Publications by authors named "Troels Herlin"

118 Publications

Initial radiological signs of dentofacial deformity in juvenile idiopathic arthritis.

Sci Rep 2021 06 23;11(1):13142. Epub 2021 Jun 23.

Section of Orthodontics, Institute for Oral Health, Aarhus University, Vennelyst Boulevard, 9-11, Aarhus, Denmark.

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood and the temporomandibular joint (TMJ) is often involved. TMJ arthritis in growing individuals can cause deformation of facial skeleton (dentofacial deformity) and TMJ components (TMJ deformity). Treatment outcome hinges on early initiation of anti-inflammatory treatment and orthopaedic treatment with dental splints. The aim of the present study was to characterize the radiological signs of dentofacial deformity in patients with a JIA-induced need for orthopaedic treatment. We retrospectively studied 96 patients with JIA and 20 non-JIA controls to identify the initial radiological signs of JIA-induced dentofacial deformity leading to initiation of orthopaedic treatment. We found that initial radiological signs of dentofacial deformities were subtle and characterized by minor mandibular asymmetry and occlusal plane steepening. Radiological findings of TMJ deformity associated with initial dentofacial deformity were frequent and characterized by condylar articular surface flattening (OR 8.42), condylar subcortical cyst (OR 5.94), condylar surface erosion (OR 5.38) and condylar deviation in form (OR 25.39). Radiological signs of TMJ deformity were also documented in TMJs considered "healthy" during initial clinical and radiological examination. This study presents new knowledge of importance for early diagnosis of dentofacial deformity in JIA. Early diagnosis of dentofacial deformity is important as treatment outcome is greatly influenced by timely initiation.
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http://dx.doi.org/10.1038/s41598-021-92575-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222246PMC
June 2021

Single nucleotide polymorphisms associated with methotrexate-induced nausea in juvenile idiopathic arthritis.

Pediatr Rheumatol Online J 2021 Apr 1;19(1):51. Epub 2021 Apr 1.

Pediatric and Adolescent Medicine, Department of Clinical Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark.

Background: Context: Methotrexate (MTX) is a cornerstone in the treatment of juvenile idiopathic arthritis (JIA). MTX treatment is commonly associated with nausea. Large inter-individual variation exists in the level of MTX-induced nausea, possibly due to genetic factors.

Purpose: To investigate whether MTX-induced nausea was associated with single nucleotide polymorphisms (SNPs) in genes encoding MTX-transporter proteins, a MTX metabolizing enzyme and a nausea receptor.

Findings: Methods: Children aged ≥9 years treated with MTX for JIA were eligible. MTX-induced nausea was registered by the children's completion of a nausea diary (min. 7 days) and the parents' completion of the MTX intolerance severity score (MISS). The selected SNPs were: SLCO1B1 (rs4149056; rs4149081), SLCO1B3 (rs2117032), SLC19A1 (rs1051266), ABCC2 (rs2273697; rs3740066; rs717620), ABCB1 (rs2032582; rs1045642), MTHFR (rs1801131, rs1801133), HTR3A (rs1062613; rs1985242; rs1176713) and HTR3B (rs1176744).

Result: Enrolled were 121 JIA patients (82 girls: 39 boys) with a median age of 13.3 years (IQR: 11.3-15.1). The median MTX dose was 9.7 mg/m/week (IQR: 9.0-10.9). The median MTX treatment duration prior to enrolment was 340 days (IQR: 142-766). The SNP analysis was available for 119 patients. MTX intolerance was associated with the genotype distribution of rs1801133 (MTHFR) (p = 0.02). There was no additive effect of the minor alleles for any of the selected SNPs, nor any significant haplotype associations.

Conclusion: Summary: MTX-induced nausea may be influenced by genetic polymorphisms in a MTX metabolizing enzyme (rs1801133; MTHFR).

Implications: Further analyses involving inclusion of larger cohorts are needed to understand the impact of SNPs on MTX-induced nausea in JIA.
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http://dx.doi.org/10.1186/s12969-021-00539-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017639PMC
April 2021

Fatigue in young adults with juvenile idiopathic arthritis 18 years after disease onset: data from the prospective Nordic JIA cohort.

Pediatr Rheumatol Online J 2021 Mar 18;19(1):33. Epub 2021 Mar 18.

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

Background: To study fatigue in young adults with juvenile idiopathic arthritis (JIA) 18 years after disease onset, and to compare with controls.

