVAS of 0, with any corticosteroid dosage) and rates of improvement at postinduction (4-6 months after diagnosis) and at 12 months, presence of damage at 12 months (measured by a modified Pediatric Vasculitis Damage Index [PVDI]; score 0 = no damage, score 1 = one damage item present), and relapse rates at 12 months.

Results: In total, 105 children with AAV were included in the study. The median age at diagnosis was 13.8 years (interquartile range 10.9-15.8 years). Among the study cohort, 42% of patients achieved remission at 12 months, 49% had inactive disease at postinduction (4-6 months), and 61% had inactive disease at 12 months. The majority of patients improved, even if they did not achieve inactive disease. An improvement in the PVAS score of at least 50% from time of diagnosis to postinduction was seen in 92% of patients. Minor relapses occurred in 12 (24%) of 51 patients after inactive disease had been achieved postinduction. The median PVDI damage score at 12 months was 1 (range 0-6), and 63% of patients had ≥1 PVDI damage item scored as present at 12 months.

Conclusion: This is the largest study to date to assess disease outcomes in pediatric AAV. Although the study showed that a significant proportion of patients did not achieve remission, the majority of patients responded to treatment. Unfortunately, more than one-half of this patient cohort experienced damage to various organ systems early in their disease course.
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http://dx.doi.org/10.1002/art.40112DOI Listing
July 2017

High-sensitive CRP as a predictive marker of long-term outcome in juvenile idiopathic arthritis.

Rheumatol Int 2017 May 10;37(5):695-703. Epub 2017 Mar 10.

Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Denmark.

To evaluate whether C-reactive protein (CRP), including variation within the normal range, is predictive of long-term disease outcome in Juvenile Idiopathic Arthritis (JIA). Consecutive patients with newly diagnosed JIA were included prospectively from defined geographic areas of the Nordic countries from 1997 to 2000. Inclusion criteria were availability of a baseline serum sample within 12 months after disease onset and 8-year clinical assessment data. Systemic onset JIA was not included. CRP was measured by high-sensitive ELISA (detection limit of 0.2 mg/l). One hundred and thirty participants with a median follow-up time of 97 months (range 95-100) were included. At follow-up, 38% of the patients were in remission off medication. Absence of remission was associated with elevated level of CRP at baseline (odds ratio (OR) 1.33, confidence interval (CI) 1.08-1.63, p = 0.007). By applying a cutoff at the normal upper limit (>10 mg/l), the risk of not achieving remission was increased to an OR of 8.60 (CI 2.98-24.81, p < 0.001). Variations of CRP within the normal range had no predictive impact on disease activity at follow-up. Baseline levels of ESR were available in 80 patients (61%) and elevated ESR was associated with absence of remission in a multivariable logistic regression analysis (OR 2.32, CI 1.35-4.00, p = 0.002). This results of this study indicate that baseline CRP concentrations above 10 mg/l are predictive of a poor outcome at 8-year follow-up. We could not demonstrate any predictive value of CRP variations within the normal range.
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http://dx.doi.org/10.1007/s00296-017-3657-xDOI Listing
May 2017

Psoriasis and associated variables in classification and outcome of juvenile idiopathic arthritis - an eight-year follow-up study.

Pediatr Rheumatol Online J 2017 Feb 22;15(1):13. Epub 2017 Feb 22.

Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.

Background: To study the impact of psoriasis and features associated with psoriasis on classification and outcome in a population-based follow-up cohort of children with juvenile idiopathic arthritis (JIA).

Methods: In all, 440 children with JIA were followed for a median of 8 years in a prospective Nordic population-based cohort study. Data for remission was available for 427 of these children. The presence of psoriasis, psoriasis-like rash, dactylitis, nail pitting, enthesitis, tenosynovitis and heredity was assessed in relation to ILAR classification and remission.

Results: Clinical findings associated with psoriasis developed consecutively during the 8-year period. Six of 14 children with psoriasis were not classified as juvenile psoriatic arthritis according to the ILAR criteria at 8 year follow-up. Dactylitis was more common in children with early onset of JIA. After 8 years we found a cumulative median number of eleven arthritic joints in children with psoriasis or psoriasis-like rash compared with six in the rest of the cohort (p = 0.02). Also, the chance for not being in remission after 8 years increased significantly in patients with psoriasis, psoriasis-like rash or at least two of: 1) first-degree heredity for psoriasis or psoriatic arthritis, 2) dactylitis or 3) nail pitting, compared with the rest of the group (OR 3.32, p = 0.010).

Conclusions: Our results indicate a more severe disease over time in psoriasis-associated JIA, as features of psoriasis develop during the disease course. This group is a major challenge to encompass in a future JIA classification in order to facilitate early tailored treatment.
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http://dx.doi.org/10.1186/s12969-017-0145-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5320636PMC
February 2017

Cognitive control dysfunction in workers exposed to manganese-containing welding fume.

Am J Ind Med 2017 Feb 15;60(2):181-188. Epub 2016 Nov 15.

Department of Neurology, Washington University in St. Louis School of Medicine, St. Louis, Missouri.

Background: Chronic exposure to manganese (Mn) is a health concern in occupations such as welding because of well-established motor effects due to basal ganglia dysfunction. We hypothesized that cognitive control (the ability to monitor, manipulate, and regulate ongoing cognitive demands) would also be affected by chronic Mn exposure.

Methods: We examined the relationship between Mn exposure and cognitive control performance in 95 workers with varying intensity and duration (median 15.5 years) of exposure to welding fume. We performed linear regression to assess the association between exposure to Mn-containing welding fume and cognitive control tasks.

Results: Overall performance was inversely related to intensity of welding exposure (P = 0.009) and was driven by the Two-Back and Letter Number Sequencing tests that assess working memory (both P = 0.02).

Conclusions: Occupational exposure to Mn-containing welding fume may be associated with poorer working memory performance, and workers may benefit from practices that reduce exposure intensity. Am. J. Ind. Med. 60:181-188, 2017. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajim.22675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501991PMC
February 2017