Methods: Consecutive children with onset of JIA between 1997 and 2000, from geographically defined areas of Norway, Sweden, Denmark and Finland were followed for 18 years in a close to population-based prospective cohort study. Clinical features, demographic and patient-reported data were collected. Inclusion criteria in the present study were a baseline visit 6 months after disease onset, followed by an 18-year follow-up with available self-reported fatigue score (Fatigue Severity Scale (FSS), 1-7). Severe fatigue was defined as FSS ≥4. For comparison, Norwegian age and sex matched controls were used.

Results: Among 377 young adults with JIA, 26% reported severe fatigue, compared to 12% among controls. We found higher burden of fatigue among participants with sleep problems, pain, poor health, reduced participation in school/work, physical disability, active disease, or use of disease-modifying anti-rheumatic drugs (DMARDs)/biologics/systemic steroids. In contrast, participants without these challenges, had fatigue scores similar to controls. Active disease assessed at all three time points (baseline, 8-year and 18-year follow-up) was associated with higher mean fatigue score and higher percentage of severe fatigue compared to disease courses characterized by periods of inactive disease. Predictors of fatigue at the 18-year follow-up were female sex and diagnostic delay of ≥6 months at baseline, and also pain, self-reported poor health, active disease, and previous/ongoing use of DMARDs/biologics at 8 years.

Conclusions: Fatigue is a prominent symptom in young adults with JIA, with higher fatigue burden among participants with poor sleep, pain, self-reported health problems, active disease, or use of DMARDs/biologics. Participants without these challenges have results similar to controls. Patient- and physician-reported variables at baseline and during disease course predicted fatigue at 18-year follow-up.
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http://dx.doi.org/10.1186/s12969-021-00499-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7976696PMC
March 2021

Idiopathic hypereosinophilic syndrome: A rare diagnosis in children.

Clin Case Rep 2020 Oct 14;8(10):2013-2016. Epub 2020 Sep 14.

Department of Dermatology Aarhus University Hospital Aarhus N Denmark.

Idiopathic hypereosinophilic syndrome (IHES) is one of numerous hypereosinophilic syndromes. The incidence of IHES among children is unknown, but it is considered a rare disease. We report a pediatric case of IHES and the challenges to finding an effective treatment. The patient described here was responsive to prednisolone and thalidomide.
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http://dx.doi.org/10.1002/ccr3.3165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563636PMC
October 2020

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

Ophthalmology 2021 04 29;128(4):598-608. 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
April 2021

Identifying acute lymphoblastic leukemia mimicking juvenile idiopathic arthritis in children.

PLoS One 2020 11;15(8):e0237530. Epub 2020 Aug 11.

Department of Pediatric and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark.

Objective: Acute lymphoblastic leukemia (ALL) may present with arthritis implying the risk of being misdiagnosed as juvenile idiopathic arthritis (JIA). The aim of this study was to identify predictors for ALL based on clinical and laboratory information.

Methods: This cross-sectional, retrospective study compared clinical presentation and laboratory results of 26 children with ALL and arthritis versus 485 children with JIA (433 non-systemic, 52 systemic JIA). Using a Bayesian score approach the findings were evaluated by calculating odds ratios (OR) and lnOR as a measure of diagnostic weight.

Results: Distinction on clinical grounds was difficult, as even a high number of joints involved did not exclude ALL. One or more hematologic cell counts were low (Hb <10 g/dL, platelet count <100 x 109/L, neutrophil count < 1.0 x 109/L) in 92% with ALL, 25% with systemic JIA and 10% with non-systemic JIA. Neutropenia and thrombocytopenia had the highest ORs of 128 (95% CI 43-387) and 129 (95% CI 26-638), each giving a diagnostic weight of 4. The estimated risks of ALL were 0.2% with normal cell counts and 9%, 67% and 100% when one, two or three cell lines were affected.

Conclusion: A simple count of cell lines with low counts can serve as a basic diagnostic strategy. Children with tri- or bilinear involvement should be referred to a bone marrow, and those with unilinear involvement a thorough screen for further evidence of ALL (organomegaly, ESR, LDH, uric acid, and blood smear).
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237530PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418991PMC
October 2020

Systemic juvenile idiopathic arthritis and recurrent macrophage activation syndrome due to a CASP1 variant causing inflammasome hyperactivation.

Rheumatology (Oxford) 2020 10;59(10):3099-3105

Department of Infectious Diseases, Aarhus University Hospital.

Objectives: We investigated a patient with systemic juvenile idiopathic arthritis (sJIA) and recurrent macrophage activation syndrome (MAS) to discover genetic and immunological contributing factors.

Methods: Severe recurrent MAS motivated whole exome sequencing (WES) to identify genetic variants potentially involved in disease pathogenesis. In vitro peripheral blood mononuclear cell (PBMC) stimulations for cytokine expression and caspase-1 activity assays as well as NF-κB reporter luciferase assays were performed to functionally characterize variants.

Results: WES revealed an extremely rare heterozygous missense variant, c.482G>A, p.R161H in the CASP1 gene encoding pro-caspase-1. Lipopolysaccharide (LPS) stimulation of patient PBMCs induced high levels of IL-6 compared to controls, and activation of the NLRP3 inflammasome resulted in increased production of IL-1β and IL-18 as well as significantly elevated caspase-1 activity. Constitutive and inducible levels of IL-18 and IFNγ in whole blood were markedly elevated. Expression of the CASP1 variant in an NF-κB reporter luciferase assay induced increased NF-κB activation in a RIP2-dependent manner. The disease course of the patient was complicated by severe recurrent MAS. However, dual IL-1 and IL-6 blockade caused disease remission.

Conclusion: For the first time, we demonstrate the involvement of a CASP1 variant in sJIA and recurrent MAS. This variant is gain-of-function for both inflammasome and NF-κB activation leading to increased production of IL-6, IL-1β and IL-18. Although dual IL-1 and IL-6 blockade may be beneficial in patients, in whom single treatment is not sufficient to control MAS, caution should be practiced, since interstitial lung disease may progress despite apparent clinical and biochemical remission.
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http://dx.doi.org/10.1093/rheumatology/keaa242DOI Listing
October 2020

Systemic Treatment for Temporomandibular Joint Arthritis in Juvenile Idiopathic Arthritis.

J Rheumatol 2020 06;47(6):793-795

Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark.

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http://dx.doi.org/10.3899/jrheum.191169DOI Listing
June 2020

Opportunistic infections in immunosuppressed patients with juvenile idiopathic arthritis: analysis by the Pharmachild Safety Adjudication Committee.

Arthritis Res Ther 2020 04 7;22(1):71. Epub 2020 Apr 7.

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

Background: To derive a list of opportunistic infections (OI) through the analysis of the juvenile idiopathic arthritis (JIA) patients in the Pharmachild registry by an independent Safety Adjudication Committee (SAC).

Methods: The SAC (3 pediatric rheumatologists and 2 pediatric infectious disease specialists) elaborated and approved by consensus a provisional list of OI for use in JIA. Through a 5 step-procedure, all the severe and serious infections, classified as per MedDRA dictionary and retrieved in the Pharmachild registry, were evaluated by the SAC by answering six questions and adjudicated with the agreement of 3/5 specialists. A final evidence-based list of OI resulted by matching the adjudicated infections with the provisional list of OI.

Results: A total of 772 infectious events in 572 eligible patients, of which 335 serious/severe/very severe non-OI and 437 OI (any intensity/severity), according to the provisional list, were retrieved. Six hundred eighty-two of 772 (88.3%) were adjudicated as infections, of them 603/682 (88.4%) as common and 119/682 (17.4%) as OI by the SAC. Matching these 119 opportunistic events with the provisional list, 106 were confirmed by the SAC as OI, and among them infections by herpes viruses were the most frequent (68%), followed by tuberculosis (27.4%). The remaining events were divided in the groups of non-OI and possible/patient and/or pathogen-related OI.

Conclusions: We found a significant number of OI in JIA patients on immunosuppressive therapy. The proposed list of OI, created by consensus and validated in the Pharmachild cohort, could facilitate comparison among future pharmacovigilance studies.

Trial Registration: Clinicaltrials.gov NCT01399281; ENCePP seal: awarded on 25 November 2011.
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http://dx.doi.org/10.1186/s13075-020-02167-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136994PMC
April 2020

Coping strategies and anxiety in association with methotrexate-induced nausea in juvenile idiopathic arthritis.

Rheumatol Int 2020 Apr 29;40(4):591-598. Epub 2020 Jan 29.

Pediatric and Adolescent Medicine, Department of Clinical Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark.

The aim of this study is to investigate whether methotrexate-induced nausea is associated with anxiety or the use of coping strategies in children with juvenile idiopathic arthritis (JIA) treated with methotrexate (MTX). This is an observational study of children diagnosed with JIA (ILAR criteria), treated with MTX and aged 9 years or above. MTX-induced nausea was determined by the children's completion of a nausea diary and the parents' completion of the Methotrexate Intolerance Severity Score (MISS). Anxiety was assessed by the Beck Youth Inventories-Anxiety Inventory (BYI-A) and coping strategies were evaluated by an adapted Nausea Coping Questionnaire. Enrolled were 121 children (82 girls: 39 boys) with a median age (IQR) of 13.3 (11.3-15.1) years. The median MTX-dose (IQR) was 9.7 (9.0-10.9) mg/m/week. The median treatment duration (IQR) was 340 (142-766) days. The MISS was completed for 120 children; 77 children completed the nausea diary for at least 7 days. MTX-induced nausea was present in 61% (73/120) of the children according to the MISS and in 73% (56/77) of the children according to the nausea diary. MTX-induced nausea was associated with a more frequent use of the coping strategy internalizing/catastrophizing (MISS, p = 0.012; diary, p < 0.0001) and higher BYI-A raw scores (diary, p = 0.016). MTX-induced nausea was associated with anxiety and the use of coping strategies in children with JIA. These psychological factors may be part of the mechanism behind the inter-individual variation in the level of nausea to MTX treatment.
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http://dx.doi.org/10.1007/s00296-020-04520-9DOI Listing
April 2020

Autoinflammatory disease with corneal and mucosal dyskeratosis caused by a novel NLRP1 variant.

Rheumatology (Oxford) 2020 09;59(9):2334-2339

Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.

Objectives: Here we investigated a patient with inflammatory corneal intraepithelial dyskeratosis, mucosal inflammation, tooth abnormalities and, eczema to uncover the genetic and immunological basis of the disease.

Methods: On suspicion of an autoinflammatory condition, Sanger sequencing of nucleotide-binding oligomerization domain-like, leucine-rich repeat pyrin domain containing 1 (NLRP1) was performed and combined with an in vitro inflammasome reconstitution assay to measure caspase-1-mediated IL-1β cleavage, stimulation of patient peripheral blood mononuclear cells (PBMCs) and whole blood to measure IL-1β, IL-18 production and quantification of apoptosis-associated speck-like protein containing CARD (ASC) speck formation as a measure of inflammasome activation by flow cytometry.

Results: Sanger sequencing revealed a novel mutation (c.175G>C, p.A59P; NM_33004.4) in the inflammasome molecule NLRP1 segregating with disease, although with incomplete penetrance, in three generations. We found that patient PBMCs produced increased IL-1β in response to inflammatory stimuli, as well as increased constitutive levels of IL-18. Moreover, we demonstrate that expression of the identified NLRP1 A59P variant caused spontaneous IL-1β cleavage to mature IL-1β. In addition, patient PBMCs responded to NLRP1 stimulation with increased ASC speck formation as a reflection of elevated inflammasome activity.

Conclusion: We demonstrate that this novel NLRP1 A59P variant caused increased activation of the NLRP1 inflammasome, resulting in constitutively and inducibly elevated IL-1β and IL-18 synthesis. We suggest the NLRP1 mutation underlies the pathogenesis of this rare autoinflammatory dyskeratotic disease inherited in an autosomal dominant manner with incomplete penetrance in the patient and within the family for several generations.
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http://dx.doi.org/10.1093/rheumatology/kez612DOI Listing
September 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

Standardizing the Clinical Orofacial Examination in Juvenile Idiopathic Arthritis: An Interdisciplinary, Consensus-based, Short Screening Protocol.

J Rheumatol 2020 09 1;47(9):1397-1404. Epub 2019 Dec 1.

From the Section of Orthodontics, Department of Dentistry and Oral Health, Aarhus University, Aarhus; Pediatric Rheumatology Clinic, Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus; Department of Oral and Maxillofacial Surgery, Aarhus University Hospital, Section of Orthodontics, Aarhus University, Aarhus, Denmark; Department of Pediatrics, Division of Rheumatology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario; Department of Pediatrics, Cumming School of Medicine, University of Calgary and Alberta Children's Hospital, Calgary, Alberta, Canada; Department of Orthodontics, University Hospital Tübingen, Tübingen, Germany.

Objective: To develop a consensus-based, standardized, short (< 3 min) clinical examination protocol to assess the multidimensional, orofacial manifestations of juvenile idiopathic arthritis (JIA).

Methods: The study was conducted by a multidisciplinary task force from the Temporomandibular Joint Juvenile Arthritis Working Group (TMJaw). The study used an acknowledged sequential approach involving (1) a global multidisciplinary online questionnaire study, (2) a systematic literature review and consensus meetings to identify items for inclusion, (3) pilot testing of included items, (4) test of reliability in 22 subjects with JIA by 4 examiners, (5) test of construct validity in a case-control study involving 167 subjects, and (6) establishment of final recommendations.

Results: Six items were recommended for the final examination protocol: (1) clinician-assessed pain location, (2) temporomandibular (TMJ) joint pain on palpation (open and closed mouth), (3) mandibular deviation at maximal mouth opening (≥ 3 mm), (4) maximal unassisted mouth opening capacity, (5) frontal facial symmetry, and (6) facial profile. All recommended items showed acceptable reliability and construct validity. The average mean examination time was 2 min and 42 s (SD ± 38.5 s).

Conclusion: A consensus-based, short clinical examination protocol was developed. The protocol takes less than 3 min to complete and provides information about orofacial symptoms, TMJ dysfunction, and dentofacial deformity. The standardized examination protocol is applicable to routine clinical care, as well as future research studies.
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http://dx.doi.org/10.3899/jrheum.190661DOI Listing
September 2020

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

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

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

Increased methotrexate intolerance in juvenile idiopathic arthritis compared to acute lymphoblastic leukaemia in children.

PLoS One 2019 11;14(7):e0219539. Epub 2019 Jul 11.

Paediatric and Adolescent Medicine, Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark.

Objectives: To analyse the internal consistency of an adaption of the methotrexate intolerance severity score (MISS); and to describe and compare the level of methotrexate intolerance evaluated by the MISS in Danish children with juvenile idiopathic arthritis (JIA) or acute lymphoblastic leukaemia (ALL), treated with low-dose methotrexate (MTX).

Methods: Cross-sectional study of children diagnosed with JIA or ALL, treated with low-dose MTX, aged 9 years or above, and cognitively intact. The patient's parents completed the MISS. MTX intolerance was defined as a total MISS score above 6.

Results: We enrolled 120 children with JIA and 23 children with ALL. The MISS had a good internal consistency in the JIA group. The median MISS score was higher in the JIA group than in the ALL group (JIA: 8; ALL: 1; p<0.0001); and the JIA group had a larger proportion of MTX intolerant children than the ALL group (JIA: 73/120; ALL: 4/23; p<0.001). Within both the JIA group and the ALL group, the MISS total score was not significantly correlated with age, MTX dose or the duration of low-dose MTX treatment.

Conclusion: In the JIA group the level of MTX intolerance was higher and more attributed to anticipatory, associative and behavioural symptoms than in the ALL group. The MISS may help to uncover whether MTX intolerance is present and which aspects are affected in the individual patient, thus guiding intervention. The MISS may also be applicable within leukaemia care.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0219539PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6622540PMC
February 2020

Response to Early-onset Pamidronate Treatment in Chronic Nonbacterial Osteomyelitis: A Retrospective Single-center Study.

J Rheumatol 2019 11 15;46(11):1515-1523. Epub 2019 Apr 15.

From the Department of Rheumatology, the Department of Radiology, and the Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital; the Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.

Objectives: Chronic nonbacterial osteomyelitis (CNO) is a sterile inflammatory bone disorder with an unpredictable disease course. The objective was to assess clinical and radiological disease activity in children with CNO including response to early-onset pamidronate treatment.

Methods: A single-center retrospective study was conducted of children fulfilling the Bristol Criteria for CNO. At the time of diagnosis, whole-body magnetic resonance imaging (WB-MRI) or local MRI was performed to assess radiological disease activity. Children with multifocal or spinal bone inflammation and clinical disease activity not responding to nonsteroidal antiinflammatory drugs were categorized as having extended CNO. Clinical disease activity was assessed annually.

Results: Fifty-one children were included. Median followup time was 4 years (interquartile range 3-7). Children categorized with extended CNO (n = 32) were treated in an early-onset 2-year pamidronate regimen. In extended CNO, WB-MRI was performed at time of diagnosis, and at years 1 and 2 in 88%, 84%, and 91% of cases, respectively. During the first year, the total number of radiologically active lesions and number of spinal lesions per patient declined (p = 0.01). Clinically inactive disease was recorded in 12/32 children (38%). However, 8/12 children (67%) experienced clinical relapse. In limited CNO (n = 19), 10/19 children (53%) presented with clinically inactive disease after 1 year and did not experience clinical relapse.

Conclusion: Pamidronate might contribute to improvement in clinical and radiological disease activity in extended CNO, especially after 1 year of treatment. However, children with continuously active disease after 2 years of pamidronate treatment were seen.
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http://dx.doi.org/10.3899/jrheum.181254DOI Listing
November 2019

Cumulative Incidence of Orofacial Manifestations in Early Juvenile Idiopathic Arthritis: A Regional, Three-Year Cohort Study.

Arthritis Care Res (Hoboken) 2020 07 31;72(7):907-916. Epub 2020 May 31.

Aarhus University Hospital and Aarhus University, Aarhus, Denmark.

Objective: To estimate the cumulative incidence of arthritis-induced orofacial symptoms, dysfunction, and dentofacial deformities in growing individuals with juvenile idiopathic arthritis (JIA) in a 36-month regional cohort study and to identify predictors for the development of arthritis-induced dentofacial deformities.

Methods: Data were retrieved from the Aarhus JIA temporomandibular joint (TMJ) cohort register, which contains standardized, longitudinal, observational data regarding orofacial conditions in patients with JIA (n = 1,040). This regional cohort represents the majority of all subjects with JIA from the western part of Denmark between 1990 and 2016, regardless of TMJ arthritis status. Cumulative incidences of orofacial conditions were reported using Kaplan-Meier methods, and predictors for dentofacial deformity were identified using Cox proportional hazards analysis.

Results: Follow-up data from 351 subjects for 36 months were included in this study. Median age at first clinical examination was 6.6 years (interquartile range 4.8-9.9 years). Orofacial symptoms and dysfunctions were common findings at 36 months after the first clinical examination and 5 years after JIA onset, with a cumulative incidence of 38% and 53%, respectively. Dentofacial deformities were found in 35% of subjects at the 36-month follow-up and were significantly associated with the presence of orofacial dysfunction.

Conclusion: Orofacial conditions were frequently observed in individuals with JIA and were represented in all JIA subcategories in this regional study. One-third of subjects had arthritis-induced dentofacial deformities that required orthopedic appliance treatment at the 36-month follow-up.
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http://dx.doi.org/10.1002/acr.23899DOI Listing
July 2020

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

Standardizing Terminology and Assessment for Orofacial Conditions in Juvenile Idiopathic Arthritis: International, Multidisciplinary Consensus-based Recommendations.

J Rheumatol 2019 05 15;46(5):518-522. Epub 2019 Jan 15.

From the Department of Dentistry and Oral Health, Aarhus University; Department of Oral and Maxillofacial Surgery, Aarhus University Hospital; Department of Orthodontics, Aarhus University; Department of Pediatrics, Aarhus University Hospital; Pediatric Rheumatology Clinic, Pediatrics and Adolescent Medicine, Aarhus University Hospital; Section of Oral Surgery and Oral Pathology, Aarhus University, Aarhus, Denmark; Harvard School of Dental Medicine and Harvard Medical School; Department of Plastic and Oral Surgery, Boston Children's Hospital; Department of Oral and Maxillofacial Surgery, Massachusetts General Hospital, Boston, Massachusetts; Oral and Maxillofacial Surgery and Pediatrics, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia; University of Alabama at Birmingham, Birmingham, Alabama; Perelman School of Medicine, University of Pennsylvania; Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Seattle Children's Hospital, Seattle, Washington, USA; Department of Neuroscience, Reproductive Sciences and Oral Sciences, Section of Orthodontics, University of Naples Federica II, Naples; Dental School, Section of Paediatric Dentistry, University of Turin, Turin, Italy; Department of Orthodontics and Pediatric Dentistry, UZB, University Center for Dental Medicine, Basel; Department of Diagnostic Imaging, University Children's Hospital Zurich, Switzerland; Department of Pediatrics, University of North Norway and Department of Clinical Medicine, UiT the Arctic University of Norway, Tromso; Section of Orthodontics, Department of Maxillofacial Radiology, Institute of Clinical Dentistry, University of Oslo, Oslo; Department of Otorhinolaryngology, Division of Oral and Maxillofacial Surgery, University Hospital North Norway; The Public Dental Service Competence Centre of North Norway; Department of Clinical Medicine, Faculty of Health Sciences, The Arctic University of Norway, Tromso, Norway; Department of Orthodontics, Faculty of Dentistry, Rigas Stradins University, Riga, Latvia; Department of Pediatrics, Division of Rheumatology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario; Department of Pediatrics, Cumming School of Medicine, University of Calgary; Alberta Children's Hospital, Calgary, Alberta, Canada; Malmo University, Faculty of Odontology, Orofacial Pain Unit, Malmo and Skane University Hospital, Specialized Pain Rehabilitation, Lund, Sweden; Department of Ear and Oral Diseases, Tampere University Hospital; Faculty of Medicine and Life Sciences, University of Tampere; Institute of Dentistry and University of Eastern Finland, Kuopio, Finland.

Objective: To propose multidisciplinary, consensus-based, standardization of operational terminology and method of assessment for temporomandibular joint (TMJ) involvement in juvenile idiopathic arthritis (JIA).

Methods: Using a sequential expert group-defined terminology and methods-of-assessment approach by (1) establishment of task force, (2) item generation, (3) working group consensus, (4) external expert content validity testing, and (5) multidisciplinary group of experts final Delphi survey consensus.

Results: Seven standardized operational terms were defined: and CONCLUSION: Definition of 7 operational standardized terms provides an optimal platform for communication across healthcare providers involved in JIA-TMJ arthritis management.
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http://dx.doi.org/10.3899/jrheum.180785DOI Listing
May 2019

A Comparison of Radiographic Joint Space Width Measurements Versus Ultrasonographic Assessment of Cartilage Thickness in Children with Juvenile Idiopathic Arthritis.

J Rheumatol 2019 03 15;46(3):301-308. Epub 2018 Nov 15.

From the Department of Pediatrics, and the Department of Radiology, Aarhus University Hospital, Aarhus, Denmark.

Objective: Joint space narrowing (JSN) is a measurable outcome of tissue degeneration in arthritis. JSN is usually assessed by conventional radiography. Ultrasonographic (US) measurement of joint cartilage thickness has been validated in healthy children, and US measurement of the distal femoral cartilage has been validated in a group of patients with juvenile idiopathic arthritis (JIA). Our aim was to compare the measures of cartilage thickness of the proximal cartilage site in the second metacarpophalangeal (MCP), second proximal interphalangeal (PIP), and knee joints as assessed by US to joint space width (JSW) as measured by computerized radiography in children with JIA.

Methods: The study included 74 children with JIA aged 5-15 years (median 11.3 yrs). MCP and PIP joints were assessed at one midline spot. Knee joints were assessed at the medial and lateral femoral condylar areas. Only the proximal cartilage site in the joints was assessed by US, whereas the complete JSW was assessed by radiography.

Results: We assessed 136 second MCP, 138 second PIP, and 146 knee joints. We found a high level of agreement between US and radiographic measures of cartilage thickness and JSW: r = 0.82-0.86 (second MCP), r = 0.50-0.55 (second PIP), and r = 0.52-0.81 (knee); p < 0.001 for all 8 assessed sites.

Conclusion: US measurements of cartilage thickness of the proximal site of the second MCP, second PIP, and knee joints correlated well with radiographic JSW measurements in the finger and knee joints of children with JIA. However, US does not measure the distal cartilage, which may limit its use in the assessment of JSN.
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http://dx.doi.org/10.3899/jrheum.170571DOI Listing
March 2019

Specific Sports Habits, Leisure-Time Physical Activity, and School-Educational Physical Activity in Children With Juvenile Idiopathic Arthritis: Patterns and Barriers.

Arthritis Care Res (Hoboken) 2019 02;71(2):271-280

Aarhus University Hospital, Aarhus, Denmark.

Objective: Juvenile idiopathic arthritis (JIA) may cause functional impairment and reduced time engaged in physical activity. The aim of this study was to investigate the habits of patients with JIA regarding participation in club sports, leisure-time physical activity, and school-educational physical activity and relate this to objectively measured physical activity using accelerometry and to compare the findings with those in healthy controls.

Methods: Consecutive patients from the Aarhus University Hospital outpatient clinic were included. Clinical characteristics, functional ability, and exploration of specific habits in club sports, leisure-time physical activity, and school-educational physical activity (based on a standardized questionnaire) in patients were recorded and compared with those in healthy controls. The intensity and frequency of physical activity were measured by accelerometer monitoring, using ActiGraph GT1M.

Results: Sixty-eight patients with JIA and 118 healthy control subjects were included. Despite having low disease activity, children with JIA had significantly lower accelerometry-monitored physical activity levels compared with healthy controls. The distribution of specific club sport activities was the same among patients and controls. However, the proportion of patients spending >3 hours/week participating in club sports was significantly lower than the proportion of controls, whereas no difference in time spent engaging in physical activity during leisure-time was observed. Participation in compulsory school-educational physical activity was equally high in patients and controls, although participation by patients was significantly less consistent than that by controls. Patient reports of time spent with club sport and leisure-time physical activity was significantly related to accelerometry measures, whereas this was not observed for school-educational physical activity.

Conclusion: The results of this study indicate the need for structured guidance for all patients with JIA (including those with minimal disease activity) in both understanding and coping with the consequences of a low level of physical activity.
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http://dx.doi.org/10.1002/acr.23795DOI Listing
February 2019

Tocilizumab for the Treatment of Mevalonate Kinase Deficiency.

Case Rep Pediatr 2018 26;2018:3514645. Epub 2018 Aug 26.

Infection and Inflammation and Rheumatology Section, University College London Great Ormond Street Institute of Child Health, 30 Guilford Street, London WC1 E1H, UK.

Mevalonate kinase deficiency (MKD) is a severe autoinflammatory disease caused by recessive mutations in MVK resulting in reduced function of the enzyme mevalonate kinase, involved in the cholesterol/isoprenoid pathway. MKD presents with periodic episodes of severe systemic inflammation, poor quality of life, and life-threatening sequelae if inadequately treated. We report the case of a 12-year-old girl with MKD and severe autoinflammation that was resistant to IL-1 and TNF- blockade. In view of this, she commenced intravenous tocilizumab (8 mg/kg every 2 weeks), a humanised monoclonal antibody targeting the IL-6 receptor (IL-6R) that binds to membrane and soluble IL-6R, inhibiting IL-6-mediated signaling. She reported immediate cessation of fever and marked improvement in her energy levels following the first infusion; after the fifth dose, she was in complete clinical and serological remission, now sustained for 24 months. This is one of the first reported cases of a child with MKD treated successfully with tocilizumab and adds to the very limited experience of this treatment for MKD. IL-6 blockade could therefore be an important addition to the armamentarium for the treatment of this rare monogenic autoinflammatory disease.
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http://dx.doi.org/10.1155/2018/3514645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129367PMC
August 2018

In silico validation of the Autoinflammatory Disease Damage Index.

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

Paediatric Pneumology and Immunology and Interdisciplinary Centre for Social Paediatrics, Charite University Medicine Berlin, Berlin, Germany.

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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8411437PMC
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

Orofacial symptoms and oral health-related quality of life in juvenile idiopathic arthritis: a two-year prospective observational study.

Pediatr Rheumatol Online J 2018 Jul 13;16(1):47. Epub 2018 Jul 13.

Section of Orthodontics, Department of Dentistry and Oral Health, Aarhus University, Vennelyst Boulevard 9-11, 8000, Aarhus C, Denmark.

Background: Little is known about the chronicity of orofacial symptoms and how this influences the oral health-related quality of life in juvenile idiopathic arthritis (JIA). Therefore, our objectives were to study the long-term changes in self-reported orofacial symptoms, and to define the impact of orofacial symptoms on oral health-related quality of life in JIA.

Methods: At baseline (T0), 157 consecutive JIA patients ≤20 years completed a patient pain questionnaire that incorporates domains related to the orofacial area. At the 2 year follow-up (T1), 113 patients completed the same questionnaire (response rate 72%) in addition to the Child Perception's Questionnaire; a validated 31-item questionnaire addressing oral health-related quality of life.

Results: At T0, 53% (60/113) of patients reported the presence of orofacial pain, and 36% (41/113) of patients reported compromised orofacial function. At T1, 77% (46/60) of patients with pain at T0 reported persistent pain, and 66% (27/41) of patients with functional disability at T0 reported persistent disability. Patients with orofacial symptoms reported a significantly greater prevalence of negative impact of orofacial conditions on general quality of life and within the domains of emotional and social well-being compared to asymptomatic patients.

Conclusion: Self-reported orofacial pain and functional disability were common findings in a cohort of JIA patients followed over 2 years. These symptoms seem to persist over time in most patients, and have a significant negative impact on oral health-related quality of life.
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http://dx.doi.org/10.1186/s12969-018-0259-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043998PMC
July 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
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